CN108484491A - A kind of acrylate compounds and application thereof - Google Patents

A kind of acrylate compounds and application thereof Download PDF

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CN108484491A
CN108484491A CN201810481958.5A CN201810481958A CN108484491A CN 108484491 A CN108484491 A CN 108484491A CN 201810481958 A CN201810481958 A CN 201810481958A CN 108484491 A CN108484491 A CN 108484491A
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pharmaceutically acceptable
acceptable salt
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CN108484491B (en
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廖杰远
陈先红
邹德超
孙志国
王珂
陈晓光
谈敦潮
杜立民
季鸣
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Beijing Micro Medical Intelligence Information Technology Co Ltd
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Abstract

The present invention relates to acrylate compounds shown in Formulas I and its preparing for preventing or treating and the purposes in IL 17F relevant diseases or the drug of symptom.

Description

A kind of acrylate compounds and application thereof
Technical field
The invention belongs to field of pharmaceutical chemistry technology, more particularly to a kind of acrylate compounds and application thereof.
Background technology
IL-17 (the interleukin 17, IL-17) family include 6 kinds of interleukins (IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F) and its receptor (IL-17RA, IL-17RB, IL-17RC, IL-17RD, IL-17RE and IL-17RF) (Gaffen, S.L. etc., immunology communicate (Nature reviews.Immunology), and 2009, (9)：556-567), wherein IF-17F is also referred to as IL-24 or ML-1, is the member of IL-17 cytokine families.IF-17F with IL-17A about 55% is identical, and be considered with IL-17A share identical receptor (Kolls and Linden 2004, Immunity, 21,467-476；Hymowitz etc., EMBO J., 2001,20 (19), 5332-5341；Kuestner etc., Journal of Immunology, 2007,179,5462-5473).The two can form homodimer and heterodimer Albumen generates (Wright etc., J Biol Chem.2007,282 (18), 13447- by people's CD4+T cells of activation 13455)。
The prior art has shown：IL-17F can be related to the generation of a variety of diseases, includes being mediated by abnormal immune reaction Disease, such as rheumatoid arthritis and respiratory inflammation and organ-graft refection and tumour or cancer；Correspondingly IL-17F presses down Preparation be likely to become these diseases promising therapeutic agent (Huichao Yan etc., Immuno-Gastroenterology, 2012,1:100-103；Yuting Ma etc., Journal of Experimental Medicine, 2011,208 (3)：491- 503).The prior art it has been shown that IL-17F it is related to autoimmune disease (Iwakura, Y., H.Ishigame etc., Immunity, 2011,34 (2)：149-162).IL-17F antagonisms to the related (Kawaguchi of antasthmatic protective effect Deng 2006, J.Allergy Clin.Immunol.117 (4)；795-801), and IL-17F also rises in arthritis Neo-Confucianism Act on (Lubberts, Current Opinion in Investigational Drugs, 2003,4 (5)：572-577).
The prior art is it has been reported that some IL-17F inhibitor, for example, some WO2014065413 report triazole type Derivative He isoxazole derivant as RORγAcceptor inhibitor, so as to inhibit the differentiation and activation of Th17 cells, and And inhibiting effect is generated to IL-17.WO201400944 and WO2016014918 report about aryl sultam derivative and As RORc conditioning agents, such compound is mainly used for treating autoimmune disease benzimidazoles derivative.
WO2016213676 reports substitution 2,3- dihydro -1H- 1-Indanone class formations as RORγt/RORγReceptor antagonist Agent, such compound can be used for adjusting RORγt/RORγActivity and for treating RORγt/RORγThe disease and illness of mediation. WO2016072402 is reported about cyclic amine derivatives to TH17 cell receptors RORγtThere is inhibiting effect, to inhibit TH17 Cell differentiation reduces IL-17 secretions.WO2016120849 reports methoxy-substituted pyrrolopyridines and is used for RORγAcceptor inhibitor, to reduce the amount of I L-17.However, the inhibiting effect of these compounds is still not satisfactory enough, or There are selective problems by person, and therefore, still there is an urgent need to develop novel I L-17 inhibitor especially IL-17F in the prior art Inhibitor is used for the prevention and/or treatment of relevant disease.
