CN104418842A - Substituted indole compound and using method and application thereof - Google Patents

Substituted indole compound and using method and application thereof Download PDF

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CN104418842A
CN104418842A CN201410455681.0A CN201410455681A CN104418842A CN 104418842 A CN104418842 A CN 104418842A CN 201410455681 A CN201410455681 A CN 201410455681A CN 104418842 A CN104418842 A CN 104418842A
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alkylidene group
group
alkyl
haloalkyl
cycloalkyl
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CN104418842B (en
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金传飞
张英俊
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Abstract

The invention relates to a new indole compound, a drug composition which contains the new indole compound and a receptor for selectivity inhibiting 5-hydroxytryptamine reuptake and/or exciting 5-HT1A. The invention also relates to a method for preparing the new indole compound and the drug composition and application of the new indole compound and the drug composition in treating the central nervous system dysfunction of mammals and especially treating the central nervous system dysfunction of human.

Description

The benzazolyl compounds replaced and using method and purposes
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to be used for the treatment of the compound of central nervous system dysfunction, compoistion and method of use and purposes.Especially, of the present invention is can as serotonin reuptake inhibitor or/and 5-HT 1Athe benzazolyl compounds of receptor stimulant.
Background technology
Serotonin, a kind of neurotransmitter of transmission of signal in brain and neural system, in central nervous system (CNS) dysfunction, especially anxiety, depression, invades and in impulsion mood, plays important role.The 5-hydroxytryptamine receptor of antagonism or exciting certain type can regulate and control central nervous system dysfunction effectively.Up to now, 14 kinds of 5-hydroxytryptamine receptors are had at least to be identified.These acceptors can be divided into different family, are denoted as 5-HT respectively 1, 5-HT 2, 5-HT 3, 5-HT 4, 5-HT 5, 5-HT 6and 5-HT 7, the different subtype in each race then uses a, the differentiations such as b and c.The serotoninergic neuron of nervus centralis is positioned at the nuclei of median raphe of brain stem, and 5-HT 1Aacceptor, a kind of g protein coupled receptor, is just extensively distributed in the region that can receive the serotonin coming from nuclei of median raphe, comprises: cortex of frontal lobe, lateral septal, amygdala, hippocampus, hypothalamus.At these cortex fringe regions, 5-HT 1Abe positioned at postsynaptic membrane.Meanwhile, 5-HT 1Aacceptor is also the presynaptic membrane autoreceptor on nuclei of median raphe, can reduce neuronic discharge rate (i.e. the quantity of every action potential release serotonin), and the synthesis of neurotransmitter, then reduces the activity of serotonin in projection area.Activate the 5-HT of presynaptic membrane 1Aacceptor can suppress the synthesis of tyrosine hydroxylase and L-glutamic acid passage (to result from inner side prefrontal cortex, point to nuclei of median raphe) activity, thus indirectly reduce serotonin transport (Jonathan Savitz, Irwin Lucki, Wayne C.Drevets.5-HT 1Areceptor function in major depressive disorder.Prog Neurobiol.2009,88 (1): 17-31).
In all indications relevant to serotonin dysfunction, dysthymia disorders is most important, because according to World Health Organization, dysthymia disorders has become the fourth-largest burden disease of the mankind.Expect the year two thousand twenty, the Disability adjusted life years of dysthymia disorders can leap to the second of all diseases.(Bromet E,Andrade LH,Hwang I,et al.,Cross-national epidemiology of DSM-IV major depressive episode.BMC Med.2011,9:90)。
In history, the pharmacological agent of emotional handicap starts from the 1950's, comprise tricyclic antidepressant (TCAs) and oxidase inhibitor (MAOIs), these drug mains will lean on neurotransmitter (Dopamine HCL, norepinephrine, and serotonin) blocking effect play curative effect.But, the non-selective and less desirable side effect of target is limited to their use.To the eighties in 20th century, the appearance of serotonin selectivity reuptake inhibitor (SSRIs), changes this situation.Compared with TCAs, this kind of curative effect of medication is suitable, but side effect is little, even if excessive use, toxicity also less (the Sarko J.Andidepressant produced, old and new.A review of their adverse effects andtoxicity in overdose.Emerg Med Clin North Am, 2000; 18 (4): 637-54).
Traditional SSRIs treatment is by suppressing the re-uptake of serotonin and regulating its transhipment to increase the content of serotonin.But after using SSRIs, the 5-HT of presynaptic membrane can be activated equally 1Aautoreceptor, causes the burst size of serotonin to reduce, and the concentration of serotonin between cynapse is reduced.But, along with the prolongation of medicine time, SSRIs can cause 5-HT 1Aautoreceptor desensitizes, and activation effect is restrained, thus the regulating effect of bringing into normal play.Infer thus, to 5-HT 1Athe activation effect of autoreceptor postpones major reason (Celada P, Puig M, Amargos-Bosch M, et al., the The therapeutic role of 5-HT that SSRIs plays drug effect 1Aand 5-HT 2Areceptors in depression.J PsychiatryNeurosci, 2004,29 (4): 252-65).Therefore, 5-HT is overcome 1Athe negative feedback of autoreceptor antagonist has the prospect strengthening and accelerate clinical antidepressants.
Compared with SSRIs, 5-HT 1Areceptor stimulant or partial agonist directly act on postsynaptic 5-hydroxytryptamine receptor, to increase the interim serotonin neurotransmission of SSRI latent effect.Feiger and Wilcox proves that buspirone and gepirone hydrochloride are effective 5-HT clinically 1Apartial agonist (Feiger, A.Psychopharmacol.Bull.1996,32:659-65).Add buspirone in standard SSRI therapy, in the unresponsive patient of the previous standard care to depression, cause significant improvement (Dimitriou, E.J.Clin.Psychopharmacol., 1998,18:465-9).
The invention provides some and there is serotonin selectivity reuptake inhibitor and/or 5-HT 1Athe new compound of receptor agonist activity, possesses good potential applicability in clinical practice.Compared with existing similar compound, compound of the present invention has better drug effect, and medicine is for character and/or toxicological characteristics.
Abstract of invention
Below only summarize aspects more of the present invention, be not limited thereto.These aspects and other parts have more complete explanation later.All reference in this specification sheets are incorporated in this by entirety.When the disclosure of the specification and citing document variant time, be as the criterion with the disclosure of the specification.
The invention provides a class new compound, this compound is to the selective restraining effect of serotonin reuptake transporter and/or to 5-HT 1Aacceptor has agonism, may be used for preparation treatment mankind central nervous system (CNS) dysfunction, the such as medicine of dysthymia disorders, anxiety disorder, bipolar disorders.
The present invention also provides the method for this compounds of preparation and the pharmaceutical composition containing this compounds.
On the one hand, the invention provides a kind of compound, its steric isomer for compound shown in the compound shown in formula (I) or formula (I), tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug
Wherein:
When for-time, G is CH or N;
When for=time, G is C;
Y is CR 4or N;
Each R 1be H, D, F, Cl, Br, I ,-NO independently 2,-CN ,-SCN ,-OR 5,-NR 6r 6a,-C (=O) R 5,-C (=O) OR 5,-C (=O) NR 6r 6a,-OC (=O) R 5,-N (R 6) C (=O) R 5, alkyl, thiazolinyl, alkynyl, haloalkyl, cycloalkyl, cycloalkyl alkylidene group-, heterocyclic radical, heterocycloalkylene-, aryl, aryl alkylene-, heteroaryl or heteroarylalkylenyl-;
Each R 2, R 3and R 4be separately H, D, F, Cl, Br, I ,-NO 2,-CN ,-OR 5,-NR 6r 6a,-SR 5,-C (=O) R 5,-C (=O) OR 5,-C (=O) NR 6r 6a,-OC (=O) R 5,-N (R 6) C (=O) R 5, R 5o-alkylidene group-, R 6r 6an-alkylidene group-, R 5s-alkylidene group-, alkyl, thiazolinyl, alkynyl, haloalkyl, cycloalkyl, cycloalkyl alkylidene group-, heterocyclic radical, heterocycloalkylene-, aryl, aryl alkylene-, heteroaryl or heteroarylalkylenyl-; Or the R on adjacent carbons 2, R 3, and together with the ring carbon atom be connected respectively with them, form carbocyclic ring or heterocycle; Or the R on adjacent carbons 3, R 4, and together with the ring carbon atom be connected respectively with them, form carbocyclic ring or heterocycle;
Each R 5be independently H, D, alkyl, thiazolinyl, alkynyl, haloalkyl, cycloalkyl, cycloalkyl alkylidene group-, heterocyclic radical or heterocycloalkylene-;
Each R 6and R 6abe separately H, D, alkyl, thiazolinyl, alkynyl, haloalkyl, cycloalkyl, cycloalkyl alkylidene group-, heterocyclic radical or heterocycloalkylene-; Or R 6, R 6a, and together with the nitrogen-atoms be connected with them, form heterocycle;
Above-described each R 5o-alkylidene group-, R 6r 6an-alkylidene group-, R 5s-alkylidene group-, alkyl, thiazolinyl, alkynyl, haloalkyl, carbocyclic ring, heterocycle, cycloalkyl, cycloalkyl alkylidene group-, heterocyclic radical, heterocycloalkylene-, aryl, aryl alkylene-, heteroaryl and heteroarylalkylenyl-be optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, alkyl, haloalkyl, alkoxyl group, alkylthio and alkylamino substituting group replaced;
M is 2,3,4 or 5; With
N is 1,2,3 or 4.
In one embodiment, each R 1be H, D, F, Cl, Br, I ,-NO independently 2,-CN ,-SCN ,-OR 5,-NR 6r 6a,-C (=O) R 5,-C (=O) OR 5,-C (=O) NR 6r 6a,-OC (=O) R 5,-N (R 6) C (=O) R 5, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 1-C 6haloalkyl, C 3-C 10cycloalkyl, (C 3-C 10cycloalkyl)-(C 1-C 6alkylidene group)-, C 2-C 10heterocyclic radical, (C 2-C 10heterocyclic radical)-(C 1-C 6alkylidene group)-, C 6-C 10aryl, (C 6-C 10aryl)-(C 1-C 6alkylidene group)-, C 1-C 9heteroaryl or (C 1-C 9heteroaryl)-(C 1-C 6alkylidene group)-; Wherein said each C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 1-C 6haloalkyl, C 3-C 10cycloalkyl, (C 3-C 10cycloalkyl)-(C 1-C 6alkylidene group)-, C 2-C 10heterocyclic radical, (C 2-C 10heterocyclic radical)-(C 1-C 6alkylidene group)-, C 6-C 10aryl, (C 6-C 10aryl)-(C 1-C 6alkylidene group)-, C 1-C 9heteroaryl and (C 1-C 9heteroaryl)-(C 1-C 6alkylidene group)-be optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, C 1-C 6alkyl, C 1-C 6haloalkyl, C 1-C 6alkoxyl group, C 1-C 6alkylthio and C 1-C 6the substituting group of alkylamino replaced.
In another embodiment, each R 2, R 3and R 4be separately H, D, F, Cl, Br, I ,-NO 2,-CN ,-OR 5,-NR 6r 6a,-SR 5,-C (=O) R 5,-C (=O) OR 5,-C (=O) NR 6r 6a,-OC (=O) R 5,-N (R 6) C (=O) R 5, R 5o-(C 1-C 6alkylidene group)-, R 6r 6an-(C 1-C 6alkylidene group)-, R 5s-(C 1-C 6alkylidene group)-, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 1-C 6haloalkyl, C 3-C 10cycloalkyl, (C 3-C 10cycloalkyl)-(C 1-C 6alkylidene group)-, C 2-C 10heterocyclic radical, (C 2-C 10heterocyclic radical)-(C 1-C 6alkylidene group)-, C 6-C 10aryl, (C 6-C 10aryl)-(C 1-C 6alkylidene group)-, C 1-C 9heteroaryl or (C 1-C 9heteroaryl)-(C 1-C 6alkylidene group)-; Or the R on adjacent carbons 2, R 3, and together with the carbon atom be connected with them, form C 3-C 10carbocyclic ring or C 2-C 9heterocycle; Or the R on adjacent carbons 3, R 4, and together with the ring carbon atom be connected respectively with them, form C 3-C 10carbocyclic ring or C 2-C 9heterocycle;
Wherein, described each R 5o-(C 1-C 6alkylidene group)-, R 6r 6an-(C 1-C 6alkylidene group)-, R 5s-(C 1-C 6alkylidene group)-, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 1-C 6haloalkyl, C 3-C 10cycloalkyl, (C 3-C 10cycloalkyl)-(C 1-C 6alkylidene group)-, C 2-c 10heterocyclic radical, (C 2-C 10heterocyclic radical)-(C 1-C 6alkylidene group)-, C 6-C 10aryl, (C 6-C 10aryl)-(C 1-C 6alkylidene group)-, C 1-C 9heteroaryl, (C 1-C 9heteroaryl)-(C 1-C 6alkylidene group)-, C 3-C 10carbocyclic ring and C 2-C 9heterocycle is optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, C 1-C 6alkyl, C 1-C 6haloalkyl, C 1-C 6alkoxyl group, C 1-C 6alkylthio and C 1-C 6the substituting group of alkylamino replaced.
In another embodiment, each R 5be H, D, C independently 1-C 6alkyl, C 1-C 6haloalkyl or C 3-C 10cycloalkyl; Wherein, described each C 1-C 6alkyl, C 1-C 6haloalkyl and C 3-C 10cycloalkyl is optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, C 1-C 6alkyl, C 1-C 6haloalkyl, C 1-C 6alkoxyl group, C 1-C 6alkylthio and C 1-C 6the substituting group of alkylamino replaced; With
Each R 6and R 6abe separately H, D, C 1-C 6alkyl, C 1-C 6haloalkyl or C 3-C 10cycloalkyl; Or R 6, R 6a, and together with the nitrogen-atoms be connected with them, form C 3-C 10heterocycle; Wherein, described each C 1-C 6alkyl, C 1-C 6haloalkyl, C 3-C 10cycloalkyl and C 3-C 10heterocycle is optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, C 1-C 6alkyl, C 1-C 6haloalkyl, C 1-C 6alkoxyl group, C 1-C 6alkylthio and C 1-C 6the substituting group of alkylamino replaced.
In another embodiment, Y is CH or N.
In another embodiment, each R 1be H, D, F, Cl ,-CN ,-OR independently 5,-NR 6r 6a,-C (=O) NR 6r 6a, C 1-C 4alkyl or C 1-C 4haloalkyl; Wherein said each C 1-C 4alkyl and C 1-C 4haloalkyl is optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, C 1-C 4alkyl, C 1-C 4haloalkyl, C 1-C 4alkoxyl group, C 1-C 4alkylthio and C 1-C 4the substituting group of alkylamino replaced.
In another embodiment, each R 2and R 3be separately H, D, F, Cl ,-CN ,-OR 5,-NR 6r 6a,-SR 5,-C (=O) OR 5,-C (=O) NR 6r 6a, R 5o-(C 1-C 4alkylidene group)-, R 6r 6aN-(C 1-C 4alkylidene group)-, R 5s-(C 1-C 4alkylidene group)-, C 1-C 4alkyl, C 2-C 4thiazolinyl, C 2-C 4alkynyl or C 1-C 4haloalkyl; Or the R on adjacent carbons 2, R 3, and together with the ring carbon atom be connected respectively with them, form C 3-C 8carbocyclic ring or C 2-C 7heterocycle;
Wherein, described each R 5o-(C 1-C 4alkylidene group)-, R 6r 6an-(C 1-C 4alkylidene group)-, R 5s-(C 1-C 4alkylidene group)-, C 1-C 4alkyl, C 2-C 4thiazolinyl, C 2-C 4alkynyl, C 1-C 4haloalkyl, C 3-C 8carbocyclic ring and C 2-C 7heterocycle is optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, C 1-C 4alkyl, C 1-C 4haloalkyl, C 1-C 4alkoxyl group, C 1-C 4alkylthio and C 1-C 4the substituting group of alkylamino replaced.
In another embodiment, each R 5be H, D or C independently 1-C 4alkyl; With
Each R 6and R 6abe separately H, D or C 1-C 4alkyl; Or R 6, R 6a, and together with the nitrogen-atoms be connected with them, form C 3-C 5heterocycle.
In another embodiment, each R 1be H, D, F, Cl ,-CN, CH independently 3,-CH (CH 3) 2,-CF 3,-OH ,-OCH 3,-NH 2or-C (=O) NH 2.
On the other hand, the present invention relates to a kind of pharmaceutical composition, it comprises the compounds of this invention, and pharmaceutically acceptable vehicle, carrier, adjuvant or their arbitrary combination.
In one embodiment, pharmaceutical composition of the present invention, comprise the medicine for the treatment of central nervous system dysfunction further, the medicine of described treatment central nervous system dysfunction be antidepressant drug, anxiolytic medicament, salts medicine as mood stabilizers, atypical antipsychotics thing, antiepileptic drug, antiparkinsonism drug, as serotonin selectivity reuptake inhibitor and/or 5-HT 1Athe medicine of receptor stimulant, central nervous stimulant, nicotinic antagonists or their arbitrary combination.
