CN104725363B - Substituted diethylenediamine compound and its application method and purposes - Google Patents

Substituted diethylenediamine compound and its application method and purposes Download PDF

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CN104725363B
CN104725363B CN201410809054.2A CN201410809054A CN104725363B CN 104725363 B CN104725363 B CN 104725363B CN 201410809054 A CN201410809054 A CN 201410809054A CN 104725363 B CN104725363 B CN 104725363B
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base
compound
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piperazine
drug
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CN104725363A (en
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张英俊
金传飞
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Guangdong HEC Pharmaceutical
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    • 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
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The present invention relates to a new class of diethylenediamine compound and comprising the pharmaceutical composition of the compound, for inhibiting serotonin reuptake transporter and/or excitement 5-HT1AReceptor.The invention further relates to the method for preparing this kind of compound and pharmaceutical composition and their purposes in pivot nervous system dysfunction in the treatment.

Description

Substituted diethylenediamine compound and its application method and purposes
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to for treating the substituted piperazine of central nervous system dysfunction Piperazine compound, composition and its application method and purposes.Particularly, of the present invention is that can be used as serotonin reuptake transporter Inhibitor or/and 5-HT1AThe diethylenediamine compound of receptor stimulating agent.
Background technique
Serotonin, a kind of neurotransmitter for transmitting signal in brain and nervous system, at central nervous system (CNS) In dysfunction, especially in anxiety, depression, invasion and impulsion mood, important role play.Antagonism or the certain class of excitement The 5-hydroxytryptamine receptor of type can effectively regulate and control central nervous system dysfunction.So far, at least 14 kinds of 5- hydroxyl colors Amine receptor is identified.These receptors can be divided into different families, be denoted as 5-HT respectively1、5-HT2、5-HT3、5-HT4、5-HT5、5-HT6 And 5-HT7, and the different subtype in each race then uses a, b and c etc. to distinguish.The serotonin neuron of nervous centralis is located at brain stem Nuclei of median raphe, and 5-HT1AReceptor, a kind of g protein coupled receptor are just widely distributed in the serotonin that can be received derived from nuclei of median raphe Region, comprising: cortex of frontal lobe, lateral septal, amygdaloid nucleus, hippocampus and hypothalamus.In these cortex fringe regions, 5-HT1AIt is located at Postsynaptic membrane.At the same time, 5-HT1AReceptor is also the presynaptic membrane autoreceptor on nuclei of median raphe, can reduce putting for neuron The synthesis of electric rate (quantity of i.e. every action potential release serotonin) and neurotransmitter, then reduces 5- in projection area The activity of hydroxytryptamine.Activate the 5-HT of presynaptic membrane1AReceptor can inhibit the synthesis of tyrosine hydroxylase and glutamic acid channel (to produce Be born in inside prefrontal cortex, be directed toward nuclei of median raphe) activity, so that reducing serotonin indirectly transports (Jonathan Savitz,Irwin Lucki,Wayne C.Drevets.5-HT1A receptor function in major depressive disorder.Prog Neurobiol.2009,88(1):17-31)。
In all indications relevant to serotonin dysfunction, depression is most important, because defending according to the world Raw Organization, depression have become the fourth-largest burden property disease of the mankind.The year two thousand twenty is expected, the disability of depression adjusts the service life Annual meeting leaps 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 drug therapy of emotional handicap start from the 1950s, include tricyclic antidepressant (TCAs) and Monoamine oxidase inhibitors (MAOIs), these drugs are mainly by neurotransmitter (dopamine, norepinephrine and 5- hydroxyl color Amine) blocking effect play curative effect.However, the non-selective and undesirable side effect to target limits making for they With.To in the 1980s, serotonin selectivity reuptaking inhibitor (SSRIs) appearance, change this situation.With TCAs is compared, and this kind of curative effect of medication is suitable, but Small side effects, even if excessive use, the also smaller (Sarko of the toxicity of generation J.Andidepressant,old and new.A review of their adverse effects and toxicity in overdose.Emerg Med Clin North Am,2000；18(4):637-54).
Traditional SSRIs treatment increases containing for serotonin by inhibiting the reuptake of serotonin and adjusting its transhipment Amount.But using after SSRIs, it can equally activate the 5-HT of presynaptic membrane1AAutoreceptor causes the burst size of serotonin to reduce, Making the concentration of serotonin between cynapse reduces.But, with the extension of medication time, SSRIs will lead to 5-HT1AAutoreceptor is de- Quick, activation effect is restrained, thus the adjustment effect brought into normal play.Thus infer, to 5-HT1AThe activation effect of autoreceptor It is major reason (Celada P, Puig M, Amargos-Bosch M, the et al., The for postponing SSRIs and playing drug effect therapeutic role of 5-HT1A and 5-HT2A receptors in depression.J Psychiatry Neurosci,2004,29(4):252-65).Therefore, overcome 5-HT1AThe negative feedback of autoreceptor antagonist have enhancing and Accelerate the prospect of clinical antidepressants.
Compared with SSRIs, 5-HT1AReceptor stimulating agent or partial agonist directly act on the serotonin in postsynaptic by Body, to increase the interim serotonin neurotransmission of SSRI latent effect.Feiger and Wilcox proves buspirone and lucky pyrrole Grand is clinically effective 5-HT1APartial agonist (Feiger, A.Psychopharmacol.Bull.1996,32:659- 65).Buspirone is added in standard SSRI therapy, causes in the unresponsive patient of standard care previously to depression significant Improve (Dimitriou, E.J.Clin.Psychopharmacol., 1998,18:465-9).
There is serotonin selectivity reuptaking inhibitor and/or 5-HT the present invention provides some1AReceptor stimulating agent is living The noval chemical compound of property, has preferable potential applicability in clinical practice.Compared with existing similar compound, the compound of the present invention has Better drug effect, medicine are for property and/or toxicological characteristics.
Abstract of invention
Only summarize some aspects of the invention below, it is not limited to this.These aspects and other parts are later There is more complete explanation.All bibliography in this specification are incorporated in this by whole.Work as the disclosure of the specification When variant with citation, it is subject to the disclosure of the specification.
The present invention provides a kind of noval chemical compound, the compound to the selective inhibiting effect of serotonin reuptake transporter and/or To 5-HT1AReceptor has agonism, can be used for preparing treatment mankind's central nervous system (CNS) dysfunction, such as depression Disease, anxiety disorder, bipolar disorders drug.The present invention also provides the method for preparing this kind of compound and contain such compound Pharmaceutical composition.
On the one hand, the present invention relates to a kind of compounds, are compound shown in formula (I) compound represented or formula (I) Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein:
X is structure shown in formula (II):
Wherein, each keyAnd keySeparately be-or=；
Each U1、U2、U3And U4It is separately CR2、N、-CR2R2aOr-NR2bOr U1And U2Or U3And U4Joint At-CR2R2a-、-NR2b,-O- or-S- form；
V is CR2Or N；
W is-NR2b,-O- or-S-；
L is-CR3R4-；
R is 3,4,5 or 6；
Q is 1,2,3 or 4；
Y be naphthenic base, heterocycle, aryl or heteroaryl, precondition be the heterocycle and heteroaryl be with it is carbon-based with Host molecule be connected, wherein the naphthenic base, heterocycle, aryl and heteroaryl it is individually optional by one or more R5Group institute Replace；
Each R1It independently is H, D, F, Cl, Br, I ,-CN ,-N3、-NO2、-NRaRb、-ORc, alkyl, alkenyl or alkynyl, wherein The alkyl, alkenyl and alkynyl it is individually optional by one or more R6Replaced group；
Each R2、R2aAnd R2bIt is separately H, D, F, Cl, Br, I ,-CN ,-N3、-NO2、-NRaRb、-ORc,-S (=O)mRc,-C (=O) Rc,-C (=O) ORc,-C (=O) NRaRb,-S (=O)2NRaRb,-OC (=O) Rc、-N(Ra) C (=O) Rc, alkane Base, alkenyl or alkynyl, wherein the alkyl, alkenyl and alkynyl it is individually optional by one or more R6Replaced group；
Each R3And R4It is separately H, D, F, Cl, Br, I ,-CN ,-N3、-NH2,-OH, alkyl, alkenyl, alkynyl, alcoxyl Base, alkylamino, naphthenic base, heterocycle, aryl or heteroaryl or R3、R4, and together with the carbon atom that they are connected jointly, shape At carbocyclic ring or heterocycle, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, naphthenic base, heterocycle, aryl, heteroaryl, Carbocyclic ring and heterocycle it is individually optional by one or more R6Replaced group；
Each R5It independently is H, D, F, Cl, Br, I ,-CN ,-N3、-NO2、-(C0-C6Alkylidene)-NRaRb、-(C0-C6Alkylene Base)-ORc、-(C0-C6Alkylidene)-S (=O)mRc,-C (=O) Rc,-C (=O) ORc,-C (=O) NRaRb,-S (=O)2NRaRb,-OC (=O) Rc、-N(Ra) C (=O) Rc, alkyl, alkenyl, alkynyl, naphthenic base, heterocycle, aryl or heteroaryl, or Two R on adjacent cyclic atom5, and together with the annular atom that they are respectively connected with, carbocyclic ring, heterocycle, aromatic ring or hetero-aromatic ring are formed, Wherein described-(C0-C6Alkylidene)-NRaRb、-(C0-C6Alkylidene)-ORc、-(C0-C6Alkylidene)-S (=O)mRc, alkyl, alkene Base, alkynyl, naphthenic base, heterocycle, aryl, heteroaryl, carbocyclic ring, heterocycle, aromatic ring and hetero-aromatic ring it is individually optional by one or more A R6Replaced group；
Each R6It independently is F, Cl, Br, I ,-CN ,-N3、-NO2、-OH、-SH、-NH2, alkyl, halogenated alkyl, alkoxy, Alkylthio group or alkylamino；
Each RaAnd RbIt is separately H, alkyl, alkenyl, alkynyl, halogenated alkyl ,-(C0-C6Alkylidene)-naphthenic base ,- (C0-C6Alkylidene)-heterocycle ,-(C0-C6Alkylidene)-aryl or-(C0-C6Alkylidene)-heteroaryl or Ra、Rb, and and it Jointly connected nitrogen-atoms together, form heterocycle；
Each RcIt independently is H, alkyl, alkenyl, alkynyl, halogenated alkyl ,-(C0-C6Alkylidene)-naphthenic base ,-(C0-C6Alkylene Base)-heterocycle ,-(C0-C6Alkylidene)-aryl or-(C0-C6Alkylidene)-heteroaryl；With
Each m independently is 0,1 or 2.
In one embodiment, each R1It independently is H, D, F, Cl, Br, I ,-CN ,-N3、-NO2、-NRaRb、-ORc、C1-C6 Alkyl, C2-C6Alkenyl or C2-C6Alkynyl, wherein the C1-C6Alkyl, C2-C6Alkenyl and C2-C6Alkynyl is individually optionally by one Or multiple R6Replaced group, wherein each Ra、Rb、RcAnd R6With definition as described in the present invention.
In another embodiment, X has the structural formula as shown in formula (II-1):
Wherein, U4For CR2Or N；
P is 1,2 or 3；
W is-NH- ,-O- or-S-；With
Each R2With definition as described in the present invention.
In another embodiment, each R2、R2aAnd R2bIt is separately H, D, F, Cl, Br, I ,-CN ,-N3、-NO2、- NRaRb、-ORc,-S (=O)mRc,-C (=O) Rc,-C (=O) ORc,-C (=O) NRaRb,-S (=O)2NRaRb,-OC (=O) Rc、-N(Ra) C (=O) Rc、C1-C6Alkyl, C2-C6Alkenyl or C2-C6Alkynyl, wherein the C1-C6Alkyl, C2-C6Alkenyl and C2- C6Alkynyl is individually optionally by one or more R6Replaced group, wherein each Ra、Rb、RcAnd R6With fixed as described in the present invention Justice.
In another embodiment, each R3And R4It is separately H, D, F, Cl, Br, I ,-CN ,-N3、-NH2、-OH、C1- C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkylamino, C3-C10Naphthenic base, 3-10 original are molecular Heterocycle, C6-C10Aryl or 5-10 former molecular heteroaryl or R3、R4, and the carbon atom one being connected jointly with them It rises, forms C3-C8Carbocyclic ring or 3-7 former molecular heterocycle, wherein the C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1- C6Alkoxy, C1-C6Alkylamino, C3-C10Naphthenic base, 3-10 former molecular heterocycle, C6-C10Aryl, 5-10 atom group At heteroaryl, C3-C8The former molecular heterocycle of carbocyclic ring and 3-7 is individually optionally by one or more R6Replaced group, Middle R6With definition as described in the present invention.
In another embodiment, Y C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C14Aryl or 5- 14 molecular heteroaryls of original, precondition are that described 3-12 former molecular heterocycle and 5-14 are former molecular miscellaneous Aryl is to be connected with carbon-based with host molecule, wherein the C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C14Virtue The former molecular heteroaryl of base and 5-14 is individually optionally by one or more R5Replaced group, wherein R5With such as this hair The bright definition.
In another embodiment, each R5It independently is H, D, F, Cl, Br, I ,-CN ,-N3、-NO2、-(C0-C6Alkylidene)- NRaRb、-(C0-C6Alkylidene)-ORc、-(C0-C6Alkylidene)-S (=O)mRc,-C (=O) Rc,-C (=O) ORc,-C (=O) NRaRb,-S (=O)2NRaRb,-OC (=O) Rc、-N(Ra) C (=O) Rc、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C10 Naphthenic base, 3-10 former molecular heterocycle, C6-C10Aryl or 5-10 former molecular heteroaryl or adjacent ring are former Two R on son5, and together with the annular atom that they are respectively connected with, form C3-C10Carbocyclic ring, 3-10 former molecular heterocycle, C6-C10Aromatic ring or 5-10 former molecular hetero-aromatic ring, wherein described-(C0-C6Alkylidene)-NRaRb、-(C0-C6Alkylidene)- ORc、-(C0-C6Alkylidene)-S (=O)mRc、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C10Naphthenic base, 3-10 atom Heterocycle, the C of composition6-C10Aryl, 5-10 former molecular heteroaryl, C3-C10Carbocyclic ring, 3-10 former molecular heterocycle, C6-C10The former molecular hetero-aromatic ring of aromatic ring and 5-10 is individually optionally by one or more R6Replaced group, wherein each Ra、 Rb、RcAnd R6With definition as described in the present invention.
In another embodiment, each R6It independently is F, Cl, Br, I ,-CN ,-N3、-NO2、-OH、-SH、-NH2、C1-C6 Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Alkylthio group or C1-C6Alkylamino.
In another embodiment, compound of the present invention is formula (III) compound represented or formula (III) Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, the pharmaceutically acceptable salt of shown compound Or its prodrug,
Wherein, 1,2 or 3 p；With
Each R1、R2, Y, L, p, r and q have as described in the present invention definition.
In another embodiment, each R1It independently is H, D, F, Cl, Br ,-CN ,-NO2、-CH3、-CH2CH3、-CH (CH3)2、-CF3、-CH2CF3、-CHFCF3、-CF2CF3、-OCH3、-OCH2CH3、-OCH(CH3)2、-OCF3、-OCH2CF3、- OCHFCF3Or-OCF2CF3。
In another embodiment, each R2、R2aAnd R2bIt is separately H, D, F, Cl, Br ,-CN ,-NO2、-NRaRb、- ORc,-C (=O) ORc,-C (=O) NRaRbOr optionally by one or more R6C replaced group1-C4Alkyl, wherein each Ra、 Rb、RcAnd R6With definition as described in the present invention.
In another embodiment, each R2、R2aAnd R2bIt is separately H, D, F, Cl, Br ,-CN ,-NO2、-NH2、-N (CH3)2、-OH、-OCH3、-OCH(CH3)2、-CH3、-CH2CH3、-CH(CH3)2、-CF3,-C (=O) OH ,-C (=O) OCH3Or- CONH2。
In another embodiment, L is-CH2-。
In another embodiment, Y is 3-10 former molecular heterocycle or the 5-10 molecular heteroaryl of original, preceding The condition of mentioning is described 3-10 former molecular heterocycle and 5-10 former molecular heteroaryl is with carbon-based and host molecule Be connected, wherein the 3-10 former molecular heterocycle and the 5-10 molecular heteroaryl of original it is individually optional by one or Multiple R5Replaced group, wherein R5With definition as described in the present invention.
In another embodiment, Y is 4-6 former molecular heterocycle or 5-6 former molecular heteroaryl, premise Condition is described 4-6 former molecular heterocycle and 5-6 former molecular heteroaryl is to be connected with carbon-based with host molecule, Wherein described 4-6 former molecular heterocycle and the 5-6 molecular heteroaryl of original it is individually optional by one or more R5 Replaced group, wherein R5With definition as described in the present invention.
In another embodiment, Y is one of minor structure shown in formula (IV-1) to (IV-14):
Wherein, each n independently is 1,2,3 or 4；With
Each R5With definition as described in the present invention.
In another embodiment, each R5It independently is H, D, F, Cl, Br ,-CN ,-NO2、-(C0-C4Alkylidene)-ORc、- (C0-C4Alkylidene)-NRaRb,-C (=O) ORc,-C (=O) NRaRb、C1-C4Alkyl, C2-C4Alkenyl or C2-C4Alkynyl, Huo Zhexiang Two R on adjacent annular atom5, and together with the annular atom that they are respectively connected with, form C3-C8Carbocyclic ring, 3-7 original are molecular The former molecular hetero-aromatic ring of heterocycle, phenyl ring or 5-6, wherein described-(C0-C4Alkylidene)-ORc、-(C0-C4Alkylidene)- NRaRb、C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C3-C8Carbocyclic ring, 3-7 former molecular heterocycle, phenyl ring and 5-6 are former Molecular hetero-aromatic ring is individually optionally by one or more R6Replaced group, wherein each Ra、Rb、RcAnd R6With such as of the invention The definition.
In another embodiment, each R5It independently is H, D, F, Cl, Br ,-CN ,-NO2、-OH、-NH2,-C (=O) OCH3,-C (=O) OCH2CH3,-C (=O) NH2、-CH3、-CH2CH3、-CH(CH3)2、-CF3、-OCH3、-OCH(CH3)2Or-N (CH3)2。
In another embodiment, each RaAnd RbIt is separately H, C1-C4Alkyl, C3-C6Alkenyl, C3-C6Alkynyl, C1- C4Halogenated alkyl ,-(C0-C4Alkylidene)-(C3-C8Naphthenic base) ,-(C0-C4Alkylidene)-(3-7 former molecular heterocycle Base) ,-(C0-C4Alkylidene)-(phenyl) or-(C0-C4Alkylidene)-(5-6 former molecular heteroaryl) or Ra、Rb, and Together with the nitrogen-atoms that they are connected jointly, 4-7 former molecular heterocycle is formed；With
Each RcIt independently is H, C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl ,-(C0-C4Alkylidene)- (C3-C8Naphthenic base) ,-(C0-C4Alkylidene)-(3-7 former molecular heterocycle) ,-(C0-C4Alkylidene)-(phenyl) or- (C0-C4Alkylidene)-(5-6 former molecular heteroaryl).
On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes chemical combination disclosed by the invention Object
In one embodiment, pharmaceutical composition of the present invention, further include pharmaceutically acceptable excipient, Carrier, adjuvant or their any combination.
In another embodiment, pharmaceutical composition of the present invention, further comprising treatment central nervous system The drug of the drug of dysfunction, the treatment central nervous system dysfunction is antidepressant, anxiolytic drugs, conduct The salts drugs of mood stabilizers, atypical antipsychotic drug, antiepileptic, antiparkinsonism drug, as 5- Hydroxytryptamine selectivity reuptaking inhibitor and/or 5-HT1ADrug, nervous stimulants, the nicotinic antagonists of receptor stimulating agent Or their any combination.
In another embodiment, it is amitriptyline that the present invention, which treats the drug of central nervous system dysfunction, (amitriptyline), desipramine (desipramine), Mirtazapine (mirtazapine), Bupropion (bupropion), Reboxetine (reboxetine), Prozac (fluoxetine), Trazodone (trazodone), Sertraline (sertraline), Duloxetine (duloxetine), Fluvoxamine (fluvoxamine), Milnacipran (milnacipran), left-handed Milnacipran (levomilnacipran), desmethylvenlafaxine (desvenlafaxine), Wella Oxazolone (vilazodone), Venlafaxine (venlafaxine), Dapoxetine hydrochloride (dapoxetine), Nefazodone (nefazodone), femoxetine (femoxetine), chlorimipramine (clomipramine), Citalopram (citalopram), escitalopram (escitalopram), Paxil (paroxetine), lithium carbonate (lithium Carbonate), buspirone (buspirone), Olanzapine (olanzapine), Quetiapine (quetiapine), Risperidone (risperidone), Ziprasidone (ziprasidone), Aripiprazole (aripiprazole), Perospirone (perospirone), Clozapine (clozapine), modafinil (modafinil), Mecamylamine (mecamylamine), card Ergot woods (cabergoline), adamantane (adamantane), imipramine (imipramine), Pramipexole (pramipexole), thyroxine (thyroxine), dextromethorphan (dextromethorphan), quinindium (quinidine), naltrexone (naltrexone), samidorphan, buprenorphine (buprenorphine), melatonin (melatonin), alprazolam (alprazolam), Pipamperone (pipamperone), dimension for smooth (vestipitant), Librium (chlordiazepoxide), perphenazine (perphenazine) or their any combination.
On the other hand, the purposes the present invention relates to compound or composition disclosed by the invention in medicine preparation, it is described Drug is for preventing, treating or mitigating central nervous system dysfunction.For example, in one embodiment, the drug is used for It prevents, treats or mitigates mammalian central nervous system dysfunction, in another embodiment, the drug is for pre- Anti-, treatment or the central nervous system dysfunction for mitigating people.
In one embodiment, the central nervous system dysfunction refers to depression, anxiety disorder, mania, essence Refreshing Split disease, bipolar disorders, sleep disturbance, besetment and behavior disorder, panic disorder, posttraumatic stress disorder, movement barrier Hinder, sex dysfunction, musculoskeletal pain obstacle, cognitive disorder, memory disorders, Parkinson's disease, Huntington's disease, terror Disease, substance abuse or habituation, drug addiction withdrawal symptom or premenstrualtension syndrome.
On the other hand, the purposes the present invention relates to compound or composition disclosed by the invention in medicine preparation, it is described Drug is for inhibiting serotonin reuptake transporter.
On the other hand, the purposes the present invention relates to compound or composition disclosed by the invention in medicine preparation, it is described Drug is used for partial agonist 5-HT1AReceptor.
On the other hand, the method for preparation, separation and the purifying of the compound for being included the present invention relates to formula (I) or (III).
Biological results show that compound provided by the invention can be used as preferable serotonin selectivity reuptake suppression Preparation and/or 5-HT1AReceptor stimulating agent.
Any embodiment in either present invention face can be combined with other embodiments, as long as they are not It will appear contradiction.In addition, any technical characteristic can be adapted for other realities in any embodiment of either side of the present invention The technical characteristic in scheme is applied, as long as they are not in contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its The content of his aspect will make more specific complete description below.
Detailed description of the invention book
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method and material described herein Trample the present invention.The present invention is not limited to method described herein and material.The one of the document, patent and the similar material that are combined Or more it is different from the application or in the case where contradicting it is (including but not limited to defined term, term application, described Technology, etc.), be subject to the application.
It will further be appreciated that certain features of the invention, be it is clearly visible, carry out in a number of independent embodiments Description, but can also provide in combination in a single embodiment.Conversely, various features of the invention, for brevity, It is described in a single embodiment, but can also be individually or with the offer of any suitable sub-portfolio.
Unless otherwise stated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
Unless otherwise stated, following definition used herein should be applied.For purposes of the present invention, chemical element with The periodic table of elements CAS editions, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can join It examines " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Description in Wiley&Sons, New York:2007, entire contents are incorporated herein by reference.
