CN104725249B - Benzylamine analog derivative and its application on drug - Google Patents
Benzylamine analog derivative and its application on drug Download PDFInfo
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Abstract
The present invention provides a kind of novel benzylamine analog derivative or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug, for treating Alzheimer's disease.The invention further relates to the pharmaceutical compositions comprising the compounds of this invention, and use the method for the compounds of this invention or its medicine composite for curing Alzheimer's disease.
Description
Technical field
The invention belongs to drug field and it is related to compound for treating Alzheimer's disease, includes the compound
Composition and application thereof and application method.Particularly, compound of the present invention is to can be used as 5-HT6Receptor antagonist
Benzylamine analog derivative.
Background technique
A variety of central nervous system diseases such as anxiety, depression etc. with neurotransmitter serotonin (5-HT) or thrombocytin
Disorder it is related.As modulability neurotransmitter main in brain, the function of neurotransmitter serotonin (5-HT) be pass through by
Referred to as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6And 5-HT7A large amount of receptor families mediate.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-HT6Selective ligands have potential treatment work to certain CNS (central nervous system) illness
With, such as Parkinson's disease, Huntington's chorea, anxiety disorder, depression, manic-depressive psychosis, mental disease, epilepsy, obsessive-compulsive disorder, inclined head
Bitterly, Alzheimer's disease (cognition and memory enhancing), sleep disturbance, eating disorder such as anorexia and bulimia nerovsa, panic attack,
ADHD (attention deficit hyperactivity disorder), attention deficit disorder, drug abuse such as cocaine, ethyl alcohol, nicotine and benzo
DiazaRecessiveness brain syndrome, schizophrenia and illness related with spinal trauma or head injury are taken off caused by class such as
Hydrocephalus.It is expected that the compound can also be used to treat certain stomach intestinal disease such as functional bowel disorders.(see, for example, Roth,
B.L. etc., J.Pharmacol.Exp.Ther., page 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).
The study found that known 5-HT6Selective antagonist significantly improves glutamic acid and asparagus fern ammonia in cortex of frontal lobe
The level of acid removes hormone, dopamine or 5-HT on first kidney without improving6Level.It is this to pay attention in memory and cognitive process
To specific neurochemical selectivity raising strongly suggested that 5-HT6Ligand in cognition effect (Dawson,
L.A.；Nguyen, H.Q.；Li, P., British Journal of Pharmacology, 2000,130 (1), 23-26).With
Known selectivity 5-HT6The research that the memory of antagonists in animals and study carry out have some positive effects (Rogers,
D.C.；Hatcher, P.D.；Hagan, J.J., Society of Neuroscience, Abstracts, 2000,26,680).
5-HT6The related potential treatment purposes of ligand is to treat the attention deficit disorder of children and adult.Because of 5-HT6Antagonist is seen
Get up to improve the activity of nigrostriatal dopamine approach, and because ADHD it is related with the exception in caudate nucleus (Ernst,
M；Zametkin, A.J.；Matochik, J.H.；Jons, P.A.；Cohen, R.M., Journal of Neuroscience,
1998,18 (5), 5901-5907), so, 5-HT6Antagonist can treat attention deficit disorder.Have also been determined that 5-HT6Antagonism
Agent is the potentially useful compound for treating obesity.See, for example, Bentley etc., Br.J.Pharmac.1999, supplementary issue 126；
Bentley etc., J.Psychopharmacol.1997, supplementary issue A64:255；Wooley etc., Neuropharmacology 2001,
41:210-129 and WO02098878.
Summary of the invention
The present invention relates to the methods of new benzylamine analog derivative and treatment Alzheimer's disease.The compounds of this invention or comprising
The pharmaceutical composition of the compound is to 5-HT6There is preferable affinity interaction, especially has to Alzheimer's disease and preferably control
Therapeutic effect.
On the one hand, the present invention relates to a kind of compounds, are compound shown in formula (I) compound represented or formula (I)
Stereoisomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, can pharmaceutically connect geometric isomer
The salt or prodrug received,
Wherein:
K is 0,1,2 or 3；
Each p independently is 0,1 or 2；
M is 0,1,2,3 or 4；
N is 1,2,3,4 or 5；
Y is CH or N；
X1And Y1It is each independently CH；
X2、X3And X4Respectively stand alone as CH or N, and X2、X3And X4In most two simultaneously be N；
Each R1And R3It independently is H, D, F, Cl, Br, I ,-CN ,-NO2、-OH、-NH2、-NR9R9a,-C (=O) R9b,-C (=
O)NR9R9a,-OC (=O) NR9R9a,-OC (=O) OR9c、-N(R9) C (=O) NR9R9a、-N(R9) C (=O) OR9c、-N(R9)C
(=O) R9b、R9R9aN-S (=O)2-、R9bS (=O)p-、R9bS (=O)2N(R9aThe C that hydroxyl)-, replaces1-6Alkyl, R9aR9N-C1-6
Alkyl, R9bS (=O)p-C1-6Alkyl, R9R9aN-C (=O)-C1-6Alkyl, R9aR9N-C1-6Alkoxy, R9bS (=O)p-C1-6Alcoxyl
Base, R9R9aN-C (=O)-C1-6Alkoxy, C6-10Aryl, C1-9Heteroaryl, C1-6Alkoxy, C1-6Alkylamino, C1-6Alkyl, C1-6
Miscellaneous alkyl, halogenated C1-6Alkyl, halogenated C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C2-10Heterocycle, C3-8Naphthenic base, C1-6Alkane sulphur
Base, C6-10Aryloxy group, C6-10Arylthio, C6-10Aryl C1-6Alkyl, C6-10Fragrant amino, C1-9Heteroaryl amino, C6-10Aryl C1-6Alkane
Amino, C1-9Heteroaryl C1-6Alkylamino, C1-9Heteroaryl oxygroup, C1-9Heteroaryl C1-6Alkyl, C6-10Aryl C1-6Alkoxy, C1-9
Heteroaryl C1-6Alkoxy, C1-6Alkyl C2-10Heterocycle, C3-8Naphthenic base C2-10Heterocycle, C2-10Heterocycle oxygroup, C2-10Heterocycle
Base C1-6Alkoxy, C2-10Heterocyclylamino group or C2-10Heterocycle alkylamino；
Each R2It independently is D, F, Br, I ,-CN ,-OH ,-NH2、-NR9R9a,-C (=O) R9b,-C (=O) NR9R9a、-OC
(=O) NR9R9a,-OC (=O) OR9c、-N(R9) C (=O) NR9R9a、-N(R9) C (=O) OR9c、-N(R9) C (=O) R9b、
R9R9aN-S (=O)2-、R9bS (=O)p-、R9bS (=O)2N(R9aThe C that hydroxyl)-, replaces1-6Alkyl, R9aR9N-C1-6Alkyl, R9bS
(=O)p-C1-6Alkyl, R9R9aN-C (=O)-C1-6Alkyl, R9aR9N-C1-6Alkoxy, R9bS (=O)p-C1-6Alkoxy,
R9R9aN-C (=O)-C1-6Alkoxy, C6-10Aryl, C1-9Heteroaryl, C2-6Alkoxy, C1-6Alkylamino, C1-6Alkyl, halogenated C1-6
Alkyl, halogenated C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C2-10Heterocycle, C3-8Naphthenic base, C1-6Alkylthio group, C6-10Arylthio,
C6-10Aryl C1-6Alkyl, C6-10Fragrant amino, C1-9Heteroaryl amino, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl C1-6Alkylamino,
C1-9Heteroaryl oxygroup, C1-9Heteroaryl C1-6Alkyl, C6-10Aryl C1-6Alkoxy, C1-9Heteroaryl C1-6Alkoxy, C2-10Heterocycle
Oxygroup, C2-10Heterocycle C1-6Alkoxy, C2-10Heterocyclylamino group or C2-10Heterocycle alkylamino；
R4For H, D, C2-6Alkyl, halogenated C1-6Alkyl, C3-8Naphthenic base ,-C (=O) R9b,-C (=O) NR9R9a、C2-6Alkenyl
Or C2-6Alkynyl；
R5、R6、R7And R8It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-OH、-NH2、C1-6Alkyl, C2-6Alkene
Base, C2-6Alkynyl, C2-10Heterocycle, C3-8Naphthenic base ,-C (=O) R9b,-C (=O) NR9R9aOr R5And R6Or R7And R8, respectively
Together with the carbon atom being connected with each, it is separately formed substituted or unsubstituted 3-8 former molecular carbocyclic ring or miscellaneous
Ring；
Each R9And R9aIt independently is H, D ,-OH, C1-6Alkyl, C1-6Miscellaneous alkyl, halogenated C1-6Alkyl, amino, C1-6Alkoxy,
C6-10Aryl, C2-10Heterocycle, C3-8Naphthenic base, C6-10Aryloxy group, C2-10Heterocycle oxygroup, C3-8Cycloalkyl oxy, C6-10Fragrant ammonia
Base, C2-10Heterocyclylamino group, C3-8Cycloalkyl amino or C1-9Heteroaryl or R9、R9a, and together with the nitrogen-atoms that they are connected,
Form substituted or unsubstituted 3-8 former molecular ring；With
Each R9bAnd R9cIt independently is H, D ,-OH, C1-6Alkyl, C1-6Miscellaneous alkyl, halogenated C1-6Alkyl, amino, C1-6Alcoxyl
Base, C6-10Aryl, C2-10Heterocycle, C3-8Naphthenic base, C6-10Aryloxy group, C2-10Heterocycle oxygroup, C3-8Cycloalkyl oxy, C6-10Virtue
Amino, C2-10Heterocyclylamino group, C3-8Cycloalkyl amino or C1-9Heteroaryl.
In one embodiment, each R1And R3It independently is H, D, F, Cl, Br, I ,-OH ,-NH2,-CN ,-C (=O) R9b、-C
(=O) NR9R9a、C1-4Alkyl, C3-6Naphthenic base, C1-4Alkoxy, halogenated C1-4Alkyl, halogenated C1-4Alkoxy, C2-4Alkenyl, C2-4
Alkynyl, C2-6Heterocycle, C1-4Alkyl C2-6Heterocycle, C3-6Naphthenic base C2-6Heterocycle or C6-10Aryl, wherein R9、R9aAnd R9bTool
There is meaning as described in the present invention.
In another embodiment, each R2It independently is D, F, Br, I ,-OH ,-NH2、-CN、C1-4Alkyl, C3-6Naphthenic base,
C2-4Alkoxy, halogenated C1-4Alkyl, halogenated C1-4Alkoxy, C2-4Alkenyl, C2-4Alkynyl, C2-6Heterocycle or C6-10Aryl.
In another embodiment, R4For H, D, C2-4Alkyl, halogenated C1-4Alkyl, C3-6Naphthenic base ,-C (=O) R9b、-C
(=O) NR9R9a、C2-4Alkenyl or C2-4Alkynyl；
Each R9And R9aIt independently is H, D ,-OH, C1-4Alkyl, C1-4Miscellaneous alkyl, halogenated C1-4Alkyl, amino, C6-10Aryl,
C2-6Heterocycle or C3-6Naphthenic base or R9、R9a, and together with the nitrogen-atoms that they are connected, form substituted or unsubstituted 3-6
Former molecular ring；With
Each R9bAnd R9cIt independently is H, D ,-OH, C1-4Alkyl, C1-4Miscellaneous alkyl, halogenated C1-4Alkyl, amino, C6-10Aryl,
C2-6Heterocycle or C3-6Naphthenic base.
In another embodiment, R5、R6、R7And R8It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-OH、-
NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C2-6Heterocycle or C3-6Naphthenic base or R5And R6Or R7And R8, respectively and and they
Respectively connected carbon atom together, is separately formed substituted or unsubstituted 3-6 former molecular carbocyclic ring.
In another embodiment, compound of the present invention, for formula (II) compound represented or formula (II) institute
Show the stereoisomer of compound, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite,
Pharmaceutically acceptable salt or prodrug,
Wherein each R1、R2、R3、R4、R5、R6、R7、R8、Y、Y1, m, n and k have meaning as described in the present invention.
In another embodiment, each R1And R3It independently is H, D, F, Cl, Br, I ,-OH ,-NH2,-CN, methyl, ethyl,
Propyl, butyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl, cyclobutyl, morpholinyl, piperazinyl, N methyl piperazine
Base, tetrahydrofuran base, nafoxidine base, tetrahydro-thienyl, N- cyclopropylpiperazin base or 1,4- dioxanes base.
In another embodiment, each R2It independently is D, F, Br, I ,-OH ,-NH2,-CN, methyl, ethyl, propyl, fourth
Base, ethyoxyl, propoxyl group, butoxy, cyclopropyl, cyclobutyl or fluoro C1-4Alkoxy.
In another embodiment, R4For H, D, ethyl, propyl or butyl.
In another embodiment, R5、R6、R7And R8It is each independently H, D, F, Cl, Br, I ,-OH ,-NH2, methyl, second
Base, propyl, butyl, cyclopropyl or cyclobutyl or R5And R6Or R7And R8, the carbon atom one that is connected respectively and with each
It rises, is separately formed substituted or unsubstituted 3-6 former molecular naphthenic base.
On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes the compound of the present invention, with
And pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium or their combination.
In one embodiment, pharmaceutical composition of the present invention further includes additional therapeutic agent, described additional
Therapeutic agent is the drug for treating azheimer's disease, the drug or their combination for treating nervous disorders.Treat Alzheimer's disease
Drug nervous disorders drug or their combination.
In another embodiment, additional therapeutic agent of the present invention is donepezil (donepezil), nalmefene
(nalmefene), Risperidone (risperidone), vitamin e (Vitamin E), SAM-760, AVN-211, AVN-101,
RP-5063, tozadenant, PRX-3140, PRX-8066, SB-742457, naluzaton, idalopirdine, Tacrine
(tacrine), Rivastigmine (rivastigmine), galanthamine (galantamine), Memantine (memantine), rice he
Prick flat (Mirtazapine), Venlafaxine (venlafaxine), desipramine (desipramine), nortriptyline
(nortriptyline), zolpidem (zolpidem), zopiclone (zopiclone), Nicergoline (nicergoline), pyrrole
La Xitan (piracetam), selegiline (selegiline), pentoxifylline (pentoxifylline) or their group
It closes.
On the other hand, the present invention relates to the compounds of this invention or pharmaceutical composition to prepare for preventing, treating or mitigating
With 5-HT6Purposes in the drug of related disease.
In one embodiment, the present invention relates to 5-HT6Related disease is CNS illness, disorder of gastrointestinal tract or fat disease.
In another embodiment, the present invention relates to 5-HT6Related CNS illness is ADHD, anxiety, with it is nervous
Relevant disease, schizophrenia, besetment and behavior disorder, manic-depressive psychosis, nervous disorders, memory disorders, attention
Defect obstacle, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease or Huntington's chorea.
Another aspect of the present invention is related to the method for preparation, separation and the purifying of formula (I) or formula (II) compound represented.
Any embodiment in either present invention face can be combined with other embodiments, as long as they are not
It will appear contradiction.In addition, any technical characteristic can be adapted for other realities in any embodiment of either side of the present invention
The technical characteristic in scheme is applied, as long as they are not in contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its
Content in terms of him will make more specific complete description below.
Specific embodiment
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This
Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim
In range.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method and material described herein
Trample the present invention.The present invention is not limited to method described herein and material.The one of the document, patent and the similar material that are combined
Or more it is different from the application or in the case where contradicting it is (including but not limited to defined term, term application, described
Technology, etc.), be subject to the application.
It will further be appreciated that certain features of the invention, be it is clearly visible, carry out in a number of independent embodiments
Description, but can also provide in combination in a single embodiment.Conversely, various features of the invention, for brevity,
It is described in a single embodiment, but can also be individually or with the offer of any suitable sub-portfolio.
Unless otherwise stated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's
It is generally understood identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference
It is bright.
Unless otherwise stated, following definition should be obtained using used herein.For purposes of the present invention, chemical element with
The periodic table of elements CAS editions, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can join
It examines " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999,
" March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John
Description in Wiley&Sons, New York:2007, entire contents are incorporated herein by reference.
There is apparent conflict unless otherwise indicated or in context, the article " one " used herein, " one (kind) "
" described " is intended to include "at least one" or " one or more ".Therefore, these articles used herein refer to one or
The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more than one
Component be taken into account in the embodiment of the embodiment and use or use.
Term " study subject " used in the present invention refers to animal.The typically described animal is mammal.It is tested right
As, such as also refer to primate (such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small
Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described by
Trying object is people.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations
In scheme, " patient " refers to people.
Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise
Content.
Term " stereoisomer " refers to identical chemical constitution, but spatially arrangement mode is different for atom or group
Compound.Stereoisomer includes that enantiomter, diastereoisomer, conformer (rotational isomer), geometry are different
Structure body (cis/trans) isomers, atropisomer, etc..
Term " chirality " be with its mirror image cannot be overlapped property molecule；And " achirality " refer to can be with its mirror image
The molecule of overlapping.
Term " enantiomter " refers to two isomers that cannot be overlapped but be mutually mirror of a compound.
Term " racemate " or " racemic mixture " are hypodactylia optically active two corresponding isomers species
Equimolar mixture.
Term " diastereoisomer " refer to there are two or multiple chiral centres and its molecule not solid of mirror image each other
Isomers.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral property and reactivity.Diastereo-isomerism
Body mixture can be operated such as electrophoresis and chromatography, such as HPLC by high resolution analysis and be separated.
Stereochemical definitions used in the present invention and rule generally follow S.P.Parker, Ed., McGraw-Hill
Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and
Eliel,E.and Wilen,S,“Stereochemistry of Organic Compounds”,John Wiley&Sons,
Inc,New York,1994.Many organic compounds exist with optical active forms, i.e., they, which have, makes the flat of linearly polarized light
The ability that face rotates.When describing optically active compound, indicate molecule about one using prefix D and L or R and S
A or multiple chiral centers absolute configurations.Prefix d and l or (+) and (-) are revolved for linearly polarized light caused by appointed compound
The symbol turned, wherein (-) or l indicate that compound is left-handed.Prefix is (+) or the compound of d is dextrorotation.It is a kind of specific
Stereoisomer is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter:
50 mixtures are known as racemic mixture or racemic modification, when in chemical reaction or in the process without stereoselectivity or three-dimensional spy
When anisotropic, such case may occur in which.
Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer
Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists
(R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake
Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer
It is excessive.
According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they
Mixture, such as the form of racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) deposits
?.Chiral synthon or chiral reagent preparation can be used in optically active (R)-or (S)-isomers, or is torn open using routine techniques
Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing disubstituted cycloalkanes in compound
The substituent group of base, naphthenic base may have cis or trans configuration.
The mixture of resulting any stereoisomer can be separated into according to the difference in component physicochemical properties
Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization
Method.
The racemic modification of any gained final product or intermediate can be passed through into those skilled in the art by known method
Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production
Object can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping
Isomers can be prepared by asymmetric syntheses, for example, can refer to Jacques, et al., Enantiomers, Racemates
and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric
Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel,
E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables
of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre
Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical
Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,
2007)。
Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low
Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can achieve
The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer)
Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and
Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the recombination of some bonding electrons come
The mutual inversion of phases carried out.The specific example of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyl are mutual
The interconversion of tautomeric.Another tautomeric example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific real
Example is the interconversion of pure and mild pyridine -4 (1H) the -one tautomer of pyridine -4-.Unless otherwise noted, the compounds of this invention is all
Tautomeric forms are within the scope of the present invention.
Term " optional " or " optionally " refer to the event then described or situation can with but not necessarily occur, and this is retouched
It states and includes the case where the case where wherein event or situation occur and wherein it does not occur.For example, " optional key " refers to
The key may exist or can be not present, and the description includes singly-bound, double or triple bonds.
One or more degrees of unsaturation are contained in term " unsaturation " or " unsaturated " expression part.
As described in the invention, the compound of the present invention can be optionally replaced one or more substituent groups, such as
General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included.
It should be appreciated that this term can be used interchangeably " optionally replacing " this term with " substituted or unsubstituted ".In general, art
" substituted " the one or more hydrogen atoms indicated in given structure of language are replaced specific substituent group.Unless other aspect tables
Bright, an optional substituent group can be replaced at various substitutable position of that group.When in given structural formula not
Only a position can be replaced one or more substituent groups selected from specific group, then substituent group can identical or differently
Replace at various locations.Wherein the substituent group can be, but be not limited to, deuterium, hydroxyl, fluorine, chlorine, bromine, iodine, cyano, hydroxyl
Base, azido, aryl, heteroaryl, alkoxy, alkylamino, alkylthio group, alkyl, alkenyl, alkynyl, naphthenic base, heterocycle, sulfydryl,
Alkyl, the hydroxyl that nitro, aryloxy group, heteroaryloxy, oxo (=O), carboxyl, halogenated alkyl, halogenated alkoxy, hydroxyl replace take
Alkyl-C (=O)-that alkoxy that the halogenated alkyl in generation, hydroxyl replace, hydroxyl replace, alkyl-C (=O)-, alkyl-S (=
O)-, alkyl-S (=O)2, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (=O)2, Carboxyalkoxy etc.
Deng.
In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode
" each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, both may be used
To refer among the different groups, does not influence mutually, can also indicate in phase between expressed specific option between the same symbol
In same group, do not influenced mutually between expressed specific option between the same symbol.With R9For, structural formula "-N (R9)C
(=O) NR9R9a" and structural formula "-N (R9) C (=O) OR9c" R between the two9Specific option it is unaffected between each other, together
When, in same structure formula "-N (R9) C (=O) NR9R9a" in, two R9Specific option it is unaffected from each other.
It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special
It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term
“C1-6Alkyl " refers in particular to the methyl being individually disclosed, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each section of the invention, connect substituent is described.When the structure clearly needs linking group, for this
Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do
The Markush group definition of variable lists " alkyl " or " aryl ", then respectively represents it should be understood that being somebody's turn to do " alkyl " or " aryl "
The alkylidene group or arylene group of connection.
Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1 to 20 carbon atom, the straight chain of saturation or
Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally by one or more present invention
Replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1-
12 carbon atoms；In another embodiment, alkyl group contains 1-6 carbon atom；In yet another embodiment, alkyl group
Contain 1-4 carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom.
The example of alkyl group includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n-
Pr、-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-
CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tert-butyl (t-Bu ,-C (CH3)3), n-pentyl (-
CH2CH2CH2CH2CH3), 2- amyl (- CH (CH3)CH2CH2CH3), 3- amyl (- CH (CH2CH3)2), 2- methyl -2- butyl (- C
(CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl-1-butyl (- CH2CH2CH(CH3)2), 2- first
Base -1- butyl (- CH2CH(CH3)CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyl (- CH (CH3)
CH2CH2CH2CH3), 3- hexyl (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyl (- C (CH3)2CH2CH2CH3), 3- first
Base -2- amyl (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyl (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- penta
Base (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C
(CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..
Two obtained saturations of hydrogen atom are removed in term " alkylidene " expression from the linear chain or branched chain alkyl of saturation
Bivalent hydrocarbon radical group.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In one embodiment, alkylene
Base group contains 1-6 carbon atom；In another embodiment, alkylidene group contains 1-4 carbon atom；In another embodiment party
In case, alkylidene group contains 1-3 carbon atom；Also in one embodiment, alkylidene group contains 1-2 carbon atom.This
The example of sample includes methylene (- CH2), ethylidene (- CH2CH2), isopropylidene (- CH (CH3)CH2), etc..The alkylene
Base group is optionally replaced one or more substituent groups described in the invention.
Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger
And site, that is, there is a carbon-to-carbon sp2Double bond, wherein the alkenyl group is optionally by one or more described in the invention
Replaced substituent group comprising the positioning of " cis " and " tans ", or the positioning of " E " and " Z ".In one embodiment, alkenyl
Group includes 2-8 carbon atom；In another embodiment, alkenyl group includes 2-6 carbon atom；In another embodiment
In, alkenyl group includes 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (- CH=CH2), alkene
Propyl (- CH2CH=CH2), etc..
Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger
And site, that is, there is tri- key of carbon-to-carbon sp, wherein the alkynyl group is optionally by one or more described in the invention
Replaced substituent group.In one embodiment, alkynyl group includes 2-8 carbon atom；In another embodiment, alkynyl group
Include 2-6 carbon atom；In yet another embodiment, alkynyl group includes 2-4 carbon atom.The example of alkynyl group includes,
But it is not limited to, acetenyl (- C ≡ CH), propargyl (- CH2C ≡ CH), 1- propinyl (- C ≡ C-CH3), etc..
No matter term " carboxyl " is single use or is used in conjunction with other terms, such as " carboxyalkyl ", expression-CO2H；Term
No matter " carbonyl " is single use or is used in conjunction with other terms, such as " amino carbonyl " or " acyloxy ", indicate-(C=O)-.
Term " H " indicates single hydrogen atom.Such atomic group can be connect with other groups, for example with oxygen atom phase
Even, hydroxyl group is formed.
Term " D " or "2H " indicates single D-atom.One such atomic group is connected with a methylene, is formed mono-
Deuterated first (- CDH2), two D-atoms are connected with a methine, form double-deuterated methyl (- CD2) and three D-atoms H
It is connected with the carbon atom of a tetravalence, forms tris-methyl (- CD3)。
Term " azido " or " N3" indicate a nitrine structure.This group can be connected with other groups, for example,
Triazonmethane (MeN can be connected to form with a methyl3), or phenylazide (PhN is connected to form with a phenyl3)。
One or more hetero atoms can be inserted in term " miscellaneous alkyl " expression alkyl chain, wherein alkyl group and hetero atom
With meaning as described in the present invention.Unless otherwise detailed instructions, miscellaneous alkyl group contains 1-10 carbon atom, in an embodiment party
In case, miscellaneous alkyl group contains 1-5 carbon atom, and in another embodiment, miscellaneous alkyl group contains 1-4 carbon atom,
In another embodiment, miscellaneous alkyl group contains 1-3 carbon atom.Such example includes, but is not limited to, CH3OCH2,
CH3CH2OCH2, CH3SCH2, (CH3)2NCH2, (CH3)2CH2OCH2, CH3OCH2CH2, CH3CH2OCH2CH2, etc..Institute
Miscellaneous alkyl group is stated optionally replaced one or more substituent groups described in the invention.
Term " hetero atom " indicates one or more oxygen (O), sulphur (S), nitrogen (N), phosphorus (P) or silicon (Si), including nitrogen (N),
The form of sulphur (S) and phosphorus (P) any oxidation state；The form of primary, secondary, tertiary amine and quaternary ammonium salt；Or the hydrogen in heterocycle on nitrogen-atoms
Substituted form, for example, N (as the N in 3,4- dihydro-2 h-pyrrole base), NH (as the NH in pyrrolidinyl) or NR are (as N-
NR in substituted pyrrolidinyl).
Term " halogen " and " halogenated " refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " hydroxyl replace alkyl " indicate alkyl group replaced one or more hydroxyl groups, wherein alkyl base
Group has meaning of the present invention.Such example includes, but is not limited to methylol, ethoxy, 1,2- dihydroxy ethyl,
Etc..
Term " halogenated alkyl " or " halogenated alkoxy " indicate alkyl or alkoxy base by one or more halogen atoms
Replaced, wherein alkyl and alkoxy base have meaning of the present invention, and such example includes, but is not limited to, and two
Methyl fluoride, trifluoromethyl, trifluoromethoxy, 2,2- difluoroethoxy, 2,2,2- trifluoro ethoxy, the third oxygen of 2,2,3,3- tetrafluoro
Base, 2,2,3,3,3- five fluorine propoxyl group, etc..The halogenated alkyl or halo alkoxy group are optionally by one or more sheets
It invents replaced described substituent group.
Term " fluoro C1-4Alkoxy " indicates C1-4The alkoxy of linear chain or branched chain is taken by one or more fluorine (F) atom
In generation, wherein alkoxy base has meaning of the present invention, and such example includes, but is not limited to, difluoro-methoxy, three
Fluorine methoxyl group, 2- fluorine ethyoxyl, 2,2- difluoroethoxy, 2,2,2- trifluoro ethoxy, 2,3- difluoro propoxyl group, 2,3,3- trifluoro
Propoxyl group, 2,3,3,3- tetrafluoro propoxyl group, 2,2,3- trifluoro propoxyl group, 2,2,3,3- tetrafluoro propoxyl group, five fluorine of 2,2,3,3,3-
Propoxyl group, etc..The fluoro C1-4Alkoxy base is optionally taken by one or more substituent groups described in the invention
Generation.
Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has
Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party
In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；?
In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base is optionally by this one or more hair
Replaced the substituent group of bright description.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,-
OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH
(CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen
Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t-
BuO, t- butoxy ,-OC (CH3)3), 1- amoxy (n- amoxy ,-OCH2CH2CH2CH2CH3), 2- amoxy (- OCH (CH3)
CH2CH2CH3), 3- amoxy (- OCH (CH2CH3)2), 2- methyl -2- butoxy (- OC (CH3)2CH2CH3), 3- methyl -2- fourth
Oxygroup (- OCH (CH3)CH(CH3)2), 3- methyl-l- butoxy (- OCH2CH2CH(CH3)2), 2- methyl-l- butoxy (-
OCH2CH(CH3)CH2CH3), etc..
Term " alkylthio group " refers to C1-6The alkyl of linear chain or branched chain is connected by sulphur atom with molecule rest part.One
In embodiment, alkylthio group is the C of lower level1-4Alkylthio group, such example include, but is not limited to methyl mercapto (CH3S-)。
The alkylthio radicals are optionally replaced one or more substituent groups described in the invention.
Term " alkylamino " or " alkyl amino " include " N- alkyl amino " and " N, N- dialkyl amido ", wherein amino base
Group is separately replaced one or two alkyl group, and wherein alkyl group has meaning as described in the present invention.?
In one embodiment, alkyl amino is one or two C1-6Alkyl is connected to the alkylamino group of the lower level on nitrogen-atoms.
In another embodiment, alkyl amino is C1-3Lower level alkylamino group.Suitable alkylamino group can be
Alkyl monosubstituted amino or dialkyl amido, such example include, but is not limited to, N- methylamino, N- ethylamino, N, N- diformazan ammonia
Base, N, N- lignocaine etc..The alkylamino radicals are optionally taken by one or more substituent groups described in the invention
Generation.
Term " aminoalkyl " includes the C replaced one or more amino1-10Linear or branched alkyl group group.One
In embodiment, aminoalkyl is the C replaced one or more amino groups1-6" aminoalkyl of lower level ", it is such
Example includes, but is not limited to, aminomethyl, aminoethyl, aminopropyl, etc..The aminoalkyl groups optionally by one or
Replaced multiple substituent groups described in the invention.
Term " n former molecular ", wherein n is integer, the number of ring member nitrogen atoms in molecule is typically described, described
The number of ring member nitrogen atoms is n in molecule.For example, piperidyl is 6 molecular Heterocyclylalkyls of original, and 1,2,3,4- naphthane is
10 molecular groups of naphthene base of original.
Term " ring " includes carbocyclic ring, heterocycle, aromatic ring, hetero-aromatic ring, loop coil, condensed ring, etc., wherein the carbocyclic ring, heterocycle, virtue
Ring, hetero-aromatic ring, loop coil, condensed ring group have meaning as described in the present invention.
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " and " condensed ring radical " are used interchangeably here, all refer to list
The unsaturated bridged-ring system of the saturation or part of valence or multivalence, the bridged-ring system refer to the bicyclic system of non-aromatic.Such as formula
Shown in a-c, indicate between two five-membered rings (formula a), between two hexatomic rings (formula b) and five-membered ring and one it is hexa-atomic
(formula c) shares the bridged-ring system of a C-C key between ring.It may include independent or conjugation unsaturated system in system, but
Its nuclear structure does not include aromatic rings or hetero-aromatic ring (but aromatic group can be used as substituent group thereon).In condensed-bicyclic
Each ring independently be carbocyclic ring or heterocycle.
The example of condensed-bicyclic includes, but are not limited to hexahydro furyl simultaneously [2,3-b] furans -3- base, hexahydro furyl simultaneously [3,
2-b] furans -3- base, octahydro pentamethylene simultaneously [c] pyrroles -5- base, octahydro pentalene -2- base, octahydro -1H- iso-indoles -5-
Base, etc..Condensed-bicyclic base can be independently unsubstituted or replaced one or more substituent group described in the invention.
Term " loop coil base ", " loop coil ", " spiral shell bicyclic group " or " spiral shell is bicyclic " are used interchangeably here, refer to unit price or more
The saturation or part unsaturated ring system of valence, one of ring is originating from specific ring carbon atom on another ring.For example, as under
Described in face formula d, formula e, a carbon atom is shared in the ring system that ring A and ring B are saturated at two, then be referred to as " loop coil " or
" spiral shell is bicyclic ".Each ring in loop coil independently is carbocyclic ring or heterocycle.Such example includes, but is not limited to 4- oxaspiro
[2.4] heptane -6- base, (R) -4- azaspiro [2.4] heptane -6- base, spiral shell bicyclic group can be independently unsubstituted or by one
Or replaced multiple substituent groups described in the invention.
Term " Heterocyclylalkyl " refers to saturation monocycle, the bicyclic or tricyclic of the unit price containing 3-12 annular atom or multivalence
System, wherein at least one annular atom are selected from nitrogen, sulphur or oxygen atom.The heterocycloalkyl is optionally by one or more sheets
It invents replaced described substituent group.
Term " carbocylic radical " or " carbocyclic ring " indicate containing 3-12 carbon atom, monovalent or multivalence nonaromatic saturation
Or part unsaturated monocycle, bicyclic or three-ring system.Carbon bicyclic group includes spiral shell carbon bicyclic group and condensed carbon bicyclic group, suitably
Carbocylic radical group includes, but is not limited to, naphthenic base, cycloalkenyl and cycloalkynyl radical.The example of carbocylic radical group further comprises ring
Propyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyl, 1- cyclopenta -2- alkenyl, 1- cyclopenta -3- alkenyl, cyclohexyl, 1-
Cyclohexyl -1- alkenyl, 1- cyclohexyl -2- alkenyl, 1- cyclohexyl -3- alkenyl, cyclohexadienyl, suberyl, cyclooctyl, ring nonyl
Base, cyclodecyl, ring undecyl, cyclo-dodecyl, etc..The carbocylic radical group is optionally by one or more institutes of the present invention
Replaced the substituent group of description.
Term " naphthenic base " indicates containing 3-12 carbon atom, monovalent or multivalence saturation monocycle, bicyclic or three ring bodies
System.Bicyclic or three-ring system may include condensed ring, bridged ring and loop coil.In one embodiment, naphthenic base includes that 3-10 carbon is former
Son；In another embodiment, naphthenic base includes 3-8 carbon atom；In yet another embodiment, naphthenic base includes 3-6 carbon
Atom.The example of group of naphthene base includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopenta, etc..The group of naphthene base
Optionally replaced one or more substituent groups described in the invention.
Term " heterocycle " and " heterocycle " are used interchangeably here, all refer to the monocycle comprising 3-12 annular atom, double
Ring or three-ring system, one or more atoms are independently replaced by hetero atom in middle ring, and the hetero atom has such as this hair
The bright meaning, ring can be fully saturated or comprising one or more degrees of unsaturation, but an armaticity ring all cannot
Have.In one embodiment, heterocyclyl groups are that (2-6 carbon atom and selected from N, O, P, 1-3 of S are miscellaneous for the monocycle of 3-8 member ring
Atom optionally obtains replaced one or more oxygen atoms in this S or P as SO, SO2, PO, PO2Group, when described
When ring is three-membered ring, only one of them hetero atom) or 7-12 member bicyclic (4-9 carbon atom and selected from N, O, P, the 1-3 of S
A hetero atom optionally obtains replaced one or more oxygen atoms in this S or P as SO, SO2, PO, PO2Group).It is described
Heterocyclyl groups are optionally replaced one or more substituent groups described in the invention.
Heterocycle can be carbon-based or heteroatom group.- the CH of its middle ring2Group is optionally substituted by-C (O)-, the sulphur of ring
Atom is optionally oxidized to S- oxide, and the nitrogen-atoms of ring is optionally oxidized to N- oxygen compound.The example packet of heterocycle
It includes, but is not limited to, Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- pyrrolinyl,
3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuryl, thiophane
Base, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranose, 4H- pyrrole
It mutters base, tetrahydro thiapyran base, piperidyl, morpholinyl (morpholine -2-base, morpholine-3- base, morpholine-4- base), thio-morpholinyl, piperazine
Base (piperazine -1- base, piperazine -2- base, piperazine -3- base), dioxanes base, dithianyl, thiophene oxane base, high piperazine base, high piperidines
Base, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase, sulphur azepineBase, 2- oxa- -5- azepine are double
Ring [2.2.1] hept- 5- base, etc..- CH in heterocycle2Group includes, but are not limited to 2- oxygen by-C (=the O)-example replaced
For pyrrolidinyl, oxo -1,3-thiazoles alkyl, 2- piperidone base, 3,5- dioxy piperazine piperidinyl, hybar X base, etc..Heterocycle
The example that sulphur atom is oxidized in base includes, but are not limited to sulfolane base, thio-morpholinyl 1,1- dioxide, etc..It is described
Heterocyclyl groups optionally replaced one or more substituent groups described in the invention.
In one embodiment, heterocycle is 4-7 former molecular heterocycle, refers to satisfying comprising 4-7 annular atom
And/or the unsaturated monocycle in part, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.4-7 former molecular heterocycle
The example of base includes, but are not limited to azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- pyrrolinyl, 3-
Pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuryl, thiophane
Base, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranose, 4H- pyrrole
It mutters base, tetrahydro thiapyran base, piperidyl, morpholinyl (morpholine -2-base, morpholine-3- base, morpholine-4- base), thio-morpholinyl, piperazine
Base (piperazine -1- base, piperazine -2- base, piperazine -3- base), dioxanes base, dithianyl, thiophene oxane base, high piperazine base, high piperidines
Base, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase, sulphur azepineBase, etc..In heterocycle-
CH2Group includes, but are not limited to 2- oxo-pyrrolidine base, oxo -1,3-thiazoles alkyl, 2- by-C (=the O)-example replaced
Piperidone base, 3,5- dioxy piperazine piperidinyl, hybar X base, etc..The example that sulphur atom is oxidized in heterocycle includes, but not
It is limited to, sulfolane base, thio-morpholinyl 1,1- dioxide, etc..The former molecular heterocyclyl groups of described 4-7 are optional
Ground is replaced one or more substituent groups described in the invention.
In another embodiment, heterocycle is 4 molecular heterocycles of original, refers to the saturation comprising 4 annular atoms
Or the unsaturated monocycle in part, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.4 molecular heterocycles of original
Example includes, but are not limited to azelidinyl, oxetanylmethoxy, thietanyl, etc..4 originals are molecular miscellaneous
Cyclic groups are optionally replaced one or more substituent groups described in the invention.
In another embodiment, heterocycle is 5 molecular heterocycles of original, refers to the saturation comprising 5 annular atoms
Or the unsaturated monocycle in part, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.5 molecular heterocycles of original
Example includes, but are not limited to pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,
Imidazolidinyl, tetrahydrofuran base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur rings penta
Base, etc..- CH in heterocycle2Group includes, but are not limited to 2- oxo-pyrrolidine base, oxygen by-C (=the O)-example replaced
Generation -1,3-thiazoles alkyl, etc..The example that sulphur atom is oxidized in heterocycle includes, but are not limited to sulfolane base, etc..Institute
The 5 molecular heterocyclyl groups of original stated are optionally replaced one or more substituent groups described in the invention.
In another embodiment, heterocycle is 6 molecular heterocycles of original, refers to the saturation comprising 6 annular atoms
Or the unsaturated monocycle in part, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.6 molecular heterocycles of original
Example includes, but are not limited to THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidines
Base, morpholinyl (morpholine -2-base, morpholine-3- base, morpholine-4- base), thio-morpholinyl, piperazinyl (piperazine-1- base, piperazine-2-
Base, piperazine -3- base), dioxanes base, dithianyl, thiophene oxane base, etc..- CH in heterocycle2Group is replaced by-C (=O)-
Example include, but are not limited to 2- piperidone base, 3,5- dioxy piperazine piperidinyl, hybar X base, etc..Sulphur is former in heterocycle
The example that son is oxidized includes, but are not limited to thio-morpholinyl 1,1- dioxide, etc..6 originals are molecular miscellaneous
Cyclic groups are optionally replaced one or more substituent groups described in the invention.
Also in one embodiment, heterocycle is 7-12 former molecular heterocycle.7-12 former molecular heterocycle
The example of base includes, but are not limited to 2- oxa- -5- azabicyclo [2.2.1] hept- 5- base, etc..The 7-12 atom group
At heterocyclyl groups optionally replaced one or more substituent groups described in the invention.
Term " heterocyclylalkyl group " indicates the alkyl that heterocycle replaces；Term " heterocyclylalkoxy " indicates that heterocycle replaces
Alkoxy, wherein oxygen atom is connected with the rest part of molecule；Term " heterocycle alkylamino " refers to the alkane that heterocycle replaces
Amino, wherein the nitrogen-atoms in alkylamino is connected with the rest part of molecule.Wherein heterocycle, alkyl, alkoxy and alkylamino
With meaning as described in the present invention, such example includes, but is not limited to pyrroles's -2- ylmethyl, morpholine -4- base ethyl,
Morpholine -4- base oxethyl, piperazine -4- base oxethyl, piperidin-4-yl ethylamino, etc..The heterocyclylalkyl group, heterocycle
Alkoxy or heterocycle alkylamino radicals are optionally replaced one or more substituent groups described in the invention.
Term " heterocycle oxygroup " indicates that the heterocycle optionally replaced is connected on oxygen atom as defined herein,
Wherein oxygen atom is connected with the rest part of molecule, and such example includes, but is not limited to pyrroles's -2- oxygroup, pyrroles's -3- oxygen
Base, piperidines -2- oxygroup, piperidines -3- oxygroup, piperazine -2- oxygroup, piperidines -4- oxygroup, etc..The heterocycle oxygroup group is appointed
Selection of land is replaced one or more substituent groups described in the invention.
Term " heterocyclylamino group " indicate amino group replaced one or two heterocyclyl groups, wherein nitrogen-atoms with
The rest part of molecule is connected, and wherein heterocycle includes with meaning as described in the present invention, such example, but and unlimited
In, pyrroles's -2- amino, pyrroles's -3- amino, piperidines -2- amino, piperidines -3- amino, piperidines -4- amino, piperazine -2- amino, two
(pyrroles -2- base)-amino, etc..The heterocyclylamino group group is optionally by one or more substitutions described in the invention
Replaced base.
Term " alkyl heterocyclic " indicate heterocyclyl groups replaced one or more alkyl groups, wherein heterocycle and
Alkyl group has meaning as described in the present invention, and such example includes, but is not limited to, N methyl piperazine base, N- ethyl
Piperazinyl, etc..The alkyl heterocyclic group is optionally replaced one or more substituent groups described in the invention.
Term " naphthenic base heterocycle " indicate heterocyclyl groups replaced one or more groups of naphthene base, wherein heterocycle
Base and group of naphthene base have meaning as described in the present invention, and such example includes, but is not limited to, N- cyclopropylpiperazin
Base, N- cyclobutyl piperazinyl, etc..The naphthenic base heterocyclyl groups optionally described in the invention are taken by one or more
Replaced Dai Ji.
Term " aryl " indicates the monocycle containing 6-14 annular atom or 6-12 annular atom or 6-10 annular atom, double
The carbocyclic ring system of ring and tricyclic, wherein at least one ring system be it is aromatic, wherein each ring system include 3-7 original
Molecular ring.Aryl group by the armaticity ring of aryl group with parent molecule in general, but unnecessarily connect.Term
" aryl " can be used interchangeably with term " aromatic rings " or " aromatic ring ".The example of aryl group may include phenyl, naphthalene and anthracene.
The aryl group is optionally replaced one or more substituent groups described in the invention.
Term " aralkyl " or " aryl alkyl " refer to the alkyl group that aryl replaces.In one embodiment, aralkyl
Group refers to that " aralkyl of lower level " group, i.e. aryl group are connected to C1-6Alkyl group on.In another embodiment
In, aromatic alkyl group refers to containing C1-4Alkyl " benzeme alkylene ".Wherein specific example includes benzyl, diphenyl methyl, benzene second
Base, etc..Aryl on aralkyl can further be taken by halogen, alkyl, alkoxy, halogenated alkyl and halogenated alkoxy
Generation.The aromatic alkyl group is optionally replaced one or more substituent groups described in the invention.
Term " aryloxy group " indicates that the aryl optionally replaced is connected on oxygen atom as defined herein, and by
Oxygen atom is connected with molecule rest part, and wherein aryl group includes with meaning as described in the present invention, such example, but
It is not limited to phenoxy group, toloxyl, ethylbenzene oxygroup, etc..The aryloxy group is optionally by one or more present invention
Replaced described substituent group.
Term " arylthio " includes that the aryl optionally replaced is connected on sulphur atom as defined herein, and by
Sulphur atom is connected with molecule rest part, and wherein aryl group includes with meaning as described in the present invention, such example, but
It is not limited to thiophenyl, Tolylsulfanvl, ethylbenzene sulfenyl, etc..The arylthio group is optionally by one or more present invention
Replaced described substituent group.
Term " fragrant amino " indicates amino group replaced one or two aryl group, and such example includes, but
It is not limited to N- phenylamino.In one embodiment, the aromatic ring in fragrant amino can be further substituted.The fragrant amino group
Optionally replaced one or more substituent groups described in the invention.
Monocycle of term " heteroaryl " expression containing 5-12 annular atom or 5-10 annular atom or 5-6 annular atom,
Bicyclic and three-ring system, wherein at least one ring system are aromatic, and at least one ring system includes one or more miscellaneous
Atom, wherein each ring system includes 5-7 former molecular ring.Heteroaryl groups are in general, but unnecessarily pass through heteroaryl
The armaticity ring of base group is connect with parent molecule.Term " heteroaryl " can be with term " hetero-aromatic ring ", " heteroaromatic " or " heteroaryl
Compounds of group " is used interchangeably.The heteroaryl groups are optionally replaced one or more substituent groups described in the invention.
In one embodiment, 5-10 former molecular heteroaryl includes 1,2,3 or 4 hetero atom for being independently selected from O, S and N.
The example of heteroaryl groups includes, but is not limited to, 2- furyl, 3- furyl, TMSIM N imidazole base, 2- imidazole radicals,
4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl, 2- oxazolyl, 4- oxazolyl, 5- oxazole
Base, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 2- pyrimidine radicals, 4- pyrimidine radicals, 5-
Pyrimidine radicals, pyridazinyl (such as 3- pyridazinyl), 2- thiazolyl, 4- thiazolyl, 5- thiazolyl, tetrazole radical (such as 5- tetrazole radical), triazole
Base (such as 2- triazolyl and 5- triazolyl), 2- thienyl, 3- thienyl, pyrazolyl (such as 2- pyrazolyl), isothiazolyl, 1,2,3-
Oxadiazoles base, 1,2,5- oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,3- triazolyl, 1,2,3- thio biphosphole base, 1,3,4- sulphur
For di azoly, 1,2,5- thio biphosphole base, pyrazinyl, cyanuro 1,3,5；Also include below bicyclic, but be not limited to these
It is bicyclic: benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2- indyl), purine radicals, quinolyl (such as 2- quinoline
Quinoline base, 3- quinolyl, 4- quinolyl), isoquinolyl (such as 1- isoquinolyl, 3- isoquinolyl or 4- isoquinolyl), imidazo
[1,2-a] pyridyl group, pyrazolo [1,5-a] pyridyl group, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazinyl, [1,
2,4] triazol [4,3-b] pyridazinyl, [1,2,4] triazol [1,5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] pyridine
Base, etc..
As described in the invention, substituent R is keyed to the ring system formed on the ring at center (such as formula f institute by one
Show) it represents substituent R and only limits any on A ring may replace or any reasonable position is replaced.For example, formula f is represented on A ring
Any possible substituted position, such as formula f1-f4It is shown:
Term " heteroaryl amino " indicates replaced the heteroaryl groups that amino group is optionally replaced by one or two,
Middle heteroaryl has meaning as described in the present invention, and such example includes, but is not limited to, N- thienyl amino, pyridine -4-
Base amino, fluorine pyridinylamino, bipyridyl amino, etc..The heteroaryl amino group is optionally one or more
Replaced substituent group described in the invention.
Term " heteroaryloxy " indicates that the heteroaryl optionally replaced is connected on oxygen atom as defined herein, and
And be connected by oxygen atom with molecule rest part, wherein heteroaryl groups have meaning as described in the present invention, such example
Include, but is not limited to pyridine oxygroup, 2-pyrimidinyl oxy, etc..The heteroaryl oxygroup group is optionally by one or more sheets
It invents replaced described substituent group.
Term " heteroaryl alkyl " indicate alkyl group replaced one or more heteroaryls, wherein heteroaryl and alkyl
Group has meaning of the present invention, and such example includes, but is not limited to imidazoles -2- methyl, furans -2- ethyl, Yin
Diindyl -3- methyl, etc..The heteroarylalkyl group is optionally taken by one or more substituent groups described in the invention
Generation.
The structure occurred in the present inventionIt indicatesOr
Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo.
Such conversion is hydrolyzed in blood by pro-drug or is that precursor structure is influenced through enzymatic conversion in blood or tissue.This hair
Bright pro-drug compounds can be ester, and ester can be used as the phenyl ester class that has of pro-drug, aliphatic in existing invention
(C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention
Compound includes hydroxyl, it can is acylated to obtain the compound of prodrug form.Other prodrug forms include
Phosphate, if these phosphate compounds are obtaining through the di on parent.It is completely begged for about pro-drug
By following documents can be referred to: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol.14,
A.C.S.Symposium Series；Roche et al.,ed.,Bioreversible Carriers in Drug
Design,American Pharmaceutical Association and Pergamon Press,1987；Rautio et
al.,Prodrugs:Design and Clinical Applications,Nature Reviews Drug Discovery,
2008,7,255-270,and Hecker et al,Prodrugs of Phosphates and Phosphonates,
J.Med.Chem., 2008,51,2328-2345, every document are included herein by reference.
Term " metabolite " used in the present invention refers to that specific compound or its salt passes through metabolism in vivo
Obtained product.The metabolite of one compound can be identified by technology well-known in the art, active
It can experimentally be characterized by adopting as described in the present invention.Such product can be through administrationization
Object is closed through peroxidating, is restored, hydrolysis, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtains.Phase
Ying Di, the present invention include the metabolite of compound, including when the compound of the present invention and mammal are come into full contact with one section
Between generated metabolite.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine
Acceptable salt is known to us in fields on, such as document: S.M.Berge et al.,
Documented by J.Pharmaceutical Sciences, 66:1-19,1977.The salt that pharmaceutically acceptable nontoxic acid is formed
It including, but is not limited to, inorganic acid salt formed by reacting with amino groups to form has a hydrochloride, hydrobromate, phosphate, sulfate,
Perchlorate and acylate such as acetate, oxalates, maleate, tartrate, citrate, succinate, malonic acid
Salt, or these salt are obtained by other methods described in the books or literature such as ion-exchange.Other are pharmaceutically acceptable
Salt include adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, boric acid
Salt, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonic acid
Salt, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproic acid
Salt, hydriodate, 2- hydroxy-ethanesulfonate salt, lactobionate, lactate, laruate, lauryl sulfate, malate,
Malonate, mesylate, 2- naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, mistake
Sulfate, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate,
Undecylate, valerate, etc..Salt obtained by an appropriate base includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4
Salt.The compound that the present invention is also intended to contemplate the group of any included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or
Dispersion product can be obtained by quaternization.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmacy
Upper acceptable salt further comprises appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halogenation
Object, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Sulphonic acid compound and aromatic sulphonic acid compound.
" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association
Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second
Acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
When the solvent is water, term " hydrate " can be used.In one embodiment, a compounds of this invention
Molecule can be combined with a hydrone, such as monohydrate；In another embodiment, a compounds of this invention molecule
It can be combined with more than one hydrone, such as dihydrate, in yet another embodiment, a compounds of this invention point
Son can be combined with the hydrone less than one, such as semihydrate.It should be noted that hydrate of the present invention remain with it is non-
The biological effectiveness of the compound of hydrated form.
When term " blocking group " or " PG " refer to a substituent group and other reacted with functional groups, commonly used to resistance
It is disconnected or protect special functionality.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group
Or the functionality of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl
(BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9- fluorenes methylene oxygen carbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl
The substituent group of base is used to block or protect the functionality of hydroxyl, and suitable blocking group includes trialkylsilkl, acetyl group,
Benzoyl and benzyl." carboxy protective group " refers to that the substituent group of carboxyl is used to block or protect the functionality of carboxyl, generally
Carboxyl-protecting group include-CH2CH2SO2Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) second
Oxygroup methyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro
Ethyl, etc..Description general for blocking group can refer to document: Greene et al., Protective Groups in
Organic Synthesis,John Wiley&Sons,New York,1991and Kocienski et al.,
Protecting Groups,Thieme,Stuttgart,2005。
Any disease of term " treatment " or illness as used in the present invention, refer to improvement disease in some of these embodiments
Disease or illness (development for slowing down or prevent or mitigate disease or its at least one clinical symptoms).In other embodiments
In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another
In a little embodiments, " treatment " refers to from body (such as stablizing perceptible symptom) or physiologically (such as stable body
Parameter) or above-mentioned two aspect adjust disease or illness.In other embodiments, " treatment ", which refers to, prevents or delays disease or disease
Breaking-out, generation or the deterioration of disease.
Term " preventing " or " prevention " refer to that the reduction for obtaining the risk of disease or obstacle (that is: makes at least one clinical condition of disease
Shape stops development in main body, which may face or be inclined in advance in face of this disease, but without undergoing or show
The symptom of disease).
Term " ADHD " is the abbreviation of Attention-deficit hyperactivity disorder, means attention
The mostly dynamic obstacle of defect, be it is a kind of childhood very common psychataxia.According to " the general disease in the world point of the World Health Organization
Class handbook " the tenth edition (ICD-10, WHO, 1992) this disease be referred to as " hyperactivity disorder " (Hyperkinetic Disorder), point
Class number is F90, general to be commonly called as again as " hyperactive children ".
Term " schizophrenia " refers to schizophrenia, schizophrenia-like disorder, schizoaffective disorder and spirit
Characteristic of disease phrenoblabia, wherein term " mental disease " refers to vain hope, apparent illusion, amorphous language or unorganized behavior or deadlock
Straightization behavior.Referring to Diagnostic and Statistical Manual of Mental Disorder, fourth edition,
American Psychiatric Association, Washington, D.C..
Pharmaceutical acid-addition salts can be formed with inorganic acid and organic acid, such as acetate, aspartate, benzoic acid
Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination
Object/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid
Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, apple
Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate,
Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly- half
Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid
Salt.
The inorganic acid that salt can be obtained by its derivative includes such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid.
The organic acid that salt can be obtained by its derivative includes such as acetic acid, propionic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two
Acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, sulfo group water
Poplar acid etc..
Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.
Can obtain the inorganic base of salt by its derivative includes, for example, ammonium salt and periodic table I race to XII race metal.?
In certain embodiments, which is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium,
Sodium, calcium and magnesium salts.
Can obtain the organic base of salt by its derivative includes primary amine, secondary amine and tertiary amine, and substituted amine includes naturally occurring
Substituted amine, cyclic amine, deacidite etc..Certain organic amines include, for example, isopropylamine, tardocillin
(benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine
And tromethamine.
Officinal salt of the invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety.
In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca,
Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or free alkali form and chemistry by making these compounds
The suitable acid reaction of metered amount is to be prepared.Such reaction usually carries out in the mixture of water or organic solvent or both.
Generally, in appropriate cases, it needs using non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.?
Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company,
Easton,Pa.,(1985)；" pharmaceutical salts handbook: property, selection and application (Handbook of Pharmaceutical
Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim,
Germany, 2002) list that other is suitable for salt can be found in.
In addition, compound disclosed by the invention, the salt including them, in the form of their hydrate or can also include it
The form of solvent (such as ethyl alcohol, DMSO, etc.) obtains, for their crystallization.Disclosed compound of present invention can be with pharmacy
Upper acceptable solvent (including water) forms solvate inherently or by design；Therefore, the present invention is intended to include solvations
And unsolvated form.
Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same
The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more
A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention
Isotope including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H,3H,11C,13C,14C,15N,17O,18O,18F,31P,32P,35S,36Cl and125I。
On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its
In there are radioactive isotopes, such as3H,14C and18Those of F compound, or wherein there is non radioactive isotope, such as2H and13C.The compound of such isotope enrichment can be used for being metabolized research and (use14C), Reaction kinetics research are (using for example2H or3H), detection or imaging technique, such as positron emission tomography (PET) or including drug or substrate tissue measure of spread
Single photon emission computed tomography (SPECT), or can be used in the radiotherapy of patient.18The compound of F enrichment to PET or
It is especially desirable for SPECT research.Compound shown in the formula (I) of isotope enrichment can be ripe by those skilled in the art
It is substituted described by the embodiment and preparation process in routine techniques or the present invention known using suitable isotope labeling reagent former
Carry out used unmarked reagent to prepare.
In addition, higher isotope especially deuterium (that is,2H or D) substitution can provide certain treatment advantages, these advantages are
By the higher bring of metabolic stability.For example, Half-life in vivo increase or reduction of volume requirements or therapeutic index obtain improving band
Come.It should be appreciated that the deuterium in the present invention is seen as the substituent group of formula (I) compound.It can be determined with isotope enrichment factor
The concentration of such adopted higher isotope especially deuterium.Term " isotope enrichment factor " used in the present invention refers to specified same
Ratio between the isotope abundance and natural abundance of position element.If the substituent group of the compounds of this invention is designated as deuterium, the change
Object is closed for each specified D-atom at least 3500 (52.5% deuterium incorporations at each specified D-atom), at least 4000
(60% deuterium incorporation), at least 4500 (67.5% deuterium incorporations), at least 5000 (75% deuterium incorporations), at least 5500
(82.5% deuterium incorporation), at least 6000 (90% deuterium incorporations), at least 6333.3 (95% deuterium incorporations), at least 6466.7
The isotope enrichment of (97% deuterium incorporation), at least 6600 (99% deuterium incorporations) or at least 6633.3 (99.5% deuterium incorporations)
The factor.The pharmaceutical solvate of the present invention includes such as D that wherein recrystallisation solvent can be isotope substitution2O, acetone-d6、
DMSO-d6Those of solvate.
The description of the compounds of this invention
Benzylamine analog derivative of the present invention, pharmaceutically acceptable salt and its pharmaceutical preparation have antagonism 5-
HT6, especially have potential purposes to the treatment of Alzheimer's disease.
On the one hand, the present invention relates to a kind of compounds, are formula (I) or (I-A) compound represented or formula (I) or (I-
A the stereoisomer of compound shown in), geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolism
Product, pharmaceutically acceptable salt or prodrug,
Wherein:
Each Y independently is CH or N；
X1And Y1It is each independently CH；
X2、X3And X4Respectively stand alone as CH or N, and X2、X3And X4In most two simultaneously be N；
Each X independently is CH or N, and most two X are simultaneously N；
Each k independently is 0,1,2 or 3；
Each p independently is 0,1 or 2；
Each m independently is 0,1,2,3 or 4；
Each n independently is 1,2,3,4 or 5；
Each R1And R3It independently is H, D, F, Cl, Br, I ,-CN ,-NO2、-OH、-NH2、-NR9R9a,-C (=O) R9b,-C (=
O)NR9R9a,-OC (=O) NR9R9a,-OC (=O) OR9c、-N(R9) C (=O) NR9R9a、-N(R9) C (=O) OR9c、-N(R9)C
(=O) R9b、R9R9aN-S (=O)2-、R9bS (=O)p-、R9bS (=O)2N(R9aThe C that hydroxyl)-, replaces1-6Alkyl, R9aR9N-C1-6
Alkyl, R9bS (=O)p-C1-6Alkyl, R9R9aN-C (=O)-C1-6Alkyl, R9aR9N-C1-6Alkoxy, R9bS (=O)p-C1-6Alcoxyl
Base, R9R9aN-C (=O)-C1-6Alkoxy, C6-10Aryl, C1-9Heteroaryl, C1-6Alkoxy, C1-6Alkylamino, C1-6Alkyl, C1-6
Miscellaneous alkyl, halogenated C1-6Alkyl, halogenated C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C2-10Heterocycle, C3-8Naphthenic base, C1-6Alkane sulphur
Base, C6-10Aryloxy group, C6-10Arylthio, C6-10Aryl C1-6Alkyl, C6-10Fragrant amino, C1-9Heteroaryl amino, C6-10Aryl C1-6Alkane
Amino, C1-9Heteroaryl C1-6Alkylamino, C1-9Heteroaryl oxygroup, C1-9Heteroaryl C1-6Alkyl, C6-10Aryl C1-6Alkoxy, C1-9
Heteroaryl C1-6Alkoxy, C1-6Alkyl C2-10Heterocycle, C3-8Naphthenic base C2-10Heterocycle, C2-10Heterocycle oxygroup, C2-10Heterocycle
Base C1-6Alkoxy, C2-10Heterocyclylamino group or C2-10Heterocycle alkylamino；
Each R2It independently is D, F, Br, I ,-CN ,-OH ,-NH2、-NR9R9a,-C (=O) R9b,-C (=O) NR9R9a、-OC
(=O) NR9R9a,-OC (=O) OR9c、-N(R9) C (=O) NR9R9a、-N(R9) C (=O) OR9c、-N(R9) C (=O) R9b、
R9R9aN-S (=O)2-、R9bS (=O)p-、R9bS (=O)2N(R9aThe C that hydroxyl)-, replaces1-6Alkyl, R9aR9N-C1-6Alkyl, R9bS
(=O)p-C1-6Alkyl, R9R9aN-C (=O)-C1-6Alkyl, R9aR9N-C1-6Alkoxy, R9bS (=O)p-C1-6Alkoxy,
R9R9aN-C (=O)-C1-6Alkoxy, C6-10Aryl, C1-9Heteroaryl, C2-6Alkoxy, C1-6Alkylamino, C1-6Alkyl, halogenated C1-6
Alkyl, halogenated C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C2-10Heterocycle, C3-8Naphthenic base, C1-6Alkylthio group, C6-10Arylthio,
C6-10Aryl C1-6Alkyl, C6-10Fragrant amino, C1-9Heteroaryl amino, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl C1-6Alkylamino,
C1-9Heteroaryl oxygroup, C1-9Heteroaryl C1-6Alkyl, C6-10Aryl C1-6Alkoxy, C1-9Heteroaryl C1-6Alkoxy, C2-10Heterocycle
Oxygroup, C2-10Heterocycle C1-6Alkoxy, C2-10Heterocyclylamino group or C2-10Heterocycle alkylamino；
Each R4It independently is H, D, C2-6Alkyl, halogenated C1-6Alkyl, C3-8Naphthenic base ,-C (=O) R9b,-C (=O) NR9R9a、
C2-6Alkenyl or C2-6Alkynyl；
Each R5、R6、R7And R8It independently is H, D, F, Cl, Br, I ,-CN ,-NO2、-OH、-NH2、C1-6Alkyl, C2-6Alkenyl,
C2-6Alkynyl, C2-10Heterocycle, C3-8Naphthenic base ,-C (=O) R9b,-C (=O) NR9R9aOr R5And R6Or R7And R8, respectively and with
The connected carbon atom of each together, is separately formed substituted or unsubstituted 3-8 former molecular carbocyclic ring or heterocycle；
Each R9And R9aIt independently is H, D ,-OH, C1-6Alkyl, C1-6Miscellaneous alkyl, halogenated C1-6Alkyl, amino, C1-6Alkoxy,
C6-10Aryl, C2-10Heterocycle, C3-8Naphthenic base, C6-10Aryloxy group, C2-10Heterocycle oxygroup, C3-8Cycloalkyl oxy, C6-10Fragrant ammonia
Base, C2-10Heterocyclylamino group, C3-8Cycloalkyl amino or C1-9Heteroaryl or R9、R9a, and together with the nitrogen-atoms that they are connected,
Form substituted or unsubstituted 3-8 former molecular ring；With
Each R9bAnd R9cIt independently is H, D ,-OH, C1-6Alkyl, C1-6Miscellaneous alkyl, halogenated C1-6Alkyl, amino, C1-6Alcoxyl
Base, C6-10Aryl, C2-10Heterocycle, C3-8Naphthenic base, C6-10Aryloxy group, C2-10Heterocycle oxygroup, C3-8Cycloalkyl oxy, C6-10Virtue
Amino, C2-10Heterocyclylamino group, C3-8Cycloalkyl amino or C1-9Heteroaryl.
In one embodiment, each R1And R3It independently is H, D, F, Cl, Br, I ,-OH ,-NH2,-CN ,-C (=O) R9b、-C
(=O) NR9R9a、C1-4Alkyl, C3-6Naphthenic base, C1-4Alkoxy, halogenated C1-4Alkyl, halogenated C1-4Alkoxy, C2-4Alkenyl, C2-4
Alkynyl, C2-6Heterocycle, C1-4Alkyl C2-6Heterocycle, C3-6Naphthenic base C2-6Heterocycle or C6-10Aryl, wherein R9、R9aAnd R9bTool
There is meaning as described in the present invention.
In another embodiment, each R2It independently is D, F, Br, I ,-OH ,-NH2、-CN、C1-4Alkyl, C3-6Naphthenic base,
C2-4Alkoxy, halogenated C1-4Alkyl, halogenated C1-4Alkoxy, C2-4Alkenyl, C2-4Alkynyl, C2-6Heterocycle or C6-10Aryl.
In another embodiment, each R4It independently is H, D, C2-4Alkyl, halogenated C1-4Alkyl, C3-6Naphthenic base ,-C (=
O)R9b,-C (=O) NR9R9a、C2-4Alkenyl or C2-4Alkynyl；
Each R9And R9aIt independently is H, D ,-OH, C1-4Alkyl, C1-4Miscellaneous alkyl, halogenated C1-4Alkyl, amino, C6-10Aryl,
C2-6Heterocycle or C3-6Naphthenic base or R9、R9a, and together with the nitrogen-atoms that they are connected, form substituted or unsubstituted 3-6
Former molecular ring；With
Each R9bAnd R9cIt independently is H, D ,-OH, C1-4Alkyl, C1-4Miscellaneous alkyl, halogenated C1-4Alkyl, amino, C6-10Aryl,
C2-6Heterocycle or C3-6Naphthenic base.
In another embodiment, each R5、R6、R7And R8It independently is H, D, F, Cl, Br, I ,-CN ,-NO2、-OH、-NH2、
C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C2-6Heterocycle or C3-6Naphthenic base or R5And R6Or R7And R8, respectively and each with them
Together from connected carbon atom, it is separately formed substituted or unsubstituted 3-6 former molecular carbocyclic ring.
In another embodiment, compound of the present invention, be formula (II) or (II-A) compound represented or
It is the stereoisomer of compound shown in formula (II) or (II-A), geometric isomer, tautomer, nitrogen oxides, hydrate, molten
Agent compound, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein each R1、R2、R3、R4、R5、R6、R7、R8、Y、Y1, m, n and k have meaning as described in the present invention.
In another embodiment, each R1And R3It independently is H, D, F, Cl, Br, I ,-OH ,-NH2,-CN, methyl, ethyl,
Propyl, butyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl, cyclobutyl, morpholinyl, piperazinyl, N methyl piperazine
Base, tetrahydrofuran base, nafoxidine base, tetrahydro-thienyl, N- cyclopropylpiperazin base or 1,4- dioxanes base.
In another embodiment, each R2It independently is D, F, Br, I ,-OH ,-NH2,-CN, methyl, ethyl, propyl, fourth
Base, ethyoxyl, propoxyl group, butoxy, cyclopropyl, cyclobutyl or fluoro C1-4Alkoxy.
In another embodiment, each R4It independently is H, D, ethyl, propyl or butyl.
In another embodiment, each R5、R6、R7And R8It independently is H, D, F, Cl, Br, I ,-OH ,-NH2, methyl, second
Base, propyl, butyl, cyclopropyl or cyclobutyl or R5And R6Or R7And R8, the carbon atom one that is connected respectively and with each
It rises, is separately formed substituted or unsubstituted 3-6 former molecular naphthenic base.
In another embodiment, compound disclosed by the invention has the structure of one of:
OrOr its stereoisomer, geometrical isomerism
Body, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug.
The present invention also includes the application of the compound of the present invention and its pharmaceutically acceptable salt, for producing medical product
Alzheimer's disease is treated, it is described in the invention including those.The compound of the present invention is equally used for producing a kind of pharmaceuticals
For mitigating, prevent, control or treatment 5-HT6The illness mediated, especially Alzheimer's disease.The present invention includes medicine group
Object is closed, which includes compound representated by formula formula (I) or formula (II) and at least one pharmaceutically acceptable load
Effective treatment dosage needed for the combination of body, adjuvant or diluent.
Unless otherwise indicated, all suitable isotope variations of the compound of the present invention, stereoisomer, geometry are different
Structure body, tautomer, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug all belong to
In the scope of the present invention.
Unless otherwise indicated, structural formula described in the invention includes that (such as mapping is different for all isomeric forms
Structure, diastereo-isomerism and geometrical isomerism (or conformational isomerism)): such as R, S configuration containing asymmetric center, (Z) of double bond,
(E) isomers, and the conformer of (Z), (E).Therefore, the single three-dimensional chemical isomer of the compound of the present invention or its is right
Reflect isomers, the mixture of diastereoisomer or geometric isomer (or conformer) belongs to the scope of the present invention.
Unless otherwise indicated, all tautomeric forms of the compound of the present invention are included in the scope of the present invention
Within.In addition, unless otherwise indicated, the structural formula of compound described in the invention includes one or more different originals
The enriched isotope of son.
Disclosed compound of present invention can contain asymmetric or chiral centre, therefore can be with different stereoisomer forms
In the presence of.It is including but not limited to diastereomeric the present invention is directed to all stereoisomer forms of compound shown in formula (I) or (II)
Isomers, enantiomter, atropisomer and geometry (or conformation) isomers and their mixture such as racemic mix
Object becomes component part of the invention.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicate, then the structure
All stereoisomers all consider within the present invention, and be included in the invention as disclosed compound of present invention.When
Spatial chemistry is expressed the real wedge-shaped line (solid wedge) of particular configuration or when dotted line indicates, then the alloisomerism of the structure
Body is with regard to this clear and definition.
The nitrogen oxides of the compounds of this invention is also contained within the scope of the present invention.It can be by an elevated temperature using normal
Corresponding nitrogen-containing basic substance is aoxidized, or pass through in the presence of the acid of such as acetic acid with oxidant (such as hydrogen peroxide)
It reacts in suitable solvent with peracid, such as is reacted in methylene chloride, ethyl acetate or methyl acetate with peracetic acid, or
It is reacted in chloroform or methylene chloride with 3- chloroperoxybenzoic acid, prepares the nitrogen oxides of the compounds of this invention.
On the other hand, the present invention relates to the intermediates of compound shown in preparation formula (I) or (II).
On the other hand, the present invention relates to the methods of preparation, separation and the purifying of compound shown in formula (I) or (II).
Compound shown in formula (I) or (II) can exist in a salt form.In one embodiment, the salt refers to pharmacy
Upper acceptable salt.Term " pharmaceutically acceptable " refer to substance or composition must with other ingredients comprising preparation and/
Or it is compatible chemically and/or in toxicology with the mammal of its treatment.In another embodiment, the salt is not necessarily medicine
Acceptable salt on can be and be used to prepare and/or purify compound shown in formula (I) or (II) and/or for separating this formula
(I) or the intermediate of the enantiomer of compound shown in (II).
If the compound of the present invention be it is alkaline, conceivable salt can be by provided in the literature any suitable
Method is prepared, for example, using inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid etc..Or using organic
Acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid；Pyrans
Saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and tartaric acid；Amino acid, such as asparatate and paddy
Propylhomoserin；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, ethanesulfonic acid, etc..
If the compound of the present invention be it is acid, conceivable salt can be prepared by suitable method, e.g.,
Using inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide or alkaline earth metal hydroxide, etc.
Deng.Suitable salt includes, but is not limited to, organic salt obtained from amino acids, such as glycine and arginine, ammonia, and such as primaquine, secondary
Ammonia and tertiary ammonia and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium
Inorganic salts.
The compounds of this invention and pharmaceutical composition, preparation and administration
When available for treatment, the formula (I) of therapeutically effective amount or formula (II) compound and its pharmaceutically acceptable salt can
It is given as unprocessed chemicals, the active constituent for being alternatively arranged as pharmaceutical composition provides.Therefore, the present invention also provides one
Kind pharmaceutical composition, compound or its individual stereoisomer including formula (I) or (II), the racemic of isomers or non-outer
Racemic mixture or its pharmaceutically acceptable salt or solvate.In an embodiment of the invention, the medicine group
Close object and further include at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally, other treatments
And/or prevention ingredient.
It is that suitable carrier, adjuvant and excipient agent are well known to those skilled in the art and be described in detail in for example
Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery
Systems(2004)Lippincott,Williams&Wilkins,Philadelphia；Gennaro A.R.et al.,
Remington:The Science and Practice of Pharmacy (2000) Lippincott, Williams&
Wilkins,Philadelphia；With Rowe R.C., Handbook of Pharmaceutical Excipients (2005)
In Pharmaceutical Press, Chicago.
It further comprise carrying out other to patient to resist comprising the treatment method that the compounds of this invention or pharmaceutical composition are administered
The administration of Alzheimer disease drug (combination therapy), wherein the drug of other anti-Alzheimer diseases is donepezil, Na Mei
Sweet smell, Risperidone, vitamin e, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-
8066, SB-742457, naluzaton, idalopirdine, Tacrine, Rivastigmine, galanthamine, Memantine, meter Ta Zha
Flat, Venlafaxine, desipramine, nortriptyline, zolpidem, zopiclone, Nicergoline, Piracetam, selegiline, hexanone can
Theobromine or their combination.
Term as used herein " therapeutically effective amount " refers to each active group for being enough to show significant patient benefit
The total amount divided.When using separate active ingredients for separate administration, which only refers to the ingredient.When combining applications, the term
Then refer to the combined amount for regardless of combination, sequential or simultaneous administration all causing the active constituent of therapeutic effect.Formula formula (I) or formula
(II) compound and its pharmaceutically acceptable salt are as described above.From it is compatible with preparation other compositions and to its recipient it is harmless
In the sense that for, carrier, diluent or excipient must be acceptable.According to another aspect of the present disclosure, it also mentions
For method for preparing pharmaceutical preparations, this method includes by formula (I) or formula (II) compound or its pharmaceutically acceptable salt
It is mixed with one or more pharmaceutically acceptable carriers, diluent or excipient.Term used in the present invention " pharmaceutically may be used
Receive " refer to such compound, raw material, composition and/or dosage form, they are applicable within the scope of reasonable medical judgment
In contacted with patient tissue and without excessive toxicity, irritation, allergy or it is relative to a reasonable benefit/risk ratio other
Problem and complication, and effective for given application.
In general, the compound of the present invention is by any conventional application method of the substance for playing similar effectiveness to treat
Effective quantity is administered.Suitable dosage range is typically daily 1-500mg, preferably daily 1-100mg, most preferably daily 1-
30mg, this depends on many factors, such as age and the relative health, institute of the seriousness of treated disease, subject
With the effect of compound, the approach of application and form, the preference of the targeted indication and related medical practitioner of application and
Experience.The those of ordinary skill for treating the disease areas relies on personal knowledge and disclosure of this application without excessive experiment
It can determine that the therapeutically effective amount of the compounds of this invention for giving disease.
In general, the compound of the present invention is applied with pharmaceutical preparation form, the pharmaceutical preparation includes that those are suitable for taking orally
(including oral cavity and sublingual), rectum, nose, part, lung, vagina or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and vein
It is interior) application pharmaceutical preparation or the pharmaceutical preparation suitable for sucking or being blown into administration form.Preferred method of application is usually to take orally,
Using suitable daily dose plan, it can be adjusted according to illness degree.
One or more compounds of the invention can be placed in together with one or more conventional adjuvants, carrier or diluent
In pharmaceutical composition and unit dosage form.Pharmaceutical composition and unit dosage form may include the conventional ingredient of conventional ratio,
With or without other reactive compound or ingredient, unit dosage form can contain and applied planned daily dose range phase
Any suitable a effective amount of active constituent claimed.The application form of pharmaceutical composition can be solid such as tablet or filling glue
Wafer, semisolid, powder, sustained release preparation or liquid such as solution, suspension, emulsion, elixir or the filling glue being administered orally
Wafer；Or for rectum or the suppository form of vaginal application；Or the sterile injectable solutions form for parenterally using.
Therefore, in every containing about 1mg active constituent or more broadly, the preparation containing about 0.01 to about 100mg active constituent is suitable
Representative unit dosage form.
The compound of the present invention can be configured to the dosage form of various oral administrations.Pharmaceutical composition and dosage form can
Using comprising one or more compound or pharmaceutically acceptable salt thereofs of the invention as active constituent.Pharmaceutical carrier can be solid
Or liquid.The preparation of solid form includes: powder agent, tablet, pill, capsule, cachet, suppository and dispersible particle
Agent.Solid carrier can be one or more substances, be also used as diluent, corrigent, solubilizer, lubricant, suspension
Agent, adhesive, preservative, tablet disintegrant or coating material.In powder, carrier is usually finely ground solid, and finely ground
Active constituent formed mixture.In tablets, active constituent is usually with the carrier with required adhesive force with suitable ratio
Example mixes and is pressed into required shapes and sizes.Powder and tablet preferably comprise from about the reactive compound of 1% to about 70%.
Suitable carrier includes but is not limited to magnesium carbonate, magnesium stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, west Huang
Alpine yarrow glue, methylcellulose, sodium carboxymethylcellulose, low melt wax, cocoa butter etc..Terms " formulation " is intended to include containing packing material
Expect as carrier to provide the preparation of the reactive compound of capsule, in the capsule the active constituent of with or without carrier
It is surrounded by the carrier in combination.It similarly, further include cachet and pastille.Tablet, powder, capsule, pill, sachet
Agent and pastille are adapted for the solid form being administered orally.
Other forms for being suitable for being administered orally include preparation (including emulsion, syrup, elixir, the aqueous solution of liquid form
Agent, aqueous suspension) or it is intended to preparation using the preceding solid form for being changed into liquid form preparation at once.Emulsion can be molten
Emulsifier such as lecithin, Sorbitan Monooleate or Arab are prepared or can contained in liquid such as aqueous solution of propylene glycol
Glue.Active constituent can be by being dissolved in water and suitable colorant, corrigent, stabilizer and thickening being added by aqueous solution agent
It is prepared by agent.Aqueous suspension can be by with for example natural or synthetic glue of stickum, resin, methylcellulose, carboxymethyl
Finely ground active constituent is dispersed in water to prepare by sodium cellulosate and other well known suspending agent.The preparation of liquid form includes
Solution, suspension and emulsion, it can also contain colorant, corrigent, stabilizer, buffer, people other than active constituent
Sweetener make and natural, dispersing agent, thickener, solubilizer etc..
The compound of the present invention can be prepared for parenteral administration (for example, passing through injection such as bolus injection or continuous defeated
Note application) and can be present in a unit ampoule, in advance filling syringe, in low capacity infusion or be present in
It is added in the multi-dose container of preservative.The adoptable form of composition has suspension for example in oily or aqueous excipients
Agent, solution or emulsion, such as solution in polyethylene glycol solution.Oiliness or non-aqueous carrier, diluent, solvent or
The example of excipient includes propylene glycol, polyethylene glycol, vegetable oil (such as olive oil) and organic esters for injection (such as oleic acid second
Ester), and formulating substances such as preservative, wetting agent, emulsifier or suspending agent, stabilizer and/or dispersing agent can be contained.Alternatively,
Active constituent can be powder type, preparation method be sterile solid is carried out it is aseptic subpackaged or by by solution be lyophilized so as to
Using preceding with suitable excipient is for example sterile, pyrogen-free water is constructed.
The compound of the present invention can be prepared in the form of ointment, cream or lotion or in a form of transdermal patch office
Portion is applied to epidermis.Ointment and cream can be for example with being added to the aqueous or oily of suitable thickener and/or gelling agent
Property matrix is prepared.Lotion can be prepared with water or oily matrix and usually also contain one or more emulsifying agents, steady
Determine agent, dispersing agent, suspending agent, thickener or colorant.Preparation suitable for topical application in the mouth includes comprising in flavoring base
The pastille of matter, usually sucrose and the active constituent in Arabic gum or tragacanth；Comprising in inert base such as gelatin and
The pastille of active constituent in glycerol or sucrose and Arabic gum；And include the active constituent in suitable liquid carrier
Collutory.
The compound of the present invention can be prepared for applying with suppository form.It can be first by low melt wax such as fatty acid glycerine
Ester admixture or cocoa butter fusing, and active constituent is for example dispersed evenly by stirring.Then by the homogeneous mixture of melting
It pours into the mold of suitable size, be allowed to cool and solidify.
The compound of the present invention can be prepared for vaginal application.Also contain carrier known in this field in addition to the active ingredient (s
Vaginal plug, tampon, milk agent, gelling agent, paste, foaming agent or spray are suitable.
The compound of the present invention can be prepared for nasal administration.Can by solution or suspension by conventional method, example
Such as nasal cavity is directly applied to dropper, suction pipe or sprayer.Preparation can be single dose or multiple dose form.For dropper or suction
The multiple dose form of pipe, this can be realized by solution that be suitable for by patient's application, predetermined volume or suspension.For
Sprayer, this can for example be realized by metering atomizing pump.
The compound of the present invention can be prepared for aerosol application, especially be applied to respiratory tract and including intranasally applying
With.Compound usually has a small granularity, such as the granularity of 5 microns or more decimal magnitude.The granularity can pass through this field
Well known method for example passes through micronization acquisition.Active constituent is to contain suitable propellant such as chlorofluorocarbon (CFC) such as dichloro
The pressurized package of difluoromethane, trichlorofluoromethane or dichlorotetra-fluoroethane or carbon dioxide or other suitable gas provides.Gas
Mist agent can also suitably contain surfactant such as lecithin.Drug dose can be controlled by metering valve.Alternatively, active constituent can
With with dry powdered form, for example in suitable powder base such as lactose, starch, starch derivatives such as hydroxypropyl methyl cellulose and
The mixture of powders form of compound in polyvinylpyrrolidone provides.Dust carrier will form gel in nasal cavity.Powder
Composition can presence can pass through inhalator for example in the form of gelatine capsule agent or cylindrantherae or blister package in a unit
By wherein applying powder.
When needing, preparation can be prepared with the enteric coating for being suitable for sustained release or controlled release application active constituent.For example, this
The compound of invention can be formulated into transdermal or subcutaneous drug delivery device.When it is necessary to release the compound and work as patient for treatment
When the compliance of scheme is most important, these delivery systems are advantageous.Compound in transdermal delivery system is often attached to
On skin-adhesive solid support.Compound of interest can also be with penetration enhancer, such as laurocapram (1- dodecane
Base azacyclo- hept- 2- ketone) it is applied in combination.It can be inserted subcutaneously into a sustained release delivery system by surgery or injection hypodermic layer.Subcutaneously
Compound is encapsulated in liquid soluble membrane, such as silicon rubber or Biodegradable polymeric such as polylactic acid for implantation material.
Pharmaceutical preparation is preferably unit dosage form.In the form, preparation is subdivided into containing appropriate amount active constituent
Unit dose.Unit dosage form can be the preparation of packaging kit, the preparation containing discrete magnitude in packaging, such as complete packet
The tablet of dress, capsule and powder or ampulla agent in the vial.In addition, unit dosage form can be capsule, tablet, flat
Wafer or pastille itself or its any one of these form that can be suitable number in package form.
Other suitable pharmaceutical carriers and their preparation are in Remington:The Science and Practice of
Pharmacy 1995Martin, E.W are edited, Mack Publishing Company, and the 19th edition, Easton,
It is described in Pennsylvania.
The purposes of the compounds of this invention and pharmaceutical composition
Compound provided by the invention and pharmaceutical composition can be used for preparing for preventing, treating or mitigating and 5-HT6Have
The drug of the disease of pass.