In another embodiment, the medicine for the treatment of central nervous system dysfunction of the present invention is amitriptyline (amitriptyline), Desipramine (desipramine), mirtazapine (mirtazapine), Bupropion (bupropion), Reboxetine (reboxetine), fluoxetine (fluoxetine), trazodone (trazodone), Sertraline (sertraline), duloxetine (duloxetine), fluvoxamine (fluvoxamine), Midalcipran (milnacipran), left-handed Midalcipran (levomilnacipran), desmethylvenlafaxine (desvenlafaxine), vilazodone (vilazodone), Venlafaxine (venlafaxine), dapoxetine (dapoxetine), nefazodone (nefazodone), femoxetine (femoxetine), chlorimipramine (clomipramine), citalopram (citalopram), S-escitalopram (escitalopram), paroxetine (paroxetine), Quilonum Retard (lithium carbonate), buspirone (buspirone), olanzapine (olanzapine), Quetiapine (quetiapine), risperidone (risperidone), Ziprasidone (ziprasidone), Aripiprazole (aripiprazole), Perospirone (perospirone), leoponex (clozapine), modafinil (modafinil), mecamylamine (mecamylamine), Cabergoline (cabergoline), diamantane (adamantane), imipramine (imipramine), pramipexole (pramipexole), thyroxine (thyroxine), Dextromethorphane Hbr (dextromethorphan), Quinidine (quinidine), TREXUPONT (naltrexone), samidorphan, buprenorphine (buprenorphine), melatonin (melatonin), alprazolam (alprazolam), pipamperone (pipamperone), dimension is for smooth (vestipitant), zeisin (chlordiazepoxide), trilafon (perphenazine) or their arbitrary combination.
On the other hand, the present invention relates to the compounds of this invention or pharmaceutical composition is preparing the purposes in medicine, described medicine is used for prevention, treats or alleviate Mammals, comprises the central nervous system dysfunction of the mankind.
In one embodiment, central nervous system dysfunction of the present invention refers to dysthymia disorders, anxiety disorder, mania, schizophrenia, bipolar disorders, somnopathy, obsessional idea and behavior disorder, panic disorder, posttraumatic stress disorder, dyskinesia, sexual dysfunction, musculoskeletal pain obstacle, cognitive disorder, dysmnesia, Parkinson's disease, Huntington's disease, phobia, substance abuse or habituation, drug addiction withdrawal symptom or premenstrualtension syndrome.
On the other hand, the present invention relates to compound of the present invention or pharmaceutical composition is preparing the purposes in medicine, described medicine be used for Selective depression 5 ?hydroxy-tryptamine re-uptake.
On the other hand, the present invention relates to the preparation of compound that formula (I) comprises, the method for abstraction and purification.
Biological results shows, compound provided by the invention can be used as good serotonin selectivity reuptake inhibitor and/or 5-HT 1Areceptor stimulant.
Arbitrary embodiment of either side of the present invention, can combine with other embodiment, as long as they there will not be contradiction.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characteristic goes for this technical characteristic in other embodiment, as long as they there will not be contradiction.
Content noted earlier only outlines some aspect of the present invention, but is not limited to these aspects.The content of these aspects and other aspect will do more specifically complete description below.
Circumstantial letter of the present invention
definition and general terms
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.The term no matter discussed occurs separately or combination appearance, and definition described herein is all applicable.
According to object of the present invention, chemical element according to the periodic table of elements, CAS version and pharmaceutical chemicals handbook, 75, thed, 1994 define.In addition, organic chemistry General Principle is shown in " Organic Chemistry; " Sorrell et al., University Science Books, Sausalito:1999, and " March's Advanced Organic Chemistry; " by Smith et al., John Wiley & Sons, New York:2007, therefore all contents have all merged reference.
Except as otherwise noted or in context, have obvious conflict, article used herein " ", " one (kind) " and " described " are intended to comprise " at least one " or " one or more ".Therefore, these articles used herein refer to the article of one or more than one (i.e. at least one) object.Such as, " component " refers to one or more component, more than one component namely may be had to be taken into account in the embodiment of described embodiment and adopt or use.
As described in the invention, compound of the present invention can optionally replace by one or more substituting group, as general formula compound above, or special example inside picture embodiment, subclass, and the compounds that the present invention comprises.
Term " optionally " or " optionally " refer to the event that describes subsequently or situation can but not necessarily occur, and this description comprises situation that wherein said event or situation occur and wherein its absent variable situation.Such as, " optional key " refers to that this key can exist or can not exist, and this description comprises singly-bound, double bond or triple bond.
Term " replacement " or " replacement ", represent one or more hydrogen atoms in described structure replace by concrete substituting group.Unless other aspects show, a group replaced can have a substituting group to replace in each commutable position of group.Not only one or more substituting groups that position can be selected from concrete group in given structural formula replaced, and so substituting group can replace in each position identical or differently.
Term " unsubstituted ", represents and specifies group without substituting group.
Term " optionally quilt .... replaced ", can " not replace or quilt ... .. replaced " to exchange with term and use, namely described structure be unsubstituted or be replaced by one or more substituting group of the present invention, substituting group of the present invention includes, but are not limited to D, F, Cl, N 3,-CN ,-OH ,-SH ,-NH 2, alkyl, alkoxyl group, alkylthio, alkylamino, cycloalkyl, heterocyclic radical, aryl, heteroaryl etc.
In addition, it should be noted that, unless otherwise explicitly pointed out, adopted in the present invention describing mode " each ... be independently " and " ... be independently of one another " and " ... be independently " can exchange, all should be interpreted broadly, it both can refer in different group, did not affect mutually between concrete option expressed between same-sign, also can represent in identical group, not affect mutually between concrete option expressed between same-sign.
Term " undersaturated " represents that part is containing one or more degree of unsaturation.
Term " comprises " for open language, namely comprises the content specified by the present invention, but does not get rid of otherwise content.
At each several part of this specification sheets, the come into the open substituting group of compound of the present invention is open according to radical species or scope.Particularly point out, each the independently sub-combinations thereof that the present invention includes each member of these radical species and scope.Such as, term " C 1-C 6alkyl " refer in particular to independent disclosed methyl, ethyl, C 3alkyl, C 4alkyl, C 5alkyl and C 6alkyl.
At each several part of the present invention, describe connection substituting group.When this structure clearly needs linking group, be interpreted as linking group for the Ma Kushi variable cited by this group.Such as, if this structure needs linking group and Ma Kushi group definition for this variable lists " alkyl " or " aryl ", then should be appreciated that, " alkyl " or " aryl " alkylidene group or the arylene group of connection should be represented respectively.
Term " halogen " and " halo " are used interchangeably in the present invention, refer to F, Cl, Br or I.
The term " alkyl " that the present invention uses or " alkyl group ", represent containing 1-20 carbon atom, saturated straight or branched univalent hydrocarbyl group, wherein, the substituting group that described alkyl group can optionally be described by one or more the present invention replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1-12 carbon atom; In another embodiment, alkyl group contains 1-6 carbon atom; In yet another embodiment, alkyl group contains 1-4 carbon atom; Also in one embodiment, alkyl group contains 1-3 carbon atom.Described alkyl group optionally replace by one or more substituting group described in the invention.
The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH 3), ethyl (Et ,-CH 2cH 3), n-propyl (n-Pr ,-CH 2cH 2cH 3), sec.-propyl (i-Pr ,-CH (CH 3) 2), normal-butyl (n-Bu ,-CH 2cH 2cH 2cH 3), isobutyl-(i-Bu ,-CH 2cH (CH 3) 2), sec-butyl (s-Bu ,-CH (CH 3) CH 2cH 3), the tertiary butyl (t-Bu ,-C (CH 3) 3), n-pentyl (-CH 2cH 2cH 2cH 2cH 3), 2-amyl group (-CH (CH 3) CH 2cH 2cH 3), 3-amyl group (-CH (CH 2cH 3) 2), 2-methyl-2-butyl (-C (CH 3) 2cH 2cH 3), 3-methyl-2-butyl (-CH (CH 3) CH (CH 3) 2), 3-methyl isophthalic acid-butyl (-CH 2cH 2cH (CH 3) 2), 2-methyl-1-butene base (-CH 2cH (CH 3) CH 2cH 3), n-hexyl (-CH 2cH 2cH 2cH 2cH 2cH 3), 2-hexyl (-CH (CH 3) CH 2cH 2cH 2cH 3), 3-hexyl (-CH (CH 2cH 3) (CH 2cH 2cH 3)), 2-methyl-2-amyl group (-C (CH 3) 2cH 2cH 2cH 3), 3-methyl-2-amyl group (-CH (CH 3) CH (CH 3) CH 2cH 3), 4-methyl-2-amyl group (-CH (CH 3) CH 2cH (CH 3) 2), 3-methyl-3-amyl group (-C (CH 3) (CH 2cH 3) 2), 2-methyl-3-amyl group (-CH (CH 2cH 3) CH (CH 3) 2), 2,3-dimethyl-2-butyl (-C (CH 3) 2cH (CH 3) 2), 3,3-dimethyl-2-butyl (-CH (CH 3) C (CH 3) 3), n-heptyl, n-octyl, etc.
Term " alkylidene group " represents the saturated bivalent hydrocarbon radical group removing two hydrogen atoms and obtain from saturated straight or branched alkyl.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In one embodiment, alkylidene group contains 1-6 carbon atom; In another embodiment, alkylidene group contains 1-4 carbon atom; In yet another embodiment, alkylidene group contains 1-3 carbon atom; Also in one embodiment, alkylidene group contains 1-2 carbon atom.Such example comprises methylene radical (-CH 2-), ethylidene (-CH 2cH 2-), isopropylidene (-CH (CH 3) CH 2-) etc.Described alkylidene group optionally replace by one or more substituting group described in the invention.
Term " thiazolinyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein has a unsaturated site at least, namely has a carbon-to-carbon sp 2double bond, wherein, described alkenyl group can optionally replace by one or more substituting group described in the invention, it comprises " cis " and the location of " tans ", or the location of " E " and " Z ".In one embodiment, alkenyl group comprises 2-8 carbon atom; In another embodiment, alkenyl group comprises 2-6 carbon atom; In yet another embodiment, alkenyl group comprises 2-4 carbon atom.The example of alkenyl group comprises, but is not limited to, vinyl (-CH=CH 2), allyl group (-CH 2cH=CH 2) etc.Described alkenyl group optionally replace by one or more substituting group described in the invention.
Term " alkynyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein has a unsaturated site at least, namely have a carbon-to-carbon sp triple bond, wherein, described alkynyl group can optionally replace by one or more substituting group described in the invention.In one embodiment, alkynyl group comprises 2-8 carbon atom; In another embodiment, alkynyl group comprises 2-6 carbon atom; In yet another embodiment, alkynyl group comprises 2-4 carbon atom.The example of alkynyl group comprises, but is not limited to, ethynyl (-C ≡ CH), propargyl (-CH 2c ≡ CH), 1-proyl (-C ≡ C-CH 3) etc.Described alkynyl group optionally replace by one or more substituting group described in the invention.
Term " alkoxyl group " represents that alkyl group is connected with molecule rest part by Sauerstoffatom, and wherein alkyl group has implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.In one embodiment, alkoxy base contains 1-6 carbon atom; In another embodiment, alkoxy base contains 1-4 carbon atom; In yet another embodiment, alkoxy base contains 1-3 carbon atom.The substituting group that described alkoxy base is optionally described by one or more the present invention replace.
The example of alkoxy base comprises, but is not limited to, methoxyl group (MeO ,-OCH 3), oxyethyl group (EtO ,-OCH 2cH 3), 1-propoxy-(n-PrO, n-propoxy-,-OCH 2cH 2cH 3), 2-propoxy-(i-PrO, i-propoxy-,-OCH (CH 3) 2), 1-butoxy (n-BuO, n-butoxy ,-OCH 2cH 2cH 2cH 3), 2-methyl-l-propoxy-(i-BuO, i-butoxy ,-OCH 2cH (CH 3) 2), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH 3) CH 2cH 3), 2-methyl-2-propoxy-(t-BuO, t-butoxy ,-OC (CH 3) 3), 1-pentyloxy (n-pentyloxy ,-OCH 2cH 2cH 2cH 2cH 3), 2-pentyloxy (-OCH (CH 3) CH 2cH 2cH 3), 3-pentyloxy (-OCH (CH 2cH 3) 2), 2-methyl-2-butoxy (-OC (CH 3) 2cH 2cH 3), 3-methyl-2-butoxy (-OCH (CH 3) CH (CH 3) 2), 3-methyl-l-butoxy (-OCH 2cH 2cH (CH 3) 2), 2-methyl-l-butoxy (-OCH 2cH (CH 3) CH 2cH 3), etc.
Term " haloalkyl " or " halogenated alkoxy " represent alkyl, or alkoxy base is replaced by one or more halogen atom, wherein alkyl and alkoxyl group have implication as described in the present invention, such example comprises, but is not limited to, chloromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, etc.The substituting group that described haloalkyl or halo alkoxy group are optionally described by one or more the present invention replace.
Term " alkylamino " or " alkylamino " comprise " N-alkylamino " and " N, N-dialkyl amido ", wherein amino group separately replace by one or two alkyl group.In one embodiment, alkylamino is one or two C 1-6alkyl is connected to the more rudimentary alkylamino group on nitrogen-atoms.In another embodiment, alkylamino is C 1-4more rudimentary alkylamino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example comprises, but is not limited to, N-methylamino-, N-ethylamino, N, N-dimethylamino, N, N-diethylin etc.And described alkylamino radicals optionally replace by one or more substituting group described in the invention.
Term " alkylthio " refers to and comprises C 1-10the alkyl of straight or branched is connected to the group on bivalent sulfur atom, and in one embodiment, alkylthio is more rudimentary C 1-4alkylthio, such embodiment comprises, but is not limited to methylthio group (CH 3s-).And described alkylthio radicals optionally replace by one or more substituting group described in the invention.
Term " cycloalkyl " refers to containing the saturated monocycle of 3-12 carbon atom, dicyclo or three-ring system.Dicyclo or three-ring system can comprise condensed ring, bridged ring and volution.In one embodiment, cycloalkyl comprises 3-10 carbon atom, and in another embodiment, cycloalkyl comprises 3-8 carbon atom, and also in one embodiment, cycloalkyl comprises 3-6 carbon atom.Described group of naphthene base optionally replace by one or more substituting group described in the invention.
Term " cycloalkyl alkylidene group " represent alkyl group can replace by one or more group of naphthene base, wherein alkyl and group of naphthene base have implication as described in the present invention.In one embodiment, cycloalkyl alkylidene group refers to " more rudimentary cycloalkyl alkylidene group " group, namely group of naphthene base is connected to C 1-6alkyl group on.In another embodiment, group of naphthene base is connected to C 1-4alkyl group on.Also in one embodiment, group of naphthene base is connected to C 1-3alkyl group on.Described cycloalkyl alkylidene group optionally replace by one or more substituting group described in the invention.
Term " heteroatoms " represents one or more oxygen (O), sulphur (S), nitrogen (N), phosphorus (P) or silicon (Si), comprise nitrogen (N), the form of sulphur (S) and phosphorus (P) any oxidation state; The form of primary, secondary, tertiary amine and quaternary ammonium salt; Or the form that the hydrogen in heterocycle on nitrogen-atoms is substituted, such as, N (N as in 3,4-dihydro-2 h-pyrrole base), NH (NH as in pyrrolidyl) or NR (NR as in the pyrrolidyl that N-replaces).
Term " heterocycle ", " heterocyclic radical " or " heterocycle " commutative use herein, all refer to monocycle, dicyclo or three-ring system, wherein on ring one or more atom independently replace by heteroatoms, described heteroatoms has implication as described in the present invention, ring can be completely saturated or comprise one or more degree of unsaturation, but an aromatic nucleus all can not have, and a tie point is only had to be connected with the rest part of molecule.Some of them embodiment is, " heterocycle ", and " heterocyclic radical " or " heterocycle " group is monocycle (2-6 carbon atom and be selected from N of 3-8 ring, 1-3 the heteroatoms of O, P, S, this S or P optionally replace by one or more Sauerstoffatom obtain picture SO, SO 2, PO, PO 2group, when described ring is triatomic ring, wherein only have a heteroatoms), or the dicyclo of 7-12 unit (4-9 carbon atom and be selected from N, 1-3 the heteroatoms of O, P, S, at this S or P optionally replace by one or more Sauerstoffatom and obtain as SO, SO 2, PO, PO 2group).Described heterocyclyl groups optionally replace by one or more substituting group described in the invention.
Heterocyclic radical can be carbon back or heteroatoms base.The example of heterocycle comprises, but be not limited to, pyrrolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, thioxane base, piperazinyl, homopiperazine base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, epoxypropyl, azacycloheptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxy amyl group, pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidyl imidazolinyl, imidazolidyl, 1, 2, 3, 4-tetrahydro isoquinolyl.The example of heterocyclic group also comprises, the pyrimidine dione base that on ring, two carbon atoms are replaced by oxygen (=O) and 1,1-dioxidothiomorpholinyl.
Term " heterocycloalkylene " represent alkyl group can replace by one or more heterocyclyl groups, wherein alkyl and heterocyclyl groups have implication as described in the present invention.In one embodiment, heterocycloalkylene group refers to " more rudimentary heterocycloalkylene " group, namely heterocyclyl groups is connected to C 1-6alkyl group on.In another embodiment, heterocyclyl groups is connected to C 1-4alkyl group on.Such example comprises, but is not limited to, 2-tetramethyleneimine ethyl etc.And described heterocycloalkylene group optionally replace by one or more substituting group described in the invention.