There is apparent conflict unless otherwise indicated or in context, the article " one " used herein, " one (kind) " " described " is intended to include "at least one" or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more than one Component be taken into account in the embodiment of the embodiment and use or use.
Term " optional " or " optionally " refer to the event then described or situation can with but not necessarily occur, and this is retouched It states and includes the case where the case where wherein event or situation occur and wherein it does not occur.For example, " optional key " refers to The key may exist or can be not present, and the description includes singly-bound, double or triple bonds.
As described in the invention, the compound of the present invention can be optionally replaced one or more substituent groups, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included.
Term " substitution " or " substituted " indicate that one or more hydrogen atoms in the structure are taken by specific substituent group Generation.Unless otherwise indicated, the group of a substitution can have a substituent group to carry out at various substitutable position of that group Replace.When in given structural formula more than one position can by selected from specific group one or more substituent groups replaced, So substituent group can replace at various locations identical or differently.
Term " unsubstituted " indicates specified group without substituent group.
Term " optionally by ... replaced " can be used interchangeably, i.e., with term " unsubstituted or by ... replaced .. " The structure is unsubstituted or is replaced by one or more substituent groups of the present invention, substituent group packet of the present invention It includes, but is not limited to D, F, Cl, N3,-CN ,-OH ,-SH ,-NH2, alkyl, alkoxy, alkylthio group, alkylamino, naphthenic base, heterocycle, Aryl, heteroaryl etc..
In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " each ... separately for ", " each ... independently to be ", " ... be each independently " and " ... independently be " between each other can be with It exchanges, shall be understood in a broad sense, either referring among the different groups, between the same symbol between expressed specific option It does not influence mutually, can also indicate in the same group, mutual not shadow between expressed specific option between the same symbol It rings.
Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise Content.
One or more degrees of unsaturation are contained in term " unsaturation " or " unsaturated " expression part.
It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C1-C6Alkyl " refers in particular to the methyl being individually disclosed, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each section of the invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then respectively represents it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.
Term " halogen " and " halogenated " are used interchangeably in the present invention, refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I)。
Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1-20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally by one or more present invention Replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1- 12 carbon atoms；In another embodiment, alkyl group contains 1-6 carbon atom；In yet another embodiment, alkyl group Contain 1-4 carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom；Also in one embodiment, alkane Base group contains 1-2 carbon atom.
The example of alkyl group includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n- Pr、-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,- CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tert-butyl (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl (- CH (CH3)CH2CH2CH3), 3- amyl (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl-1-butyl (- CH2CH2CH(CH3)2), 2- first Base -1- butyl (- CH2CH(CH3)CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyl (- CH (CH3) CH2CH2CH2CH3), 3- hexyl (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyl (- C (CH3)2CH2CH2CH3), 3- first Base -2- amyl (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyl (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- penta Base (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..
Two obtained saturations of hydrogen atom are removed in term " alkylidene " expression from the linear chain or branched chain alkyl of saturation Bivalent hydrocarbon radical group.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In one embodiment, alkylene Base group contains 1-6 carbon atom；In another embodiment, alkylidene group contains 1-4 carbon atom；In another embodiment party In case, alkylidene group contains 1-3 carbon atom；Also in one embodiment, alkylidene group contains 1-2 carbon atom.This The example of sample includes methylene (- CH2), ethylidene (- CH2CH2), isopropylidene (- CH (CH3)CH2) etc..The alkylene Base group is optionally replaced one or more substituent groups described in the invention.
Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is a carbon-to-carbon sp2Double bond, wherein the alkenyl group can be retouched optionally by one or more present invention Replaced the substituent group stated comprising the positioning of " cis " and " tans ", or the positioning of " E " and " Z ".In one embodiment, Alkenyl group includes 2-8 carbon atom；In another embodiment, alkenyl group includes 2-6 carbon atom；In another embodiment party In case, alkenyl group includes 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (- CH=CH2)、 Allyl (- CH2CH=CH2) etc..
Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is tri- key of carbon-to-carbon sp, wherein the alkynyl group can be retouched optionally by one or more present invention Replaced the substituent group stated.In one embodiment, alkynyl group includes 2-8 carbon atom；In another embodiment, alkynyl Group includes 2-6 carbon atom；In yet another embodiment, alkynyl group includes 2-4 carbon atom.The example packet of alkynyl group It includes, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH2C ≡ CH), 1- propinyl (- C ≡ C-CH3) etc..
Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；? In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally one or more Replaced the substituent group that the present invention describes.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH3)3), 1- amoxy (n- amoxy ,-OCH2CH2CH2CH2CH3), 2- amoxy (- OCH (CH3) CH2CH2CH3), 3- amoxy (- OCH (CH2CH3)2), 2- methyl -2- butoxy (- OC (CH3)2CH2CH3), 3- methyl -2- fourth Oxygroup (- OCH (CH3)CH(CH3)2), 3- methyl-l- butoxy (- OCH2CH2CH(CH3)2), 2- methyl-l- butoxy (- OCH2CH(CH3)CH2CH3), etc..
Term " halogenated alkyl ", " halogenated alkenyl " or " halogenated alkoxy " indicate alkyl, and alkenyl or alkoxy base are by one Replaced a or multiple halogen atoms, wherein alkyl, alkenyl and alkoxy have meaning as described in the present invention, such example Include, but is not limited to, trifluoromethyl, trifluoromethoxy etc..The halogenated alkyl, halogenated alkenyl or halo alkoxy group are appointed Replaced the substituent group that selection of land is described by one or more present invention.
Term " aminoalkyl " includes the C replaced one or more amino1-C10Linear or branched alkyl group group, Middle alkyl group has meaning as described in the present invention.Wherein in an embodiment, aminoalkyl is by one or more amino C replaced group1-C6The aminoalkyl of lower level, such example include, but is not limited to, aminomethyl, aminoethyl, ammonia third Base, etc..The aminoalkyl groups are optionally replaced one or more substituent groups described in the invention.
Term " alkylamino " or " alkyl amino " include " N- alkyl amino " and " N, N- dialkyl amido ", wherein amino base Group is separately replaced one or two alkyl group.In one embodiment, alkyl amino is one or two C1-6 Alkyl is connected to the alkylamino group of the lower level on nitrogen-atoms.In another embodiment, alkyl amino is C1-3It is lower The alkylamino group of grade.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, such example packet It includes, but is not limited to, N- methylamino, N- ethylamino, N, N- dimethylamino, N, N- lignocaine, etc..The alkylamino radicals Optionally replaced one or more substituent groups described in the invention.
Term " alkylthio group " refers to C1-10The alkyl of linear chain or branched chain is connected to the group on bivalent sulfur atom, implements one In scheme, alkylthio group is the C of lower level1-4Alkylthio group, such embodiment include, but is not limited to methyl mercapto (CH3S-).Institute Alkylthio radicals are stated optionally replaced one or more substituent groups described in the invention.
Term " carbocylic radical " or " carbocyclic ring " indicate containing 3-12 carbon atom, monovalent or multivalence nonaromatic saturation Or part unsaturated monocycle, bicyclic or three-ring system.Carbon bicyclic group includes spiral shell carbon bicyclic group and condensed carbon bicyclic group, suitably Carbocylic radical group includes, but is not limited to, naphthenic base, cycloalkenyl and cycloalkynyl radical.The example of carbocylic radical group further comprises ring Propyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyl, 1- cyclopenta -2- alkenyl, 1- cyclopenta -3- alkenyl, cyclohexyl, 1- Cyclohexyl -1- alkenyl, 1- cyclohexyl -2- alkenyl, 1- cyclohexyl -3- alkenyl, cyclohexadienyl, suberyl, cyclooctyl, ring nonyl Base, cyclodecyl, ring undecyl, cyclo-dodecyl, etc..The carbocylic radical group is optionally by one or more institutes of the present invention Replaced the substituent group of description.
Term " naphthenic base " indicates containing 3-12 carbon atom, monovalent or multivalence saturation monocycle, bicyclic or three ring bodies System.Bicyclic or three-ring system may include condensed ring, bridged ring and loop coil.In one embodiment, naphthenic base includes that 3-10 carbon is former Son；In another embodiment, naphthenic base includes 3-8 carbon atom；In yet another embodiment, naphthenic base includes 3-6 carbon Atom.The group of naphthene base is optionally replaced one or more substituent groups described in the invention.
The one or more oxygen (O) of term " hetero atom " expression, sulphur (S), nitrogen (N), phosphorus (P) or silicon (Si), including 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 hydrogen in heterocycle on nitrogen-atoms Substituted form, for example, N (as the N in 3,4- dihydro-2 h-pyrrole base), NH (as the NH in pyrrolidinyl) or NR are (as N- NR in substituted pyrrolidinyl).
Term " heterocycle ", " heterocycle " or " heterocycle " is used interchangeably here, all refers to comprising 3-12 annular atom The unsaturated monocyclic, bicyclic or tricyclic of saturation or part, one or more atoms are independently replaced by hetero atom in middle ring It changes, the hetero atom has meaning as described in the present invention, and ring can be fully saturated or unsaturated comprising one or more Degree, but an armaticity ring cannot all have.Wherein an embodiment is " heterocycle ", and " heterocycle " or " heterocycle " group is 3-8 Member ring monocycle (2-6 carbon atom and be selected from N, O, P, the 1-3 hetero atom of S, in this S or P optionally by one or more oxygen It is obtained replaced atom as SO, SO2, PO, PO2Group, when the ring is a three-membered ring, only one of them hetero atom), Or bicyclic (4-9 carbon atom and selected from N, O, P, the 1-3 hetero atom of S, in this S or P optionally by one or more of 7-12 member It is obtained replaced a oxygen atom as SO, SO2, PO, PO2Group).The heterocyclyl groups are optionally by this one or more hair Replaced bright described substituent group.
Heterocycle can be carbon-based or heteroatom group.- the CH of its middle ring2Group can be substituted optionally by-C (=O)-, The sulphur atom of ring, which can optionally be oxidized to S- oxide and the nitrogen-atoms of ring, can optionally be oxidized to N- oxidation conjunction Object.The example of heterocycle includes, but are not limited to Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrroles Alkyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, two Hydrogen furyl, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydropyran Base, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, two Thiophene alkyl, thiophene oxane base, high piperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase, sulphur azepineBase, 2- oxa- -5- azabicyclo [2.2.1] hept- 5- base, etc..- CH in heterocycle2Group quilt-C (= O)-substitution example includes, but are not limited to 2- oxo-pyrrolidine base, oxo -1,3-thiazoles alkyl, 2- piperidone base, 3,5- bis- Oxo-piperidine base, hybar X base, etc..The example that sulphur atom is oxidized in heterocycle include, but are not limited to sulfolane base, Thio-morpholinyl 1,1- dioxide, etc..The heterocyclyl groups are optionally by one or more described in the invention Replaced substituent group.
In one embodiment, heterocycle is 3-8 former molecular heterocycle.3-8 former molecular heterocycle Example includes, but are not limited to Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- pyrroles Quinoline base, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuryl, four Hydrogen thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyrans Base, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, dithianyl, thiophene Oxane base, high piperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase, sulphur nitrogen It is miscellaneousBase, 2- oxa- -5- azabicyclo [2.2.1] hept- 5- base, etc..- CH in heterocycle2Group is replaced by-C (=O)- Example includes, but are not limited to 2- oxo-pyrrolidine base, oxo -1,3-thiazoles alkyl, 2- piperidone base, 3,5- dioxopiperidine Base, hybar X base, etc..The example that sulphur atom is oxidized in heterocycle includes, but are not limited to sulfolane base, thiomorpholine Base 1,1- dioxide, etc..The former molecular heterocyclyl groups of described 3-8 are optionally by one or more institutes of the present invention Replaced the substituent group of description.
In another embodiment, heterocycle is 4-6 former molecular heterocycle.4-6 former molecular heterocycle Example include, but are not limited to azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- pyrrolinyl, 3- pyrrole Cough up quinoline base, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuryl, tetrahydro-thienyl, Dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranose, 4H- pyrans Base, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, dithianyl, thiophene oxane base, etc. Deng.- CH in heterocycle2Group includes, but are not limited to 2- oxo-pyrrolidine base, oxo -1 by-C (=the O)-example replaced, 3- thiazolidinyl, 2- piperidone base, 3,5- dioxy piperazine piperidinyl, hybar X base, etc..Sulphur atom is oxidized in heterocycle Example includes, but are not limited to sulfolane base, 1,1- dioxothiomorpholinyl, etc..Described 4-6 is former molecular miscellaneous Cyclic groups are optionally replaced one or more substituent groups described in the invention.
In yet another embodiment, heterocycle is 7-12 former molecular heterocycle.7-12 former molecular heterocycle The example of base includes, but are not limited to 2- oxa- -5- azabicyclo [2.2.1] hept- 5- base, etc..The 7-12 atom group At heterocyclyl groups optionally replaced one or more substituent groups described in the invention.
Term " Heterocyclylalkyl " refers to saturation monocycle, the bicyclic or tricyclic of the unit price containing 3-12 annular atom or multivalence System, wherein at least one annular atom are selected from nitrogen, sulphur or oxygen atom.
Term " aryl " indicates the monocycle containing 6-14 annular atom or 6-12 annular atom or 6-10 annular atom, double The carbocyclic ring system of ring and tricyclic, wherein at least one ring system be it is aromatic, wherein each ring system include 3-7 original Molecular ring.Aryl group by the armaticity ring of aryl group with parent molecule in general, but unnecessarily connect.Term " aryl " can be used interchangeably with term " aromatic rings " or " aromatic ring ".The example of aryl group includes, but are not limited to phenyl, naphthalene Base, anthracene, etc..The aryl group is optionally replaced one or more substituent groups described in the invention.
Term " fragrant amino " indicates amino group replaced one or two aryl group, and such example includes, but It is not limited to N- phenylamino, etc..Wherein an embodiment is that the aromatic ring in fragrant amino can be further substituted.
Term " heteroaryl " is indicated containing 5-14 annular atom or 5-12 annular atom or 5-10 annular atom or 5-6 The monocycle of a annular atom, bicyclic and three-ring system, wherein at least one ring system are aromatic, and at least one ring system packet Containing one or more hetero atoms, wherein each ring system includes 5-7 former molecular ring.Heteroaryl groups are not in general, but Necessarily it is connect by the armaticity ring of heteroaryl groups with parent molecule.Term " heteroaryl " can with term " hetero-aromatic ring " or " heteroaromatics " is used interchangeably.The heteroaryl groups are optionally by one or more substituent group institutes described in the invention Replace.In one embodiment, 5-10 former molecular heteroaryl includes 1,2,3 or 4 miscellaneous original for being independently selected from O, S and N Son.
The example of heteroaryl groups includes, but is not limited to, 2- furyl, 3- furyl, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl, 2- oxazolyl, 4- oxazolyl, 5- oxazole Base, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- Pyrimidine radicals, pyridazinyl (such as 3- pyridazinyl), 2- thiazolyl, 4- thiazolyl, 5- thiazolyl, tetrazole radical (such as 5- tetrazole radical), triazole Base (such as 2- triazolyl and 5- triazolyl), 2- thienyl, 3- thienyl, pyrazolyl (such as 2- pyrazolyl), isothiazolyl, 1,2,3- Oxadiazoles base, 1,2,5- oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,3- triazolyl, 1,2,3- thio biphosphole base, 1,3,4- sulphur For di azoly, 1,2,5- thio biphosphole bases, pyrazinyl, 1,3,5-triazines base, etc.；Also include below bicyclic, but never limit It is bicyclic in these, benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2- indyl), purine radicals, quinolyl (such as 2- quinolyl, 3- quinolyl, 4- quinolyl), isoquinolyl (such as 1- isoquinolyl, 3- isoquinolyl or 4- isoquinolyl), Imidazo [1,2-a] pyridyl group, pyrazolo [1,5-a] pyridyl group, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazine Base, [1,2,4] triazol [4,3-b] pyridazinyl, [1,2,4] triazol [1,5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] Pyridyl group, etc..
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " and " condensed ring radical " are used interchangeably here, all refer to list The unsaturated bridged-ring system of the saturation or part of valence or multivalence, the bridged-ring system refer to the bicyclic system of non-aromatic.Such as formula Shown in a-c, indicate between two five-membered rings (formula a), between two hexatomic rings (formula b) and five-membered ring and one it is hexa-atomic (formula c) shares the bridged-ring system of a C-C key between ring.System may include independent or conjugation unsaturated system, but its Nuclear structure does not include aromatic rings or heteroaromatic (but aromatic group can be used as substituent group thereon).In condensed-bicyclic Each ring independently is carbocyclic ring or heterocycle.
The example of condensed-bicyclic include, but are not limited to hexahydro furyl simultaneously [2,3-b] furans -3- base, hexahydro furyl simultaneously [3, 2-b] furans -3- base, octahydro pentamethylene simultaneously [c] pyrroles -5- base, octahydro pentalene -2- base, octahydro -1H- iso-indoles -5- Base, etc..Condensed-bicyclic base can be independently unsubstituted or replaced one or more substituent group described in the invention.
Term " loop coil base ", " loop coil ", " spiral shell bicyclic group " or " spiral shell is bicyclic " are used interchangeably here, refer to unit price or more The saturation or part unsaturated ring system of valence, one of ring is originating from specific ring carbon atom on another ring.For example, as under Described in face formula d, formula e, a carbon atom is shared in the ring system that ring A and ring B are saturated at two, then be referred to as " loop coil " or " spiral shell is bicyclic ".Each ring in loop coil independently is carbocyclic ring or heterocycle.Such example includes, but is not limited to 4- oxaspiro [2.4] heptane -6- base, (R) -4- azaspiro [2.4] heptane -6- base, etc..Spiral shell bicyclic group can it is independently unsubstituted or by Replaced one or more substituent groups described in the invention.
Term " n former molecular ", wherein n is integer, the number of ring member nitrogen atoms in molecule is typically described, described The number of ring member nitrogen atoms is n in molecule.For example, piperidyl is 6 molecular Heterocyclylalkyls of original, and 1,2,3,4- naphthane is 10 molecular groups of naphthene base of original.
Term " azido " or " N3" indicate a nitrine structure.This group can be connected with other groups, for example, Triazonmethane (MeN can be connected to form with a methyl3), or phenylazide (PhN is connected to form with a phenyl3)。
No matter term " carboxyl " is single use or is used in conjunction with other terms, such as " carboxyalkyl ", expression-CO2H；Term No matter " carbonyl " is single use or is used in conjunction with other terms, such as " amino carbonyl " or " acyloxy ", indicate-(C=O)-.
As described in the present invention, substituent R is keyed to the ring system formed on the ring at center by one and represents substituent R It any on ring can may replace or any reasonable position is replaced.For example, formula f represents any possibility quilt on A ring or B ring Substituted position can be replaced by R, as shown in formula g, formula h, formula i, formula j, formula k, formula l and formula m.
Term " study subject " used in the present invention refers to animal.The typically described animal is mammal, including people Class.Study subject, for example, also refer to primate (such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, Rat, mouse, fish, bird, etc..In one embodiment, the study subject is primate.In another embodiment In, the study subject is people.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.
Term " stereoisomer " refers to identical chemical constitution, but spatially arrangement mode is different for atom or group Compound.Stereoisomer includes that enantiomter, diastereoisomer, conformer (rotational isomer), geometry are different Structure body (cis/trans) isomers, atropisomer, etc..
Term " chirality " be with its mirror image cannot be overlapped property molecule；And " achirality " refer to can be with its mirror image The molecule of overlapping.
" enantiomter " refers to two isomers that cannot be overlapped but be mutually mirror of a compound.
" diastereoisomer " refer to there are two or multiple chiral centres and its molecule not alloisomerism of mirror image each other Body.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral property and reactivity.Diastereoisomer is mixed Such as electrophoresis and chromatography, such as HPLC can be operated by high resolution analysis to separate by closing object.
Stereochemical definitions used in the present invention and rule generally follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York；and Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley&Sons, Inc.,New York,1994.Many organic compounds exist with optical active forms, i.e., they, which have, makes linearly polarized light The ability that plane rotates.When describing optically active compound, indicate molecule about it using prefix D and L or R and S The absolute configuration of one or more chiral centres.Prefix d and l or (+) and (-) are for linearly polarized light caused by appointed compound The symbol of rotation, wherein (-) or l indicate that compound is left-handed.Prefix is (+) or the compound of d is dextrorotation.It is a kind of specific Stereoisomer be enantiomter, the mixture of this isomers is referred to as enantiomeric mixture.Enantiomter 50:50 mixture is known as racemic mixture or racemic modification, when in chemical reaction or in the process without stereoselectivity or vertical When body specificity, such case may occur in which.
Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer It is excessive.
According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) deposits ?.Chiral synthon or chiral reagent preparation can be used in optically active (R)-or (S)-isomers, or is torn open using routine techniques Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing disubstituted cycloalkanes in compound The substituent group of base, naphthenic base may have cis or trans configuration.
The mixture of resulting any stereoisomer can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.
The racemic modification of any gained final product or intermediate can be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Object can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can be prepared by asymmetric syntheses, for example, can refer to Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。
Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can achieve The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the recombination of some bonding electrons come The mutual inversion of phases carried out.The specific example of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyl are mutual The interconversion of tautomeric.Another tautomeric example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific real Example is the interconversion of pure and mild pyridine -4 (1H) the -one tautomer of pyridine -4-.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.
" pharmaceutically acceptable " refers to compounds some in this way, raw material, composition and/or dosage form, they are cured rationally Learn judgement in the range of, be suitable for contacted with patient tissue and without excessive toxicity, irritation, allergy or with reasonable benefit The symmetrical other problems of benefit/Hazard ratio and complication, and effective for given application.
Unless otherwise indicated, structural formula described in the invention includes that (such as mapping is different for all isomeric forms Structure, diastereo-isomerism and geometrical isomerism (or conformational isomerism)): such as R, S configuration containing asymmetric center, (Z) of double bond, (E) isomers, and the conformer of (Z), (E).Therefore, the single three-dimensional chemical isomer of the compound of the present invention or its is right Reflect isomers, the mixture of diastereoisomer or geometric isomer (or conformer) belongs to the scope of the present invention.
Unless otherwise indicated, all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.In addition, unless otherwise indicated, the structural formula of compound described in the invention includes one or more different originals The enriched isotope of son.
When term " blocking group " or " PG " refer to a substituent group and other reacted with functional groups, commonly used to resistance It is disconnected or protect special functionality.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group Or the functionality of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9- fluorenes methylene oxygen carbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substituent group of base is used to block or protect the functionality of hydroxyl, and suitable blocking group includes trialkylsilkl, acetyl group, Benzoyl and benzyl." carboxy protective group " refers to that the substituent group of carboxyl is used to block or protect the functionality of carboxyl, generally Carboxyl-protecting group include-CH2CH2SO2Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) second Oxygroup methyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro Ethyl, etc..Description general for blocking group can refer to document: Greene et al., Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991and Kocienski et al., Protecting Groups,Thieme,Stuttgart,2005。
Term " prodrug " used in the present invention represents a compound and is converted into shown in formula (I) or (III) in vivo Compound.Such conversion is hydrolyzed in blood by pro-drug or the shadow in blood or tissue through enzymatic conversion for precursor structure It rings.Pro-drug compounds of the present invention can be ester, and what ester can be used as pro-drug in existing invention has phenyl ester class, Aliphatic (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as in the present invention A compound include hydroxyl, it can be acylated to obtain the compound of prodrug form.Other pro-drug shapes Formula includes phosphate, if these phosphate compounds are obtaining through the di on parent.It is complete about pro-drug Whole discussion can refer to following documents: Higuchi et al., Pro-drugs as Novel Delivery Systems, 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:Design and 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 document are included herein by reference.
