CN106699729A - Benzamide compounds containing acetenyl group - Google Patents
Benzamide compounds containing acetenyl group Download PDFInfo
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- CN106699729A CN106699729A CN201510772131.6A CN201510772131A CN106699729A CN 106699729 A CN106699729 A CN 106699729A CN 201510772131 A CN201510772131 A CN 201510772131A CN 106699729 A CN106699729 A CN 106699729A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/36—Sulfur atom
- C07D473/38—Sulfur atom attached in position 6
Abstract
The invention provides acetenyl group-containing benzamide compounds as shown in a formula (I) and used for treating or preventing diseases related to protein kinase, and medicinal salts or configurational isomers thereof. A connection group L<1>, a ring A and substituents R<1>, R<2>, R<3>, R<4> and R <5> in the formula (I) are as defined in the specification. The invention also discloses a preparation method and a pharmaceutical composition of the compounds as shown in the formula (I), and application of the compounds to preparation or prevention of drugs used for preventing diseases related to protein kinase.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a class contains the benzamides chemical combination of acetenyl
Thing, or such compound pharmaceutically acceptable salt, individually or optionally other pharmacy are lived with one or more
Property compound combine for treating for suppressing protein kinase activity and have the disease of response, especially leukaemia.
Background technology
Protein kinase is a class phosphotransferase, and its effect is that the γ phosphates of ATP are transferred into substrate
On specific amino acid residue, make protein phosphorylation.These phosphorylations serve as adjustable or goal of regulation and control egg
The converter of the molecule ON/OFF of the biological function of white matter, finally in response to various kinds of cell is outer and other stimulants and
It is triggered.These stimulants include that (for example shock, heat shock, ultraviolet shine for environment and Chemical stress signal
Penetrate, bacterial endotoxin and H2O2), cell factor (such as bag cell stay -1 and neoplasm necrosis shadow α and
Growth factor).Extracellular stimulus thing may influence cell growth, migration, differentiation, hormone secretion, turn
Record one or more thin such as factors activated, contraction of muscle, glucose metabolism, protein synthesis control
Born of the same parents react.
Protein kinase activity it is not normal, can cause it is many correlation diseases.These diseases include cancer, from
Body immunity disease, inflammation, metabolic disease, neurogenic disease, angiocardiopathy close Alzheimer
(Alzheimer ' s disease) etc..Under many circumstances, protein kinase can be utilized by vitro and in vivo
Inhibitor treats this kind of disease.
ABL (Abelson leukemia virus) EGFR-TK is present in cytoplasm and nucleus, in cell
Played an important role during differentiation, division, cell adhesion and stress reaction, gene transposition causes B cell to be received
Body (B cell receptor, BCR) and abl gene merge to form fusion BCR-ABL end to end.
BCR-ABL kinases has multiple functional domains, including SH2, SH3 domain, appraises and decides nuclear localization sequence and 3
Individual DNA structure domain, its activation contributes to the generation of leukaemia.Tyrosine kinase activity is for BCR-ABL
Function be required, the approach phase that is activated with hemopoieticgrowth factor of some signal pathways of BCR-ABL activation
Seemingly, such as Ras, PI3K, JAK/STAT.The excessive activation of BCR-ABL changes sticking for hematopoietic cell
Property, inducing cell skeleton dysfunction, by number of ways interference cell cycle and cell adhesion, promote tumour
Occurrence and development.
The Imatinib that early 1990s find being capable of specific suppression BCR-ABL tyrosine proteins
The activity of kinases.It can effectively suppress ABL, PDGF acceptor under micro-molar concentration
(PDGFR), the autophosphorylation of Kit acceptors and ARG EGFR-TKs, becomes clinical treatment leukaemia
One line important drugs, but resistance phenomenon is found that after patient's long-term use.Research finds the molecular basis of drug resistance
That the kinase domain region of BCR-ABL occurs to the variant of Imatinib resistances, mutant include Y253H,
E255V、E255K、F359V、T315I、G250E、F317L、E355G、H396P、M351T、
M253H, L248V, Q252H, Y253H and Y253C etc..
In view of the big kinds of Diseases related to proliferative and other protein kinases of kinases inhibitor quantity
As many as, and existing medicine is the problems such as occur in that drug resistance, it would be desirable to the compound of new species is developed,
For use as kinases inhibitor, the disease related for treating these protein kinases.Therefore, present invention hair
A kind of new benzamide derivatives containing acetenyl are showed, have been lived with protein kinase for preventing or treating
Sexual abnormality or related disease out of control.
The content of the invention
The compound that is represented containing following formula (I) the invention provides one kind or its is pharmaceutically acceptable
Salt：
Wherein
Linking group L is-NHC (O)-or-C (O) NH-；
Ring A represents 5,6 or 7 yuan of nitrogenous or oxygen containing Heterocyclylalkyls；
R1Selected from hydrogen, C1-C4Alkyl, cycloalkyl, alkoxy, hydroxyl, amino, by alkyl-substituted amino,
Alkyl carbonyl；
R2, R3Independently selected from hydrogen, C1-C4Alkyl, or link together and adjacent phenyl ring forms five-membered ring；
R4It is hydrogen, fluorine or trifluoromethyl；
R5It is the heterocycle of nitrogenous, sulphur or oxygen, or fused ring compound is formed with pyrimidine.