Invention content
The present inventor by research it was unexpectedly found that, Formulas I compound represented or its pharmaceutically acceptable salt tool There is unexpected IL-17F inhibiting effect：
Wherein, Q is selected from O and N；X, Y, Z are each independently selected from C, O, S and N；
R1And R2It is identical or different, independently selected from hydrogen, unsubstituted or substituted alkyl radical, unsubstituted or substituted alkenyl, not The naphthenic base of substitution or substitution, unsubstituted or substituted aryl, unsubstituted or substituted aryl alkyl, unsubstituted or substituted acyl Base；Alternatively, R1And R2Oxygen adjacent thereto forms acetal；
R3Selected from hydrogen, unsubstituted or substituted alkyl radical, unsubstituted or substituted alkenyl, unsubstituted or substituted naphthenic base, Unsubstituted or substituted aryl, unsubstituted or substituted acyl group；
R4Selected from hydrogen, unsubstituted or substituted alkyl radical, unsubstituted or substituted alkenyl, unsubstituted or substituted naphthenic base, Unsubstituted or substituted aryl, unsubstituted or substituted aryl alkyl；
R5Selected from hydrogen, halogen, cyano, nitro, unsubstituted or substituted hydroxyl, unsubstituted or substituted alkyl radical.
In some preferred embodiments, at least one in X, Y, Z is N, but is asynchronously N.
In some preferred embodiments, Q is selected from O, R3And R4Oxygen adjacent thereto forms lactone.
In some preferred embodiments, R1And R2Oxygen adjacent thereto forms acetal.
In some preferred embodiments, R1And R2It is identical.
In some preferred embodiments, R1And R2Independently selected from hydrogen, C1-C3 alkyl and C1-C5 alkyl acyls.
In some preferred embodiments, R1And R2Oxygen adjacent thereto forms acetal shown in following formula：
Wherein, R6、R7Independently selected from hydrogen, C1-C5 alkyl, C2-C5 alkenyls, substituted or unsubstituted phenyl and phenyl C2- C5 alkenyls.
In some preferred embodiments, R6、R7C adjacent thereto forms 3~6 membered rings.
In some preferred embodiments, R5Selected from hydrogen, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, bromine and iodine.
In some preferred embodiments, X, Y, Z are C or N.
In some particularly preferred embodiments, compound of formula I of the invention is particular compound selected from the following：
Therefore, in a first aspect, the present invention provides above-mentioned compound of formula I or its pharmaceutically acceptable salts.For example, working as When QR4 is hydroxyl, the salt can be the salt that compound of formula I is formed with alkali metal, alkaline-earth metal, transition metal or amine；As X, Y Or having the N atomic time in Z, the salt can be that compound of formula I is formed by salt with organic acid or inorganic acid.
On the other hand, the present invention provides a kind of pharmaceutical compositions, and it includes the compound of formula I or its pharmacy of the present invention Upper acceptable salt and optional pharmaceutically acceptable carrier or excipient.
It yet still another aspect, the present invention also provides the above-mentioned compound of formula I of the present invention or its pharmaceutically acceptable salt to exist Prepare the purposes in the secretion and active drug for inhibiting IL-17F.
Inventors have surprisingly found that the compound and its pharmaceutically acceptable salt of Formulas I, which have, inhibits interleukin-17 F's The effect of secretion, therefore can be used as the conditioning agent of interleukin-17 F.