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, restoring, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. documented.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by recorded in books, literature Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphur Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that alkali appropriate obtains includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any The compound of the group of included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be turned by quaternary ammonium With obtaining.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C1-8Sulphonic acid compound and aromatic sulphonic acid compound.
" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
When the solvent is water, term " hydrate " can be used.In one embodiment, a compounds of this invention Molecule can be combined with a hydrone, such as monohydrate；In another embodiment, a compounds of this invention molecule It can be combined with more than one hydrone, such as dihydrate, in yet another embodiment, a compounds of this invention point Son can be combined with the hydrone less than one, such as semihydrate.It should be noted that hydrate of the present invention remain with it is non- The biological effectiveness of the compound of hydrated form.
Term " preventing " or " prevention " refer to that the reduction for obtaining the risk of disease or obstacle (that is: makes at least one clinical condition of disease Shape stops development in main body, which may face or be inclined in advance in face of this disease, but without undergoing or show The symptom of disease).
Term " therapeutically effective amount " refers to that when delivering medicine to main body to treat disease, the component of compound is enough to this disease The treatment of disease works." therapeutically effective amount " can be with the item of compound, disease and severity and main body to be treated Part, the age, weight, gender etc. and change.
Any disease of term " treatment " or illness as used in the present invention, refer to improvement disease in some of these embodiments Disease or illness (development for slowing down or prevent or mitigate disease or its at least one clinical symptoms).In other embodiments In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another In a little embodiments, " treatment " refers to from body (such as stablizing perceptible symptom) or physiologically (such as stable body Parameter) or above-mentioned two aspect adjust disease or illness.In other embodiments, " treatment ", which refers to, prevents or delays disease or disease Breaking-out, generation or the deterioration of disease.
" effective quantity " of the present invention or " effective dose " refer to for treating or mitigating one or more present invention The disorder or disease referred to is effectively measured.Disclosed compound or composition according to the present invention can be used any effective Quantity and any effective administration route treatment treatment or the seriousness for mitigating disorder or disease.Required exact amount is by root It is different according to different themes, according to the ordinary circumstance of species, age and theme, the severity of infection, special preparation, administration Mode etc..Compound or composition can also be given together with one or more other drugs, as described above.
The description of the compounds of this invention
Diethylenediamine compound of the present invention, pharmaceutically acceptable salt, pharmaceutical preparation and combinations thereof may be used as Serotonin selectivity reuptaking inhibitor and/or 5-HT1AReceptor stimulating agent, to mankind's central nervous system dysfunction, than Such as depression, the treatment of anxiety disorder, bipolar disorders has potential purposes.
On the one hand, the present invention relates to a kind of compounds, are compound shown in formula (I) compound represented or formula (I) Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein:
X is structure shown in formula (II):
Wherein, each keyAnd keySeparately be-or=；
Each U1、U2、U3And U4It is separately CR2、N、-CR2R2aOr-NR2bOr U1And U2Or U3And U4Joint At-CR2R2a-、-NR2b,-O- or-S- form；
V is CR2Or N；
W is-NR2b,-O- or-S-；
L is-CR3R4-；
R is 3,4,5 or 6；
Q is 1,2,3 or 4；
Y be naphthenic base, heterocycle, aryl or heteroaryl, precondition be the heterocycle and heteroaryl be with it is carbon-based with Host molecule be connected, wherein the naphthenic base, heterocycle, aryl and heteroaryl it is individually optional by one or more R5Group institute Replace；
Each R1It independently is H, D, F, Cl, Br, I ,-CN ,-N3、-NO2、-NRaRb、-ORc, alkyl, alkenyl or alkynyl, wherein The alkyl, alkenyl and alkynyl it is individually optional by one or more R6Replaced group；
Each R2And R2aIt is separately H, D, F, Cl, Br, I ,-CN ,-N3、-NO2、-NRaRb、-ORc,-S (=O)mRc、- C (=O) Rc,-C (=O) ORc,-C (=O) NRaRb,-S (=O)2NRaRb,-OC (=O) Rc、-N(Ra) C (=O) Rc, alkyl, alkene Base or alkynyl, wherein the alkyl, alkenyl and alkynyl it is individually optional by one or more R6Replaced group；
Each R2bIt independently is H, D, F, Cl, Br, I ,-CN ,-N3、-NO2、-NRaRb、-ORc,-S (=O)mRc,-C (=O) Rc,-C (=O) ORc,-C (=O) NRaRb,-S (=O)2NRaRb,-OC (=O) Rc、-N(Ra) C (=O) Rc, alkyl, alkenyl or alkynes Base, wherein the alkyl, alkenyl and alkynyl it is individually optional by one or more R6Replaced group；
Each R3And R4It is separately H, D, F, Cl, Br, I ,-CN ,-N3、-NH2,-OH, alkyl, alkenyl, alkynyl, alcoxyl Base, alkylamino, naphthenic base, heterocycle, aryl or heteroaryl or R3、R4, and together with the carbon atom that they are connected jointly, shape At carbocyclic ring or heterocycle, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, naphthenic base, heterocycle, aryl, heteroaryl, Carbocyclic ring and heterocycle it is individually optional by one or more R6Replaced group；
Each R5It independently is H, D, F, Cl, Br, I ,-CN ,-N3、-NO2、-(C0-C6Alkylidene)-NRaRb、-(C0-C6Alkylene Base)-ORc、-(C0-C6Alkylidene)-S (=O)mRc,-C (=O) Rc,-C (=O) ORc,-C (=O) NRaRb,-S (=O)2NRaRb,-OC (=O) Rc、-N(Ra) C (=O) Rc, alkyl, alkenyl, alkynyl, naphthenic base, heterocycle, aryl or heteroaryl, or Two R on adjacent cyclic atom5, and together with the annular atom that they are respectively connected with, carbocyclic ring, heterocycle, aromatic ring or hetero-aromatic ring are formed, Wherein described-(C0-C6Alkylidene)-NRaRb、-(C0-C6Alkylidene)-ORc、-(C0-C6Alkylidene)-S (=O)mRc, alkyl, alkene Base, alkynyl, naphthenic base, heterocycle, aryl, heteroaryl, carbocyclic ring, heterocycle, aromatic ring and hetero-aromatic ring it is individually optional by one or more A R6Replaced group；
Each R6It independently is F, Cl, Br, I ,-CN ,-N3、-NO2、-OH、-SH、-NH2, alkyl, halogenated alkyl, alkoxy, Alkylthio group or alkylamino；
Each RaAnd RbIt is separately H, alkyl, alkenyl, alkynyl, halogenated alkyl ,-(C0-C6Alkylidene)-naphthenic base ,- (C0-C6Alkylidene)-heterocycle ,-(C0-C6Alkylidene)-aryl or-(C0-C6Alkylidene)-heteroaryl or Ra、Rb, and and it Jointly connected nitrogen-atoms together, form heterocycle；
Each RcIt independently is H, alkyl, alkenyl, alkynyl, halogenated alkyl ,-(C0-C6Alkylidene)-naphthenic base ,-(C0-C6Alkylene Base)-heterocycle ,-(C0-C6Alkylidene)-aryl or-(C0-C6Alkylidene)-heteroaryl；With
Each m independently is 0,1 or 2.
In one embodiment, each R1It independently is H, D, F, Cl, Br, I ,-CN ,-N3、-NO2、-NRaRb、-ORc、C1-C6 Alkyl, C2-C6Alkenyl or C2-C6Alkynyl, wherein the C1-C6Alkyl, C2-C6Alkenyl and C2-C6Alkynyl is individually optionally by one Or multiple R6Replaced group, wherein each Ra、Rb、RcAnd R6With definition as described in the present invention.
In another embodiment, X has the structural formula as shown in formula (II-1):
Wherein, U4For CR2Or N；
P is 1,2 or 3；
W is-NH- ,-O- or-S-；With
Each R2With definition as described in the present invention.
In another embodiment, each R2And R2aIt is separately H, D, F, Cl, Br, I ,-CN ,-N3、-NO2、- NRaRb、-ORc,-S (=O)mRc,-C (=O) Rc,-C (=O) ORc,-C (=O) NRaRb,-S (=O)2NRaRb,-OC (=O) Rc、-N(Ra) C (=O) Rc、C1-C6Alkyl, C2-C6Alkenyl or C2-C6Alkynyl, wherein the C1-C6Alkyl, C2-C6Alkenyl and C2- C6Alkynyl is individually optionally by one or more R6Replaced group；
Each R2bIt independently is H, D, F, Cl, Br, I ,-CN ,-N3、-NO2、-NRaRb、-ORc,-S (=O)mRc,-C (=O) Rc,-C (=O) ORc,-C (=O) NRaRb,-S (=O)2NRaRb,-OC (=O) Rc、-N(Ra) C (=O) Rc、C1-C6Alkyl, C2-C6 Alkenyl or C2-C6Alkynyl, wherein the C1-C6Alkyl, C2-C6Alkenyl and C2-C6Alkynyl is individually optionally by one or more R6Base Replaced group；With
Each Ra、Rb、RcAnd R6With definition as described in the present invention.
In another embodiment, each R3And R4It is separately H, D, F, Cl, Br, I ,-CN ,-N3、-NH2、-OH、C1- C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkylamino, C3-C10Naphthenic base, 3-10 original are molecular Heterocycle, C6-C10Aryl or 5-10 former molecular heteroaryl or R3、R4, and the carbon atom one being connected jointly with them It rises, forms C3-C8Carbocyclic ring or 3-7 former molecular heterocycle, wherein the C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1- C6Alkoxy, C1-C6Alkylamino, C3-C10Naphthenic base, 3-10 former molecular heterocycle, C6-C10Aryl, 5-10 atom group At heteroaryl, C3-C8The former molecular heterocycle of carbocyclic ring and 3-7 is individually optionally by one or more R6Replaced group, Middle R6With definition as described in the present invention.
In another embodiment, Y C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C14Aryl or 5- 14 molecular heteroaryls of original, precondition are that described 3-12 former molecular heterocycle and 5-14 are former molecular miscellaneous Aryl is to be connected with carbon-based with host molecule, wherein the C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C14Virtue The former molecular heteroaryl of base and 5-14 is individually optionally by one or more R5Replaced group, wherein R5With such as this hair The bright definition.
In another embodiment, each R5It independently is H, D, F, Cl, Br, I ,-CN ,-N3、-NO2、-(C0-C6Alkylidene)- NRaRb、-(C0-C6Alkylidene)-ORc、-(C0-C6Alkylidene)-S (=O)mRc,-C (=O) Rc,-C (=O) ORc,-C (=O) NRaRb,-S (=O)2NRaRb,-OC (=O) Rc、-N(Ra) C (=O) Rc、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C10 Naphthenic base, 3-10 former molecular heterocycle, C6-C10Aryl or 5-10 former molecular heteroaryl or adjacent ring are former Two R on son5, and together with the annular atom that they are respectively connected with, form C3-C10Carbocyclic ring, 3-10 former molecular heterocycle, C6-C10Aromatic ring or 5-10 former molecular hetero-aromatic ring, wherein described-(C0-C6Alkylidene)-NRaRb、-(C0-C6Alkylidene)- ORc、-(C0-C6Alkylidene)-S (=O)mRc、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C10Naphthenic base, 3-10 atom Heterocycle, the C of composition6-C10Aryl, 5-10 former molecular heteroaryl, C3-C10Carbocyclic ring, 3-10 former molecular heterocycle, C6-C10The former molecular hetero-aromatic ring of aromatic ring and 5-10 is individually optionally by one or more R6Replaced group, wherein each Ra、 Rb、RcAnd R6With definition as described in the present invention.
In another embodiment, each R6It independently is F, Cl, Br, I ,-CN ,-N3、-NO2、-OH、-SH、-NH2、C1-C6 Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Alkylthio group or C1-C6Alkylamino.
In another embodiment, compound of the present invention is formula (III) compound represented or formula (III) Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, the pharmaceutically acceptable salt of shown compound Or its prodrug,
Wherein, 1,2 or 3 p；With
Each R1、R2, Y, L, p, r and q have as described in the present invention definition.
In another embodiment, each R1It independently is H, D, F, Cl, Br ,-CN ,-NO2、-CH3、-CH2CH3、-CH (CH3)2、-CF3、-CH2CF3、-CHFCF3、-CF2CF3、-OCH3、-OCH2CH3、-OCH(CH3)2、-OCF3、-OCH2CF3、- OCHFCF3Or-OCF2CF3。
In another embodiment, each R2And R2aIt is separately H, D, F, Cl, Br ,-CN ,-NO2、-NRaRb、- ORc,-C (=O) ORc,-C (=O) NRaRbOr optionally by one or more R6C replaced group1-C4Alkyl；
Each R2bIt independently is H, D, F, Cl, Br ,-CN ,-NO2、-NRaRb、-ORc,-C (=O) ORc,-C (=O) NRaRbOr Optionally by one or more R6C replaced group1-C4Alkyl；With
Each Ra、Rb、RcAnd R6With definition as described in the present invention.
In another embodiment, each R2And R2aIt is separately H, D, F, Cl, Br ,-CN ,-NO2、-NH2、-N (CH3)2、-OH、-OCH3、-OCH(CH3)2、-CH3、-CH2CH3、-CH(CH3)2、-CF3,-C (=O) OH ,-C (=O) OCH3Or- CONH2；With
Each R2bIt independently is H, D, F, Cl, Br ,-CN ,-NO2、-NH2、-N(CH3)2、-OH、-OCH3、-OCH(CH3)2、- CH3、-CH2CH3、-CH(CH3)2、-CF3,-C (=O) OH ,-C (=O) OCH3Or-CONH2。
In another embodiment, L is-CH2-。
In another embodiment, Y is 3-10 former molecular heterocycle or the 5-10 molecular heteroaryl of original, preceding The condition of mentioning is described 3-10 former molecular heterocycle and 5-10 former molecular heteroaryl is with carbon-based and host molecule Be connected, wherein the 3-10 former molecular heterocycle and the 5-10 molecular heteroaryl of original it is individually optional by one or Multiple R5Replaced group, wherein R5With definition as described in the present invention.
In another embodiment, Y is 4-6 former molecular heterocycle or 5-6 former molecular heteroaryl, premise Condition is described 4-6 former molecular heterocycle and 5-6 former molecular heteroaryl is to be connected with carbon-based with host molecule, Wherein described 4-6 former molecular heterocycle and the 5-6 molecular heteroaryl of original it is individually optional by one or more R5 Replaced group, wherein R5With definition as described in the present invention.
In another embodiment, Y is one of minor structure shown in formula (IV-1) to (IV-14):
Wherein, each n independently is 1,2,3 or 4；With
Each R5With definition as described in the present invention.
In another embodiment, each R5It independently is H, D, F, Cl, Br ,-CN ,-NO2、-(C0-C4Alkylidene)-ORc、- (C0-C4Alkylidene)-NRaRb,-C (=O) ORc,-C (=O) NRaRb、C1-C4Alkyl, C2-C4Alkenyl or C2-C4Alkynyl, Huo Zhexiang Two R on adjacent annular atom5, and together with the annular atom that they are respectively connected with, form C3-C8Carbocyclic ring, 3-7 original are molecular The former molecular hetero-aromatic ring of heterocycle, phenyl ring or 5-6, wherein described-(C0-C4Alkylidene)-ORc、-(C0-C4Alkylidene)- NRaRb、C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C3-C8Carbocyclic ring, 3-7 former molecular heterocycle, phenyl ring and 5-6 are former Molecular hetero-aromatic ring is individually optionally by one or more R6Replaced group, wherein each Ra、Rb、RcAnd R6With such as of the invention The definition.
In another embodiment, each R5It independently is H, D, F, Cl, Br ,-CN ,-NO2、-OH、-NH2,-C (=O) OCH3,-C (=O) OCH2CH3,-C (=O) NH2、-CH3、-CH2CH3、-CH(CH3)2、-CF3、-OCH3、-OCH(CH3)2Or-N (CH3)2。
In another embodiment, each RaAnd RbIt is separately H, C1-C4Alkyl, C3-C6Alkenyl, C3-C6Alkynyl, C1- C4Halogenated alkyl ,-(C0-C4Alkylidene)-(C3-C8Naphthenic base) ,-(C0-C4Alkylidene)-(3-7 former molecular heterocycle Base) ,-(C0-C4Alkylidene)-(phenyl) or-(C0-C4Alkylidene)-(5-6 former molecular heteroaryl) or Ra、Rb, and Together with the nitrogen-atoms that they are connected jointly, 4-7 former molecular heterocycle is formed；With
Each RcIt independently is H, C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl ,-(C0-C4Alkylidene)- (C3-C8Naphthenic base) ,-(C0-C4Alkylidene)-(3-7 former molecular heterocycle) ,-(C0-C4Alkylidene)-(phenyl) or- (C0-C4Alkylidene)-(5-6 former molecular heteroaryl).
In another embodiment, compound of the present invention has following one structure:
Or its stereoisomer, tautomer, nitrogen oxidation Object, solvate, metabolite, pharmaceutically acceptable salt or its prodrug.
Unless otherwise mentioned, all suitable isotope variations of the compound of the present invention, stereoisomer, tautomerism Body, solvate, metabolite, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.
Disclosed compound of present invention can contain asymmetric or chiral centre, therefore can be with different stereoisomer forms In the presence of.It is including but not limited to non-right the present invention is directed to all stereoisomer forms of compound shown in formula (I) or (III) It reflects isomers, enantiomter, atropisomer and geometry (or conformation) isomers and their mixture such as racemic is mixed Object is closed, component part of the invention is become.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicate, then the structure All stereoisomers all consider within the present invention, and be included in the invention as disclosed compound of present invention.When Spatial chemistry is expressed the real wedge-shaped line (solid wedge) of particular configuration or when dotted line indicates, then the alloisomerism of the structure Body is with regard to this clear and definition.
Compound shown in formula (I) or (III) can exist with different tautomeric forms, and all these interconversions Isomers is included within the scope of the present invention as is described in the claims.
The nitrogen oxides of the compounds of this invention is also contained within the scope of the present invention.It can be by an elevated temperature using normal Corresponding nitrogen-containing basic substance is aoxidized, or pass through in the presence of the acid of such as acetic acid with oxidant (such as hydrogen peroxide) It reacts in suitable solvent with peracid, such as is reacted in methylene chloride, ethyl acetate or methyl acetate with peracetic acid, or It is reacted in chloroform or methylene chloride with 3- chloroperoxybenzoic acid, prepares the nitrogen oxides of the compounds of this invention.
Compound shown in formula (I) or (III) can exist in a salt form.In one embodiment, the salt refers to medicine Acceptable salt on.Term " pharmaceutically acceptable " refers to that substance or composition must be with other ingredients comprising preparation And/or it is compatible chemically and/or in toxicology with the mammal of its treatment.In another embodiment, the salt is not necessarily It is pharmaceutically acceptable salt, can be and be used to prepare and/or purify compound shown in formula (I) or (III) and/or for separating The intermediate of the enantiomer of compound shown in this formula (I) or (III).
Pharmaceutical acid-addition salts can be formed with inorganic acid and organic acid, such as acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Object/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, apple Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly- half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.
The inorganic acid that salt can be obtained by its derivative includes such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid.
The organic acid that salt can be obtained by its derivative includes such as acetic acid, propionic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..
Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.
Can obtain the inorganic base of salt by its derivative includes, for example, ammonium salt and periodic table I race to XII race metal.? In certain embodiments, which is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salts.
Can obtain the organic base of salt by its derivative includes primary amine, secondary amine and tertiary amine, and substituted amine includes naturally occurring Substituted amine, cyclic amine, deacidite etc..Certain organic amines include, for example, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine And tromethamine.
Officinal salt of the invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or free alkali form and chemistry by making these compounds The suitable acid reaction of metered amount is to be prepared.Such reaction usually carries out in the mixture of water or organic solvent or both. Generally, in appropriate cases, it needs using non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton,Pa.,(1985)；" pharmaceutical salts handbook: property, selection and application (Handbook of Pharmaceutical Salts:Properties,Selection,and Use)”,Stahl and Wermuth(Wiley-VCH,Weinheim, Germany, 2002) list that other is suitable for salt can be found in.
In addition, compound disclosed by the invention, the salt including them, in the form of their hydrate or can also include it The form of solvent (such as ethyl alcohol, DMSO, etc.) obtains, for their crystallization.Disclosed compound of present invention can be with pharmacy Upper acceptable solvent (including water) forms solvate inherently or by design；Therefore, the present invention is intended to include solvations And unsolvated form.
Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Isotope including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its In there are radioactive isotopes, such as3H、14C and18Those of F compound, or wherein there is non radioactive isotope, such as2H and13C.The compound of such isotope enrichment can be used for being metabolized research and (use14C), Reaction kinetics research are (using for example2H or3H), detection or imaging technique, such as positron emission tomography (PET) or including drug or substrate tissue measure of spread Single photon emission computed tomography (SPECT), or can be used in the radiotherapy of patient.18The compound of F enrichment to PET or It is especially desirable for SPECT research.Compound shown in the formula (I) of isotope enrichment can be ripe by those skilled in the art It is substituted described by the embodiment and preparation process in routine techniques or the present invention known using suitable isotope labeling reagent former Carry out used unmarked reagent to prepare.
In addition, higher isotope especially deuterium (that is,2H or D) substitution can provide certain treatment advantages, these advantages are By the higher bring of metabolic stability.For example, Half-life in vivo increase or reduction of volume requirements or therapeutic index obtain improving band Come.It should be appreciated that the deuterium in the present invention is counted as the substituent group of compound shown in formula (I) or (III).It can be rich with isotope Collect the factor to define the concentration of such higher isotope especially deuterium.Term " isotope enrichment factor " used in the present invention is Refer to the ratio between the isotope abundance and natural abundance of specified isotope.If the substituent group of the compounds of this invention is designated For deuterium, the compound for each specified D-atom at least 3500 (52.5% deuterium incorporations at each specified D-atom), At least 4000 (60% deuterium incorporations), at least 4500 (67.5% deuterium incorporations), at least 5000 (75% deuterium incorporations), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporations), at least 6333.3 (95% deuterium incorporations), at least The same position of 6466.7 (97% deuterium incorporations), at least 6600 (99% deuterium incorporations) or at least 6633.3 (99.5% deuterium incorporations) Plain enrichment factor.The pharmaceutical solvate of the present invention includes such as D that wherein recrystallisation solvent can be isotope substitution2O, third Ketone-d6、DMSO-d6Those of solvate.
On the other hand, the present invention relates to the intermediates of compound shown in preparation formula (I) or (III).
On the other hand, the present invention relates to the methods of preparation, separation and the purifying of compound shown in formula (I) or (III).
On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the compounds of this invention.One In embodiment, pharmaceutical composition of the present invention further includes pharmaceutically acceptable carrier, excipient, adjuvant, molten Matchmaker or their combination.In another embodiment, pharmaceutical composition can be liquid, solid, semisolid, gel or spray Type.
Pharmaceutical composition, preparation and the administration of the compounds of this invention
The present invention provides a kind of pharmaceutical composition, compound or its individual alloisomerism including formula (I) or (III) Body, the racemic or non-racemic mixture of isomers or its pharmaceutically acceptable salt or solvate.Of the invention one In a embodiment, described pharmaceutical composition further includes at least one pharmaceutically acceptable carrier, adjuvant or figuration Agent, and optionally, other treatment and/or prevention ingredient.
It is that suitable carrier, adjuvant and excipient agent are well known to those skilled in the art and be described in detail in for example 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) In Pharmaceutical Press, Chicago.
It will also be appreciated that certain compounds of the invention can exist for treating in a free form, or if appropriate Can exist in the form of its pharmaceutically acceptable derivates.Some unrestricted implementations of pharmaceutically acceptable derivative Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need is administered can directly or Any other adduct or derivative of compound of the present invention or its metabolite or residue are provided indirectly.