In compound of the present invention (I) or pharmaceutically acceptable salt, wherein
Ring A preferably is selected from pyrrolidines, piperazine, homopiperazine, morpholine；
R1It preferably is selected from hydrogen, methyl, isopropyl, ethoxy, dimethylamino；
R2, R3Hydrogen preferably is selected from, or is linked together and adjacent phenyl ring formation five-membered ring；
R4It is hydrogen, fluorine or trifluoromethyl；
R5It preferably is selected from pyridine radicals, pyrrole radicals, thienyl；Or form purine radicals, thio-purine base with the pyrimidine being connected.
Formula (I) compound of the present invention or its pharmaceutically acceptable salt, wherein described compound is more preferably
From：
Formula (I) compound of the present invention pharmaceutically acceptable salt, or containing at least one alkalescence into alkali
Group, can be pharmaceutically conventional inorganic acid or organic acid with the acid of its into salt, including inorganic acid：Hydrochloric acid, sulphur
Acid, phosphoric acid；Organic carboxyl acid：Acetic acid, propionic acid, trifluoroacetic acid, glycolic, butanedioic acid, maleic acid, rich horse
Acid, malic acid, tartaric acid, citric acid, oxalic acid, amino acid, benzoic acid, the water of various natural or synthesis
Poplar acid, 4-ASA, mandelic acid, cinnamic acid, nicotinic acid, isonicotinic acid；Organic sulfonic acid：Methanesulfonic acid, three
Fluorine methanesulfonic acid, ethyl sulfonic acid, 2- ethylenehydrinsulfonic acids, benzene sulfonic acid, p-methyl benzenesulfonic acid, 2- naphthalene sulfonic acids.It is many when existing
During individual basic group, many acid-addition salts can be generated.
Compound of the invention and pharmaceutically acceptable salt also include the form of solvate or hydrate.One
As for, the form of solvate or hydrate is equal to non-solvated or non-hydrated form, contains in the lump
Lid is within the scope of the invention.Some compounds in the present invention there may exist polycrystal or unbodied shape
Formula.Generally speaking, all of physical form has equal purposes, and covers within the scope of the invention.
The present invention covers all alloisomerisms of the compounds of this invention in form of mixtures or in pure form
Body.The definition of the compounds of this invention includes all possible stereoisomer and its mixture.It is very specific
Ground includes racemic form and the separate optical isomer with given activity.Racemic form can be by thing
Reason method is split, the physical method such as diastereoisomer derivative is carried out fractional crystallization,
Separate or separated by chiral column chromatography.Can be by conventional method such as optically active acid form into salt
Then crystallize and obtain single optical isomer from racemic modification.
Present invention additionally comprises the prodrug of the compound.Prodrug is a kind of chemical combination being derived by parent drug
Thing, it is internal once that it enter, and prodrug is just metabolized and is changed into parent drug.Prodrug can be by parent drug
One or more functional groups replaced and prepared, its substituted radical can be discharged by enzymatic in vivo
Parent compound comes.The preparation and use of prodrug can be in T.Higuchi and V.Stella, " Pro-drugs as
Novel Delivery System ", Vol.14 of the A.C.S.Symposium Serier and Bioreversible
Carriers in Drug Design,ed.Edward B.Roche,AmericanPharmaceutical Association
And Pergamon Press, find in 1987.
Additionally, present invention also offers the method for one kind synthesis compound (I).
Compound (I) of the present invention can be connected by compound a and compound b and be obtained, synthetic method
It is as follows：
In the synthetic method, solvent for use is generally the big pole such as DMF, DMSO, 1-METHYLPYRROLIDONE
Property aprotic solvent, and add the catalyst containing palladium, such as palladium bichloride, palladium, triphenyl phosphorus base palladium,
And add appropriate organic base, such as triethylamine, diisopropylethylamine, DMAP etc..Reaction is general higher
Temperature (such as larger than 100 DEG C) under carry out, reaction terminate after can use the means separating-purifying reactant such as column chromatography.
Compound a can typically be prepared by the following：
Compound c by diazotising, upper trimethyl silicane ethyl-acetylene, slough trimethyl silicon-based protecting group three-step reaction
Obtain compound a.Wherein diazotising is by NaNO2/ HBr or nitrite tert-butyl/HBr reactions are realized
's.Diazotizing product d and trimethyl silicane ethyl-acetylene reacting generating compound e in polar non-solute,
Add containing palladium compound as catalyst in reaction, organic amine is used as alkali.Then compound e sloughs TMS guarantors
Shield base, the reaction can be readily accomplished under conditions of appropriate tetrabutyl ammonium fluoride.
Additionally, compound b can be synthesized by following method：
In reaction equation, if R6It is amino, R7It is carboxyl；If R6Be carboxyl, then R7It is amino.The reaction
It is the reaction of amino and carboxylic acid generation acid amides, can be completed with method well-known to those skilled in the art, including
Reacted with amino after carboxyl generation acyl chlorides or acid amides is directly synthesized by activated ester intermediate.