The feature of pharmaceutical composition of the invention includes listed by formula (I) or formula (II) compound represented or the present invention
Compound and pharmaceutically acceptable carrier, adjuvant or excipient.The amount of compound can be effective in composition of the invention
Ground detectably antagonism 5-HT6To treat obesity, enterogastric diseases, CNS illness, wherein the CNS illness is ADHD, it is burnt
Consider, disease relating to mental stress, schizophrenia, besetment and behavior disorder, manic-depressive psychosis, nervous disorders, note
Recall obstacle, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's chorea, etc.
Deng.
" effective quantity " or " effective dose " of the compound of the present invention or pharmaceutically acceptable composition refer to processing or
Mitigate the effective quantity that one or more present invention are previously mentioned the severity of illness.According to the method for the present invention, compound and combination
Object can be any dosage and any administration route to be efficiently used for handling or mitigate the severity of disease.Required standard
True amount will change according to the case where patient, this is depending on ethnic, the age, the general condition of patient, the severity of infection,
Special factor, administration mode, etc..Compound or composition can be administered in combination with one or more other therapeutic agents, such as
What the present invention was discussed.
The compound of the present invention and pharmaceutical composition to human treatment in addition to beneficial to other than, applying also for veterinary treatment and doting on
Mammal in the animal of object, the animal of introduced variety and farm.The example of other animal includes horse, dog and cat.?
This, the compound of the present invention includes its pharmaceutically acceptable derivates.
The general synthetic method of the compounds of this invention
For the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only
Method of the invention is practiced in offer.
Generally, the compound of the present invention described method can be prepared through the invention, unless there are further
Explanation, wherein shown in the definition of substituent group such as formula (I) or formula (II).Following reaction scheme and embodiment is for further lifting
Example illustrates the contents of the present invention.
Those skilled in the art will realize that: chemical reaction described in the invention can be used to suitably prepare perhaps
Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention
Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention
It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention
, or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged
Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient
Product supplier such as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical
Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou
Imperial chemistry examination is risen in factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Qingdao
Agent Co., Ltd and Haiyang Chemical Plant, Qingdao are commercially available.
Anhydrous tetrahydro furan is dried to obtain by sodium metal reflux.Anhydrous methylene chloride and chloroform are returned by calcium hydride
Stream is dried to obtain.Ethyl acetate, petroleum ether, n,N-dimethylacetamide and n,N-Dimethylformamide are through anhydrous sodium sulfate thing
It is first dry to use.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below
Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR spectrum with
CDC13、DMSO-d6、CD3OD or acetone-d6It (is reported as unit of ppm) for solvent, with TMS (0ppm) or chloroform (7.25ppm)
As reference standard.When there is multiplet, following abbreviation will be used: s (singlet, unimodal), d (doublet, it is double
Peak), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of
Doublets, quartet), dt (doublet of triplets, double triplets).Coupling constant is indicated with hertz (Hz).
By outfit G1312A binary pump and a G1316A TCC, (column temperature is maintained at 30 to low resolution mass spectrometry (MS) data
DEG C) the spectrometer of Agilent6320 series LC-MS measure, G1329A automatic sampler and G1315B DAD detector
Applied to analysis, the source ESI is applied to LC-MS spectrometer.
Low resolution mass spectrometry (MS) data are by being equipped with G1311A quaternary pump and G1316A TCC (column temperature is maintained at 30 DEG C)
6120 series LC-MS of Agilent spectrometer come what is measured, G1329A automatic sampler and G1315D DAD detector are answered
For analyzing, the source ESI is applied to LC-MS spectrometer.
Both the above spectrometer is provided with Agilent Zorbax SB-C18 column, and specification is 2.1 × 30mm, and 5 μm.Note
Beam product is 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.Mobile phase is that 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid are ultrapure water-soluble
Liquid (phase B).Condition of gradient elution is as shown in table 1:
Table 1
| Time (min) | A(CH3CN, 0.1%HCOOH) | B(H2O, 0.1%HCOOH) |
| 0-3 | 5-100 | 95-0 |
| 3-6 | 100 | 0 |
| 6-6.1 | 100-5 | 0-95 |
| 6.1-8 | 5 | 95 |
Compound purifying is by 1100 series of high efficiency liquid chromatogram (HPLC) of Agilent come what is evaluated, and wherein UV is detected
At 210nm and 254nm, Zorbax SB-C18 column, specification be 2.1 × 30mm, 4 μm, 10 minutes, flow velocity 0.6mL/min,
(0.1% aqueous formic acid) of (0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.
The use of logogram word below is through the present invention:
HCOOH formic acid
NH4OAc ammonium acetate
MeCN, CH3CN acetonitrile
CNCH2COOH 2- cyanoacetic acid
CH3NO2Nitromethane
C7H8Toluene
C7H9N benzylamine
DDQ dichlorocyanobenzoquinone
C2H4Br2Glycol dibromide
C2H4Cl21,2- dichloroethanes
CH3I iodomethane
CHCl3Chloroform
CDC13Deuterated chloroform
DMSO dimethyl sulfoxide
DMSO-d6Deuterated dimethyl sulfoxide
EtOAc, EA ethyl acetate
MgSO4Magnesium sulfate
MeOH,CH3OH methanol
EtOH ethyl alcohol
CH2Cl2, DCM methylene chloride
ML, ml milliliters
PE petroleum ether (60-90 DEG C)
NaOH sodium hydroxide
NaHCO3Sodium bicarbonate
KOH potassium hydroxide
Rt retention time
H, hr hours
NaBH4Sodium borohydride
LiAlH4Lithium aluminium hydride reduction
NaCl sodium chloride
MgCl2Magnesium chloride
NaH sodium hydride
Na2SO4Sodium sulphate
THF tetrahydrofuran
DMF N,N-dimethylformamide
H2O water
D2O deuterium-oxide
EDTA ethylenediamine tetra-acetic acid
PEI polyethyleneimine
Pargyline Pargyline
Tris-HCl tri- (methylol) aminomethane-hydrochloric acid
Following synthetic schemes describes the step of preparation disclosed compound of present invention.Unless otherwise stated, each m, n, k, R1,
R2And R3With definition as described in the present invention.
Synthetic schemes 1
The general synthetic method that disclosed compound of present invention can be described by synthetic schemes 1 is prepared, specific steps
It can refer to embodiment.Compound (1) react to obtain with cyanoacetic acid compound (2), compound (2) oxidant (such as DDQ,
Deng) under the action of dehydroaromatizationof obtain compound (3), then compound (3) in the work of reducing agent (such as Lithium Aluminium Hydride, etc.)
Obtained under compound (4), compound (4) reacted again with substituted benzaldehyde, obtained after reduction amination target compound (5)。
Synthetic schemes 2
The general synthetic method that disclosed compound of present invention can be described by synthetic schemes 2 is prepared, specific steps
It can refer to embodiment.Compound (1) react to obtain with cyanoacetic acid compound (2), compound (2) oxidant (such as DDQ,
Deng) under the action of dehydroaromatizationof obtain compound (3), then compound (3) under the action of alkali (such as sodium hydride, etc.) with
Halohydrocarbons reaction obtain compound (6), compound (6) under the action of reducing agent (such as Lithium Aluminium Hydride, etc.) obtain compound
(7), compound (7) reacted again with substituted benzaldehyde, obtained after reduction amination target compound (8)。
Synthetic schemes 3
The general synthetic method that disclosed compound of present invention can be described by synthetic schemes 3 is prepared, specific steps
It can refer to embodiment.Compound (9) with the effect of nitromethane obtain compound (10), compound (10) reducing agent (such as
Lithium Aluminium Hydride, etc.) under the action of reduction obtain compound (11), compound (11) further reacted with substituted benzaldehyde, also
Obtained after former amination target compound (12)。
Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.
Embodiment
The synthesis of embodiment 1N- (3- (2,2- difluoroethoxy) benzyl) -2- (naphthalene -1- base) ethamine
The synthesis of step 1) 2- (3,4- dihydronaphthalene -1- base) acetonitrile
By 3,4- dihydronaphthalene -1 (2H) -one (4g, 24.4mmol), 2- cyanoacetic acid (3.1g, 36.6mmol), enanthic acid
(794mg, 6.1mmol) and benzylamine (0.67mL, 6.1mmol) are added in toluene (30mL), are reacted 36h under 135 DEG C of oil baths, are stopped
Only react, be cooled to 25 DEG C, ethyl acetate (60mL) dilution is added, then successively with potassium hydroxide solution (0.5mmol/mL,
40mL), saturated sodium bicarbonate solution (40mL) and saturated salt solution (40mL) washing, organic phase is dry with anhydrous sodium sulfate after liquid separation
It is dry.Filtering, filtrate decompression are spin-dried for, and crude product obtains titled through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=60/1)
Conjunction object is faint yellow solid (1.73g, 42%).
MS(ESI,pos.ion)m/z:170.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.59 (d, J=7.9Hz, 1H), 7.36 (td, J=7.5,1.1Hz,
1H), 7.22 (t, J=7.3Hz, 2H), 5.76 (s, 1H), 2.96-2.87 (m, 4H), 2.02-1.93 (m, 2H).
The synthesis of step 2) 2- (naphthalene -1- base) acetonitrile
2- (3,4- dihydronaphthalene -1- base) acetonitrile (1.69g, 10.0mmol) and DDQ (2.986g, 13.16mmol) are added
Into 1,2- dichloroethanes (30mL), is reacted under 100 DEG C of oil baths for 24 hours, stop reaction, be cooled to 25 DEG C, ethyl acetate is added
(60mL) dilution, filtering, filtrate is successively washed with saturated sodium bicarbonate solution (40mL) and saturated salt solution (40mL), after liquid separation
Organic phase is dry with anhydrous sodium sulfate.Filtering, filtrate decompression are spin-dried for, and crude product is through silica gel column chromatography (petrol ether/ethyl acetate
(v/v)=60/1) obtaining title compound is pale white solid (1.5g, 90%).
1H NMR(400MHz,CDCl3)δ(ppm):7.94-7.90(m,1H),7.87(s,1H),7.85(s,1H),7.64-
7.54(m,3H),7.50-7.45(m,1H),4.10(s,2H)。
The synthesis of step 3) 2- (naphthalene -1- base) ethamine
2- (naphthalene -1- base) acetonitrile (835mg, 5.0mmol) is added in tetrahydrofuran (25.0mL) at 0 DEG C, then
It is slowly added to LiAlH4(950mg,25.0mmol).Reaction ten minutes later, is warming up to 25 DEG C, is stirred to react for 24 hours.It sequentially adds
H2O(1.23g,1.3g/g LiAlH4), 15%NaOH solution (1.23g, 1.3g/g LiAlH4), H2O(3.08g,3.25g/g
LiAlH4) be quenched, ethyl acetate (30mL) then is added, filters, filtrate washs (40mL) with saturated sodium chloride solution, after liquid separation
Organic phase is dry with anhydrous sodium sulfate.Filtering, filtrate decompression are spin-dried for, and crude product is through silica gel column chromatography (methylene chloride/methanol (v/
V)=20/1) obtaining title compound is yellow oil (274mg, 32%).
MS(ESI,pos.ion)m/z:172.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.05 (d, J=8.1Hz, 1H), 7.88-7.83 (m, 1H), 7.73 (d,
J=8.1Hz, 1H), 7.54-7.45 (m, 2H), 7.43-7.37 (m, 1H), 7.34 (d, J=6.2Hz, 1H), 3.26 (t, J=
7.0Hz, 2H), 3.12 (t, J=7.0Hz, 2H).
The synthesis of step 4) N- (3- (2,2- difluoroethoxy) benzyl) -2- (naphthalene -1- base) ethamine
By 2- (naphthalene -1- base) ethamine (171mg, 1.0mmol), 3- (2,2- difluoroethoxy) benzaldehyde (186mg,
1.0mmol) and MgSO4(240mg, 2.0mmol) is added in EtOH (10mL), and 6h is reacted under 60 DEG C of oil baths, stops reaction, mistake
Filtrate is collected in filter.At 25 DEG C, NaBH is added into filtrate4(76mg, 2.0mmol), overnight, decompression is spin-dried for for reaction, crude product warp
It is yellow oil (187mg, 55%) that silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), which obtains title compound,.
MS(ESI,pos.ion)m/z:342.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.09-8.06 (m, 1H), 7.88 (dd, J=7.0,2.4Hz, 1H),
(7.76 d, J=8.0Hz, 1H), 7.53-7.50 (m, 2H), 7.44-7.40 (m, 1H), 7.39-7.37 (m, 1H), 7.25 (dd, J
=16.1,8.2Hz, 1H), 6.95 (d, J=7.6Hz, 1H), 6.90 (s, 1H), 6.79 (dd, J=8.1,2.2Hz, 1H), 6.07
(tt, J=55.2,4.1Hz, 1H), 4.14 (td, J=13.1,4.1Hz, 2H), 3.84 (s, 2H), 3.34 (t, J=7.3Hz,
2H), 3.06 (t, J=7.3Hz, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):162.5,157.8,141.3,135.7,133.9,131.9,129.6,
128.8,127.0,126.6,125.9,125.5,125.4,123.6,121.7,114.1,113.4,77.0,67.1,53.3,
49.5,33.1。
The synthesis of 2 2- of embodiment (naphthalene -1- base)-N- (3- (2,2,2- trifluoro ethoxy) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (naphthalene -1- base)
Ethamine (171mg, 1.0mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (204mg, 1.0mmol), MgSO4(240mg,
2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography (petroleum
Ether/ethyl acetate (v/v)=2/1), it is yellow oil (144mg, 40%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:360.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.08 (d, J=7.5Hz, 1H), 7.90-7.88 (m, 1H), 7.77 (d,
J=7.9Hz, 1H), 7.55-7.49 (m, 2H), 7.45-7.41 (m, 1H), 7.39 (d, J=6.3Hz, 1H), 7.28-7.24 (m,
1H), 6.99 (d, J=7.5Hz, 1H), 6.92 (s, 1H), 6.83 (dd, J=8.2,2.2Hz, 1H), 4.31 (q, J=8.2Hz,
2H), 3.85 (s, 2H), 3.35 (t, J=7.2Hz, 2H), 3.07 (t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.5,141.7,135.,133.9,131.9,129.6,128.8,
127.1,126.6,125.9,125.6,125.5,123.7,122.2,114.3,113.7,65.753.4,49.6,33.2。
The synthesis of 3 2- of embodiment (naphthalene -1- base)-N- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (naphthalene -1- base)
Ethamine (171mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (236mg, 1.0mmol), MgSO4(240mg,
2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography (petroleum
Ether/ethyl acetate (v/v)=2/1), it is yellow oil (144mg, 40%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:392.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.09-8.07 (m, 1H), 7.89 (dd, J=6.8,2.6Hz, 1H),
7.77 (d, J=8.0Hz, 1H), 7.54-7.51 (m, 2H), 7.45-7.41 (m, 1H), 7.39-7.38 (m, 1H), 7.28-7.24
(m, 1H), 6.98 (d, J=7.8Hz, 1H), 6.91 (s, 1H), 6.81 (dd, J=8.1,2.3Hz, 1H), 6.09 (tdd, J=
53.1,6.7,3.4Hz, 1H), 4.32 (td, J=11.8,5.9Hz, 2H), 3.85 (s, 2H), 3.35 (t, J=7.2Hz, 2H),
3.07 (t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.5,135.7,133.9,131.9,129.6,128.8,127.1,
126.6,125.91,125.6,125.5,123.7,122.2,114.1,113.4,111.6,109.0,65.1,53.4,49.6,
33.2。
The synthesis of 4 2- of embodiment (naphthalene -1- base)-N- (3- (five fluorine propoxyl group of 2,2,3,3,3-) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (naphthalene -1- base)
Ethamine (171mg, 1.0mmol), 3- (2,2,3,3,3- five fluorine propoxyl group) benzaldehyde (254mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil (200mg, 49%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:410.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.08 (d, J=7.5Hz, 1H), 7.90-7.87 (m, 1H), 7.76 (d,
J=7.9Hz, 1H), 7.55-7.49 (m, 2H), 7.45-7.41 (m, 1H), 7.38 (d, J=6.0Hz, 1H), 7.28-7.24 (m,
1H), 6.99 (d, J=7.5Hz, 1H), 6.92 (s, 1H), 6.83 (dd, J=8.1,2.3Hz, 1H), 4.39 (t, J=12.3Hz,
2H), 3.84 (s, 2H), 3.34 (t, J=7.2Hz, 2H), 3.07 (t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.6,141.8,135.8,133.9,131.9,129.6,128.8,
127.1,126.6,125.9,125.6,125.5,123.7,122.3,114.3,113.6,64.9,53.4,49.7,33.2。
The synthesis of embodiment 5N- (3- (2,2- difluoroethoxy) benzyl) -2- (5- methoxynaphthalene -1- base) ethamine
The synthesis of step 1) 2- (5- methoxyl group -3,4- dihydronaphthalene -1- base) acetonitrile
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by methoxyl group -3 5-,
4- dihydronaphthalene -1 (2H) -one (4g, 22.7mmol), 2- cyanoacetic acid (3.1g, 36.6mmol), enanthic acid (794mg, 6.1mmol)
The reaction preparation in (30mL) in toluene with benzylamine (0.67mL, 6.1mmol), crude product is through silica gel column chromatography (petroleum ether/acetic acid
Ethyl ester (v/v)=60/1), it is white solid (1.9g, 42%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:200.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.20 (t, J=8.0Hz, 1H), 6.85 (d, J=8.2Hz, 1H),
6.76 (d, J=7.8Hz, 1H), 6.27 (ddd, J=4.6,3.2,1.6Hz, 1H), 3.85 (s, 3H), 3.47 (dd, J=3.4,
1.7Hz, 2H), 2.80 (t, J=8.3Hz, 2H), 2.35-2.30 (m, 2H).
The synthesis of step 2) 2- (5- methoxynaphthalene -1- base) acetonitrile
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e., by 2- (5- methoxyl group-
3,4- dihydronaphthalene -1- base) acetonitrile (1.78g, 9.0mmol) and DDQ (2.45g, 10.8mmol) be 25 in methylene chloride (30mL)
Preparation is reacted at DEG C, crude product obtains title through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=60/1), concentrate drying
Compound is white solid (1.36g, 77%).
MS(ESI,pos.ion)m/z:198.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.32 (d, J=8.5Hz, 1H), 7.61 (dd, J=7.0,0.9Hz,
1H), 7.51 (dd, J=15.4,7.6Hz, 1H), 7.46-7.41 (m, 2H), 6.90 (d, J=7.6Hz, 1H), 4.11 (s, 2H),
4.02(s,3H)。
The synthesis of step 3) 2- (5- methoxynaphthalene -1- base) ethamine
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 2- (5- methoxyl group
Naphthalene -1- base) acetonitrile (985mg, 5.0mmol) and LiAlH4(950mg, 25.0mmol) reacts system in THF (25mL) at 25 DEG C
Standby, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is colourless that concentrate drying, which obtains title compound,
Grease (553mg, 55%).
MS(ESI,pos.ion)m/z:202.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.20 (d, J=8.2Hz, 1H), 7.62 (d, J=8.6Hz, 1H),
7.43 (d, J=7.9Hz, 1H), 7.40-7.35 (m, 2H), 6.83 (d, J=7.6Hz, 1H), 4.00 (s, 3H), 3.20 (t, J=
6.8Hz, 2H), 3.09 (t, J=6.8Hz, 2H).
The synthesis of step 4) N- (3- (2,2- difluoroethoxy) benzyl) -2- (5- methoxynaphthalene -1- base) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (5- methoxyl group
Naphthalene -1- base) ethamine (201mg, 1.0mmol), 3- (2,2- difluoroethoxy) benzaldehyde (186mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil (260mg, 70%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:372.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.21 (dd, J=7.6,1.7Hz, 1H), 7.65 (d, J=8.6Hz,
1H), 7.44 (d, J=7.8Hz, 1H), 7.40 (dd, J=7.5,1.2Hz, 2H), 7.25 (dd, J=15.5,7.6Hz, 1H),
6.95 (d, J=7.6Hz, 1H), 6.88 (s, 1H), 6.85 (d, J=7.6Hz, 1H), 6.79 (dd, J=8.2,2.2Hz, 1H),
6.08 (tt, J=55.2,4.1Hz, 1H), 4.14 (td, J=13.1,4.1Hz, 2H), 4.02 (s, 3H), 3.83 (s, 2H),
3.31 (t, J=7.2Hz, 2H), 3.05 (t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.9,156.0,142.0,135.5,133.0,129.5,127.2,
125.8,124.8,121.6,120.8,116.0,114.0,113.7,113.3,103.6,77.0,67.2,55.5,53.5,
49.7,33.7。
The synthesis of 6 2- of embodiment (5- methoxynaphthalene -1- base)-N- (3- (2,2,2- trifluoro ethoxy) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (5- methoxyl group
Naphthalene -1- base) ethamine (201mg, 1.0mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (204mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil (222mg, 57%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:390.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.23 (dd, J=7.5,1.9Hz, 1H), 7.65 (d, J=8.6Hz,
1H), 7.45 (d, J=7.6Hz, 1H), 7.42 (d, J=2.1Hz, 1H), 7.41 (s, 1H), 7.27 (dd, J=13.9,6.0Hz,
1H), 6.99 (d, J=7.5Hz, 1H), 6.92 (s, 1H), 6.86 (d, J=7.6Hz, 1H), 6.83 (dd, J=8.2,2.2Hz,
1H), 4.31 (q, J=8.2Hz, 2H), 4.03 (s, 3H), 3.85 (s, 2H), 3.32 (t, J=7.2Hz, 2H), 3.06 (t, J=
7.2Hz,2H)；
13C NMR(CDCl3,100MHz)δ(ppm):157.5,156.0,141.8,135.3,133.0,129.6,127.3,
126.1,125.9,124.8,122.2,120.9,116.0,114.2,113.7,103.6,100.0,65.7,55.5,53.4,
49.6,33.6。
The synthesis of 7 2- of embodiment (5- methoxynaphthalene -1- base)-N- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (5- methoxyl group
Naphthalene -1- base) ethamine (201mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (236mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil (181mg, 43%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:422.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.23 (dd, J=7.5,1.9Hz, 1H), 7.66 (d, J=8.6Hz,
1H), 7.44 (dd, J=11.5,4.7Hz, 2H), 7.41 (s, 1H), 7.29-7.24 (m, 1H), 6.98 (d, J=7.6Hz, 1H),
6.90 (s, 1H), 6.86 (d, J=7.6Hz, 1H), 6.80 (dd, J=8.1,2.2Hz, 1H), 6.09 (tt, J=53.1,
5.1Hz, 1H), 4.31 (t, J=11.8Hz, 2H), 4.03 (s, 3H), 3.84 (s, 2H), 3.32 (t, J=7.2Hz, 2H), 3.06
(t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.5,156.0,141.7,135.3,133.0,129.6,127.3,
126.0,125.9,124.8,122.2,120.9,116.0,114.1,113.4,111.5,109.0,103.6,65.2,55.5,
53.3,49.6,33.5。
The conjunction of 8 2- of embodiment (5- methoxynaphthalene -1- base)-N- (3- (five fluorine propoxyl group of 2,2,3,3,3-) benzyl) ethamine
At
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (5- methoxyl group
Naphthalene -1- base) ethamine (201mg, 1.0mmol), 3- (2,2,3,3,3- five fluorine propoxyl group) benzaldehyde (254mg, 1.0mmol),
MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silicagel column
Chromatograph (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtain title compound be yellow oil (237mg,
54%).
MS(ESI,pos.ion)m/z:440.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.22 (dd, J=7.5,2.0Hz, 1H), 7.65 (d, J=8.6Hz,
1H), 7.45 (d, J=7.8Hz, 1H), 7.42 (d, J=1.3Hz, 1H), 7.40 (s, 1H), 7.27 (dd, J=12.7,4.8Hz,
1H), 6.99 (d, J=7.6Hz, 1H), 6.93 (s, 1H), 6.86 (d, J=7.6Hz, 1H), 6.83 (dd, J=8.2,2.4Hz,
1H), 4.39 (td, J=12.3,0.8Hz, 2H), 4.03 (s, 3H), 3.84 (s, 2H), 3.32 (t, J=7.2Hz, 2H), 3.06
(t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.5,156.0,141.8,135.3,133.0,129.6,127.2,
126.0,125.9,124.8,122.3,120.9,116.0,114.3,113.7,103.6,100.0,64.8,55.5,53.4,
49.7,33.6。
The synthesis of embodiment 9N- (3- (2,2- difluoroethoxy) benzyl) -2- (6- fluoronaphthalene -1- base) ethamine
The synthesis of step 1) 2- (the fluoro- 3,4- dihydronaphthalene -1- base of 6-) acetonitrile
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by fluoro- 3, the 4- bis- of 6-
Hydrogen naphthalene -1 (2H) -one (4g, 24.4mmol), 2- cyanoacetic acid (3.1g, 36.6mmol), enanthic acid (794mg, 6.1mmol) and benzyl
Amine (0.67mL, 6.1mmol) reaction preparation in (30mL) in toluene, crude product is through silica gel column chromatography (petrol ether/ethyl acetate
(v/v)=60/1), being concentrated and dried and obtaining title compound is white solid (4.1g, 90%).
MS(ESI,pos.ion)m/z:188.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.07 (dd, J=8.0,5.6Hz, 1H), 6.93-6.89 (m, 2H),
6.21 (t, J=4.8Hz, 1H), 3.46 (dd, J=3.2,1.6Hz, 2H), 2.79 (t, J=8.0Hz, 2H), 2.37-2.32 (m,
2H)。
The synthesis of step 2) 2- (6- fluoronaphthalene -1- base) acetonitrile
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e., by 2- (6- fluoro- 3,4-
Dihydronaphthalene -1- base) acetonitrile (1.87g, 10.0mmol) and DDQ (2.72g, 12.0mmol) be anti-in 1,2- dichloroethanes (30mL)
It should prepare, crude product obtains title compound through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=60/1), concentrate drying
For white solid (666mg, 36%).
MS(ESI,pos.ion)m/z:186.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): (ppm) 7.87 (dd, J=9.2,5.2Hz, 1H), 7.80 (d, J=
8.0Hz, 1H), 7.56-7.47 (m, 3H), 7.38 (td, J=8.4,2.8Hz, 1H), 4.11 (s, 2H).
The synthesis of step 3) 2- (6- fluoronaphthalene -1- base) ethamine
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 2- (6- fluoronaphthalene -1-
Base) acetonitrile (925mg, 5.0mmol) and LiAlH4(950mg, 25.0mmol) reaction preparation in THF (25mL), crude product warp
Silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is colorless oil that concentrate drying, which obtains title compound,
(463mg, 49%).
MS(ESI,pos.ion)m/z:190.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): (ppm) 8.04 (dd, J=9.2,5.6Hz, 1H), 7.67 (d, J=
8.4Hz, 1H), 7.47-7.40 (m, 2H), 7.30-7.26 (m, 2H), 3.22 (t, J=6.8Hz, 2H), 3.09 (t, J=
6.8Hz,2H)。
The synthesis of step 4) N- (3- (2,2- difluoroethoxy) benzyl) -2- (6- fluoronaphthalene -1- base) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (6- fluoronaphthalene -1-
Base) ethamine (189mg, 1.0mmol), 3- (2,2- difluoroethoxy) benzaldehyde (186mg, 1.0mmol), MgSO4(240mg,
2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography (petroleum
Ether/ethyl acetate (v/v)=2/1), it is yellow oil (269mg, 75%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:360.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.04 (dd, J=9.6,5.6Hz, 1H), 7.67 (d, J=8.4Hz,
1H), 7.48-7.40 (m, 2H), 7.32-7.27 (m, 2H), 7.25-7.21 (m, 1H), 6.93 (d, J=7.6Hz, 1H), 6.87
(s, 1H), 6.79 (dd, J=8.4,2.4Hz, 1H), 6.07 (tt, J=55.2,4.0Hz, 1H), 4.13 (td, J=13.2,
4.0Hz, 2H), 3.81 (s, 2H), 3.29 (t, J=7.2Hz, 2H), 3.02 (t, J=7.2Hz, 2H), 1.86 (s, 1H)；
13C NMR(100MHz,CDCl3)δ(ppm):160.3(JC-F=244.7Hz), 157.9,141.9,136.2,
134.9(JC-F=8.9Hz), 129.6,129.0,126.7,126.4 (JC-F=5.1Hz), 126.3 (JC-F=8.8Hz), 125.8
(JC-F=2.2Hz), 121.6,116.0 (JC-F=24.6Hz), 114.1,113.2,111.6 (JC-F=19.7Hz), 67.2 (JC-F
=29.1Hz), 53.5,49.7,33.5.