Term " aryl " represents containing 6-14 annular atoms, or 6-10 annular atoms, or the carbocyclic ring system of the monocycle of 6 annular atomses, dicyclo and three rings, and wherein, at least one member ring systems is aromatic, and wherein each member ring systems comprises 3-7 former molecular ring.Aromatic yl group is usual, but is necessarily connected with parent molecule by the aromatic nucleus of aromatic yl group.Term " aryl " can exchange with term " aromatic nucleus " and use.The example of aromatic yl group can comprise phenyl, naphthyl and anthracene.Described aromatic yl group optionally replace by one or more substituting group described in the invention.
Term " aryl alkylene " represent alkyl group can replace by one or more aromatic yl group, wherein alkyl and aromatic yl group have implication as described in the present invention, in one embodiment, arylalkylene groups refers to " more rudimentary aryl alkylene " group, namely aromatic yl group is connected to C 1-6alkyl group on.In another embodiment, arylalkylene groups refers to containing C 1-4" the benzene alkylene " of alkyl.Wherein specific examples comprises benzyl, diphenyl methyl, styroyl etc.And described arylalkylene groups optionally replace by one or more substituting group described in the invention.
Term " heteroaryl " represents containing 5-14 annular atoms, or 5-10 annular atoms, or the monocycle of 5-6 annular atoms, dicyclo and three-ring system, wherein at least one member ring systems is aromatic, and at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 5-7 former molecular ring.Heteroaryl groups is usual, but is necessarily connected with parent molecule by the aromatic nucleus of heteroaryl groups.Term " heteroaryl " can exchange with term " hetero-aromatic ring " or " heteroaromatics " and use.Described heteroaryl groups optionally replace by one or more substituting group described in the invention.In one embodiment, 5-10 former molecular heteroaryl comprises the heteroatoms that 1,2,3 or 4 is independently selected from O, S and N.
The example of heteroaryl groups comprises, but be not limited to, 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, pyridazinyl (as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazyl (as 5-tetrazyl), triazolyl (as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (as 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thio biphosphole base, 1, 3, 4-thio biphosphole base, 1, 2, 5-thio biphosphole base, pyrazinyl, 1, 3, 5-triazinyl, also following dicyclo is comprised, but be never limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, indyl (as 2-indyl), purine radicals, quinolyl is (as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl is (as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), imidazo [1, 2-a] pyridyl, pyrazolo [1, 5-a] pyridyl, pyrazolo [1, 5-a] pyrimidyl, imidazo [1, 2-b] pyridazinyl, [1, 2, 4] triazolo [4, 3-b] pyridazinyl, [1, 2, 4] triazolo [1, 5-a] pyrimidyl, [1, 2, 4] triazolo [1, 5-a] pyridyl, etc..
Term " heteroarylalkylenyl " represent alkyl group can replace by one or more heteroaryl groups, wherein alkyl and heteroaryl groups have implication as described in the present invention, in one embodiment, heteroarylalkylenyl group refers to " more rudimentary heteroarylalkylenyl " group, namely heteroaryl groups is connected to C 1-6alkyl group on.In another embodiment, heteroaryl groups is connected to C 1-4alkyl group on.Wherein specific examples comprises 2-picolyl, 3-furylethyl etc.And described heteroarylalkylenyl group optionally replace by one or more substituting group described in the invention.
Term " carbonyl ", represent-(C=O)-, can be used alone or be used in conjunction with other terms; Term " acyl group " expression-(C=O)-R; " amide group " represents-NH (C=O)-R; " carbamyl " represents-C (=O) NH 2.
Term " azido-" represents nitrine structure (-N 3).This group can be connected with other groups, such as, is connected with methyl group, can form triazonmethane (triazo-methane, MeN 3); And be connected with phenyl group, then form aziminobenzene (PhN 3).
As described in the invention, substituting group is drawn a key and is connected to the member ring systems that the ring at center is formed and represents substituting group any commutable position on ring and can replace.Such as, formula a represents any position that may be substituted on A ring, such as formula b 1-b 4shown in:
Term " volution base ", " volution ", represents that a ring originates from ring-type carbon special on another ring, such as, as formula c below, described by formula d, ring A and ring B shares a carbon atom in two saturated member ring systems, be then called as " volution " or " spiral shell dicyclo ".Each ring in volution is carbocyclic ring or heterocycle independently.Such example comprises, but be not limited to 4-oxaspiro [2.4] heptane-6-base, (R)-4-azaspiro [2.4] heptane-6-base, spiral shell bicyclic group can not be substituted independently or replace by one or more substituting group described in the invention.
Term " condensed-bicyclic ", " fused rings ", " condensed-bicyclic base " or " condensing cyclic group ", shown in e-g, represent between two five-rings (formula e), between two six-rings (formula f), and between a five-ring and a six-ring, (formula g) shares the bridged-ring system of a C-C key.Unsaturated link(age) that is isolated or conjugation can be comprised in system, but in core ring structure, do not comprise aromatic nucleus or hetero-aromatic ring (substituting group can be aromaticity).Each ring in condensed-bicyclic is carbocyclic ring or heterocycle independently.
The example of condensed-bicyclic includes, but not limited to hexahydro furyl also [2,3-b] furans-3-base, hexahydro furyl is [3,2-b] furans-3-base also, and octahydro pentamethylene is [c] pyrroles-5-base also, octahydro pentalene-2-base, octahydro-1H-isoindole-5-base, etc.Condensed-bicyclic base can not be substituted independently or replace by one or more substituting group described in the invention.
Term " steric isomer " refers to have identical chemical constitution, but atom or the group compound that spatially arrangement mode is different.Steric isomer comprises enantiomer, diastereomer, conformer (rotational isomer), geometry (cis/trans) isomer, atropisomer, etc.
Term " diastereomer " refers to two or more chiral centres and the steric isomer of its molecule not mirror image each other.Diastereomer has different physical propertiess, as fusing point, boiling point, spectral quality and reactivity.Non-enantiomer mixture is by high resolution analysis operation as electrophoresis and chromatogram, and such as HPLC is separated.
Term " enantiomer " refer to two of a compound can not be overlapping but be mutually the isomer of mirror.
Term " racemoid " or " racemic mixture " be optically active two the corresponding isomer species of hypodactylia etc. molar mixture.
Term " chirality " is that have can not the molecule of overlapping character with its mirror image; And " achirality " refer to can be overlapping with its mirror image molecule.
Stereochemical definitions Sum fanction used in the present invention generally follows S.P.Parker, Ed., McGraw-Hill Dictionary of ChemicalTerms (1984) McGraw-Hill Book Company, New York; And Eliel, E.and Wilen, S., " Stereochemistry of OrganicCompounds ", John Wiley & Sons, Inc., New York, 1994.
Many organic compound exist with optical active forms, and namely they have the ability that the plane of plane polarized light is rotated.When describing optically active compound, prefix D and L or R and S is used to represent the absolute configuration of molecule about one or more chiral centre.Prefix d and l or (+) and (-) are the symbols being used to specify plane polarized light rotation caused by compound, and wherein (-) or l represent that compound is left-handed.Prefix is the compound of (+) or d is dextrorotation.Concrete steric isomer is an enantiomer, and the mixture of this isomer is called enantiomeric mixture.The 50:50 mixture of enantiomer is called racemic mixture or racemic modification, when not having stereoselectivity or stereospecificity in chemical reaction or process, can occur this situation.
Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can exist with the form of racemize or enantiomorph enrichment, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess in (R)-or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
According to the selection of starting material and method, the compounds of this invention can with in possible isomer or their mixture, and the form of such as racemic modification and non-corresponding isomer mixture (this depends on the quantity of unsymmetrical carbon) exists.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent preparation, or use routine techniques to split.If compound contains a double bond, substituting group may be E or Z configuration; If containing dibasic cycloalkyl in compound, the substituting group of cycloalkyl may have cis or transconfiguration.
The mixture of any steric isomer of gained can be separated into pure or substantially pure geometrical isomer according to the difference in component physicochemical property, enantiomer, diastereomer, such as, by chromatography and/or Steppecd crystallization.
By known method, the method that the racemic modification of any gained end product or intermediate is familiar with by those skilled in the art can be split into optical antipode, e.g., by being separated its diastereoisomeric salt obtained.Racemic product also can be separated by chiral chromatography, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, enantiomer can be prepared by asymmetric synthesis, such as, can with reference to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nded.Robert E.Gawley, Jeffrey Aub é, Elsevier, Oxford, UK, 2012); Eliel, E.L.Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H.Tables of Resolving Agentsand Optical Resolutions p.268 (E.L.Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, IN 1972); ChiralSeparation Techniques:A Practical Approach (Subramanian, G.Ed., Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim, Germany, 2007).
Term " tautomer " or " tautomeric form " refer to the constitutional isomer transformed mutually by low energy barrier (low energy barrier) with different-energy.If tautomerism is possible (as in the solution), then can reach the chemical equilibrium of tautomer.Such as, proton tautomer (protontautomer) (also referred to as Prototropic tautomers (prototropic tautomer)) comprises the mutual conversion undertaken by proton shifting, as keto-enol isomerization and imine-enamine isomerizations.Valence tautomerism body (valence tautomer) comprises the mutual conversion undertaken by the restructuring of some bonding electronss.The specific examples of keto-enol tautomerism is the change of pentane-2,4-diketone and 4-hydroxyl penta-3-alkene-2-keto tautomer.Another example tautomeric is phenol-keto tautomerism.A specific examples of phenol-keto tautomerism is the change of pyridine-4-alcohol and pyridine-4 (1H)-one tautomer.Unless otherwise noted, all tautomeric forms of the compounds of this invention all within the scope of the present invention.
" pharmaceutically acceptable " refers to some compounds, raw material, composition and/or formulation like this, they are in the scope that rational medicine judges, to be applicable to patient tissue contacts and without excessive toxicity, pungency, transformation reactions or the other problems symmetrical with rational interests/Hazard ratio and complication, and to be effective to given application.
Unless other aspects show, structural formula described in the invention comprises all isomeric forms (as enantiomerism, diastereo-isomerism, with rotamerism (or conformational isomerism)): R, S configuration such as containing asymmetric center, (Z), (E) isomer of double bond, and (Z), (E) conformer.Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.
Unless other aspects show, all tautomeric forms of compound of the present invention are included within scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atom.
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug 1-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.Such as, a compound in the present invention comprises OH group, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that di on parent obtains.Can with reference to Publication about Document about the complete discussion of prodrug: Higuchi et al., Pro-drugs as Novel Deliver ys ystems, Vol.14, A.C.S.Symposium Series; Roche et al., ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs:Designand Clinical Applications, Nature Reviews Drug Discovery, 2008,7,255-270, and Hecker et al, Prodrugs of Phosphates and Phosphonates, J.Med.Chem., 2008,51,2328-2345, every section of document is contained in this by reference.
" meta-bolites " refers to concrete compound or its salt in vivo by product that metabolism obtains.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.Such product can be by passing through oxidation to drug compound, and reduction, hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise and compound of the present invention and Mammals fully contacted the meta-bolites that for some time produces.
Term " pharmacy acceptable salt " refers within the scope of reliable medical judgment, is suitable for not occurring excessive toxicity, stimulation, anaphylaxis etc. with the mankind and zootic contact tissue, and the salt matched with rational effect/Hazard ratio.Pharmacologically acceptable salts is well known in the art.Such as, S.M.Berge, et al., J.Pharmaceutical Sciences, has been described in detail pharmacologically acceptable salts in 1977,66:1.
The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to, acetate, adipate, alginates, Citrate trianion, ascorbate salt, aspartate, benzoate, benzene sulfonate, hydrosulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, maleate, lauroleate, lauryl sulfate, malate, malonate, mesylate, nicotinate, 2-naphthalenesulfonate, oxalate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, stearate, thiocyanate-, phosphoric acid salt, glutaminate, supercarbonate, tosilate, undecane hydrochlorate, valerate etc.The salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N +(C 1-C 4alkyl) 4salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water-soluble or oil soluble or dispersion product can be obtained by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium, etc.Pharmacy acceptable salt comprises suitable, nontoxic ammonium further, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, and oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C 1-C 8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
Term " solvate " refers to the associated complex that one or more solvent molecule and compound of the present invention are formed.The solvent forming solvate comprises, but is not limited to, water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid, thanomin or its mixture.
When described solvent is water, term " hydrate " can be used.In certain embodiments, a compounds of this invention molecule can combine with a water molecules, such as monohydrate; In other embodiment, a compounds of this invention molecule can combine with more than one water molecules, such as dihydrate, also has in some embodiments, a compounds of this invention molecule can combine with the water molecules being less than, such as semihydrate.It should be noted that hydrate of the present invention remains with the biological effectiveness of the described compound of nonhydrated form.
Time term " blocking group " or " PG " refer to a substituting group and other reacted with functional groups, be commonly used to block or protect special functional.Such as; " amino blocking group " refer to a substituting group be connected with amino group block or protect in compound amino functional; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; benzoyl, ethoxy carbonyl, tertbutyloxycarbonyl (BOC); carbobenzoxy-(Cbz) (CBZ), the sub-methoxycarbonyl (Fmoc) of 9-fluorenes and benzyl.Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises trialkylsilkl, ethanoyl, benzoyl and benzyl." carboxy protective group " refers to that the substituting group of carboxyl is used for blocking or protecting the functional of carboxyl, and general carboxyl-protecting group comprises-CH 2cH 2sO 2ph; cyano ethyl; 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl; 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino) ethyl; nitro-ethyl, etc.Can reference for the general description of blocking group: Greene et al.; Protective Groups inOrganic Synthesis; John Wiley & Sons; New York; 1991and Kocienski et al., Protecting Groups, Thieme; Stuttgart, 2005.
Term " prevents " or " prevention " refers to that the minimizing of the risk obtaining disease or obstacle (that is: makes at least one clinical symptom of disease in main body, stop development, this main body may in the face of or in advance tendency in the face of this disease, but also do not experience or show the symptom of disease).
Term " treatment significant quantity " refers to when delivering medicine to main body and carrying out disease therapy, and the component of compound is enough to the treatment onset of this disease." treatment significant quantity " can along with compound, disease and severity, and the condition having main body to be treated, the age, body weight, sex etc. and changing.
" treatment " of morbid state comprises: (i) preventing disease state, that is, make to be exposed to or susceptible disease state but also do not experience or show the clinical symptom not developing deeply of morbid state of experimenter of symptom of morbid state; (ii) suppress morbid state, that is, stop the development of morbid state or its clinical symptom, or (iii) alleviates morbid state, that is, make morbid state or its clinical symptom temporarily or forever disappear.
the description of compound of the present invention
The benzazolyl compounds that the present invention relates to, its pharmacy acceptable salt, pharmaceutical preparation and composition thereof, can be used as serotonin selectivity reuptake inhibitor and/or 5-HT 1Areceptor stimulant, to mankind's central nervous system dysfunction, such as dysthymia disorders, the treatment of anxiety disorder, bipolar disorders has potential purposes.
On the one hand, the invention provides a kind of compound, its steric isomer for compound shown in the compound shown in formula (I) or formula (I), tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug
Wherein:
When for-time, G is CH or N;
When for=time, G is C;
Y is CR 4or N;
Each R 1be H, D, F, Cl, Br, I ,-NO independently 2,-CN ,-SCN ,-OR 5,-NR 6r 6a,-C (=O) R 5,-C (=O) OR 5,-C (=O) NR 6r 6a,-OC (=O) R 5,-N (R 6) C (=O) R 5, alkyl, thiazolinyl, alkynyl, haloalkyl, cycloalkyl, cycloalkyl alkylidene group-, heterocyclic radical, heterocycloalkylene-, aryl, aryl alkylene-, heteroaryl or heteroarylalkylenyl-;
Each R 2, R 3and R 4be separately H, D, F, Cl, Br, I ,-NO 2,-CN ,-OR 5,-NR 6r 6a,-SR 5,-C (=O) R 5,-C (=O) OR 5,-C (=O) NR 6r 6a,-OC (=O) R 5,-N (R 6) C (=O) R 5, R 5o-alkylidene group-, R 6r 6an-alkylidene group-, R 5s-alkylidene group-, alkyl, thiazolinyl, alkynyl, haloalkyl, cycloalkyl, cycloalkyl alkylidene group-, heterocyclic radical, heterocycloalkylene-, aryl, aryl alkylene-, heteroaryl or heteroarylalkylenyl-; Or the R on adjacent carbons 2, R 3, and together with the ring carbon atom be connected respectively with them, form carbocyclic ring or heterocycle; Or the R on adjacent carbons 3, R 4, and together with the ring carbon atom be connected respectively with them, form carbocyclic ring or heterocycle;
Each R 5be independently H, D, alkyl, thiazolinyl, alkynyl, haloalkyl, cycloalkyl, cycloalkyl alkylidene group-, heterocyclic radical or heterocycloalkylene-;
Each R 6and R 6abe separately H, D, alkyl, thiazolinyl, alkynyl, haloalkyl, cycloalkyl, cycloalkyl alkylidene group-, heterocyclic radical or heterocycloalkylene-; Or R 6, R 6a, and together with the nitrogen-atoms be connected with them, form heterocycle;
Above-described each R 5o-alkylidene group-, R 6r 6an-alkylidene group-, R 5s-alkylidene group-, alkyl, thiazolinyl, alkynyl, haloalkyl, carbocyclic ring, heterocycle, cycloalkyl, cycloalkyl alkylidene group-, heterocyclic radical, heterocycloalkylene-, aryl, aryl alkylene-, heteroaryl and heteroarylalkylenyl-be optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, alkyl, haloalkyl, alkoxyl group, alkylthio and alkylamino substituting group replaced;
M is 2,3,4 or 5; With
N is 1,2,3 or 4.