Compound g includes following two structure：
Its synthetic method is described as follows respectively：
The invention further relates to formula (I) compound comprising effective dose and the pharmacologically medicine of acceptable carrier
Composition, said composition is applied to local, enteral or parenteral administration, can be inorganic or organic
, it is solid-state or liquid.For oral, especially with tablet or capsule.This tablet or capsule include work
Property composition and diluent (such as lactose, glucose, sucrose, mannitol, sorbierite, cellulose, the third three
Alcohol), lubricant (such as talcum, stearate), polyethylene glycol.Tablet can also include adhesive, starch,
Gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, can also include powder if necessary
Broken dose (such as starch, agar, alginic acid and its salt), effervescent mixture, or adsorbent, dyestuff, flavor enhancement,
Sweetener.These compositions can be applicable in the form of parenteral or in the form of injection.Such dose
The preferred isotonic aqueous solution of type or emulsion, as being only made up of active component and a kind of carrier (such as mannitol)
In the case of freeze-dried composition, such solution can use preceding preparation.These pharmaceutical compositions can be nothing
Bacterium, or comprising excipient, or solubilizer, the salt of regulation osmotic pressure.
Present invention also offers a kind of method of regulatory protein kinase activity, including by the protein kinase
Contacted with formula (I) compound.Wherein described protein kinase is selected from wherein described protein kinase and is selected from Abl,
Bcr-Abl。
Present invention also offers a kind of pharmaceutical composition, it includes can preventing or treatment albumen for effective therapeutic dose
Formula (I) compound of Mnase-associated disease state, and pharmaceutically acceptable carrier or diluent.
Present invention also offers application of formula (I) compound in the medicine for being used for treating disease or imbalance is prepared,
Wherein described disease or imbalance is related to protein kinase activity or related with cell proliferative disorder, such as cancer
Disease, inflammation, autoimmune disease, metabolic disease, central nervous system disease and angiocardiopathy.
Specific embodiment
Exemplary of the invention is described more fully below.However, these embodiments are only explanation
Purpose, it is no intended to limit the scope of the present invention.
The following is the definition of the term that can be used in this manual.Unless otherwise indicated, this patent is with regard to group
Or for term provide original definition suitable for specification in the whole text the group or term, no matter
It is single use or is used as the part of another group.
Term " alkyl " refers to straight chain or side chain unsubstituted alkyl, and it has 1-20 carbon atom,
Preferably 1-6 carbon atom, refer in particular to methyl, ethyl, propyl group (including n-propyl and isopropyl),
Butyl (including normal-butyl, isobutyl group, tert-butyl group) etc..
Term " alkynyl " refers to an alkyl for multiple triple carbon-carbon bonds, such as acetenyl, propinyl.
Term " halogen " or " halo " refer to fluorine (fluoro), chlorine (chloro), bromine (bromo),
Iodine (iodo).
Term " heterocyclic aryl " refers to optionally substituted aromatic cyclic groups, and wherein at least contains a carbon
Atom is replaced by other hetero atoms, and hetero atom includes nitrogen, oxygen, sulphur.The nitrogen and sulfur heteroatom also can optional quilts
Oxidation, nitrogen heteroatom also can optionally be quaternized.The heterocyclic group can connect at any hetero atom or carbon atom
Connect.Preferred heterocyclic aryl is included but is not limited to, pyridine, pyrazine, pyrimidine, pyridazine, triazine, furans,
Thiophene, imidazoles, triazole, tetrazolium, thiazole, isothiazole, pyrroles, pyrazoles, oxazole, isoxazoles, benzo
Furans, benzothiazole, benzothiophene, indoles, quinoline, isoquinolin, purine, carbazole, benzimidazole,
Pyrrolopyridine, pyrrolopyrimidine etc..
Term " cycloalkyl " refers to the carbocyclic ring of non-aromatic, including monocyclic, condensed ring or volution.Cycloalkyl is also
Including the ring for being condensed with one or more aromatic rings (have a common key), there are one or more virtues
The cycloalkyl that fragrant ring is condensed can be connected by aromatic rings or non-aromatic ring part with other groups.
Term " Heterocyclylalkyl " refers to nonaromatic heterocycles, and wherein one or more ring member nitrogen atoms are hetero atoms,
Such as oxygen, nitrogen, sulphur atom.Heterocyclylalkyl can include monocyclic or polycyclic (if any 2,3,4 fused rings),
Volution.Preferred Heterocyclylalkyl includes aziridine, azetidine, tetrahydrofuran, thiophane, pyrroles
Wan, oxazolidines, thiazolidine, isothiazolidine, imidazolidine, pyrazolidine, morpholine, thiomorpholine, piperazine,
Piperidines etc..Heterocyclylalkyl also includes the heterocycle condensed with one or more aromatic rings, such as 2,3- dihydrobenzenes
And furans, 1,3- benzodioxolanes, phendioxin, 4- dioxs, benzenedicarboxamide etc..With one or many
The Heterocyclylalkyl that individual aromatic rings is condensed can be connected by aromatic rings or non-aromatic ring part with other groups.
Term " amide groups " refers to group-C (=O) NH-.
Term " cyano group " refers to group-CN.
Term " alkylamino " refers to by an alkyl-substituted amino.
Term " dialkylamine " refers to group by two identical or different alkyl-substituted amino.
Term " carboxyl " refers to group-COOH.
Term " alkane is carbon-based " refers to that group-C (=O) R, wherein R refers to alkyl
" optional " means that the event or situation of subsequent description can occur or not occur, the description
The example that wherein described event of parading one's wealth or situation occur and the example that wherein it does not occur.
" pharmaceutically acceptable carrier " used herein include the whole solvent of any core, decentralized medium, coating,
Antibacterium and antifungal medicine, etc. blend absorption delaying agent etc..Such medium and medicament are used for pharmaceutically active substances
It is well known in the art.Unless any conventional media or medicament are incompatible with Mars composition, it is in treatment group
It is expected during application in compound.The active component of supplement also may be incorporated into composition.