Drug pharmaceutical compositions disclosed by the invention can prepare and be packaged as (bulk) form in bulk, wherein extractable safety A effective amount of formula (I) or (III) compound represented, then give patient with powder or syrup form.Alternatively, the present invention discloses Pharmaceutical composition can prepare and be packaged as unit dosage forms, wherein each physically discrete unit contains the formula of safe and effective amount (I) or (III) compound represented.When being prepared with unit dosage forms, pharmaceutical composition disclosed by the invention can usually contain, example Such as, the compound disclosed by the invention of 0.5mg to 1g or 1mg to 700mg or 5mg to 100mg.
" pharmaceutically acceptable excipient " used in the present invention means related to form of administration or pharmaceutical composition consistency Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient mixing when must with pharmaceutical composition it is other at Split-phase is held, and interaction the effect of to avoid will be greatly reduced disclosed compound of present invention when administering to a patient and will lead to not It is the interaction of pharmaceutically acceptable pharmaceutical composition.In addition, every kind of excipient must be pharmaceutically acceptable, example Such as, there is sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected specific dosage form.In addition, can be according to them in group The specific function in object is closed to select pharmaceutically acceptable excipient.For example, may be selected to can help to produce equal one dosage type low temperature Certain pharmaceutically acceptable excipient.The certain pharmaceutically acceptable figurations that can help to produce stabilizer type may be selected Agent.Facilitate to carry or transport when may be selected to administer to a patient disclosed compound of present invention from an organ of body or part to Another organ of body or partial certain pharmaceutically acceptable excipient.Certain medicines of enhancing patient compliance may be selected Acceptable excipient on.
Suitable pharmaceutically acceptable excipient includes following kind of excipient: diluent, filler, adhesive, Disintegrating agent, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifier, sweetener, is rectified lubricant Taste agent, odor mask, colorant, anticaking agent, moisturizer, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilization Agent, surfactant and buffer.Technical staff can be appreciated that certain pharmaceutically acceptable excipient can provide more than one Function, and provide alternative function, this depends in preparation existing in how much excipient and preparation there are those other Excipient.
Technical staff grasps the knowledge and skills of this field, so that they can select for the suitable of appropriate amount of the invention Pharmaceutically acceptable excipient.Additionally, there are resources obtained by a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and for selecting suitable pharmaceutically acceptable excipient.Example includes Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。
In Remington:The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy,Lippincott Williams &Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel The various carriers for configuring pharmaceutically acceptable composition are disclosed in Dekker, New York, and for its preparation Well-known technique, the respective content of these documents are incorporated by reference into the present invention.Except any such as because generating any undesirable life Object effect, or with interaction occurs for any other ingredient in harmful way and pharmaceutically acceptable composition and with the present invention Outside the incompatible any commonly employed carrier of open compound, pays close attention to its application and belong to the scope of the present invention.
Pharmaceutical composition disclosed by the invention is prepared using technology and methods well known by persons skilled in the art.This field The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company)。
Therefore, on the other hand, the present invention relates to the technique of preparation pharmaceutical composition, described pharmaceutical composition includes the present invention Open compound and pharmaceutically acceptable excipient, carrier, adjuvant, solvent or their combination, the technique include that mixing is each Kind ingredient.Pharmaceutical composition comprising disclosed compound of present invention can mix under such as environment temperature and atmospheric pressure to make It is standby.
Compound disclosed by the invention is usually formulated as the dosage form for being suitable for administering to a patient by required approach.Example Such as, dosage form includes those dosage forms for being suitable for following administration route: (1) being administered orally, such as tablet, capsule, caplet agent, ball Agent contains tablet, pulvis, syrup, elixir, suspension, solution, emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, suspension and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) it sucks, such as aerosol, solution and dry powder doses；(6) local administration, for example, it is cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gelling agent.
In one embodiment, compound disclosed by the invention can be configured to peroral dosage form.In another embodiment, Compound disclosed by the invention can be configured to inhalant dosage form.In another embodiment, compound disclosed by the invention can be with It is configured to nose administration dosage form.In yet another embodiment, compound disclosed by the invention can be configured to transdermal administration. Also in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.
Pharmaceutical composition provided by the invention can with compressed tablets, develop piece, chewable pastille, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.Enteric coatel tablets are with the substance packet for being resistant to gastric acid effect but dissolving or being disintegrated in intestines The compressed tablets of clothing, to prevent the acidic environment of active ingredient contacts stomach.Enteric coating includes, but are not limited to fatty acid, rouge Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.Sugar coated tablet is the compacting that sugar-coat surrounds Piece can be conducive to cover taste or smell beastly and can prevent tablet from aoxidizing.Thin membrane coated tablet is with water-soluble The compressed tablets of thin layer or the film covering of substance.Film coating includes, but are not limited to hydroxyethyl cellulose, carboxymethyl cellulose Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses general characteristic identical with sweet tablet.It is multiple Tabletting is the compressed tablets by preparing more than a press cycles, including multilayer tablet and pressed coated or dry coating tablet.
Tabules can be by one kind that powder, crystallization or granular active constituent are individual or describe with the present invention Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrating agent, controlled release polymer, profit Lubrication prescription, diluent and/or colorant.Fumet and sweetener are particularly useful when forming chewable tablets and pastille.
Pharmaceutical composition provided by the invention can be provided with soft capsule or hard capsule, can be fine by gelatin, methyl Element, starch or calcium alginate are tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, and one section It fills in another section, therefore encloses active constituent completely.Soft elastic capsules (SEC) are soft, spherical shell, such as gelatin shell, It is by being added glycerol, sorbierite or the plasticizing of similar polyalcohol.It is raw that soft gelatin shell may include the pre- preventing microorganism of preservative It is long.Suitable preservative be as described in the present invention those, including methylparaben and propylben and sorbic acid.This Liquid, semisolid and the solid dosage forms that invention provides can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in Solution and suspension in propene carbonate, vegetable oil or triglycerides.Capsule comprising such solution can be such as in the U.S. Patent U.S.Pat.Nos.4,328,245；It is prepared described in 4,409,239 and 4,410,545.The capsule can also be adopted With coating as is known to persons skilled in the art, so as to improve or maintain the dissolution of active constituent.
Pharmaceutical composition provided by the invention can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.Emulsion is two-phase system, and one of liquid is thoroughly dispersed in pellet form in another liquid, It can be oil-in-water type or water-in-oil type.Emulsion may include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifier and Preservative.Suspension may include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions may include pharmaceutically may be used The acetal of receiving, such as two (low alkyl group) acetals of low alkyl group aldehyde, such as acetaldehyde diethyl acetal；And have one or more The water-soluble solvent of a hydroxyl, such as propylene glycol and ethyl alcohol.Elixir is transparent, sweet taste water-alcohol solution.Syrup is dense The aqueous solution of sugared such as sucrose, and can also include preservative.For liquid dosage form, for example, the solution in polyethylene glycol It can be diluted with enough pharmaceutically acceptable liquid-carriers such as water, to be accurately, conveniently administered.
Other useful liquid and semisolid dosage form include, but are not limited to comprising active constituent provided by the invention and second level Change those of mono- or poly- alkylene glycol dosage form, described mono- or poly- alkylene glycol includes: 1,2- dimethoxymethane, diethylene glycol (DEG) Dimethyl ether, triglyme, tetraethylene glycol dimethyl ether, polyethylene glycol -350- dimethyl ether, polyethylene glycol -550- dimethyl ether, poly- second The approximate average molecular weight of glycol -750- dimethyl ether, wherein 350,550,750 finger polyethylene glycol.These preparations can be further Including one or more antioxidant, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propylgallate, vitamin E, hydrogen Quinone, Hydroxycoumarin, ethanol amine, lecithin, cephalin, ascorbic acid, malic acid, sorbierite, phosphoric acid, bisulfites, coke Sodium sulfite, thio-2 acid and its ester and dithiocarbamate.
Where appropriate, can be by the dosage unit preparations microencapsulation of oral administration.It can also be prepared into extending or tie up Hold the composition of release, such as by being coated by microparticle material or be embedded in polymer, wax or the like.
Combination of oral medication provided by the invention can also be mentioned in the form of liposome, micella, microballoon or nanometer system For.Micella dosage form can be prepared with the method that U.S.Pat.No.6,350,458 is described.
Pharmaceutical composition provided by the invention can be provided with the granule and pulvis of non-effervesce or effervesce, to be reconstructed into Liquid dosage form.The pharmaceutically acceptable carrier used in non-effervescent or pulvis and excipient may include dilution Agent, sweetener and wetting agent.The pharmaceutically acceptable carrier used in effervescent or pulvis and excipient can wrap Include organic acid and carbon dioxide source.
Colorant and flavoring agent can be used in all above-mentioned dosage forms.
Compound disclosed in this invention can also be in conjunction with the soluble polymer as target medicine carrier.It is such Polymer includes polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, poly-hydroxyethyl asparagus fern acyl The oxide polylysine that amine phenol or palmitoyl residues replace.In addition, compound disclosed in this invention can in reality One kind Biodegradable polymeric used in the control release of existing drug combines, for example, polylactic acid, poly-epsilon-caprolactone, gathering Hydroxybutyric acid, polyorthoester, polyacetals, poly- dihydropyran, the crosslinking of polybutylcyanoacrylate and hydrogel or amphiphilic block are total Polymers.
Pharmaceutical composition provided by the invention can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.
Pharmaceutical composition provided by the invention can be common with the other active constituents that will not damage expected therapeutic effect It prepares, or the substance co-formulation with the expected effect of supplement.
Pharmaceutical composition provided by the invention can be by injection, infusion or implantation parenteral administration, for part or entirely Body administration.As the parenteral administration that uses of the present invention includes in intravenous, intra-arterial, peritonaeum, in intrathecal, intra-ventricle, urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.
Pharmaceutical composition provided by the invention can be configured to any dosage form suitable for parenteral administration, including solution, mixed Suspension, emulsion, micella, liposome, microballoon, nanometer system and suitable for consolidating for solution or suspension is made in a liquid before the injection Body form.Such dosage form can be prepared according to conventional method known to the technical staff in pharmaceutical science field (referring to Remington:The Science and Practice of Pharmacy, ibid).
Be intended for parenteral administration pharmaceutical composition may include one or more pharmaceutically acceptable carriers and Excipient includes, but are not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resists micro- life Preservative, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and the dispersion of object growth Agent, wetting agent or emulsifier, complexing agent, sequestering agent or chelating agent, antifreezing agent, cryoprotector, thickener, pH adjusting agent And inert gas.
Suitably include, but are not limited to containing transporter: water, salt water, physiological saline or phosphate buffered saline (PBS) (PBS), Sodium chloride injection, Ringers injection, isotonic glucose injection, Sterile Water Injection, glucose and Lactated Ringers injection.Non- transporter includes, but are not limited to fixed oil, castor oil, corn oil, the cottonseed of plant origin Oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soya-bean oil, hydrogenated vegetable oil, hydrogenated soybean oil and coconut oil middle chain Triglycerides and palm seed oil.Water miscibility carrier includes, but are not limited to the poly- second two of ethyl alcohol, 1,3-BDO, liquid Alcohol (such as Liquid Macrogol and polyethylene glycol 400), propylene glycol, glycerol, n-methyl-2-pyrrolidone, N, N- dimethylacetamide Amine and dimethyl sulfoxide.
Suitable antimicrobial or preservative include, but are not limited to phenol, cresols, mercurial, benzyl alcohol, chlorobutanol, Methyl p-hydroxybenzoate and propylparaben, thimerosal, benzalkonium chloride (such as benzethonium chloride), methylparaben and Propylben and sorbic acid.Suitable isotonic agent includes, but are not limited to sodium chloride, glycerol and glucose.Suitable buffer Include, but are not limited to phosphate and citrate.Suitable antioxidant is such as those of present invention description, including sulfurous acid Hydrogen salt and sodium metabisulfite.Suitable local anesthetic includes, but are not limited to procaine hydrochloride.Suitable suspending agent and point Powder is such as those of present invention description, including sodium carboxymethylcellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone. Suitable emulsifier includes those of present invention description, including polyoxyethylene sorbitan monolaurate, polyoxyethylene move back Tax sorbitol monooleate 80 and triethanolamine oleate ester.Suitable sequestering agent or chelating agent include, but are not limited to EDTA. Suitable pH adjusting agent includes, but are not limited to sodium hydroxide, hydrochloric acid, citric acid and lactic acid.Suitable complexing agent includes, but unlimited In cyclodextrin, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-β-cyclodextrin, Sulfobutylether-beta-cyclodextrin and sulfobutyl group Ether 7- beta-cyclodextrin (CyDex,Lenexa,KS)。
Pharmaceutical composition provided by the invention can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped In ampulla, bottle or syringe.The multi-dose parenteral administration must comprising it is antibacterial or fungistatic concentrations resist it is micro- Biological agent.All parenteral administrations all must be it is sterile, as known in the art and practice.
In one embodiment, pharmaceutical composition is provided with instant sterile solution.In another embodiment, drug Composition is provided with sterile dried soluble product, including freeze-dried powder and hypodermic tablet, and carrier is used before use Reconstruct.In yet another embodiment, pharmaceutical composition is formulated into instant sterile suspensions.In yet another embodiment, medicine Compositions are formulated into the sterile dry insolubility product reconstructed before use with carrier.Also in one embodiment, Pharmaceutical composition is formulated into instant without bacterial emulsion.
Pharmaceutical composition can be configured to suspension, solid, semisolid or thixotropic liquid, the reservoir administration as implantation. In one embodiment, pharmaceutical composition disclosed in this invention is dispersed in solid interior matrix, be insoluble to body fluid but The external polymeric membrane for allowing the active constituent in pharmaceutical composition to diffuse through is surrounded.
Suitable internal matrix include polymethyl methacrylate, poly- butyl methacrylate, plasticising or it is unplasticizied Polyvinyl chloride, the nylon of plasticising, the polyethylene terephthalate of plasticising, the polyethylene terephthalate of plasticising, natural rubber, Polyisoprene, polyisobutene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, poly- diformazan silicon oxygen Alkane, silicone carbonate copolymer, the hydrogel of the ester of hydrophilic polymer such as acrylic acid and methacrylic acid, collagen, crosslinking The polyvinyl acetate of the partial hydrolysis of polyvinyl alcohol and crosslinking.
Suitable external polymeric membrane includes polyethylene, polypropylene, ethylene/propene copolymer, ethylene/ethyl acrylate copolymerization Object, ethylene/vinyl acetate copolymer, silicone rubber, dimethyl silicone polymer, neoprene, haloflex, polychlorostyrene second Alkene, the copolymer of ethlyene dichloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer are poly- to benzene two Formic acid second diester, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymer, Ethylene/vinyl acetate/vinyl alcohol trimer and Ethylene/vinyl ethoxy-ethanol copolymer.
On the other hand, pharmaceutical composition disclosed in this invention can be configured to be suitable for any dose to patient's inhalation Type, such as dry powder doses, aerosol, suspension or liquid composite.In one embodiment, pharmaceutical composition disclosed in this invention Object can be configured to be suitable for the dosage form with dry powder doses to patient's inhalation.In yet another embodiment, disclosed in this invention Pharmaceutical composition can be configured to be suitable for the dosage form by sprayer to patient's inhalation.Pass through the dry powder of inhalation delivery to lung Composition generally comprise fine powdered compound disclosed in this invention and it is one or more it is fine powdered pharmaceutically Acceptable excipient.Pharmaceutically acceptable excipient be especially suitable for dry powder doses is known to those skilled in the art Dawn comprising lactose, starch, mannitol and mono-, two- and polysaccharide.Fine powder can be for example, by being micronized and grinding preparation It obtains.In general, (as being micronized) compound that size reduces can be by about 1 to 10 micron of D50Value is (for example, with swashing The measurement of optical diffraction method) Lai Dingyi.
Aerosol can be prepared by the way that compound disclosed in this invention to be suspended or dissolved in liquefied propellant.It is suitble to Propellant include chlorohydrocarbon, hydro carbons and other liquefied gas.Representative propellant includes: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetra-fluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1- difluoro Ethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoro-propane (HFA-227a), perfluoropropane, Perfluorinated butane, perflenapent, butane, iso-butane and pentane.Aerosol comprising compound disclosed in this invention usually passes through Metered dose inhaler (MDI) administers to a patient.Such device dawn known to those skilled in the art.
Aerosol may include pharmaceutically acceptable excipient that is additional, being used by MDIs, such as surface-active Agent, lubricant, cosolvent and other excipient, with improve preparation physical stability, improve valve characteristic, improve dissolubility, Or improve taste.
The pharmaceutical composition for being suitable for cutaneous penetration can be prepared into discontinuous patch agent, it is intended that keep with the epidermis of patient It is in close contact the time of an elongated segment.For example, the delivering active ingredients from patch agent can be permeated by ion, such as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for local administration pharmaceutical composition can be formulated into ointment, cream, suspension, lotion, pulvis, Solution, paste, gelling agent, spray, aerosol or finish.For example, ointment, cream and gelling agent can use water or oil Matrix, and suitable thickener and/or gelling agent and/or solvent configure.Such matrix may include water, and/or oily example Such as liquid-liquid paraffin and vegetable oil (such as peanut oil or castor oil) or solvent such as polyethylene glycol.Made according to medium property Thickener and gelling agent include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, poly- carboxylic second Alkene and cellulose derivative and/or single stearic acid glycerine lipoprotein and/or nonionic emulsifier.
Lotion can be prepared with water or oil matrix, and generally also contain one or more emulsifying agents, stabilizer, dispersion Agent, suspending agent or thickener.
Externally-applied powder can form in the presence of any suitable powder matrix such as talcum powder, lactose or starch.Drops It can be formulated with the water comprising one or more dispersing agents, solubilizer, suspending agent or preservative or non-aqueous matrix.
Topical formulations can be by being administered using one or many daily in affected part；The impermeable plastic wound dressing for covering skin is preferential It is used.Adhesiveness store system can realize continuous or extended administration.
When treating eyes or other organs such as mouth and skin, the combination as topical ointment or cream can be applied Object.When being formulated as ointment, compound disclosed in this invention can be used together with paraffin or water-soluble ointment matrix.Or Person, compound disclosed in this invention can be configured to cream together with Oil-in-water emulsifiable paste agent matrix or oil-in-water base.
The purposes of the compounds of this invention and composition
Above compound and pharmaceutical composition provided by the invention can be used for preparing dynamic for preventing, treating or mitigating lactation Object, the drug of the central nervous system dysfunction including the mankind can be used for preparation for inhibiting serotonin reuptake transporter And/or excitement 5-HT1AThe drug of receptor.
Specifically, the amount of compound effectively detectably can selectively inhibit 5- hydroxyl in composition of the invention The reuptake of tryptamines and to 5-HT1AReceptor has agonism, and the compound of the present invention can be used as treatment mankind's central nervous system The drug for (CNS) dysfunction such as depression, anxiety disorder of uniting.
The compound of the present invention can be applied to, but be not limited to, and use the effective of the compound of the present invention or composition Amount administers to a patient the central nervous system dysfunction disease to prevent, treat or mitigate mammal, including the mankind.Institute The central nervous system dysfunction disease of the mankind in response to 5-hydroxytryptamine receptor regulation stated further comprises but not It is limited to, depression, anxiety disorder, mania, schizophrenia, sleep disturbance, bipolar disorders, besetment and behavior disorder, shies Probably obstacle, posttraumatic stress disorder, dyskinesia, sex dysfunction, musculoskeletal pain obstacle, cognitive disorder, memory disorders, Parkinson's disease, Huntington's disease, phobia, substance abuse or habituation, drug addiction withdrawal symptom and premenstrual tension are comprehensive Disease etc..
The compound of the present invention and pharmaceutical composition to human treatment in addition to beneficial to other than, applying also for veterinary treatment and doting on Mammal in the animal of object, the animal of introduced variety and farm.The example of other animal includes horse, dog and cat.? This, the compound of the present invention includes its pharmaceutically acceptable derivates.
Treatment method
In one embodiment, treatment method disclosed by the invention includes giving safe and effective amount to patient in need The compounds of this invention or pharmaceutical composition comprising the compounds of this invention.Each embodiment disclosed by the invention includes by having The patient needed gives the disclosed compound of present invention of safe and effective amount or the pharmaceutical composition comprising disclosed compound of present invention, Method to treat disease mentioned above.
In one embodiment, disclosed compound of present invention or pharmaceutical composition comprising disclosed compound of present invention can be with It is administered by any suitable administration route, including Formulations for systemic administration and local administration.Formulations for systemic administration includes oral administration, stomach and intestine External administration, cutaneous penetration and rectally.Typically parenteral refers to through injection or administered by infusion, including intravenous, Intramuscular and subcutaneous injection or administered by infusion.Local administration includes being applied to skin and intraocular, ear, intravaginal, sucking and intranasally Administration.In one embodiment, disclosed compound of present invention or pharmaceutical composition comprising disclosed compound of present invention can be with It is oral administration.In another embodiment, disclosed compound of present invention or the pharmaceutical composition comprising disclosed compound of present invention Object can be inhalation.In a further embodiment, disclosed compound of present invention or it can be comprising disclosed compound of present invention Intranasal administration.
In one embodiment, disclosed compound of present invention or pharmaceutical composition comprising disclosed compound of present invention can be with Once daily, or according to dosage regimen, at the appointed time in section, doses at intervals is several times in different times.For example, every It is administered once, twice, three times or four times.In one embodiment, it is administered once a day.In yet another embodiment, daily It is administered twice.It can be administered until reaching desired therapeutic effect or indefinitely maintaining desired therapeutic effect.It is of the invention public Open medicine generation of the appropriate dosage regimen of compound or the pharmaceutical composition comprising disclosed compound of present invention depending on the compound Kinetic property, such as dilution, distribution and half-life period, these can be by determination of technical staff.In addition, disclosed compound of present invention Or the appropriate dosage regimen of the pharmaceutical composition comprising disclosed compound of present invention, it the duration including implementing the program, takes Certainly in treated disease, the severity of disease being treated, the age of patient under consideration and physical condition, patient under consideration Medical history, the simultaneously factor within the scope of technical staff's knowledge and experience such as property, desired therapeutic effect of therapy.It is such Technical staff should also be understood that the reaction for individual patient to dosage regimen, or individual patient needs to become as time goes by When change it may require that adjust the dosage regimen of matters.
Disclosed compound of present invention can be administered simultaneously, or before it or later with one or more other therapeutic agents. The compounds of this invention can be administered with other therapeutic agents by identical or different administration route respectively, or therewith with medicine group Solvate form administration.
For the individual of about 50-70kg, the present invention discloses pharmaceutical composition and combination can be containing about 1-1000mg, Or the unit dose of about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg or about 1-50mg active constituent Amount form.The therapeutically effective amount of compound, pharmaceutical composition or its combination be depending on individual species, weight, the age and Individual instances, treated disease (disorder) or disease (disease) or its severity.The doctor for having common technical ability Teacher, clinician or animal doctor can be easy to determine to prevent, treat or inhibit disease (disorder) or disease (disease) development The effective quantity of each active constituent needed in the process.
Dose Characteristics cited above using advantageous mammal (such as mouse, rat, dog, monkey) or its from It is confirmed in the external and in vivo studies of body organ, tissue and sample.Disclosed compound of present invention is with solution, such as aqueous solution form Use in vitro, can also such as enteral of suspension or aqueous solution form in vivo, it is parenterally, especially intravenous to use.
In one embodiment, the treatment effective dose of disclosed compound of present invention is daily about 0.1mg to about 2, 000mg.Its pharmaceutical composition should provide the compound of about 0.1mg to about 2,000mg dosage.In a specific embodiment In, the pharmaceutical dosage unit forms of preparation can provide about 1mg to about 2,000mg, and about 10mg to about 1,000mg, about 20mg is to about 500mg, or about 25mg to about 250mg main active or each main component in every dosage unit form combination.One In specific embodiment, the pharmaceutical dosage unit forms of preparation can provide about 10mg, 20mg, 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg or 2000mg main active.