The synthesis of 10 2- of embodiment (6- fluoronaphthalene -1- base)-N- (3- (2,2,2- trifluoro ethoxy) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (6- fluoronaphthalene -1-
Base) ethamine (189mg, 1.0mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (204mg, 1.0mmol), MgSO4(240mg,
2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography (petroleum
Ether/ethyl acetate (v/v)=2/1), it is yellow oil (241mg, 64%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:378.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.08 (dd, J=9.2,5.6Hz, 1H), 7.71 (d, J=8.4Hz,
1H), 7.52-7.44 (m, 2H), 7.36-7.28 (m, 3H), 7.01 (d, J=7.6Hz, 1H), 6.96 (s, 1H), 6.85 (dd, J
=8.0,2.4Hz, 1H), 4.34 (q, J=8.0Hz, 2H), 3.87 (s, 2H), 3.34 (t, J=7.2Hz, 2H), 3.07 (t, J=
7.2Hz,2H)；
13C NMR(100MHz,CDCl3)δ(ppm):160.4(JC-F=244.7Hz), 157.5,141.7,136.1,
134.9(JC-F=8.9Hz), 129.6,128.9,126.7,126.4 (JC-F=5.2Hz), 126.2 (JC-F=8.8Hz), 125.9
(JC-F=2.2Hz), 122.2,116.1 (JC-F=24.8Hz), 114.4,113.6,111.6 (JC-F=19.8Hz), 65.7 (q,
JC-F=35.3Hz), 53.3,49.6,33.3.
The synthesis of 11 2- of embodiment (6- fluoronaphthalene -1- base)-N- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (6- fluoronaphthalene -1-
Base) ethamine (189mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (236mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil (172mg, 42%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:410.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.08 (dd, J=9.6,5.6Hz, 1H), 7.72 (d, J=8.0Hz,
1H), 7.51 (dd, J=9.6,2.4Hz, 1H), 7.46 (t, J=7.2Hz, 1H), 7.36-7.28 (m, 3H), 6.99 (d, J=
7.6Hz, 1H), 6.93 (s, 1H), 6.83 (dd, J=8.4,2.4Hz, 1H), 6.10 (tt, J=53.2,5.2Hz, 1H), 4.34
(t, J=11.6Hz, 2H), 3.86 (s, 2H), 3.34 (t, J=7.2Hz, 2H), 3.07 (t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):160.4(JC-F=244.4Hz), 157.5,142.0,136.2,
134.9(JC-F=8.8Hz), 130.9,129.6,129.0,128.8,126.7,126.4 (JC-F=5.1Hz), 126.3 (JC-F=
8.8Hz),125.8(JC-F=2.2Hz) 122.1,116.1 (JC-F=24.8Hz), 114.2,113.3,111.6 (JC-F=
19.7Hz),65.4(t,JC-F=29.6Hz), 53.4,49.7,33.5.
The synthesis of embodiment 12N- (3- (2,2- difluoroethoxy) benzyl) -2- (7- methoxynaphthalene -1- base) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- methoxyl group
Naphthalene -1- base) ethamine (201mg, 1.0mmol), 3- (2,2- difluoroethoxy) benzaldehyde (186mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil (178mg, 48%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:372.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.77 (d, J=8.9Hz, 1H), 7.68 (d, J=8.0Hz, 1H),
7.34 (d, J=6.5Hz, 1H), 7.32 (d, J=2.2Hz, 1H), 7.29-7.27 (m, 1H), 7.23 (t, J=7.9Hz, 1H),
7.17 (dd, J=8.9,2.4Hz, 1H), 6.95 (d, J=7.5Hz, 1H), 6.89 (s, 1H), 6.78 (dd, J=8.2,2.2Hz,
1H), 6.07 (tt, J=55.2,4.1Hz, 1H), 4.13 (td, J=13.1,4.1Hz, 2H), 3.92 (s, 3H), 3.84 (s,
2H), 3.28 (t, J=7.2Hz, 2H), 3.07 (t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.9,157.7,142.0,134.5,133.1,130.3,129.6,
129.3,127.0,126.7,123.2,121.6,117.9,114.1,113.7 (t, J=239.7Hz), 113.2,102.52,
67.2 (t, J=29.3Hz), 55.3,53.5,49.2,33.5.
The synthesis of 13 2- of embodiment (7- methoxynaphthalene -1- base)-N- (3- (2,2,2- trifluoro ethoxy) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- methoxyl group
Naphthalene -1- base) ethamine (201mg, 1.0mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (204mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is colorless oil (175mg, 45%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:390.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.79 (d, J=9.0Hz, 1H), 7.36 (d, J=8.0Hz, 1H),
7.36-7.33 (m, 2H), 7.31-7.24 (m, 2H), 7.19 (dd, J=8.9,2.5Hz, 1H), 6.98 (d, J=7.6Hz, 1H),
6.92 (s, 1H), 6.83 (dd, J=8.1,2.4Hz, 1H), 4.31 (q, J=8.2Hz, 2H), 3.93 (s, 3H), 3.85 (s,
2H), 3.29 (t, J=7.2Hz, 2H), 3.08 (t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.9,157.8,142.6,134.8,133.3,130.5,129.8,
129.6,127.3,127.0,123.6 (q, J=276.0Hz), 123.4,122.3,118.1,114.5,113.7,102.7,
65.1 (q, J=35.0Hz), 55.5,53.7,49.5,33.8.
The synthesis of 14 2- of embodiment (7- methoxynaphthalene -1- base)-N- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- methoxyl group
Naphthalene -1- base) ethamine (201mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (236mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil (223mg, 53%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:422.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.74 (d, J=8.9Hz, 1H), 7.65 (d, J=7.9Hz, 1H),
7.31-7.19 (m, 4H), 7.14 (dd, J=8.9,2.4Hz, 1H), 7.00-6.91 (m, 2H), 6.85 (s, 1H), 6.82-6.75
(m, 1H), 6.04 (tt, J=53.0,5.0Hz, 1H), 4.34-4.24 (m, 2H), 3.88 (s, 3H), 3.78 (s, 2H), 3.24
(t, J=7.1Hz, 2H), 3.02 (t, J=7.1Hz, 2H).
The conjunction of 15 2- of embodiment (7- methoxynaphthalene -1- base)-N- (3- (five fluorine propoxyl group of 2,2,3,3,3-) benzyl) ethamine
At
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- methoxyl group
Naphthalene -1- base) ethamine (201mg, 1.0mmol), 3- (2,2,3,3,3- five fluorine propoxyl group) benzaldehyde (254mg, 1.0mmol),
MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silicagel column
Chromatograph (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtain title compound be yellow oil (197mg,
45%).
MS(ESI,pos.ion)m/z:440.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.76 (d, J=9.0Hz, 1H), 7.67 (d, J=8.0Hz, 1H),
7.34-7.30 (m, 2H), 7.27 (d, J=8.0Hz, 1H), 7.25-7.22 (m, 1H), 7.16 (dd, J=8.9,2.4Hz, 1H),
6.96 (d, J=7.6Hz, 1H), 6.90 (s, 1H), 6.81 (dd, J=8.2,2.3Hz, 1H), 4.37 (td, J=12.3,
0.8Hz, 2H), 3.91 (s, 3H), 3.82 (s, 2H), 3.26 (t, J=7.2Hz, 2H), 3.05 (t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.9,157.8,142.6,134.8,133.3,130.5,129.8,
129.6,127.2,127.0,123.4,122.4,118.1,114.5,113.6,102.8,65 .1 (t, J=28.0Hz), 55.5,
53.7,49.6,33.8。
The synthesis of embodiment 16N- (3- (2,2- difluoroethoxy) benzyl) -2- (7- fluoronaphthalene -1- base) ethamine
The synthesis of step 1) 2- (the fluoro- 3,4- dihydronaphthalene -1- base of 7-) acetonitrile
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by fluoro- 3, the 4- bis- of 7-
Hydrogen naphthalene -1 (2H) -one (4g, 24.4mmol), 2- cyanoacetic acid (3.1g, 36.6mmol), enanthic acid (794mg, 6.1mmol) and benzyl
Amine (0.67mL, 6.1mmol) reaction preparation in (30mL) in toluene, crude product is through silica gel column chromatography (petrol ether/ethyl acetate
(v/v)=60/1), being concentrated and dried and obtaining title compound is white solid (4.15g, 91%).
1H NMR(400MHz,CDCl3) δ (ppm): 7.15 (dd, J=8.2,5.8Hz, 1H), 6.92 (td, J=8.4,
2.5Hz, 1H), 6.83 (dd, J=9.9,2.5Hz, 1H), 6.36 (t, J=4.2Hz, 1H), 3.47 (dd, J=3.4,1.7Hz,
2H), 2.78 (t, J=8.1Hz, 2H), 2.41-2.36 (m, 2H).
The synthesis of step 2) 2- (7- fluoronaphthalene -1- base) acetonitrile
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e., by 2- (7- fluoro- 3,4-
Dihydronaphthalene -1- base) acetonitrile (1.87g, 10.0mmol) and DDQ (2.72g, 12.0mmol) be anti-in 1,2- dichloroethanes (30mL)
It should prepare, crude product obtains title compound through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=60/1), concentrate drying
For white solid (1.03g, 56%).
MS(ESI,pos.ion)m/z:186.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.94 (dd, J=9.0,5.8Hz, 1H), 7.88 (d, J=8.3Hz,
1H), 7.66 (d, J=7.1Hz, 1H), 7.53-7.44 (m, 2H), 7.40-7.32 (m, 1H), 4.10 (s, 2H).
The synthesis of step 3) 2- (7- fluoronaphthalene -1- base) ethamine
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 2- (7- fluoronaphthalene -1-
Base) acetonitrile (925mg, 5.0mmol) and LiAlH4(950mg, 25.0mmol) reaction preparation in THF (25mL), crude product warp
Silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is colorless oil that concentrate drying, which obtains title compound,
(406mg, 43%).
MS(ESI,pos.ion)m/z:190.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.86 (dd, J=9.0,5.9Hz, 1H), 7.74 (dd, J=6.1,
3.4Hz, 1H), 7.66 (dd, J=11.2,2.3Hz, 1H), 7.41-7.36 (m, 2H), 7.28-7.24 (m, 1H), 3.23 (t, J
=6.4Hz, 2H), 3.19-3.11 (m, 2H).
The synthesis of step 4) N- (3- (2,2- difluoroethoxy) benzyl) -2- (7- fluoronaphthalene -1- base) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- fluoronaphthalene -1-
Base) ethamine (189mg, 1.0mmol), 3- (2,2- difluoroethoxy) benzaldehyde (186mg, 1.0mmol), MgSO4(240mg,
2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography (petroleum
Ether/ethyl acetate (v/v)=2:1), it is yellow oil (269mg, 75%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:360.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.87 (dd, J=9.0,6.0Hz, 1H), 7.75 (dd, J=7.2,
2.1Hz, 1H), 7.68 (dd, J=11.3,2.4Hz, 1H), 7.43-7.36 (m, 2H), 7.33-7.23 (m, 2H), 6.96 (d, J
=7.6Hz, 1H), 6.90 (s, 1H), 6.82 (dd, J=8.2,2.4Hz, 1H), 6.10 (tt, J=55.2,4.1Hz, 1H),
4.17 (td, J=13.1,4.1Hz, 2H), 3.84 (s, 2H), 3.26 (t, J=7.2Hz, 2H), 3.05 (t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3) δ (ppm): 160.8 (d, J=243.8Hz), 157.9,142.3,135.6 (d, J
=5.7Hz), 132.9 (d, J=8.4Hz), 131.1 (d, J=9.1Hz), 130.9,129.6,127.4,126.9,124.7 (d,
), J=2.5Hz 121.6,115.9 (d, J=25.2Hz), 113.8 (d, J=77.9Hz), 113.7 (t, J=239.6Hz),
107.4 (d, J=21.1Hz), 67.3 (t, J=29.4Hz), 53.6,49.5,33.6.
The synthesis of 17 2- of embodiment (7- fluoronaphthalene -1- base)-N- (3- (2,2,2- trifluoro ethoxy) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- fluoronaphthalene -1-
Base) ethamine (189mg, 1.0mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (204mg, 1.0mmol), MgSO4(240mg,
2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography (petroleum
Ether/ethyl acetate (v/v)=2/1), it is colorless oil (200mg, 53%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:378.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.87 (dd, J=9.0,6.0Hz, 1H), 7.75 (dd, J=7.1,
2.2Hz, 1H), 7.68 (dd, J=11.3,2.4Hz, 1H), 7.45-7.36 (m, 2H), 7.32-7.24 (m, 2H), 6.99 (d, J
=7.6Hz, 1H), 6.93 (s, 1H), 6.84 (dd, J=8.2,2.4Hz, 1H), 4.33 (q, J=8.2Hz, 2H), 3.85 (s,
2H), 3.26 (t, J=7.2Hz, 2H), 3.05 (t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3) δ (ppm): 160.8 (d, J=243.9Hz), 157.6,142.4,135.6 (d, J
=5.6Hz), 132.9 (d, J=8.4Hz), 131.1 (d, J=9.1Hz), 130.9,129.6,127.4,126.9 (d, J=
0.8Hz), 124.7 (d, J=2.4Hz), 123.4 (q, J=276.3Hz), 122.1,115.9 (d, J=25.1Hz), 113.9
(d, J=67.7Hz), 107.4 (d, J=21.2Hz), 65.8 (q, J=35.4Hz), 53.5,49.5,33.6.
The synthesis of 18 2- of embodiment (7- fluoronaphthalene -1- base)-N- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- fluoronaphthalene -1-
Base) ethamine (189mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (236mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil (290mg, 71%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:410.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.87 (dd, J=9.0,6.0Hz, 1H), 7.75 (dd, J=7.1,
2.1Hz, 1H), 7.68 (dd, J=11.3,2.4Hz, 1H), 7.44-7.36 (m, 2H), 7.32-7.24 (m, 2H), 6.99 (d, J
=7.6Hz, 1H), 6.91 (s, 1H), 6.82 (dd, J=8.2,2.4Hz, 1H), 6.10 (tt, J=53.1,5.1Hz, 1H),
4.33 (t, J=11.8Hz, 2H), 3.85 (s, 2H), 3.26 (t, J=7.2Hz, 2H), 3.05 (t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3) δ (ppm): 160.8 (d, J=243.9Hz), 157.5,142.4,135.6 (d, J
=5.7Hz), 132.9 (d, J=8.4Hz), 131.1 (d, J=9.0Hz), 130.9,129.6,127.4,126.9,124.7 (d,
), J=2.4Hz 122.1,115.9 (d, J=25.1Hz), 114.6 (tt, J=248.5,26.5Hz), 113.7 (d, J=
83.3Hz), 109.0 (tt, J=248.3,33.8Hz), 107.4 (d, J=21.1Hz), 65.3 (t, J=29.9Hz), 53.5,
49.5,33.6。
The synthesis of 19 2- of embodiment (7- fluoronaphthalene -1- base)-N- (3- (five fluorine propoxyl group of 2,2,3,3,3-) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- fluoronaphthalene -1-
Base) ethamine (189mg, 1.0mmol), 3- (2,2,3,3,3- five fluorine propoxyl group) benzaldehyde (254mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil (226mg, 53%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:428.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.87 (dd, J=9.0,6.0Hz, 1H), 7.75 (dd, J=7.2,
2.1Hz, 1H), 7.68 (dd, J=11.3,2.4Hz, 1H), 7.45-7.36 (m, 2H), 7.32-7.24 (m, 2H), 7.00 (d, J
=7.6Hz, 1H), 6.93 (s, 1H), 6.84 (dd, J=8.2,2.4Hz, 1H), 4.41 (td, J=12.3,0.8Hz, 2H),
3.85 (s, 2H), 3.26 (t, J=7.2Hz, 2H), 3.05 (t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3) δ (ppm): 160.8 (d, J=243.9Hz), 157.6,142.5,135.6 (d, J
=5.7Hz), 132.9 (d, J=8.5Hz), 131.1 (d, J=9.1Hz), 130.9,129.6,127.4,126.9,124.7 (d,
), J=2.4Hz 122.2,115.9 (d, J=25.2Hz), 113.9 (d, J=74.7Hz), 107.4 (d, J=21.2Hz), 64.9
(t, J=27.6Hz), 53.5,49.5,33.6.
The synthesis of embodiment 20N- (3- (2,2- difluoroethoxy) benzyl) -2- (7- bromonaphthalene -1- base) ethamine
The synthesis of step 1) 2- (the bromo- 3,4- dihydronaphthalene -1- base of 7-) acetonitrile
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by bromo- 3, the 4- bis- of 7-
Hydrogen naphthalene -1 (2H) -one (4g, 17.8mmol), 2- cyanoacetic acid (3.1g, 36.6mmol), enanthic acid (794mg, 6.1mmol) and benzyl
Amine (0.67mL, 6.1mmol) reaction preparation in (30mL) in toluene, crude product is through silica gel column chromatography (petrol ether/ethyl acetate
(v/v)=60/1), being concentrated and dried and obtaining title compound is white solid (4.2g, 95%).
1H NMR(400MHz,CDCl3) δ (ppm): 7.32 (dd, J=8.0,1.9Hz, 1H), 7.19 (d, J=1.8Hz,
1H), 7.05 (d, J=8.0Hz, 1H), 6.33 (dd, J=3.7,2.3Hz, 1H), 3.45 (dd, J=3.4,1.7Hz, 2H),
(2.74 t, J=8.1Hz, 2H), 2.36 (tdd, J=7.8,4.4,2.1Hz, 2H).
The synthesis of step 2) 2- (7- bromonaphthalene -1- base) acetonitrile
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e., by 2- (7- bromo- 3,4-
Dihydronaphthalene -1- base) acetonitrile (2.48g, 10.0mmol) and DDQ (2.72g, 12.0mmol) be anti-in 1,2- dichloroethanes (30mL)
It should prepare, crude product obtains title compound through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=60/1), concentrate drying
For white solid (1.21g, 49%).
MS(ESI,pos.ion)m/z:245.9[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.00 (d, J=0.7Hz, 1H), 7.82 (d, J=8.3Hz, 1H),
7.77 (d, J=8.7Hz, 1H), 7.63 (ddd, J=6.1,3.9,1.3Hz, 2H), 7.49 (dd, J=8.2,7.2Hz, 1H),
4.09(s,2H)。
The synthesis of step 3) 2- (7- bromonaphthalene -1- base) ethamine
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 2- (7- bromonaphthalene -1-
Base) acetonitrile (1.2g, 4.9mmol) and LiAlH4(950mg, 25.0mmol) reacts preparation in THF (25mL) at 25 DEG C, thick to produce
For object through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is colorless oil that concentrate drying, which obtains title compound,
(649mg, 53%).
MS(ESI,pos.ion)m/z:250.0[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.19 (d, J=1.5Hz, 1H), 7.71 (t, J=8.7Hz, 2H),
7.55 (dd, J=8.7,1.9Hz, 1H), 7.43-7.40 (m, 1H), 7.37 (d, J=6.0Hz, 1H), 3.19 (t, J=6.6Hz,
2H), 3.10 (t, J=6.6Hz, 2H).
The synthesis of step 4) N- (3- (2,2- difluoroethoxy) benzyl) -2- (7- bromonaphthalene -1- base) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- bromonaphthalene -1-
Base) ethamine (250mg, 1.0mmol), 3- (2,2- difluoroethoxy) benzaldehyde (186mg, 1.0mmol), MgSO4(240mg,
2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography (petroleum
Ether/ethyl acetate (v/v)=2/1), it is yellow oil (273mg, 65%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:420.0[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.22 (d, J=1.2Hz, 1H), 7.73 (t, J=9.0Hz, 2H),
7.57 (dd, J=8.7,1.9Hz, 1H), 7.45-7.42 (m, 1H), 7.41-7.39 (m, 1H), 7.28-7.24 (m, 1H), 6.97
(d, J=7.6Hz, 1H), 6.90 (s, 1H), 6.81 (dd, J=8.1,2.3Hz, 1H), 6.10 (tt, J=55.2,4.2Hz,
1H), 4.17 (td, J=13.1,4.1Hz, 2H), 3.84 (s, 2H), 3.27 (t, J=7.2Hz, 2H), 3.04 (t, J=7.2Hz,
2H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.9,142.0,135.3,133.2,132.3,130.4,129.6,
128.9,127.5,126.9,126.1,125.9,121.5,120.2,114.0,113.3,77.00,67.2,53.5,49.6,
33.3。
The synthesis of 21 2- of embodiment (7- bromonaphthalene -1- base)-N- (3- (2,2,2- trifluoro ethoxy) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- bromonaphthalene -1-
Base) ethamine (250mg, 1.0mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (204mg, 1.0mmol), MgSO4(240mg,
2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography (petroleum
Ether/ethyl acetate (v/v)=2/1), it is yellow oil (180mg, 41%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:438.0[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.21 (d, J=1.5Hz, 1H), 7.72 (t, J=8.8Hz, 2H),
(7.56 dd, J=8.7,1.9Hz, 1H), 7.44-7.41 (m, 1H), 7.39 (t, J=3.5Hz, 1H), 7.26 (dd, J=10.4,
5.3Hz 1H), 6.99 (d, J=7.6Hz, 1H), 6.93 (s, 1H), 6.82 (dd, J=8.1,2.3Hz, 1H), 4.32 (q, J=
8.2Hz, 2H), 3.84 (s, 2H), 3.27 (t, J=7.2Hz, 2H), 3.03 (t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.6,141.7,135.2,133.2,132.3,130.4,129.7,
129.0,127.6,126.9,126.1,125.9,122.2,120.3,114.3,113.8,77.00,65.61,53.4,49.5,
33.1。
The synthesis of 22 2- of embodiment (7- bromonaphthalene -1- base)-N- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- bromonaphthalene -1-
Base) ethamine (250mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (236mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil (207mg, 44%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:470.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.24 (s, 1H), 7.74 (t, J=8.7Hz, 2H), 7.58 (dd, J=
8.7,1.8Hz, 1H), 7.43 (dt, J=6.9,6.4Hz, 2H), 7.29 (t, J=3.9Hz, 1H), 7.01 (d, J=7.1Hz,
1H), 6.94 (s, 1H), 6.82 (dd, J=8.1,2.3Hz, 1H), 6.26-5.93 (m, 1H), 4.34 (t, J=11.8Hz, 2H),
3.86 (s, 2H), 3.29 (t, J=7.2Hz, 2H), 3.06 (t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.5,141.7,135.1,133.1,132.3,130.4,129.7,
129.0,127.6,126.9,126.1,125.9,122.1,120.7,120.3,114.2,113.4,109.0,65.0,53.4,
49.5,33.1。
The synthesis of 23 2- of embodiment (7- bromonaphthalene -1- base)-N- (3- (five fluorine propoxyl group of 2,2,3,3,3-) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- bromonaphthalene -1-
Base) ethamine (250mg, 1.0mmol), 3- (2,2,3,3,3- five fluorine propoxyl group) benzaldehyde (254mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil (298mg, 61%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:488.0[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.23 (d, J=1.5Hz, 1H), 7.73 (t, J=8.8Hz, 2H),
7.57 (dd, J=8.7,1.9Hz, 1H), 7.46-7.42 (m, 1H), 7.40 (dd, J=7.0,1.4Hz, 1H), 7.28 (dd, J=
8.9,6.8Hz, 1H), 7.01 (d, J=7.7Hz, 1H), 6.94 (s, 1H), 6.84 (dd, J=8.1,2.3Hz, 1H), 4.41
(td, J=12.3,0.9Hz, 2H), 3.85 (s, 2H), 3.28 (t, J=7.2Hz, 2H), 3.05 (t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.5,142.0,135.2,133.1,132.3,130.4,129.7,
129.0,127.6,126.9,126.1,125.9,122.2,120.2,114.2,113.6,77.00,64.8,53.45,49.6,
33.2。
The synthesis of embodiment 24N- (3- (2,2- difluoroethoxy) benzyl) -2- methyl -2- (naphthalene -1- base) propane -1- amine
The synthesis of step 1) 2- methyl -2- (naphthalene -1- base) propionitrile
At -30 DEG C, by 2- (naphthalene -1- base) acetonitrile (1.67g, 10.0mmol) and sodium hydride, (60% is dispersed in mineral oil
In, 2.0g, 50.0mmol) it is added in anhydrous DMF (10mL), after being stirred to react 1h, addition iodomethane (5.0mL,
80.0mmol), 65 DEG C are to slowly warm up to, reaction is overnight.Stop reaction, saturated salt solution (30mL) is added and is quenched, with acetic acid second
Ester extracts (30mL x 3), and it is dry with anhydrous sodium sulfate to merge organic phase.Filtering, filtrate decompression are spin-dried for, and crude product is through silicagel column
It is faint yellow solid (1.5g, 77%) that chromatography (petrol ether/ethyl acetate (v/v)=50/1), which obtains title compound,.
MS(ESI,pos.ion)m/z:196.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.57 (d, J=8.7Hz, 1H), 7.93 (d, J=8.2Hz, 1H),
7.86 (d, J=8.1Hz, 1H), 7.64 (m, 1H), 7.56 (d, J=7.5Hz, 1H), 7.50 (d, J=7.0Hz, 1H), 7.46
(t, J=7.7Hz, 1H), 1.99 (s, 6H)；
13C NMR(150MHz,CDCl3)δ(ppm):135.7,134.7,130.2,129.6,129.5,126.4,125.8,
125.1,125.0,124.6,122.8,34.7,28.8。
The synthesis of step 2) 2- methyl -2- (naphthalene -1- base) propane -1- amine
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 2- methyl -2-
(naphthalene -1- base) propionitrile (975mg, 5.0mmol) and LiAlH4(950mg, 25.0mmol) reacts system in THF (25mL) at 25 DEG C
Standby, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is colourless that concentrate drying, which obtains title compound,
Grease (587mg, 59%).
MS(ESI,pos.ion)m/z:200.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.40 (d, J=8.5Hz, 1H), 7.93-7.88 (m, 1H), 7.76 (d,
J=8.1Hz, 1H), 7.52-7.46 (m, 3H), 7.43 (t, J=7.7Hz, 1H), 3.31 (s, 2H), 1.63 (s, 6H).
The synthesis of step 3) N- (3- (2,2- difluoroethoxy) benzyl) -2- methyl -2- (naphthalene -1- base) propane -1- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- methyl -2-
(naphthalene -1- base) propane -1- amine (199mg, 1.0mmol), 3- (2,2- difluoroethoxy) benzaldehyde (186mg, 1.0mmol),
MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silicagel column
Chromatograph (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtain title compound be yellow oil (199mg,
54%).
MS(ESI,pos.ion)m/z:370.3[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.38 (d, J=8.7Hz, 1H), 7.92 (d, J=7.9Hz, 1H),
7.79 (d, J=8.1Hz, 1H), 7.60 (d, J=7.3Hz, 1H), 7.47 (m, 3H), 7.19 (t, J=7.8Hz, 1H), 6.85-
6.75 (m, 2H), 6.70 (s, 1H), 6.08 (tt, J=55.2,4.1Hz, 1H), 4.05 (td, J=13.1,4.1Hz, 2H),
3.69(s,2H),3.22(s,2H),1.70(s,6H)；
13C NMR(150MHz,CDCl3)δ(ppm):157.83,142.76,142.56,135.04,131.71,129.79,
129.36,128.00,125.94,125.79,125.33,124.89,124.88,121.49,115.44,113.85,113.48,
(113.22,112.25,67.10 t, J=30Hz), 59.61,53.89,40.73,29.22.