Embodiment 1
4- methyl-N- (4- ((4- methylpiperazine-1-yls) methyl) -3- (trifluoromethyl) phenyl) -3- ((4- (piperidines -3- bases)
Pyrimidine -2-base) acetenyl) benzamide
I) 2- trifluoromethyl-benzyl-alcohols
In there-necked flask, 2- trifluoromethylated benzaldehyde 500g, absolute ethyl alcohol 1500ml, tetrabutyl bromine are added
Change ammonium 50g, stirring and dissolving, and maintain the temperature at 0 DEG C, be dividedly in some parts sodium borohydride 150g, 30g is added every time.
30min is stirred after adding, then is warming up to 40 DEG C, reaction 2h, TLC tracking, reaction completion.It is concentrated under reduced pressure,
500ml water is added, 30min is stirred, the extraction of 1500ml ether is added, washed, after anhydrous magnesium sulfate is dried,
Filtering, concentration, obtains 2- trifluoromethyl-benzyl-alcohol 450g, yield 89%.MS (M+1)=177.04.1HNMR
Data (300MHz, CDCl3)：7.50-7.33 (m, 4H, phenyl ring), 5.87 (s, 1H ,-OH), 4.20 (s,
2H ,-CH2-)。
Ii) 4- nitros -2- trifluoromethyl-benzyl-alcohols
Concentrated sulfuric acid 1L is added in four-hole boiling flask, -20 DEG C are cooled to, stirring is slowly added dropwise concentrated nitric acid 1L.
After stirring 0.5h, 2- trifluoromethyl-benzyl-alcohol 450g are slowly added dropwise, reaction temperature is maintained at -10 DEG C -0 DEG C, 2h
Inside drip off, continue to stir 1h, reaction is completed.Reacted liquid is poured into the mixture of ice and water being stirred vigorously
In, 2h is then stirred for, there is solid to separate out, upper strata acid solution, solid 1000ml second are poured out after standing overnight
Ether is dissolved, point liquid, is washed with saturated sodium bicarbonate solution to neutrality, and anhydrous magnesium sulfate is dried, and concentration is obtained
Solid 4- nitro -2- trifluoromethyl-benzyl-alcohol 236g, yield 42%.MS (M+1)=222.14.1HNMR data
(300MHz, CDCl3)：8.44 (s, 1H, phenyl ring), 8.20 (d, 1H, phenyl ring), 7.47 (d, 1H,
Phenyl ring), 5.87 (s, 1H ,-OH), 4.61 (s, 2H ,-CH2-)。
Iii) 4- nitros -2- trifluoromethyl cylites
4- nitro -2- trifluoromethyl-benzyl-alcohol 75g, toluene 750ml, stirring, ice bath drop are added in there-necked flask
Temperature, is slowly added dropwise PBr332.3ml, after dripping off, continues to stir 2h, TLC tracking.After the completion of reaction, drop
Plus saturated sodium bicarbonate solution, until being released without gas, then divide liquid, upper organic phase is used saturation NaCl again
Solution is washed 3 times, and anhydrous magnesium sulfate is dried, filtering, and concentration obtains 4- nitro -2- trifluoromethyl cylites
50g, yield 52%.MS (M+1)=285.03.1HNMR data (300MHz, CDCl3)：8.44 (s,
1H, phenyl ring), 8.20 (d, 1H, phenyl ring), 7.47 (d, 1H, phenyl ring), 4.56 (s, 2H ,-CH2-)。
Iv) 1- methyl -4- (4- nitros -2- (trifluoromethyl) benzyl) piperazine
The product that previous step reaction is obtained is dissolved in 500ml chloroforms, diisopropylethylamine 80ml is added, stirred,
N methyl piperazine 50g is added dropwise, 60 DEG C are warming up to after dripping off, reaction is overnight.After the completion of reaction, it is concentrated to dryness,
Obtain sticky oily liquids.The dissolving of 500ml ethyl acetate is added, is washed 3 times, anhydrous magnesium sulfate is dried,
Concentrate again, obtain crude product 35g.
V) 4- ((4- methylpiperazine-1-yls) methylene) -3- (trifluoromethyl) aniline
Crude product obtained in the previous step is dissolved in 300ml isopropanols, Raney's nickel 20g is added, H is passed through2Gas
Body, is heated to reflux 3h, and TLC tracking after the completion of reaction, is lowered the temperature, and filtering is concentrated under reduced pressure and removes solvent,
Thick liquid, pillar layer separation are obtained, eluant, eluent is methylene chloride/methanol=9, cut needed for collecting, concentration
After obtain target product 4- ((4- methylpiperazine-1-yls) methylene) -3- (trifluoromethyl) aniline 26g.