In addition, compound disclosed by the invention can be administered with prodrug forms.In the present invention, disclosed compound of present invention " prodrug " be that can finally release the functional derivatives of disclosed compound of present invention in vivo when administering to a patient.In the past When medicine form gives compound disclosed by the invention, one of implementable following manner of those skilled in the art or more: (a) Change the internal onset time of compound；(b) the internal acting duration of compound is changed；(c) the internal of compound is changed Conveying or distribution；(d) the internal solubility of compound is changed；And the side effect or other difficult points for (e) overcoming compound to be faced. The typical functional derivatives of prodrug are used to prepare, comprising in vivo chemically or the mode of the enzyme compound that cracks Variant.Comprising preparing these variants of phosphate, amide, ester, monothioester, carbonate and carbaminate to those skilled in the art It is well-known for member.
General synthesis step
For the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only Method of the invention is practiced in offer.
Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I) or (III).Following reaction scheme and embodiment is for further lifting Example illustrates the contents of the present invention.
The professional of fields will be appreciated that chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan development in science and technology Co., Ltd, Qingdao Tenglong Chemical Reagent Co., Ltd. and Haiyang Chemical Plant, Qingdao's purchase It can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride It with chloroform is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
1H H NMR spectroscopy is recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.1H H NMR spectroscopy is with CDC13、 DMSO-d6、CD3OD or acetone-d6For solvent (as unit of ppm), use TMS (0ppm) or chloroform (7.26ppm) as referring to mark It is quasi-.When there is multiplet, following abbreviation: s (singlet, unimodal), d (doublet, bimodal), t will be used (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, double doublet), dt (doublet of triplets, double triplets).Coupling constant is indicated with hertz (Hz).
The determination condition of low resolution mass spectrometry (MS) data is: 6120 level four bars HPLC-MS of Agilent (column model: Zorbax SB-C18,2.1x30mm, 3.5 microns, 6min, flow velocity 0.6mL/min).Mobile phase: 5%-95% (contains 0.1% The CH of formic acid3CN) in (H containing 0.1% formic acid2O the ratio in), using electrospray ionisation (ESI), at 210nm/254nm, It is detected with UV.
Pure compound uses 1260 pre-HPLC or Calesep pump250pre-HPLC (pillar type of Agilent Number: NOVASEP50/80mm DAC), at 210nm/254nm, detected with UV.
The use of logogram word below is through the present invention:
AcOH、HOAc、CH3COOH acetic acid
BOC, Boc tert-butoxycarbonyl
N-BuOH n-butanol
Cbz-Cl benzyl chloroformate
CH2Cl2, DCM methylene chloride
CDC13Deuterated chloroform
DIEA、DIPEA、i-Pr2NEt diisopropyl ethyl amine
DMF dimethylformamide
DMAP 4-dimethylaminopyridine
DMSO dimethyl sulfoxide
EDC, EDCI 1- (3- dimethylamino-propyl) -3- ethyl-carboddiimide hydrochloride
EDTA ethylenediamine tetra-acetic acid
Et3N, TEA triethylamine
EtOAc, EA ethyl acetate
G grams
H hours
HCl hydrochloric acid
MeCN、CH3CN acetonitrile
ML, ml milliliters
Pd/C palladium/carbon
Pd(OH)2Palladium dydroxide
PE petroleum ether (60-90 DEG C)
RT, rt, r.t. room temperature
Rt retention time
TFA trifluoroacetic acid
(Boc)2O di-tert-butyl dicarbonate
Pd(dppf)Cl2[1,1 '-bis- (diphenylphosphino) ferrocene] palladium chloride
Following synthetic schemes describes the step of preparation disclosed compound of present invention.Unless otherwise stated, each R2、R5、p、n There is definition as described in the present invention with r.
Synthetic schemes 1
The general synthetic method that disclosed compound of present invention can be described by synthetic schemes 1 is prepared, specific steps It can refer to embodiment.In synthetic schemes 1, formula (8) compound represented can be prepared by following process: firstly, 1- (4- Bromophenyl) piperazine (1) in alkali, under triethylamine effect, with Boc2O reaction, obtain compound (2).Compound (2) and connection boric acid Pinacol ester (3) in Pd catalyst and alkali appropriate, under the action of sodium tert-butoxide or potassium tert-butoxide, in suitable solvent, such as In DMF or DMSO, reaction generation compound (4).Later, compound (4) under Pd catalyst action, with compound (5) occur Suzuki coupling reaction, obtain compound (6).Finally, compound (6) in Hydrochloride/ethyl acetate processing, slough Boc Protecting group, gained intermediate and compound (7) in alkali appropriate, under the effect of potassium carbonate, sodium carbonate or triethylamine, in suitable Solvent, in acetonitrile, tetrahydrofuran, ethyl alcohol, DMF or DMSO, occur nucleophilic substitution, obtain target compound (8)。
Synthetic schemes 2
The general synthetic method that disclosed compound of present invention can be described by synthetic schemes 2 is prepared, and wherein X is O Or S, specific steps can refer to embodiment.In synthetic schemes 2, formula (11) compound represented can be prepared by following process It arrives: firstly, compound (4) in Pd catalyst and alkali appropriate, under the action of sodium carbonate or potassium carbonate, in suitable solvent, In DMF or DMSO, with compound (9) occur Suzuki coupling reaction, obtain compound (10).Later, compound (10) In the ethyl acetate solution of hydrogen chloride, Boc protecting group is sloughed, gained intermediate and compound (7) in alkali appropriate, such as carbonic acid Under potassium, sodium carbonate or triethylamine effect, in suitable solvent, in acetonitrile, tetrahydrofuran, ethyl alcohol, DMF or DMSO, parent occurs Core substitution reaction, obtain target compound (11)。
Synthetic schemes 3
The general synthetic method that disclosed compound of present invention can be described by synthetic schemes 3 is prepared, specific steps It can refer to embodiment.In synthetic schemes 3, compound (14) can be prepared by following process: firstly, compound (4) Pd catalyst and alkali appropriate, under the action of sodium carbonate or potassium carbonate, in suitable solvent, in DMF or DMSO, with chemical combination Object (12) occur Suzuki coupling reaction, obtain compound (13).Later, compound (13) in the ethyl acetate solution of hydrogen chloride In, slough Boc protecting group, then with compound (7) in alkali appropriate, under the effect of potassium carbonate, sodium carbonate or triethylamine, Yu Heshi Solvent, in acetonitrile, tetrahydrofuran, ethyl alcohol, DMF or DMSO, occur nucleophilic substitution, obtain target compound (14)。
Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.
Embodiment
1 3- of embodiment (3- (4- (4- (4,6- dimethoxypyridin -2- base) phenyl) piperazine -1- base) propyl) -5- is fluoro- 1H- indoles
Step 1) 4- (4- bromophenyl) piperazine -1- t-butyl formate
Under nitrogen protection, 1- (4- bromophenyl) piperazine (2.41g, 10.0mmol) is dissolved in methylene chloride (25mL), 0 DEG C Under, sequentially add triethylamine (2.1mL, 15.0mmol) and (Boc)2O (2.40g, 11.0mmol), finishes, and moves to room temperature reaction Solvent is evaporated off in 3h, end of reaction, and residue is concentrated through silica gel column purification (petrol ether/ethyl acetate (v/v)=2/1), dry Obtaining title compound is white solid (3.07g, 90.0%).
MS(ESI,pos.ion)m/z:341.2[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 7.34 (d, J=7.8Hz, 2H), 6.82 (d, J=7.8Hz, 2H), 3.62-3.53(m,4H),3.16-3.05(m,4H),1.48(s,9H)。
Step 2) 4- (4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) piperazine -1- formic acid The tert-butyl ester
Under nitrogen protection, by 4- (4- bromophenyl) piperazine -1- t-butyl formate (2.50g, 7.3mmol), connection boric acid frequency that Alcohol ester (2.04g, 8.0mmol), potassium tert-butoxide (1.23g, 11.0mmol) and Pd (dppf) Cl2(0.27g, 0.37mmol) is added To in anhydrous DMF (25mL), after replacing nitrogen three times, 90 DEG C of reaction 20h are warming up to, end of reaction is cooled to room temperature, will mix Object is washed with water (30mL), and methylene chloride (20mL x 3) extraction, combined organic phase is dried, filtered with anhydrous sodium sulfate, is depressurized Filtrate is concentrated.Residue is dried to obtain title compound through silica gel column purification (petrol ether/ethyl acetate (v/v)=10/1), concentration Object is white solid (1.98g, 69.7%).
MS(ESI,pos.ion)m/z:389.2[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):7.76(s,1H),7.74(s,1H),7.08-6.95(m,2H),3.65 (t, J=4.8Hz, 4H), 3.25 (t, J=4.8Hz, 4H), 1.48 (s, 9H), 1.33 (s, 12H).
Step 3) 4- (4- (4,6- dimethoxypyridin -2- base) phenyl) piperazine -1- t-butyl formate
Under nitrogen protection, by 4- (4- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) phenyl) piperazine The chloro- 4,6- dimethoxypyridin (0.23g, 1.3mmol) of piperazine -1- t-butyl formate (0.50g, 1.3mmol), 2-, sodium carbonate (0.41g, 3.9mmol) and Pd (dppf) Cl2(0.51g, 0.07mmol) is added in DMF (10mL) and water (5mL), replaces nitrogen Gas three times after, be warming up to 90 DEG C reaction for 24 hours, end of reaction is cooled to room temperature, and mixture is washed with water (30mL), methylene chloride (20mL × 3) extraction, combined organic phase are dried, filtered with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure.Residue is pure through silicagel column Change (petrol ether/ethyl acetate (v/v)=8/1), concentration, be dried to obtain title compound be white solid (0.32g, 62.1%).
MS(ESI,pos.ion)m/z:401.3[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.38 (d, J=8.8Hz, 2H), 6.97 (d, J=8.8Hz, 2H), 5.91(s,1H),4.04(s,6H),3.63-3.61(m,4H),3.30-3.27(m,4H),1.51(s,9H)。
Step 4) 3- (3- (4- (4- (4,6- dimethoxypyridin -2- base) phenyl) piperazine -1- base) propyl) fluoro- 1H- of -5- Indoles
By 4- (4- (4,6- dimethoxypyridin -2- base) phenyl) piperazine -1- t-butyl formate (0.23g, 0.57mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (120mg, 0.87mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 3- (the fluoro- 1H- indol-3-yl of 5-) propyl 4- oluene sulfonic acides ester (200mg, 0.57mmol).Reaction solution heating To 80 DEG C, after stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petroleum ether/second Acetoacetic ester (v/v)=1/1), obtaining title compound is white solid (0.22g, 80.6%).MS(ESI,pos.ion)m/z: 476.2[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.46 (brs, 1H), 8.43 (d, J=8.8Hz, 2H), 7.31 (dd, J =9.6,2.4Hz, 1H), 7.22 (dd, J=8.8,4.4Hz, 1H), 7.00-6.94 (m, 4H), 5.94 (s, 1H), 4.06 (s, 6H), 3.36-3.34 (m, 4H), 2.79 (t, J=7.2Hz, 2H), 2.65-2.63 (m, 4H), 2.52-2.49 (m, 2H), 2.00- 1.92(m,2H)。
2 3- of embodiment (4- (4- (4- (4,6- dimethoxypyridin -2- base) phenyl) piperazine -1- base) butyl) -5- is fluoro- 1H- indoles
By 4- (4- (4,6- dimethoxypyridin -2- base) phenyl) piperazine -1- t-butyl formate (0.23g, 0.57mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (120mg, 0.87mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 4- (the fluoro- 1H- indol-3-yl of 5-) butyl 4- oluene sulfonic acides ester (207mg, 0.57mmol).Reaction solution heating To 80 DEG C, after stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petroleum ether/second Acetoacetic ester (v/v)=1/1), obtaining title compound is white solid (0.21g, 74.7%).MS(ESI,pos.ion)m/z: 490.2[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.40 (d, J=8.8Hz, 2H), 8.24 (brs, 1H), 7.31 (dd, J =9.6,2.4Hz, 1H), 7.22 (dd, J=8.8,4.4Hz, 1H), 7.01-6.93 (m, 4H), 5.92 (s, 1H), 4.05 (s, 6H), 3.36-3.33 (m, 4H), 2.77 (t, J=7.2Hz, 2H), 2.64-2.61 (m, 4H), 2.49-2.45 (m, 2H), 1.77- 1.75(m,2H),1.67-1.65(m,2H)。
3 3- of embodiment (3- (4- (4- (4,6- dimethoxypyridin -2- base) phenyl) piperazine -1- base) propyl) -5- methoxy Base -1H- indoles
By 4- (4- (4,6- dimethoxypyridin -2- base) phenyl) piperazine -1- t-butyl formate (0.23g, 0.57mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (120mg, 0.87mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 3- (5- methoxyl group -1H- indol-3-yl) propyl 4- oluene sulfonic acides ester (206mg, 0.58mmol).Reaction solution After being heated to 80 DEG C, stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petroleum Ether/ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.18g, 64.3%).
MS(ESI,pos.ion)m/z:488.2[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.40 (d, J=9.2Hz, 2H), 8.16 (brs, 1H), 7.24 (d, J= 8.8Hz, 1H), 7.09 (d, J=2.4Hz, 1H), 6.99-6.97 (m, 3H), 6.88 (dd, J=8.8,2.4Hz, 1H), 5.92 (s, 1H), 4.05 (s, 6H), 3.90 (s, 3H), 3.38-3.35 (m, 4H), 2.81 (t, J=7.2Hz, 2H), 2.67-2.65 (m, 4H),2.57-2.53(m,2H),2.01-1.98(m,2H)。
4 3- of embodiment (4- (4- (4- (4,6- dimethoxypyridin -2- base) phenyl) piperazine -1- base) butyl) -5- methoxy Base -1H- indoles
By 4- (4- (4,6- dimethoxypyridin -2- base) phenyl) piperazine -1- t-butyl formate (0.23g, 0.57mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (120mg, 0.87mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 4- (5- methoxyl group -1H- indol-3-yl) butyl 4- oluene sulfonic acides ester (214mg, 0.57mmol).Reaction solution After being heated to 80 DEG C, stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petroleum Ether/ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.16g, 55.5%).
MS(ESI,pos.ion)m/z:502.0[M+H]+；
1H NMR(CDCl3, 400MHz) δ (ppm): 9.07 (brs, 1H), 8.36 (d, J=8.8Hz, 2H), 7.95 (s, 1H), 7.37-7.34 (m, 2H), 7.07 (d, J=2.0Hz, 1H), 6.95 (d, J=8.8Hz, 2H), 5.89 (s, 1H), 4.02 (s, 6H), 3.85 (s, 3H), 3.34-3.31 (m, 4H), 2.77 (t, J=7.2Hz, 2H), 2.62-2.60 (m, 4H), 2.49- 2.43(m,2H),1.75-1.73(m,2H),1.65-1.63(m,2H)。
5 3- of embodiment (3- (4- (4- (4,6- dimethoxypyridin -2- base) phenyl) piperazine -1- base) propyl) -1H- Yin Diindyl -5- formonitrile HCN
By 4- (4- (4,6- dimethoxypyridin -2- base) phenyl) piperazine -1- t-butyl formate (0.23g, 0.57mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (120mg, 0.87mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 3- (5- cyano-1 H-indol -3- base) propyl 4- oluene sulfonic acides ester (204mg, 0.57mmol).Reaction solution adds Heat after stirring 20 hours, is cooled to room temperature, filters, filtrate is concentrated under reduced pressure to 80 DEG C.Residue through silica gel column purification (petroleum ether/ Ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.17g, 63.9%).
MS(ESI,pos.ion)m/z:483.2[M+H]+；
1H NMR(MeOD/CDCl3, 400MHz) and δ (ppm): 8.31 (d, J=8.8Hz, 2H), 7.92 (s, 1H), 7.33- 7.32 (m, 2H), 7.07 (s, 1H), 6.90 (d, J=8.8Hz, 2H), 5.85 (s, 1H), 3.97 (s, 6H), 3.29-3.27 (m, 4H), 2.74 (t, J=7.2Hz, 2H), 2.58-2.56 (m, 4H), 2.45-2.41 (m, 2H), 1.91-1.87 (m, 2H).
6 3- of embodiment (4- (4- (4- (4,6- dimethoxypyridin -2- base) phenyl) piperazine -1- base) butyl) -1H- Yin Diindyl -5- formonitrile HCN
By 4- (4- (4,6- dimethoxypyridin -2- base) phenyl) piperazine -1- t-butyl formate (0.23g, 0.57mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (120mg, 0.87mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 4- (5- cyano-1 H-indol -3- base) butyl 4- oluene sulfonic acides ester (211mg, 0.57mmol).Reaction solution adds Heat after stirring 20 hours, is cooled to room temperature, filters, filtrate is concentrated under reduced pressure to 80 DEG C.Residue through silica gel column purification (petroleum ether/ Ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.16g, 56.1%).
MS(ESI,pos.ion)m/z:497.0[M+H]+；
1H NMR(CDCl3, 400MHz) δ (ppm): 9.07 (brs, 1H), 8.36 (d, J=8.8Hz, 2H), 7.95 (s, 1H), 7.37-7.34 (m, 2H), 7.07 (d, J=2.0Hz, 1H), 6.95 (d, J=8.8Hz, 2H), 5.89 (s, 1H), 4.02 (s, 6H), 3.34-3.31 (m, 4H), 2.77 (t, J=7.2Hz, 2H), 2.62-2.60 (m, 4H), 2.49-2.43 (m, 2H), 1.75-1.73(m,2H),1.65-1.63(m,2H)。
7 3- of embodiment (3- (4- (4- (4,6- dimethyl pyrimidine -2- base) phenyl) piperazine -1- base) propyl) fluoro- 1H- of -5- Indoles
Step 1) 4- (4- (4,6- dimethyl pyrimidine -2- base) phenyl) piperazine -1- t-butyl formate
This step title compound is referred to method described in 1 step 3 of embodiment and is prepared, i.e., by 4- (4- (4, 4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) piperazine -1- t-butyl formate (0.50g, 1.3mmol), The chloro- 4,6- dimethyl pyrimidine (0.18g, 1.3mmol) of 2-, sodium carbonate (0.41g, 3.9mmol) and Pd (dppf) Cl2(0.51g, It 0.07mmol) is suspended in reaction preparation in DMF (10mL) and water (5mL), crude product is through silica gel column purification (petroleum ether/acetic acid second Ester (v/v)=5/1), obtaining title compound is white solid (0.31g, 65.3%).
MS(ESI,pos.ion)m/z:369.4[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.37 (d, J=8.8Hz, 2H), 6.97 (d, J=8.8Hz, 2H), 6.84(s,1H),3.62-3.60(m,4H),3.28-3.26(m,4H),2.51(s,6H),1.50(s,9H)。
Step 2) 3- (3- (4- (4- (4,6- dimethyl pyrimidine -2- base) phenyl) piperazine -1- base) propyl) fluoro- 1H- Yin of -5- Diindyl
4- (4- (4,6- dimethyl pyrimidine -2- base) phenyl) piperazine -1- t-butyl formate (0.21g, 0.57mmol) is added Enter in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved In acetonitrile (15mL), and sequentially add thereto potassium carbonate (118mg, 0.85mmol), catalytic amount potassium iodide (19mg, 0.11mmol) and 3- (the fluoro- 1H- indol-3-yl of 5-) propyl 4- oluene sulfonic acides ester (198mg, 0.57mmol).Reaction solution heating To 80 DEG C, after stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petroleum ether/second Acetoacetic ester (v/v)=1/1), obtaining title compound is white solid (0.21g, 83.0%).MS(ESI,pos.ion)m/z: 444.2[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.39-8.37 (m, 3H), 7.27 (d, J=7.6Hz, 1H), 7.21 (dd, J=8.8,4.4Hz, 1H), 7.00-6.94 (m, 4H), 6.83 (s, 1H), 3.34-3.32 (m, 4H), 2.77 (t, J= 7.2Hz,2H),2.64-2.62(m,4H),2.52-2.28(m,8H),1.97-1.93(m,2H)。
8 3- of embodiment (4- (4- (4- (4,6- dimethyl pyrimidine -2- base) phenyl) piperazine -1- base) butyl) fluoro- 1H- of -5- Indoles
4- (4- (4,6- dimethyl pyrimidine -2- base) phenyl) piperazine -1- t-butyl formate (0.21g, 0.57mmol) is added Enter in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved In acetonitrile (15mL), and sequentially add thereto potassium carbonate (118mg, 0.85mmol), catalytic amount potassium iodide (19mg, 0.11mmol) and 4- (the fluoro- 1H- indol-3-yl of 5-) butyl 4- oluene sulfonic acides ester (206mg, 0.57mmol).Reaction solution heating To 80 DEG C, after stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petroleum ether/second Acetoacetic ester (v/v)=1/1), obtaining title compound is white solid (0.20g, 76.6%).MS(ESI,pos.ion)m/z: 458.2[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.38-8.33(m,3H),7.25-7.21(m,2H),6.99-6.93 (m, 4H), 6.83 (s, 1H), 3.33-3.31 (m, 4H), 2.76 (t, J=7.2Hz, 2H), 2.62-2.60 (m, 4H), 2.52 (s, 6H),2.48-2.46(m,2H),1.75-1.73(m,2H),1.66-1.65(m,2H)。
9 3- of embodiment (3- (4- (4- (4,6- dimethyl pyrimidine -2- base) phenyl) piperazine -1- base) propyl) -5- methoxy Base -1H- indoles
4- (4- (4,6- dimethyl pyrimidine -2- base) phenyl) piperazine -1- t-butyl formate (0.21g, 0.57mmol) is added Enter in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved In acetonitrile (15mL), and sequentially add thereto potassium carbonate (118mg, 0.85mmol), catalytic amount potassium iodide (19mg, 0.11mmol) and 3- (5- methoxyl group -1H- indol-3-yl) propyl 4- oluene sulfonic acides ester (205mg, 0.57mmol).Reaction solution After being heated to 80 DEG C, stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petroleum Ether/ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.13g, 43.4%).
MS(ESI,pos.ion)m/z:456.3[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.37 (d, J=8.8Hz, 2H), 8.20 (brs, 1H), 7.23 (d, J= 8.8Hz, 1H), 7.07 (d, J=2.0Hz, 1H), 6.99-6.97 (m, 3H), 6.87 (dd, J=8.8,2.4Hz, 1H), 6.84 (s, 1H), 3.89 (s, 3H), 3.36-3.34 (m, 4H), 2.80 (t, J=7.2Hz, 2H), 2.67-2.64 (m, 4H), 2.56- 2.52(m,8H),2.01-1.97(m,2H)。
10 3- of embodiment (4- (4- (4- (4,6- dimethyl pyrimidine -2- base) phenyl) piperazine -1- base) butyl) -5- methoxy Base -1H- indoles
4- (4- (4,6- dimethyl pyrimidine -2- base) phenyl) piperazine -1- t-butyl formate (0.21g, 0.57mmol) is added Enter in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved In acetonitrile (15mL), and sequentially add thereto potassium carbonate (118mg, 0.85mmol), catalytic amount potassium iodide (19mg, 0.11mmol) and 4- (5- methoxyl group -1H- indol-3-yl) butyl 4- oluene sulfonic acides ester (213mg, 0.57mmol).Reaction solution After being heated to 80 DEG C, stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petroleum Ether/ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.11g, 41.2%).