The synthesis of embodiment 25 2- methyl -2- (naphthalene -1- base)-N- (3- (2,2,2- trifluoroethoxy) benzyl) propane -1- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- methyl -2-
(naphthalene -1- base) propane -1- amine (199mg, 1.0mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (204mg, 1.0mmol),
MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silicagel column
Chromatograph (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtain title compound be yellow oil (205mg,
53%).
MS(ESI,pos.ion)m/z:388.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.34 (d, J=8.6Hz, 1H), 7.95-7.87 (m, 1H), 7.77 (d,
J=8.1Hz, 1H), 7.57 (d, J=6.8Hz, 1H), 7.50-7.38 (m, 3H), 7.17 (t, J=7.9Hz, 1H), 6.86-
6.74 (m, 2H), 6.70 (s, 1H), 6.08 (tt, J=55.2,4.1Hz, 1H), 4.05 (td, J=13.1,4.1Hz, 2H),
3.69(s,2H),3.22(s,2H),1.70(s,6H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.49,142.86,142.57,135.02,131.68,129.72,
129.36,127.92,125.89,125.70,125.26,124.82,122.00,113.70 113.54,65.69 (q, J=
35Hz),59.62,53.81,40.70,29.73。
Embodiment 26 2- methyl -2- (naphthalene -1- base)-N- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) propane -1- amine
Synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- methyl -2-
(naphthalene -1- base) propane -1- amine (199mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (236mg,
1.0mmol), MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), it is thick to produce
For object through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil that concentrate drying, which obtains title compound,
(276mg, 66%).
MS(ESI,pos.ion)m/z:420.3[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.72 (d, J=8.7Hz, 1H), 8.27 (d, J=8.0Hz, 1H),
8.14 (d, J=8.1Hz, 1H), 7.95 (d, J=7.4Hz, 1H), 7.87-7.76 (m, 3H), 7.54 (t, J=7.8Hz, 1H),
7.19 (d, J=7.5Hz, 1H), 7.12 (dd, J=8.1,2.2Hz, 1H), 7.03 (s, 1H), 6.61-6.30 (m, 1H), 4.57
(t, J=11.8Hz, 2H), 4.03 (s, 2H), 3.57 (s, 2H), 2.05 (s, 6H)；
13C NMR(150MHz,CDCl3)δ(ppm):157.44,142.85,142.51,135.05,131.71,129.81,
130.01,129.43,128.02,125.91,125.82,125.34,124.90,122.19 121.99,114.69 (tt, J=
250,26Hz), 113.58,113.27,109.11 (tt, J=249,33Hz), 65.16 (t, J=30Hz), 59.60,53.81,
40.73,29.82。
Embodiment 27 2- methyl -2- (naphthalene -1- base)-N- (3- (five fluorine propoxyl group of 2,2,3,3,3-) benzyl) propane -1- amine
Synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- methyl -2-
(naphthalene -1- base) propane -1- amine (199mg, 1.0mmol), 3- (2,2,3,3,3- five fluorine propoxyl group) benzaldehyde (254mg,
1.0mmol), MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), it is thick to produce
For object through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil that concentrate drying, which obtains title compound,
(227mg, 52%).
MS(ESI,pos.ion)m/z:438.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.33 (d, J=8.7Hz, 1H), 7.89 (dd, J=8.0,1.4Hz,
1H), 7.76 (d, J=8.1Hz, 1H), 7.56 (dd, J=7.4,1.0Hz, 1H), 7.50-7.36 (m, 3H), 7.17 (t, J=
7.9Hz, 1H), 6.84-6.74 (m, 2H), 6.68 (s, 1H), 4.27 (td, J=12.4,0.9Hz, 2H), 3.66 (s, 2H),
3.19(s,2H),1.67(s,6H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.5,142.8,142.5,135.0,131.7,129.7,129.4,
127.9,125.9,125.7,125.2,124.8,122.1,113.7,113.5,64.8 (t, J=27Hz), 59.6,53.8,
40.7,29.1。
Embodiment 28N- (3- (2,2- difluoroethoxy) benzyl) -2- (6- fluoronaphthalene -1- base) -2- methylpropane -1- amine
Synthesis
The synthesis of step 1) 2- (6- fluoronaphthalene -1- base) -2- methyl propionitrile
This step title compound method referring to described in 24 step 1 of embodiment is prepared, i.e., by 2- (6- fluoronaphthalene-
1- yl) acetonitrile (1.85g, 10.0mmol), sodium hydride (60% is dispersed in mineral oil, 2.0g, 50.0mmol) and iodomethane
(5.0mL, 80.0mmol) reaction preparation in anhydrous DMF (10mL), crude product is through silica gel column chromatography (petrol ether/ethyl acetate
(v/v)=60/1), being concentrated and dried and obtaining title compound is yellow solid (1.94g, 91%).
1H NMR(600MHz,CDCl3) δ (ppm): 8.59 (dd, J=9.5,5.3Hz, 1H), 7.80 (dd, J=7.2,
1.9Hz, 1H), 7.55 (dd, J=9.4,2.7Hz, 1H), 7.51-7.46 (m, 2H), 7.43 (ddd, J=9.5,8.1,2.8Hz,
1H),1.99(s,6H)；
13C NMR(150MHz,CDCl3) δ (ppm): 160.0 (d, J=246Hz), 136.1 (d, J=1.5Hz), 135.9
(d, J=9.0Hz), 128.9 (d, J=4.5Hz), 127.2 (d, J=1.5Hz), 127.1 (d, J=9.0Hz), 126.2,
124.9,122.2, (d, J=3.0Hz), 116.5 (d, J=25.5Hz), 112.5 (d, J=19.5Hz), 34.63,28.9.
The synthesis of step 2) 2- (6- fluoronaphthalene -1- base) -2- methylpropane -1- amine
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 2- (6- fluoronaphthalene -1-
Base) -2- methyl propionitrile (1.06g, 5.0mmol) and LiAlH4(950mg, 25.0mmol) reacts at 25 DEG C in THF (25mL)
Preparation, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is nothing that concentrate drying, which obtains title compound,
Color grease (705mg, 65%).
MS(ESI,pos.ion)m/z:218.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.98 (dd, J=13.0,2.2Hz, 1H), 7.86 (dd, J=9.0,
6.5Hz 1H), 7.73 (d, J=8.1Hz, 1H), 7.51 (d, J=7.4Hz, 1H), 7.37 (t, J=7.8Hz, 1H), 7.29-
7.22(m,1H),3.26(s,2H),1.59(s,6H)。
The conjunction of step 3) N- (3- (2,2- difluoroethoxy) benzyl) -2- (6- fluoronaphthalene -1- base) -2- methylpropane -1- amine
At
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (6- fluoronaphthalene -1-
Base) -2- methylpropane -1- amine (217mg, 1.0mmol), 3- (2,2- difluoroethoxy) benzaldehyde (186mg, 1.0mmol),
MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silicagel column
Chromatograph (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtain title compound be yellow oil (50mg,
13%).
MS(ESI,pos.ion)m/z:388.0[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.92 (d, J=4.7Hz, 1H), 7.66 (d, J=7.5Hz, 1H),
7.43-7.39 (m, 3H), 7.19 (t, J=7.5Hz, 1H), 7.08 (t, J=7.3Hz, 1H), 6.84 (d, J=7.2Hz, 2H),
6.78 (s, 1H), 6.03 (t, J=55.0Hz, 1H), 3.94 (t, J=11.6Hz, 2H), 3.81 (s, 2H), 3.44 (s, 2H),
1.65(s,6H)；
13C NMR(150MHz,CDCl3) δ (ppm): 159.5 (d, J=245Hz), 158.20,138.68,136.3 (d, J
=9.0Hz), 131.7,130.2,128.7 (d, J=6.0Hz), 127.6,127.2 (d, J=9.0Hz), 126.3,125.3,
123.5,116.5,115.5,115.7,115.1,114.6,113.5,112.9,112.7,11 1.9,66.9 (t, J=30Hz),
54.7,51.1,38.8,29.7。
29 2- of embodiment (6- fluoronaphthalene -1- base) -2- methyl-N- (3- (2,2,2- trifluoro ethoxy) benzyl) propane -1- amine
Synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (6- fluoronaphthalene -1-
Base) -2- methylpropane -1- amine (217mg, 1.0mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (204mg, 1.0mmol),
MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silicagel column
Chromatograph (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtain title compound be yellow oil (158mg,
39%).
MS(ESI,pos.ion)m/z:406.0[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.90 (dd, J=9.1,5.0Hz, 1H), 7.66 (d, J=7.7Hz,
1H), 7.46-7.35 (m, 3H), 7.20 (t, J=7.8Hz, 1H), 7.07 (t, J=7.4Hz, 1H), 6.87 (d, J=7.5Hz,
2H), 6.81 (s, 1H), 4.08 (dd, J=15.8,7.9Hz, 2H), 3.83 (s, 2H), 3.46 (s, 2H), 1.65 (s, 6H)；
13C NMR(150MHz,CDCl3) δ (ppm): 159.5 (d, J=246Hz), 157.7,138.5,136.3 (d, J=
7.5Hz), 131.8,130.3,128.7 (d, J=4.5Hz), 127.6,127.1 (d, J=7.5Hz), 126.3,125.4,
124.1,117.1,115.6 (d, J=25.5Hz), 114.2,112.8 (d, J=19.5Hz), 65.3 (q, J=35Hz), 54.7,
51.1,38.8,27.9。
30 2- of embodiment (6- fluoronaphthalene -1- base) -2- methyl-N- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) propane -1-
The synthesis of amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (6- fluoronaphthalene -1-
Base) -2- methylpropane -1- amine (217mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (236mg,
1.0mmol), MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), it is thick to produce
For object through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil that concentrate drying, which obtains title compound,
(170mg, 39%).
MS(ESI,pos.ion)m/z:438.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.95-7.93 (m, 1H), 7.68 (d, J=7.5Hz, 1H), 7.48-
7.38 (m, 3H), 7.22 (t, J=7.5Hz, 1H), 7.09 (t, J=7.3Hz, 1H), 6.89 (d, J=6.7Hz, 1H), 6.86-
6.84 (m, 2H), 6.05 (t, J=54,1H), 4.16-4.11 (m, 2H), 3.84 (s, 2H), 3.48 (s, 2H), 1.67 (s, 6H)；
13C NMR(150MHz,CDCl3) δ (ppm): 159.5 (d, J=244.5Hz), 157.7,138.6,138.3 (d, J
=9.0Hz), 131.8,130.3,128.7 (d, J=4.5Hz), 127.6,127.1 (d, J=7.5Hz), 126.3,125.3,
124.1,116.4,115.6 (d, J=24.0Hz), 115.1 (tt, J=247.5,27Hz), 114.8,112.8 (d, J=
19.5Hz), 109.0 (tt, J=247.5,33Hz), 64.8 (t, 28.5Hz), 54.7,51.1,38.8,29.7.
31 2- of embodiment (6- fluoronaphthalene -1- base) -2- methyl-N- (3- (five fluorine propoxyl group of 2,2,3,3,3-) benzyl) propane -
The synthesis of 1- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (6- fluoronaphthalene -1-
Base) -2- methylpropane -1- amine (217mg, 1.0mmol), 3- (2,2,3,3,3- five fluorine propoxyl group) benzaldehyde (254mg,
1.0mmol), MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), it is thick to produce
For object through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil that concentrate drying, which obtains title compound,
(91mg, 20%).
MS(ESI,pos.ion)m/z:456.0[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.91 (dd, J=9.4,5.1Hz, 1H), 7.65 (d, J=7.8Hz,
1H), 7.44-7.36 (m, 3H), 7.21 (t, J=7.8Hz, 1H), 7.10-7.04 (m, 1H), 6.88 (t, J=9.1Hz, 2H),
6.84 (s, 1H), 4.16 (t, J=12.4Hz, 2H), 3.82 (s, 2H), 3.46 (s, 2H), 1.65 (s, 6H)；
13C NMR(150MHz,CDCl3) δ (ppm): 159.5 (d, J=246Hz), 157.7,138.6,136.3 (d, J=
7.5Hz), 131.8,130.3,128.6,128.6,127.6,127.1 (d, J=7.5Hz), 126.3,125.3,124.2,
119.6 (tt, J=285,33Hz), 117.1,115.6 (d, J=24Hz), 114.2,112.8 (d, J=19.5Hz), 112.4
(tq, J=253.5,37,5Hz), 64.3 (t, J=27Hz), 54.7,51.0,38.8,29.7.
Embodiment 32N- (3- (2,2- difluoroethoxy) benzyl) -2- (7- methoxynaphthalene -1- base) -2- methylpropane -1-
The synthesis of amine
The synthesis of step 1) 2- (7- methoxynaphthalene -1- base) -2- methyl propionitrile
This step title compound method referring to described in 24 step 1 of embodiment is prepared, i.e., by 2- (7- methoxyl group
Naphthalene -1- base) acetonitrile (1.97g, 10.0mmol), sodium hydride (60% is dispersed in mineral oil, 2.0g, 50.0mmol) and iodomethane
(5.0mL, 80.0mmol) reaction preparation in anhydrous DMF (10mL), crude product is through silica gel column chromatography (petrol ether/ethyl acetate
(v/v)=60/1), being concentrated and dried and obtaining title compound is yellow solid (1.8g, 80%).
MS(ESI,pos.ion)m/z:226.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.90-7.73 (m, 3H), 7.48 (dd, J=7.4,0.9Hz, 1H),
7.34 (t, J=7.8Hz, 1H), 7.24 (dd, J=9.0,2.4Hz, 1H), 4.03 (s, 3H), 2.00 (s, 6H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.8,134.27,131.3,130.9,130.0,129.2,
124.8,123.2,122.8,118.4,103.8,55.4,34.6,28.6。
The synthesis of step 2) 2- (7- methoxynaphthalene -1- base) -2- methylpropane -1- amine
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 2- (7- methoxyl group
Naphthalene -1- base) -2- methyl propionitrile (1.12g, 5.0mmol) and LiAlH4(950mg, 25.0mmol) is in THF (25mL) at 25 DEG C
Reaction preparation, crude product obtain title compound through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), concentrate drying
For colorless oil (790mg, 69%).
MS(ESI,pos.ion)m/z:230.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.80 (d, J=8.9Hz, 1H), 7.70 (m, 2H), 7.46 (m, 1H),
7.29 (m, 1H), 7.17 (dd, J=8.9,2.4Hz, 1H), 3.95 (s, 3H), 3.30 (s, 2H), 1.62 (s, 6H).
Step 3) N- (3- (2,2- difluoroethoxy) benzyl) -2- (7- methoxynaphthalene -1- base) -2- methylpropane -1- amine
Synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- methoxyl group
Naphthalene -1- base) -2- methylpropane -1- amine (229mg, 1.0mmol), 3- (2,2- difluoroethoxy) benzaldehyde (186mg,
1.0mmol), MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), it is thick to produce
For object through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil that concentrate drying, which obtains title compound,
(76mg, 19%).
MS(ESI,pos.ion)m/z:400.0[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.78 (d, J=8.9Hz, 1H), 7.68 (d, J=8.0Hz, 1H),
7.53 (d, J=6.4Hz, 2H), 7.30 (t, J=7.7Hz, 1H), 7.16-7.09 (m, 2H), 6.73 (t, J=6.9Hz, 2H),
6.59 (s, 1H), 6.05 (tt, J=55.2,4.1Hz, 1H), 4.04-3.94 (m, 2H), 3.75 (s, 3H), 3.67 (s, 2H),
3.17(s,2H),1.66(s,6H)；
13C NMR(150MHz,CDCl3)δ(ppm):157.8,156.4,132.5,130.9,130.2,129.3,127.7,
126.4,123.1,121.5,117.0,115.4,113.8,113.4,113.3,112.2,10 5.4,67.0 (t, J=30Hz),
55.1,53.6,40.4,28.9。
33 2- of embodiment (7- methoxynaphthalene -1- base) -2- methyl-N- (3- (2,2,2- trifluoro ethoxy) benzyl) propane -
The synthesis of 1- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- methoxyl group
Naphthalene -1- base) -2- methylpropane -1- amine (229mg, 1.0mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (204mg,
1.0mmol), MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), it is thick to produce
For object through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil that concentrate drying, which obtains title compound,
(83mg, 20%).
MS(ESI,pos.ion)m/z:418.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.77 (d, J=8.9Hz, 1H), 7.67 (d, J=8.0Hz, 1H),
7.56-7.48 (m, 2H), 7.29 (t, J=7.7Hz, 1H), 7.13 (t, J=7.8Hz, 2H), 6.75 (t, J=6.0Hz, 2H),
6.58 (s, 1H), 4.14 (q, J=8.1Hz, 2H), 3.74 (s, 3H), 3.64 (s, 2H), 3.14 (s, 2H), 1.64 (s, 6H)；
13C NMR(150MHz,CDCl3)δ(ppm):157.4,156.3,142.7,140.8,130.9,130.2,129.3,
(127.6,126.3,123.1,121.9,116.9,113.5 d, J=7.0Hz), 105.4,65.5 (q, J=36Hz), 58.8,
55.0,53.7,40.5,29.7。
34 2- of embodiment (7- methoxynaphthalene -1- base) -2- methyl-N- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) third
The synthesis of alkane -1- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- methoxyl group
Naphthalene -1- base) -2- methylpropane -1- amine (229mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (236mg,
1.0mmol), MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), it is thick to produce
For object through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil that concentrate drying, which obtains title compound,
(63mg, 14%).
MS(ESI,pos.ion)m/z:450.0[M+H]+；
1H NMR (600MHz, CDCl3) δ (ppm): 7.77 (d, J=8.9Hz, 1H), 7.68 (d, J=8.0Hz, 1H),
7.52 (d, J=7.4Hz, 1H), 7.45 (s, 1H), 7.30 (t, J=7.7Hz, 1H), 7.12 (t, J=7.5Hz, 2H), 6.74
(t, J=8.4Hz, 2H), 6.65 (s, 1H), 6.05 (tt, J=53.1,4.8Hz, 1H), 4.15 (t, J=11.8Hz, 2H),
3.75(s,3H),3.71(s,2H),3.22(s,2H),1.67(s,6H)；
13C NMR(150MHz,CDCl3)δ(ppm):157.4,156.4,132.4,131.0,130.2,129.5,127.9,
(126.5,123.1,122.3,113.9,110.9,110.7,110.6 tt, J=248,28Hz), 109.0 (tt, J=248,
33Hz),105.2,65.2,65.0,64.8,55.1,53.1,40.2,29.7。
35 2- of embodiment (7- methoxynaphthalene -1- base) -2- methyl-N- (3- (five fluorine propoxyl group of 2,2,3,3,3-) benzyl)
The synthesis of propane -1- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- methoxyl group
Naphthalene -1- base) -2- methylpropane -1- amine (229mg, 1.0mmol), 3- (2,2,3,3,3- five fluorine propoxyl group) benzaldehyde (254mg,
1.0mmol), MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), it is thick to produce
For object through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil that concentrate drying, which obtains title compound,
(79mg, 17%).
MS(ESI,pos.ion)m/z:468.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.80 (d, J=8.9Hz, 1H), 7.71 (d, J=8.0Hz, 1H),
7.57-7.55 (m, 2H), 7.33 (t, J=7.7Hz, 1H), 7.18-7.13 (m, 2H), 6.81-6.75 (m, 2H), 6.63 (s,
1H), 4.26 (t, J=12.4Hz, 2H), 3.77 (s, 3H), 3.67 (s, 2H), 3.18 (s, 2H), 1.68 (s, 6H)；
13C NMR(150MHz,CDCl3)δ(ppm):157.5,156.5,142.7,140.8,132.6,131.0,130.3,
129.4,127.7,126.4,123.2,122.2,120.9,119.7 (tt, J=285,35Hz), 117.1,113.9,113.7,
113.6,113.2,112.7 (tq, J=254,37.5Hz), 105.5,64.9,64.7,64.7,64.6,58.9,55.1,53.7,
40.6,29.8。
36 2- of embodiment (7- fluoronaphthalene -1- base) -2- methyl-N- (3- (2,2,2- trifluoro ethoxy) benzyl) propane -1- amine
Synthesis
The synthesis of step 1) 2- (7- fluoronaphthalene -1- base) -2- methyl propionitrile
This step title compound method referring to described in 24 step 1 of embodiment is prepared, i.e., by 2- (7- fluoronaphthalene-
1- yl) acetonitrile (1.85g, 10.0mmol), sodium hydride (60% is dispersed in mineral oil, 2.0g, 50.0mmol) and iodomethane
(5.0mL, 80.0mmol) reaction preparation in anhydrous DMF (10mL), crude product is through silica gel column chromatography (petrol ether/ethyl acetate
(v/v)=60/1), being concentrated and dried and obtaining title compound is yellow solid (1.38g, 65%).
1H NMR(600MHz,CDCl3) δ (ppm): 8.17 (d, J=11.9Hz, 1H), 7.91 (dd, J=8.8,6.2Hz,
1H), 7.84 (d, J=8.1Hz, 1H), 7.54 (d, J=7.2Hz, 1H), 7.42 (t, J=7.8Hz, 1H), 7.34-7.31 (m,
1H),1.97(s,6H)。
The synthesis of step 2) 2- (7- fluoronaphthalene -1- base) -2- methylpropane -1- amine
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 2- (7- fluoronaphthalene -1-
Base) -2- methyl propionitrile (1.06g, 5.0mmol) and LiAlH4(950mg, 25.0mmol) reacts at 25 DEG C in THF (25mL)
Preparation, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is nothing that concentrate drying, which obtains title compound,
Color grease (651mg, 60%).
MS(ESI,pos.ion)m/z:218.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.37 (dd, J=9.5,5.5Hz, 1H), 7.70-7.63 (m, 2H),
7.48 (dd, J=9.7,2.6Hz, 1H), 7.44-7.41 (m, 2H), 3.25 (s, 2H), 1.58 (s, 6H).
Step 3) 2- (7- fluoronaphthalene -1- base) -2- methyl-N- (3- (2,2,2- trifluoro ethoxy) benzyl) propane -1- amine
Synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- fluoronaphthalene -1-
Base) -2- methylpropane -1- amine (217mg, 1.0mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (204mg, 1.0mmol),
MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silicagel column
Chromatograph (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtain title compound be yellow oil (142mg,
35%).
MS(ESI,pos.ion)m/z:406.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.92 (dd, J=9.0,4.8Hz, 1H), 7.65 (d, J=7.9Hz,
1H), 7.47-7.35 (m, 3H), 7.22 (t, J=7.8Hz, 1H), 7.07 (t, J=7.6Hz, 1H), 6.89 (d, J=7.5Hz,
2H), 6.82 (s, 1H), 4.09 (dd, J=15.9,7.9Hz, 2H), 3.84 (s, 2H), 3.45 (s, 2H), 1.66 (s, 6H).
37 2- of embodiment (7- fluoronaphthalene -1- base) -2- methyl-N- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) propane -1-
The synthesis of amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- fluoronaphthalene -1-
Base) -2- methylpropane -1- amine (217mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (236mg,
1.0mmol), MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), it is thick to produce
For object through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil that concentrate drying, which obtains title compound,
(197mg, 45%).
MS(ESI,pos.ion)m/z:438.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.97 (dd, J=13.1,1.6Hz, 1H), 7.90 (dd, J=8.8,
6.6Hz, 1H), 7.78 (d, J=8.1Hz, 1H), 7.62 (d, J=7.4Hz, 1H), 7.44 (t, J=7.7Hz, 1H), 7.30-
(7.27 m, 1H), 7.21 (t, J=7.9Hz, 1H), 6.84 (d, J=7.5Hz, 1H), 6.79 (dd, J=8.1,2.0Hz, 1H),
6.71 (s, 1H), 6.12 (tt, J=53.1,5.0Hz, 1H), 4.26 (t, J=11.8Hz, 2H), 3.70 (s, 2H), 3.18 (s,
2H),1.68(s,6H)；
13C NMR(150MHz,CDCl3) δ (ppm): 159.5 (d, J=242.1Hz), 157.3,142.6,142.0 (d, J
=6.0Hz), 132.2 (d, J=9.0Hz), 131.8,131.7 (d, J=9.0Hz), 129.3,127.7,126.6,124.5 (d,
), J=3.0Hz 121.9,115.0 (d, J=25.0Hz), 114.6 (tt, J=248.6,26.4Hz), 113.6,113.1,
109.9 (d, J=22.5Hz), 109.20,109.0 (tt, J=248.1,33.8Hz), 65.1 (t, J=30.0Hz) 59.0,
53.6,40.5,28.8。
38 2- of embodiment (7- bromonaphthalene -1- base) -2- methyl-N- (3- (2,2,2- trifluoro ethoxy) benzyl) propane -1- amine
Synthesis
The synthesis of step 1) 2- (7- bromonaphthalene -1- base) -2- methyl propionitrile
This step title compound method referring to described in 24 step 1 of embodiment is prepared, i.e., by 2- (7- bromonaphthalene-
1- yl) acetonitrile (2.5g, 10.0mmol), sodium hydride (60% is dispersed in mineral oil, 2.0g, 50.0mmol) and iodomethane
(5.0mL, 80.0mmol) reaction preparation in anhydrous DMF (10mL), crude product is through silica gel column chromatography (petrol ether/ethyl acetate
(v/v)=60/1), being concentrated and dried and obtaining title compound is yellow solid (1.64g, 60%).
1H NMR(600MHz,CDCl3) δ (ppm): 8.69 (s, 1H), 7.81 (d, J=8.1Hz, 1H), 7.78 (d, J=
8.7Hz, 1H), 7.62 (d, J=8.7Hz, 1H), 7.53 (d, J=7.4Hz, 1H), 7.46 (t, J=7.8Hz, 1H), 1.97 (s,
6H)。
The synthesis of step 2) 2- (7- bromonaphthalene -1- base) -2- methylpropane -1- amine
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 2- (7- bromonaphthalene -1-
Base) -2- methyl propionitrile (1.37g, 5.0mmol) and LiAlH4(950mg, 25.0mmol) reacts at 25 DEG C in THF (25mL)
Preparation, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is nothing that concentrate drying, which obtains title compound,
Color grease (778mg, 56%).
MS(ESI,pos.ion)m/z:278.0[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.52 (s, 1H), 7.74 (d, J=8.0Hz, 1H), 7.70 (d, J=
6.8Hz 1H), 7.54 (d, J=8.7Hz, 1H), 7.51-7.50 (m, 1H), 7.41-7.39 (m, 1H), 3.27 (s, 2H), 1.67
(dd, J=5.2,3.5Hz, 6H).
Step 3) 2- (7- bromonaphthalene -1- base) -2- methyl-N- (3- (2,2,2- trifluoro ethoxy) benzyl) propane -1- amine
Synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- bromonaphthalene -1-
Base) -2- methylpropane -1- amine (278mg, 1.0mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (204mg, 1.0mmol),
MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silicagel column
Chromatograph (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtain title compound be yellow oil (228mg,
49%).
MS(ESI,pos.ion)m/z:466.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.44 (s, 1H), 7.73 (d, J=8.7Hz, 1H), 7.70 (d, J=
8.1Hz, 1H), 7.55 (d, J=7.3Hz, 1H), 7.51 (dd, J=8.7,1.4Hz, 1H), 7.43 (t, J=7.7Hz, 1H),
7.15 (t, J=7.8Hz, 1H), 6.75-6.72 (m, 2H), 6.63 (s, 1H), 6.05 (tt, J=55.3,4.1Hz, 1H), 4.04
(td, J=13.1,4.1Hz, 2H), 3.65 (s, 2H), 3.11 (s, 2H), 1.62 (s, 6H)；
13C NMR(150MHz,CDCl3)δ(ppm):157.7,142.4,141.9,133.3,132.6,131.2,129.4,
128.2,128.2,127.7,126.7,125.7,121.3,119.1,113.8 (t, J=239.4Hz), 113.5,113.1,
67.0 (t, J=29.4Hz), 59.3,53.7,40.6,29.1.
39 2- of embodiment (7- bromonaphthalene -1- base) -2- methyl-N- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) propane -1-
The synthesis of amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- bromonaphthalene -1-
Base) -2- methylpropane -1- amine (278mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (236mg,
1.0mmol), MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), it is thick to produce
For object through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil that concentrate drying, which obtains title compound,
(279mg, 56%).