In one embodiment, each R 1be H, D, F, Cl, Br, I ,-NO independently 2,-CN ,-SCN ,-OR 5,-NR 6r 6a,-C (=O) R 5,-C (=O) OR 5,-C (=O) NR 6r 6a,-OC (=O) R 5,-N (R 6) C (=O) R 5, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 1-C 6haloalkyl, C 3-C 10cycloalkyl, (C 3-C 10cycloalkyl)-(C 1-C 6alkylidene group)-, C 2-C 10heterocyclic radical, (C 2-C 10heterocyclic radical)-(C 1-C 6alkylidene group)-, C 6-C 10aryl, (C 6-C 10aryl)-(C 1-C 6alkylidene group)-, C 1-C 9heteroaryl or (C 1-C 9heteroaryl)-(C 1-C 6alkylidene group)-; Wherein said each C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 1-C 6haloalkyl, C 3-C 10cycloalkyl, (C 3-C 10cycloalkyl)-(C 1-C 6alkylidene group)-, C 2-C 10heterocyclic radical, (C 2-C 10heterocyclic radical)-(C 1-C 6alkylidene group)-, C 6-C 10aryl, (C 6-C 10aryl)-(C 1-C 6alkylidene group)-, C 1-C 9heteroaryl and (C 1-C 9heteroaryl)-(C 1-C 6alkylidene group)-be optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, C 1-C 6alkyl, C 1-C 6haloalkyl, C 1-C 6alkoxyl group, C 1-C 6alkylthio and C 1-C 6the substituting group of alkylamino replaced.
In another embodiment, each R 2, R 3and R 4be separately H, D, F, Cl, Br, I ,-NO 2,-CN ,-OR 5,-NR 6r 6a,-SR 5,-C (=O) R 5,-C (=O) OR 5,-C (=O) NR 6r 6a,-OC (=O) R 5,-N (R 6) C (=O) R 5, R 5o-(C 1-C 6alkylidene group)-, R 6r 6an-(C 1-C 6alkylidene group)-, R 5s-(C 1-C 6alkylidene group)-, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 1-C 6haloalkyl, C 3-C 10cycloalkyl, (C 3-C 10cycloalkyl)-(C 1-C 6alkylidene group)-, C 2-C 10heterocyclic radical, (C 2-C 10heterocyclic radical)-(C 1-C 6alkylidene group)-, C 6-C 10aryl, (C 6-C 10aryl)-(C 1-C 6alkylidene group)-, C 1-C 9heteroaryl or (C 1-C 9heteroaryl)-(C 1-C 6alkylidene group)-; Or the R on adjacent carbons 2, R 3, and together with the carbon atom be connected with them, form C 3-C 10carbocyclic ring or C 2-C 9heterocycle; Or the R on adjacent carbons 3, R 4, and together with the ring carbon atom be connected respectively with them, form C 3-C 10carbocyclic ring or C 2-C 9heterocycle;
Wherein, described each R 5o-(C 1-C 6alkylidene group)-, R 6r 6an-(C 1-C 6alkylidene group)-, R 5s-(C 1-C 6alkylidene group)-, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 1-C 6haloalkyl, C 3-C 10cycloalkyl, (C 3-C 10cycloalkyl)-(C 1-C 6alkylidene group)-, C 2-c 10heterocyclic radical, (C 2-C 10heterocyclic radical)-(C 1-C 6alkylidene group)-, C 6-C 10aryl, (C 6-C 10aryl)-(C 1-C 6alkylidene group)-, C 1-C 9heteroaryl, (C 1-C 9heteroaryl)-(C 1-C 6alkylidene group)-, C 3-C 10carbocyclic ring and C 2-C 9heterocycle is optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, C 1-C 6alkyl, C 1-C 6haloalkyl, C 1-C 6alkoxyl group, C 1-C 6alkylthio and C 1-C 6the substituting group of alkylamino replaced.
In another embodiment, each R 5be H, D, C independently 1-C 6alkyl, C 1-C 6haloalkyl or C 3-C 10cycloalkyl; Wherein, described each C 1-C 6alkyl, C 1-C 6haloalkyl and C 3-C 10cycloalkyl is optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, C 1-C 6alkyl, C 1-C 6haloalkyl, C 1-C 6alkoxyl group, C 1-C 6alkylthio and C 1-C 6the substituting group of alkylamino replaced; With
Each R 6and R 6abe separately H, D, C 1-C 6alkyl, C 1-C 6haloalkyl or C 3-C 10cycloalkyl; Or R 6, R 6a, and together with the nitrogen-atoms be connected with them, form C 3-C 10heterocycle; Wherein, described each C 1-C 6alkyl, C 1-C 6haloalkyl, C 3-C 10cycloalkyl and C 3-C 10heterocycle is optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, C 1-C 6alkyl, C 1-C 6haloalkyl, C 1-C 6alkoxyl group, C 1-C 6alkylthio and C 1-C 6the substituting group of alkylamino replaced.
In another embodiment, Y is CH or N.
In another embodiment, each R 1be H, D, F, Cl ,-CN ,-OR independently 5,-NR 6r 6a,-C (=O) NR 6r 6a, C 1-C 4alkyl or C 1-C 4haloalkyl; Wherein said each C 1-C 4alkyl and C 1-C 4haloalkyl is optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, C 1-C 4alkyl, C 1-C 4haloalkyl, C 1-C 4alkoxyl group, C 1-C 4alkylthio and C 1-C 4the substituting group of alkylamino replaced.
In another embodiment, each R 2and R 3be separately H, D, F, Cl ,-CN ,-OR 5,-NR 6r 6a,-SR 5,-C (=O) OR 5,-C (=O) NR 6r 6a, R 5o-(C 1-C 4alkylidene group)-, R 6r 6an-(C 1-C 4alkylidene group)-, R 5s-(C 1-C 4alkylidene group)-, C 1-C 4alkyl, C 2-C 4thiazolinyl, C 2-C 4alkynyl or C 1-C 4haloalkyl; Or the R on adjacent carbons 2, R 3, and together with the ring carbon atom be connected respectively with them, form C 3-C 8carbocyclic ring or C 2-C 7heterocycle;
Wherein, described each R 5o-(C 1-C 4alkylidene group)-, R 6r 6an-(C 1-C 4alkylidene group)-, R 5s-(C 1-C 4alkylidene group)-, C 1-C 4alkyl, C 2-C 4thiazolinyl, C 2-C 4alkynyl, C 1-C 4haloalkyl, C 3-C 8carbocyclic ring and C 2-C 7heterocycle is optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, C 1-C 4alkyl, C 1-C 4haloalkyl, C 1-C 4alkoxyl group, C 1-C 4alkylthio and C 1-C 4the substituting group of alkylamino replaced.
In another embodiment, each R 5be H, D or C independently 1-C 4alkyl; With
Each R 6and R 6abe separately H, D or C 1-C 4alkyl; Or R 6, R 6a, and together with the nitrogen-atoms be connected with them, form C 3-C 5heterocycle.
In another embodiment, each R 1be H, D, F, Cl ,-CN, CH independently 3,-CH (CH 3) 2,-CF 3,-OH ,-OCH 3,-NH 2or-C (=O) NH 2.
In further embodiments, the present invention has one of them structure following:
Unless otherwise indicated, all suitable isotropic substance changes of compound of the present invention, steric isomer, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt and prodrug all belong to scope of the present invention.
Specifically:
On the one hand, the present invention includes all suitable isotropic substance change of different compound.The isotropic substance change of the compounds of this invention is defined as: wherein at least one atom is had same atoms ordinal number but different from the atomic mass that usual occurring in nature finds, and preferably enriches most isotopic atom and replaces.The isotopic example can introducing the compounds of this invention comprises hydrogen, carbon, nitrogen, oxygen, sulphur, and fluorine and chlorine, such as, be respectively: H 2, H 3, C 11, C 13, C 14, N 15, O 17, O 18, S 35, F 18and Cl 36.Some isotropic substance change of the present invention, such as, those wherein introduce radioisotopic compound, such as: introduce H 3or C 14, very useful in the research that medicine and/or matrix organization distribute.Containing tritium, that is: H 3, and carbon-14, that is: C 14isotropic substance because they are easy to preparation and detectability and particularly preferably.In addition, due to larger metabolic stability, by isotropic substance, such as: deuterium, that is: H 2replace the treatment advantage that can provide certain, such as, the transformation period in vivo increased, the dose demand of minimizing, and be therefore preferred in some cases.The isotropic substance change of the compounds of this invention can be prepared by traditional method substantially, uses the suitable isotropic substance change of suitable agent.
Wherein at least one atom the compound that replaces by the isotropic substance of different atoms equally as a part of the present invention, this not homoatomic isotropic substance may be used for the activation imaging technique in body, such as: single photon emission computed tomography (SPECT) or Positron emission computed tomography (PET).Example for these derivatives that can be used in SPECT research has: wherein introduce Tc 99m, In 111, Rb 82, Cs 137, I 123, Ga 67, lr 192or Ti 201, and be preferably I 123compound (for iodization, asking for an interview: such as " reaction of the radioiodination of medicine, the summary of effective synthesis strategy " Coenen HH, Springer, Dordrecht 2006), and in PTE application: can C be used 11, N 13, O 15, F 18, Rb 82, Sr 82, and be preferably F 18(Value linear marking method: the feature of primitive reaction and possibility (Features and possibilities of basicreactions) Coenen, HH, Ernst Schering Res Found Workshop 2007, Vol62, p15-50; Miller, PW Ang Chem Int Ed2008, Vol the 47,8998th page).
On the other hand, structural formula described in the invention comprises all stereoisomeric forms in any ratio (enantiomerisms, diastereo-isomerism, with rotamerism (or conformational isomerism)): R, S configuration such as containing asymmetric center, (Z), (E) isomer of double bond, and (Z), (E) conformer.Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.
On the other hand, all tautomeric forms of compound of the present invention are included within scope of the present invention.
On the other hand, the oxynitride of the compounds of this invention is also contained within scope of the present invention.Can by using conventional oxygenant (such as hydrogen peroxide) at an elevated temperature, under having the acid of such as acetic acid to exist, be oxidized corresponding nitrogenous alkaline matter, or by be applicable to solvent in cross acid-respons, such as react with peracetic acid in methylene dichloride, ethyl acetate or methyl acetate, or react with 3-chloroperoxybenzoic acid in chloroform or methylene dichloride, prepare the oxynitride of the compounds of this invention.
On the other hand, the salt of the compounds of this invention comprises pharmacy acceptable salt; Also comprise for the preparation of or purifying formula (I) shown in the salt of enantiomer of compound separation shown in the intermediate of compound or formula (I), but not necessarily pharmacy acceptable salt.
If compound of the present invention is alkaline, then conceivable salt can be prepared by any suitable method that document provides, and such as, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Or use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; Pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartrate; Amino acid, as aspartic acid and L-glutamic acid; Aromatic acid, as phenylformic acid and styracin; Sulfonic acid, as tosic acid, ethyl sulfonic acid, etc.
If compound of the present invention is acid, then conceivable salt can be prepared by suitable method, e.g., uses mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), and alkali metal hydroxide or alkaline earth metal hydroxides, etc.Suitable salt comprises, but is not limited to, from the organic salt that amino acid obtains, as glycine and arginine, and ammonia, as uncle ammonia, parahelium and tertiary ammonia, and ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.
the composition of compound of the present invention, preparation and administration
The invention provides a kind of pharmaceutical composition, comprise compound or its independent steric isomer of formula (I), the racemize of isomer or non-racemic mixture or its pharmacy acceptable salt or solvate, and the pharmaceutically acceptable carrier of at least one, assistant agent or vehicle, and optionally, other treat and/or prevent composition.
Suitable carrier, assistant agent and vehicle agent be for those skilled in the art know and be described in detail in such as Ansel H.C.et al., Ansel ' s Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro A.R.et al., Remington:The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; With Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, in Chicago.
Compound of the present invention or composition can by any suitable method administrations, comprise oral (comprise containing clothes and sublingual), locally, rectum, vagina, transdermal, parenteral (intramuscular, intravenously, intra-arterial, intraperitoneal or subcutaneous), in lung, intracutaneous, in sheath and in epidural and nose, and if need for topical therapeutic, intralesional administration.Preferred mode is oral administration, to Intraperitoneal medication or intravenous injection.
For Orally administered, described pharmaceutical composition can adopt such as following form: the tablet prepared by the pharmaceutically acceptable vehicle of ordinary method or capsule, and described vehicle is tackiness agent (such as pregelatinized corn starch, Polyvinylpyrolidone (PVP) or Vltra tears) such as; Weighting agent (such as lactose, Microcrystalline Cellulose or calcium phosphate); Lubricant (such as Magnesium Stearate, talcum or silicon-dioxide); Disintegrating agent (such as yam starch or sodium starch glycolate); Or wetting agent (such as Sodium Lauryl Sulphate BP/USP).Tablet can dressing by means commonly known in the art.
Orally administered liquid preparation can adopt such as following form: solution, syrup or suspension, or can the form of desciccate exist, with the carrier reconstruct be applicable to water or other before use.These liquid preparations can adopt pharmaceutically acceptable additive to prepare by ordinary method, and described additive is suspension agent (edible fat of such as sorbitol syrup, methylcellulose gum or hydrogenation) such as; Emulsifying agent (such as Yelkin TTS and Sudan Gum-arabic); Nonaqueous carrier (such as Prunus amygdalus oil, oily ester or ethanol) and sanitas (as methyl p-hydroxybenzoate or propylparaben or Sorbic Acid).
For sucking and using, described composition can adopt the form of tablet or the lozenge prepared in conventional manner.
The composition being suitable for parental injection can comprise physiologically acceptable sterile, aqueous or non-aqueous liquor, dispersion agent, suspensoid or emulsion, and for reconstructing the sterile powders of sterile injectable solution agent or dispersion agent.Suitable moisture or nonaqueous carrier, thinner, solvent or vectorial example comprise water, ethanol, polyvalent alcohol (propylene glycol, polyoxyethylene glycol, glycerine etc.), vegetables oil (as sweet oil), injectable organic ester as ethyl oleate and their suitable mixture.
These compositions also can contain auxiliary material, as sanitas, wetting agent, emulsifying agent and dispersion agent.By various antibacterial agent and anti-mycotic agent, such as parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc., can guarantee the effect preventing microorganism.Also expect to comprise isotonic agent, such as carbohydrate, sodium-chlor etc.Such as, by using the material that can postpone to absorb, aluminum monostearate and gelatin, the prolongation that can reach injectable drug form absorbs.
Also suspension agent can be contained in addition to the active compound, the mixture etc. of such as ethoxylation i-octadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, Microcrystalline Cellulose, partially aluminium hydroxide, wilkinite, agar and tragacanth gum or these materials in suspensoid.
In some cases, be the effect of prolong drug, expect absorption that is subcutaneous or intramuscular injection of drugs of slowing down.This realizes by using the crystal of poorly water-soluble or the liquid suspension of amorphous substance.Like this, the absorption rate of medicine depends on its dissolution rate, and dissolution rate can be depending on crystallographic dimension and crystal formation.Or, the delay of the medicament forms of parenteral admin absorb by by this medicine dissolution in or be suspended in oily vehicle and realize.
Injectable depot formulations form is by preparing at the microcapsule matrix of biodegradable polymer as formed medicine in polylactide-polyglycolide (polylactide-polyglycolide).According to the character of the ratio of medicine and polymkeric substance and the concrete polymkeric substance adopted, drug releasing rate can be controlled.The example of other biological degradable polymer comprises poe class (poly (orthoesters)) and polyanhydrides (poly (anhydrides)).Injectable depot formulations also can be prepared in the liposome compatible with bodily tissue or micro emulsion by pharmaceutical pack being embedded in.
Injectable formulation can such as by filtering with bacterial filter or carrying out sterilizing by the disinfectant mixing aseptic solid composite form, and described solids composition can be dissolved or dispersed in sterilized water or other sterile injectable medium before use.
The compounds of this invention can be prepared as paste, creme or lotion or be used for epidermis topical as pasting through skin.Paste and creme such as use or oil binder (base) can add suitable thickening material and/or jelling agent preparation.Lotion can use or oil binder preparation, and usually also will containing one or more emulsifying agents, stablizer, dispersion agent, suspension agent, thickening material or tinting material.Be suitable for the formulation of topical in mouth to comprise: lozenge, it is included in flavouring base, the promoting agent in usually sucrose and Acacia or tragacanth gum; Pastille, it is included in the activeconstituents in inertia base-material such as gelatin and glycerine or sucrose and Acacia; And collutory, it is included in the activeconstituents in suitable liquid vehicle.In addition, the pharmaceutical preparation of ophthalmology, ear drop and eye drops are all the scopes that the present invention considers.
The pharmaceutically acceptable composition of the present invention can with the form rectum of suppository or vagina administration.These can form by reagent and suitable non-perfusing adjuvant being mixed with, and this adjuvant is at room temperature solid but is then liquid at the temperature of rectum or vagina, thus melts in rectum or vagina and discharge medicine.Such material comprises cocoa butter, beeswax, and polyethylene glycols.
For using for intranasal administration or by suction, active compound of the present invention is sent easily with the form of the aerosol spray in pressurizing vessel or atomizer or in the capsule of employing sucker or insufflator.In the case of a pressurized aerosol, suitable propellent (such as Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, carbonic acid gas or other gas be applicable to) and unitary dose can be determined by the amount providing valve to send through metering.The medicine of pressurizing vessel or atomizer can comprise solution or the suspension of active compound, concerning then its preferred powder type capsule.The capsule and cartridge case (being made up of such as gelatin) that are used for sucker or insufflator can be mixed with the powdered mixture comprising the compounds of this invention and suitable powdered substrate (such as lactose or starch).
