CN106045966A - Substituted heterocyclic compounds and application of same to medicines - Google Patents

Substituted heterocyclic compounds and application of same to medicines Download PDF

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Publication number
CN106045966A
CN106045966A CN201610209049.7A CN201610209049A CN106045966A CN 106045966 A CN106045966 A CN 106045966A CN 201610209049 A CN201610209049 A CN 201610209049A CN 106045966 A CN106045966 A CN 106045966A
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alkylidene
compound
group
alkyl
base
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CN106045966B (en
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金传飞
钟文和
张英俊
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond

Abstract

The invention relates to substituted heterocyclic compounds and application of the same to medicines and specifically provides the novel substituted heterocyclic compounds or stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and preparation methods thereof. The invention also relates to pharmaceutical compositions containing the compounds and application of the compounds or pharmaceutical compositions to treatment of diseases related to 5-HT6 receptors, especially Alzheimer's disease.

Description

Substituted heterocyclic compound and the application on medicine thereof
Technical field
The invention belongs to technical field of pharmaceuticals, be particularly used for treating Alzheimer's disease compound, comprise described The medical composition and its use of compound.Especially, compound of the present invention is can be as 5-HT6Receptor antagonist Substituted heterocyclic compound.
Background technology
Multiple central nervous system disease such as anxiety, depression etc. all with neurotransmitter serotonin (5-HT) or serotonin Disorder relevant.As modulability neurotransmitter main in brain, the function of neurotransmitter serotonin (5-HT) is by quilt It is referred to as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6And 5-HT7A large amount of receptor families mediation.Based on Gao Shui in brain Flat 5-HT6Receptor mrna, it has been suggested that 5-HT6Receptor may play in the pathology of central nervous system disorders and treatment Effect.Specifically, it has been determined that 5-HT6Some CNS (central nervous system) disease is had potential treatment to make by selective ligands With, such as parkinson disease, Huntington Chorea, anxiety neurosis, depression, manic depressive illness, psychosis, epilepsy, obsession, inclined head Bitterly, Alzheimer's disease (cognition and memory enhancing), sleep disorder, eating disorders such as anorexia and bulimia nerovsa, panic attack, ADHD (attention deficit hyperactivity disorder), attention deficit disorder, Drug abuse such as cocaine, ethanol, nicotine and benzo DiazaDe-recessive brain syndrome, schizophrenia and the disease relevant with spinal trauma or head injury that class causes are such as Hydrocephalus.Anticipated described compound can be additionally used in some stomach intestinal disease such as functional intestinal disease for the treatment of.(see for example Roth, B.L. etc., J.Pharmacol.Exp.Ther., 268,1403-14120 (1994), Sibley, D.R. etc., Mol, Pharmacol., 43,320-327 (1993), A.J.Sleight etc., Neurotransmission, 11,1-5 (1995) and Sleight, A.J. etc., Serotonin ID Research Alert, 1997,2 (3), 115-118).
Research find, it is known that 5-HT6Receptor selective antagonists improves the glutamic acid in cortex of frontal lobe and sky significantly The level of winter propylhomoserin, and do not improve the level of hormone, dopamine or 5-HT on nor-kidney.This note in memory and cognitive process The selectivity of the specific neurochemical anticipated raises and has strongly suggested that 5-HT6Part effect in cognition (Dawson, L.A.；Nguyen, H.Q.；Li, P., British Journal of Pharmacology, 2000,130 (1), 23-26).With Known selectivity 5-HT6The research that memory and the study of animal are carried out by receptor antagonist has some positive effects (Rogers, D.C.；Hatcher, P.D.；Hagan, J.J., Society of Neuroscience, Abstracts, 2000, 26,680).5-HT6The relevant potential therapeutic use of part is treatment child and the ADD of adult.Because 5-HT6 Receptor antagonist seems to improve the activity of nigrostriatal dopamine approach, and because ADHD and the exception in caudatum Relevant (Ernst, M；Zametkin, A.J.；Matochik, J.H.；Jons, P.A.；Cohen, R.M., Journal of Neuroscience, 1998,18 (5), 5901-5907), so, 5-HT6Receptor antagonist can treat ADD. It has also been determined that 5-HT6Receptor antagonist is the potentially useful compound for the treatment of obesity.See for example Bentley etc., Br.J.Pharmac.1999, supplementary issue 126；Bentley etc., J.Psychopharmacol.1997, supplementary issue A64:255；Wooley Deng, Neuropharmacology 2001,41:210-129 and WO02098878.
The invention provides a class and there is 5-HT6The noval chemical compound of receptor antagonist activity, possesses preferable clinical practice Prospect.Compared with existing similar compound, the compound of the present invention has more preferable drug effect, medicine for character and/or toxicity spy Property.
Summary of the invention
The present invention relates to a substituted heterocyclic compound of class, different from existing disclosed compound, it has good 5- HT6Receptor antagonist activity.Further, compared to existing 5-HT6Receptor antagonist, the compounds of this invention novel structure, character is steady Fixed, preparation cost is low, has pharmacodynamics and pharmacokinetic advantage, and safety is good, therefore possess the most clinical answering Use prospect.
The compounds of this invention and comprise the pharmaceutical composition of described compound to 5-HT6Receptor has preferable affinity interaction, For treatment and 5-HT6Receptor related disease, particularly has preferable therapeutic effect to Alzheimer's disease.
On the one hand, the present invention relates to a kind of compound, it is compound shown in the compound shown in formula (I) or formula (I) Stereoisomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or front Medicine,
Wherein:
For singly-bound or double bond；
N is 0,1,2 or 3；With
Each R1、R2、R3、R4、R5、R6、R7With Cy, there is implication of the present invention.
In one embodiment, R1、R2、R3、R4And R5It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-OH、- NRaRb,-C (=O) Rc,-S (=O)2Rc,-C (=O) NRaRb,-S (=O)2NRaRb、C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynes Base, C1-C6Alkoxyl, C1-C6Alkylthio group, (C3-C8Cycloalkyl)-(C0-C6Alkylidene)-, (C2-C10Heterocyclic radical)-(C0-C6Alkylene Base)-, (C6-C10Aryl)-(C0-C6Alkylidene)-or (C1-C9Heteroaryl)-(C0-C6Alkylidene)-, wherein said C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Alkoxyl, C1-C6Alkylthio group, (C3-C8Cycloalkyl)-(C0-C6Alkylidene)-, (C2-C10Miscellaneous Ring group)-(C0-C6Alkylidene)-, (C6-C10Aryl)-(C0-C6Alkylidene)-and (C1-C9Heteroaryl)-(C0-C6Alkylidene)-solely Stand and be optionally independently selected from D, F, Cl, Br, I ,-CN ,-NO by one or more2、-NH2,-OH ,-SH ,-COOH, oxo (=O), C1-C6Alkyl, C1-C6Alkoxyl, C1-C6Alkylthio group or C1-C6The substituent group of alkylamino is replaced；With each Ra、RbAnd RcHave as Implication of the present invention.
In one embodiment, each R6And R7Independently be H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-COOH、 C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Alkoxyl, C1-C6Alkylamino, C1-C6Alkylthio group, (C3-C8Cycloalkyl)- (C0-C6Alkylidene)-, (C2-C10Heterocyclic radical)-(C0-C6Alkylidene)-, (C6-C10Aryl)-(C0-C6Alkylidene)-or (C1-C9Miscellaneous Aryl)-(C0-C6Alkylidene)-, wherein said C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Alkoxyl, C1-C6Alkane ammonia Base, C1-C6Alkylthio group, (C3-C8Cycloalkyl)-(C0-C6Alkylidene)-, (C2-C10Heterocyclic radical)-(C0-C6Alkylidene)-, (C6-C10 Aryl)-(C0-C6Alkylidene)-and (C1-C9Heteroaryl)-(C0-C6Alkylidene)-individually optionally by one or more independent choosings From D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-SH ,-COOH, oxo (=O), C1-C6Alkyl, C1-C6Alkoxyl, C1-C6 Alkylthio group or C1-C6The substituent group of alkylamino is replaced.
In one embodiment, Cy is C3-C6Cycloalkyl or the heterocyclic radical of 4-7 annular atoms composition, wherein said C3- C6The heterocyclic radical of cycloalkyl and 4-7 annular atoms composition individually optionally by one or more be independently selected from D, F, Cl, Br, I ,- CN、-NO2、-OH、-SH、-NRaRb,-C (=O) Rc,-S (=O)2Rc,-C (=O) NRaRb,-S (=O)2NRaRb, oxo (=O), C1-C6Alkyl, C1-C6Alkoxyl, C1-C6Haloalkyl, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, (C3-C8Cycloalkyl)- (C0-C6Alkylidene)-, (C2-C10Heterocyclic radical)-(C0-C6Alkylidene)-, (C6-C10Aryl)-(C0-C6Alkylidene)-or (C1-C9Miscellaneous Aryl)-(C0-C6Alkylidene)-substituent group replaced；With each Ra、RbAnd RcThere is implication as described in the present invention.
In one embodiment, each Ra、RbAnd RcIndependently be H ,-OH, C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxyl, C1-C6Halogenated alkoxy, (C3-C8Cycloalkyl)-(C0-C6Alkylidene)-, (C2-C10Miscellaneous Ring group)-(C0-C6Alkylidene)-, (C6-C10Aryl)-(C0-C6Alkylidene)-or (C1-C9Heteroaryl)-(C0-C6Alkylidene)-.
In one embodiment, R1、R2、R3、R4And R5It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-OH、- NRaRb,-C (=O) Rc,-S (=O)2Rc,-C (=O) NRaRb,-S (=O)2NRaRb、C1-C4Alkyl, C2-C4Thiazolinyl, C2-C4Alkynes Base, C1-C4Alkoxyl, C1-C4Alkylthio group, (C3-C6Cycloalkyl)-(C0-C4Alkylidene)-, (C2-C6Heterocyclic radical)-(C0-C4Alkylene Base)-, (C6-C10Aryl)-(C0-C4Alkylidene)-or (C1-C5Heteroaryl)-(C0-C4Alkylidene)-, wherein said C1-C4Alkyl, C2-C4Thiazolinyl, C2-C4Alkynyl, C1-C4Alkoxyl, C1-C4Alkylthio group, (C3-C6Cycloalkyl)-(C0-C4Alkylidene)-, (C2-C6Miscellaneous Ring group)-(C0-C4Alkylidene)-, (C6-C10Aryl)-(C0-C4Alkylidene)-and (C1-C5Heteroaryl)-(C0-C4Alkylidene)-solely Stand and be optionally independently selected from D, F, Cl, Br, I ,-CN ,-NO by one or more2、-NH2,-OH ,-SH ,-COOH, oxo (=O), C1-C4Alkyl, C1-C4Alkoxyl, C1-C4Alkylthio group or C1-C4The substituent group of alkylamino is replaced；With each Ra、RbAnd RcHave as Implication of the present invention.
In one embodiment, R1、R2、R3、R4And R5It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-OH、- NH2、-N(CH3)2,-C (=O) CH3,-C (=O) OH ,-C (=O) OCH3、-CONH2, methyl, ethyl, n-pro-pyl, isopropyl, first Epoxide, ethyoxyl, positive propoxy, isopropoxy ,-CF3Or-OCF3。
In one embodiment, each R6And R7Independently be H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-COOH、 C1-C4Alkyl, C2-C4Thiazolinyl, C2-C4Alkynyl, C1-C4Alkoxyl, C1-C4Alkylamino, C1-C4Alkylthio group, (C3-C6Cycloalkyl)- (C0-C4Alkylidene)-, (C2-C6Heterocyclic radical)-(C0-C4Alkylidene)-, (C6-C10Aryl)-(C0-C4Alkylidene)-or (C1-C5Miscellaneous Aryl)-(C0-C4Alkylidene)-, wherein said C1-C4Alkyl, C2-C4Thiazolinyl, C2-C4Alkynyl, C1-C4Alkoxyl, C1-C4Alkane ammonia Base, C1-C4Alkylthio group, (C3-C6Cycloalkyl)-(C0-C4Alkylidene)-, (C2-C6Heterocyclic radical)-(C0-C4Alkylidene)-, (C6-C10 Aryl)-(C0-C4Alkylidene)-and (C1-C5Heteroaryl)-(C0-C4Alkylidene)-individually optionally by one or more independent choosings From D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-SH ,-COOH, oxo (=O), C1-C4Alkyl, C1-C4Alkoxyl, C1-C4 Alkylthio group or C1-C4The substituent group of alkylamino is replaced；With each Ra、RbAnd RcThere is implication as described in the present invention.
In one embodiment, each Ra、RbAnd RcIndependently be H ,-OH, C1-C4Alkyl, C2-C4Thiazolinyl, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxyl, C1-C4Halogenated alkoxy, (C3-C6Cycloalkyl)-(C0-C4Alkylidene)-, (C2-C6Heterocycle Base)-(C0-C4Alkylidene)-, (C6-C10Aryl)-(C0-C4Alkylidene)-or (C1-C5Heteroaryl)-(C0-C4Alkylidene)-.
In one embodiment, each R6And R7Independently be H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-COOH、 Methyl, ethyl, n-pro-pyl, isopropyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, secondary Butoxy or tert-butoxy.
In one embodiment, each Ra、RbAnd RcIndependently be H ,-OH, methyl, ethyl, n-pro-pyl, isopropyl, methoxy Base, ethyoxyl, positive propoxy, isopropoxy or phenyl.
In one embodiment, Cy is following subformula:
Wherein, Q is CH or N；
E and M is each independently-CH2-、-CHRx-,-C (=O)-,-NH-,-NRy-,-O-,-S-,-S (=O)-or-S (=O)2-；
T is 0,1,2 or 3；
R is 0 or 1；With
Each RxAnd RyThere is implication as described in the present invention.
In one embodiment, each RxAnd RyIndependently be D, F, Cl, Br, I ,-CN ,-NO2、-OH、-SH、-NRaRb、-C (=O) Rc,-S (=O)2Rc,-C (=O) NRaRb,-S (=O)2NRaRb、C1-C4Alkyl, C1-C4Alkoxyl, C1-C4Haloalkyl, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, (C3-C6Cycloalkyl)-(C0-C4Alkylidene)-, (C2-C6Heterocyclic radical)-(C0-C4Alkylene Base)-, (C6-C10Aryl)-(C0-C4Alkylidene)-or (C1-C5Heteroaryl)-(C0-C4Alkylidene)-.
In one embodiment, Cy is following subformula:
Wherein, each RxAnd RyThere is implication as described in the present invention.
In one embodiment, each RxAnd RyIndependently be D, F, Cl, Br, I ,-CN ,-NO2、-OH、-SH、-NH2、-N (CH3)2,-C (=O) CH3,-C (=O) OH ,-C (=O) OCH3、-CONH2, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, Isobutyl group, the tert-butyl group, cyclopropyl, cyclobutyl, cyclopenta, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl Or tetrahydrofuran base.
In one embodiment, compound of the present invention, it is to have the compound of one of following structure or have One of the following stereoisomer of compound of structure, tautomer, nitrogen oxides, hydrate, solvate, metabolism are produced Thing, pharmaceutically acceptable salt or prodrug:
On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition comprises the compound of the present invention.
In one embodiment, pharmaceutical composition of the present invention, comprise pharmaceutically acceptable carrier, tax further Shape agent, diluent, adjuvant, vehicle or their combination in any.