The application also demonstrates, also having prevention and treatment tumour such as the compound of Formulas I and its pharmaceutically acceptable salt Effect, therefore can be as the medicinal application of prevention and treatment tumour.Specifically, the tumour includes solid tumor and non-physical knurl, The tumour includes but not limited to melanoma, cancer of pancreas, colorectal cancer, lung cancer, liver cancer, gastric cancer, laryngocarcinoma, nasopharyngeal carcinoma, cancer of the esophagus, more Hair property myeloma, lymph cancer, leukaemia, carcinoma of urinary bladder, prostate cancer, cholangiocarcinoma, cervical carcinoma, oophoroma, breast cancer, carcinoma of endometrium, Cutaneum carcinoma, head and neck cancer, gallbladder cancer, kidney etc..It is particularly preferred that the tumour is colorectal cancer, gastric cancer, carcinoma of urinary bladder and breast cancer.
On the other hand the compound of formula I of the present invention or its pharmaceutically acceptable salt also there are prevention and treatment itself to exempt from The effect of epidemic disease, therefore, it is possible to the medicinal application as prevention and treatment autoimmune disease.Specifically, it is described itself Immunological diseases include but not limited to lupus erythematosus, psoriasis, rheumatoid arthritis, chorionitis etc..It is particularly preferred that it is described from Body immunological diseases are selected from lupus erythematosus and psoriasis.
In the present invention, the pharmaceutically acceptable salt of compound of formula I means to be suitble within a reasonable range of medical judgment For being contacted with human body and lower animal tissue, without unsuitable toxicity, irritation, allergy etc., with rational interests/ Hazard ratio matches.
Pharmaceutically acceptable salt is well known in the art.For example, S.M.Berge etc. is in J.Pharmaceutical Sciences is described in detail pharmaceutically acceptable salt in 1977,66,1-19, is incorporated herein by reference herein.The present invention The salt of compound includes from suitable those of inorganic and organic base derivative.Inorganic base salts include and ammonia, alkali metal, alkaline-earth metal Or the salt that transition metal is formed, such as ammonium salt and lithium salts, sodium salt, sylvite, calcium salt, zinc salt, molysite, ferrous salt etc..Organic base Salt includes amine salt, including the salt that compound of formula I is formed with primary, secondary or tertiary amine, can be selected from the salt formed with following organic base：Example Such as arginine, ethylenediamine, triethylamine, caffeine, glycine betaine, ethanol amine, trimethylamine, piperidines.
Specific implementation mode
In the present invention, compound of formula I is as follows：
In some preferred embodiments, Q is selected from O.In some preferred embodiments, X, Y, Z are selected from C or N.
In some preferred embodiments, R1And R2It is identical；It is particularly preferred that R1And R2Independently selected from hydrogen, C1-C3 Alkyl or C1-C5 alkyl acyls.
In some preferred embodiments, R1And R2Oxygen adjacent thereto forms acetal shown in following formula：
Wherein, R6、R7Independently selected from hydrogen, C1-C5 alkyl, C2-C5 alkenyls, substituted or unsubstituted phenyl, phenyl C2- C5 alkenyls；Alternatively, R6、R7C adjacent thereto forms 3~6 membered rings.
In some preferred embodiments, R3Selected from hydrogen, methyl, ethyl, propyl, isopropyl.
In some preferred embodiments, R4Selected from hydrogen, methyl, ethyl, propyl, isopropyl.
In some preferred embodiments, R3And R4Oxygen adjacent thereto is at lactone.
In some preferred embodiments, R5Selected from hydrogen, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, bromine, iodine.
In preferred embodiments, compound of formula I below is provided：
Wherein, at least one in X, Y, Z is N, but is asynchronously N；R1Or R2It is identical, independently selected from hydrogen, methyl, ethyl, Propyl, isopropyl or C1-C5 alkyl acyls；R3Selected from hydrogen, methyl, ethyl, propyl, isopropyl；R4Selected from hydrogen, methyl, ethyl, Propyl, isopropyl；R5Selected from hydrogen, methyl, ethyl, propyl, isopropyl, nitro, fluorine, chlorine, bromine and iodine.Formula in these cases In Compound I, R1And R2Acetal, and R are not formed3And R4Also lactone is not formed.