" often spraying (puff) " that aerosol formulation for treating above-mentioned illness (such as migraine) in average adult is preferably prepared as each dosing or aerosol comprises the compounds of this invention of 20 μ g to 1000 μ g.Every TDD of aerosol is in the scope of 100 μ g to 10mg.Can use several times in one day, such as 2,3,4 or 8 times, give such as 1,2 or 3 dosage at every turn.
Pharmaceutical preparation is preferably unit dosage.In this form, preparation is subdivided into the unitary dose containing appropriate active ingredient.Unit dosage can be the preparation of packaging, and this packaging contains the preparation of discrete magnitude, as tablet, capsule and the powder in bottle or ampoule packed.In addition, unit dosage can be capsule, tablet, cachet or lozenge itself, or can be the packaged form of these formulations any of proper amt.
It should be understood that total daily dosage portion of the compounds of this invention and composition must be maked decision within the scope of reliable medical judgment by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises treated obstacle and the severity of this obstacle; The activity of the particular compound adopted; The concrete composition adopted; Age of patient, body weight, general health situation, sex and diet; The administration time of the particular compound adopted, route of administration and excretion rate; The treatment time length; The medicine combinationally using with adopted particular compound or use simultaneously; And the known similar factor of medical field.Such as, the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.In general, the dosage that formula (I) compound is used for Mammals particularly people can be 0.1-1000mg/kg/day, be preferably 1-100mg/kg/day, taking can be once a day or for several times, and takes medicine for each time and can comprise 1,2 or 3 dosage.
Can by individually dosed for compound formula (I) Suo Shi, or with another kind of therapeutical active compound Combined Preparation, wherein by these two kinds of compounds or can give, or order gives simultaneously.Tranquilizer or soporific can be included, but are not limited to, as benzodiazepines with the example of the therapeutical active compound of compound Combined Preparation formula (I) Suo Shi; Anticonvulsive drug, as lamotrigine, valproic acid, topiramate, gabapentin, Carbamzepine; Mood stabilizer, as lithium; Dopaminergic, as dopamine agonist and levodopa; The medicine for the treatment of ADHD, as Tomoxetine hydrochloride; Psychostimulant, as modafinil, ketamine, Ritalin and amphetamine; Other thymoleptic, as mirtazapine, mianserin and Bupropion; Hormones, as T3, oestrogenic hormon, DHEA and testosterone; Atypical antipsychotic agents, as olanzapine and Aripiprazole; Classical antipsychotic, as haloperidol; The medicine for the treatment of alzheimer's disease, as anticholinesterase and memantine, folate (folate); S-Adenosyl-Methionine; Immunomodulator, as interferons; Opiates, as buprenorphine; Angiotensin-ii receptor 1 antagonist (AT1 antagonist); ACE inhibitor; Statins; With alpha-1 adrenergic (adrenergic) antagonist, as Prazosin.
the purposes of compound of the present invention and composition
Above-claimed cpd provided by the invention and pharmaceutical composition can be used for for the preparation of prevention, treat or alleviate Mammals, comprise the medicine of the central nervous system dysfunction of the mankind, also may be used for for the preparation of suppression serotonin reuptake transporter and/or exciting 5-HT 1Athe medicine of acceptor.
Specifically, in composition of the present invention the amount of compound can effectively detectably optionally suppress serotonin re-uptake and to 5-HT 1Aacceptor has agonism, and compound of the present invention can as the medicine for the treatment of mankind's central nervous system (CNS) dysfunction such as dysthymia disorders, anxiety disorder.
Compound of the present invention can be applied to, but is never limited to, and uses the significant quantity of compound of the present invention or composition to prevent patient's administration, treats or alleviate Mammals, comprises the central nervous system dysfunction disease of the mankind.The central nervous system dysfunction disease of the described mankind in response to 5-hydroxytryptamine receptor regulation and control, includes, but are not limited to, dysthymia disorders further, anxiety disorder, mania, schizophrenia, somnopathy, bipolar disorders, obsessional idea and behavior disorder, panic disorder, posttraumatic stress disorder, dyskinesia, sexual dysfunction, musculoskeletal pain obstacle, cognitive disorder, dysmnesia, Parkinson's disease, Huntington's disease, phobia, substance abuse or habituation, drug addiction withdrawal symptom and premenstrualtension syndrome etc.
Compound of the present invention and pharmaceutical composition, except useful to human treatment, also can be applicable to the Mammals in veterinary treatment pet, the animal of introduced variety and the animal on farm.The example of other animal comprises horse, dog and cat.At this, compound of the present invention comprises its pharmaceutically acceptable derivates.
the synthetic method of compound
For describing the present invention, below list embodiment.But need be appreciated that and the invention is not restricted to these embodiments, only be to provide and put into practice method of the present invention.
Usually, compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein substituent definition is such as formula shown in (I).Reaction scheme below and embodiment are used for illustrating content of the present invention further.
The professional in affiliated field will recognize: chemical reaction described in the invention can be used for preparing many other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by modifying method by those skilled in the art; as suitable protection interference group, by the reagent that utilizes other known except described in the invention, or reaction conditions is made the amendment of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, to be decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as AldrichChemical Company, Arco Chemical Company and Alfa Chemical Company, unless other aspects show, all not through being further purified during use.General reagent is from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Tianjin good fortune chemical reagent factory in morning, Wuhan Xin Huayuan development in science and technology company limited, Qingdao Teng Long chemical reagent company limited and Haiyang Chemical Plant, Qingdao buy and obtain.
Anhydrous tetrahydro furan, dioxane, toluene, ether is through sodium Metal 99.5 backflow drying and obtains.Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.
Below reacting is generally under nitrogen or argon gas positive pressure or on anhydrous solvent, overlap a drying tube (unless showing in other), the soft rubber ball that reaction flask is suitable all beyond the Great Wall, and substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column uses silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDC1 3, d 6-DMSO, CD 3oD or d 6-acetone is solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, quartet), dt (doublet of triplets, two triplet).Coupling constant, represents with hertz (Hz).
The condition of Algorithm (MS) data is: (3.5 microns, 6min, flow velocity is 0.6mL/min to Agilent 1200 or Agilent 6120Series LCMS for pillar model: ZorbaxSB-C18,2.1 × 30mm.Moving phase: 5-95% is (containing the CH of 0.1% formic acid 3cN) (containing the H of 0.1% formic acid 2o) ratio in, detects at 210/254nm UV, by low-response EFI pattern (ESI).
The characteristic manner of pure compound is: Agilent 1100Series high speed liquid chromatography (HPLC), detects at 210nm and 254nm UV.Pillar operates usually at 40 DEG C.
The use of brief word below runs through the present invention:
Aq. the aqueous solution
Ascorbic acid xitix
CH 2cl 2, DCM methylene dichloride
CDC1 3deuterochloroform
DIEA, DIPEA diisopropyl ethyl amine
DMF DMF
DMAP DMAP
DMSO dimethyl sulfoxide (DMSO)
EtOAc, EA ethyl acetate
Et 3n, TEA triethylamine
EDTA ethylenediamine tetraacetic acid (EDTA)
EGTA ethylene glycol diethyl ether ethylenediamine tetraacetic acid (EDTA)
G gram
Glucose glucose
H hour
H 2sO 4sulfuric acid
HBTU benzotriazole-N, N, N', N'-tetramethyl-urea hexafluorophosphate
K 2cO 3salt of wormwood
KI potassiumiodide
KCl Repone K
MeOH, CH 3oH methyl alcohol
MgSO 4magnesium sulfate
ML, ml milliliter
Min minute
N 2nitrogen
RT, rt, r.t. room temperature
NaBH 4sodium borohydride
NH 4c1 ammonia chloride
NaHCO 3sodium bicarbonate
NaH 2pO 4sODIUM PHOSPHATE, MONOBASIC
NaCl sodium-chlor
Na 2sO 4sodium sulfate
PCC pyridinium chloro-chromate
PE sherwood oil (60-90 DEG C)
THF tetrahydrofuran (THF)
Tri-HCl Tri(Hydroxymethyl) Amino Methane Hydrochloride
TsCl Tosyl chloride
Following synthetic schemes describes preparation the present invention and to come into the open the step of compound.Unless otherwise indicated, R 1, R 2, R 3with n, there is definition as described in the present invention; W is-(CR xr y)-,-(NR x)-,-O-,-S-, wherein each R xand R ybe separately H, D, F, Cl, N 3,-CN ,-OH ,-SH ,-NH 2, alkyl, haloalkyl, alkoxyl group, alkylthio or alkylamino; P is 1 or 2; Q is 1,2,3,4 or 5.
Synthetic schemes 1:
Formula ( 8) shown in compound can be prepared by the method described in synthetic schemes 1: first, 2,6-dichloropyridine ( 1) at alkali, as under the effect of sodium hydride, with benzylalcohol ( 2) effect, obtain compound ( 3).Then, compound ( 3) in suitable solvent, as in acetonitrile, tetrahydrofuran (THF), ethanol, DMF or DMSO, with piperazine ( 4) reaction, generation compound ( 5).Compound ( 5) through palladium carbon reduction obtain compound ( 6).Finally, compound ( 6) and compound ( 7) at suitable alkali, as salt of wormwood, sodium carbonate, under triethylamine effect, in suitable solvent, as in acetonitrile, tetrahydrofuran (THF), ethanol, DMF and DMSO, occur nucleophilic substitution reaction, obtain target compound ( 8).
Synthetic method 2:
Formula ( 12) shown in compound can be prepared by the method described in synthetic schemes 2: first, by compound ( 9) and 1-Benzyloxycarbonylpiperazin ( 10) be placed in suitable solvent, as in acetonitrile, tetrahydrofuran (THF), at suitable alkali, as under salt of wormwood effect, be obtained by reacting compound ( 11).Compound ( 11) through Hydrochloride/ethyl acetate process, slough Boc protection after, continue with compound ( 7) at suitable alkali, as salt of wormwood, sodium carbonate, under triethylamine effect, in suitable solvent, as in acetonitrile, tetrahydrofuran (THF), ethanol, DMF or DMSO, occur nucleophilic substitution reaction, obtain target compound ( 12).
Synthetic method 3:
Formula ( 18) shown in compound can be prepared by the method described in synthetic schemes 3: first, by compound ( 13) and chloroacetyl chloride ( 14) carry out friedel-crafts acylation, obtain compound ( 15).Then by compound ( 15) be placed in suitable solvent, as in Virahol, at reductive agent, as under sodium borohydride, Lithium Aluminium Hydride effect, obtain reduzate ( 16).Afterwards, by compound ( 16) under the effect of oxygenant IBX, obtain compound ( 17).Finally, compound ( 17) and compound ( 6) at suitable alkali, as under salt of wormwood, sodium carbonate, triethylamine effect, in suitable solvent, as in acetonitrile, tetrahydrofuran (THF), ethanol, DMF or DMSO, occur nucleophilic substitution reaction, obtain target compound ( 18).
Synthetic method 4:
Formula ( 22) shown in compound can be prepared by the method described in synthetic method 4: first, by compound ( 13) and chlorine valeryl chloride ( 19) carry out friedel-crafts acylation, generation compound ( 20).Compound ( 20) at suitable solvent, as in the trimethyl carbinol, Virahol, react with the reductive agent such as sodium borohydride, Lithium Aluminium Hydride, obtain compound ( 21).Afterwards, by compound (18) and compound ( 6) at suitable alkali, as salt of wormwood, under triethylamine effect, there is nucleophilic substitution reaction in sodium carbonate in acetonitrile, tetrahydrofuran (THF), ethanol, DMF or DMSO, obtain target compound ( 22).
Below in conjunction with embodiment, compound provided by the invention, pharmaceutical composition and application thereof are further described.
Embodiment
embodiment 16-(4-(3-(the fluoro-1H-indol-3-yl of 5-) propyl group) piperazine-1-base) pyridine-2 (1H)-one
step 1) 2-(benzyloxy)-6-chloropyridine
Under nitrogen protection; 2,6-dichloropyridine (1.48g, 0.01mol) is dissolved in anhydrous N; in dinethylformamide (25mL); be cooled to 0 DEG C, (60% is dispersed in mineral oil, 0.8g to add sodium hydride wherein; 0.02mol); after mixed solution stirs 30 minutes, continue to add benzylalcohol (1.2g, 0.01mmol) wherein.Reaction solution stirs 30 minutes at 0 DEG C, returns to room temperature, continues stirring 12 hours.React complete, mixture use water (30mL) is diluted, and extract with methylene dichloride (20mL x 3), the organic phase anhydrous sodium sulfate drying of merging, filter, and concentrating under reduced pressure.Gained residue is through purification by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/1), and obtaining title compound is white solid (1.75g, 80.0%).
MS(ESI,pos.ion)m/z:220.1[M+H] +。
step 2) 1-(6-(benzyloxy) pyridine-2-base) piperazine
Under nitrogen protection, 2-(benzyloxy)-6-chloropyridine (880mg, 4.00mmol) is joined in DMF (25mL) with Piperazine anhydrous (1.03g, 12.00mmol).Reaction solution is warming up to 100 DEG C, reacts after 20 hours, is cooled to room temperature, and add water (30mL) dilution, and extract with methylene dichloride (20mL x 3).The organic phase anhydrous sodium sulfate drying merged, filter, and concentrating under reduced pressure, gained residue is through purification by silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), obtaining title compound is white solid (805mg, 75.0%).
MS(ESI,pos.ion)m/z:270.2[M+H] +；
1H NMR(DMSO-d 6,400MHz)δ(ppm):7.45(t,J＝4.4Hz,2H),7.42(d,J＝5.2Hz,1H),7.38(t,J＝5.0Hz,2H),7.35-7.33(m,1H),6.19-6.17(m,2H),5.35(s,2H),3.50(t,J＝3.4Hz,4H),2.99(t,J＝3.4Hz,4H)。
step 3) 6-(piperazine-1-base) pyridine-2 (1H)-one
Pd/C (10%, 100mg) is added in methyl alcohol (15mL) solution of 1-(6-(benzyloxy) pyridine-2-base) piperazine (810mg, 3.00mmol).Reaction system is placed in nitrogen atmosphere, and stirring at room temperature is after 20 hours, suction filtration.Filtrate is after concentrating under reduced pressure, and vacuum-drying, obtaining title compound is white solid (510mg, 95.0%).
MS(ESI,pos.ion)m/z:180.1[M+H] +；
1H NMR(MeOD,400MHz)δ(ppm):7.31(t,J＝8.1Hz,1H),5.91-5.89(m,1H),5.61-5.59(m,1H),3.26(t,J＝4.8Hz,4H),2.97(t,J＝4.8Hz,4H)。
step 4) synthesis of 6-(4-(3-(the fluoro-1H-indol-3-yl of 5-) propyl group) piperazine-1-base) pyridine-2 (1H)-one
Under nitrogen protection; by 3-(the fluoro-1H-indol-3-yl of 5-) propyl group 4-toluene sulfonic acide ester (200mg; 0.58mmol) with 6-(piperazine-1-base) pyridine-2 (1H)-one (105mg; 0.58mmol) be dissolved in acetonitrile (15mL); and add salt of wormwood (120mg wherein; 0.87mmol) and the potassiumiodide (20mg, 0.12mmol) of catalytic amount.Reaction solution is heated to 80 DEG C, stirs after 20 hours, is cooled to room temperature, concentrating under reduced pressure.Gained residue is through purification by silica gel column chromatography (methylene chloride/methanol (v/v)=15/1), and obtaining title compound is yellow solid (133mg, 65.0%).
MS(ESI,pos.ion)m/z:355.0[M+H] +；
1H NMR(DMSO-d 6,600MHz)δ(ppm):10.86(s,1H),7.35-7.31(m,2H),7.26(dd,J＝9.6,2.4Hz,1H),7.21(d,J＝2.4Hz,1H),6.89(td,J＝9.6,2.4Hz,1H),6.03(d,J＝7.8Hz,1H),5.84(d,J＝7.8Hz,1H),3.36-3.33(m,4H),2.68(t,J＝7.2Hz,2H),2.44-2.43(m,4H),2.37-2.35(m,2H),1.82-1.80(m,2H)。
embodiment 23-(3-(4-(6-oxo-1,6-dihydropyridine-2-base) piperazine-1-base) propyl group)-1H-indoles-5-formonitrile HCN
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 3-(5-cyano-1 H-indol--3-base) propyl group 4-toluene sulfonic acide ester (205mg, 0.58mmol), 6-(piperazine-1-base) pyridine-2 (1H)-one (105mg, 0.58mmol), salt of wormwood (120mg, 0.87mmol) and the potassiumiodide (20mg of catalytic amount, 0.12mmol) be suspended in reaction preparation in acetonitrile (15mL), crude on silica gel column chromatography purification (methylene chloride/methanol (v/v)=15/1), obtaining title compound is yellow solid (125mg, 60.0%).