In one embodiment, pharmaceutical composition of the present invention, it comprises additional treatment agent further, described additional Therapeutic agent is the medicine for the treatment of A Cihaimo disease, the medicine for the treatment of nervous disorders or combinations thereof.
In one embodiment, additional treatment agent of the present invention is donepezil (donepezil), nalmefene (nalmefene), risperidone (risperidone), vitamin e (Vitamin E), AVN-211, AVN-101, RP-5063, Tozadenant, PRX-3140, intepirdine, idalopirdine, tacrine (tacrine), Rivastigmine (rivastigmine), galantamine (galantamine), memantine (memantine), meter Ta Zhaping (Mirtazapine), Venlafaxine (venlafaxine), desipramine (desipramine), nortriptyline (nortriptyline), zolpidem (zolpidem), zopiclone (zopiclone), nicergoline (nicergoline), piracetam (piracetam), department come Ji Lan (selegiline), pentoxifylline (pentoxifylline) or their combination in any.
On the other hand, the present invention relates to the compounds of this invention or the pharmaceutical composition purposes in preparing medicine, described medicine Thing is used for preventing, treat or alleviating and 5-HT6Receptor related disease.
In one embodiment, the present invention relates to and 5-HT6Receptor related disease is CNS disease.
In one embodiment, the present invention relates to and 5-HT6Receptor related disease is CNS disease, wherein said CNS Disease, schizophrenia, obsessive idea and behavior disorder, the manicdepressive that disease is ADHD, anxiety is relevant to psychentonia Disease, nervous disorders, dysmnesia, attention deficit disorder, parkinson disease, amyotrophic lateral sclerosis, Alzheimer's disease or Huntington Chorea.
In another embodiment, the present invention relates to and 5-HT6Receptor related disease is disorder of gastrointestinal tract.
In another embodiment, the present invention relates to and 5-HT6Receptor related disease is obesity.
Another aspect of the present invention relates to the method for the preparation of compound, separation and the purification shown in formula (I).
Any embodiment of the either side of the present invention, can be combined with other embodiment, as long as they are not There will be contradiction.Additionally, in any embodiment of either side of the present invention, it is real that arbitrary technical characteristic goes for other Execute this technical characteristic in scheme, as long as they do not have contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspects and Content in terms of him will make more specific complete description below.All lists of references in this specification are quoted by entirety In this.
Detailed description of the invention book
Definition and general terms
Certain embodiments of the present invention be will now be described in more detail, and the example is by the structural formula enclosed and chemical formula explanation.This Invention intention contains all of replacement, amendment and equivalent technical solutions, and they are included in such as the present invention of claim definition In the range of.Those skilled in the art will appreciate that many similar with the described herein or method of equivalent and material can be used in reality Trample the present invention.The present invention is not limited to method described herein and material.At the document combined, patent and similar material one Or many different from the application or conflicting in the case of (include but not limited to defined term, term application, described Technology, etc.), be as the criterion with the application.
It will further be appreciated that some feature of the present invention, for clearly visible, carry out in multiple independent embodiments Describe but it also may provide in combination in single embodiment.Otherwise, the various features of the present invention, for brevity, Single embodiment is described but it also may individually or with the sub-portfolio being arbitrarily suitable for provide.
Unless otherwise indicated, 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 that identical implication.The all patents that the present invention relates to and public publication are integrally incorporated this by reference Bright.
Unless otherwise indicated, it should apply following definition used herein.For purposes of the present invention, chemical element with Periodic table of elements CAS version, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can be joined Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Description in Wiley&Sons, New York:2007, entire contents is incorporated herein by.
Context except as otherwise noted or has significantly conflict, article 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.Such as, " component " refers to one or more component, it is possible to have more than one Component be taken into account in the embodiment of described embodiment and use or use.
Term used in the present invention " patient " refers to people's (including adult and child) or other animals.Implement at some In scheme, " patient " refers to people.
It is open language that term " comprises ", i.e. includes the content specified by the present invention, but is not precluded from otherwise Content.
Term " stereoisomer " refers to have identical chemical constitution, but atom or group spatially arrangement mode is different Compound.Stereoisomer includes that enantiomer, diastereomer, conformer (rotamer), geometry are different Structure body (cis/trans) isomer, atropisomer, etc..
Term " chirality " is that have can not the molecule of overlapping character with its mirror image；And " achirality " refers to permissible with its mirror image Overlapping molecule.
Term " enantiomer " refer to two of a compound can not be overlapping but be mutually the isomer of mirror image relationship.
Term " racemate " or " racemic mixture " be optically active two enantiomers of hypodactylia etc. rub That mixture.
Term " diastereomer " refers to two or more chiral centre and the solid of its molecule mirror image the most each other Isomer.Diastereomer has different physical propertys, such as fusing point, boiling point, spectral quality and reactivity.Diastereo-isomerism Body mixture can be separated by high resolution analysis operation such as electrophoresis and chromatograph, such as HPLC.
Stereochemical definitions used in the present invention and rule typically 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 compound exist with optical active forms, and i.e. they have and make the flat of linearly polarized light The ability that face rotates.When describing optically active compound, prefix D and L or R and S is used to represent that molecule is about one Individual or the absolute configuration of mulitiple chiral centers.Prefix d and l or (+) and (-) are to revolve for linearly polarized light caused by appointed compound Turn symbol, wherein (-) or l represent that compound is left-handed.Prefix for (+) or the compound of d be dextrorotation.A kind of concrete Stereoisomer is enantiomer, and the mixture of this isomer is referred to as enantiomeric mixture.The 50 of enantiomer: 50 mixture are referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereo selectivity or three-dimensional special During the opposite sex, may occur in which this situation.
Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can be enriched with raceme or enantiomer Presented in, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration aspect there is 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 Excess.
According to starting material and the selection of method, the compounds of this invention can with in possible isomer or they Mixture, the such as form of racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) is deposited ?.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent to prepare, or use routine techniques to tear open Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing dibasic cycloalkanes in compound Base, the substituent group of cycloalkyl may have cis or trans configuration.
The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or the purest geometric isomer, enantiomer, diastereomer, such as, by chromatography and/or fractional crystallization Method.
What term " tautomer " or " tautomeric form " referred to have different-energy can be by low energy barrier (low Energy barrier) constitutional isomer of mutual inversion of phases.If tautomerism is possible (as in the solution), then can reach The chemical equilibrium of tautomer.Such as, (also referred to as proton translocation makes a variation proton tautomer (protontautomer) mutually Structure body (prototropic tautomer)) include being migrated the mutual inversion of phases carried out by proton, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) includes being come by the restructuring of some bonding electronss The mutual inversion of phases carried out.The instantiation of ketoenol tautomerization be pentane-2,4-diketone and 4-hydroxyl amyl-3-alkene-2-ketone mutual The change of tautomeric.Another example tautomeric is phenol-keto tautomerism.One concrete reality of phenol-keto tautomerism Example is pyridine-4-alcohol and the change of pyridine-4 (1H)-one tautomer.Unless otherwise noted, the compounds of this invention is all Tautomeric forms is within the scope of the present invention.
Term " optionally " or " optionally " refer to the event described subsequently or situation can but not necessarily occur, and this is retouched State and include situation that wherein said event or situation occur and wherein its absent variable situation.Such as, " optional key " refers to This key can exist or can not exist, and this description includes singly-bound, double or triple bonds.
Term " unsaturated " or " undersaturated " represent that part is containing one or more degrees of unsaturation.
As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, as General formula compound above, or as example special inside embodiment, subclass, and the compounds that the present invention is comprised. Should be appreciated that " optionally substituted " this term and " substituted or unsubstituted " this term can exchange use.It is said that in general, art Language " replaces " or " substituted " represents that the one or more hydrogen atoms in given structure are replaced by concrete substituent group.Unless other Aspect shows, an optional substituted radical can replace in each commutable position of group.When given structure In formula, more than one position can be selected from one or more substituent groups of concrete group and replaced, then substituent group can identical or Differently replace in each position.Wherein said substituent group is it may be that but be not limited to, D, F, Cl, Br, I ,-CN ,-NO2、- NH2,-OH, oxo (=O), carboxyl, alkyl, thiazolinyl, alkynyl, alkoxyl, alkylamino, alkylthio group, haloalkyl, haloalkoxy The substituted alkyl of base, hydroxyl, the substituted haloalkyl of hydroxyl, the substituted alkoxyl of hydroxyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl Base, aryloxy group, heteroaryloxy, hydroxyl substituted alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (= O)2-, hydroxyl substituted alkyl-S (=O)-, hydroxyl substituted alkyl-S (=O)2-, etc..
In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode used in the present invention " each ... to independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, and it both may be used To refer in different groups, do not affect mutually between concrete option expressed between same-sign, it is also possible to represent in phase In same group, do not affect mutually between concrete option expressed between same-sign.Such as, structural formula "-NRaRb" and knot Structure formula "-C (=O) NRaRb" R between the twoaAnd RbConcrete option the most unaffected.
At each several part of this specification, the come into the open substituent group of compound of the present invention is open according to radical species or scope.Special Not pointing out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.Such as, term “C1-C6Alkyl " refer in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
At each several part of the present invention, describe connection substituent group.When this structure clearly needs linking group, for this Ma Kushi variable cited by group is interpreted as linking group.Such as, if this structure needs linking group and for this The Ma Kushi group definition of variable lists " alkyl " or " aryl ", then it should be understood that should " alkyl " or " aryl " represent respectively The alkylidene group connected or arylene group.
Terminology used in the present invention " alkyl " or " alkyl group ", represent containing 1 to 20 carbon atom, saturated straight chain or Side chain univalent hydrocarbyl group, wherein, the substituent group institute that described alkyl group can optionally be described 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 Containing 1-4 carbon atom；The most in one embodiment, alkyl group contains 1-3 carbon atom.
The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-pro-pyl (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), the tert-butyl group (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2-amyl group (-CH (CH3)CH2CH2CH3), 3-amyl group (-CH (CH2CH3)2), 2-methyl-2-butyl (-C (CH3)2CH2CH3), 3-methyl-2-butyl (-CH (CH3)CH(CH3)2), 3-methyl isophthalic acid-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 group (-C (CH3)2CH2CH2CH3), 3-first Base-2-amyl group (-CH (CH3)CH(CH3)CH2CH3), 4-methyl-2-amyl group (-CH (CH3)CH2CH(CH3)2), 3-methyl-3-penta Base (-C (CH3)(CH2CH3)2), 2-methyl-3-amyl group (-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..
Term " alkylidene " represents remove obtained by two hydrogen atoms from saturated straight or branched alkyl saturated 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；Another embodiment party In case, alkylidene group contains 1-3 carbon atom；The most 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..Described alkylene Base group is optionally replaced by one or more substituent groups described in the invention.
Term " thiazolinyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, at least one of which insatiable hunger And site, i.e. there is a carbon-to-carbon sp2Double bond, wherein, described alkenyl group is optionally by one or more described in the invention Substituent group is replaced, and it includes " cis " and the location of " trans ", or " E " and the location of " Z ".
Term " alkynyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, at least one of which insatiable hunger And site, i.e. there is carbon-to-carbon sp tri-key, wherein, described alkynyl group is optionally by one or more described in the invention Substituent group is replaced.
Term " hetero atom " represents one or more oxygen (O), sulfur (S), nitrogen (N), phosphorus (P) or silicon (Si), including nitrogen (N), Sulfur (S) and the form of phosphorus (P) any oxidation state；Primary, secondary, tertiary amine and the form of quaternary ammonium salt；Or the hydrogen on nitrogen-atoms in heterocycle The form being replaced, such as, N (as 3, the N in 4-dihydro-2 h-pyrrole base), NH (NH as in pyrrolidinyl) or NR is (as N- NR in substituted pyrrolidinyl).
Term " halogen " and " halo " refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represents that alkyl, thiazolinyl or alkoxy base are by one Individual or multiple halogen atoms are replaced, and wherein alkyl, thiazolinyl and alkoxy base have implication of the present invention, such reality Example comprises, but is not limited to, difluoromethyl, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoro ethoxies, 2,2,3,3-tetrafluoros Propoxyl group, etc..Described haloalkyl, haloalkenyl group or halo alkoxy group are optionally retouched by one or more present invention The substituent group stated is replaced.
Term " alkoxyl " represents that alkyl group is connected with molecule remainder by oxygen atom, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.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.Described alkoxy base is optionally sent out by one or more The substituent group of bright description is replaced.
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 Epoxide (-OCH (CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (- OCH2CH(CH3)CH2CH3), etc..
Term " alkylthio group " refers to C1-C6The alkyl of straight or branched is connected with molecule remainder by sulphur atom.
Term " alkylamino " or " alkyl amino " include " N-alkyl amino " and " N, N-dialkyl amido ", wherein amino base Group is separately replaced by one or two alkyl group, and wherein alkyl group has implication as described in the present invention.
Term " cycloalkyl " represents containing 3-12 carbon atom, unit price or the saturated monocycle of multivalence, dicyclo or three ring bodies System.In one embodiment, cycloalkyl comprises 3-10 carbon atom；In another embodiment, to comprise 3-8 carbon former for cycloalkyl Son；In yet another embodiment, cycloalkyl comprises 3-6 carbon atom.The example of group of naphthene base includes, but not limited to ring third Base, cyclobutyl, cyclopenta, cyclohexyl, etc..Described group of naphthene base is optionally by one or more described in the invention taking Replaced for base.
Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, all referring to comprising the monocycle of 3-12 annular atoms, double Ring or three-ring system, on its medium ring, one or more atoms are replaced by hetero atom independently, and described hetero atom has such as this Bright described implication, ring can be fully saturated or comprise one or more degree of unsaturation, but an armaticity ring all can not Have.Described heterocyclyl groups is optionally replaced by one or more substituent groups described in the invention.
Heterocyclic radical can be carbon back or hetero atom base.-the CH of its medium ring2-group optionally by-C (=O)-replacement, ring Sulphur atom is optionally oxidized to S-oxide, and the nitrogen-atoms of ring is optionally oxidized to N-oxygen compound.
In one embodiment, heterocyclic radical is the heterocyclic radical of 4-7 annular atoms composition, refers to comprise 4-7 annular atoms The undersaturated ring of saturated or part, at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom.4-7 annular atoms composition miscellaneous The example of ring group includes, but not limited to azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, Tetramethylene sulfide Base, dihydro-thiophene base, 1,3-dioxy cyclopenta, two sulfur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H-pyranose, 4H-pyrrole Mutter base, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dialkyl group, dithiane base, thiophene alkyl is high Piperazinyl, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase, sulfur azepineBase, etc. Deng.-CH in heterocyclic radical2-group is included, but not limited to 2-oxo-pyrrolidine base, oxo-1 by the example of-C (=O)-replacement, 3-thiazolidinyl, 2-piperidone base, 3,5-dioxy piperazine piperidinyl, hybar X base, etc..In heterocyclic radical, sulphur atom is oxidized Example includes, but not limited to sulfolane base, thio-morpholinyl 1,1-dioxide, etc..4-7 described annular atoms composition Heterocyclyl groups optionally replaced by one or more substituent groups described in the invention.
In another embodiment, heterocyclic radical is the heterocyclic radical of 4 annular atoms compositions, refers to comprise the full of 4 annular atomses With or the undersaturated monocycle of part, at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom.The heterocycle of 4 annular atoms compositions The example of base includes, but not limited to azelidinyl, oxetanylmethoxy, thietanyl, etc..4 described annular atoms groups The heterocyclyl groups become optionally is replaced by one or more substituent groups described in the invention.