Above-mentioned typical compound is shown in Table 1.
Table 1
At some specific aspects, compound of formula I of the invention has following formula I-2 structures：
Wherein, R1With R2Can be identical, it is independent to be selected from hydrogen, methyl, ethyl, propyl, isopropyl or C1-C5 alkyl acyls；
R5Selected from hydrogen, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, bromine, iodine.
That is, in compound of formula I in these cases, R3And R4Form lactone.
Typical compound shown in Formulas I -2 is shown in Table 2.
Table 2
At some specific aspects, compound of formula I has following formula I-3 structures：
Wherein, R6、R7Independently selected from hydrogen, C1-C5 alkyl, C2-C5 alkenyls, substituted or unsubstituted phenyl, phenyl C2- C5 alkenyls；
R3Selected from hydrogen, methyl, ethyl, propyl, isopropyl；
R4Selected from hydrogen, methyl, ethyl, propyl, isopropyl.
R5Selected from hydrogen, methyl, ethyl, propyl, isopropyl.
That is, in compound of formula I in these cases, R1And R2Form acetal.
Typical compound shown in Formulas I -3 is shown in Table 3.
Table 3
At some specific aspects, compound of formula I has following formula I-4 structures：
Wherein, R3Selected from hydrogen, methyl, ethyl, propyl, isopropyl；
R4Selected from hydrogen, methyl, ethyl, propyl, isopropyl；
R5Selected from hydrogen, methyl, ethyl, propyl, isopropyl；
N is selected from 1,2,3 and 4.
That is, in compound of formula I in these cases, R1And R2Acetal is formed, and substituent group thereon forms 3~6 yuan Ring.
Typical compound shown in Formulas I -4 is shown in Table 4.
Table 4
At some specific aspects, compound of formula I has following formula I-5 structures：
Wherein, R6、R7Independently selected from hydrogen, C1-C5 alkyl, C2-C5 alkenyls, substituted or unsubstituted phenyl, phenyl C2- C5 alkenyls；
R5Selected from hydrogen, methyl, ethyl, propyl, isopropyl.
That is, in compound of formula I in these cases, R1And R2Form acetal, and R3And R4Form lactone.
Typical compound shown in Formulas I -5 is shown in Table 5.
Table 5
At some specific aspects, compound of formula I has following formula I-6 structures：
Wherein, R5Selected from hydrogen, methyl, ethyl, propyl, isopropyl；
N is selected from 1,2,3 or 4.
That is, in compound of formula I in these cases, R1And R2Acetal is formed, substituent group thereon forms 3~6 membered rings, And at the same time R3And R4Form lactone.
Typical compound shown in Formulas I -6 is shown in Table 6.
Table 6
In the present invention, compound of formula I can be prepared in accordance with the following methods：
First, starting material D- (-)-quininic acid is in the presence of a catalyst at lactone, while introducing protecting group at 3,4 and obtaining To intermediate 1, intermediate 1 carries out esterification with intermediate 2 and obtains intermediate 3, and intermediate 3 under alkaline condition, carries out ester Hydrolysis obtains intermediate 4, and in acid condition, further Deprotection obtains type I compound to intermediate 4.
Reaction process is as follows：
Wherein：
`R1、`R2、`R3、`R4、`R5Definition respectively with R in Formulas I1、R2、R3、R4、R5、Define identical, other variable Xs, Y, Z Definition it is identical with Formulas I；L is halogen or hydroxyl selected from fluorine, chlorine, bromine, iodine.
In the synthetic route of the present invention, when preparing intermediate 3, usually it is there are two types of method at the method for ester：In the middle It, can be in conventional condensing reagents (such as N, N`- dicyclohexylcarbodiimide (DCC), 1- ethyls-(3- dimethyl when mesosome 2 is carboxylic acid Aminopropyl) carbodiimide (EDC) etc.) in the presence of at ester；It, can (example under alkaline condition when intermediate 2 is corresponding carboxylic acid halides Such as pyridine, triethylamine, N, N- diisopropylethylamine, 1,8- diazacyclos [5,4,0] hendecene -7 etc.) directly at ester.