MS(ESI,pos.ion)m/z:362.2[M+H] +。
1H NMR(CDCl 3,600MHz)δ(ppm):8.82(s,1H),7.92(s,1H),7.43-7.40(m,1H),7.39-7.37(m,2H),7.10(m,1H),6.15(d,J＝7.9Hz,1H),6.12(d,J＝7.9Hz,1H),4.28(J＝6.3Hz,2H),3.49(t,J＝5.0Hz,4H),3.00(t,J＝5.0Hz,4H),2.91-2.87(m,2H),2.16-2.11(m,2H)。
embodiment 36-(4-(3-(5-methoxyl group-1H-indol-3-yl) propyl group) piperazine-1-base) pyridine-2 (1H)-one
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 3-(5-methoxyl group-1H-indol-3-yl) propyl group 4-toluene sulfonic acide ester (208mg, 0.58mmol), 6-(piperazine-1-base) pyridine-2 (1H)-one (105mg, 0.58mmol), salt of wormwood (120mg, 0.87mmol) and the potassiumiodide (20mg of catalytic amount, 0.12mmol) be suspended in reaction preparation in acetonitrile (15mL), crude on silica gel column chromatography purification (methylene chloride/methanol (v/v)=15/1), obtaining title compound is yellow solid (96mg, 45.0%).
MS(ESI,pos.ion)m/z:367.2[M+H] +；
1H NMR(DMSO-d 6,600MHz)δ(ppm):10.84(s,1H),7.34-7.30(m,2H),7.25(dd,J＝9.6,2.4Hz,1H),7.19(d,J＝2.4Hz,1H),6.90(td,J＝9.6,2.4Hz,1H),6.04(d,J＝7.8Hz,1H),5.86(d,J＝7.8Hz,1H),3.87(s,3H),3.34-3.31(m,4H),2.69(t,J＝7.2Hz,2H),2.41-2.38(m,4H),2.36-2.32(m,2H),1.83-1.80(m,2H)。
embodiment 46-(4-(4-(the fluoro-1H-indol-3-yl of 5-) butyl) piperazine-1-base) pyridine-2 (1H)-one
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(the fluoro-1H-indol-3-yl of 5-) butyl 4-toluene sulfonic acide ester (210mg, 0.58mmol), 6-(piperazine-1-base) pyridine-2 (1H)-one (105mg, 0.58mmol), salt of wormwood (120mg, 0.87mmol) and the potassiumiodide (20mg of catalytic amount, 0.12mmol) be suspended in reaction preparation in acetonitrile (15mL), crude on silica gel column chromatography purification (methylene chloride/methanol (v/v)=15/1), obtaining title compound is yellow solid (160mg, 75.0%).
MS(ESI,pos.ion)m/z:369.2[M+H] +；
1H NMR(DMSO-d 6,600MHz)δ(ppm):10.80(s,1H),7.32-7.28(m,2H),7.23(dd,J＝9.6,2.4Hz,1H),7.16(d,J＝2.4Hz,1H),6.88(td,J＝9.6,2.4Hz,1H),6.02(d,J＝7.8Hz,1H),5.84(d,J＝7.7Hz,1H),3.36-3.33(m,4H),2.70(t,J＝7.2Hz,2H),2.40-2.37(m,4H),2.35-2.31(m,2H),1.75-1.69(m,2H),1.66-1.58(m,2H)。
embodiment 53-(4-(4-(6-oxo-1,6-dihydropyridine-2-base) piperazine-1-base) butyl)-1H-indoles-5-formonitrile HCN
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(5-cyano-1 H-indol--3-base) butyl 4-toluene sulfonic acide ester (213mg, 0.58mmol), 6-(piperazine-1-base) pyridine-2 (1H)-one (105mg, 0.58mmol), salt of wormwood (120mg, 0.87mmol) and the potassiumiodide (20mg of catalytic amount, 0.12mmol) be suspended in reaction preparation in acetonitrile (15mL), crude on silica gel column chromatography purification (methylene chloride/methanol (v/v)=15/1), obtaining title compound is yellow solid (120mg, 55.0%).
MS(ESI,pos.ion)m/z:376.2[M+H] +；
1H NMR(CDCl 3,600MHz)δ(ppm):8.88(s,1H),7.90(s,1H),7.41-7.38(m,1H),7.36-7.35(m,2H),7.10(m，1H),6.12-6.11(m,2H),4.24(t,J＝5.9Hz,2H),3.61(t,J＝4.8Hz,4H),3.01(t,J＝4.9Hz,4H),2.80(t,J＝6.3Hz,2H),1.85-1.83(m,4H)。
embodiment 66-(4-(4-(5-methoxyl group-1H-indol-3-yl) butyl) piperazine-1-base) pyridine-2 (1H)-one
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(5-methoxyl group-1H-indol-3-yl) butyl 4-toluene sulfonic acide ester (216mg, 0.58mmol), 6-(piperazine-1-base) pyridine-2 (1H)-one (105mg, 0.58mmol), salt of wormwood (120mg, 0.87mmol) and the potassiumiodide (20mg of catalytic amount, 0.1mol) be suspended in reaction preparation in acetonitrile (15mL), crude on silica gel column chromatography purification (methylene chloride/methanol (v/v)=15/1), obtaining title compound is yellow solid (110mg, 50.0%).
MS(ESI,pos.ion)m/z:381.2[M+H] +；
1H NMR(DMSO-d 6,600MHz)δ(ppm):10.78(s,1H),7.31-7.28(m,2H),7.23(dd,J＝9.6,2.4Hz,1H),7.17(d,J＝2.4Hz,1H),6.85(td,J＝9.6,2.4Hz,1H),6.05(d,J＝7.8Hz,1H),5.84(d,J＝7.7Hz,1H),3.87(s,3H),3.36-3.34(m,4H),2.70(t,J＝7.2Hz,2H),2.40-2.38(m,4H),2.35-2.31(m,2H),1.78-1.69(m,2H),1.66-1.59(m,2H)。
embodiment 73-(2-(4-(6-oxo-1,6-dihydropyridine-2-base) piperazine-1-base) ethyl)-1H-indoles-5-formonitrile HCN
step 1) 3-(2-chloracetyl)-1H-indoles-5-formonitrile HCN
At 0 DEG C, by chloroacetyl chloride (7.7g, 68.0mmol) be added drop-wise to containing aluminum chloride (9.0g, in methylene dichloride (90mL) 68.0mmol), dropwise, continue stirring 30 minutes, then drip methylene dichloride (800mL) solution of 5-cyanoindole (8.1g, 57.0mmol) wherein.Reaction solution returns to room temperature, stirs after 2 hours, by the mixing solutions of its impouring 50g ice and 50mL concentrated hydrochloric acid.Mixed solution stirring at room temperature 20 hours, suction filtration, washing filter cake, gained solid is washed through ethyl acetate, and after vacuum-drying, obtaining title compound is yellow solid (8.0g, 54%).MS(ESI,pos.ion)m/z:219.1[M+H] +。
step 2) 3-(2-hydroxyethyl)-1H-indoles-5-formonitrile HCN
0 DEG C, in Virahol (100mL) solution of 3-(2-chloracetyl)-1H-indoles-5-formonitrile HCN (4.36g, 20mmol), add sodium borohydride (2.3g, 60mmol) in batches.Reaction solution is warming up to 80 DEG C, stirs after 6 hours, is cooled to 0 DEG C, drips saturated sodium carbonate solution (10mL) cancellation.By mixture suction filtration, filtrate reduced in volume, gained residue is through purification by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), and obtaining title compound is white solid (3g, 80%).
MS(ESI,pos.ion)m/z:187.1[M+H] +；
1H NMR(MeOD,400MHz)δ(ppm):7.99(s,1H),7.45(d,J＝8.4Hz,1H),7.35(dd,J＝8.4,1.2Hz,1H),7.26(s,1H),3.81(t,J＝6.9Hz,2H),2.97(t,J＝6.9Hz,2H)。
step 2) 3-(2-oxoethyl)-1H-indoles-5-formonitrile HCN
2-iodosobenzoic acid (2.9g, 10.4mmol) is added in methyl-sulphoxide (15mL) solution of 3-(2-hydroxyethyl)-1H-indoles-5-formonitrile HCN (1.6g, 8.6mmol).Reaction solution stirring at room temperature is after 4 hours, and add water (30mL) dilution, and extract by ethyl acetate (20mL x 3).The organic phase merged is after anhydrous sodium sulfate drying, and with purification by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1), obtaining title compound is white solid (0.79g, 40.0%).
MS(ESI,pos.ion)m/z:185.1[M+H] +；
1H NMR(CDCl 3,400MHz)δ(ppm):9.80(t,J＝2.0Hz,1H),8.87(s,1H),7.86(s,1H),7.43-7.42(m,2H),7.29(t,J＝2.2Hz,1H),3.86(m,2H)。
step 3) 3-(2-(4-(6-oxo-1,6-dihydropyridine-2-base) piperazine-1-base) ethyl)-1H-indoles-5-formonitrile HCN
At 0 DEG C, to 3-(2-oxoethyl)-1H-indoles-5-formonitrile HCN (106mg, 6-(piperazine-1-base) pyridine-2 (1H)-one (105mg is added successively in methyl alcohol/tetrahydrofuran (THF) (15mL/15mL) solution 0.58mmol), 0.58mmol), sodium cyanoborohydride (55g, 0.87mmol) and acetic acid (0.1mL).Reaction solution stirring at room temperature is after 10 hours, and concentrating under reduced pressure, gained residue water (20mL) is washed, dry, obtains crude product.By crude product through purification by silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), obtaining title compound is faint yellow solid (150mg, 60.0%).
MS(ESI,pos.ion)m/z:348.2[M+H] +；
1H NMR(CDCl 3,600MHz)δ(ppm):8.84(s,1H),7.93(s,1H),7.45-7.41(m,1H),7.40-7.38(m,2H),7.12-7.10(m,1H),6.13(d,J＝7.9Hz,1H),6.10(d,J＝7.9Hz,1H),4.27(t,J＝6.3Hz,2H),3.51(t,J＝5.0Hz,4H),3.00(t,J＝5.0Hz,4H),2.95(t,J＝6.9Hz,2H)。
embodiment 83-(5-(4-(6-oxo-1,6-dihydropyridine-2-base) piperazine-1-base) phenyl)-1H-indoles-5-formonitrile HCN
step 1) 3-(5-chlorine pentanoyl)-1H-indoles-5-formonitrile HCN
At 0 DEG C, by 5-Chlorovaleryl Chloride (10.5g, 68.0mmol) be added drop-wise to aluminum chloride (9.0g, in methylene dichloride (90mL) solution 68.0mmol), mixed solution stirs 30 minutes, continue methylene dichloride (800mL) solution dripping 5-cyanoindole (8.1g, 57.0mmol) wherein.Reaction solution returns to room temperature, stirs after 2 hours, pours in the mixing solutions of 50g ice and 50mL concentrated hydrochloric acid.Mixture is continued stirring at room temperature 20 hours, suction filtration, water (50mL) used successively by gained solid, ethyl acetate (30mL) washes, after drying, obtaining title compound is yellow solid (12.3g, 70%).
MS(ESI,pos.ion)m/z:261.0[M+H] +。
step 2) 3-(5-chlorine amyl group)-1H-indoles-5-formonitrile HCN
At 0 DEG C, in Virahol (20mL) solution of 3-(5-chlorine pentanoyl)-1H-indoles-5-formonitrile HCN (520mg, 2.0mmol), add sodium borohydride (230mg, 6.0mmol) in batches.Reaction solution is warming up to 80 DEG C, stirs after 6 hours, is cooled to 0 DEG C, and drip saturated sodium carbonate solution (10mL) cancellation.By mixture suction filtration, filtrate reduced in volume, residue is through purification by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), and obtaining title compound is white solid (343mg, 80%).
MS(ESI,pos.ion)m/z:247.1[M+H] +；
1H NMR(CDCl 3,400MHz)δ(ppm):8.31(s,1H),7.94(s,1H),7.41-7.38(m,2H),7.10(d,J＝0.8Hz,1H),3.54(t,J＝6.6Hz,2H),2.77(m,J＝7.5Hz,2H),1.86-1.77(m,2H),1.75-1.69(m,2H),1.57-1.50(m,2H)。
step 3) 3-(5-(4-(6-oxo-1,6-dihydropyridine-2-base) piperazine-1-base) amyl group)-1H-indoles-5-formonitrile HCN
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 3-(5-chlorine amyl group)-1H-indoles-5-formonitrile HCN (143mg, 0.58mmol), 6-(piperazine-1-base) pyridine-2 (1H)-one (105mg, 0.58mmol), salt of wormwood (120mg, 0.87mmol) and the potassiumiodide (20mg of catalytic amount, 0.12mmol) be suspended in reaction preparation in acetonitrile (15mL), crude on silica gel column chromatography purification (methylene chloride/methanol (v/v)=15/1), obtaining title compound is yellow solid (157mg, 50.0%).
MS(ESI,pos.ion)m/z:390.2[M+H] +；
1H NMR(CDCl 3,600MHz)δ(ppm):8.84(s,1H),7.88(s,1H),7.40-7.37(m,1H),7.35-7.31(m,2H),7.08-7.09(m,1H),6.10-6.09(m,2H),4.22(t,J＝5.9Hz,2H),3.60(t,J＝4.8Hz,4H),3.03(t,J＝4.9Hz,4H),2.79(t,J＝6.3Hz,2H),1.75-1.73(m,2H),1.38-1.35(m,2H),1.29-1.24(m,2H)。
embodiment 92-(4-(3-(the fluoro-1H-indol-3-yl of 5-) propyl group) piperazine-1-base)-6,7-dihydro-3H-cyclopentano [d] pyrimidine-4 (5H)-one
step 1) 4-(4-oxo-4,5,6,7-tetrahydrochysene-3H-cyclopentano [d] pyrimidine-2-base) piperazine-1-t-butyl formate
Under nitrogen protection; by chloro-for 2-6; 7-dihydro-3H-cyclopentano [d] pyrimidine-4 (5H)-one (680g; 4.0mmol), piperazine-1-t-butyl formate (744mg, 4.0mmol) and triethylamine (3mL) join in propyl carbinol (15mL).Reaction solution is heated to 120 DEG C, stirs after 20 hours, is cooled to room temperature, concentrating under reduced pressure.Gained residue is through purification by silica gel column chromatography (methylene chloride/methanol (v/v)=30/1), and obtaining title compound is white solid (768mg, 60.0%).
MS(ESI,pos.ion)m/z:321.3[M+H] +；
1H NMR(CDCl 3,400MHz)δ(ppm):3.73-3.70(m,4H),3.54-3.51(m,4H),2.75-2.71(m,2H),2.70-2.66(m,2H),2.06-1.99(m,2H),1.49(s,9H)。
step 2) 2-(4-(3-(the fluoro-1H-indol-3-yl of 5-) propyl group) piperazine-1-base)-6,7-dihydro-3H-cyclopentano [d] pyrimidine-4 (5H)-one
4-(4-oxo-4,5,6,7-tetrahydrochysene-3H-cyclopentano [d] pyrimidine-2-base) piperazine-1-t-butyl formate (185mg, 0.58mmol) is joined in Hydrochloride/ethyl acetate (4M, 5mL).Reaction solution stirring at room temperature is after 1 hour, concentrating under reduced pressure.Residue is dissolved in acetonitrile (15mL), and add salt of wormwood (120mg successively wherein, 0.87mmol), the potassiumiodide (20mg of catalytic amount, 0.12mmol) with 3-(the fluoro-1H-indol-3-yl of 5-) propyl group 4-toluene sulfonic acide ester (201mg, 0.58mmol).Reaction solution is heated to 80 DEG C, stirs after 20 hours, is cooled to room temperature, concentrating under reduced pressure.Gained residue is through purification by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/1), and obtaining title compound is white solid (91mg, 40.0%).
MS(ESI,pos.ion)m/z:396.3[M+H] +；
1H NMR(MeOD/CDCl 3,600MHz)δ(ppm):7.88(s,1H),7.46-7.43(m,1H),7.34(d,J＝7.8Hz,1H),7.25(s,1H),3.34-3.16(m,10H),2.85-2.83(m,2H),2.77-2.75(m,2H),2.62-2.61(m,2H),2.16-2.13(m,2H),2.08-2.06(m,2H)。
embodiment 103-(3-(4-(4-oxo-4,5,6,7-tetrahydrochysene-3H-cyclopentano [d] pyrimidine-2-base) piperazine-1-base) propyl group)-1H-indoles-5-formonitrile HCN
4-(4-oxo-4,5,6,7-tetrahydrochysene-3H-cyclopentano [d] pyrimidine-2-base) piperazine-1-t-butyl formate (185mg, 0.58mmol) is joined in Hydrochloride/ethyl acetate (4M, 5mL).Reaction solution stirring at room temperature is after 1 hour, concentrating under reduced pressure.Residue is dissolved in acetonitrile (15mL), and add salt of wormwood (120mg successively wherein, 0.87mmol), the potassiumiodide (20mg of catalytic amount, 0.12mmol) with 3-(5-cyano-1 H-indol--3-base) propyl group 4-toluene sulfonic acide ester (205mg, 0.58mmol).Reaction solution is heated to backflow, stirs after 20 hours, is cooled to room temperature, concentrating under reduced pressure.Gained residue is through purification by silica gel column chromatography (methylene chloride/methanol (v/v)=15/1), and obtaining title compound is yellow solid (95mg, 41.0%).