In another embodiment, heterocyclic radical is the heterocyclic radical of 5 annular atoms compositions, refers to comprise the full of 5 annular atomses With or the undersaturated monocycle of part, at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom.The heterocycle of 5 annular atoms compositions The example of base includes, but not limited to pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazoline Base, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3-dioxy cyclopenta, two sulfur rings Amyl group, etc..-CH in heterocyclic radical2-group by-C (=O)-substitute example include, but not limited to 2-oxo-pyrrolidine base, Oxo-1,3-thiazoles alkyl, etc..The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to sulfolane base, etc.. The heterocyclyl groups of 5 described annular atoms compositions is optionally replaced by one or more substituent groups described in the invention.
In another embodiment, heterocyclic radical is the heterocyclic radical of 6 annular atoms compositions, refers to comprise the full of 6 annular atomses With or the undersaturated monocycle of part, at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom.The heterocycle of 6 annular atoms compositions The example of base includes, but not limited to THP trtrahydropyranyl, dihydro pyranyl, 2H-pyranose, 4H-pyranose, tetrahydro thiapyran base, piperazine Piperidinyl, morpholinyl, thio-morpholinyl, piperazinyl, dialkyl group, dithiane base, thiophene alkyl, etc..-CH in heterocyclic radical2-base Group by-C (=O)-substitute example include, but not limited to 2-piperidone base, 3,5-dioxy piperazine piperidinyl, hybar X base, etc. Deng.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to thio-morpholinyl 1,1-dioxide, etc..Described The heterocyclyl groups of 6 annular atoms compositions is optionally replaced by one or more substituent groups described in the invention.
Term " aryl " represents containing 6-14 annular atoms, or 6-12 annular atoms, or the monocycle of 6-10 annular atoms, double Ring and the carbocyclic ring system of three rings, at least one of which ring is aromatic.
Term " heteroaryl " represents containing 5-12 annular atoms, or 5-10 annular atoms, or the monocycle of 5-6 annular atoms, Dicyclo and three-ring system, at least one of which ring is aromatic, and at least one ring comprises one or more hetero atom.
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo. Such conversion is hydrolyzed in blood by prodrug or is that precursor structure is affected through enzymatic conversion in blood or tissue.This Bright prodrug compounds can be ester, and in existing invention, ester can have phenyl ester class, aliphatic as prodrug (C1-C24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as in the present invention one Compound comprises hydroxyl, i.e. can be acylated the compound obtaining prodrug form.Other prodrug form includes Phosphate ester, if these phosphate compounds are that the di on parent obtains.About complete the begging for of prodrug Discuss and be referred to documents below: 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 is incorporated herein by this.
Term used in the present invention " metabolite " refers to that concrete compound or its salt passes through metabolism in vivo Obtained product.The metabolite of one compound can be identified by technology known to art, its activity Can adopt as passing through as described in the present invention and experimentally characterize.Such product can be by administration Compound is through peroxidating, reduction, hydrolysis, amidated, desamido-effect, and esterification, degreasing, enzymatic lysis etc. method obtains.Phase Ying Di, the present invention includes the metabolite of compound, including when the compound of the present invention and mammal are fully contacted one section Metabolite produced by between.
" pharmaceutically acceptable salt " used in the present invention refers to organic salt and the inorganic salt of the compound of the present invention.Medicine On, acceptable salt is known to us at art, such as document: S.M.Berge et al., Described in J.Pharmaceutical Sciences, 66:1-19,1977.The salt that pharmaceutically acceptable nontoxic acid is formed Including, but is not limited to, reacting, with amino group, the inorganic acid salt formed has a hydrochlorate, hydrobromate, phosphate, sulfate, Perchlorate, and acylate such as acetate, oxalates, maleate, tartrate, citrate, succinate, malonic acid Salt, or obtain these salt by additive method such as ion exchange described on books document.Other are pharmaceutically acceptable Salt include adipate, alginate, Ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, boric acid Salt, butyrate, Camphora hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, ethyl sulfonic acid Salt, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproic acid Salt, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactate, laruate, lauryl sulfate, malate, Mesylate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- Phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, Valerate, etc..The salt obtained by suitable alkali includes alkali metal, alkaline-earth metal, ammonium and N+(C1-C4Alkyl)4Salt.This Invention is also intended to contemplate the quaternary ammonium salt that the compound of the group of any comprised N is formed.Water solublity or oil-soluble or dispersion produce Thing can be obtained by quaternization.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically can connect The salt being subject to farther includes the amine cation that suitable, nontoxic ammonium, quaternary ammonium salt and gegenions are formed, such as halogenide, hydrogen Oxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-C8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the association that the compound of one or more solvent molecule and the present invention is formed Thing.The solvent forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
When described solvent is water, it is possible to use term " hydrate ".In one embodiment, a compounds of this invention Molecule can combine with a hydrone, such as monohydrate；In another embodiment, a compounds of this invention molecule Can combine with more than one hydrone, such as dihydrate, in yet another embodiment, a compounds of this invention divides Son can combine with the hydrone less than, such as semihydrate.It should be noted that hydrate of the present invention remains with non- The biological effectiveness of the described compound of hydrated form.
The when that term " blocking group " or " PG " referring to a substituent group and other reacted with functional groups, it is commonly used to resistance Disconnected or protect special functional.Such as, " blocking group of amino " refers to that a substituent group is connected with amino group and blocks Or amino functional in protection compound, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl Substituent group be used for block or protect the functional of hydroxyl, suitable blocking group to include trialkylsilkl, acetyl group, benzene Formoxyl and benzyl." carboxy protective group " refer to the substituent group of carboxyl for blocking or protect the functional of carboxyl, general Carboxyl-protecting group includes-CH2CH2SO2Ph, cyano ethyl, 2-(TMS) ethyl, 2-(TMS) ethoxy Ylmethyl, 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl sulfonyl) ethyl, 2-(diphenylphosphino) ethyl, nitro second Base, etc..Document refers to for the description that blocking group is general: Greene et al., Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991and Kocienski et al., Protecting Groups,Thieme,Stuttgart,2005。
Any disease or disease " treated " in term as used in the present invention, and some embodiment middle fingers improve disease wherein Disease or disease (i.e. slow down or stop or palliate a disease or the development of its at least one clinical symptoms).In other embodiments In, " treatment " refers to relax or improve at least one body parameter, including the body parameter may not discovered by patient.At another In a little embodiments, " treatment " refers to (such as stablize perceptible symptom) from health or physiologically (such as stablize health Parameter) or above-mentioned two aspect regulation disease or diseases.In other embodiments, " treat " and refer to prevention or postpone disease or disease The outbreak of disease, occur or deteriorate.
Term " prevents " or " prevention " refers to obtain the minimizing of the risk of disease or obstacle and (that is: make at least one clinical condition of disease Shape stops development in main body, this main body may in the face of or tendency is in the face of this disease, but without experience or show in advance The symptom of disease).
The officinal salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes. It is said that in general, such salt can free acid form Yu stoichiometry by making these compounds suitable alkali (as Na, Ca, The hydroxide of Mg or K, carbonate, bicarbonate etc.) reaction, or by making free alkali form and the chemistry of these compounds The suitable acid reaction of metered amount is prepared.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, in the case of suitably, need to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton,Pa.,(1985)；" pharmaceutical salts handbook: character, select and apply (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list of the suitable salt of other can be found in.
It addition, compound disclosed by the invention, include their salt, it is also possible to their hydrate forms or comprise it The form of solvent (such as ethanol, DMSO, etc.) obtains, for their crystallization.The present invention comes into the open compound can be with pharmacy Upper acceptable solvent (including water) inherently or passes through design forming solvate；Therefore, it is contemplated that include solvation And unsolvated form.
Any structural formula that the present invention is given be also intended to represent these compounds not by isotope enrichment form and with The form of position element enrichment.The compound of isotope enrichment has the structure of the formula description that the present invention provides, except one or many Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes in the compounds of this invention can be introduced Including the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, 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, such as, and its In there is radiosiotope, as3H,14C and18Those compounds of F, or wherein there is non radioactive isotope, as2H and13C.The compound of such isotope enrichment can be used for metabolism research and (uses14C), kinetics research (uses such as2H or3H), detection or imaging technique, such as positron emission tomography (PET) or include medicine or substrate tissue measure of spread SPECT (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 Embodiment and the preparation process suitable isotope labeling reagent of described use in the routine techniques known or the present invention substitute former Carry out used unmarked reagent to prepare.
Additionally, higher isotope particularly deuterium is (i.e.,2H or D) replacement can provide some treat advantage, these advantages are Brought by metabolic stability is higher.Such as, Half-life in vivo increases or volume requirements reduces or therapeutic index obtains improving band Come.Should be appreciated that the deuterium in the present invention is seen as the substituent group of formula (I) compound.Can determine by the isotope enrichment factor The concentration of justice such higher isotope particularly deuterium.Term used in the present invention " the isotope enrichment factor " refers to specified same Ratio between isotope abundance and the natural abundance of position element.If the substituent group of the compounds of this invention is designated as deuterium, this change Compound for each D-atom specified, have at least 3500 (each specify the deuterium of 52.5% at D-atom to mix), at least 4000 (deuterium of 60% mixes), at least 4500 (deuterium of 67.5% mixes), at least 5000 (deuterium of 75% mixes), at least 5500 The deuterium of 82.5% (mix), at least 6000 (deuterium of 90% mixes), at least 6333.3 (deuterium of 95% mixes), at least 6466.7 (deuterium of 97% mixes), at least 6600 (deuterium of 99% mixes) or the isotope enrichment of at least 6633.3 (deuterium of 99.5% mixes) The factor.The pharmaceutically useful solvate of the present invention includes that wherein recrystallisation solvent can be the substituted such as D of isotope2O, acetone-d6、 DMSO-d6Those solvates.
Unless other aspects show, all suitable isotope changes of compound of the present invention, stereoisomer, make a variation mutually Structure body, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug broadly fall into the model of the present invention Enclose.
Present invention compound of coming into the open can contain asymmetric or chiral centre, therefore can be with different stereoisomer forms Exist.It is contemplated that all stereoisomer forms of compound shown in formula (I), include but not limited to diastereo-isomerism Body, enantiomer, atropisomer and geometry (or conformation) isomer, and their mixture such as racemic mixture, Become the ingredient of the present invention.
Unless other aspects show, all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.It addition, unless other aspects show, the structural formula of compound described in the invention includes one or more different former The enriched isotope of son.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicates, then this structure All stereoisomers all consider within the present invention, and be included in the invention as present invention compound of coming into the open.When Spatial chemistry is expressed the real wedge shape line (solid wedge) of particular configuration or time dotted line indicates, then the stereoisomerism of this structure Body clearly and defines with regard to this.
Within the nitrogen oxides of the compounds of this invention is also contained in the scope of the present invention.Can be by often using at an elevated temperature With oxidant (such as hydrogen peroxide), in the presence of the acid of such as acetic acid, aoxidize corresponding nitrogen-containing basic material, or pass through With acid reaction excessively in applicable solvent, such as, react with peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or Chloroform or dichloromethane react with 3-chloroperoxybenzoic acid, prepares the nitrogen oxides of the compounds of this invention.
On the other hand, the present invention relates to prepare the intermediate of compound shown in formula (I).
On the other hand, the present invention relates to the preparation of compound shown in formula (I), separation and the method for purification.
Compound shown in formula (I) can exist in a salt form.In one embodiment, described salt refers to pharmaceutically can connect The salt being subject to.Term " pharmaceutically acceptable " refers to that material or compositions must be with other compositions comprising preparation and/or use it The mammal for the treatment of is chemically and/or compatible in toxicology.In another embodiment, described salt is not necessarily and pharmaceutically may be used The salt accepted, could be for compound shown in preparation and/or purification formula (I) and/or is used for separating compound shown in this formula (I) The intermediate of enantiomer.
If the compound of the present invention is alkaline, the most conceivable salt can by provide on document any suitably Method prepares, and such as, uses mineral acid, example hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid and phosphoric acid etc..Or use organic Acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, acetone acid, oxalic acid, glycolic and salicylic acid；Pyrans Saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and tartaric acid；Aminoacid, such as aspartic acid and paddy Propylhomoserin；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, ethyl sulfonic acid, etc..
If the compound of the present invention is acid, the most conceivable salt can be prepared by suitable method, e.g., Use inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide or alkaline earth metal hydroxide, etc. Deng.Suitably salt includes, but is not limited to, the organic salt obtained from aminoacid, and such as glycine and arginine, ammonia, such as primaquine, secondary Ammonia and tertiary ammonia, and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtain from sodium, calcium, potassium, magnesium, manganese, ferrum, copper, zinc, aluminum and lithium Inorganic salt.
On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises the compounds of this invention.One In embodiment, pharmaceutical composition of the present invention, further include pharmaceutically acceptable carrier, excipient, adjuvant, molten Matchmaker or combinations thereof.In another embodiment, pharmaceutical composition can be liquid, solid, semisolid, gel or spray Type.
The compounds of this invention and pharmaceutical composition, preparation and administration
When can be used for treatment, formula (I) compound of therapeutically effective amount and pharmaceutically acceptable salt thereof can be as not adding The chemical drugs of work gives, and the active component being alternatively arranged as pharmaceutical composition provides.Therefore, the present invention also provides for a kind of medicine group Compound, including the compound shown in formula (I) or its single stereoisomer, the raceme of isomer or non-racemic mixture Or its pharmaceutically acceptable salt or solvate.In an embodiment of the invention, described pharmaceutical composition is further Comprise at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally, other treatment and/or prevent into Point.
Suitably carrier, adjuvant and excipient agent be well known to those skilled in the art and be described in detail in such as Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins,Philadelphia；Gennaro A.R.et al., Remington:The Science and Practice of Pharmacy (2000) Lippincott, Williams& Wilkins,Philadelphia；With Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, in Chicago.
Comprise the compounds of this invention or the Therapeutic Method of pharmaceutical composition administration, farther include that patient is carried out other and resist The administration of Alzheimer disease drug (therapeutic alliance), wherein the medicine of other anti-Alzheimer diseases is donepezil, Na Mei Sweet smell, risperidone, vitamin e, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, intepirdine, Idalopirdine, tacrine, Rivastigmine, galantamine, memantine, meter Ta Zhaping, venlafaxine, desipramine, nor-replace Woods, zolpidem, zopiclone, nicergoline, piracetam, selegiline, pentoxifylline or their combination in any.
Term as used herein " therapeutically effective amount " refers to be enough to demonstrate each activity group of significant patient benefit The total amount divided.When using single active component individually dosed, this term only refers to this composition.When combination application, this term No matter then refer to combination, be sequentially or simultaneously administered, all cause the combined amount of the active component of therapeutic effect.Formula (I) compound And pharmaceutically acceptable salt is described above.From compatible with other compositions of preparation and to its receiver harmless in the sense that come Saying, carrier, diluent or excipient must be acceptable.According to the another aspect of present disclosure, also provide for for preparing The method of pharmaceutical preparation, the method includes by formula (I) compound or its pharmaceutically acceptable salt with one or more pharmaceutically Acceptable carrier, diluent or excipient mixing.Term used in the present invention " pharmaceutically acceptable " refers to such Compound, raw material, compositions and/or dosage form, they rational medicine judge in the range of, it is adaptable to patient tissue contacts and Without excessive toxicity, zest, allergy or the other problems symmetrical with rational interests/Hazard ratio and complication, and have Effectiveness is in given application.