MS(ESI,pos.ion)m/z:470.3[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.38 (d, J=8.8Hz, 2H), 8.30 (brs, 1H), 7.20 (d, J= 8.8Hz, 1H), 7.08 (d, J=2.4Hz, 1H), 6.98 (d, J=8.8Hz, 2H), 6.94-6.93 (m, 1H), 6.87 (dd, J= 8.8,2.4Hz, 1H), 6.83 (s, 1H), 3.89 (s, 3H), 3.36-3.34 (m, 4H), 2.80 (t, J=7.2Hz, 2H), 2.67- 2.64(m,4H),2.56-2.52(m,8H),2.01-1.97(m,2H),1.64-1.61(m,2H)。
11 3- of embodiment (3- (4- (4- (4,6- dimethyl pyrimidine -2- base) phenyl) piperazine -1- base) propyl) -1H- Yin Diindyl -5- formonitrile HCN
4- (4- (4,6- dimethyl pyrimidine -2- base) phenyl) piperazine -1- t-butyl formate (0.21g, 0.57mmol) is added Enter in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved In acetonitrile (15mL), and sequentially add thereto potassium carbonate (118mg, 0.85mmol), catalytic amount potassium iodide (19mg, 0.11mmol) and 3- (5- cyano-1 H-indol -3- base) propyl 4- oluene sulfonic acides ester (202mg, 0.57mmol).Reaction solution adds Heat after stirring 20 hours, is cooled to room temperature, filters, filtrate is concentrated under reduced pressure to 80 DEG C.Residue through silica gel column purification (petroleum ether/ Ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.16g, 62.3%).MS(ESI,pos.ion)m/ z:451.0[M+H]+；
1H NMR(MeOD/CDCl3, 400MHz) δ (ppm): 8.21 (d, J=8.8Hz, 2H), 7.89 (s, 1H), 7.31 (d, J=8.4Hz, 1H), 7.30 (d, J=8.4Hz, 1H), 7.06 (s, 1H), 6.90 (d, J=8.8Hz, 2H), 6.79 (s, 1H), 3.27-3.26 (m, 4H), 2.73 (t, J=7.2Hz, 2H), 2.58-2.55 (m, 4H), 2.43-2.41 (m, 8H), 1.91-1.87 (m,2H)。
12 3- of embodiment (4- (4- (4- (4,6- dimethyl pyrimidine -2- base) phenyl) piperazine -1- base) butyl) -1H- Yin Diindyl -5- formonitrile HCN
4- (4- (4,6- dimethyl pyrimidine -2- base) phenyl) piperazine -1- t-butyl formate (0.21g, 0.57mmol) is added Enter in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved In acetonitrile (15mL), and sequentially add thereto potassium carbonate (118mg, 0.85mmol), catalytic amount potassium iodide (19mg, 0.11mmol) and 4- (5- cyano-1 H-indol -3- base) butyl 4- oluene sulfonic acides ester (210mg, 0.57mmol).Reaction solution adds Heat after stirring 20 hours, is cooled to room temperature, filters, filtrate is concentrated under reduced pressure to 80 DEG C.Residue through silica gel column purification (petroleum ether/ Ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.17g, 64.1%).MS(ESI,pos.ion)m/ z:465.0[M+H]+；
1H NMR(MeOD/CDCl3, 400MHz) δ (ppm): 8.14 (d, J=8.8Hz, 2H), 7.83 (s, 1H), 7.31 (d, J=8.4Hz, 1H), 7.25 (d, J=8.4Hz, 1H), 7.02 (s, 1H), 6.87 (d, J=8.8Hz, 2H), 6.77 (s, 1H), 3.23-3.21 (m, 4H), 2.69 (t, J=7.2Hz, 2H), 2.56-2.54 (m, 4H), 2.40-2.37 (m, 8H), 1.64-1.62 (m,2H),1.56-1.53(m,2H)。
The fluoro- 3- of 13 5- of embodiment (3- (4- (4- (4- (trifluoromethyl) pyrimidine -2-base) phenyl) piperazine -1- base) propyl) - 1H- indoles
Step 1) 4- (4- (4- (trifluoromethyl) pyrimidine -2-base) phenyl) piperazine -1- t-butyl formate
This step title compound is referred to method described in 1 step 3 of embodiment and is prepared, i.e., by 4- (4- (4, 4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) piperazine -1- t-butyl formate (0.50g, 1.3mmol), 2- chloro- 4- (trifluoromethyl) pyrimidine (0.24g, 1.3mmol), sodium carbonate (0.41g, 3.9mmol) and Pd (dppf) Cl2 (0.51g, 0.07mmol) is suspended in reaction preparation in DMF (10mL) and water (5mL), crude product through silica gel column purification (petroleum ether/ Ethyl acetate (v/v)=5/1), obtaining title compound is yellow oily liquid (0.27g, 51.3%).
MS(ESI,pos.ion)m/z:409.3[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.95 (d, J=4.8Hz, 1H), 8.43 (d, J=8.8Hz, 2H), 7.38 (d, J=4.8Hz, 1H), 6.99 (d, J=8.8Hz, 2H), 3.64-3.62 (m, 4H), 3.35-3.33 (m, 4H), 1.52 (s,9H)。
The fluoro- 3- of step 2) 5- (3- (4- (4- (4- (trifluoromethyl) pyrimidine -2-base) phenyl) piperazine -1- base) propyl) -1H- Indoles
By 4- (4- (4- (trifluoromethyl) pyrimidine -2-base) phenyl) piperazine -1- t-butyl formate (0.24g, 0.59mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (122mg, 0.88mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 3- (the fluoro- 1H- indol-3-yl of 5-) propyl 4- oluene sulfonic acides ester (203mg, 0.59mmol).Reaction solution heating To 80 DEG C, after stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petroleum ether/second Acetoacetic ester (v/v)=1/1), obtaining title compound is white solid (0.22g, 77.5%).MS(ESI,pos.ion)m/z: 484.3[M+H]+；
1H NMR(MeOD/CDCl3, 400MHz) and δ (ppm): 8.88 (d, J=4.8Hz, 1H), 8.85 (brs, 1H), 8.37 (d, J=8.8Hz, 2H), 7.32 (d, J=4.8Hz, 1H), 7.25-7.21 (m, 2H), 7.01 (s, 1H), 6.95 (d, J= 8.8Hz, 2H), 6.92-6.89 (m, 1H), 3.36-3.35 (m, 4H), 2.75 (t, J=7.2Hz, 2H), 2.61-2.59 (m, 4H),2.50-2.46(m,2H),1.97-1.94(m,2H)。
The fluoro- 3- of 14 5- of embodiment (4- (4- (4- (4- (trifluoromethyl) pyrimidine -2-base) phenyl) piperazine -1- base) butyl) - 1H- indoles
By 4- (4- (4- (trifluoromethyl) pyrimidine -2-base) phenyl) piperazine -1- t-butyl formate (0.24g, 0.59mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (122mg, 0.88mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 4- (the fluoro- 1H- indol-3-yl of 5-) butyl 4- oluene sulfonic acides ester (212mg, 0.59mmol).Reaction solution heating To 80 DEG C, after stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petroleum ether/second Acetoacetic ester (v/v)=1/1), obtaining title compound is white solid (0.23g, 78.8%).MS(ESI,pos.ion)m/z: 498.3[M+H]+；
1H NMR(MeOD/CDCl3, 400MHz) δ (ppm): 8.90 (d, J=4.8Hz, 1H), 8.40 (d, J=8.8Hz, 2H), 7.34 (d, J=4.8Hz, 1H), 7.22-7.26 (m, 2H), 7.01 (s, 1H), 6.96 (d, J=9.2Hz, 2H), 6.92 (td, J=8.8,2.4Hz, 1H), 3.36-3.34 (m, 4H), 2.75 (t, J=7.2Hz, 2H), 2.62-2.59 (m, 4H), 2.47-2.43(m,2H),1.74-1.72(m,2H),1.66-1.64(m,2H)。
15 5- methoxyl group -3- of embodiment (3- (4- (4- (4- (trifluoromethyl) pyrimidine -2-base) phenyl) piperazine -1- base) third Base) -1H- indoles
By 4- (4- (4- (trifluoromethyl) pyrimidine -2-base) phenyl) piperazine -1- t-butyl formate (0.24g, 0.59mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (122mg, 0.88mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 3- (5- methoxyl group -1H- indol-3-yl) propyl 4- oluene sulfonic acides ester (211mg, 0.59mmol).Reaction solution After being heated to 80 DEG C, stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petroleum Ether/ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.14g, 48.1%).
MS(ESI,pos.ion)m/z:496.1[M+H]+；
1H NMR(CDCl3, 600MHz) and δ (ppm): 8.94 (d, J=4.8Hz, 1H), 8.41 (d, J=9.0Hz, 2H), 8.00 (brs, 1H), 7.37 (d, J=4.8Hz, 1H), 7.27 (d, J=9.0Hz, 1H), 7.07 (d, J=2.4Hz, 1H), 7.01 (d, J=1.2Hz, 1H), 6.99 (d, J=8.4Hz, 2H), 6.88 (dd, J=8.4,2.4Hz, 1H), 3.89 (s, 3H), 3.43- 3.41 (m, 4H), 2.81 (t, J=7.2Hz, 2H), 2.69-2.67 (m, 4H), 2.58-2.56 (m, 2H), 2.04-1.99 (m, 2H)。
16 5- methoxyl group -3- of embodiment (4- (4- (4- (4- (trifluoromethyl) pyrimidine -2-base) phenyl) piperazine -1- base) fourth Base) -1H- indoles
By 4- (4- (4- (trifluoromethyl) pyrimidine -2-base) phenyl) piperazine -1- t-butyl formate (0.24g, 0.59mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (122mg, 0.88mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 4- (5- methoxyl group -1H- indol-3-yl) butyl 4- oluene sulfonic acides ester (219mg, 0.59mmol).Reaction solution After being heated to 80 DEG C, stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petroleum Ether/ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.12g, 40.1%).
MS(ESI,pos.ion)m/z:510.3[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.90 (d, J=5.2Hz, 1H), 8.44 (d, J=9.2Hz, 2H), 8.24 (brs, 1H), 7.33 (d, J=4.8Hz, 1H), 7.23 (d, J=8.8Hz, 1H), 7.10 (d, J=2.4Hz, 1H), 6.99-6.96 (m, 3H), 6.90 (dd, J=8.8,2.4Hz, 1H), 3.92 (s, 3H), 3.38-3.35 (m, 4H), 2.80 (t, J =7.2Hz, 2H), 2.63-2.60 (m, 4H), 2.50-2.46 (m, 2H), 1.80-1.78 (m, 2H), 1.70-1.68 (m, 2H).
17 3- of embodiment (3- (4- (4- (4- (trifluoromethyl) pyrimidine -2-base) phenyl) piperazine -1- base) propyl) -1H- Yin Diindyl -5- formonitrile HCN
By 4- (4- (4- (trifluoromethyl) pyrimidine -2-base) phenyl) piperazine -1- t-butyl formate (0.24g, 0.59mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (122mg, 0.88mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 3- (5- cyano-1 H-indol -3- base) propyl 4- oluene sulfonic acides ester (208mg, 0.59mmol).Reaction solution adds Heat after stirring 20 hours, is cooled to room temperature, filters, filtrate is concentrated under reduced pressure to 80 DEG C.Residue through silica gel column purification (petroleum ether/ Ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.11g, 38.2%).
MS(ESI,pos.ion)m/z:491.3[M+H]+；
1H NMR(MeOD/CDCl3, 400MHz) δ (ppm): 8.93 (d, J=4.8Hz, 1H), 8.39 (d, J=9.2Hz, 2H), 7.97 (s, 1H), 7.40 (s, 2H), 7.36 (d, J=4.8Hz, 1H), 7.14 (s, 1H), 6.97 (d, J=8.8Hz, 2H), 3.42-3.40 (m, 4H), 2.82 (t, J=7.2Hz, 2H), 2.69-2.66 (m, 4H), 2.55-2.51 (m, 2H), 2.00-1.96 (m,2H)。
18 3- of embodiment (4- (4- (4- (4- (trifluoromethyl) pyrimidine -2-base) phenyl) piperazine -1- base) butyl) -1H- Yin Diindyl -5- formonitrile HCN
By 4- (4- (4- (trifluoromethyl) pyrimidine -2-base) phenyl) piperazine -1- t-butyl formate (0.24g, 0.59mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (122mg, 0.88mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 4- (5- cyano-1 H-indol -3- base) butyl 4- oluene sulfonic acides ester (217mg, 0.59mmol).Reaction solution adds Heat after stirring 20 hours, is cooled to room temperature, filters, filtrate is concentrated under reduced pressure to 80 DEG C.Residue through silica gel column purification (petroleum ether/ Ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.13g, 43.8%).
MS(ESI,pos.ion)m/z:505.3[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.94 (d, J=4.8Hz, 1H), 8.83 (brs, 1H), 8.40 (d, J= 9.2Hz, 2H), 7.95 (s, 1H), 7.40 (s, 2H), 7.37 (d, J=4.8Hz, 1H), 7.11 (s, 1H), 6.96 (d, J= 8.8Hz, 2H), 3.42-3.40 (m, 4H), 2.79 (t, J=7.2Hz, 2H), 2.74-2.71 (m, 4H), 2.57-2.53 (m, 2H),1.76-1.72(m,2H),1.70-1.68(m,2H)。
19 2- of embodiment (4- (4- (3- (5- cyano-1 H-indol -3- base) propyl) piperazine -1- base) phenyl) pyrimidine -4- Formamide
Step 1) 4- (4- (4- carbamyl pyrimidine -2-base) phenyl) piperazine -1- t-butyl formate
This step title compound is referred to method described in 1 step 3 of embodiment and is prepared, i.e. 4- (4- (4,4, 5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) piperazine -1- t-butyl formate (0.50g, 1.3mmol), 2- Chlorine pyrimidine -4- formamide (0.21g, 1.3mmol), sodium carbonate (0.41g, 3.9mmol) and Pd (dppf) Cl2(0.51g, It 0.07mmol) is suspended in reaction preparation in DMF (10mL) and water (5mL), crude product is through silica gel column purification (petroleum ether/acetic acid second Ester (v/v)=5/1), obtaining title compound is yellow oily liquid (0.20g, 40.5%).MS(ESI,pos.ion)m/z: 384.3[M+H]+；
Step 2) 2- (4- (4- (3- (5- cyano-1 H-indol -3- base) propyl) piperazine -1- base) phenyl) pyrimidine -4- formyl Amine
4- (4- (4- carbamyl pyrimidine -2-base) phenyl) piperazine -1- t-butyl formate (0.22g, 0.57mmol) is added Enter in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved In acetonitrile (15mL), and sequentially add thereto potassium carbonate (119mg, 0.86mmol), catalytic amount potassium iodide (19mg, 0.11mmol) and 3- (5- cyano-1 H-indol -3- base) propyl 4- oluene sulfonic acides ester (203mg, 0.57mmol).Reaction solution adds Heat after stirring 20 hours, is cooled to room temperature, filters, filtrate is concentrated under reduced pressure to 80 DEG C.Residue through silica gel column purification (petroleum ether/ Ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.16g, 59.9%).MS(ESI,pos.ion)m/ z:466.2[M+H]+；
1H NMR(DMSO-d6, 600MHz) δ (ppm): 11.39 (s, 1H), 8.99 (d, J=4.9Hz, 1H), 8.52 (s, 1H), 8.44 (d, J=8.9Hz, 2H), 8.10 (s, 1H), 7.94 (s, 1H), 7.74 (d, J=4.9Hz, 1H), 7.50 (d, J= 8.4Hz, 1H), 7.40 (dd, J=8.4,1.3Hz, 1H), 7.35 (d, J=1.5Hz, 1H), 7.03 (d, J=9.0Hz, 2H), 3.32-3.30 (m, 4H), 2.75 (t, J=7.4Hz, 2H), 2.54-2.52 (m, 4H), 2.40-2.37 (m, 2H), 1.93-1.78 (m,2H)。
20 2- of embodiment (4- (4- (4- (5- cyano-1 H-indol -3- base) butyl) piperazine -1- base) phenyl) pyrimidine -4- Formamide
4- (4- (4- carbamyl pyrimidine -2-base) phenyl) piperazine -1- t-butyl formate (0.22g, 0.57mmol) is added Enter in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved In acetonitrile (15mL), and sequentially add thereto potassium carbonate (119mg, 0.86mmol), catalytic amount potassium iodide (19mg, 0.11mmol) and 4- (5- cyano-1 H-indol -3- base) butyl 4- oluene sulfonic acides ester (211mg, 0.57mmol).Reaction solution adds Heat after stirring 20 hours, is cooled to room temperature, filters, filtrate is concentrated under reduced pressure to 80 DEG C.Residue through silica gel column purification (petroleum ether/ Ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.16g, 58.1%).MS(ESI,pos.ion)m/ z:480.2[M+H]+；
1H NMR(DMSO-d6, 600MHz) δ (ppm): 11.37 (s, 1H), 8.98 (d, J=4.8Hz, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 8.44 (s, 1H), 8.07 (s, 1H), 7.94 (s, 1H), 7.74 (d, J=4.8Hz, 1H), 7.50 (d, J =8.4Hz, 1H), 7.40 (d, J=8.4Hz, 1H), 7.33 (s, 1H), 7.00 (d, J=8.6Hz, 2H), 3.27-3.24 (m, 4H), 2.73 (t, J=7.3Hz, 2H), 2.47-2.45 (m, 4H), 2.35 (t, J=6.9Hz, 2H), 1.68-1.65 (m, 2H), 1.56-1.46(m,2H)。
21 2- of embodiment (4- (4- (3- (5- cyano-1 H-indol -3- base) propyl) piperazine -1- base) phenyl) -4- methyl Thiazole -5- Ethyl formate
Step 1) 2- (4- (4- (tertbutyloxycarbonyl) piperazine -1- base) phenyl) -4- methylthiazole-5-carboxylate
This step title compound is referred to method described in 1 step 3 of embodiment and is prepared, i.e., by 4- (4- (4, 4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) piperazine -1- t-butyl formate (0.50g, 1.3mmol), The bromo- 4- methylthiazole-5-carboxylate (0.32g, 1.3mmol) of 2-, sodium carbonate (0.41g, 3.9mmol) and Pd (dppf) Cl2 (0.51g, 0.07mmol) is suspended in reaction preparation in DMF (10mL) and water (5mL), crude product through silica gel column purification (petroleum ether/ Ethyl acetate (v/v)=5/1), obtaining title compound is yellow oily liquid (0.45g, 81.0%).
MS(ESI,pos.ion)m/z:432.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.87 (d, J=8.8Hz, 2H), 6.91 (d, J=8.8Hz, 2H), 4.34 (q, J=7.2Hz, 2H), 3.59 (t, J=4.8Hz, 4H), 3.28 (t, J=4.8Hz, 4H), 2.75 (s, 3H), 1.48 (s, 9H), 1.38 (t, J=7.2Hz, 3H).
Step 2) 2- (4- (4- (3- (5- cyano-1 H-indol -3- base) propyl) piperazine -1- base) phenyl) -4- methyl thiazolium Azoles -5- Ethyl formate
By 2- (4- (4- (tertbutyloxycarbonyl) piperazine -1- base) phenyl) -4- methylthiazole-5-carboxylate (0.25g, It 0.58mmol) is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.It will Residue is dissolved in acetonitrile (15mL), and sequentially adds the iodate of potassium carbonate (120mg, 0.87mmol), catalytic amount thereto Potassium (20mg, 0.12mmol) and 3- (5- cyano-1 H-indol -3- base) propyl 4- oluene sulfonic acides ester (205mg, 0.58mmol). After reaction solution is heated to 80 DEG C, stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petrol ether/ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.20g, 67.2%).
MS(ESI,pos.ion)m/z:514.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.88 (s, 1H), 7.74 (d, J=8.5Hz, 2H), 7.34 (d, J= 8.4Hz, 1H), 7.29 (d, J=8.4Hz, 1H), 7.06 (s, 1H), 6.84 (d, J=8.5Hz, 2H), 4.27-4.24 (m, 2H), 3.38-3.37(m,4H),2.78-2.76(m,4H),2.65(s,3H),2.55-2.52(m,2H),2.42-2.39(m,2H), 1.94-1.83 (m, 2H), 1.38 (t, J=7.2Hz, 3H).
22 2- of embodiment (4- (4- (4- (5- cyano-1 H-indol -3- base) butyl) piperazine -1- base) phenyl) -4- methyl Thiazole -5- Ethyl formate
By 2- (4- (4- (tertbutyloxycarbonyl) piperazine -1- base) phenyl) -4- methylthiazole-5-carboxylate (0.25g, It 0.58mmol) is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.It will Residue is dissolved in acetonitrile (15mL), and sequentially adds the iodate of potassium carbonate (120mg, 0.87mmol), catalytic amount thereto Potassium (20mg, 0.12mmol) and 4- (5- cyano-1 H-indol -3- base) butyl 4- oluene sulfonic acides ester (213mg, 0.58mmol). After reaction solution is heated to 80 DEG C, stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petrol ether/ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.18g, 58.9%).
MS(ESI,pos.ion)m/z:528.2[M+H]+；
1H NMR(MeOD/CDCl3, 600MHz) δ (ppm): 7.77 (s, 1H), 7.66 (d, J=8.7Hz, 2H), 7.27 (d, J=8.2Hz, 1H), 7.20 (d, J=8.3Hz, 1H), 7.00 (s, 1H), 6.78 (d, J=8.7Hz, 2H), 4.20-4.15 (m, 2H),3.38-3.36(m,4H),2.75-2.73(m,4H),2.67-2.64(m,2H),2.56(s,3H),2.50-2.49(m, 2H), 1.69-1.67 (m, 2H), 1.58-1.56 (m, 2H), 1.37 (t, J=7.2Hz, 3H).
23 2- of embodiment (4- (4- (3- (5- cyano-1 H-indol -3- base) propyl) piperazine -1- base) phenyl) -4- methyl Thiazole -5- formonitrile HCN
Step 1) 4- (4- (5- cyano -4- methylthiazol -2- base) phenyl) piperazine -1- t-butyl formate
This step title compound is referred to method described in 1 step 3 of embodiment and is prepared, i.e., by 4- (4- (4, 4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) piperazine -1- t-butyl formate (0.50g, 1.3mmol), The bromo- 4- methylthiazol -5- formonitrile HCN (0.26g, 1.3mmol) of 2-, sodium carbonate (0.41g, 3.9mmol) and Pd (dppf) Cl2 (0.51g, 0.07mmol) is suspended in reaction preparation in DMF (10mL) and water (5mL), crude product through silica gel column purification (petroleum ether/ Ethyl acetate (v/v)=5/1), obtaining title compound is yellow oily liquid (0.17g, 34.3%).
MS(ESI,pos.ion)m/z:385.2[M+H]+。
Step 2) 2- (4- (4- (3- (5- cyano-1 H-indol -3- base) propyl) piperazine -1- base) phenyl) -4- methyl thiazolium Azoles -5- formonitrile HCN
By 4- (4- (5- cyano -4- methylthiazol -2- base) phenyl) piperazine -1- t-butyl formate (0.22g, 0.57mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (119mg, 0.86mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 3- (5- cyano-1 H-indol -3- base) propyl 4- oluene sulfonic acides ester (203mg, 0.57mmol).Reaction solution adds Heat after stirring 20 hours, is cooled to room temperature, is concentrated under reduced pressure to 80 DEG C.By raffinate silica gel column purification (petrol ether/ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.11g, 41.2%).
MS(ESI,pos.ion)m/z:467.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.58 (brs, 1H), 7.84 (s, 1H), 7.72 (d, J=8.5Hz, 2H), 7.33 (d, J=8.4Hz, 1H), 7.29 (d, J=8.4Hz, 1H), 7.04 (s, 1H), 6.84 (d, J=8.5Hz, 2H), 3.39-3.37(m,4H),2.75-2.74(m,2H),2.73-2.71(m,4H),2.65(s,3H),2.53-2.50(m,2H), 2.42-2.39(m,2H),1.93-1.90(m,2H)。
24 2- of embodiment (4- (4- (4- (5- cyano-1 H-indol -3- base) butyl) piperazine -1- base) phenyl) -4- methyl Thiazole -5- formonitrile HCN
By 4- (4- (5- cyano -4- methylthiazol -2- base) phenyl) piperazine -1- t-butyl formate (0.22g, 0.57mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (119mg, 0.86mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 4- (5- cyano-1 H-indol -3- base) butyl 4- oluene sulfonic acides ester (211mg, 0.57mmol).Reaction solution adds Heat after stirring 20 hours, is cooled to room temperature, filters, filtrate is concentrated under reduced pressure to 80 DEG C.Residue through silica gel column purification (petroleum ether/ Ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.10g, 36.4%).