MS (M+1)=274.30.1HNMR data (300MHz, DMSO-d6)：7.21 (s, 1H, phenyl ring), 7.06
(d, 1H, phenyl ring), 6.48 (d, 1H, phenyl ring), 5.28 (s, 2H, amino), 3.54 (s, 2H ,-CH2-),
2.48 (m, 4H, piperazine rings), 2.34 (m, 4H, piperazine rings), 2.14 (s, 3H ,-CH3)。
Vi) the iodo- 4- methyl-N- of 3- (4- ((4- methylpiperazine-1-yls) methyl) -3- (trifluoromethyl) phenyl) benzamide
The thionyl chloride iodo- 4- methyl benzoic acids 25g of 250ml, 3- is added in flask, stirring is heated to reflux 6h,
It is concentrated under reduced pressure after doing, adds dry dichloroethanes, removal of solvent under reduced pressure.Chloroform 250ml is sequentially added,
Diisopropylethylamine 20ml, 4- ((4- methylpiperazine-1-yls) methylene) -3- (trifluoromethyl) aniline 26g, heats up
To 60 DEG C, 5h, TLC tracking are reacted.After reaction terminates, it is concentrated under reduced pressure, removes solvent.Add acetic acid second
Ester 200ml dissolves, and washes 3 times, dries, concentration, the solid pillar layer separation for obtaining, and eluant, eluent is
Methylene chloride/methanol=9, the cut needed for collecting, obtain solid 41g after concentration.
This solid is dissolved with acetone 250ml again, monohydrate potassium 25g is added, stirring and dissolving is heated to
50 DEG C, 4h is reacted, filtering, the solid that will be obtained 200ml ethanol dissolves, and 5% NaOH solution is added dropwise
To 8 or so, filtering is dried regulation pH value, obtains white solid 28g, yield 57%.MS (M+1)=518.33.1HNMR data (300MHz, DMSO-d6)：10.32 (s, 1H, acid amides), 8.28-7.21 (m, 6H, benzene
Ring), 3.54 (s, 2H ,-CH2-), 2.48 (m, 4H, piperazine rings), 2.34 (m, 4H, piperazine rings), 2.24
(s, 3H ,-CH3), 2.14 (s, 3H ,-CH3)。
Vii) 2- acetenyls -4- (pyridin-3-yl) pyrimidine
2- bromo- 4- (pyridin-3-yl) pyrimidine 12g, is dissolved in 120mlDMF, adds trimethyl silicane ethyl-acetylene 20ml,
Cuprous iodide 1g, palladium bichloride 0.5g, DIPEA 20ml, is heated to 120 DEG C, instead in closed pressure vessel
After answering 3h, cool down and pour into beaker reaction solution, add ethyl acetate 200ml, wash 3 times, it is anhydrous
Magnesium sulfate is dried, filtering, and concentration obtains 2- trimethyl silicane ethyl-acetylene base -4- (pyridin-3-yl) pyrimidine 8.5g,
Yield：66%.
Previous step product is dissolved in 70mlTHF, tetrabutyl ammonium fluoride 6.6g, normal-temperature reaction 3h is added,
TLC is tracked, and after the completion of reaction, reaction solution is concentrated to dryness.Plus ethyl acetate 100ml dissolvings, washing 2
Secondary, anhydrous magnesium sulfate is dried, filtering, and concentration obtains solid 2- acetenyls -4- (pyridin-3-yl) pyrimidine 5.2g,
Yield 87%.MS (M+1)=182.20.1HNMR data (300MHz, DMSO-d6)：9.24-8.42 (m,
5H, heterocycle), 7.57 (s, 1H, heterocycles), 4.08 (s, 1H, alkynyls).
Viii) 4- methyl-N- (4- ((4- methylpiperazine-1-yls) methyl) -3- (trifluoromethyl) phenyl) -3- ((4- (piperidines -3-
Base) pyrimidine -2-base) acetenyl) benzamide
By 2- acetenyls -4- (pyridin-3-yl) pyrimidine 3g and 3- iodo- 4- methyl-N- (4- ((4- methylpiperazine-1-yls) first
Base) -3- (trifluoromethyl) phenyl) benzamide 8.5g is dissolved in 100mlDMF, adds DIPEA10ml and two
Palladium bichloride 0.1g, stirring is heated to 100 DEG C, reacts 3h, TLC tracking.After reaction terminates, concentration,
Pillar layer separation.Eluant, eluent is methylene chloride/methanol (9/1), and after cut needed for collecting, concentration obtains shallow
Yellow solid is compound described in title, yield 5.4g, yield 58%.MS (M+1)=571.62.1HNMR
Data (300MHz, DMSO-d6)：10.23 (s, 1H, acid amides), 9.24-8.42 (m, 5H, heterocycle), 8.28-7.21
(m, 7H, phenyl ring), 3.34 (s, 2H ,-CH2-), 2.48 (m, 4H, piperazine rings), 2.40 (s, 3H ,-CH3),
2.34 (m, 4H, piperazine rings), 2.14 (s, 3H ,-CH3)。
Embodiment 2
4- methyl-N- (4- ((4- methylpiperazine-1-yls) methyl) -3- (trifluoromethyl) phenyl) -3- ((4- (piperidines -3- bases)
Pyrimidine -2-base) acetenyl) benzamide methanesulfonate preparation
Compound 5.4g obtained by embodiment 1 is dissolved in 250ml acetone, monohydrate potassium 3g is added,
Stirring and dissolving, is heated to reflux 1h, has solid to separate out, cooling, filtering.The solid that will be filtrated to get is dissolved in 500ml
In water, 1% sodium hydroxide solution, regulation pH value to 9 or so, filtering, then the solid that will be obtained is added dropwise
Operation more than repeating is once.
Product after purification is re-dissolved in acetone, appropriate methanesulfonic acid is added, stirring is heated to reflux 1h, has
Solid is separated out, cooling, and filtering is dried, and is obtained final product.