Generally, the compound of the present invention passes through any conventional method of application of the material for playing similar effectiveness with treatment Effective dose is applied.Suitable dosage range is typically 1-500mg every day, preferably 1-100mg every day, most preferably 1-every day 30mg, this depends on many factors, the seriousness of treated disease, the age of subject and relative health, institute Approach and the form by the effect of compound, used, use targeted indication and the preference of relevant medical practitioner and Experience.The those of ordinary skill treating described disease areas relies on personal knowledge and present disclosure without too much experiment I.e. can determine that the therapeutically effective amount of the compounds of this invention for giving disease.
Generally, the compound of the present invention is used with pharmaceutical dosage forms, and described pharmaceutical preparation includes that those are suitable to be administered orally (including oral cavity and Sublingual), rectum, nose, locally, lung, vagina or parenteral (include that intramuscular, intra-arterial, sheath be interior, subcutaneous and vein In) pharmaceutical preparation used or be suitable to suck or be blown into the pharmaceutical preparation of administration form.Preferably method of application is the most oral, Use suitable daily dose scheme, according to disease degree, it can be adjusted.
One or more compounds of the present invention can be placed in together with one or more conventional adjuvant, carrier or diluent In pharmaceutical composition and unit dosage form.Pharmaceutical composition and unit dosage form can comprise the conventional ingredient of conventional ratio, With or without other reactive compound or composition, unit dosage form can contain and the plan daily dose scope phase applied The active component of any suitable effective dose claimed.The application form of pharmaceutical composition can be solid such as tablet or fill glue Wafer, semisolid, powder, slow releasing preparation or liquid such as solution, suspensoid, Emulsion, elixir or the filling glue orally used Wafer；Or for rectum or the suppository form of vaginal application；Or the sterile injectable solutions form for parenteral use. Therefore, every contains about 1mg active component or more broadly, the preparation containing about 0.01 to about 100mg active component is suitable Representational unit dosage form.
The compound of the present invention can be configured to various Orally administered dosage form.Pharmaceutical composition and dosage form can To comprise one or more compound or pharmaceutically acceptable salt thereofs of the present invention as active component.Pharmaceutically useful carrier can be solid Or liquid.The preparation bag of solid form: powder, tablet, pill, capsule, cachet, suppository and dispersible granule.Gu Body carrier can be one or more materials, and it is also used as diluent, correctives, solubilizing agent, lubricant, suspending agent, glues Mixture, preservative, tablet disintegrant or coating material.In powder, carrier is usually finely ground solid, itself and finely ground activity Composition forms mixture.In tablets, active component generally mixes with suitable ratio mutually with the carrier with required adhesive power Merge and be pressed into required shapes and sizes.Powder and tablet preferably comprise from about the reactive compound of 1% to about 70%.Suitable Carrier include but not limited to magnesium carbonate, magnesium stearate, Pulvis Talci, sugar, lactose, pectin, dextrin, starch, gelatin, tragakanta, Methylcellulose, sodium carboxymethyl cellulose, low melt wax, cocoa butter etc..Terms " formulation " is intended to include making containing coating material For carrier to provide the preparation of reactive compound of capsule, in described capsule the active component of with or without carrier by with This carrier of combination surrounded.Similarly, cachet and lozenge are also included.Tablet, powder, capsule, pill, cachet and Lozenge is all adapted for Orally administered solid form.
Other is suitable to Orally administered form and includes that the preparation of liquid form (includes Emulsion, syrup, elixir, aqueous solution Agent, aqueous suspension) or purport be the most at once changed into the preparation of solid form of liquid form preparation.Emulsion can be molten Prepared by liquid such as aqueous solution of propylene glycol maybe can contain emulsifying agent such as lecithin, Arlacel-80 or Arab Glue.Aqueous solution agent by being dissolved in water by active component and can add suitable coloring agent, correctives, stabilizer and thickening Prepared by agent.Aqueous suspension can be by the glue the most naturally occurring or synthetic with stickum, resin, methylcellulose, carboxymethyl Finely ground active component is dispersed in water and prepares by sodium cellulosate and suspending agent known to other.The preparation of liquid form includes Solution, suspensoid and Emulsion, in addition to active component, it can also contain coloring agent, correctives, stabilizer, buffer agent, people That make and natural sweeting agent, dispersant, thickening agent, solubilizing agent etc..
The compound of the present invention can be formulated for parenteral administration (such as, by injection such as bolus injection or the most defeated Note is used) and can be present in a unit in the syringe of ampoule, in advance fill, low capacity transfusion or be present in With the addition of in the multi-dose container of preservative.The suspendible that the adoptable form of compositions has such as in oiliness or aqueous vehicle Agent, solution or Emulsion, the such as solution in Aqueous Solutions of Polyethylene Glycol.Oiliness or non-aqueous carrier, diluent, solvent or The example of excipient includes propylene glycol, Polyethylene Glycol, vegetable oil (such as olive oil) and injection organic ester (such as oleic acid second Ester), and formulating substances such as preservative, wetting agent, emulsifying agent or suspending agent, stabilizer and/or dispersant can be contained.Or, Active component can be powder type, its preparation method be sterile solid is carried out aseptic subpackaged or by by solution lyophilizing so that Build with suitable excipients water the most aseptic, pyrogen-free before use.
The compound of the present invention can be formulated for ointment, ointment or lotion form or with transdermal patch form office Portion is applied to epidermis.Ointment and ointment can be such as with the addition of suitable thickening agent and/or the aqueous of gellant or oil Property substrate is prepared.Lotion can be prepared with aqueous or oleaginous base and generally possibly together with one or more emulsifying agents, steady Determine agent, dispersant, suspending agent, thickening agent or coloring agent.Be suitable to the preparation of local application in mouth include comprising and be in taste masking base Matter, the lozenge of the active component being usually in sucrose and arabic gum or tragakanta；Comprise be in inert base such as gelatin and The lozenge of the active component in glycerol or sucrose and arabic gum；And comprise the active component that is in suitable liquid carrier Collutory.
The compound of the present invention can be formulated for using with suppository form.Can be first by low melt wax such as fatty acid glycerine Ester admixture or cocoa butter fusing, and by active component such as by stirring dispersion.Then by melted homogeneous mixture Pour in the mould of suitable size so that it is cool down and solidify.
The compound of the present invention can be formulated for vaginal application.In addition to the active ingredient (s possibly together with carrier known in this field The blue or green agent of vaginal suppository, tampon, breast, gel, paste, foam or spray are suitable.
The compound of the present invention can be formulated for nasal administration.Solution or suspensoid can be passed through conventional method, example As directly applied to nasal cavity with dropper, suction pipe or aerosol apparatus.Preparation can be to be single dose or multiple dose form.For dropper or suction The multiple dose form of pipe, this can be by being used suitable, the solution of predetermined by patient or suspensoid realizes.For Aerosol apparatus, this can such as be realized by metering atomising atomizing pump.
The compound of the present invention can be formulated for aerosol and use, and is particularly applied to respiratory tract and includes that intranasal is executed With.Compound is generally of little granularity, such as 5 microns or the granularity of more decimal magnitude.Described granularity can pass through this area Known method, such as obtained by micronization.Active component is with containing suitable propellant such as chlorofluorocarbon (CFC) such as dichloro The pressurized package of difluoromethane, Arcton 11 or dichlorotetra-fluoroethane or carbon dioxide or other suitable gas provides.Gas Mist agent also can contain surfactant such as lecithin suitably.Drug dose can be controlled by metering valve.Or, active component can With with dry powdered form, such as at suitable powder base such as lactose, starch, starch derivatives such as hydroxypropyl methyl cellulose and The mixture of powders form of the compound in polyvinylpyrrolidone provides.Dust carrier will form gel in nasal cavity.Powder Compositions can pass through inhaler the most such as to exist with gelatine capsule agent or cartridge case or blister package form By wherein using powder.
When needing, preparation can be with being suitable to slow release or controlled release is used the enteric coating of active component and is prepared.Such as, originally The compound of invention can be formulated into transdermal or subcutaneous drug delivery device.When must slow release compounds time and work as patient for treatment When the compliance of scheme is most important, these delivery systems are favourable.Compound in transdermal delivery system is often attached to On skin-adhesive solid support.The compound paid close attention to can also be with penetration enhancer, such as laurocapram (1-dodecane Base azacyclo-hept-2-ketone) it is applied in combination.By operation or injection, Sustained release delivery systems can be subcutaneously inserted hypodermic layer.Subcutaneous Compound is encapsulated in lipid soluble membrane, such as silicone rubber or Biodegradable polymeric such as polylactic acid by implant.
Pharmaceutical preparation is preferably unit dosage form.In this form, preparation is subdivided into containing Sq active component Unit dose.Unit dosage form can be the preparation of packaging kit, contains the preparation of discrete magnitude, the most complete bag in packaging Tablet, capsule and the powder in the vial of dress or ampulla agent.It addition, unit dosage form can be capsule, tablet, flat Wafer or lozenge itself, or it can be to be any one of these forms of suitable number in packaging kit form.
Other suitable pharmaceutical carrier and their preparation are at Remington:The Science and Practice of Pharmacy 1995Martin, E.W edit, Mack Publishing Company, the 19th edition, Easton, Pennsylvania is described.
The compounds of this invention and the purposes of pharmaceutical composition
Above-claimed cpd and pharmaceutical composition that the present invention provides can be used for preparation prevention, treat or alleviate Alzheimer The medicine of disease, it is also possible to be used for preparing prevention, treating or alleviate and 5-HT6The medicine of receptor related disease.
The feature of the pharmaceutical composition of the present invention includes the compound shown in formula (I) or the compound listed by the present invention, And pharmaceutically acceptable carrier, adjuvant or excipient.In the compositions of the present invention, the amount of compound can be visited effectively Geodetic antagonism 5-HT6Receptor is to treat CNS disease, and gastroenteropathy and obesity, wherein said CNS disease is ADHD, burnt Consider, the disease relevant to psychentonia, schizophrenia, obsessive idea and behavior disorder, manic depressive illness, nervous disorders, note Recall obstacle, attention deficit disorder, parkinson disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington Chorea, etc. Deng.
The compound of the present invention or " effective dose " of pharmaceutically acceptable compositions or " effective dose " refer to process or Alleviate the effective dose that one or more present invention is previously mentioned the severity of disease.The method according to the invention, compound and combination Thing can be any dosage and any route of administration is efficiently used for the order of severity that processes or palliate a disease.Required standard Situation according to patient is changed by true amount, and this depends on race, the age, the generic condition of patient, the order of severity of infection, Special factor, administering mode, etc..Compound or compositions can with one or more other therapeutic agents administering drug combinations, as The present invention is discussed.
The compound of the present invention and pharmaceutical composition, in addition to useful to human treatment, apply also for veterinary treatment and dote on Mammal in the animal on thing, the animal of introduced variety and farm.The example of other animal includes horse, Canis familiaris L. and cat.? This, the compound of the present invention includes its pharmaceutically acceptable derivates.
The general synthetic method of the compounds of this invention
For describing the present invention, it is listed below embodiment.But it is to be understood that the invention is not restricted to these embodiments, simply The method putting into practice the present invention is provided.
Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment are used for being further illustrated by this The content of invention.
Those skilled in the art will realize that: chemical reaction described in the invention can be used to prepare perhaps suitably Other compounds of many present invention, and it is considered as the model in the present invention for other method of the compound of preparing the present invention Within enclosing.Such as, the synthesis according to the compound of those non-illustrations of the present invention can be successfully by those skilled in the art Completed by method of modifying, as group is disturbed in suitable protection, by utilizing reagent known to other except described in the invention , or reaction condition is made the amendment of some routines.It addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applicable to the preparation of other compounds of the present invention.
The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business Product supplier such as Ling Kai medicine, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, the most not through being further purified, unless other aspects show during use.General reagent is from Shantou Chemical plant, western Gansu Province, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao is risen Dragon chemical reagent company limited, and Haiyang Chemical Plant, Qingdao is commercially available.
Anhydrous tetrahydro furan is to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride and chloroform are to return through calcium hydride Fluidized drying obtains.Ethyl acetate, N,N-dimethylacetamide and petroleum ether are to be dried in advance through anhydrous sodium sulfate to use.
Hereinafter reaction is usually and overlaps a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb the most suitable rubber closure, substrate is squeezed into by syringe.Glass drying oven is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum with CDC13、DMSO-d6、CD3OD or acetone-d6For solvent (report in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) As reference standard.When multiplet occurs when, the abbreviation by following for use: s (singlet, unimodal), d (doublet, double Peak), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, double doublet), dt (doublet of triplets, double triplets).Coupling constant, represents with hertz (Hz).
By outfit G1312A binary pump and a G1316A TCC, (column temperature is maintained at 30 to Algorithm (MS) data DEG C) the spectrogrph of Agilent6320 series LC-MS measure, G1329A automatic sampler and G1315B DAD detector Being applied to analyze, ESI source is applied to LC-MS spectrogrph.
Algorithm (MS) data are by being equipped with G1311A quaternary pump and G1316A TCC (column temperature is maintained at 30 DEG C) The spectrogrph of Agilent 6120 series LC-MS measure, G1329A automatic sampler and G1315D DAD detector should For analyzing, ESI source is applied to LC-MS spectrogrph.
Both the above spectrogrph is provided with Agilent Zorbax SB-C18 post, and specification is 2.1 × 30mm, 5 μm.Note Beam is long-pending is to be determined by sample concentration；Flow velocity is 0.6mL/min；The peak value of HPLC is by 210nm and 254nm UV-Vis wavelength records reading.Flowing be mutually 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure water-soluble Liquid (phase B).
Compound purification is evaluated by Agilent 1100 series of high efficiency liquid chromatograph (HPLC), wherein UV detection At 210nm and 254nm, Zorbax SB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, and flow velocity is 0.6mL/min, (0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.
The use of brief word below runs through the present invention:
Pd/C palladium carbon catalyst
HOAc acetic acid
MeCN,CH3CN acetonitrile
CHCl3Chloroform
CDC13Deuterochloroform
DMSO dimethyl sulfoxide
DMSO-d6Deuterated dimethyl sulfoxide
DMF N,N-dimethylformamide
ClSO2OH chlorosulfonic acid
EtOAc, EA ethyl acetate
HCl hydrochloric acid
MgSO4Magnesium sulfate
MgCl2Magnesium chloride
MeOH,CH3OH methanol
HCHO formaldehyde
CH2Cl2, DCM dichloromethane
ML, ml milliliter
PE petroleum ether (60-90 DEG C)
Na2CO3Sodium carbonate
NaHCO3Sodium bicarbonate
M, mol/L mol/L
K2CO3Potassium carbonate
KOH potassium hydroxide
RT room temperature
Rt retention time
H, hr hour
NaBH3CN sodium cyanoborohydride
NaCl sodium chloride
KCl potassium chloride
Na2SO4Sodium sulfate
THF oxolane
Et3N, TEA triethylamine
H2O water
EDTA ethylenediaminetetraacetic acid
PEI polymine
Pargyline pargyline
Tris-HCl tri-(methylol) aminomethane-hydrochloric acid
NADPH DPNH I
Following synthetic schemes describes the preparation present invention and comes into the open the step of compound.Unless otherwise indicated,For singly-bound or It it is double bond；Each R1、R2、R3、R4、R5、R6And RyThere is definition as described in the present invention.