MS(ESI,pos.ion)m/z:481.2[M+H]+；
1H NMR(CDCl3/ MeOD, 600MHz) δ (ppm): 7.76 (s, 1H), 7.64 (d, J=8.7Hz, 2H), 7.26- 7.25 (m, 1H), 7.23 (d, J=8.3Hz, 1H), 7.01 (s, 1H), 6.77 (d, J=8.7Hz, 2H), 3.24-3.21 (m, 4H),2.80-2.78(m,2H),2.60-2.58(m,4H),2.55(s,3H),2.49-2.47(m,2H),1.91-1.89(m, 2H),1.56-1.54(m,2H)。
25 2- of embodiment (4- (4- (3- (5- cyano-1 H-indol -3- base) propyl) piperazine -1- base) phenyl) -4- methyl Thiazole -5- formamide
Step 1) 4- (4- (5- carbamyl -4- methylthiazol -2- base) phenyl) piperazine -1- t-butyl formate
This step title compound is referred to method described in 1 step 3 of embodiment and is prepared, i.e., by 4- (4- (4, 4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) piperazine -1- t-butyl formate (0.50g, 1.3mmol), The bromo- 4- methylthiazol -5- formamide (0.28g, 1.3mmol) of 2-, sodium carbonate (0.41g, 3.9mmol) and Pd (dppf) Cl2 (0.51g, 0.07mmol) is suspended in reaction preparation in DMF (10mL) and water (5mL), crude product through silica gel column purification (petroleum ether/ Ethyl acetate (v/v)=5/1), obtaining title compound is yellow oily liquid (0.16g, 30.9%).
MS(ESI,pos.ion)m/z:403.2[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):7.80-7.78(m,2H),6.91-6.88(m,2H),3.58-3.56 (m,4H),3.29-3.26(m,4H),2.63(s,3H),1.49(s,9H)。
Step 2) 2- (4- (4- (3- (5- cyano-1 H-indol -3- base) propyl) piperazine -1- base) phenyl) -4- methyl thiazolium Azoles -5- formamide
By 4- (4- (5- carbamyl -4- methylthiazol -2- base) phenyl) piperazine -1- t-butyl formate (0.23g, It 0.57mmol) is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.It will Residue is dissolved in acetonitrile (15mL), and sequentially adds the iodate of potassium carbonate (118mg, 0.86mmol), catalytic amount thereto Potassium (20mg, 0.12mmol) and 3- (5- cyano-1 H-indol -3- base) propyl 4- oluene sulfonic acides ester (203mg, 0.57mmol). After reaction solution is heated to 80 DEG C, stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petrol ether/ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.14g, 50.5%).
MS(ESI,pos.ion)m/z:485.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 9.26 (brs, 1H), 7.86 (s, 1H), 7.71 (d, J=8.5Hz, 2H), 7.32 (d, J=8.4Hz, 1H), 7.27 (d, J=8.4Hz, 1H), 7.03 (s, 1H), 6.84 (d, J=8.5Hz, 2H), 3.41-3.39(m,4H),2.73-2.71(m,2H),2.67-2.65(m,4H),2.63(s,3H),2.52-2.50(m,2H), 1.93-1.91(m,2H)。
26 2- of embodiment (4- (4- (4- (5- cyano-1 H-indol -3- base) butyl) piperazine -1- base) phenyl) -4- methyl Thiazole -5- formamide
By 4- (4- (5- carbamyl -4- methylthiazol -2- base) phenyl) piperazine -1- t-butyl formate (0.23g, It 0.57mmol) is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.It will Residue is dissolved in acetonitrile (15mL), and sequentially adds the iodate of potassium carbonate (118mg, 0.86mmol), catalytic amount thereto Potassium (20mg, 0.12mmol) and 4- (5- cyano-1 H-indol -3- base) butyl 4- oluene sulfonic acides ester (211mg, 0.57mmol). After reaction solution is heated to 80 DEG C, stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petrol ether/ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.13g, 45.6%).
MS(ESI,pos.ion)m/z:499.2[M+H]+；
1H NMR(CDCl3/ MeOD, 600MHz) δ (ppm): 7.73 (s, 1H), 7.62 (d, J=8.7Hz, 2H), 7.25- 7.23 (m, 1H), 7.21 (d, J=8.3Hz, 1H), 7.00 (s, 1H), 6.75 (d, J=8.7Hz, 2H), 3.31-3.29 (m, 4H), 2.73 (t, J=7.2Hz, 2H), 2.65-2.62 (m, 4H), 2.53 (s, 3H), 2.49-2.46 (m, 2H), 1.71-1.70 (m,2H),1.55-1.52(m,2H)。
The fluoro- 3- of 27 5- of embodiment (3- (4- (4- (pyridine -2- base) phenyl) piperazine -1- base) propyl) -1H- indoles
Step 1) 4- (4- (pyridine -2- base) phenyl) piperazine -1- t-butyl formate
This step title compound is referred to method described in 1 step 3 of embodiment and is prepared, i.e., by 4- (4- (4, 4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) piperazine -1- t-butyl formate (0.50g, 1.3mmol), The chloro- pyridine of 2- (0.15g, 1.3mmol), sodium carbonate (0.41g, 3.9mmol) and Pd (dppf) Cl2(0.51g, 0.07mmol) is outstanding Reaction preparation in DMF (10mL) and water (5mL) is floated on, crude product is through silica gel column purification (petrol ether/ethyl acetate (v/v)=5/ 1), obtaining title compound is yellow oil (0.22g, 46.5%).
MS(ESI,pos.ion)m/z:340.3[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.65 (d, J=4.4Hz, 1H), 7.95 (d, J=8.4Hz, 2H), 7.68-7.74 (m, 2H), 7.15-7.18 (m, 1H), 7.01 (d, J=8.4Hz, 2H), 3.61-3.63 (m, 4H), 3.24-3.27 (m,4H),1.51(s,9H)。
The fluoro- 3- of step 2) 5- (3- (4- (4- (pyridine -2- base) phenyl) piperazine -1- base) propyl) -1H- indoles
4- (4- (pyridine -2- base) phenyl) piperazine -1- t-butyl formate (0.20g, 0.59mmol) is added to hydrogen chloride In ethyl acetate solution (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved in acetonitrile In (15mL), and the potassium iodide (20mg, 0.12mmol) of potassium carbonate (122mg, 0.88mmol), catalytic amount is sequentially added thereto With 3- (the fluoro- 1H- indol-3-yl of 5-) propyl 4- oluene sulfonic acides ester (205mg, 0.59mmol).Reaction solution is heated to 80 DEG C, stirs It after mixing 20 hours, is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petrol ether/ethyl acetate (v/ V)=1/1), obtaining title compound is white solid (0.20g, 82.0%).
MS(ESI,pos.ion)m/z:415.2[M+H]+；
1H NMR(MeOD/CDCl3, 400MHz) and δ (ppm): 8.85 (brs, 1H), 8.60 (d, J=4.8Hz, 1H), 7.88 (d, J=8.4Hz, 2H), 7.71-7.63 (m, 2H), 7.28-7.25 (m, 2H), 7.23-7.21 (m, 1H), 7.02-6.97 (m, 3H), 6.93-6.88 (m, 1H), 3.31-3.28 (m, 4H), 2.74 (d, J=7.2Hz, 2H), 2.64-2.62 (m, 4H), 2.52- 2.48(m,2H),1.96-1.92(m,2H)。
The fluoro- 3- of 28 5- of embodiment (4- (4- (4- (pyridine -2- base) phenyl) piperazine -1- base) butyl) -1H- indoles
4- (4- (pyridine -2- base) phenyl) piperazine -1- t-butyl formate (0.20g, 0.59mmol) is added to hydrogen chloride In ethyl acetate solution (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved in acetonitrile In (15mL), and the potassium iodide (20mg, 0.12mmol) of potassium carbonate (122mg, 0.88mmol), catalytic amount is sequentially added thereto With 4- (the fluoro- 1H- indol-3-yl of 5-) butyl 4- oluene sulfonic acides ester (213mg, 0.59mmol).Reaction solution is heated to 80 DEG C, stirs It after mixing 20 hours, is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petrol ether/ethyl acetate (v/ V)=1/1), obtaining title compound is white solid (0.21g, 83.2%).
MS(ESI,pos.ion)m/z:429.2[M+H]+；
1H NMR(MeOD/CDCl3, 400MHz) and δ (ppm): 8.97 (brs, 1H), 8.55 (d, J=2.8Hz, 1H), 7.84 (d, J=9.2Hz, 2H), 7.68-7.66 (m, 1H), 7.63-7.61 (m, 1H), 7.24-7.19 (m, 2H), 7.15-7.12 (m, 1H), 7.00-6.96 (m, 3H), 6.90-6.85 (m, 1H), 3.26-3.25 (m, 4H), 2.72 (d, J=7.2Hz, 2H), 2.60- 2.58(m,4H),2.44-2.40(m,2H),1.71-1.69(m,2H),1.63-1.61(m,2H)。
29 5- methoxyl group -3- of embodiment (3- (4- (4- (pyridine -2- base) phenyl) piperazine -1- base) propyl) -1H- indoles
4- (4- (pyridine -2- base) phenyl) piperazine -1- t-butyl formate (0.20g, 0.59mmol) is added to hydrogen chloride In ethyl acetate solution (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved in acetonitrile In (15mL), and the potassium iodide (20mg, 0.12mmol) of potassium carbonate (122mg, 0.88mmol), catalytic amount is sequentially added thereto With 3- (5- methoxyl group -1H- indol-3-yl) propyl 4- oluene sulfonic acides ester (212mg, 0.59mmol).Reaction solution is heated to 80 DEG C, it after stirring 20 hours, is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petroleum ether/acetic acid second Ester (v/v)=1/1), obtaining title compound is white solid (0.10g, 39.8%).
MS(ESI,pos.ion)m/z:427.2[M+H]+；
1H NMR(MeOD/CDCl3, 600MHz) δ (ppm): 8.56 (d, J=4.8Hz, 1H), 7.84 (d, J=8.4Hz, 2H),7.76-7.75(m,1H),7.68-7.66(m,1H),7.28-7.25(m,1H),7.22-7.19(m,1H),7.04-7.01 (m, 4H), 6.83 (d, J=9.0Hz, 1H), 3.88 (s, 3H), 3.34-3.31 (m, 4H), 2.80-2.78 (m, 2H), 2.74- 2.72(m,4H),2.60-2.59(m,2H),2.03-2.00(m,2H)。
30 5- methoxyl group -3- of embodiment (4- (4- (4- (pyridine -2- base) phenyl) piperazine -1- base) butyl) -1H- indoles
4- (4- (pyridine -2- base) phenyl) piperazine -1- t-butyl formate (0.20g, 0.59mmol) is added to hydrogen chloride In ethyl acetate solution (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved in acetonitrile In (15mL), and the potassium iodide (20mg, 0.12mmol) of potassium carbonate (122mg, 0.88mmol), catalytic amount is sequentially added thereto With 4- (5- methoxyl group -1H- indol-3-yl) butyl 4- tosylate (220mg, 0.59mmol).Reaction solution is heated to 80 DEG C, It after stirring 20 hours, is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petrol ether/ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.10g, 38.5%).
MS(ESI,pos.ion)m/z:441.3[M+H]+；
1H NMR(MeOD/CDCl3,400MHz)δ(ppm):8.62-8.61(m,1H),8.32(brs,1H),7.90(d,J =8.8Hz, 2H), 7.70 (td, J=8.0,1.6Hz, 1H), 7.67-7.65 (m, 1H), 7.24 (d, J=8.8Hz, 1H), 7.17-7.14 (m, 1H), 7.05 (d, J=2.4Hz, 1H), 7.00 (d, J=9.2Hz, 2H), 6.97 (s, 1H), 6.85 (dd, J =8.8,2.4Hz, 1H), 3.88 (s, 3H), 3.32-3.30 (m, 4H), 2.79-2.75 (m, 2H), 2.66-2.63 (m, 4H), 2.50-2.47(m,2H),1.76-1.74(m,2H),1.69-1.67(m,2H)。
31 3- of embodiment (3- (4- (4- (pyridine -2- base) phenyl) piperazine -1- base) propyl) -1H- indoles -5- formonitrile HCN
4- (4- (pyridine -2- base) phenyl) piperazine -1- t-butyl formate (0.20g, 0.59mmol) is added to hydrogen chloride In ethyl acetate solution (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved in acetonitrile In (15mL), and sequentially add thereto potassium carbonate (122mg, 0.88mmol), catalytic amount potassium iodide (20mg, 0.1mol) and 3- (5- cyano-1 H-indol -3- base) propyl 4- oluene sulfonic acides ester (209mg, 0.59mmol).Reaction solution is heated to 80 DEG C, stirs It after mixing 20 hours, is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petrol ether/ethyl acetate (v/ V)=1/1), obtaining title compound is white solid (0.15g, 60.5%).
MS(ESI,pos.ion)m/z:422.1[M+H]+；
1H NMR(MeOD/CDCl3, 400MHz) δ (ppm): 8.55 (d, J=4.4Hz, 1H), 7.97 (s, 1H), 7.84 (d, J=8.8Hz, 2H), 7.76-7.74 (m, 1H), 7.67 (d, J=8.0Hz, 1H), 7.45-7.42 (m, 1H), 7.37 (dd, J= 8.4,1.6Hz, 1H), 7.22-7.18 (m, 2H), 7.02 (d, J=8.8Hz, 2H), 3.36-3.33 (m, 4H), 2.85-2.81 (m,2H),2.74-2.71(m,4H),2.59-2.55(m,2H),2.02-1.99(m,2H)。
32 3- of embodiment (4- (4- (4- (pyridine -2- base) phenyl) piperazine -1- base) butyl) -1H- indoles -5- formonitrile HCN
4- (4- (pyridine -2- base) phenyl) piperazine -1- t-butyl formate (0.20g, 0.59mmol) is added to hydrogen chloride In ethyl acetate solution (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved in acetonitrile In (15mL), and the potassium iodide (20mg, 0.12mmol) of potassium carbonate (122mg, 0.88mmol), catalytic amount is sequentially added thereto With 4- (5- cyano-1 H-indol -3- base) butyl 4- oluene sulfonic acides ester (217mg, 0.59mmol).Reaction solution is heated to 80 DEG C, It after stirring 20 hours, is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petrol ether/ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.14g, 54.6%).
MS(ESI,pos.ion)m/z:436.1[M+H]+；
1H NMR(MeOD/CDCl3, 400MHz) δ (ppm): 8.55 (d, J=4.4Hz, 1H), 7.91 (s, 1H), 7.83 (d, J=8.8Hz, 2H), 7.70-7.66 (m, 1H), 7.62 (d, J=8.0Hz, 1H), 7.37-7.31 (m, 2H), 7.15-7.12 (m, 1H), 7.07 (s, 1H), 6.95 (d, J=8.8Hz, 2H), 3.27-3.25 (m, 4H), 2.75 (d, J=7.2Hz, 2H), 2.62- 2.59(m,4H),2.45-2.42(m,2H),1.71-1.69(m,2H),1.63-1.61(m,2H)。
The fluoro- 3- of 33 5- of embodiment (3- (4- (4- (4- (trifluoromethyl) pyridine -2- base) phenyl) piperazine -1- base) propyl) - 1H- indoles
Step 1) 4- (4- (4- (trifluoromethyl) pyridine -2- base) phenyl) piperazine -1- t-butyl formate
This step title compound is referred to method described in 1 step 3 of embodiment and is prepared, i.e., by 4- (4- (4, 4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) piperazine -1- t-butyl formate (0.50g, 1.3mmol), 2- chloro- 4- (trifluoromethyl) pyridine (0.24g, 1.3mmol), sodium carbonate (0.41g, 3.9mmol) and Pd (dppf) Cl2 (0.51g, 0.07mmol) is suspended in reaction preparation in DMF (10mL) and water (5mL), crude product through silica gel column purification (petroleum ether/ Ethyl acetate (v/v)=5/1), obtaining title compound is yellow oily liquid (0.26g, 49.6%).
MS(ESI,pos.ion)m/z:408.3[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.80 (d, J=4.8Hz, 1H), 7.99 (d, J=8.8Hz, 2H), 7.86 (s, 1H), 7.36 (d, J=4.8Hz, 1H), 7.02 (d, J=8.8Hz, 2H), 3.61-3.64 (m, 4H), 3.27-3.30 (m,4H),1.51(s,9H)。
The fluoro- 3- of step 2) 5- (3- (4- (4- (4- (trifluoromethyl) pyridine -2- base) phenyl) piperazine -1- base) propyl) -1H- Indoles
By 4- (4- (4- (trifluoromethyl) pyridine -2- base) phenyl) piperazine -1- t-butyl formate (0.24g, 0.59mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (122mg, 0.88mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 3- (the fluoro- 1H- indol-3-yl of 5-) propyl 4- oluene sulfonic acides ester (205mg, 0.59mmol).Reaction solution heating To 80 DEG C, after stirring 20 hours, it is cooled to room temperature, is concentrated under reduced pressure.Residue is through silica gel column purification (petrol ether/ethyl acetate (v/ V)=1/1), obtaining title compound is white solid (0.21g, 73.9%).
MS(ESI,pos.ion)m/z:483.2[M+H]+；
1H NMR(MeOD/CDCl3, 400MHz) and δ (ppm): 9.02 (brs, 1H), 8.76 (d, J=5.2Hz, 1H), 7.94 (d, J=8.8Hz, 2H), 7.86 (s, 1H), 7.34 (d, J=5.2Hz, 1H), 7.21-7.28 (m, 2H), 7.02 (s, 1H), 6.98 (d, J=8.8Hz, 2H), 6.92 (td, J=8.8,2.4Hz, 1H), 3.32-3.31 (m, 4H), 2.76 (t, J=7.2Hz, 2H),2.64-2.61(m,4H),2.52-2.48(m,2H),1.97-1.93(m,2H)。
The fluoro- 3- of 34 5- of embodiment (4- (4- (4- (4- (trifluoromethyl) pyridine -2- base) phenyl) piperazine -1- base) butyl) - 1H- indoles
By 4- (4- (4- (trifluoromethyl) pyridine -2- base) phenyl) piperazine -1- t-butyl formate (0.24g, 0.59mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (122mg, 0.88mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 4- (the fluoro- 1H- indol-3-yl of 5-) butyl 4- oluene sulfonic acides ester (213mg, 0.59mmol).Reaction solution heating To 80 DEG C, after stirring 20 hours, it is cooled to room temperature, is concentrated under reduced pressure.Residue is through silica gel column purification (petrol ether/ethyl acetate (v/ V)=1/1), obtaining title compound is white solid (0.23g, 78.6%).
MS(ESI,pos.ion)m/z:497.2[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.81 (d, J=5.2Hz, 1H), 8.40 (brs, 1H), 7.99 (d, J= 9.2Hz, 2H), 7.88 (s, 1H), 7.35 (d, J=5.2Hz, 1H), 7.29 (dd, J=9.6,2.4Hz, 1H), 7.35 (dd, J= 8.8,4.4Hz, 1H), 7.03-7.01 (m, 3H), 6.95 (td, J=9.2,2.4Hz, 1H), 3.35-3.33 (m, 4H), 2.78 (t, J=7.2Hz, 2H), 2.65-2.62 (m, 4H), 2.50-2.46 (m, 2H), 1.78-1.76 (m, 2H), 1.69-1.67 (m, 2H)。
35 5- methoxyl group -3- of embodiment (3- (4- (4- (4- (trifluoromethyl) pyridine -2- base) phenyl) piperazine -1- base) third Base) -1H- indoles
By 4- (4- (4- (trifluoromethyl) pyridine -2- base) phenyl) piperazine -1- t-butyl formate (0.24g, 0.59mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (122mg, 0.88mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 3- (5- methoxyl group -1H- indol-3-yl) propyl 4- oluene sulfonic acides ester (212mg, 0.59mmol).Reaction solution After being heated to 80 DEG C, stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petroleum Ether/ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.12g, 41.2%).
MS(ESI,pos.ion)m/z:495.2[M+H]+；
1H NMR(CDCl3, 600MHz) and δ (ppm): 8.81 (d, J=4.8Hz, 1H), 8.05 (brs, 1H), 7.98 (d, J= 8.4Hz, 2H), 7.87 (s, 1H), 7.35 (d, J=4.8Hz, 1H), 7.27 (d, J=9.0Hz, 1H), 7.07 (d, J=2.4Hz, 1H), 7.03-7.01 (m, 3H), 6.89 (dd, J=8.4,2.4Hz, 1H), 3.90 (s, 3H), 3.39-3.37 (m, 4H), 2.81 (t, J=7.2Hz, 2H), 2.71-2.69 (m, 4H), 2.59-2.57 (m, 2H), 2.05-2.00 (m, 2H).
36 5- methoxyl group -3- of embodiment (4- (4- (4- (4- (trifluoromethyl) pyridine -2- base) phenyl) piperazine -1- base) fourth Base) -1H- indoles
By 4- (4- (4- (trifluoromethyl) pyridine -2- base) phenyl) piperazine -1- t-butyl formate (0.24g, 0.59mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (122mg, 0.88mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 4- (5- methoxyl group -1H- indol-3-yl) butyl 4- oluene sulfonic acides ester (220mg, 0.59mmol).Reaction solution After being heated to 80 DEG C, stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petroleum Ether/ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.25g, 83.4%).
MS(ESI,pos.ion)m/z:509.2[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.80 (d, J=4.8Hz, 1H), 8.14 (brs, 1H), 7.99 (d, J= 8.8Hz, 2H), 7.88 (s, 1H), 7.35 (d, J=4.8Hz, 1H), 7.24 (d, J=8.8Hz, 1H), 7.09 (d, J=2.4Hz, 1H), 7.01 (d, J=9.2Hz, 2H), 6.97 (d, J=2.0Hz, 1H), 6.89 (dd, J=8.8,2.4Hz, 1H), 3.91 (s, 3H), 3.35-3.33 (m, 4H), 2.80 (t, J=7.2Hz, 2H), 2.65-2.63 (m, 4H), 2.51-2.47 (m, 2H), 1.81- 1.78(m,2H),1.71-1.69(m,2H)。
37 3- of embodiment (3- (4- (4- (4- (trifluoromethyl) pyridine -2- base) phenyl) piperazine -1- base) propyl) -1H- Yin Diindyl -5- formonitrile HCN
By 4- (4- (4- (trifluoromethyl) pyridine -2- base) phenyl) piperazine -1- t-butyl formate (0.24g, 0.59mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (122mg, 0.88mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 3- (5- cyano-1 H-indol -3- base) propyl 4- oluene sulfonic acides ester (209mg, 0.59mmol).Reaction solution adds Heat after stirring 20 hours, is cooled to room temperature, filters, filtrate is concentrated under reduced pressure to 80 DEG C.Residue through silica gel column purification (petroleum ether/ Ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.14g, 48.6%).