MS(ESI,pos.ion)m/z:498.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.45 (s, 1H), 7.73 (d, J=8.7Hz, 1H), 7.70 (d, J=
8.1Hz, 1H), 7.56 (d, J=7.4Hz, 1H), 7.51 (dd, J=8.7,1.4Hz, 1H), 7.43 (t, J=7.7Hz, 1H),
7.16 (t, J=7.8Hz, 1H), 6.77 (d, J=7.5Hz, 1H), 6.74 (dd, J=8.1,2.2Hz, 1H), 6.63 (s, 1H),
6.06 (tt, J=53.1,5.0Hz, 1H), 4.21 (t, J=11.8Hz, 2H), 3.65 (s, 2H), 3.11 (s, 2H), 1.62 (s,
6H)；
13C NMR(150MHz,CDCl3)δ(ppm):157.3,142.6,141.9,133.3,132.6,131.1,129.4,
128.2,128.1,127.7,126.7,125.7,121.8,119.1,114.5 (tt, J=247.5,27.0Hz), 113.6,
113.2,109.0 (tt, J=249.0,33.0Hz), 65.1 (t, J=28.5Hz), 59.4,53.7,40.6,29.1.
The synthesis of embodiment 40N- (3- (2,2- difluoroethoxy) benzyl) -1- (1- (naphthalene -1- base) cyclopropyl) methylamine
The synthesis of step 1) 1- (naphthalene -1- base) cyclopropyl formonitrile HCN
At -30 DEG C, by 2- (naphthalene -1- base) acetonitrile (1.67g, 10.0mmol) and sodium hydride, (60% is dispersed in mineral oil
In, 1.2g, 30.0mmol) it is added in anhydrous DMF (10mL), after being stirred to react 1h, it is slowly added dropwise into 1,2- Bromofume
(1.75mL, 20.0mmol are dissolved in the DMF of 10mL) is to slowly warm up to 25 DEG C, reacts 30 minutes.Stop reaction, saturation food is added
Salt water (30mL) is quenched, and is extracted with ethyl acetate (30mL x 3), and it is dry with anhydrous sodium sulfate to merge organic phase.Filtering, filtrate
Decompression is spin-dried for, and it is white solid that crude product, which obtains title compound through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=50/1),
Body (1.16g, 60%).
MS(ESI,pos.ion)m/z:194.1[M+H]+；
1H NMR(600MHz,CDCl3) δ: 8.40 (d, J=8.4Hz, 1H), 7.91 (d, J=8.4Hz, 1H), 7.86 (d, J
=8.4Hz, 1H), 7.66 (t, J=7.2Hz, 1H), 7.57 (t, J=7.2Hz, 1H), 7.49 (d, J=7.2Hz, 1H), 7.43
(t, J=7.2Hz, 1H), 1.86 (q, J=4.8Hz, 2H), 1.45 (q, J=4.8Hz, 2H).
The synthesis of step 2) (1- (naphthalene -1- base) cyclopropyl) methylamine
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 1- (naphthalene -1- base)
Cyclopropyl formonitrile HCN (965mg, 5.0mmol) and LiAlH4(950mg, 25.0mmol) reacts preparation in THF (25mL) at 25 DEG C,
For crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is colorless oil that concentrate drying, which obtains title compound,
Object (857mg, 87%).
MS(ESI,pos.ion)m/z:198.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.35 (d, J=7.8Hz, 1H), 7.87 (d, J=7.8Hz, 1H),
7.75 (t, J=7.8Hz, 1H), 7.54 (t, J=7.8Hz, 1H), 7.49 (t, J=7.8Hz, 1H), 7.46 (d, J=6.6Hz,
1H), 7.40 (t, J=7.8Hz, 1H), 2.88 (s, br, 2H), 0.98-0.97 (m, 4H).
The synthesis of step 3) N- (3- (2,2- difluoroethoxy) benzyl) -1- (1- (naphthalene -1- base) cyclopropyl) methylamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by (1- (naphthalene -1- base)
Cyclopropyl) methylamine (197mg, 1.0mmol), 3- (2,2- difluoroethoxy) benzaldehyde (186mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil (228mg, 62%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:368.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.37 (d, J=7.8Hz, 1H), 7.89-7.87 (m, 1H), 7.78 (d,
J=8.4Hz, 1H), 7.58 (d, J=6.6Hz, 1H), 7.53-7.48 (m, 2H), 7.43 (t, J=7.8Hz, 1H), 7.12 (t, J
=7.8Hz, 1H), 6.75 (d, J=7.2Hz, 1H), 6.72 (dd, J=8.4,2.4Hz, 1H), 6.67 (s, 1H), 6.02 (tt, J
=55.2,4.2Hz, 1H), 3.99 (td, J=13.2,4.2Hz, 2H), 3.68 (s, 2H), 2.89 (s, br, 2H), 0.99 (s,
2H), 0.89 (t, J=7.2Hz, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):157.8,141.8,139.1,134.1,132.5,129.8,129.4,
128.4,127.7,125.7,125.6,125.4,124.8,121.4,120.3,113.7 (t, J=239.55Hz), 113.4,
67.0 (t, J=29.25Hz), 57.3,52.9,22.7,12.2.
The synthesis of 41 1- of embodiment (1- (naphthalene -1- base) cyclopropyl)-N- (3- (2,2,2- trifluoro ethoxy) benzyl) methylamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by (1- (naphthalene -1- base)
Cyclopropyl) methylamine (197mg, 1.0mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (204mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil (192mg, 50%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:386.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.36 (d, J=7.8Hz, 1H), 7.89-7.88 (m, 1H), 7.78 (d,
J=8.4Hz, 1H), 7.58 (d, J=6.6Hz, 1H), 7.53-7.48 (m, 2H), 7.43 (t, J=7.8Hz, 1H), 7.13 (t, J
=7.8Hz, 1H), 6.76 (d, J=7.8Hz, 1H), 6.74 (dd, J=7.8,2.4Hz, 1H), 6.66 (s, 1H), 4.13 (q, J
=8.4Hz, 2H), 3.69 (s, 2H), 2.79 (s, br, 2H), 1.00 (s, 2H), 0.90 (t, J=8.4Hz, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):157.4,141.7,139.0,134.1,132.5,129.5,128.9,
128.4,127.7,126.1,125.8,125.6,124.7,123.4 (q, J=276.3Hz), 122.0,113.8,113.6,
65.6 (q, J=35.25Hz), 57.2,52.7,24.5,12.2.
The conjunction of 42 1- of embodiment (1- (naphthalene -1- base) cyclopropyl)-N- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) methylamine
At
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by (1- (naphthalene -1- base)
Cyclopropyl) methylamine (197mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (236mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil (342mg, 82%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:418.0[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.32 (d, J=7.8Hz, 1H), 7.83-7.82 (m, 1H), 7.72 (d,
J=8.4Hz, 1H), 7.52 (d, J=6.6Hz, 1H), 7.47-7.43 (m, 2H), 7.38 (t, J=7.2Hz, 1H), 7.08 (t, J
=7.8Hz, 1H), 6.73 (d, J=7.8Hz, 1H), 6.66 (dd, J=8.4,2.4Hz, 1H), 6.61 (s, 1H), 5.98 (tt, J
=53.4,5.4Hz, 1H), 4.10 (t, J=12.0Hz, 2H), 3.63 (s, 2H), 2.82 (s, br, 2H), 0.96-0.94 (m
Hz,4H)；
13C NMR(150MHz,CDCl3)δ(ppm):157.3,142.3,139.2,134.0,132.5,129.5,
(128.85,128.4,127.6,125.7,125.6,125.3,124.8,121.8,114.6 tt, J=248.4,26.55Hz),
113.5,113.3,109.0 (tt, J=248.1,33.6Hz), 65.1 (t, J=29.7Hz), 57.5,53.0,24.7,12.2.
43 1- of embodiment (1- (naphthalene -1- base) cyclopropyl)-N- (3- (five fluorine propoxyl group of 2,2,3,3,3-) benzyl) methylamine
Synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by (1- (naphthalene -1- base)
Cyclopropyl) methylamine (197mg, 1.0mmol), 3- (2,2,3,3,3- five fluorine propoxyl group) benzaldehyde (254mg, 1.0mmol),
MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silicagel column
Chromatograph (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtain title compound be yellow oil (221mg,
51%).
MS(ESI,pos.ion)m/z:436.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.38 (d, J=7.8Hz, 1H), 7.89-7.87 (m, 1H), 7.78 (d,
J=8.4Hz, 1H), 7.58 (d, J=6.6Hz, 1H), 7.53-7.48 (m, 2H), 7.43 (t, J=7.8Hz, 1H), 7.15 (t, J
=7.8Hz, 1H), 6.80 (d, J=7.2Hz, 1H), 6.74 (dd, J=7.8,2.4Hz, 1H), 6.71 (s, 1H), 4.24 (t, J
=12.0Hz, 2H), 3.69 (s, 2H), 2.91 (s, br, 2H), 1.01-1.00 (m, 4H)；
13C NMR(150MHz,CDCl3)δ(ppm):157.4,142.3,139.2,134.0,132.5,129.5,128.8,
128.4,127.6,125.7,125.6,125.3,124.8,122.0,118.7 (qt, J=284.25,34.5Hz), 113.6,
113.6,112.5 (tq, J=253.5,37.5Hz), 64.7 (t, J=27.6Hz), 57.5,53.0,24.7,12.2.
The conjunction of embodiment 44N- (3- (2,2- difluoroethoxy) benzyl) -1- (1- (6- fluoronaphthalene -1- base) cyclopropyl) methylamine
At
The synthesis of step 1) 1- (6- fluoronaphthalene -1- base) cyclopropyl formonitrile HCN
This step title compound method referring to described in 40 step 1 of embodiment is prepared, i.e., by 2- (6- fluoronaphthalene-
1- yl) acetonitrile (1.85g, 10.0mmol), sodium hydride (60% is dispersed in mineral oil, 1.2g, 30.0mmol) and 1,2- dibromo
Ethane (1.75mL, 20.0mmol are dissolved in 10mLDMF) reaction preparation in (10mL) in anhydrous DMF, crude product is through silica gel column layer
Analyse (petrol ether/ethyl acetate (v/v)=60/1), concentrate drying obtain title compound be celadon color solid (1.6g,
76%).
MS(ESI,pos.ion)m/z:212.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.35 (dd, J=9.1,5.6Hz, 1H), 7.72-7.69 (m, 1H),
7.45 (dd, J=9.1,2.4Hz, 1H), 7.43-7.41 (m, 2H), 7.29 (td, J=8.8,2.8Hz, 1H), 0.99 (s, 2H),
0.94(s,2H)。
The synthesis of step 2) (1- (6- fluoronaphthalene -1- base) cyclopropyl) methylamine
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 1- (6- fluoronaphthalene -1-
Base) cyclopropyl formonitrile HCN (1.05g, 5.0mmol) and LiAlH4(950mg, 25.0mmol) reacts system in THF (25mL) at 25 DEG C
Standby, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is colourless that concentrate drying, which obtains title compound,
Grease (957mg, 89%).
MS(ESI,pos.ion)m/z:216.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.37 (dd, J=9.3,5.6Hz, 1H), 7.70-7.68 (m, 1H),
7.47 (dd, J=9.6,2.4Hz, 1H), 7.43-7.41 (m, 2H), 7.31 (td, J=8.8,2.8Hz, 1H), 2.87 (s, br,
2H),0.97(s,2H),0.93(s,2H)。
The synthesis of step 3) N- (3- (2,2- difluoroethoxy) benzyl) -1- (1- (6- fluoronaphthalene -1- base) cyclopropyl) methylamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by (1- (6- fluoronaphthalene-
1- yl) cyclopropyl) methylamine (215mg, 1.0mmol), 3- (2,2- difluoroethoxy) benzaldehyde (186mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil (246mg, 64%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:386.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.39 (dd, J=9.6,6.0Hz, 1H), 7.70 (d, J=8.4Hz,
1H), 7.52-7.42 (m, 3H), 7.31-7.26 (m, 1H), 7.14 (t, J=8.0Hz, 1H), 6.76 (d, J=7.6Hz, 1H),
6.73 (dd, J=8.0,2.4Hz, 1H), 6.68 (s, 1H), 6.04 (tt, J=4.0Hz, 1H), 4.02 (td, J=12.8,
4.0Hz,2H),3.68(s,2H),2.86(s,br,2H),1.00(s,2H),0.96(s,2H)；
13C NMR(100MHz,CDCl3) δ (ppm): 160.5 (d, J=244.6Hz), 157.8,142.4,139.8,
(135.0 d, J=8.9Hz), 129.6,129.4,127.6 (d, J=2.4Hz), 127.5 (d, J=8.7Hz), 126.9 (d, J=
5.1Hz), 126.5,123.1,115.9 (d, J=24.7Hz), 113.7 (t, J=239.6Hz), 113.6,113.2,111.6
(d, J=19.8Hz), 67.2 (t, J=29.4Hz), 57.7,53.2,24.9,12.1.
45 1- of embodiment (1- (6- fluoronaphthalene -1- base) cyclopropyl)-N- (3- (2,2,2- trifluoro ethoxy) benzyl) methylamine
Synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by (1- (6- fluoronaphthalene-
1- yl) cyclopropyl) methylamine (215mg, 1.0mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (204mg, 1.0mmol),
MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silicagel column
Chromatograph (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtain title compound be yellow oil (185mg,
46%).
MS(ESI,pos.ion)m/z:404.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.38 (dd, J=9.6,6.0Hz, 1H), 7.70 (d, J=7.8Hz,
1H), 7.51 (d, J=6.6Hz, 1H), 7.47 (dd, J=9.6,2.4Hz, 1H), 7.44 (t, J=7.8Hz, 1H), 7.28 (dd,
J=9.0,3.0Hz, 1H), 7.14 (t, J=7.8Hz, 1H), 6.78 (d, J=7.8Hz, 1H), 6.74 (dd, J=7.8,
2.4Hz, 1H), 6.69 (s, 1H), 4.17 (q, J=7.8Hz, 2H), 3.67 (s, 2H), 2.85 (s, br, 2H), 1.00 (s, 2H),
0.96(s,2H)；
13C NMR(150MHz,CDCl3) δ (ppm): 160.4 (d, J=244.5Hz), 157.4,142.4,139.7,
(135.0 d, J=8.85Hz), 129.5,129.4,127.6 (d, J=2.25Hz), 127.4 (d, J=8.7Hz), 126.9 (d, J
=5.1Hz), 126.5,123.4 (q, J=276.15Hz), 121.8,115.9 (d, J=24.6Hz), 113.7,113.4,
111.6 (d, J=19.95Hz), 65.6 (q, J=35.4Hz), 57.6,53.0,24.9,12.1.
46 1- of embodiment (1- (6- fluoronaphthalene -1- base) cyclopropyl)-N- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) methylamine
Synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by (1- (6- fluoronaphthalene-
1- yl) cyclopropyl) methylamine (215mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (236mg, 1.0mmol),
MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silicagel column
Chromatograph (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtain title compound be yellow oil (213mg,
49%).
MS(ESI,pos.ion)m/z:436.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.39 (dd, J=9.2,5.6Hz, 1H), 7.71 (d, J=8.2Hz,
1H), 7.53-7.42 (m, 3H), 7.30-7.26 (m, 1H), 7.15 (t, J=8.0Hz, 1H), 6.79 (d, J=7.6Hz, 1H),
6.73 (dd, J=8.0,2.4Hz, 1H), 6.69 (s, 1H), 6.04 (tt, J=52.8,4.8Hz, 1H), 4.12 (t, J=
11.6Hz,2H),3.68(s,2H),2.86(s,2H),1.00(s,2H),0.97(s,2H)；
13C NMR(100MHz,CDCl3) δ (ppm): 160.5 (d, J=224.6Hz), 157.4,142.6,139.8,
(135.0 d, J=8.9Hz), 129.6,129.4,127.6 (d, J=2.3Hz), 127.4 (d, J=8.7Hz), 126.9 (d, J=
5.1Hz), 126.5,121.8,116.0 (d, J=24.7Hz), 113.8,113.7,113.2,111.6 (d, J=19.9Hz),
109.0 (q, J=33.9Hz), 65.2 (q, J=29.8Hz), 57.7,53.1,24.9,12.1.
47 1- of embodiment (1- (6- fluoronaphthalene -1- base) cyclopropyl)-N- (3- (five fluorine propoxyl group of 2,2,3,3,3-) benzyl) first
The synthesis of amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by (1- (6- fluoronaphthalene-
1- yl) cyclopropyl) methylamine (215mg, 1.0mmol), 3- (2,2,3,3,3- five fluorine propoxyl group) benzaldehyde (254mg,
1.0mmol), MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), it is thick to produce
For object through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil that concentrate drying, which obtains title compound,
(245mg, 54%).
MS(ESI,pos.ion)m/z:454.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.39 (dd, J=9.2,5.6Hz, 1H), 7.70 (d, J=8.0Hz,
1H), 7.51 (dd, J=6.8,1.2Hz, 1H), 7.51-7.43 (m, 2H), 7.29 (dd, J=9.2,2.8Hz, 1H), 7.15 (t,
J=7.8Hz, 1H), 6.79 (d, J=7.6Hz, 1H), 6.75 (dd, J=8.0,2.4Hz, 1H), 6.72 (s, 1H), 4.27 (td,
J=12.0,0.8Hz, 2H), 3.68 (s, 2H), 2.87 (s, br, 2H), 0.99 (d, J=14.6Hz, 4H)；
13C NMR(100MHz,CDCl3) δ (ppm): 160.4 (d, J=244.7Hz), 157.5,142.6,139.8,
135.0 (d, J=8.9Hz), 129.6,129.4,127.6 (d, J=2.0Hz), 127.4 (d, J=8.7Hz), 126.9 (d, J=
5.2Hz), 126.5,121.9,118.7 (dt, J=34.5,284.2Hz), 115.8 (d, J=24.7Hz), 113.9,113.4,
(112.6 q, J=38.1Hz), 111.6 (d, J=19.8Hz), 65.9 (q, J=27.7Hz), 57.7,53.1,24.9,12.1.
Embodiment 48N- (3- (2,2- difluoroethoxy) benzyl) -1- (1- (7- methoxynaphthalene -1- base) cyclopropyl) methylamine
Synthesis
The synthesis of step 1) 1- (7- methoxynaphthalene -1- base) cyclopropyl formonitrile HCN
This step title compound method referring to described in 40 step 1 of embodiment is prepared, i.e., by 2- (7- methoxyl group
Naphthalene -1- base) acetonitrile (1.97g, 10.0mmol), sodium hydride (60% is dispersed in mineral oil, 1.2g, 30.0mmol) and 1,2- bis-
Bromoethane (1.75mL, 20.0mmol are dissolved in 10mL DMF) reaction preparation in anhydrous DMF (10mL), crude product is through silicagel column
Chromatograph (petrol ether/ethyl acetate (v/v)=60/1), concentrate drying obtain title compound be celadon color solid (1.45g,
65%).
MS(ESI,pos.ion)m/z:224.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.81 (d, J=9.0Hz, 1H), 7.78 (d, J=7.8Hz, 1H),
7.61 (d, J=1.8Hz, 1H), 7.46 (d, J=6.6Hz, 1H), 7.29 (t, J=7.2Hz, 1H), 7.23 (dd, J=9.0,
2.4Hz, 1H), 4.02 (s, 3H), 1.85 (q, J=4.8Hz, 2H), 1.44 (q, J=4.8Hz, 2H).
The synthesis of step 2) (1- (7- methoxynaphthalene -1- base) cyclopropyl) methylamine
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 1- (7- methoxyl group
Naphthalene -1- base) cyclopropyl formonitrile HCN (1.12g, 5.0mmol) and LiAlH4(950mg, 25.0mmol) is in THF (25mL) at 25 DEG C
Reaction preparation, crude product obtain title compound through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), concentrate drying
For colorless oil (817mg, 72%).
MS(ESI,pos.ion)m/z:228.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.76 (d, J=9.0Hz, 1H), 7.67 (d, J=7.8Hz, 1H),
7.62 (d, J=2.4Hz, 1H), 7.43 (d, J=7.2Hz, 1H), 7.26 (t, J=8.4Hz, 1H), 7.17 (dd, J=9.0,
2.4Hz,1H),3.95(s,3H),2.87(s,br,2H),0.95(s,4H)。
Step 3) N- (3- (2,2- difluoroethoxy) benzyl) -1- (1- (7- methoxynaphthalene -1- base) cyclopropyl) methylamine
Synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by (1- (7- methoxyl group
Naphthalene -1- base) cyclopropyl) methylamine (227mg, 1.0mmol), 3- (2,2- difluoroethoxy) benzaldehyde (186mg, 1.0mmol),
MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silicagel column
Chromatograph (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtain title compound be yellow oil (262mg,
66%).
MS(ESI,pos.ion)m/z:398.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.78 (d, J=9.0Hz, 1H), 7.70 (d, J=8.4Hz, 1H),
(7.66 d, J=1.8Hz, 1H), 7.54 (d, J=7.2Hz, 1H), 7.31-7.28 (m, 1H), 7.17 (dd, J=9.0,2.4Hz,
1H), 7.14 (t, J=7.8Hz, 1H), 6.77 (d, J=7.8Hz, 1H), 6.72 (dd, J=7.8,1.8Hz, 1H), 6.69 (s,
1H), 6.03 (tt, J=55.2,2.4Hz, 1H), 4.01 (td, J=13.2,4.2Hz, 2H), 3.91 (s, 3H), 3.68 (s,
2H),2.86(s,br,2H),1.00(s,4H)；
13C NMR(150MHz,CDCl3)δ(ppm):157.8,157.4,142.1,137.7,133.7,130.3,129.4,
129.4,128.9,127.3,123.1,121.4,120.3,117.9,113.7 (t, J=239.4Hz), 113.5,113.3,
67.1 (t, J=29.25Hz), 56.9,55.3,53.0,24.7,12.2.
49 1- of embodiment (1- (7- methoxynaphthalene -1- base) cyclopropyl)-N- (3- (2,2,2- trifluoro ethoxy) benzyl) first
The synthesis of amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by (1- (7- methoxyl group
Naphthalene -1- base) cyclopropyl) methylamine (227mg, 1.0mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (204mg, 1.0mmol),
MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silicagel column
Chromatograph (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtain title compound be yellow oil (245mg,
59%).
MS(ESI,pos.ion)m/z:416.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.78 (d, J=8.8Hz, 1H), 7.71 (d, J=8.4Hz, 1H),
7.68 (d, J=2.4Hz, 1H), 7.54 (dd, J=6.8,1.2Hz, 1H), 7.32-7.28 (m, 1H), 7.20-7.13 (m, 2H),
6.81 (d, J=7.6Hz, 1H), 6.75 (dd, J=8.0,2.4Hz, 1H), 6.71 (s, 1H), 4.17 (q, J=8.4Hz, 2H),
3.93(s,3H),3.70(s,2H),2.89(s,br,2H),1.00-0.99(m,4H)；13C NMR(100MHz,CDCl3)δ
(ppm): 157.5,157.4,142.6,137.9,133.7,130.3,129.5,129.4,128.9,12 7.2,123.4 (q, J=
276.3Hz), 123.1,121.9,117.9,113.7,113.6,103.8,65.7 (q, J=35.2Hz), 57.1,55.2,
53.1,24.8,12.1。
50 1- of embodiment (1- (7- methoxynaphthalene -1- base) cyclopropyl)-N- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl)
The synthesis of methylamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by (1- (7- methoxyl group
Naphthalene -1- base) cyclopropyl) methylamine (227mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (236mg,
1.0mmol), MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), it is thick to produce
For object through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil that concentrate drying, which obtains title compound,
(246mg, 55%).
MS(ESI,pos.ion)m/z:448.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.79 (d, J=8.4Hz, 1H), 7.71 (d, J=7.8Hz, 1H),
7.67 (d, J=2.4Hz, 1H), 7.55 (d, J=7.2Hz, 1H), 7.30 (t, J=7.2Hz, 1H), 7.17 (dd, J=9.0,
2.4Hz 1H), 7.14 (t, J=7.8Hz, 1H), 6.80 (d, J=7.8Hz, 1H), 6.73-6.71 (m, 1H), 6.70 (s, 1H),
6.05 (tt, J=53.4,5.4Hz, 1H), 4.18 (t, J=12.0Hz, 2H), 3.92 (s, 3H), 3.69 (s, 2H), 2.88 (s,
br,2H),,1.00(s,4H)；
13C NMR(150MHz,CDCl3)δ(ppm):157.4,157.4,142.4,137.7,133.7,130.3,129.4,
129.4,128.9,127.3,123.1,121.9,117.9,114.6 (tt, J=248.4,26.55Hz), 113.6,113.2,
109.0 (tt, J=248.1,33.75Hz), 103.7,65.1 (t, J=29.85Hz), 57.0,55.3,53.0,24.8,12.2.
51 1- of embodiment (1- (7- methoxynaphthalene -1- base) cyclopropyl)-N- (3- (five fluorine propoxyl group of 2,2,3,3,3-) benzyl
Base) methylamine synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by (1- (7- methoxyl group
Naphthalene -1- base) cyclopropyl) methylamine (227mg, 1.0mmol), 3- (2,2,3,3,3- five fluorine propoxyl group) benzaldehyde (254mg,
1.0mmol), MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), it is thick to produce
For object through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil that concentrate drying, which obtains title compound,
(288mg, 62%).
MS(ESI,pos.ion)m/z:466.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.78 (d, J=8.8Hz, 1H), 7.70 (d, J=8.0Hz, 1H),
7.67 (d, J=2.8Hz, 1H), 7.53 (dd, J=7.2,1.2Hz, 1H), 7.29 (dd, J=8.2,7.2Hz, 1H), 7.18-
7.13 (m, 2H), 6.81 (d, J=7.6Hz, 1H), 6.76-6.72 (m, 2H), 4.26 (td, J=12.4,0.8Hz, 2H), 3.92
(s,3H),3.69(s,2H),2.88(s,br,2H),0.99(s,4H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.5,157.4,142.6,137.8,133.7,130.3,129.5,
129.4,128.9,127.2,123.0,122.0,117.8,113.8,113.5,103.8,64 .8 (t, J=27.5Hz),
57.1,55.2,53.1,24.8,12.1。
52 1- of embodiment (1- (7- fluoronaphthalene -1- base) cyclopropyl)-N- (3- (2,2,2- trifluoro ethoxy) benzyl) methylamine
Synthesis
The synthesis of step 1) 1- (7- fluoronaphthalene -1- base) cyclopropyl formonitrile HCN
This step title compound method referring to described in 40 step 1 of embodiment is prepared, i.e., by 2- (7- fluoronaphthalene-
1- yl) acetonitrile (1.85g, 10.0mmol), sodium hydride (60% is dispersed in mineral oil, 1.2g, 30.0mmol) and 1,2- dibromo
Ethane (1.75mL, 20.0mmol are dissolved in 10mLDMF) reaction preparation in anhydrous DMF (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=60/1), concentrate drying obtain title compound be celadon color solid (1.33g,
63%).
MS(ESI,pos.ion)m/z:212.0[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.98 (d, J=10.6Hz, 1H), 7.90 (dd, J=8.9,5.8Hz,
1H), 7.85 (d, J=8.3Hz, 1H), 7.53 (d, J=7.1Hz, 1H), 7.41 (d, J=7.8Hz, 1H), 7.38-7.32 (m,
1H), 1.87 (q, J=4.9Hz, 2H), 1.43 (q, J=4.9Hz, 2H).
The synthesis of step 2) (1- (7- fluoronaphthalene -1- base) cyclopropyl) methylamine
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 1- (7- fluoronaphthalene -1-
Base) cyclopropyl formonitrile HCN (1.05g, 5.0mmol) and LiAlH4(950mg, 25.0mmol) reacts system in THF (25mL) at 25 DEG C
Standby, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is colourless that concentrate drying, which obtains title compound,
Grease (623mg, 58%).
MS(ESI,pos.ion)m/z:216.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.96 (dd, J=11.3,2.3Hz, 1H), 7.87 (dd, J=8.9,
5.9Hz, 1H), 7.76 (d, J=8.2Hz, 1H), 7.50 (d, J=7.0Hz, 1H), 7.38 (t, J=7.6Hz, 1H), 7.28
(td, J=8.9,2.5Hz, 1H), 2.35 (s, 2H), 0.99-0.94 (m, 4H).