Synthetic schemes 1
Formula (5) and (6Compound shown in) can be prepared by the method described by synthetic schemes 1.Formula (1Shown in) Compound react with derivative of piperidone under the effect of alkali, obtain formula (2Product shown in)；Then formula (2Change shown in) Compound deprotection base obtain formula (3Compound shown in).Formula (3Compound shown in) and sulfonyl chloride intermediate (M) react To formula (4Compound shown in)；Then formula (4Compound deprotection base shown in) obtain formula (5Target compound shown in). Formula (5Piperazine in target compound shown in) obtain after being substituted formula (6Another target compound shown in).
The compound, pharmaceutical composition and the application thereof that there is provided the present invention below in conjunction with embodiment are further described.
Embodiment
Embodiment 1 3-(1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl) piperidin-4-yl)-1H-indole Synthesis
Step 1) synthesis of 4-(1H-indol-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
Indole (5.0g, 42.7mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (10.1g, 51.2mmol) are joined In methanol (50mL), it is subsequently adding KOH (4.78g, 85.4mmol), stopped reaction after reacting 8 hours at oil bath 70 DEG C, add Water (150mL) cancellation, separates out a large amount of yellow solid, filters, and it is yellow-brown solid that filtering residue vacuum drying i.e. obtains title compound (10.9g, 86.2%).
MS(ESI,pos.ion)m/z:299.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.43 (s, 1H), 7.74 (d, J=8.2Hz, 1H), 7.31 (d, J= 8.2Hz, 1H), 7.18 7.15 (m, 1H), 7.08 7.05 (m, 1H), 6.94 (d, J=2.4Hz, 1H), 6.08 (brs, 1H), 4.12 (d, J=2.0Hz, 2H), 3.65 (t, J=5.6Hz, 2H), 2.53 (brs, 2H), 1.49 (s, 9H).
Step 2) synthesis of 4-(1H-indol-3-yl) piperidines-1-carboxylic acid tert-butyl ester
4-(1H-indol-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (10.0g, 33.5mmol) is added In the mixed solvent of methanol (30mL) and oxolane (30mL), it is subsequently adding Pd/C (3.0g, 10%).1atm at 25 DEG C H2React 15 hours under pressure.Stopped reaction, filters, and filtrate decompression is spin-dried for, column chromatography purification (petrol ether/ethyl acetate (v/v) =10/1) obtaining title compound is white solid (9.14g, 91%).
MS(ESI,pos.ion)m/z:201.1[M+H-100]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.24 (s, 1H), 7.82 (d, J=8.4Hz, 1H), 7.35 (d, J= 7.8Hz, 1H), 7.24 7.21 (m, 1H), 7.19 7.16 (m, 1H), 7.09 (d, J=3.0Hz, 1H), 4.22 (t, J= 9.2Hz,2H),2.95–2.84(m,3H),2.03–1.98(m,2H),1.68–1.54(m,2H),1.47(s,9H).
Step 3) synthesis of 3-(piperidin-4-yl)-1H-indole
At 25 DEG C, 4-(1H-indol-3-yl) piperidines-1-carboxylic acid tert-butyl ester (9.0g, 30mmol) is joined dichloromethane In alkane (50mL), being subsequently adding the ethyl acetate solution (20mL, 2mmol/mL) of hydrogen chloride, stirring reaction stops anti-after 3 hours Should, adding saturated sodium bicarbonate solution cancellation (50mL), after separatory, organic facies anhydrous sodium sulfate is dried.Filter, filtrate decompression Be spin-dried for, column chromatography purification (methylene chloride/methanol (v/v)=10/1) obtain title compound be pale yellow oil (5.46g, 91%).
MS(ESI,pos.ion)m/z:201.1[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 8.47 (s, 1H), 7.75 (d, J=8.4Hz, 1H), 7.32 (d, J= 8.4Hz, 1H), 7.17 7.14 (m, 1H), 7.09 7.04 (m, 1H), 6.93 (d, J=2.4Hz, 1H), 3.37 (brs, 2H), 3.07–2.99(m,3H),2.06–2.04(m,2H),2.02–1.90(m,2H).
Step 4) synthesis of the fluoro-1-of 2,2,2-tri-(4-(2-methoxyphenyl) piperazine-1-base) ethyl ketone
By 1-(2-methoxyphenyl) piperazine hydrochloride (5.0g, 21.9mmol) and triethylamine (10.0mL, 70.8mmol) Join in dichloromethane (50mL), be slowly added dropwise trifluoroacetic anhydride (4.6mL, 33.0mmol) under 0 DEG C of low temperature bath, drip After, it is transferred at 25 DEG C reaction 2 hours, stopped reaction, adds dichloromethane (50mL), with saturated sodium bicarbonate solution (60mL) Washing, after separatory, organic facies anhydrous sodium sulfate is dried.Filtering, filtrate decompression is spin-dried for, column chromatography purification (petroleum ether/acetic acid second Ester (v/v)=10/1) to obtain title compound be pale yellow oil (5.98g, 95%).
MS(ESI,pos.ion)m/z:289.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.25 7.19 (m, 1H), 7.15 (dd, J=7.9,1.3Hz, 1H), 7.03–6.98(m,2H),4.06–3.96(m,2H),3.93(brs,5H),3.37–3.35(m,4H).
Step 5) synthesis of 4-methoxyl group-3-(4-(2,2,2-trifluoroacetyl group) piperazine-1-base) benzene-1-sulfonic acid chloride
Fluoro-for 2,2,2-tri-1-(4-(2-methoxyphenyl) piperazine-1-base) ethyl ketone (5.0g, 17.4mmol) is dissolved in dichloro In methane (5mL), then it is added drop-wise in chlorosulfonic acid (15mL) under 0 DEG C of low temperature bath, after reacting 1 hour, reactant liquor is poured into In the mixed liquor of frozen water (30mL) and dichloromethane (50mL), being stirred vigorously rear separatory, organic facies anhydrous magnesium sulfate is dried.Cross Filter, it is faint yellow solid (5.6g, 83%) that filtrate decompression is spin-dried for i.e. obtaining title compound.
MS(ESI,pos.ion)m/z:387.0[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.78 (dd, J=8.7,2.3Hz, 1H), 7.49 (d, J=2.3Hz, 1H), 7.04 (d, J=8.8Hz, 1H), 4.03 (s, 3H), 3.94 3.87 (m, 2H), 3.86 3.77 (m, 2H), 3.25 3.16 (m,4H).
Step 6) 1-(4-(5-((4-(1H-indol-3-yl) piperidin-1-yl) sulfonyl)-2-methoxyphenyl) piperazine- 1-yl) synthesis of-2,2,2-trifluoroethanone
By 3-(piperidin-4-yl)-1H-indole (402mg, 2.0mmol) and triethylamine (566 μ L, 4.0mmol) at 0 DEG C Join in dichloromethane (10mL), be the most slowly dividedly in some parts 4-methoxyl group-3-(4-(2,2,2-trifluoroacetyl group) piperazine- 1-yl) benzene-1-sulfonic acid chloride (835mg, 2.5mmol), after reacting ten minutes, it is warming up to 25 DEG C of reactions overnight.Add dichloromethane (50mL), then washing (40mL) with saturated nacl aqueous solution, after separatory, organic facies anhydrous sodium sulfate is dried.Filter, filtrate Decompression is spin-dried for, and it is faint yellow solid that column chromatography purification (petrol ether/ethyl acetate (v/v)=1/1) obtains title compound (937mg, 85%).
MS(ESI,pos.ion)m/z:551.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.17 (s, 1H), 7.37 (dd, J=8.2,2.4Hz, 1H), 7.33 (t, J=8.2Hz, 2H), 7.14 7.09 (m, 1H), 6.99 (t, J=2.4Hz, 2H), 6.89 6.86 (m, 1H), 6.81 (d, J= 8.2Hz,1H),3.97(s,3H),3.95–3.85(m,4H),3.79–3.76(m,2H),3.16(brs,4H),2.74–2.65 (m, 1H), 2.42 (t, J=12.0Hz, 2H), 2.11 2.06 (m, 2H), 1.85 (qd, J=12.8,3.6Hz, 2H).
Step 7) conjunction of 3-(1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl) piperidin-4-yl)-1H-indole Become
At 25 DEG C, by 1-(4-(5-((4-(1H-indol-3-yl) piperidin-1-yl) sulfonyl)-2-methoxyphenyl) Piperazine-1-base)-2,2,2-trifluoroethanone (900mg, 1.63mmol) is dissolved in oxolane (10mL), ethanol (10mL) and water (10mL), in mixed solvent, it is subsequently adding potassium carbonate (662mg, 4.8mmol).After reactant liquor stirring reaction 24 hours, add Dichloromethane (60mL), washs (30mL) with saturated nacl aqueous solution, and after separatory, organic facies anhydrous sodium sulfate is dried.Filter, Filtrate decompression being spin-dried for, it is white solid that column chromatography purification (methylene chloride/methanol (v/v)=20/1) obtains title compound (690mg, 93%).
MS(ESI,pos.ion)m/z:455.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.16 (s, 1H), 7.37 (dd, J=8.4,2.4Hz, 1H), 7.34 (t, J=8.2Hz, 2H), 7.13 7.09 (m, 1H), 6.99 (t, J=2.4Hz, 2H), 6.89 6.87 (m, 1H), 6.81 (d, J= 8.4Hz, 1H), 3.91 (s, 3H), 3.88 (d, J=11.4Hz, 2H), 3.09 (brs, 8H), 2.71 2.62 (m, 1H), 2.43 2.37 (m, 2H), 2.08 2.05 (m, 2H), 1.83 (qd, J=12.6,3.6Hz, 2H).
Embodiment 2 3-(1-((4-methoxyl group-3-(4-methylpiperazine-1-yl) phenyl) sulfonyl) piperidin-4-yl)-1H- The synthesis of indole
By 3-(1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl) piperidin-4-yl)-1H-indole (350mg, 0.77mmol) be dissolved in methanol (5mL), add two acetic acid, at 0 DEG C, be slowly added to sodium cyanoborohydride (139mg, 2.2mmol) with formaldehyde (40%, 0.17mL, 2.2mmol).After reacting ten minutes, it is warming up to 25 DEG C and continues reaction 5 hours.Add Water (10mL) and sodium carbonate (200mg, 1.88mmol) cancellation, then extract (20mL x 3) with dichloromethane.Merge organic facies, Anhydrous sodium sulfate is dried；Filtering, filtrate decompression is spin-dried for, and column chromatography purification (methylene chloride/methanol (v/v)=20/1) obtains title Compound is white solid (263mg, 73%).
MS(ESI,pos.ion)m/z:469.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.82 (s, 1H), 7.60 (d, J=8.2Hz, 1H), 7.49 (dd, J= 8.4,2.4Hz, 1H), 7.33 (d, J=2.4Hz, 1H), 7.27 (d, J=8.4Hz, 1H), 7.12 (t, J=7.2Hz, 1H), 7.06 (t, J=7.2Hz, 1H), 6.93 (d, J=8.4Hz, 1H), 3.93 (s, 3H), 3.90 3.88 (m, 2H), 3.14 (brs, 4H), 2.70 2.58 (m, 4H), 2.39 (t, J=12.0Hz, 2H), 2.36 (s, 3H), 2.08 2.05 (m, 2H), 1.83 (qd, J =12.6,3.6Hz, 2H).
Embodiment 3 5-methoxyl group-3-(1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl) piperazine-4-base)- The synthesis of 1H-indole
Step 1) synthesis of 4-(5-methoxyl group-1H-indol-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
This step title compound prepares with reference to the method described by embodiment 1 step 1, will 5-methoxy-Indole (5.0g, 34.0mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (8.1g, 41.0mmol) and potassium hydroxide (3.8g, 68.0mmol) reaction preparation in the methanol (50mL), filtration drying obtain title compound be brown solid (10.3g, 92.3%).
MS(ESI,pos.ion)m/z:329.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.27 (s, 1H), 7.29 (d, J=2.4Hz, 1H), 7.24 (d, J= 8.8Hz, 1H), 7.12 (d, J=2.4Hz, 1H), 6.86 (dd, J=8.8,2.4Hz, 1H), 6.08 (s, 1H), 4.12 (d, J= 2.0Hz, 2H), 3.85 (s, 3H), 3.65 (t, J=5.6Hz, 2H), 2.53 (brs, 2H), 1.49 (s, 9H).
Step 2) synthesis of 4-(5-methoxyl group-1H-indol-3-yl) piperidines-1-carboxylic acid tert-butyl ester
This step title compound prepares with reference to the method described by embodiment 1 step 2, will 4-(5-methoxyl group- 1H-indol-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (10.0g, 30.5mmol) and Pd/C (3.0g, 10%) reaction preparation, crude on silica gel column chromatography (petroleum ether/second in the mixed solvent of THF (30mL) and MeOH (20mL) Acetoacetic ester (v/v)=10/1) purification, it is white solid (8.6g, 85.0%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:231.3[M+H-100]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.95 (s, 1H), 7.23 (d, J=8.8Hz, 1H), 7.03 (d, J= 2.0Hz, 1H), 6.91 (d, J=2.0Hz, 1H), 6.84 (dd, J=8.8,2.4Hz, 1H), 4.22 (t, J=9.2Hz, 2H), 3.85(s,3H),2.95–2.84(m,3H),2.03–2.00(m,2H),1.68–1.54(m,2H),1.47(s,9H).
Step 3) synthesis of 5-methoxyl group-3-(piperidin-4-yl)-1H-indole
This step title compound prepares with reference to the method described by embodiment 1 step 3, will 4-(5-methoxyl group- 1H-indol-3-yl) piperidines-1-carboxylic acid tert-butyl ester (8.6g, 26.0mmol) and hydrogen chloride ethyl acetate solution (20mL, 2mmol/mL) reaction preparation in dichloromethane (50mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)= 30/1) purification, it is faint yellow solid (4.86g, 81.0%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:231.1[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 10.72 (s, 1H), 7.23 (d, J=8.8Hz, 1H), 7.13 (d, J =2.4Hz, 1H), 7.07 (d, J=2.0Hz, 1H), 6.72 (dd, J=8.8,2.4Hz, 1H), 3.77 (s, 3H), 3.35 (brs, 2H),3.06–2.99(m,3H),2.05–2.02(m,2H),2.01–1.90(m,2H).
Step 4) the fluoro-1-of 2,2,2-tri-(4-(2-methoxyl group-5-((4-(5-methoxyl group-1H-indol-3-yl) piperidines-1- Base) sulfonyl) phenyl) piperazine-1-base) synthesis of ethyl ketone
The method that this step title compound describes with reference to embodiment 1 step 6 prepares, will 5-methoxyl group-3-(piperazine Pyridine-4-base)-1H-indole (1.5g, 6.50mmol), 4-methoxyl group-3-(4-(2,2,2-trifluoroacetyl group) piperazine-1-base) benzene- The reaction preparation in dichloromethane (30mL) of 1-sulfonic acid chloride (2.6g, 6.7mmol) and triethylamine (2.1mL, 15.0mmol), slightly produces Thing is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification, and it is faint yellow that concentrate drying obtains title compound Solid (2.44g, 65.0%).
MS(ESI,pos.ion)m/z:581.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.91 (s, 1H), 7.51 (dd, J=8.4,2.0Hz, 1H), 7.26 (d, J=2.0Hz, 1H), 7.22 (s, 1H), 6.99 (d, J=8.8Hz, 1H), 6.91 (dd, J=4.8,2.0Hz, 2H), 6.83 (dd, J=8.8,2.4Hz, 1H), 3.96 (s, 3H), 3.95 3.85 (m, 4H), 3.81 (s, 3H), 3.78 (d, J=4.8Hz, 2H), 3.15 (brs, 4H), 2.74 2.65 (m, 1H), 2.41 (t, J=12.0Hz, 2H), 2.08 (d, J=11.6Hz, 2H), 1.85 (qd, J=12.8,3.6Hz, 2H).