MS(ESI,pos.ion)m/z:490.1[M+H]+；
1H NMR(CDCl3, 400MHz) δ (ppm): 9.28 (brs, 1H), 8.78 (d, J=4.8Hz, 1H), 7.98 (s, 1H), 7.96 (d, J=8.8Hz, 2H), 7.85 (s, 1H), 7.37-7.32 (m, 3H), 7.11 (d, J=1.6Hz, 1H), 6.99 (d, J=8.8Hz, 2H), 3.35-3.32 (m, 4H), 2.81 (t, J=7.2Hz, 2H), 2.64-2.62 (m, 4H), 2.51-2.47 (m,2H),1.97-1.93(m,2H)。
38 3- of embodiment (4- (4- (4- (4- (trifluoromethyl) pyridine -2- base) phenyl) piperazine -1- base) butyl) -1H- Yin Diindyl -5- formonitrile HCN
By 4- (4- (4- (trifluoromethyl) pyridine -2- base) phenyl) piperazine -1- t-butyl formate (0.24g, 0.59mmol) It is added in Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is molten Solution in acetonitrile (15mL), and sequentially add thereto potassium carbonate (122mg, 0.88mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 4- (5- cyano-1 H-indol -3- base) butyl 4- oluene sulfonic acides ester (217mg, 0.59mmol).Reaction solution adds Heat after stirring 20 hours, is cooled to room temperature, filters, filtrate is concentrated under reduced pressure to 80 DEG C.Residue through silica gel column purification (petroleum ether/ Ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.18g, 60.7%).
MS(ESI,pos.ion)m/z:504.2[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.83 (brs, 1H), 8.80 (d, J=5.2Hz, 1H), 7.98-7.96 (m, 3H), 7.86 (s, 1H), 7.40-7.34 (m, 3H), 7.11 (s, 1H), 7.01 (d, J=8.8Hz, 2H), 3.36-3.33 (m, 4H), 2.80 (t, J=7.2Hz, 2H), 2.67-2.65 (m, 4H), 2.51-2.47 (m, 2H), 1.77-1.75 (m, 2H), 1.68- 1.66(m,2H)。
The fluoro- 3- of 39 5- of embodiment (3- (4- (4- (3- picoline -2- base) phenyl) piperazine -1- base) propyl) -1H- Yin Diindyl
Step 1) 4- (4- (3- picoline -2- base) phenyl) piperazine -1- t-butyl formate
This step title compound is referred to method described in 1 step 3 of embodiment and is prepared, i.e., by 4- (4- (4, 4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) piperazine -1- t-butyl formate (0.50g, 1.3mmol), Chloro- 3 picoline (0.17g, 1.3mmol) of 2-, sodium carbonate (0.41g, 3.9mmol) and Pd (dppf) Cl2(0.51g, It 0.07mmol) is suspended in reaction preparation in DMF (10mL) and water (5mL), crude product is through silica gel column purification (petroleum ether/acetic acid second Ester (v/v)=5/1), obtaining title compound is yellow oily liquid (0.14g, 30.8%).
MS(ESI,pos.ion)m/z:354.3[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.79 (d, J=5.6Hz, 1H), 8.02 (d, J=8.0Hz, 1H), 7.54-7.49 (m, 3H), 7.01 (d, J=8.8Hz, 2H), 3.63-3.61 (m, 4H), 3.33-3.30 (m, 4H), 2.52 (s, 3H),1.51(s,9H)。
The fluoro- 3- of step 2) 5- (3- (4- (4- (3- picoline -2- base) phenyl) piperazine -1- base) propyl) -1H- indoles
4- (4- (3- picoline -2- base) phenyl) piperazine -1- t-butyl formate (0.21g, 0.59mmol) is added to In Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved in second In nitrile (15mL), and sequentially add thereto potassium carbonate (123mg, 0.89mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 3- (the fluoro- 1H- indol-3-yl of 5-) propyl 4- oluene sulfonic acides ester (206mg, 0.59mmol).Reaction solution heating To 80 DEG C, after stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petroleum ether/second Acetoacetic ester (v/v)=1/1), obtaining title compound is white solid (0.20g, 78.6%).
MS(ESI,pos.ion)m/z:429.2[M+H]+；
1H NMR(MeOD/CDCl3, 400MHz) δ (ppm): 8.31 (d, J=4.4Hz, 1H), 7.49 (d, J=7.6Hz, 1H), 7.32 (d, J=8.4Hz, 2H), 7.17-7.13 (m, 2H), 7.08-7.05 (m, 1H), 6.95 (s, 1H), 6.89 (d, J= 8.8Hz, 2H), 6.80 (d, J=8.8,2.0Hz, 1H), 3.20-3.18 (m, 4H), 2.67 (t, J=7.2Hz, 2H), 2.57- 2.55(m,4H),2.44-2.40(m,2H),2.26(s,3H),1.89-1.85(m,2H)。
The fluoro- 3- of 40 5- of embodiment (4- (4- (4- (3- picoline -2- base) phenyl) piperazine -1- base) butyl) -1H- Yin Diindyl
4- (4- (3- picoline -2- base) phenyl) piperazine -1- t-butyl formate (0.21g, 0.59mmol) is added to In Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved in second In nitrile (15mL), and sequentially add thereto potassium carbonate (123mg, 0.89mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 4- (the fluoro- 1H- indol-3-yl of 5-) butyl 4- oluene sulfonic acides ester (215mg, 0.59mmol).Reaction solution heating To 80 DEG C, after stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petroleum ether/second Acetoacetic ester (v/v)=1/1), obtaining title compound is white solid (0.22g, 83.7%).
MS(ESI,pos.ion)m/z:443.0[M+H]+；
1H NMR(MeOD/CDCl3, 400MHz) δ (ppm): 8.40 (d, J=4.4Hz, 1H), 7.55 (d, J=7.6Hz, 1H), 7.40 (d, J=8.4Hz, 2H), 7.22-7.19 (m, 2H), 7.14-7.11 (m, 1H), 6.99 (s, 1H), 6.85 (d, J= 8.4Hz, 2H), 6.80 (d, J=8.8,1.6Hz, 1H), 3.26-3.24 (m, 4H), 2.72 (t, J=7.2Hz, 2H), 2.62- 2.60(m,4H),2.46-2.42(m,2H),2.33(s,3H),1.71-1.69(m,2H),1.64-1.62(m,2H)。
41 5- methoxyl group -3- of embodiment (3- (4- (4- (3- picoline -2- base) phenyl) piperazine -1- base) propyl) - 1H- indoles
4- (4- (3- picoline -2- base) phenyl) piperazine -1- t-butyl formate (0.21g, 0.59mmol) is added to In Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved in second In nitrile (15mL), and sequentially add thereto potassium carbonate (123mg, 0.89mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 3- (5- methoxyl group -1H- indol-3-yl) propyl 4- oluene sulfonic acides ester (214mg, 0.59mmol).Reaction solution After being heated to 80 DEG C, stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petroleum Ether/ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.10g, 38.2%).MS(ESI,pos.ion) m/z:441.2[M+H]+；
1H NMR(CDCl3, 600MHz) and δ (ppm): 8.52-8.51 (m, 1H), 8.17 (brs, 1H), 7.57 (d, J= 7.8Hz, 1H), 7.49 (d, J=9.0Hz, 2H), 7.25 (d, J=8.4Hz, 1H), 7.14 (dd, J=7.2,4.8Hz, 1H), 7.07 (d, J=1.8Hz, 1H), 7.01-7.00 (m, 3H), 6.87 (dd, J=8.4,2.4Hz, 1H), 3.89 (s, 3H), 3.36- 3.34(m,4H),2.82-2.80(m,2H),2.73-2.72(m,4H),2.61-2.58(m,2H),2.40(s,3H),2.04- 2.00(m,2H)。
42 5- methoxyl group -3- of embodiment (4- (4- (4- (3- picoline -2- base) phenyl) piperazine -1- base) butyl) - 1H- indoles
4- (4- (3- picoline -2- base) phenyl) piperazine -1- t-butyl formate (0.21g, 0.59mmol) is added to In Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved in second In nitrile (15mL), and sequentially add thereto potassium carbonate (123mg, 0.89mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 4- (5- methoxyl group -1H- indol-3-yl) butyl 4- oluene sulfonic acides ester (222mg, 0.59mmol).Reaction solution After being heated to 80 DEG C, stirring 20 hours, it is cooled to room temperature, filters, filtrate is concentrated under reduced pressure.Residue is through silica gel column purification (petroleum Ether/ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.11g, 40.7%).MS(ESI,pos.ion) m/z:455.3[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.52 (dd, J=4.8,1.2Hz, 1H), 8.17 (brs, 1H), 7.58- 7.56 (m, 1H), 7.49 (d, J=8.8Hz, 2H), 7.23 (d, J=8.8Hz, 1H), 7.14 (dd, J=7.6,4.8Hz, 1H), 7.07 (d, J=2.4Hz, 1H), 7.00 (d, J=8.8Hz, 2H), 6.96 (d, J=2.0,1H), 6.87 (dd, J=8.4, 2.4Hz,1H),3.89(s,3H),3.32-3.30(m,4H),2.81-2.77(m,2H),2.67-2.65(m,4H),2.52- 2.48(m,2H),2.41(s,3H),1.79-1.77(m,2H),1.71-1.69(m,2H)。
43 3- of embodiment (3- (4- (4- (3- picoline -2- base) phenyl) piperazine -1- base) propyl) -1H- indoles -5- Formonitrile HCN
4- (4- (3- picoline -2- base) phenyl) piperazine -1- t-butyl formate (0.21g, 0.59mmol) is added to In Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved in second In nitrile (15mL), and sequentially add thereto potassium carbonate (123mg, 0.89mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 3- (5- cyano-1 H-indol -3- base) propyl 4- oluene sulfonic acides ester (211mg, 0.59mmol).Reaction solution adds Heat after stirring 20 hours, is cooled to room temperature, filters, filtrate is concentrated under reduced pressure to 80 DEG C.Residue through silica gel column purification (petroleum ether/ Ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.13g, 50.2%).
MS(ESI,pos.ion)m/z:436.0[M+H]+；
1H NMR(CDCl3, 600MHz) δ (ppm): 10.09 (brs, 1H), 8.52 (d, J=4.8Hz, 1H), 7.95 (s, 1H), 7.58 (d, J=6.6Hz, 1H), 7.46 (d, J=9.0Hz, 2H), 7.33 (d, J=7.0,1.5Hz, 1H), 7.24 (d, J =7.0Hz, 1H), 7.17 (d, J=7.8,4.8Hz, 1H), 6.98-6.96 (m, 3H), 3.31-3.29 (m, 4H), 2.78 (t, J =7.2Hz, 2H), 2.67-2.65 (m, 4H), 2.52-2.49 (m, 2H), 2.39 (s, 3H), 1.96-1.93 (m, 2H).
44 3- of embodiment (4- (4- (4- (3- picoline -2- base) phenyl) piperazine -1- base) butyl) -1H- indoles -5- Formonitrile HCN
4- (4- (3- picoline -2- base) phenyl) piperazine -1- t-butyl formate (0.21g, 0.59mmol) is added to In Hydrochloride/ethyl acetate (4M, 5mL).After reaction solution is stirred at room temperature 1 hour, it is concentrated under reduced pressure.Residue is dissolved in second In nitrile (15mL), and sequentially add thereto potassium carbonate (123mg, 0.89mmol), catalytic amount potassium iodide (20mg, 0.12mmol) and 4- (5- cyano-1 H-indol -3- base) butyl 4- oluene sulfonic acides ester (219mg, 0.59mmol).Reaction solution adds Heat after stirring 20 hours, is cooled to room temperature, filters, filtrate is concentrated under reduced pressure to 80 DEG C.Residue through silica gel column purification (petroleum ether/ Ethyl acetate (v/v)=1/1), obtaining title compound is white solid (0.11g, 41.2%).
MS(ESI,pos.ion)m/z:450.0[M+H]+；
1H NMR(MeOD/CDCl3, 400MHz) δ (ppm): 8.37 (d, J=4.0Hz, 1H), 7.92 (s, 1H), 7.58 (d, J=7.6Hz, 1H), 7.40-7.37 (m, 3H), 7.34-7.32 (m, 1H), 7.15 (d, J=7.8,4.8Hz, 1H), 7.11- 7.08 (m, 2H), 6.97 (d, J=8.8Hz, 2H), 3.28-3.25 (m, 4H), 2.78 (t, J=7.2Hz, 2H), 2.66-2.64 (m,4H),2.49-2.45(m,2H),2.33(s,3H),1.73-1.71(m,2H),1.65-1.64(m,2H)。
Biologic test
The LC/MS/MS system of analysis includes the serial vacuum degassing furnace of Agilent 1200, and binary syringe pump, orifice plate is certainly Dynamic sampler, column insulating box, charged spray ionize the Agilent G6430 three-level level four bars mass spectrograph in the source (ESI).Quantitative analysis It is carried out under MRM mode, the parameter of MRM conversion is as in Table A:
Table A
More reaction detection scannings 490.2→383.1
Fragmentation voltage 230V
Capillary voltage 55V
Dryer temperature 350℃
Atomizer 40psi
Drier flow velocity 10L/min
Analysis uses Agilent XDB-C18,2.1x 30mm, and 3.5 μM of columns inject 5 μ L samples.Analysis condition: mobile phase For 0.1% aqueous formic acid (mobile phase A) and 0.1% formic acid methanol solution (Mobile phase B).Flow velocity is 0.4mL/min.Stream Dynamic phase gradient is as shown in tableb:
Table B
Time The gradient of Mobile phase B
0.5min 5%
1.0min 95%
2.2min 95%
2.3min 5%
5.0min stop
In addition, the also 6330 series LC/MS/MS spectrometer of Agilent for analysis, is infused equipped with G1312A binary Penetrate pump, G1367A automatic sampler and G1314C UV detector；LC/MS/MS spectrometer uses ESI radioactive source.Use titer Suitable cationic model treatment is carried out to each analyte and MRM conversion carries out optimal analysis.It uses during analysis Capcell MP-C18 column, specification are as follows: 100x4.6mm I.D., 5 μM (Phenomenex, Torrance, California, USA).Mobile phase is the acetonitrile solution of aqueous solution (A) and 5mM ammonium acetate and 0.1% methanol of 5mM ammonium acetate and 0.1% methanol (B) (A/B (v/v)=70/30)；Flow velocity is 0.6mL/min；Column temperature is maintained at room temperature；Inject 20 μ L samples.
Embodiment A: compound in synaptosomes in rat brain in vivo to [3H] 5-HT intake the Inhibitory Effects
Test method
Under the conditions of 37 DEG C, to buffer (106.2mM NaCl, 4.5mM KCl, 2.25mM MgSO4,1.08mM NaH2PO4,22.5mMNaHCO3, 45 μM of ascorbic acid (pH 7.4) of 9.9mM glucose, 9 μM of EGTA and), it dashes forward Contact (150 μ g) and 0.1 μ Ci [3H] in the mixed system that is formed of serotonin, test compound or positive drug or yin is added Property control, altogether be incubated for 15 minutes.
Imipramine is added in above-mentioned identical mixed system as the standard positive compound for inhibiting serotonin intake 10 μM of imipramine, blocking 5-hydroxytryptamine intake, are incubated for 15 minutes, to measure Basal control activity value under the conditions of 4 DEG C.Pass through Experiment, tests intake inhibiting value of the imipramine to rat brain synaptosome of various concentration, produces suppression curve.
Sample after incubation passes through glass fibers with 96 like cell collectors (Unifilter, Packard) under vacuum conditions It ties up filter membrane (GF/B, Packard) quickly to filter, and is rinsed twice in ice-cold incubation buffer, thus what elimination dissociated [3H] serotonin.Dry filter membrane, in scintillation counter (Topcount, Packard), with scintillation solution (Microscint 0, Packard remaining radioactivity) is calculated.Experimental result with relative to control group [3H] serotonin intake suppression percentage It indicates.
Data analysis
The SERT transporter inhibiting effect of synaptosomes in rat brain in vivo by [3H] concentration of 5-HT measures.Test-compound needs It in the case of concentration is more than 6log, at least tests twice, data carry out nonlinear regression analysis through Hill equation curve, obtain IC50Value. As a result referring to table 1.
Experimental result shows, compound provided in an embodiment of the present invention to [3H] reuptake of 5-HT has preferable inhibit Activity.
Embodiment B:h5-HT1ABinding affinity test
Test method
Under the conditions of 22 DEG C, to people HEK-293 cell membrane homogenate (36 μ g albumen), 0.3nM [3H]8-OH-DPAT (Perkin-Elmer) and buffer (50mM Tris-HCl (pH 7.4), 10mM MgSO4,0.5mM EDTA,2μg/ml Aprotinine) in the mixed system formed, it is added or is added without test compound, is incubated for 60 minutes altogether.
Standard reference compound is that 10 μM of 8-OH-DPAT are added in the mixed system of above-mentioned condition in 8-OH-DPAT, For measuring non-specific binding value.By the data of the 8-OH-DPAT of different experiments test series concentration, obtain competitive bent Line.
Sample after incubation is with 96 like cell collectors (Unifilter, Packard) under vacuum conditions by pre- dipped The glass fiber filter (GF/B, Packard) of 0.3%PEI quickly filters, and is rushed repeatedly using ice-cold 50mM Tris-HCl It washes several times.Dry filter membrane, in scintillation counter (Topcount, Packard), with scintillation solution (Microscint 0, Packard remaining radioactivity) is calculated.Inhibition hundred of the experimental result to be specifically bound relative to control group radioligand Divide than indicating.
Data analysis
[3H] 8-OH-DPAT (0.3nM) and 5-HT in people HEK-293 cell1AThe flashing that the combination test of receptor passes through film Proximity test method is completed.Test-compound is needed when concentration is more than 6log, is at least tested three times, data are through the side Hill Journey curve carries out nonlinear regression analysis, obtains IC50Value, then calculated through ChengPrusoff equation, Ki value is obtained, Ki indicates to inhibit Constant.As a result referring to table 1.
Experimental result shows that the compounds of this invention is to 5-HT1AReceptor shows stronger binding affinity.
Embodiment C:hD2The test of receptor binding affinity
Test method
Under the conditions of 22 DEG C, cell membrane homogenate (24 μ g albumen), 0.3nM [3H] methyl-spiperone and buffer The mixed system that (50mM Tris-HCl (pH7.4), 120mM NaCl, 5mM KCl, 5mM MgCl2and 1mM EDTA) is formed In, it is added or is added without test compound, is incubated for 60 minutes altogether.
In the mixed system of above-mentioned condition, 10 μM of (+) butaclamol are added, for measuring non-specific binding value.
Sample after incubation is with 96 like cell collectors (Unifilter, Packard) under vacuum conditions by pre- dipped The glass fiber filter (GF/B, Packard) of 0.3%PEI, and several times using ice-cold 50mM Tris-HCl repeated flushing.It is dry Dry filter membrane is calculated residual in scintillation counter (Topcount, Packard) with scintillation solution (Microscint 0, Packard) The radioactivity stayed.
Data analysis
Experimental result is indicated with the suppression percentage specifically bound relative to control group radioligand.Standard referenceization Conjunction object is (+) butaclamol.By the data of (+) butaclamol of different experiments test series concentration, obtain competitive Curve, to calculate IC50, then calculate through ChengPrusoff equation, obtain KiValue, wherein Ki indicates inhibition constant.As a result Referring to table 1.
Experimental result shows that the compounds of this invention is to D2The binding affinity of receptor is poor.The compounds of this invention is to D2Receptor With preferable selectivity.
Table 1 it is provided in an embodiment of the present invention to [3H] 5-HT intake inhibiting effect result,
To h5-HT1AThe binding affinity result of receptor and to hD2The binding affinity experimental result of receptor
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means particular features, structures, materials, or characteristics described in conjunction with this embodiment or example It is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms need not It must be directed to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be any It can be combined in any suitable manner in a or multiple embodiment or examples.In addition, without conflicting with each other, the technology of this field The feature of different embodiments or examples described in this specification and different embodiments or examples can be combined by personnel And combination.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned Embodiment is changed, modifies, replacement and variant.

Claims (13)

1. a kind of compound is stereoisomer, the interconversion of compound shown in formula (III) compound represented or formula (III) Isomers or pharmaceutically acceptable salt,
Wherein: p 1；
L is-CR3R4-；
R is 3 or 4；
Q is 1,2,3 or 4；
Y is one of minor structure shown in formula (IV-7) to (IV-9):
Wherein, each n independently is 1 or 2；
Each R1It independently is H or D；
Each R2It is separately-CN；
Each R3And R4It is separately H or D；
Each R5It independently is H, D ,-CN ,-C (=O) ORc,-C (=O) NRaRbOr C1-C6Alkyl；
Each RaAnd RbIt is separately H；
Each RcIt independently is C1-C4Alkyl.
2. compound according to claim 1, wherein L is-CH2-。
3. compound according to claim 1, wherein each R5It independently is H, D ,-CN ,-C (=O) ORc,-C (=O) NRaRbOr C1-C4Alkyl.
4. compound according to claim 3, wherein each R5It independently is H, D ,-CN ,-C (=O) OCH3,-C (=O) OCH2CH3,-C (=O) NH2、-CH3、-CH2CH3Or-CH (CH3)2。
5. compound according to claim 1, with following one structure:
Or its stereoisomer, tautomer or pharmaceutically Acceptable salt.
6. a kind of pharmaceutical composition includes compound described in claim 1-5 any one.
7. pharmaceutical composition according to claim 6, further include pharmaceutically acceptable excipient, carrier or they Any combination.
8. pharmaceutical composition according to claim 7 further includes treatment central nervous system dysfunction The drug of drug, the treatment central nervous system dysfunction is antidepressant, anxiolytic drugs, as mood stabilizers Salts drug, atypical antipsychotic drug, antiepileptic, antiparkinsonism drug, as serotonin select Property reuptaking inhibitor and/or 5-HT1ADrug, nervous stimulants, nicotinic antagonists or their times of receptor stimulating agent Meaning combination.
9. pharmaceutical composition according to claim 8, wherein it is described treatment central nervous system dysfunction drug be Amitriptyline, desipramine, Mirtazapine, Bupropion, Reboxetine, Prozac, Trazodone, Sertraline, Duloxetine, fluorine volt Sha Ming, Milnacipran, left-handed Milnacipran, desmethylvenlafaxine, vilazodone, Venlafaxine, Dapoxetine hydrochloride, Nefazodone, Femoxetine, chlorimipramine, Citalopram, escitalopram, Paxil, lithium carbonate, buspirone, Olanzapine, quinoline sulphur Flat, Risperidone, Ziprasidone, Aripiprazole, Perospirone, Clozapine, modafinil, Mecamylamine, Cabergoline, Buddha's warrior attendant Alkane, imipramine, Pramipexole, thyroxine, dextromethorphan, quinindium, naltrexone, samidorphan, buprenorphine, take off it is black Hormone, alprazolam, Pipamperone, dimension replace a smooth, librium, perphenazine or their any combination.
10. pharmaceutical composition described in compound described in claim 1-5 any one or claim 6-9 any one exists The purposes in drug is prepared, the drug is for preventing, treating or mitigating central nervous system dysfunction.
11. purposes according to claim 10, the central nervous system dysfunction refer to depression, anxiety disorder, It stress hinder after mania, schizophrenia, bipolar disorders, sleep disturbance, besetment and behavior disorder, panic disorder, wound Hinder, dyskinesia, sex dysfunction, musculoskeletal pain obstacle, cognitive disorder, memory disorders, Parkinson's disease, Heng Tingdunshi Disease, phobia, substance abuse or habituation, drug addiction withdrawal symptom or premenstrualtension syndrome.
12. pharmaceutical composition described in compound described in claim 1-5 any one or claim 6-9 any one exists The purposes in drug is prepared, the drug is for inhibiting serotonin reuptake transporter.
13. pharmaceutical composition described in compound described in claim 1-5 any one or claim 6-9 any one exists The purposes in drug is prepared, the drug is used for partial agonist 5-HT1AReceptor.
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US9714232B2 (en) 2013-12-20 2017-07-25 Sunshine Lake Pharma Co., Ltd. Substituted piperazine compounds and methods of use thereof
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