Embodiment 3
The preparation of hydrochloride
By purified 4- methyl-N- (4- ((4- methylpiperazine-1-yls) methyl) -3- (trifluoromethyl) benzene
Base) -3- ((4- (piperidines -3- bases) pyrimidine -2-base) acetenyl) benzamide is dissolved in ethanol, adds 10% hydrochloric acid molten
Liquid, stirring is heated to 60 DEG C, reacts 2h, and after reaction terminates, vacuum distillation removes ethanol, adds acetone,
Stirring 30min, has solid to separate out, and filters, and dries, and obtains final product.
Embodiment 4-18
Prepare compound
Following compound is prepared according to the similar method described in embodiment 1：
Embodiment 19
N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidine -2-base) acetenyl) phenyl) -1- (4- methyl piperazines -1-
Base) -7- (trifluoromethyl) -2,3- dihydro -1H- indenes -5- formamides
I) synthesis of the bromo- 7- trifluoromethyls -2,3- indenones of 5-
The bromo- 2- trifluoromethylbenzoic acids 134.5g of 4- are dissolved in 750ml thionyl chlorides, stirring, are heated to reflux 4h.
After decompression boils off solvent thionyl chloride, product is steamed into 133 DEG C/10mmHg with decompression rectification device, obtain 4-
Bromo- 2- trifluoromethyl benzoyl chlorides 133.9g, yield 90%.
The bromo- 2- trifluoromethyl benzoyl chlorides 28.8g of 4- are dissolved in 100ml dichloroethanes, and three are added dropwise at room temperature
In the dichloroethanes suspension of aluminium chloride 13.3g.Then suspension is placed in the dark, and is cooled with an ice bath,
Ethylene gas 3h is passed through, until acyl chloride reaction is complete.Reaction solution is stirred at room temperature overnight.Reaction solution is cold
But to 0 DEG C, then it is quenched with the hydrochloric acid solution 30ml of 4M.Liquid, water is divided to be extracted with dichloroethanes.Close
And organic phase, respectively with water, saturated sodium bicarbonate solution, saturated common salt water washing is dried, filtering, concentration,
Crude product is obtained, the next step is directly used in.
After alchlor 159.6g, sodium chloride 42.1g mixing, 130 DEG C of pulps are heated to.Add previous step
The bromo- 2- trifluoromethyls chloropropyl ketone of 4- that reaction is obtained, stirs and is warmed up to 180 DEG C, reacts 6h.Instead
Liquid ice and concentrated hydrochloric acid 120ml is answered to be quenched.Then extracted with dichloroethanes, organic phase uses water, saturation respectively
Sodium acid carbonate, saturated common salt water washing is dried, and filtering is concentrated under reduced pressure.Pillar layer separation, eluant, eluent is stone
Oily ether/ethyl acetate=4, obtain bromo- 7- trifluoromethyl -2 of solid 5-, 3- indenone 15.3g, yield 55%.
MS (M+1)=278.0.1HNMR data (300MHz, CDCl3)：7.61 (s, 1H), 7.44 (s, 1H),
3.06 (m, 2H), 2.54 (m, 2H).
Ii) the synthesis of 1- (4- methyl piperazines base) -7- trifluoromethyl -2,3- dihydroindene -5- formic acid
Bromo- 7- trifluoromethyl -2 of 5-, 3- indenones 27.9g is dissolved in 250mlDMF, adds cuprous cyanide
13.5g, stirring is heated to backflow, reacts 24h.After reaction terminates, room temperature is cooled to, reaction solution is being stirred
Mix down and pour into 1000ml water, extracted 3 times with 500ml ethyl acetate, collect organic phase, wash 2 times,
Anhydrous magnesium sulfate is dried, filtering, concentration.Pillar layer separation, eluant, eluent is petrol ether/ethyl acetate=4, is obtained
To solid 5- cyano group -7- trifluoromethyl -2,3- indenone 10.1g, yield 45%.MS (M+1)=225.0.
5- cyano group -7- trifluoromethyl -2,3- indenones 22.5g is dissolved in 100ml methyl alcohol, after dissolving, slowly
It is dividedly in some parts sodium borohydride 4.6g.4h is stirred at room temperature, filters, concentration.Residue is dissolved in ethyl acetate, plus
Enter saturated solution of sodium bicarbonate to wash 2 times, saturated salt is washed 2 times, anhydrous magnesium sulfate is dried, filtering, concentration
Obtain 5- cyano group -7- Trifluoromethyl-1s-hydroxyl -2,3- dihydroindene 21.1g, yield 93%.MS (M+1)=227.0.
5- cyano group -7- Trifluoromethyl-1s-hydroxyl -2,3- dihydroindene 22.1g are dissolved in 50ml dichloromethane,
Sulphinyl chlorine 10.2ml is added dropwise under ice cooling, 4, is dripped off in 20min.Ice bath is removed, reaction solution is flowed back
5h, cooling, concentration.Reaction solution residue is dissolved in ethyl acetate, saturated solution of sodium bicarbonate washing 2 is added
Secondary, saturated salt is washed 2 times, and anhydrous magnesium sulfate is dried, and filtering obtains 5- cyano group -7- trifluoromethyls after concentration
The chloro- 2,3- dihydroindene of -1-.