Step 5) 5-methoxyl group-3-(1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl) piperazine-4-base)- The synthesis of 1H-indole
This step title compound prepares with reference to the method described by embodiment 1 step 7, will be 2,2,2-tri-fluoro- 1-(4-(2-methoxyl group-5-((4-(5-methoxyl group-1H-indol-3-yl) piperidin-1-yl) sulfonyl) phenyl) piperazine-1-base) Ethyl ketone (2.44g, 4.20mmol) and potassium carbonate (1.16g, 8.4mmol) are at oxolane (10mL), ethanol (10mL) and water (10mL) reaction preparation in, crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purification, concentrate drying obtains It is white solid (1.78g, 87.4%) to title compound.
MS(ESI,pos.ion)m/z:485.4[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.00 (s, 1H), 7.45 (dd, J=8.4,1.8Hz, 1H), 7.28 (d, J=1.8Hz, 1H), 7.22 (d, J=9.0Hz, 1H), 6.94 (d, J=9.0Hz, 1H), 6.92 (d, J=2.4Hz, 1H), 6.90 (s, 1H), 6.82 (dd, J=9.0,2.4Hz, 1H), 3.93 (s, 3H), 3.88 (d, J=11.4Hz, 2H), 3.81 (s, 3H), 3.09 (brs, 8H), 2.71 2.62 (m, 1H), 2.43 2.37 (m, 2H), 2.06 (d, J=12.0Hz, 2H), 1.83 (qd, J= 12.6,3.6Hz,2H)；
13C NMR(150MHz,CDCl3)δ(ppm):155.8,154.0,142.1,131.7,128.2,126.9,123.5, 120.8,112.0,117.7,112.4,112.2,111.0,101.0,56.2,56.1,51.7,47.2,46.2,33.0,32.3.
Embodiment 4 5-methoxyl group-3-(1-((4-methoxyl group-3-(4-methylpiperazine-1-yl) phenyl) sulfonyl) piperidines- 4-yl) synthesis of-1H-indole
This step title compound prepares with reference to the method described by embodiment 2, will 5-methoxyl group-3-(1- ((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl) piperazine-4-base)-1H-indole (200mg, 0.41mmol), cyano group boron Sodium hydride (76mg, 1.2mmol) and formaldehyde (40%, 0.09mL, 1.2mmol) reaction preparation, crude product in methanol (10mL) Through silica gel column chromatography (methylene chloride/methanol (v/v)=50/1) purification, it is white solid that concentrate drying obtains title compound (128mg, 62.2%).
MS(ESI,pos.ion)m/z:499.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.95 (s, 1H), 7.45 (dd, J=8.4,1.8Hz, 1H), 7.29 (d, J=1.8Hz, 1H), 7.22 (d, J=9.0Hz, 1H), 6.94 (d, J=8.4Hz, 1H), 6.92 (d, J=1.8Hz, 1H), 6.90 (d, J=2.4Hz, 1H), 6.82 (dd, J=8.4,2.4Hz, 1H), 3.93 (s, 3H), 3.88 (d, J=11.4Hz, 2H), 3.82 (s, 3H), 3.14 (brs, 4H), 2.70 2.58 (m, 5H), 2.39 (t, J=12.0Hz, 2H), 2.36 (s, 3H), 2.06 (d, J =12.6Hz, 2H), 1.83 (qd, J=12.6,3.6Hz, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):155.8,154.1,141.8,131.7,128.2,126.9,123.4, 120.8,120.0,117.6,112.5,112.2,110.9,100.9,56.2,56.1,55.3,50.6,47.2,46.3,33.1, 32.3.
Embodiment 5 3-(1-((3-(4-isopropyl piperazine-1-base)-4-methoxyphenyl) sulfonyl) piperidin-4-yl)- The synthesis of 5-methoxyl group-1H-indole
This step title compound prepares with reference to the method described by embodiment 2, will 5-methoxyl group-3-(1- ((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl) piperazine-4-base)-1H-indole (200mg, 0.41mmol), cyano group boron Sodium hydride (63mg, 1.0mmol), acetic acid (60 μ L, 1.0mmol) and acetone (1.0mL) is reaction preparation in methanol (10mL), slightly Product is through silica gel column chromatography (methylene chloride/methanol (v/v)=50/1) purification, and it is solid for white that concentrate drying obtains title compound Body (95mg, 43.7%).
MS(ESI,pos.ion)m/z:527.4[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.02 (s, 1H), 7.45 (dd, J=8.4,1.8Hz, 1H), 7.29 (d, J=1.8Hz, 1H), 7.22 (d, J=8.4Hz, 1H), 6.94 (d, J=8.4Hz, 1H), 6.92 (d, J=1.8Hz, 1H), 6.89 (d, J=1.8Hz, 1H), 6.82 (dd, J=8.4,2.4Hz, 1H), 3.93 (s, 3H), 3.87 (d, J=11.4Hz, 2H), 3.82 (s, 3H), 3.16 (brs, 4H), 2.78 2.72 (m, 5H), 2.69 2.64 (m, 1H), 2.38 (t, J=11.4Hz, 2H), 2.06 (d, J=12.6Hz, 2H), 1.82 (qd, J=12.6,3.6Hz, 2H), 1.11 (s, 3H), 1.10 (s, 3H)；
13C NMR(150MHz,CDCl3)δ(ppm):155.8,154.0,141.8,131.7,128.1,126.8,123.5, 120.8,119.9,117.5,112.5,112.2,110.8,100.8,56.2,56.1,54.9,50.8,48.9,47.2,33.0, 32.3,18.7.
Embodiment 6 3-(1-((3-(4-cyclobutyl piperazine-1-base)-4-methoxyphenyl) sulfonyl) piperidin-4-yl)- The synthesis of 5-methoxyl group-1H-indole
This step title compound prepares with reference to the method described by embodiment 2, will 5-methoxyl group-3-(1- ((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl) piperazine-4-base)-1H-indole (200mg, 0.41mmol), cyano group boron Sodium hydride (63mg, 1.0mmol), acetic acid (60 μ L, 1.0mmol) and cyclobutanone (87mg, 1.24mmol) are in methanol (10mL) Reaction preparation, crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1) purification, concentrate drying obtains titled Compound is white solid (72mg, 32.4%).
MS(ESI,pos.ion)m/z:539.4[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.96 (s, 1H), 7.46 (dd, J=8.4,1.8Hz, 1H), 7.29 (d, J=1.8Hz, 1H), 7.22 (d, J=9.0Hz, 1H), 6.94 (d, J=9.0Hz, 1H), 6.92 (d, J=1.8Hz, 1H), 6.90 (d, J=1.8Hz, 1H), 6.82 (dd, J=9.0,2.4Hz, 1H), 3.93 (s, 3H), 3.87 (d, J=11.4Hz, 2H), 3.82 (s, 3H), 3.16 (brs, 4H), 2.90 2.82 (m, 1H), 2.70 2.64 (m, 1H), 2.59 (brs, 4H), 2.39 (t, J= 11.4Hz, 2H), 2.08 2.05 (m, 4H), 1.98 1.93 (m, 2H), 1.82 (qd, J=12.6,3.6Hz, 2H), 1.77 1.67(m,2H)；
13C NMR(150MHz,CDCl3)δ(ppm):155.8,154.1,141.7,131.7,128.2,126.9,123.6, 120.8,120.0,117.6,112.5,112.2,110.9,100.8,60.4,56.2,56.1,50.1,49.6,47.2,33.0, 32.3,27.1,14.5.
The fluoro-3-of embodiment 7 5-(1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl) piperidin-4-yl)-1H- The synthesis of indole
Step 1) synthesis of 4-(5-fluoro-1H-indol-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
This step title compound prepares with reference to the method described by embodiment 1 step 1, will 5-fluoro indole (5.0g, 37.0mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (8.1g, 41.0mmol) and potassium hydroxide (4.14g, 74.0mmol) reaction preparation in methanol (50mL), it is yellow solid (9.47g, 81%) that filtration drying obtains title compound.
MS(ESI,pos.ion)m/z:317.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.17 (s, 1H), 7.26 7.21 (m, 2H), 7.08 (d, J=2.4Hz, 1H), 6.93 (td, J=8.6,2.4Hz, 1H), 6.12 (brs, 1H), 4.11 (d, J=2.0Hz, 2H), 3.66 (t, J= 5.6Hz,2H),2.54(brs,2H),1.49(s,9H).
Step 2) synthesis of 4-(5-fluoro-1H-indol-3-yl) piperidines-1-carboxylic acid tert-butyl ester
This step title compound prepares with reference to the method described by embodiment 1 step 2, will 4-(the fluoro-1H-of 5- Indol-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (9.0g, 28.5mmol) and Pd/C (3.0g, 10%) be at THF (30mL) and the mixed solvent of MeOH (20mL) reacts and prepare, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/ V)=10/1) purification, it is white solid (7.9g, 87.2%) that concentrate drying obtains title compound.
1H NMR(400MHz,CDCl3) δ (ppm): 8.15 (s, 1H), 7.26 7.22 (m, 2H), 7.09 (d, J=2.4Hz, 1H),6.94–6.92(m,1H),4.09–4.02(m,2H),2.99–2.88(m,2H),2.86(brs,1H),1.94-1.91(m, 2H),1.53–1.46(m,2H),1.41(s,9H).
Step 3) synthesis of 5-fluoro-3-(piperidin-4-yl)-1H-indole
This step title compound prepares with reference to the method described by embodiment 1 step 3, will 4-(the fluoro-1H-of 5- Indol-3-yl) piperidines-1-carboxylic acid tert-butyl ester (7.0g, 22.0mmol) and ethyl acetate solution (20mL, the 2mmol/ of hydrogen chloride ML) reaction preparation in dichloromethane (50mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=30/1) is pure Changing, it is pale yellow oil (4.56g, 95%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:219.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.19 (s, 1H), 7.26 7.22 (m, 2H), 7.09 (d, J=2.4Hz, 1H), 6.93 (td, J=8.4,2.4Hz, 1H), 3.04-3.02 (m, 2H), 2.80 (tt, J=12.0,3.0Hz, 1H), 2.65 2.59 (m, 2H), 1.86 1.80 (m, 2H), 1.53 (qd, J=12.0,3.6Hz, 2H).
Step 4) the fluoro-1-of 2,2,2-tri-(4-(5-((4-(5-fluoro-1H-indol-3-yl) piperidin-1-yl) sulfonyl)-2- Methoxyphenyl) piperazine-1-base) synthesis of ethyl ketone
The method that this step title compound describes with reference to embodiment 1 step 6 prepares, will the fluoro-3-of 5-(piperidines- 4-yl)-1H-indole (436mg, 2.0mmol), 4-methoxyl group-3-(4-(2,2,2-trifluoroacetyl group) piperazine-1-base) benzene-1- The reaction preparation in dichloromethane (20mL) of sulfonic acid chloride (970mg, 2.5mmol) and triethylamine (0.42mL, 3.0mmol), slightly produces Thing is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification, and it is faint yellow that concentrate drying obtains title compound Solid (829mg, 73%).
MS(ESI,pos.ion)m/z:569.1[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 10.91 (s, 1H), 7.44 (dd, J=8.4,1.9Hz, 1H), 7.32 7.29 (m, 1H), 7.28 (d, J=2.1Hz, 1H), 7.12 7.08 (m, 1H), 6.96 (t, J=9.8Hz, 2H), 6.89 (td, J=9.0,2.0Hz, 1H), 3.89 (s, 3H), 3.82 2.76 (m, 4H), 3.74 3.71 (m, 2H), 3.12 3.08 (m, 4H), 2.63 (tt, J=12.0,3.0Hz, 1H), 2.37 (td, J=12.0,1.8Hz, 2H), 2.01 1.98 (m, 2H), 1.77 (qd, J=12.6,3.6Hz, 2H).
Step 5) the fluoro-3-of 5-(1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl) piperidin-4-yl)-1H-Yin The synthesis of diindyl
This step title compound prepares with reference to the method described by embodiment 1 step 7, will be 2,2,2-tri-fluoro- 1-(4-(5-((4-(5-fluoro-1H-indol-3-yl) piperidin-1-yl) sulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone (570mg, 1.0mmol) and potassium carbonate (276mg, 2.0mmol) are anti-in oxolane (5mL), ethanol (5mL) and water (5mL) Should prepare, crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purification, concentrate drying obtains title compound Thing is white solid (373mg, 79%).
MS(ESI,pos.ion)m/z:473.1[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 10.93 (s, 1H), 7.39 (dd, J=8.4,1.8Hz, 1H), 7.32 (dd, J=8.4,4.5Hz, 1H), 7.24 (d, J=1.8Hz, 1H), 7.19 (d, J=1.2Hz, 1H), 7.08 (dd, J=9.9, 2.2Hz, 1H), 7.06 (d, J=8.4Hz, 1H), 6.90 6.87 (m, 1H), 3.89 (s, 3H), 3.73 (d, J=11.4Hz, 2H),2.97–2.92(m,4H),2.88–2.83(m,4H),2.74–2.68(m,1H),2.43–2.34(m,2H),2.01–1.97 (m, 2H), 1.65 (qd, J=12.6,3.6Hz, 2H).
Embodiment 8 The fluoro-3-of 5-(1-((4-methoxyl group-3-(4-methylpiperazine-1-yl) phenyl) sulfonyl) piperidines-4- Base) synthesis of-1H-indole
This step title compound prepares with reference to the method described by embodiment 2, will the fluoro-3-of 5-(1-((4-first Epoxide-3-(piperazine-1-base) phenyl) sulfonyl) piperidin-4-yl)-1H-indole (200mg, 0.42mmol), sodium cyanoborohydride (76mg, 1.2mmol) and formaldehyde (40%, 0.09mL, 1.2mmol) is reaction preparation, crude on silica gel in methanol (10mL) Column chromatography (methylene chloride/methanol (v/v)=50/1) purification, concentrate drying obtain title compound be white solid (137mg, 67%).
MS(ESI,pos.ion)m/z:487.1[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 10.93 (s, 1H), 7.39 (dd, J=8.6,2.1Hz, 1H), 7.32 (dd, J=8.8,4.2Hz, 1H), 7.26 (d, J=2.2Hz, 1H), 7.19 (s, 1H), 7.08 (dd, J=10.0,2.3Hz, 1H), 7.07 (d, J=8.4Hz, 1H), 6.89 (td, J=9.2,2.4Hz, 1H), 3.93 (s, 3H), 3.84 (d, J=11.4Hz, 2H), 3.14 (brs, 4H), 2.70 2.58 (m, 5H), 2.39 (t, J=12.0Hz, 2H), 2.36 (s, 3H), 2.06 (d, J= 12.6Hz, 2H), 1.74 (qd, J=12.6,3.6Hz, 2H).
Embodiment 9 The chloro-3-of 5-(1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl) piperidin-4-yl)-1H- The synthesis of indole
Step 1) synthesis of 4-(5-chloro-1H-indol-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
This step title compound prepares with reference to the method described by embodiment 1 step 1, will 5-chloro-indole (5.0g, 33.1mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (8.0g, 40.2mmol) and potassium hydroxide (3.70g, 66.0mmol) reaction preparation in methanol (50mL), it is yellow solid (9.12g, 83%) that filtration drying obtains title compound.