MS(ESI,pos.ion)m/z:403.3[M+H] +；
1H NMR(MeOD/CDCl 3,600MHz)δ(ppm):7.91(s,1H),7.46(d,J＝8.4Hz,1H),7.36(d,J＝7.8Hz,1H),7.23(s,1H),3.36-3.17(m,10H),2.87-2.84(m,2H),2.79-2.71(m,2H),2.67-2.65(m,2H),2.19-2.18(m,2H),2.08-2.05(m,2H)。
embodiment 112-(4-(3-(5-methoxyl group-1H-indol-3-yl) propyl group) piperazine-1-base)-6,7-dihydro-3H-cyclopentano [d] pyrimidine-4 (5H)-one
4-(4-oxo-4,5,6,7-tetrahydrochysene-3H-cyclopentano [d] pyrimidine-2-base) piperazine-1-t-butyl formate (185mg, 0.58mmol) is joined in Hydrochloride/ethyl acetate (4M, 5mL).Reaction solution stirring at room temperature is after 1 hour, concentrating under reduced pressure.Residue is dissolved in acetonitrile (15mL), and add salt of wormwood (120mg successively wherein, 0.87mmol), the potassiumiodide (20mg of catalytic amount, 0.12mmol) with 3-(5-methoxyl group-1H-indol-3-yl) propyl group 4-toluene sulfonic acide ester (208mg, 0.58mmol).Reaction solution is heated to backflow, stirs after 20 hours, is cooled to room temperature, concentrating under reduced pressure.Gained residue is through purification by silica gel column chromatography (methylene chloride/methanol (v/v)=15/1), and obtaining title compound is yellow solid (106mg, 45.0%).
MS(ESI,pos.ion)m/z:408.2[M+H] +；
1H NMR(MeOD/CDCl 3,600MHz)δ(ppm):7.92(s,1H),7.47(d,J＝8.4Hz,1H),7.35(d,J＝7.8Hz,1H),7.22(s,1H),3.84(s,3H),3.35-3.13(m,10H),2.85-2.81(m,2H),2.78-2.77(m,2H),2.65-2.62(m,2H),2.17-2.14(m,2H),2.07-2.04(m,2H)。
embodiment 122-(4-(4-(the fluoro-1H-indol-3-yl of 5-) butyl) piperazine-1-base)-6,7-dihydro-3H-cyclopentano [d] pyrimidine-4 (5H)-one
4-(4-oxo-4,5,6,7-tetrahydrochysene-3H-cyclopentano [d] pyrimidine-2-base) piperazine-1-t-butyl formate (185mg, 0.58mmol) is joined in Hydrochloride/ethyl acetate (4M, 5mL).Reaction solution stirring at room temperature is after 1 hour, concentrating under reduced pressure.Residue is dissolved in acetonitrile (15mL), and add salt of wormwood (120mg successively wherein, 0.87mmol), the potassiumiodide (20mg of catalytic amount, 0.12mmol) with 4-(the fluoro-1H-indol-3-yl of 5-) butyl 4-toluene sulfonic acide ester (210mg, 0.58mmol).Reaction solution is heated to backflow, stirs after 20 hours, is cooled to room temperature, concentrating under reduced pressure.Gained residue is through purification by silica gel column chromatography (methylene chloride/methanol (v/v)=15/1), and obtaining title compound is yellow solid (85mg, 36.0%).
MS(ESI,pos.ion)m/z:410.2[M+H] +。
1H NMR(MeOD/CDCl 3,600MHz)δ(ppm):7.89(s,1H),7.44(d,J＝8.4Hz,1H),7.36(d,J＝8.4Hz,1H),7.16(s,1H),3.38-3.32(m,10H),2.81-2.79(m,2H),2.75-2.72(m,2H),2.68-2.61(m,2H),2.04-2.01(m,2H),1.83-1.75(m,4H)。
embodiment 133-(4-(4-(4-oxo-4,5,6,7-tetrahydrochysene-3H-cyclopentano [d] pyrimidine-2-base) piperazine-1-base) butyl)-1H-indoles-5-formonitrile HCN
4-(4-oxo-4,5,6,7-tetrahydrochysene-3H-cyclopentano [d] pyrimidine-2-base) piperazine-1-t-butyl formate (185mg, 0.58mmol) is joined in Hydrochloride/ethyl acetate (4M, 5mL).Reaction solution stirring at room temperature is after 1 hour, concentrating under reduced pressure.Residue is dissolved in acetonitrile (15mL), and add salt of wormwood (120mg successively wherein, 0.87mmol), the potassiumiodide (20mg of catalytic amount, 0.12mmol) with 4-(5-cyano-1 H-indol--3-base) butyl 4-toluene sulfonic acide ester (213mg, 0.58mmol).Reaction solution is heated to backflow, stirs after 20 hours, is cooled to room temperature, concentrating under reduced pressure.Gained residue is through purification by silica gel column chromatography (methylene chloride/methanol (v/v)=15/1), and obtaining title compound is yellow solid (108mg, 45.0%).
MS(ESI,pos.ion)m/z:417.4[M+H] +；
1H NMR(MeOD/CDCl 3,600MHz)δ(ppm):7.91(s,1H),7.42(d,J＝7.8Hz,1H),7.35(d,J＝7.8Hz,1H),7.21(s,1H),3.35-3.29(m,10H),2.81-2.75(m,4H),2.68-2.61(m,2H),2.04-1.99(m,2H),1.82-1.76(m,4H)。
embodiment 142-(4-(4-(5-methoxyl group-1H-indol-3-yl) butyl) piperazine-1-base)-6,7-dihydro-3H-cyclopentano [d] pyrimidine-4 (5H)-one
4-(4-oxo-4,5,6,7-tetrahydrochysene-3H-cyclopentano [d] pyrimidine-2-base) piperazine-1-t-butyl formate (185mg, 0.58mmol) is joined in Hydrochloride/ethyl acetate (4M, 5mL).Reaction solution stirring at room temperature is after 1 hour, concentrating under reduced pressure.Residue is dissolved in acetonitrile (15mL), and add salt of wormwood (120mg successively wherein, 0.87mmol), the potassiumiodide (20mg of catalytic amount, 0.12mmol) with 4-(5-methoxyl group-1H-indol-3-yl) butyl 4-toluene sulfonic acide ester (216mg, 0.58mmol).Reaction solution is heated to backflow, stirs after 20 hours, is cooled to room temperature, concentrating under reduced pressure.Gained residue is through purification by silica gel column chromatography (methylene chloride/methanol (v/v)=15/1), and obtaining title compound is yellow solid (98mg, 40.0%).
MS(ESI,pos.ion)m/z:422.2[M+H] +；
1H NMR(MeOD/CDCl 3,600MHz)δ(ppm):7.93(s,1H),7.42(d,J＝8.4Hz,1H),7.35(d,J＝8.4Hz,1H),7.13(s,1H),3.82(s,3H),3.41-3.35(m,10H),2.83-2.81(m,2H),2.72-2.70(m,2H),2.65-2.58(m,2H),2.05-2.02(m,2H),1.80-1.75(m,4H)。
embodiment 152-(4-(3-(the fluoro-1H-indol-3-yl of 5-) propyl group) piperazine-1-base)-5,6,7,8-tetrahydro quinazoline-4 (3H)-one
step 1) 4-(4-oxo-3,4,5,6,7,8-six hydrogen quinazoline-2-base) piperazine-1-t-butyl formate
Under nitrogen protection, by chloro-for 2-5,6; 7; 8-tetrahydro quinazoline-4 (3H)-one (738mg, 4.0mmol), piperazine-1-t-butyl formate (744mg, 4.0mmol) and triethylamine (3mL) join in propyl carbinol (15mL).Reaction solution is heated to 120 DEG C, stirs after 20 hours, is cooled to room temperature, and concentrating under reduced pressure.Gained residue is through purification by silica gel column chromatography (methylene chloride/methanol (v/v)=30/1), and obtaining title compound is white solid (868mg, 65.0%).
MS(ESI,pos.ion)m/z:335.1[M+H] +；
1H NMR(CDCl 3,400MHz)δ(ppm):3.50-3.49(m,4H),3.37-3.34(m,4H),2.37-2.34(m,2H),2.26-2.23(m,2H),1.67-1.61(m,4H),1.49(s,9H)。
step 2) 2-(4-(3-(the fluoro-1H-indol-3-yl of 5-) propyl group) piperazine-1-base)-5,6,7,8-tetrahydro quinazoline-4 (3H)-one
4-(4-oxo-3,4,5,6,7,8-six hydrogen quinazoline-2-base) piperazine-1-t-butyl formate (194mg, 0.58mmol) is joined in Hydrochloride/ethyl acetate (4M, 5mL).Reaction solution stirring at room temperature is after 1 hour, concentrating under reduced pressure.Residue is dissolved in acetonitrile (15mL), and add salt of wormwood (120mg successively wherein, 0.87mmol), the potassiumiodide (20mg of catalytic amount, 0.12mmol) with 3-(the fluoro-1H-indol-3-yl of 5-) propyl group 4-toluene sulfonic acide ester (201mg, 0.58mmol).Reaction solution is heated to backflow, stirs after 20 hours, is cooled to room temperature, concentrating under reduced pressure.Gained residue is through purification by silica gel column chromatography (methylene chloride/methanol (v/v)=15/1), and obtaining title compound is yellow solid (140mg, 59.0%).
MS(ESI,pos.ion)m/z:410.2[M+H] +；
1H NMR(MeOD,600MHz)δ(ppm):8.03(s,1H),7.50-7.47(m,1H),7.36(d,J＝8.0Hz,1H),7.32(s,1H),3.42-3.28(m,10H),2.94-2.91(m,2H),2.61-2.56(m,2H),2.41-2.36(m,2H),2.21-2.18(m,2H),1.81-1.76(m,4H)。
embodiment 163-(3-(4-(4-oxo-3,4,5,6,7,8-six hydrogen quinazoline-2-base) piperazine-1-base) propyl group)-1H-indoles-5-formonitrile HCN
4-(4-oxo-3,4,5,6,7,8-six hydrogen quinazoline-2-base) piperazine-1-t-butyl formate (194mg, 0.58mmol) is joined in Hydrochloride/ethyl acetate (4M, 5mL).Reaction solution stirring at room temperature is after 1 hour, concentrating under reduced pressure.Residue is dissolved in acetonitrile (15mL), and add salt of wormwood (120mg successively wherein, 0.87mmol), the potassiumiodide (20mg of catalytic amount, 0.12mmol) with 3-(5-cyano-1 H-indol--3-base) propyl group 4-toluene sulfonic acide ester (205mg, 0.58mmol).Reaction solution is heated to backflow, stirs after 20 hours, is cooled to room temperature, concentrating under reduced pressure.Gained residue is through purification by silica gel column chromatography (methylene chloride/methanol (v/v)=15/1), and obtaining title compound is yellow solid (140mg, 59.0%).
MS(ESI,pos.ion)m/z:417.2[M+H] +；
1H NMR(MeOD,600MHz)δ(ppm):8.03(s,1H),7.49(d,J＝8.0Hz,1H),7.38(d,J＝8.0Hz,1H),7.32(s,1H),3.43-3.26(m,10H),2.93-2.92(m,2H),2.62-2.58(m,2H),2.40-2.36(m,2H),2.22-2.21(m,2H),1.80-1.77(m,4H)。
embodiment 172-(4-(3-(5-methoxyl group-1H-indol-3-yl) propyl group) piperazine-1-base)-5,6,7,8-tetrahydro quinazoline-4 (3H)-one
4-(4-oxo-3,4,5,6,7,8-six hydrogen quinazoline-2-base) piperazine-1-t-butyl formate (194mg, 0.58mmol) is joined in Hydrochloride/ethyl acetate (4M, 5mL).Reaction solution stirring at room temperature is after 1 hour, concentrating under reduced pressure.Residue is dissolved in acetonitrile (15mL), and add salt of wormwood (120mg successively wherein, 0.87mmol), the potassiumiodide (20mg of catalytic amount, 0.12mmol) with 3-(5-methoxyl group-1H-indol-3-yl) propyl group 4-toluene sulfonic acide ester (208mg, 0.58mmol).Reaction solution is heated to backflow, stirs after 20 hours, is cooled to room temperature, concentrating under reduced pressure.Gained residue is through purification by silica gel column chromatography (methylene chloride/methanol (v/v)=15/1), and obtaining title compound is yellow solid (104mg, 43.0%).
MS(ESI,pos.ion)m/z:422.2[M+H] +；
1H NMR(MeOD,600MHz)δ(ppm):8.01(s,1H),7.46(d,J＝8.0Hz,1H),7.37(d,J＝8.0Hz,1H),7.30(s,1H),3.84(s,3H),3.40-3.24(m,10H),2.85-2.80(m,2H),2.60-2.56(m,2H),2.37-2.34(m,2H),2.26-2.23(m,2H),1.67-1.61(m,4H)。
embodiment 182-(4-(4-(the fluoro-1H-indol-3-yl of 5-) butyl) piperazine-1-base)-5,6,7,8-tetrahydro quinazoline-4 (3H)-one
4-(4-oxo-3,4,5,6,7,8-six hydrogen quinazoline-2-base) piperazine-1-t-butyl formate (194mg, 0.58mmol) is joined in Hydrochloride/ethyl acetate (4M, 5mL).Reaction solution stirring at room temperature is after 1 hour, concentrating under reduced pressure.Residue is dissolved in acetonitrile (15mL), and add salt of wormwood (120mg successively wherein, 0.87mmol), the potassiumiodide (20mg of catalytic amount, 0.12mmol) with 4-(the fluoro-1H-indol-3-yl of 5-) butyl 4-toluene sulfonic acide ester (209mg, 0.58mmol).Reaction solution is heated to backflow, stirs after 20 hours, is cooled to room temperature, concentrating under reduced pressure.Gained residue is through purification by silica gel column chromatography (methylene chloride/methanol (v/v)=15/1), and obtaining title compound is yellow solid (98mg, 40.0%).MS(ESI,pos.ion)m/z:424.2[M+H] +；
1H NMR(MeOD,600MHz)δ(ppm):7.99(s,1H),7.42(d,J＝8.0Hz,1H),7.39(d,J＝8.0Hz,1H),7.30(s,1H),3.41-3.32(m,10H),2.83-2.80(m,2H),2.57-2.55(m,2H),2.34-2.30(m,2H),2.24-2.19(m,2H),1.75-1.69(m,2H),1.68-1.63(m,4H)。
embodiment 193-(4-(4-(4-oxo-3,4,5,6,7,8-six hydrogen quinazoline-2-base) piperazine-1-base) butyl)-1H-indoles-5-formonitrile HCN
4-(4-oxo-3,4,5,6,7,8-six hydrogen quinazoline-2-base) piperazine-1-t-butyl formate (194mg, 0.58mmol) is joined in Hydrochloride/ethyl acetate (4M, 5mL).Reaction solution stirring at room temperature is after 1 hour, concentrating under reduced pressure.Residue is dissolved in acetonitrile (15mL), and add salt of wormwood (120mg successively wherein, 0.87mmol), the potassiumiodide (20mg of catalytic amount, 0.12mmol) with 4-(5-cyano-1 H-indol--3-base) butyl 4-toluene sulfonic acide ester (213mg, 0.58mmol).Reaction solution is heated to backflow, stirs after 20 hours, is cooled to room temperature, concentrating under reduced pressure.Gained residue is through purification by silica gel column chromatography (methylene chloride/methanol (v/v)=15/1), and obtaining title compound is yellow solid (108mg, 44.0%).
MS(ESI,pos.ion)m/z:431.3[M+H] +；
1H NMR(MeOD,600MHz)δ(ppm):8.03(s,1H),7.39(d,J＝8.0Hz,1H),7.35(d,J＝8.0Hz,1H),7.30(s,1H),3.41-3.33(m,10H),2.84-2.81(m,2H),2.59-2.57(m,2H),2.34-2.31(m,2H),2.27-2.22(m,2H),1.75-1.69(m,2H),1.67-1.63(m,4H)。
embodiment 202-(4-(4-(5-methoxyl group-1H-indol-3-yl) butyl) piperazine-1-base)-5,6,7,8-tetrahydro quinazoline-4 (3H)-one
4-(4-oxo-3,4,5,6,7,8-six hydrogen quinazoline-2-base) piperazine-1-t-butyl formate (194mg, 0.58mmol) is joined in Hydrochloride/ethyl acetate (4M, 5mL).Reaction solution stirring at room temperature is after 1 hour, concentrating under reduced pressure.Residue is dissolved in acetonitrile (15mL), and add salt of wormwood (120mg successively wherein, 0.87mmol), the potassiumiodide (20mg of catalytic amount, 0.12mmol) with 4-(5-methoxyl group-1H-indol-3-yl) butyl 4-toluene sulfonic acide ester (216mg, 0.58mmol.Reaction solution is heated to backflow, stirs after 20 hours, is cooled to room temperature, concentrating under reduced pressure.Gained residue is through purification by silica gel column chromatography (methylene chloride/methanol (v/v)=15/1), and obtaining title compound is yellow solid (104mg, 43.0%).
MS(ESI,pos.ion)m/z:436.3[M+H] +；
1H NMR(MeOD,600MHz)δ(ppm):8.05(s,1H),7.41(d,J＝8.0Hz,1H),7.38(d,J＝8.0Hz,1H),7.31(s,1H),3.87(s,3H),3.39-3.31(m,10H),2.82-2.80(m,2H),2.58-2.57(m,2H),2.33-2.31(m,2H),2.25-2.21(m,2H),1.77-1.70(m,2H),1.69-1.65(m,4H)。
Biological test
embodiment A: compound in synaptosomes in rat brain in vivo to [ 3 h] 5-HT picked-up the Inhibitory Effects
test method
Under 37 DEG C of conditions, to damping fluid (106.2mM NaCl, 4.5mM KCl, 2.25mM MgSO 4, 1.08mM NaH 2pO 4, 22.5mM NaHCO 3, 9.9mM glucose, 9 μMs of EGTA and, 45 μMs of ascorbic acid (pH 7.4)), synaptosome (150 μ g) and 0.1 μ Ci [ 3h] in the mixed system that formed of serotonin, add test compounds or positive drug or negative control, hatch 15 minutes altogether.