5- cyano group -7- Trifluoromethyl-1s obtained above-chloro- 2,3- dihydroindene is dissolved in 100ml chloroforms,
1- methyl piperazine 9.3g are added, potassium carbonate 20g, agitating heating is reacted overnight at 60 DEG C.After reaction terminates
Reacting liquid filtering, washing are dried, concentration.With silica gel column chromatogram separating purification, with methylene chloride/methanol
It is eluant, eluent, obtains the dihydro -1H- indenes 16.7g of 5- cyano group -7- Trifluoromethyl-1s-(4- methylpiperazine-1-yls) -2,3,
Yield 58%.MS (M+1)=309.1.
Dihydro -1H- indenes (15.5g, 0.05mol) of 5- cyano group -7- Trifluoromethyl-1s-(4- methylpiperazine-1-yls) -2,3 is added
To in 0.1M sodium hydroxide solutions (100ml), 100 DEG C are heated to, be stirred overnight.After cooling, 0.1M is added
Hydrochloric acid solution the pH value of reaction solution is adjusted to 8.0, there is white solid to separate out, filter.By consolidating for filtering
Body recrystallizing methanol, obtains 1- (4- methylpiperazine-1-yls) -7- trifluoromethyl -2,3 dihydroindene -5- formic acid 10g,
Yield 61%.MS (M+1)=328.2.1HNMR data (300MHz, DMSO-d6)：8.44 (s, 1H,
Phenyl ring), 8.20 (d, 1H, phenyl ring), 7.47 (d, 1H, phenyl ring), 4.56 (s, 2H ,-CH2-)。
Iii) N- (the iodo- 4- aminomethyl phenyls of 3-) -1- (4- methylpiperazine-1-yls) -7- (trifluoromethyl) -2,3- dihydro -1H- indenes
- 5- formamides
In ice bath, by 1- (4- methylpiperazine-1-yls) -7- trifluoromethyl -2,3 dihydroindene -5- formic acid 32.8g are molten
In 200mlDMF, 1- hydroxy benzo triazole 16.1g are added, are subsequently added DCC 24.6g, stir 1h,
DMF (200ml) solution of the iodo- 4- methylanilines 28g of 3- is added dropwise, then 24h is stirred at 25 DEG C.Filtering
Not tolerant is removed, filtrate is concentrated under vacuum.Residue 600ml ether dissolutions, filtering, then distinguish
With 10%HCl solution (2 × 100mL), saturation NaHCO3Solution (2 × 100mL) and the saturated common salt aqueous solution
(2 × 50mL) is washed, and anhydrous magnesium sulfate is dried.Column chromatography separating purification is used after concentration, with petroleum ether/EtOAc
(1:1) it is eluant, eluent, obtains target product 27.7g, yield 51%.MS (M+1)=544.4.1HNMR data
(300MHz, DMSO-d6)：10.21 (s, 1H, acid amides), 8.08-7.47 (m, 5H, phenyl ring), 4.04 (m,
1H), 3.21 (m, 2H), 2.48 (m, 4H, piperazine rings), 2.33 (m, 4H, piperazine rings), 2.25 (m,
2H), 2.21 (s, 3H ,-CH3), 2.14 (s, 3H ,-CH3)。
Iv) N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidine -2-base) acetenyl) phenyl) -1- (4- methyl piperazines -1-
Base) -7- (trifluoromethyl) -2,3- dihydro -1H- indenes -5- formamides synthesis
By 2- acetenyls -4- (pyridin-3-yl) pyrimidine 3g and N- (the iodo- 4- aminomethyl phenyls of 3-) -1- (4- methyl piperazines -1-
Base) -7- (trifluoromethyl) -2,3- dihydro -1H- indenes -5- formamides 9g is dissolved in 100mlDMF, adds
DIPEA10ml and palladium chloride 0.1g, stirring is heated to 100 DEG C, reacts 3h, TLC tracking.Reaction
After end, concentration, pillar layer separation.Eluant, eluent is methylene chloride/methanol (9/1), after cut needed for collecting,
Concentration, obtains compound described in light yellow solid as title, yield 4.7g, yield 48%.
MS (M+1)=571.62.1HNMR data (300MHz, DMSO-d6)：10.23 (s, 1H, acid amides), 9.24 (s,
1H, pyridine ring), 9.01 (d, 1H, pyrimidine rings), 8.70 (d, 1H, pyridine rings), 8.42 (d, 1H, pyridine
Ring), 8.07 (d, 1H, pyrimidine rings), 7.89 (m, 2H, phenyl ring), 7.46 (m, 2H, phenyl ring), 7.23 (m,
1H, phenyl ring), 4.04 (m, 1H ,-CH-), 3.21 (m, 2H), 2.71-2.58 (m, 8H, piperazine ring),
2.40 (s, 3H ,-CH3), 2.31 (m, 2H), 2.14 (s, 3H ,-CH3)。
Embodiment 20-28
Prepare compound
Synthesize following compound according to the similar method of embodiment 13：
Embodiment 29
Pharmaceutical formulation
The invention provides several pharmaceutical compositions for treating or preventing the disease related to protein kinase
Formula, its pharmaceutical composition has tablet, capsule, injection, aerosol etc..Below with " active ingredient
Thing " represents the compound shown in the present invention.