MS(ESI,pos.ion)m/z:333.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.31 (s, 1H), 7.56 (d, J=2.0Hz, 1H), 7.22 (d, J= 8.4Hz, 1H), 7.13 (dd, J=8.6,2.0Hz, 1H), 7.02 (d, J=2.0Hz, 1H), 6.09 (s, 1H), 4.13 (d, J= 2.0Hz, 2H), 3.67 (t, J=5.6Hz, 2H), 2.54 (brs, 2H), 1.48 (s, 9H).
Step 2) synthesis of 4-(5-chloro-1H-indol-3-yl) piperidines-1-carboxylic acid tert-butyl ester
This step title compound prepares with reference to the method described by embodiment 1 step 2, will 4-(the chloro-1H-of 5- Indol-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (9.0g, 27.1mmol) and Pd/C (3.0g, 10%) be at THF (30mL) and the mixed solvent of MeOH (20mL) reacts and prepare, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/ V)=10/1) purification, it is white solid (7.15g, 79%) that concentrate drying obtains title compound.
1H NMR(400MHz,CDCl3) δ (ppm): 8.30 (s, 1H), 7.57 (d, J=2.0Hz, 1H), 7.22 (d, J= 8.6Hz, 1H), 7.12 (dd, J=8.6,2.0Hz, 1H), 7.01 (d, J=2.0Hz, 1H), 4.09 4.03 (m, 2H), 2.98 2.88(m,2H),2.87(brs,1H),1.95–1.91(m,2H),1.53–1.47(m,2H),1.43(s,9H).
Step 3) synthesis of 5-chloro-3-(piperidin-4-yl)-1H-indole
This step title compound prepares with reference to the method described by embodiment 1 step 3, will 4-(the chloro-1H-of 5- Indol-3-yl) piperidines-1-carboxylic acid tert-butyl ester (7.0g, 20.9mmol) and ethyl acetate solution (20mL, the 2mmol/ of hydrogen chloride ML) reaction preparation in dichloromethane (50mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=30/1) is pure Changing, it is pale yellow oil (4.55g, 93%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:235.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.27 (s, 1H), 7.58 (d, J=2.0Hz, 1H), 7.22 (d, J= 8.4Hz, 1H), 7.14 7.11 (m, 1H), 7.02 (d, J=2.0Hz, 1H), 3.05 3.02 (m, 2H), 2.81 (tt, J= 12.0,3.0Hz, 1H), 2.65 2.60 (m, 2H), 1.86 1.81 (m, 2H), 1.54 (qd, J=12.0,3.6Hz, 2H).
Step 4) the fluoro-1-of 2,2,2-tri-(4-(5-((4-(5-chloro-1H-indol-3-yl) piperidin-1-yl) sulfonyl)-2- Methoxyphenyl) piperazine-1-base) synthesis of ethyl ketone
The method that this step title compound describes with reference to embodiment 1 step 6 prepares, will the chloro-3-of 5-(piperidines- 4-yl)-1H-indole (470mg, 2.0mmol), 4-methoxyl group-3-(4-(2,2,2-trifluoroacetyl group) piperazine-1-base) benzene-1- The reaction preparation in dichloromethane (20mL) of sulfonic acid chloride (970mg, 2.5mmol) and triethylamine (0.42mL, 3.0mmol), slightly produces Thing is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification, and it is faint yellow that concentrate drying obtains title compound Solid (910mg, 78%).
MS(ESI,pos.ion)m/z:585.1[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 11.01 (s, 1H), 7.43 (dd, J=8.4,2.0Hz, 1H), 7.39 (d, J=1.9Hz, 1H), 7.34 (d, J=8.6Hz, 1H), 7.29 (d, J=2.1Hz, 1H), 7.19 (d, J=2.0Hz, 1H), 7.10 (d, J=8.6Hz, 1H), 7.05 (dd, J=8.6,2.0Hz, 1H), 3.91 (s, 3H), 3.81 2.78 (m, 4H), 3.74 3.71 (m, 2H), 3.11 (brs, 4H), 2.63 (tt, J=12.0,3.0Hz, 1H), 2.37 2.34 (m, 2H), 1.99 (brs, 2H), 1.77 (qd, J=12.6,3.6Hz, 2H).
Step 5) the chloro-3-of 5-(1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl) piperidin-4-yl)-1H-Yin The synthesis of diindyl
This step title compound prepares with reference to the method described by embodiment 1 step 7, will be 2,2,2-tri-fluoro- 1-(4-(5-((4-(5-chloro-1H-indol-3-yl) piperidin-1-yl) sulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone (585mg, 1.0mmol) and potassium carbonate (276mg, 2.0mmol) are in oxolane (10mL), ethanol (10mL) and water (10mL) Reaction preparation, crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purification, concentrate drying obtains titled Compound is white solid (405mg, 83%).
MS(ESI,pos.ion)m/z:489.1[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 11.06 (s, 1H), 7.41 7.39 (m, 2H), 7.34 (d, J= 8.6Hz, 1H), 7.26 (d, J=1.8Hz, 1H), 7.21 (s, 1H), 7.07 (d, J=8.5Hz, 1H), 7.03 (dd, J=8.6, 1.8Hz,1H),3.89(s,3H),3.73–3.71(m,2H),2.95(br,4H),2.88–2.85(m,4H),2.83–2.72(m, 1H), 2.41 2.34 (m, 2H), 1.98 1.93 (m, 2H), 1.66 (qd, J=12.6,3.6Hz, 2H).
Embodiment 10 The chloro-3-of 5-(1-((4-methoxyl group-3-(4-methylpiperazine-1-yl) phenyl) sulfonyl) piperidines-4- Base) synthesis of-1H-indole
This step title compound prepares with reference to the method described by embodiment 2, will the chloro-3-of 5-(1-((4-first Epoxide-3-(piperazine-1-base) phenyl) sulfonyl) piperidin-4-yl)-1H-indole (200mg, 0.41mmol), sodium cyanoborohydride (76mg, 1.2mmol) and formaldehyde (40%, 0.09mL, 1.2mmol) is reaction preparation, crude on silica gel in methanol (10mL) Column chromatography (methylene chloride/methanol (v/v)=50/1) purification, concentrate drying obtain title compound be white solid (134mg, 65%).
MS(ESI,pos.ion)m/z:503.1[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.39–7.36(m,1H),7.27–7.25(m,1H),7.19–7.15 (m, 2H), 7.03 6.99 (m, 1H), 6.89 (s, 1H), 6.79 (dd, J=8.6,1.1Hz, 1H), 3.91 (s, 3H), 3.84 (3.82 m, 2H), 3.14 (brs, 4H), 2.70 2.58 (m, 5H), 2.37 (t, J=12.0Hz, 2H), 2.35 (s, 3H), 2.08 2.05 (m, 2H), 1.73 (qd, J=12.6,3.6Hz, 2H).
Embodiment 11 The fluoro-3-of 6-(1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl) piperidin-4-yl)-1H- The synthesis of indole
Step 1) synthesis of 4-(6-fluoro-1H-indol-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
This step title compound prepares with reference to the method described by embodiment 1 step 1, will 6-fluoro indole (3.0g, 22.2mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.3g, 26.6mmol) and potassium hydroxide (1.78g, 31.8mmol) reaction preparation in methanol (50mL), it is yellow solid (6.87g, 98%) that filtration drying obtains title compound.
MS(ESI,pos.ion)m/z:317.3[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 11.23 (s, 1H), 7.80 (dd, J=9.0,5.4Hz, 1H), 7.42 (s, 1H), 7.15 (dd, J=10.2,2.4Hz, 1H), 6.89 (td, J=11.4,2.4Hz, 1H), 6.12 (s, 1H), 4.03 (brs, 2H), 3.55 (d, J=5.4Hz, 2H), 2.48 (brs, 2H), 1.43 (s, 9H).
Step 2) synthesis of 4-(6-fluoro-1H-indol-3-yl) piperidines-1-carboxylic acid tert-butyl ester
This step title compound prepares with reference to the method described by embodiment 1 step 2, will 4-(the fluoro-1H-of 6- Indol-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (3.5g, 11.0mmol) and Pd/C (310mg, 10%) exist Reaction preparation, crude on silica gel column chromatography (petrol ether/ethyl acetate in the mixed solvent of THF (15mL) and MeOH (10mL) (v/v)=10/1) purification, it is white solid (3.16g, 90.0%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:219.3[M+H-100]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 10.87 (s, 1H), 7.53 (dd, J=9.0,5.4Hz, 1H), 7.09 (dd, J=9.6,2.4Hz, 2H), 6.81 (td, J=9.6,2.4Hz, 1H), 4.04 (t, J=7.2Hz, 2H), 2.97 2.77 (m,3H),1.94–1.91(m,2H),1.50–1.47(m,2H),1.41(s,9H).
Step 3) synthesis of 6-fluoro-3-(piperidin-4-yl)-1H-indole
This step title compound prepares with reference to the method described by embodiment 1 step 3, will 4-(the fluoro-1H-of 6- Indol-3-yl) piperidines-1-carboxylic acid tert-butyl ester (3.1g, 9.7mmol) and ethyl acetate solution (10mL, the 2mmol/ of hydrogen chloride ML) reaction preparation in dichloromethane (30mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=30/1) is pure Changing, it is pale yellow oil (1.75g, 83%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:219.1[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 10.83 (s, 1H), 7.53 (dd, J=9.0,5.4Hz, 1H), 7.09 (dd, J=10.2,2.4Hz, 1H), 7.05 (d, J=1.8Hz, 1H), 6.80 (ddd, J=9.6,8.4,2.4Hz, 1H), 3.00 (t, J=12.0Hz, 2H), 2.80 (tt, J=11.4,3.0Hz, 1H), 2.63 (td, J=12.0,1.8Hz, 2H), 1.86 1.82 (m, 2H), 1.53 (qd, J=12.0,3.6Hz, 2H).
Step 4) the fluoro-1-of 2,2,2-tri-(4-(5-((4-(6-fluoro-1H-indol-3-yl) piperidin-1-yl) sulfonyl)-2- Methoxyphenyl) piperazine-1-base) synthesis of ethyl ketone
The method that this step title compound describes with reference to embodiment 1 step 6 prepares, will the fluoro-3-of 6-(piperidines- 4-yl)-1H-indole (350mg, 1.60mmol), 4-methoxyl group-3-(4-(2,2,2-trifluoroacetyl group) piperazine-1-base) benzene-1- The reaction preparation in dichloromethane (10mL) of sulfonic acid chloride (620mg, 1.60mmol) and triethylamine (0.42mL, 3.0mmol), slightly produces Thing is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification, and it is faint yellow that concentrate drying obtains title compound Solid (185mg, 20.3%).
MS(ESI,pos.ion)m/z:569.1[M+H]+；
1H NMR(600MHz,CD3OD) δ (ppm): 7.43 (dd, J=8.4,2.4Hz, 1H), 7.29 (dd, J=8.4, 5.4Hz, 1H), 7.18 (d, J=1.8Hz, 1H), 6.96 6.92 (m, 2H), 6.83 (s, 1H), 6.71 (td, J=9.6, 2.4Hz, 1H), 3.89 (s, 3H), 3.82 2.76 (m, 4H), 3.74 3.71 (m, 2H), 3.09 (dd, J=9.0,4.2Hz, 4H), 2.63 (tt, J=12.0,3.0Hz, 1H), 2.35 (td, J=12.0,1.8Hz, 2H), 1.99 (d, J=12.0Hz, 2H), 1.76 (qd, J=12.6,3.6Hz, 2H).
Step 5) the fluoro-3-of 6-(1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl) piperidin-4-yl)-1H-Yin The synthesis of diindyl
This step title compound prepares with reference to the method described by embodiment 1 step 7, will be 2,2,2-tri-fluoro- 1-(4-(5-((4-(6-fluoro-1H-indol-3-yl) piperidin-1-yl) sulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone (160mg, 0.28mmol) and potassium carbonate (124mg, 0.9mmol) are anti-in oxolane (5mL), ethanol (5mL) and water (5mL) Should prepare, crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purification, concentrate drying obtains title compound Thing is white solid (117mg, 88.0%).
MS(ESI,pos.ion)m/z:473.2[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 10.87 (s, 1H), 7.45 (dd, J=9.0,5.4Hz, 1H), 7.38 (dd, J=8.4,1.8Hz, 1H), 7.17 (d, J=8.4Hz, 1H), 7.12 (d, J=2.4Hz, 1H), 7.08 (dd, J=9.6, 2.4Hz, 2H), 6.77 (td, J=9.6,2.4Hz, 1H), 3.89 (s, 3H), 3.72 (d, J=11.4Hz, 2H), 3.17 (s, 1H),2.97–2.92(m,4H),2.88–2.84(m,4H),2.75–2.68(m,1H),2.43–2.34(m,2H),1.97(d,J =11.4Hz, 2H), 1.64 (qd, J=12.6,3.6Hz, 2H)；
13C NMR(150MHz,DMSO-d6) δ (ppm): 158.7 (d, J=289.6Hz), 155.4,141.9,136.1 (d, J=12.5Hz), 127.2,123.0,122.4,121.2 (d, J=3.3Hz), 119.4 (d, J=10.1Hz), 118.9, (116.5,111.6,106.5 d, J=24.2Hz), 97.1 (d, J=25.4Hz), 55.8,50.9,48.6,46.5,45.5, 31.8.
Embodiment 12 The chloro-3-of 6-(1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl) piperidin-4-yl)-1H- The synthesis of indole
Step 1) synthesis of 4-(6-chloro-1H-indol-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
This step title compound prepares with reference to the method described by embodiment 1 step 1, will 6-chloro-indole (3.0g, 19.8mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.7g, 24.0mmol) and potassium hydroxide (1.58g, 28.2mmol) reaction preparation in the methanol (50mL), filtration drying obtain title compound be yellow solid (6.1g, 92.8%).
MS(ESI,pos.ion)m/z:333.2[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 11.31 (s, 1H), 7.83 (d, J=8.4Hz, 1H), 7.48 (s, 1H), 7.44 (d, J=1.8Hz, 1H), 7.06 (dd, J=8.4,1.8Hz, 1H), 6.13 (s, 1H), 4.05 (brs, 2H), 3.57 (t, J=4.8Hz, 2H), 3.37 (brs, 2H), 1.45 (s, 9H).
Step 2) synthesis of 4-(6-chloro-1H-indol-3-yl) piperidines-1-carboxylic acid tert-butyl ester
This step title compound prepares with reference to the method described by embodiment 1 step 2, will 4-(the chloro-1H-of 6- Indol-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (3.5g, 10.5mmol) and Pd/C (310mg, 10%) exist Reaction preparation, crude on silica gel column chromatography (petrol ether/ethyl acetate in the mixed solvent of THF (15mL) and MeOH (10mL) (v/v)=10/1) purification, it is white solid (2.52g, 72.0%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:235.1[M+H-100]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 10.95 (s, 1H), 7.55 (d, J=8.4Hz, 1H), 7.37 (d, J =1.8Hz, 1H), 7.15 (d, J=1.8Hz, 1H), 6.97 (dd, J=8.4,1.8Hz, 1H), 4.09 4.01 (m, 2H), 2.97–2.88(m,2H),2.87(brs,1H),1.94–1.90(m,2H),1.53–1.45(m,2H),1.41(s,9H).