Imipramine, as the standard positive compound suppressing serotonin picked-up, adds 10 μMs of imipramine in above-mentioned identical mixed system, and blocking 5-hydroxytryptamine absorbs, and hatches 15 minutes, thus record Basal control activity value under 4 DEG C of conditions.By experiment, the imipramine of test different concns, to the picked-up inhibiting value of rat brain synaptosome, produces suppression curve.
Sample after hatching 96 like cell collector (Unifilter, Packard) under vacuum by glass fiber filter (GF/B, Packard) fast filtering, and rinse twice in ice-cold incubation buffer, thus eliminate free [ 3h] serotonin.Dry filter membrane, in scintillometer (Topcount, Packard), calculates residual radioactivity with scintillation solution (Microscint 0, Packard).Experimental result with relative to control group [ 3h] serotonin picked-up suppression per-cent represent.
data analysis
The SERT transporter restraining effect of synaptosomes in rat brain in vivo by [ 3h] concentration of 5-HT weighs.Test-compound needs in concentration more than in 6log situation, and at least test twice, data carry out nonlinear regression analysis through Hill equation curve, obtain IC 50value.Result see table 1, table 1 be embodiment of the present invention compound in synaptosomes in rat brain in vivo to [ 3h] 5-HT picked-up restraining effect experimental result.
Experimental result shows, and the re-uptake of the compound that the embodiment of the present invention provides to 5-HT has good inhibit activities.
embodiment B: h5-HT 1A binding affinity is tested
test method
Under 22 DEG C of conditions, to people HEK-293 cell membrane homogenate, 36 μ g albumen, 0.3nM [ 3h] 8-OH-DPAT (Perkin-Elmer) and damping fluid (50mM Tris-HCl (pH 7.4), 10mM MgSO 4, 0.5mM EDTA, 2 μ g/ml aprotinine) in the mixed system that formed, add or do not add test compounds, hatching 60 minutes altogether.
Standard reference compound is 8-OH-DPAT, in the mixed system of above-mentioned condition, adds 10 μMs of 8-OH-DPAT, for recording non-specific binding value.By the data of the 8-OH-DPAT of different experiments test series concentration, obtain competitive curve.
Sample after hatching 96 like cell collector (Unifilter, Packard) under vacuum by the glass fiber filter (GF/B of pre-dipped 0.3%PEI, Packard) fast filtering, and use ice-cold 50mM Tris-HCl repeatedly to rinse several times.Dry filter membrane, in scintillometer (Topcount, Packard), calculates residual radioactivity with scintillation solution (Microscint 0, Packard).Experimental result is to represent relative to the suppression per-cent of control group radioligand specific binding, and Ki represents suppression constant.
data analysis
[ 3h] 8-OH-DPAT (0.3nM) and 5-HT in people HEK-293 cell 1Athe binding tests of acceptor has been come by the flicker proximity test method of film.Test-compound needs in concentration more than in 6log situation, and at least test three times, data carry out nonlinear regression analysis through Hill equation curve, obtain IC 50value, then calculate through ChengPrusoff equation, obtain Ki value.
Experimental result shows, and the compounds of this invention is to 5-HT 1Aacceptor demonstrates stronger binding affinity.
Table 1 embodiment of the present invention provide in synaptosomes in rat brain in vivo to [ 3h] 5-HT picked-up restraining effect result and to 5-HT 1Athe binding affinity result of acceptor
In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not must for be identical embodiment or example.And the specific features of description, structure, material or feature can combine in one or more embodiment in office or example in an appropriate manner.In addition, when not conflicting, the feature of the different embodiment described in this specification sheets or example and different embodiment or example can carry out combining and combining by those skilled in the art.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, and those of ordinary skill in the art can change above-described embodiment within the scope of the invention, revises, replace and modification.

Claims (16)

1. a compound, its steric isomer for compound shown in the compound shown in formula (I) or formula (I), tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug,
Wherein:
When for-time, G is CH or N;
When for=time, G is C;
Y is CR 4or N;
Each R 1be H, D, F, Cl, Br, I ,-NO independently 2,-CN ,-SCN ,-OR 5,-NR 6r 6a,-C (=O) R 5,-C (=O) OR 5,-C (=O) NR 6r 6a,-OC (=O) R 5,-N (R 6) C (=O) R 5, alkyl, thiazolinyl, alkynyl, haloalkyl, cycloalkyl, cycloalkyl alkylidene group-, heterocyclic radical, heterocycloalkylene-, aryl, aryl alkylene-, heteroaryl or heteroarylalkylenyl-;
Each R 2, R 3and R 4be separately H, D, F, Cl, Br, I ,-NO 2,-CN ,-OR 5,-NR 6r 6a,-SR 5,-C (=O) R 5,-C (=O) OR 5,-C (=O) NR 6r 6a,-OC (=O) R 5,-N (R 6) C (=O) R 5, R 5o-alkylidene group-, R 6r 6an-alkylidene group-, R 5s-alkylidene group-, alkyl, thiazolinyl, alkynyl, haloalkyl, cycloalkyl, cycloalkyl alkylidene group-, heterocyclic radical, heterocycloalkylene-, aryl, aryl alkylene-, heteroaryl or heteroarylalkylenyl-; Or the R on adjacent carbons 2, R 3, and together with the ring carbon atom be connected respectively with them, form carbocyclic ring or heterocycle; Or the R on adjacent carbons 3, R 4, and together with the ring carbon atom be connected respectively with them, form carbocyclic ring or heterocycle;
Each R 5be independently H, D, alkyl, thiazolinyl, alkynyl, haloalkyl, cycloalkyl, cycloalkyl alkylidene group-, heterocyclic radical or heterocycloalkylene-;
Each R 6and R 6abe separately H, D, alkyl, thiazolinyl, alkynyl, haloalkyl, cycloalkyl, cycloalkyl alkylidene group-, heterocyclic radical or heterocycloalkylene-; Or R 6, R 6a, and together with the nitrogen-atoms be connected with them, form heterocycle;
Above-described each R 5o-alkylidene group-, R 6r 6an-alkylidene group-, R 5s-alkylidene group-, alkyl, thiazolinyl, alkynyl, haloalkyl, carbocyclic ring, heterocycle, cycloalkyl, cycloalkyl alkylidene group-, heterocyclic radical, heterocycloalkylene-, aryl, aryl alkylene-, heteroaryl and heteroarylalkylenyl-be optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, alkyl, haloalkyl, alkoxyl group, alkylthio and alkylamino substituting group replaced;
M is 2,3,4 or 5; With
N is 1,2,3 or 4.
2. compound according to claim 1, wherein, each R 1be H, D, F, Cl, Br, I ,-NO independently 2,-CN ,-SCN ,-OR 5,-NR 6r 6a,-C (=O) R 5,-C (=O) OR 5,-C (=O) NR 6r 6a,-OC (=O) R 5,-N (R 6) C (=O) R 5, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 1-C 6haloalkyl, C 3-C 10cycloalkyl, (C 3-C 10cycloalkyl)-(C 1-C 6alkylidene group)-, C 2-C 10heterocyclic radical, (C 2-C 10heterocyclic radical)-(C 1-C 6alkylidene group)-, C 6-C 10aryl, (C 6-C 10aryl)-(C 1-C 6alkylidene group)-, C 1-C 9heteroaryl or (C 1-C 9heteroaryl)-(C 1-C 6alkylidene group)-; Wherein said each C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 1-C 6haloalkyl, C 3-C 10cycloalkyl, (C 3-C 10cycloalkyl)-(C 1-C 6alkylidene group)-, C 2-C 10heterocyclic radical, (C 2-C 10heterocyclic radical)-(C 1-C 6alkylidene group)-, C 6-C 10aryl, (C 6-C 10aryl)-(C 1-C 6alkylidene group)-, C 1-C 9heteroaryl and (C 1-C 9heteroaryl)-(C 1-C 6alkylidene group)-be optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, C 1-C 6alkyl, C 1-C 6haloalkyl, C 1-C 6alkoxyl group, C 1-C 6alkylthio and C 1-C 6the substituting group of alkylamino replaced.
3. compound according to claim 1, wherein, each R 2, R 3and R 4be separately H, D, F, Cl, Br, I ,-NO 2,-CN ,-OR 5,-NR 6r 6a,-SR 5,-C (=O) R 5,-C (=O) OR 5,-C (=O) NR 6r 6a,-OC (=O) R 5,-N (R 6) C (=O) R 5, R 5o-(C 1-C 6alkylidene group)-, R 6r 6an-(C 1-C 6alkylidene group)-, R 5s-(C 1-C 6alkylidene group)-, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 1-C 6haloalkyl, C 3-C 10cycloalkyl, (C 3-C 10cycloalkyl)-(C 1-C 6alkylidene group)-, C 2-C 10heterocyclic radical, (C 2-C 10heterocyclic radical)-(C 1-C 6alkylidene group)-, C 6-C 10aryl, (C 6-C 10aryl)-(C 1-C 6alkylidene group)-, C 1-C 9heteroaryl or (C 1-C 9heteroaryl)-(C 1-C 6alkylidene group)-; Or the R on adjacent carbons 2, R 3, and together with the carbon atom be connected with them, form C 3-C 10carbocyclic ring or C 2-C 9heterocycle; Or the R on adjacent carbons 3, R 4, and together with the ring carbon atom be connected respectively with them, form C 3-C 10carbocyclic ring or C 2-C 9heterocycle;
Wherein, described each R 5o-(C 1-C 6alkylidene group)-, R 6r 6an-(C 1-C 6alkylidene group)-, R 5s-(C 1-C 6alkylidene group)-, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 1-C 6haloalkyl, C 3-C 10cycloalkyl, (C 3-C 10cycloalkyl)-(C 1-C 6alkylidene group)-, C 2-c 10heterocyclic radical, (C 2-C 10heterocyclic radical)-(C 1-C 6alkylidene group)-, C 6-C 10aryl, (C 6-C 10aryl)-(C 1-C 6alkylidene group)-, C 1-C 9heteroaryl, (C 1-C 9heteroaryl)-(C 1-C 6alkylidene group)-, C 3-C 10carbocyclic ring and C 2-C 9heterocycle is optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, C 1-C 6alkyl, C 1-C 6haloalkyl, C 1-C 6alkoxyl group, C 1-C 6alkylthio and C 1-C 6the substituting group of alkylamino replaced.
4. compound according to claim 1, wherein, each R 5be H, D, C independently 1-C 6alkyl, C 1-C 6haloalkyl or C 3-C 10cycloalkyl; Wherein, described each C 1-C 6alkyl, C 1-C 6haloalkyl and C 3-C 10cycloalkyl is optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, C 1-C 6alkyl, C 1-C 6haloalkyl, C 1-C 6alkoxyl group, C 1-C 6alkylthio and C 1-C 6the substituting group of alkylamino replaced; With
Each R 6and R 6abe separately H, D, C 1-C 6alkyl, C 1-C 6haloalkyl or C 3-C 10cycloalkyl; Or R 6, R 6a, and together with the nitrogen-atoms be connected with them, form C 3-C 10heterocycle; Wherein, described each C 1-C 6alkyl, C 1-C 6haloalkyl, C 3-C 10cycloalkyl and C 3-C 10heterocycle is optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, C 1-C 6alkyl, C 1-C 6haloalkyl, C 1-C 6alkoxyl group, C 1-C 6alkylthio and C 1-C 6the substituting group of alkylamino replaced.
5. compound according to claim 1, wherein, Y is CH or N.
6. compound according to claim 1, wherein, each R 1be H, D, F, Cl ,-CN ,-OR independently 5,-NR 6r 6a,-C (=O) NR 6r 6a, C 1-C 4alkyl or C 1-C 4haloalkyl; Wherein said each C 1-C 4alkyl and C 1-C 4haloalkyl is optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, C 1-C 4alkyl, C 1-C 4haloalkyl, C 1-C 4alkoxyl group, C 1-C 4alkylthio and C 1-C 4the substituting group of alkylamino replaced.
7. compound according to claim 1, wherein, each R 2and R 3be separately H, D, F, Cl ,-CN ,-OR 5,-NR 6r 6a,-SR 5,-C (=O) OR 5,-C (=O) NR 6r 6a, R 5o-(C 1-C 4alkylidene group)-, R 6r 6an-(C 1-C 4alkylidene group)-, R 5s-(C 1-C 4alkylidene group)-, C 1-C 4alkyl, C 2-C 4thiazolinyl, C 2-C 4alkynyl or C 1-C 4haloalkyl; Or the R on adjacent carbons 2, R 3, and together with the ring carbon atom be connected respectively with them, form C 3-C 8carbocyclic ring or C 2-C 7heterocycle;
Wherein, described each R 5o-(C 1-C 4alkylidene group)-, R 6r 6an-(C 1-C 4alkylidene group)-, R 5s-(C 1-C 4alkylidene group)-, C 1-C 4alkyl, C 2-C 4thiazolinyl, C 2-C 4alkynyl, C 1-C 4haloalkyl, C 3-C 8carbocyclic ring and C 2-C 7heterocycle is optionally independently selected from D, F, Cl, N by one or more respectively 3,-CN ,-OH ,-SH ,-NH 2, C 1-C 4alkyl, C 1-C 4haloalkyl, C 1-C 4alkoxyl group, C 1-C 4alkylthio and C 1-C 4the substituting group of alkylamino replaced.
8. compound according to claim 1, wherein, each R 5be H, D or C independently 1-C 4alkyl; With
Each R 6and R 6abe separately H, D or C 1-C 4alkyl; Or R 6, R 6a, and together with the nitrogen-atoms be connected with them, form C 3-C 5heterocycle.
9. compound according to claim 1, wherein, each R 1be H, D, F, Cl ,-CN, CH independently 3,-CH (CH 3) 2,-CF 3,-OH ,-OCH 3,-NH 2or-C (=O) NH 2.
10. compound according to claim 1, has one of them structure following:
Or its steric isomer, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug.
11. 1 kinds of pharmaceutical compositions, comprise the compound described in claim 1 ?10 any one, and pharmaceutically acceptable vehicle, carrier, adjuvant or their arbitrary combination.
12. pharmaceutical compositions according to claim 11, wherein comprise the medicine for the treatment of central nervous system dysfunction further, the medicine of described treatment central nervous system dysfunction be antidepressant drug, anxiolytic medicament, salts medicine as mood stabilizers, atypical antipsychotics thing, antiepileptic drug, antiparkinsonism drug, as serotonin selectivity reuptake inhibitor and/or 5-HT 1Athe medicine of receptor stimulant, central nervous stimulant, nicotinic antagonists or their arbitrary combination.
13. pharmaceutical compositions according to claim 12, wherein, the medicine of described treatment central nervous system dysfunction is amitriptyline (amitriptyline), Desipramine (desipramine), mirtazapine (mirtazapine), Bupropion (bupropion), Reboxetine (reboxetine), fluoxetine (fluoxetine), trazodone (trazodone), Sertraline (sertraline), duloxetine (duloxetine), fluvoxamine (fluvoxamine), Midalcipran (milnacipran), left-handed Midalcipran (levomilnacipran), desmethylvenlafaxine (desvenlafaxine), vilazodone (vilazodone), Venlafaxine (venlafaxine), dapoxetine (dapoxetine), nefazodone (nefazodone), femoxetine (femoxetine), chlorimipramine (clomipramine), citalopram (citalopram), S-escitalopram (escitalopram), paroxetine (paroxetine), Quilonum Retard (lithium carbonate), buspirone (buspirone), olanzapine (olanzapine), Quetiapine (quetiapine), risperidone (risperidone), Ziprasidone (ziprasidone), Aripiprazole (aripiprazole), Perospirone (perospirone), leoponex (clozapine), modafinil (modafinil), mecamylamine (mecamylamine), Cabergoline (cabergoline), diamantane (adamantane), imipramine (imipramine), pramipexole (pramipexole), thyroxine (thyroxine), Dextromethorphane Hbr (dextromethorphan), Quinidine (quinidine), TREXUPONT (naltrexone), samidorphan, buprenorphine (buprenorphine), melatonin (melatonin), alprazolam (alprazolam), pipamperone (pipamperone), dimension is for smooth (vestipitant), zeisin (chlordiazepoxide), trilafon (perphenazine) or their arbitrary combination.
Compound described in 14. claim 1-10 any one or the pharmaceutical composition described in claim 21-23 any one are preparing the purposes in medicine, described medicine is used for prevention, treats or alleviate Mammals, comprises the central nervous system dysfunction of the mankind.
15. purposes according to claim 14, wherein, described central nervous system function barrier refers to dysthymia disorders, anxiety disorder, mania, schizophrenia, bipolar disorders, somnopathy, obsessional idea and behavior disorder, panic disorder, posttraumatic stress disorder, dyskinesia, sexual dysfunction, musculoskeletal pain obstacle, cognitive disorder, dysmnesia, Parkinson's disease, Huntington's disease, phobia, substance abuse or habituation, drug addiction withdrawal symptom or premenstrualtension syndrome.
Compound described in 16. claim 1-10 any one or the pharmaceutical composition described in claim 11-13 any one are preparing the purposes in medicine, and described medicine is used for Selective depression serotonin reuptake transporter.
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CN106065018A (en) * 2015-04-23 2016-11-02 广东东阳光药业有限公司 Substituted benzazolyl compounds and using method thereof and purposes
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JP2020535205A (en) * 2017-09-29 2020-12-03 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． Substituted pyrimidine piperazine compounds and their use
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