Embodiment 30
External activity test
The inhibitory action of the regulation of compound for protein kinase activity of the invention and cell propagation is surveyed
Examination, (human promyelocytic leukemia is thin for the K562 (human leukemia cell) being mutated to BCR-ABL and HL-60
Born of the same parents) it is tested, its method is as follows：
Take the logarithm two kinds of cells in growth period, be made single cell suspension, be divided into 2 groups:Blank control group,
2 μm of ol/L active component groups.Cell suspension final concentration of 5 × 104/mL.Enter 96 orifice plates with 200 μ L/ holes kinds.
It is placed in the RPMI RPMI-1640s containing 10% hyclone, in 37 DEG C, 5%CO2Trained respectively in incubator
72h is supported, every group sets 3 multiple holes per concentration, and nutrient solution is added in time according to cell growth status.Cell end
Only 4h adds 5g/LMTT20 μ L before culture, continues to add 150 μ L dimethyl sulfoxide (DMSO)s (DMSO) after cultivating 4h
Terminating reaction, vibrates 10min, and the cell suspension for taking abundant mixing counts cell number on blood counting chamber,
Cell count is with n × 104/ mL is represented, and calculates inhibiting rate.
The reactive compound of table 1 suppresses situation to cytoactive
Can be seen that compound shown in the embodiment of the present invention from result shown in table 1 all has suppression leukaemia thin
The ability of cytoactive, it is especially better to people in loop.
Presently preferred embodiments of the present invention is the foregoing is only, substantial technological of the invention is not limited to
Context, substantial technological content of the invention is broadly to be defined in the right of application, is appointed
What other people technology entities that complete or method, if with phase completely defined in the right of application
Together, also or a kind of equivalent change, will be considered as being covered by among the right.
Claims (9)
1. it is a kind of to contain compound or its pharmaceutically acceptable salt that following formula (I) is represented：
Wherein
Linking group L is-NHC (O)-or-C (O) NH-；
Ring A represents 5,6 or 7 yuan of nitrogenous or oxygen containing Heterocyclylalkyls；
R1Selected from hydrogen, C1-C4Alkyl, cycloalkyl, alkoxy, hydroxyl, amino, by alkyl-substituted amino,
Alkyl carbonyl；
R2, R3Independently selected from hydrogen, C1-C4Alkyl, or link together and adjacent phenyl ring forms five-membered ring；
R4It is hydrogen, fluorine or trifluoromethyl；
R5It is the heterocycle of nitrogenous, sulphur or oxygen, or fused ring compound is formed with pyrimidine.
2. compound according to claim 1 or pharmaceutically acceptable salt, wherein
Ring A preferably is selected from pyrrolidines, piperazine, homopiperazine, morpholine；
R1It preferably is selected from hydrogen, methyl, isopropyl, ethoxy, dimethylamino；
R2, R3Hydrogen preferably is selected from, or is linked together and adjacent phenyl ring formation five-membered ring；
R4It is hydrogen, fluorine or trifluoromethyl；
R5It preferably is selected from pyridine radicals, pyrrole radicals, thienyl；Or form purine radicals, thio-purine base with the pyrimidine being connected.
3. compound according to claim 2 or its pharmaceutically acceptable salt, wherein described compound is excellent
It is selected from：
4. the pharmaceutically acceptable salt of the compound according to claim any one of 1-3, or containing at least
One basic salt-forming groups, with its into the acid of salt can be pharmaceutically conventional inorganic acid or organic acid, including
Inorganic acid：Hydrochloric acid, sulfuric acid, phosphoric acid；Organic carboxyl acid：Acetic acid, propionic acid, trifluoroacetic acid, glycolic, amber
Amber acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, oxalic acid, various natural or synthesis
Amino acid, benzoic acid, salicylic acid, 4-ASA, mandelic acid, cinnamic acid, nicotinic acid, isonicotinic acid；
Organic sulfonic acid：Methanesulfonic acid, TFMS, ethyl sulfonic acid, 2- ethylenehydrinsulfonic acids, benzene sulfonic acid, to toluene sulphur
Acid, 2- naphthalene sulfonic acids.When there is multiple basic groups, many acid-addition salts can be generated.
5. a kind of pharmaceutical composition, its at least one any one of claim 1-4 for including effective therapeutic dose can be pre-
The compound of anti-or treatment albumen Mnase-associated disease state, and pharmaceutically acceptable carrier or diluent.
6. the compound according to claim any one of 1-4 is in the medicine for treating disease or imbalance is prepared
Application, wherein described disease or imbalance be it is related to protein kinase activity or with cell proliferative disorder correlation
's.
7. application according to claim 6, wherein the disease related to protein kinase is selected from cancer with imbalance
Disease, inflammation, autoimmune disease, metabolic disease, central nervous system disease and angiocardiopathy.
8. application according to claim 7, wherein described disease is related to cell proliferative disorder various
Cancer, it is selected from leukaemia, lymthoma, prostate cancer, colon cancer, breast cancer, liver cancer, bronchiolar carcinoma, courage
Pipe cancer, stomach cancer, oophoroma, cervical carcinoma, lung cancer, ED-SCLC, kidney, carcinoma of urinary bladder, cancer of pancreas, stomach and intestine
Road mesenchymoma, spongioblastoma, brain tumor, melanoma, gonioma, neuroblastoma fat meat
Knurl, chondrosarcoma, osteogenic sarcoma, angiosarcoma, endotheliosarcoma, muscle tumor, one or more in chordoma.
9. application according to claim 8, wherein described autoimmune disease is selected from patients with type Ⅰ DM,
Autoimmune Thyroid disorder and alzheimer's disease.
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