Step 3) synthesis of 6-chloro-3-(piperidin-4-yl)-1H-indole
This step title compound prepares with reference to the method described by embodiment 1 step 3, will 4-(the chloro-1H-of 6- Indol-3-yl) piperidines-1-carboxylic acid tert-butyl ester (2.5g, 7.5mmol) and ethyl acetate solution (10mL, the 2mmol/ of hydrogen chloride ML) reaction preparation in dichloromethane (30mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=30/1) is pure Changing, it is pale yellow oil (1.58g, 90.0%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:235.1[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 10.92 (s, 1H), 7.55 (d, J=8.4Hz, 1H), 7.37 (d, J =1.8Hz, 1H), 7.10 (s, 1H), 6.95 (dd, J=8.4,1.8Hz, 1H), 3.02 2.99 (m, 2H), 2.80 (tt, J= 12.0,3.0Hz, 1H), 2.65 2.59 (m, 2H), 1.86 1.80 (m, 2H), 1.53 (qd, J=12.0,3.6Hz, 2H).
Step 4) 1-(4-(5-((4-(6-chloro-1H-indol-3-yl) piperidin-1-yl) sulfonyl)-2-methoxyphenyl) Piperazine-1-base) synthesis of-2,2,2-trifluoroethanone
The method that this step title compound describes with reference to embodiment 1 step 6 prepares, will the chloro-3-of 6-(piperidines- 4-yl)-1H-indole (400mg, 1.70mmol), 4-methoxyl group-3-(4-(2,2,2-trifluoroacetyl group) piperazine-1-base) benzene-1- The reaction preparation in dichloromethane (10mL) of sulfonic acid chloride (660mg, 1.70mmol) and triethylamine (0.42mL, 3.0mmol), slightly produces Thing is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification, and it is faint yellow that concentrate drying obtains title compound Solid (730mg, 73.2%).
MS(ESI,pos.ion)m/z:584.9[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 10.94 (s, 1H), 7.45 (dd, J=8.4,2.1Hz, 1H), 7.39 7.35 (m, 2H), 7.28 (t, J=4.2Hz, 1H), 7.01 (dd, J=8.5,1.8Hz, 2H), 6.84 (d, J=8.6Hz, 1H),3.92(s,3H),3.74(brs,4H),3.13(brs,4H),2.74–2.71(m,1H),2.37–2.35(m,2H), 2.24–2.22(m,4H),1.67(brs,2H).
Step 5) the chloro-3-of 6-(1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl) piperidin-4-yl)-1H-Yin The synthesis of diindyl
This step title compound prepares with reference to the method described by embodiment 1 step 7, will 1-(4-(5-((4- (6-chloro-1H-indol-3-yl) piperidin-1-yl) sulfonyl)-2-methoxyphenyl) piperazine-1-base)-2,2,2-trifluoroethanone (700mg, 1.2mmol) and potassium carbonate (330mg, 2.4mmol) are anti-in oxolane (5mL), ethanol (5mL) and water (5mL) Should prepare, crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purification, concentrate drying obtains title compound Thing is white solid (500mg, 85.5%).
MS(ESI,pos.ion)m/z:489.1[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 10.95 (s, 1H), 7.48 (d, J=8.4Hz, 1H), 7.38 (dd, J =8.4,1.8Hz, 1H), 7.35 (d, J=1.8Hz, 1H), 7.17 (d, J=8.4Hz, 1H), 7.12 (dd, J=4.8,2.4Hz, 2H), 6.92 (dd, J=8.4,1.8Hz, 1H), 3.89 (s, 3H), 3.72 (d, J=12.0Hz, 2H), 3.17 (s, 1H), 2.95 (br,4H),2.88–2.86(m,4H),2.86–2.72(m,1H),2.41–2.34(m,2H),1.99–1.93(m,2H),1.65 (qd, J=12.6,3.6Hz, 2H)；
13C NMR(150MHz,DMSO-d6)δ(ppm):155.4,141.8,136.6,127.2,125.6,124.9, 122.5,121.8,119.9,119.0,118.4,116.5,111.6,110.9,55.9,50.9,48.6,46.5,45.5, 31.7.
Biologic test
Embodiment A. radio ligand binding assay evaluates the compounds of this invention to expressing the people source 5-on Chinese hamster ovary celI HT6The affinity of receptor
The expression that 32 μ g prepare there is people source 5-HT6The Chinese hamster ovary celI memebrane protein of receptor, 2nM radioactive marker [3H] LSD, the different compound of test concentrations, 100 μMs of 5-HT (5-HT is used for removing nonspecific binding site) and test buffering Liquid mix homogeneously, then hatches 120min by mixed liquor at 37 DEG C；Wherein, assay buffer composition is: 50mM Tris-HCl (pH 7.4), 10mM MgCl2, 0.5mM EDTA, 10 μMs of pargylines and 20mg/L protease inhibitor.
After hatching, above-mentioned mixed liquor is filtered with glass fiber filter (GF/B, Packard) under vacuum, filter The filter membrane of device the most first presoaks with 0.3%PEI.After filtration, with 50mM Tris-HCl, filter membrane is rinsed several times.To be filtered Film is dried, with scintillation mixed solution at the upper radioactivity counting filter membrane of scintillation counter (Topcount, Packard).Standard Reference compound is 5-HT, and all tests multiple concentration in every time experiment to obtain its Competitive assays curve, through Hill equation Curve carries out nonlinear regression analysis, obtains IC50Value, then calculate through ChengPrusoff equation, obtain Ki value.
Carry out the compounds of this invention according to the method described above to expressing the people source 5-HT on Chinese hamster ovary celI6The affinity of receptor Test, result shows that the compounds of this invention is to people source 5-HT6Receptor has higher affinity.In the particular embodiment, originally Invention compound is to expressing the people source 5-HT on Chinese hamster ovary celI6The Ki value that receptor combines is less than 10nM；Preferably, Ki value is less than 5nM.More specifically, the Ki value of compound that embodiment 3 and embodiment 7 prepare is less than 10nM；Embodiment 4, embodiment 8, The Ki value of the compound that embodiment 11 and embodiment 12 prepare is less than 5nM.
In the description of this specification, reference term " embodiment ", " some embodiments ", " embodiment ", " show Example ", the description of " concrete example " or " some examples " etc. mean to combine that this embodiment, embodiment or example describe is concrete special Levy, structure, material or feature are contained at least one embodiment, embodiment or the example of the present invention.In this specification In, the schematic representation of above-mentioned term is necessarily directed to identical embodiment, embodiment or example.And, describe Specific features, structure, material or feature can with in one or more embodiments in office, embodiment or example with suitably Mode combines.Additionally, in the case of the most conflicting, those skilled in the art can be by the difference described in this specification The feature of embodiment, embodiment or example and different embodiment, embodiment or example is combined and combines.
Although above it has been shown and described that embodiments of the invention, it is to be understood that above-described embodiment is example Property, it is impossible to being interpreted as limitation of the present invention, those of ordinary skill in the art within the scope of the invention can be to above-mentioned Embodiment is changed, revises, replaces and modification.

Claims (10)

1. a compound, it is the stereoisomer of compound, tautomerism shown in the compound shown in formula (I) or formula (I) Body, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein:
For singly-bound or double bond；
R1、R2、R3、R4And R5It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-OH、-NRaRb,-C (=O) Rc,-S (= O)2Rc,-C (=O) NRaRb,-S (=O)2NRaRb、C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Alkoxyl, C1-C6Alkane Sulfenyl, (C3-C8Cycloalkyl)-(C0-C6Alkylidene)-, (C2-C10Heterocyclic radical)-(C0-C6Alkylidene)-, (C6-C10Aryl)-(C0- C6Alkylidene)-or (C1-C9Heteroaryl)-(C0-C6Alkylidene)-, wherein said C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Alkoxyl, C1-C6Alkylthio group, (C3-C8Cycloalkyl)-(C0-C6Alkylidene)-, (C2-C10Heterocyclic radical)-(C0-C6Alkylene Base)-, (C6-C10Aryl)-(C0-C6Alkylidene)-and (C1-C9Heteroaryl)-(C0-C6Alkylidene)-individually optionally by one or Multiple it is independently selected from D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-SH ,-COOH, oxo (=O), C1-C6Alkyl, C1-C6Alkane Epoxide, C1-C6Alkylthio group or C1-C6The substituent group of alkylamino is replaced；
Each R6And R7Independently be H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-COOH、C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Alkoxyl, C1-C6Alkylamino, C1-C6Alkylthio group, (C3-C8Cycloalkyl)-(C0-C6Alkylidene)-, (C2-C10 Heterocyclic radical)-(C0-C6Alkylidene)-, (C6-C10Aryl)-(C0-C6Alkylidene)-or (C1-C9Heteroaryl)-(C0-C6Alkylidene)-, Wherein said C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Alkoxyl, C1-C6Alkylamino, C1-C6Alkylthio group, (C3-C8Ring Alkyl)-(C0-C6Alkylidene)-, (C2-C10Heterocyclic radical)-(C0-C6Alkylidene)-, (C6-C10Aryl)-(C0-C6Alkylidene)-and (C1-C9Heteroaryl)-(C0-C6Alkylidene)-individually optionally by one or more be independently selected from D, F, Cl, Br, I ,-CN ,- NO2、-NH2,-OH ,-SH ,-COOH, oxo (=O), C1-C6Alkyl, C1-C6Alkoxyl, C1-C6Alkylthio group or C1-C6Alkylamino Substituent group replaced；
Cy is C3-C6Cycloalkyl or the heterocyclic radical of 4-7 annular atoms composition, wherein said C3-C6Cycloalkyl and 4-7 annular atoms The heterocyclic radical of composition is independently selected from D, F, Cl, Br, I ,-CN ,-NO by one or more individually optionally2、-OH、-SH、- NRaRb,-C (=O) Rc,-S (=O)2Rc,-C (=O) NRaRb,-S (=O)2NRaRb, oxo (=O), C1-C6Alkyl, C1-C6Alkane Epoxide, C1-C6Haloalkyl, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, (C3-C8Cycloalkyl)-(C0-C6Alkylidene)-, (C2- C10Heterocyclic radical)-(C0-C6Alkylidene)-, (C6-C10Aryl)-(C0-C6Alkylidene)-or (C1-C9Heteroaryl)-(C0-C6Alkylene Base)-substituent group replaced；
Each Ra、RbAnd RcIndependently be H ,-OH, C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alcoxyl Base, C1-C6Halogenated alkoxy, (C3-C8Cycloalkyl)-(C0-C6Alkylidene)-, (C2-C10Heterocyclic radical)-(C0-C6Alkylidene)-, (C6-C10Aryl)-(C0-C6Alkylidene)-or (C1-C9Heteroaryl)-(C0-C6Alkylidene)-；With
N is 0,1,2 or 3.
Compound the most according to claim 1, wherein R1、R2、R3、R4And R5Be each independently H, D, F, Cl, Br, I ,- CN、-NO2、-OH、-NRaRb,-C (=O) Rc,-S (=O)2Rc,-C (=O) NRaRb,-S (=O)2NRaRb、C1-C4Alkyl, C2-C4 Thiazolinyl, C2-C4Alkynyl, C1-C4Alkoxyl, C1-C4Alkylthio group, (C3-C6Cycloalkyl)-(C0-C4Alkylidene)-, (C2-C6Heterocycle Base)-(C0-C4Alkylidene)-, (C6-C10Aryl)-(C0-C4Alkylidene)-or (C1-C5Heteroaryl)-(C0-C4Alkylidene)-, wherein Described C1-C4Alkyl, C2-C4Thiazolinyl, C2-C4Alkynyl, C1-C4Alkoxyl, C1-C4Alkylthio group, (C3-C6Cycloalkyl)-(C0-C4Alkylene Base)-, (C2-C6Heterocyclic radical)-(C0-C4Alkylidene)-, (C6-C10Aryl)-(C0-C4Alkylidene)-and (C1-C5Heteroaryl)-(C0- C4Alkylidene)-it is independently selected from D, F, Cl, Br, I ,-CN ,-NO by one or more individually optionally2、-NH2、-OH、-SH、- COOH, oxo (=O), C1-C4Alkyl, C1-C4Alkoxyl, C1-C4Alkylthio group or C1-C4The substituent group of alkylamino is replaced.
Compound the most according to claim 1, wherein R1、R2、R3、R4And R5Be each independently H, D, F, Cl, Br, I ,- CN、-NO2、-OH、-NH2、-N(CH3)2,-C (=O) CH3,-C (=O) OH ,-C (=O) OCH3、-CONH2, methyl, ethyl, just Propyl group, isopropyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy ,-CF3Or-OCF3。
Compound the most according to claim 1, the most each R6And R7Independently be H, D, F, Cl, Br, I ,-CN ,-NO2、- NH2,-OH ,-COOH, methyl, ethyl, n-pro-pyl, isopropyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, positive fourth oxygen Base, isobutoxy, sec-butoxy or tert-butoxy；With
Each Ra、RbAnd RcIndependently be H ,-OH, methyl, ethyl, n-pro-pyl, isopropyl, methoxyl group, ethyoxyl, positive propoxy, different Propoxyl group or phenyl.
Compound the most according to claim 1, wherein Cy is following subformula:
Wherein, Q is CH or N；
E and M is each independently-CH2-、-CHRx-,-C (=O)-,-NH-,-NRy-,-O-,-S-,-S (=O)-or-S (=O )2-；
Each RxAnd RyIndependently be D, F, Cl, Br, I ,-CN ,-NO2、-OH、-SH、-NRaRb,-C (=O) Rc,-S (=O)2Rc、-C (=O) NRaRb,-S (=O)2NRaRb、C1-C4Alkyl, C1-C4Alkoxyl, C1-C4Haloalkyl, C1-C4Halogenated alkoxy, C1-C4 Alkylthio group, (C3-C6Cycloalkyl)-(C0-C4Alkylidene)-, (C2-C6Heterocyclic radical)-(C0-C4Alkylidene)-, (C6-C10Aryl)- (C0-C4Alkylidene)-or (C1-C5Heteroaryl)-(C0-C4Alkylidene)-；
T is 0,1,2 or 3；With
R is 0 or 1.
Compound the most according to claim 5, the most each RxAnd RyIndependently be D, F, Cl, Br, I ,-CN ,-NO2、-OH、- SH、-NH2、-N(CH3)2,-C (=O) CH3,-C (=O) OH ,-C (=O) OCH3、-CONH2, methyl, ethyl, n-pro-pyl, isopropyl Base, normal-butyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclobutyl, cyclopenta, azelidinyl, oxetanylmethoxy, thia ring fourth Base, pyrrolidinyl or tetrahydrofuran base.
Compound the most according to claim 1, it is to have the compound of one of following structure or have one of following knot The stereoisomer of the compound of structure, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically may be used The salt accepted or prodrug:
8. pharmaceutical composition comprises the compound described in claim 1-7 any one, and optionally further comprises medicine Acceptable carrier, excipient, diluent, adjuvant, vehicle or their combination in any on.
Pharmaceutical composition the most according to claim 8, it comprises additional treatment agent, wherein said additional treatment agent further For donepezil, nalmefene, risperidone, vitamin e, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, Intepirdine, idalopirdine, tacrine, Rivastigmine, galantamine, memantine, meter Ta Zhaping, venlafaxine, go Yu Min, nortriptyline, zolpidem, zopiclone, nicergoline, piracetam, selegiline, pentoxifylline or they appoint Meaning combination.
10. the compound used described in claim 1-7 any one or the medicine described in claim 8-9 any one Compositions purposes in preparing medicine, described medicine is used for preventing, treat or alleviating and 5-HT6Receptor related disease.
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