The conjunction of step 3) 1- (1- (7- fluoronaphthalene -1- base) cyclopropyl)-N- (3- (2,2,2- trifluoro ethoxy) benzyl) methylamine
At
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by (1- (7- fluoronaphthalene-
1- yl) cyclopropyl) methylamine (215mg, 1.0mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (204mg, 1.0mmol),
MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silicagel column
Chromatograph (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtain title compound be yellow oil (129mg,
32%).
MS(ESI,pos.ion)m/z:404.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.01 (dd, J=11.3,2.1Hz, 1H), 7.89 (dd, J=8.9,
5.9Hz, 1H), 7.79 (d, J=8.2Hz, 1H), 7.61 (d, J=7.0Hz, 1H), 7.43 (t, J=7.6Hz, 1H), 7.31-
7.29 (m, 1H), 7.18 (t, J=7.8Hz, 1H), 6.83 (d, J=7.5Hz, 1H), 6.78 (dd, J=8.1,2.0Hz, 1H),
(6.73 s, 1H), 4.20 (q, J=8.2Hz, 2H), 3.72 (s, 2H), 2.89 (s, 2H), 1.04-0.98 (m, 4H)；
13C NMR(150MHz,CDCl3) δ (ppm): 160.4 (d, J=243.7Hz), 157.4,142.4,138.9 (d, J
=5.7Hz), 133.5 (d, J=8.7Hz), 131.1 (d, J=9.1Hz), 130.9,129.4,129.3,127.4,124.5 (d,
), J=2.4Hz 121.8,115.9 (d, J=25.3Hz), 113.5,113.4,108.4 (d, J=21.3Hz), 65.5 (q, J=
32.3Hz),57.2,53.0,24.8,12.0。
53 1- of embodiment (1- (7- fluoronaphthalene -1- base) cyclopropyl)-N- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) methylamine
Synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by (1- (7- fluoronaphthalene-
1- yl) cyclopropyl) methylamine (215mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (236mg, 1.0mmol),
MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silicagel column
Chromatograph (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtain title compound be yellow oil (209mg,
48%).
MS(ESI,pos.ion)m/z:436.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.99 (dd, J=11.3,1.8Hz, 1H), 7.88 (dd, J=8.8,
6.0Hz, 1H), 7.78 (d, J=8.2Hz, 1H), 7.60 (d, J=7.0Hz, 1H), 7.42 (t, J=7.6Hz, 1H), 7.28 (s,
1H), 7.17 (t, J=7.8Hz, 1H), 6.81 (d, J=7.5Hz, 1H), 6.74 (d, J=8.2Hz, 1H), 6.71 (s, 1H),
(6.06 tt, J=53.1,5.0Hz, 1H), 4.20 (t, J=11.7Hz, 2H), 3.71 (s, 2H), 2.93-2.81 (m, 2H),
0.91 (t, J=7.0Hz, 4H)；
13C NMR(150MHz,CDCl3) δ (ppm): 160.5 (d, J=243.7Hz), 157.4,142.4,138.8 (d, J
=5.7Hz), 133.5 (d, J=8.7Hz), 131.1 (d, J=9.1Hz), 131.0,129.4,129.3,127.4,124.5 (d,
), J=2.3Hz 121.8,115.9 (d, J=25.2Hz), 113.5,113.2,108.4 (d, J=21.2Hz), 65.1 (t, J=
29.7Hz)57.2,53.0,31.9,29.7。
54 1- of embodiment (1- (7- bromonaphthalene -1- base) cyclopropyl)-N- (3- (2,2,2- trifluoro ethoxy) benzyl) methylamine
Synthesis
The synthesis of step 1) 1- (7- bromonaphthalene -1- base) cyclopropyl formonitrile HCN
This step title compound method referring to described in 40 step 1 of embodiment is prepared, i.e., by 2- (7- bromonaphthalene-
1- yl) acetonitrile (2.46g, 10.0mmol), sodium hydride (60% is dispersed in mineral oil, 1.2g, 30.0mmol) and 1,2- dibromo
Ethane (1.75mL, 20.0mmol are dissolved in 10mLDMF) reaction preparation in (10mL) in anhydrous DMF, crude product is through silica gel column layer
Analyse (petrol ether/ethyl acetate (v/v)=60/1), concentrate drying obtain title compound be celadon color solid (1.58g,
58%).
1H NMR(600MHz,CDCl3) δ (ppm): 8.52 (s, 1H), 7.82 (d, J=8.2Hz, 1H), 7.77 (d, J=
8.7Hz, 1H), 7.64 (dd, J=8.7,1.7Hz, 1H), 7.52 (d, J=7.1Hz, 1H), 7.45-7.43 (m, 1H), 1.88
(q, J=4.9Hz, 2H), 1.43 (q, J=4.9Hz, 2H).
The synthesis of step 2) (1- (7- bromonaphthalene -1- base) cyclopropyl) methylamine
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 1- (7- bromonaphthalene -1-
Base) cyclopropyl formonitrile HCN (1.36g, 5.0mmol) and LiAlH4(950mg, 25.0mmol) reacts system in THF (25mL) at 25 DEG C
Standby, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is colourless that concentrate drying, which obtains title compound,
Grease (1.17g, 85%).
MS(ESI,pos.ion)m/z:276.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.46-8.37 (m, 1H), 7.90-7.84 (m, 1H), 7.74 (t, J=
8.4Hz, 1H), 7.47 (dd, J=6.4,3.1Hz, 1H), 7.42-7.38 (m, 2H), 2.86 (s, br, 2H), 1.74 (d, J=
10.0Hz,4H)。
The conjunction of step 3) 1- (1- (7- bromonaphthalene -1- base) cyclopropyl)-N- (3- (2,2,2- trifluoro ethoxy) benzyl) methylamine
At
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by (1- (7- bromonaphthalene-
1- yl) cyclopropyl) methylamine (276mg, 1.0mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (204mg, 1.0mmol),
MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silicagel column
Chromatograph (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtain title compound be yellow oil (264mg,
57%).
MS(ESI,pos.ion)m/z:464.1[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.56(s,1H),7.77-7.75(m,2H),7.62-7.58(m,2H),
7.50-7.45 (m, 1H), 7.19 (t, J=7.8Hz, 1H), 6.85 (d, J=7.5Hz, 1H), 6.78 (dd, J=8.2,2.0Hz,
1H), 6.75 (s, 1H), 4.23 (q, J=8.2Hz, 2H), 3.71 (s, 2H), 2.90 (brs, 2H), 1.05 (s, 2H), 0.99 (s,
2H)；
13C NMR(150MHz,CDCl3)δ(ppm):157.4,142.4,138.7,133.7,132.4,130.4,129.4,
129.4,128.9,127.4,127.1,125.7,123.3 (q, J=276.3Hz), 121.8,120.0,113.6,113.5,
65.6 (q, J=36.0Hz), 57.5,53.0,24.6,12.0.
55 1- of embodiment (1- (7- bromonaphthalene -1- base) cyclopropyl)-N- (3- (five fluorine propoxyl group of 2,2,3,3,3-) benzyl) first
The synthesis of amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by (1- (7- bromonaphthalene-
1- yl) cyclopropyl) methylamine (276mg, 1.0mmol), 3- (2,2,3,3,3- five fluorine propoxyl group) benzaldehyde (254mg,
1.0mmol), MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), it is thick to produce
For object through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil that concentrate drying, which obtains title compound,
(308mg, 60%).
MS(ESI,pos.ion)m/z:514.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.54 (s, 1H), 7.73 (dd, J=8.3,3.9Hz, 2H), 7.57 (t,
J=8.3Hz, 2H), 7.44 (t, J=7.6Hz, 1H), 7.17 (t, J=7.8Hz, 1H), 6.83 (d, J=7.5Hz, 1H),
6.76-6.74 (m, 2H), 4.29 (t, J=12.3Hz, 2H), 3.69 (s, 2H), 2.87 (s, 2H), 1.01-0.96 (m, 4H)；
13C NMR(150MHz,CDCl3)δ(ppm):157.4,142.5,138.7,133.7,132.4,130.4,129.4,
129.4,128.9,127.4,127.1,125.7,121.9,120.0,113.7,113.4,64 .7 (t, J=27.5Hz), 57.6,
53.1,24.7,12.0。
The synthesis of embodiment 56N- (3- (2,2- difluoroethoxy) benzyl) -2- (4- methoxynaphthalene -1- base) ethamine
The synthesis of step 1) (E) -1- methoxyl group -4- (2- nitroethenyl group) naphthalene
By 4- methoxy-1-naphthalene formaldehyde (1.0g, 5.4mmol) and NH4OAc (0.208g, 2.7mmol) is added to nitro first
In alkane (10mL), 7h is reacted at 120 DEG C of oil bath, stops reaction, ethyl acetate dilution (60mL) is added, then saturated salt solution
(40mL x 3) washing, organic phase is dry with anhydrous sodium sulfate after liquid separation.Filtering, filtrate decompression are spin-dried for, and crude product is through silicagel column
It is yellow solid (1.1g, 89%) that chromatography (methylene chloride), which obtains title compound,.
MS(ESI,pos.ion)m/z:230.2[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.78 (d, J=13.3Hz, 1H), 8.30-8.17 (m, 4H), 7.72-
7.68 (m, 1H), 7.63-7.59 (m, 1H), 7.11 (d, J=8.3Hz, 1H), 4.07 (s, 3H).
The synthesis of step 2) 2- (4- methoxynaphthalene -1- base) ethamine
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by (E) -1- methoxy
Base -4- (2- nitroethenyl group) naphthalene (1.1g, 4.8mmol) and LiAlH4(950mg, 25.0mmol) is 25 DEG C in THF (25mL)
Lower reaction preparation, crude product obtain title compound through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), concentrate drying
Object is brown oil (360mg, 37%).
MS(ESI,pos.ion)m/z:202.1[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.35-8.33 (m, 1H), 8.00 (d, J=8.5Hz, 1H), 7.58-
7.49 (m, 2H), 7.28-7.25 (m, 1H), 6.77 (d, J=7.8Hz, 1H), 4.01 (s, 3H), 3.16 (t, J=6.5Hz,
2H),3.09-3.06(m,2H)。
The synthesis of step 3) N- (3- (2,2- difluoroethoxy) benzyl) -2- (4- methoxynaphthalene -1- base) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (4- methoxyl group
Naphthalene -1- base) ethamine (201mg, 1.0mmol), 3- (2,2- difluoroethoxy) benzaldehyde (186mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil (200mg, 54%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:372.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.35-8.32 (m, 1H), 8.00 (d, J=7.9Hz, 1H), 7.57-
(7.49 m, 2H), 7.27 (dd, J=7.8,3.9Hz, 1H), 7.23 (d, J=7.9Hz, 1H), 6.95 (d, J=7.5Hz, 1H),
(6.89 s, 1H), 6.80 (dd, J=8.2,2.4Hz, 1H), 6.76 (d, J=7.8Hz, 1H), 6.08 (tt, J=55.2,
4.1Hz, 1H), 4.14 (td, J=13.2,4.1Hz, 2H), 4.01 (s, 3H), 3.83 (s, 2H), 3.26 (t, J=7.1Hz,
2H), 3.02 (t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.9,154.4,141.9,132.7,129.5,127.6,126.4,
126.3,126.0,124.9,123.5,122.6,121.7,114.1,113.7 (t, J=239.5Hz), 113.3,103.4,
67.2 (t, J=29.0Hz), 55.4,53.5,49.7,32.8.
The synthesis of 57 2- of embodiment (4- methoxynaphthalene -1- base)-N- (3- (2,2,2- trifluoro ethoxy) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (4- methoxyl group
Naphthalene -1- base) ethamine (201mg, 1.0mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (204mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is colorless oil (148mg, 38%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:390.2[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.35-8.33(m,1H),8.02-7.99(m,1H),7.53(tdd,J
=14.7,6.8,1.4Hz, 2H), 7.29-7.27 (m, 1H), 7.24 (d, J=7.9Hz, 1H), 6.98 (d, J=7.6Hz, 1H),
6.92 (s, 1H), 6.83 (dd, J=8.1,2.3Hz, 1H), 6.77 (d, J=7.8Hz, 1H), 4.31 (q, J=8.2Hz, 2H),
(4.01 s, 3H), 3.84 (s, 2H), 3.26 (t, J=7.1Hz, 2H), 3.03 (t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.6,154.4,142.0,132.7,129.6,127.6,126.4,
126.3,126.0,124.9,123.5,123.4 (q, J=276.3Hz), 122.6,122.2,114.3,113.6,103.3,
65.8 (q, J=35.3Hz), 55.4,53.4,49.7,32.8.
The synthesis of 58 2- of embodiment (4- methoxynaphthalene -1- base)-N- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (4- methoxyl group
Naphthalene -1- base) ethamine (201mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (236mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil (181mg, 43%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:422.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.35 (dd, J=8.2,1.3Hz, 1H), 8.02-8.00 (m, 1H),
7.57-7.49 (m, 2H), 7.30-7.28 (m, 1H), 7.25 (d, J=7.9Hz, 1H), 6.99 (d, J=7.6Hz, 1H), 6.92
(s, 1H), 6.81 (dd, J=8.1,2.3Hz, 1H), 6.77 (d, J=7.8Hz, 1H), 6.09 (tt, J=53.1,5.1Hz,
1H), 4.33 (t, J=11.8Hz, 2H), 4.02 (s, 3H), 3.85 (s, 2H), 3.28 (t, J=7.2Hz, 2H), 3.04 (t, J=
7.2Hz,2H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.5,154.5,141.9,132.7,129.6,127.5,126.4,
126.3,126.0,124.9,123.5,122.7,122.2,114.2,113.4,103.6,65 .3 (t, J=59.3Hz), 55.4,
53.4,49.7,32.8。
The conjunction of 59 2- of embodiment (4- methoxynaphthalene -1- base)-N- (3- (five fluorine propoxyl group of 2,2,3,3,3-) benzyl) ethamine
At
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (4- methoxyl group
Naphthalene -1- base) ethamine (201mg, 1.0mmol), 3- (2,2,3,3,3- five fluorine propoxyl group) benzaldehyde (254mg, 1.0mmol),
MgSO4(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silicagel column
Chromatograph (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtain title compound be yellow oil (202mg,
46%).
MS(ESI,pos.ion)m/z:440.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.34 (dd, J=8.2,1.2Hz, 1H), 8.02-8.00 (m, 1H),
7.53 (tdd, J=14.7,6.8,1.4Hz, 2H), 7.29 (d, J=2.8Hz, 1H), 7.28 (d, J=1.6Hz, 1H), 7.25
(d, J=7.9Hz, 1H), 6.99 (d, J=7.6Hz, 1H), 6.94 (s, 1H), 6.83 (dd, J=8.2,2.2Hz, 1H), 6.77
(d, J=7.8Hz, 1H), 4.40 (td, J=12.3,0.9Hz, 2H), 4.01 (s, 3H), 3.84 (s, 2H), 3.27 (t, J=
7.2Hz, 2H), 3.03 (t, J=7.2Hz, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.6,154.5,141.9,132.7,129.6,127.5,126.4,
126.3,126.0,124.9,123.5,122.7,122.3,114.3,113.6,103.3,64 .90 (t, J=27.5Hz),
55.4,53.4,49.8,32.8。
The synthesis of embodiment 60N- (3- (2,2- difluoroethoxy) benzyl) -2- (4- fluoronaphthalene -1- base) ethamine
The synthesis of step 1) (E) -1- fluoro- 4- (2- nitroethenyl group) naphthalene
This step title compound method referring to described in 56 step 1 of embodiment is prepared, i.e., by the fluoro- 1- naphthalene first of 4-
Aldehyde (1.0g, 5.75mmol) and NH4OAc (0.22g, 2.9mmol) reaction preparation in nitromethane (10mL), crude product is through silicon
Plastic column chromatography (methylene chloride), it is celadon color solid (1.0g, 80%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:218.2[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 8.76 (d, J=13.3Hz, 1H), 8.34 (d, J=8.2Hz, 1H),
8.21 (d, J=13.3Hz, 1H), 8.14-8.10 (m, 2H), 7.79-7.71 (m, 2H), 7.45 (dd, J=10.4,8.3Hz,
1H)。
The synthesis of step 2) 2- (4- fluoronaphthalene -1- base) ethamine
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by the fluoro- 4- of (E) -1-
(2- nitroethenyl group) naphthalene (1.0g, 4.6mmol) and LiAlH4(950mg, 25.0mmol) reacts at 25 DEG C in THF (25mL)
Preparation, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), concentrate drying obtains title compound as palm fibre
Color grease (443mg, 51%).
MS(ESI,pos.ion)m/z:190.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.13-8.11(m,1H),δ8.10-7.99(m,1H),7.56-7.50
(m, 2H), 7.23 (dd, J=7.8,5.5Hz, 1H), 7.04 (dd, J=10.3,7.8Hz, 1H), 3.18 (t, J=7.0Hz,
2H), 3.06 (t, J=6.9Hz, 2H).
The synthesis of step 3) N- (3- (2,2- difluoroethoxy) benzyl) -2- (4- fluoronaphthalene -1- base) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (4- fluoronaphthalene -1-
Base) ethamine (189mg, 1.0mmol), 3- (2,2- difluoroethoxy) benzaldehyde (186mg, 1.0mmol), MgSO4(240mg,
2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography (petroleum
Ether/ethyl acetate (v/v)=2/1), it is yellow oil (190mg, 53%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:360.2[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.16-8.14(m,1H),8.04-8.02(m,1H),7.58-7.55
(m, 2H), 7.28-7.27 (m, 1H), 7.23 (t, J=7.9Hz, 1H), 7.07 (dd, J=10.2,7.9Hz, 1H), 6.94 (d, J
=7.5Hz, 1H), 6.90 (s, 1H), 6.78 (dd, J=8.2,2.1Hz, 1H), 6.06 (tt, J=55.2,4.1Hz, 1H),
4.13 (td, J=13.1,4.1Hz, 2H), 3.83 (s, 2H), 3.27 (t, J=7.3Hz, 2H), 3.03 (t, J=7.3Hz, 2H)；
13C NMR(150MHz,CDCl3) δ (ppm): 157.9,157.8 (d, J=248.9Hz), 141.0,133.0 (d, J
=4.3Hz), 131.4 (d, J=4.4Hz), 129.6,126.8,126.2 (d, J=8.1Hz), 125.9 (d, J=1.6Hz),
124.0 (d, J=15.9Hz), 123.7 (d, J=2.7Hz), 121.7,121.2 (d, J=5.7Hz), 114.2,113.6 (t, J
=239.5Hz), 113.4,108.8 (d, J=19.5Hz), 67.1 (d, J=29.3Hz), 53.2,49.4,32.6.
The synthesis of 61 2- of embodiment (4- fluoronaphthalene -1- base)-N- (3- (2,2,2- trifluoro ethoxy) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (4- fluoronaphthalene -1-
Base) ethamine (189mg, 1.0mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (204mg, 1.0mmol), MgSO4(240mg,
2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography (petroleum
Ether/ethyl acetate (v/v)=2/1), it is colorless oil (158mg, 42%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:378.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.19-8.17 (m, 1H), 8.06 (d, J=7.9Hz, 1H), 7.61-
7.57 (m, 2H), 7.31-7.27 (m, 2H), 7.10 (dd, J=10.3,7.8Hz, 1H), 7.00 (d, J=7.5Hz, 1H), 6.95
(s, 1H), 6.84 (dd, J=8.2,2.3Hz, 1H), 4.34 (q, J=8.2Hz, 2H), 3.85 (s, 2H), 3.30 (t, J=
7.3Hz, 2H), 3.04 (t, J=7.3Hz, 2H)；13C NMR(150MHz,CDCl3) δ (ppm): 157.8 (d, J=248.8Hz),
157.5,141.9,133.0 (d, J=4.2Hz), 131.6 (d, J=4.4Hz), 129.6,126.8,126.1 (d, J=
8.1Hz), 125.8 (d, J=1.6Hz), 124.0 (d, J=15.9Hz), 123.7 (d, J=2.7Hz), 123.3 (q, J=
276.2Hz), 122.1,121.2 (d, J=15.9Hz), 114.4,113.5,108.8 (d, J=19.5Hz), 65.7 (q, J=
35.3Hz),53.4,49.6,32.9。
The synthesis of 62 2- of embodiment (4- fluoronaphthalene -1- base)-N- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (4- fluoronaphthalene -1-
Base) ethamine (189mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (236mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil (208mg, 51%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:410.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.17-8.16 (m, 1H), 8.05 (d, J=7.7Hz, 1H), 7.59-
7.56 (m, 2H), 7.30-7.25 (m, 2H), 7.09 (dd, J=10.2,7.9Hz, 1H), 6.98 (d, J=7.4Hz, 1H), 6.91
(s, 1H), 6.81 (dd, J=8.1,2.2Hz, 1H), 6.09 (tt, J=53.1,4.9Hz, 1H), 4.33 (t, J=11.8Hz,
2H), 3.84 (s, 2H), 3.28 (t, J=7.2Hz, 2H), 3.03 (t, J=7.2Hz, 2H)；
13C NMR(150MHz,CDCl3) δ (ppm): 157.8 (d, J=248.8Hz), 157.5,142.1,133.0 (d, J
=4.3Hz), 131.6 (d, J=4.4Hz), 129.6,126.8,126.1 (d, J=8.1Hz), 125.8 (d, J=1.7Hz),
124.0 (d, J=15.9Hz), 123.8 (d, J=2.7Hz), 122.1,121.2 (d, J=5.7Hz), 114.5 (tt, J=
), 248.4,26.8Hz 114.2,113.2,109.0 (tt, J=248.2,33.9Hz), 108.8 (d, J=19.4Hz), 65.2
(d, J=29.7Hz), 53.5,49.7,32.9.
The synthesis of 63 2- of embodiment (4- fluoronaphthalene -1- base)-N- (3- (five fluorine propoxyl group of 2,2,3,3,3-) benzyl) ethamine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (4- fluoronaphthalene -1-
Base) ethamine (189mg, 1.0mmol), 3- (2,2,3,3,3- five fluorine propoxyl group) benzaldehyde (254mg, 1.0mmol), MgSO4
(240mg, 2.0mmol) and NaBH4(76mg, 2.0mmol) reaction preparation in EtOH (10mL), crude product is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil (188mg, 44%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:428.3[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.18-8.16 (m, 1H), 8.06 (d, J=7.9Hz, 1H), 7.60-
7.56 (m, 2H), 7.30-7.26 (m, 2H), 7.09 (dd, J=10.3,7.9Hz, 1H), 6.99 (d, J=7.5Hz, 1H), 6.93
(s, 1H), 6.84 (dd, J=8.2,2.2Hz, 1H), 4.41 (t, J=12.4Hz, 2H), 3.84 (s, 2H), 3.28 (t, J=
7.2Hz, 2H), 3.03 (t, J=7.2Hz, 2H)；
13C NMR(150MHz,CDCl3) δ (ppm): 157.8 (d, J=248.8Hz), 157.6,142.4,133.1 (d, J
=4.3Hz), 131.8 (d, J=4.4Hz), 129.7,126.8,126.1 (d, J=8.1Hz), 125.9 (d, J=1.6Hz),
124.1 (d, J=15.9Hz), 123.8 (d, J=2.7Hz), 122.2,121.2 (d, J=5.8Hz), 117.7 (tt, J=
284.9,34.6Hz), 114.4,113.4,112.5 (q, J=43.1Hz), 108.9 (d, J=19.5Hz), 64.9 (td, J=
27.5,7.9Hz),53.6,49.9,33.1。
Biologic test
The present invention carries out biologic test to the compounds of this invention using following methods:
A. with radio ligand binding assay evaluation compound to the source of people 5-HT being expressed on CHO cells6The parent of receptor
And power
The 32 μ g expression prepared there is into source of people 5-HT6The CHO cell membrane protein of receptor, 2nM radioactively labelled substance [3H]
LSD, the compound of different test concentrations and test buffer are uniformly mixed, 37 DEG C of incubation 120min；Test buffer ingredient
Are as follows: 50mM Tris-HCl (pH 7.4), 10mM MgCl2, 0.5mM EDTA, 10 μM of Pargylines and 20mg/l protease inhibit
Agent.
100 μM of 5-HT removal nonspecific binding sites are added.After incubation, above-mentioned mixed liquor is used under vacuum conditions
Glass filter filtering, filter are first presoaked with 0.3%PEI before filtration.It is rinsed several times with 50mM Tris-HCl again after filtering.
After the filter is dry, radioactivity is counted on the scintillometer with scintillation mixed solution.Standard reference compounds are 5-HT, each real
Several concentration are tested in testing to obtain its competition inhibition curve and calculate IC50。
Radio ligand binding assay is carried out to compound provided in an embodiment of the present invention according to the method described above and evaluates chemical combination
Object is to the source of people 5-HT being expressed on CHO cells6The affinity determination of receptor, as a result referring to table 2, table 2 is the embodiment of the present invention
The affinity measurement result of offer.
The affinity measurement result of the compound provided in an embodiment of the present invention of table 2
| Embodiment | IC50(nM) | Embodiment | IC50(nM) | Embodiment | IC50(nM) |
| Embodiment 1 | A | Embodiment 12 | A | Embodiment 23 | B |
| Embodiment 2 | A | Embodiment 13 | A | Embodiment 56 | B |
| Embodiment 3 | B | Embodiment 14 | A | Embodiment 57 | B |
| Embodiment 4 | B | Embodiment 15 | A | Embodiment 58 | B |
| Embodiment 5 | B | Embodiment 16 | B | Embodiment 59 | B |
| Embodiment 6 | C | Embodiment 17 | B | Embodiment 60 | A |
| Embodiment 7 | B | Embodiment 18 | B | Embodiment 61 | A |
| Embodiment 8 | C | Embodiment 19 | B | Embodiment 62 | A |
| Embodiment 9 | A | Embodiment 20 | B | Embodiment 63 | A |
| Embodiment 10 | A | Embodiment 21 | A | -- | -- |
| Embodiment 11 | A | Embodiment 22 | B | -- | -- |
Note: A≤10nM, 10<B<100nM, C>=100nM.
As shown in Table 2, compound of the present invention is thin in CHO to expressing in radio ligand binding assay evaluation compound
Source of people 5-HT on born of the same parents6Higher activity is generally shown in the affinity test of receptor.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means particular features, structures, materials, or characteristics described in conjunction with this embodiment or example
It is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms need not
It must be directed to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be any
It can be combined in any suitable manner in a or multiple embodiment or examples.In addition, without conflicting with each other, the technology of this field
The feature of different embodiments or examples described in this specification and different embodiments or examples can be combined by personnel
And combination.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example
Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, modifies, replacement and variant.
Claims (7)
1. a kind of compound, the structure with one of:
Or its pharmaceutically acceptable salt.
2. a kind of pharmaceutical composition includes compound described in claim 1 and pharmaceutically acceptable carrier, excipient, dilute
Release agent, adjuvant, medium or their combination.
3. pharmaceutical composition according to claim 2, further includes additional therapeutic agent, the additional therapeutic agent is to use
In treatment azheimer's disease drug, treat nervous disorders drug or their combination.
4. pharmaceutical composition according to claim 3, wherein the additional therapeutic agent is donepezil, nalmefene, Li Pei
Ketone, vitamin e, Tacrine, Rivastigmine, galanthamine, Memantine, mitzapine, Venlafaxine, desipramine, nortriptyline,
Zolpidem, zopiclone, Nicergoline, Piracetam, selegiline, pentoxifylline or their combination.
5. a kind of made using pharmaceutical composition described in compound described in claim 1 or claim 2-4 any one
It is ready for use on and prevents, treats or mitigate and 5-HT6Purposes in the drug of related disease.
6. purposes according to claim 5, wherein described and 5-HT6Related disease be CNS illness, disorder of gastrointestinal tract or
Obesity.
7. purposes according to claim 6, wherein the CNS illness is ADHD, anxiety, disease relating to mental stress
Disease, schizophrenia, besetment and behavior disorder, manic-depressive psychosis, nervous disorders, memory disorders, attention deficit disorder,
Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease or Huntington's chorea.
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