In synthetic method of the present invention, by intermediate 3 carry out ester hydrolysis used in alkali can be lithium hydroxide, sodium hydroxide, Potassium hydroxide etc.；It can be aqueous hydrochloric acid solution, aqueous sulfuric acid, trifluoroacetic acid aqueous solution etc. that intermediate 4, which is deprotected used acid,.
In the present invention, the saturated straight chain or branched hydrocarbyl of 1 to 12 carbon atom of term " alkyl " expression, preferably 1 to 6 The saturated straight chain or branched hydrocarbyl of a carbon atom, the saturated straight chain or branched hydrocarbyl of more preferably 1 to 5 carbon atom are especially excellent It is selected as the saturated straight chain or branched hydrocarbyl of 1 to 4 carbon atom, particularly preferred methyl, ethyl, propyl, isopropyl.Alkyl group Example include but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, sec-butyl, tertiary butyl, amyl, isopentyl, 2- methyl butyls, neopentyl, hexyl, heptyl, octyl.
In the present invention, term " alkenyl " indicates the monoradical that hydrocarbon part is derived from by removing single hydrogen atom, Middle hydrocarbyl portion is respectively provided at least one carbon-carbon double bond and includes 2 to 12 carbon atoms.Preferred alkenyl is C2-C6 alkene Base, more preferable C2-C5 alkenyls.Representative alkenyl includes but not limited to vinyl, acrylic, cyclobutenyl, 1- methyl-2-butenes- 1- bases, heptenyl and similar group.
In the present invention, term " naphthenic base " indicates that saturated carbon ring compound has 3 to 12 annular atoms, preferred cycloalkanes Base has 3 to 6 carbon atoms, the more preferably naphthenic base with 3 to 5 carbon atoms.The example of naphthenic base includes but not limited to ring Propyl, cyclobutyl, cyclopenta, cyclohexyl.
In the present invention, term " acyl group " includes the derivative residue to acid, which includes but not limited to carboxylic acid, amino first Acid, carbonic acid, sulfonic acid and phosphoric acid.Example includes aliphatic Oxo, aromatics carbonyl, aliphat sulfonic group.The example of aliphatic Oxo Including but not limited to, acetyl group, propiono, bytyry and similar group.Preferred acyl group is alkyl acyl in the present invention, especially It is C1-C6 alkyl acyls.
In the present invention, term " halogen " refers to fluorine, chlorine, bromine, iodine.
In the present invention, term " aryl " refers to the monocyclic, bicyclic or tricyclic carbon-loop system with 1 to 3 aromatic ring, preferably The aryl that carbon atom number is 6 to 14, including but not limited to, phenyl, naphthalene, tetralyl, anthryl and similar group.
In the present invention, term " aryl alkyl " refers to investing parent by alkyl as defined herein as used herein The aryl as defined herein of molecule.Example includes but not limited to benzyl, phenethyl and similar group.
In the present invention, term " substitution " refers to that the substituted base of one, two or three or more hydrogen atom is only thereon On the spot replace, which includes but not limited to, halogen ,-OH, by protection hydroxyl ,-NO2、-CN、-NH2, protected amino, Alkoxy etc..Preferred substituent group includes halogen ,-OH, C1-C4 alkyl, C1-C4 alkoxies ,-NO2, acetyl group.
The present invention also provides a kind of pharmaceutical composition, including compound of formula I or its pharmaceutically acceptable salt and appointing The pharmaceutically acceptable auxiliary material (excipient or diluent) of choosing.
In the present invention term " pharmaceutical composition " refer to include be suitable for required particular dosage form arbitrary and all molten Agent, diluent or other liquid excipients, dispersion or suspension aids, surfactant, isotonic agent, thickening or emulsifier, anti-corrosion Agent, solid binder, lubricant etc..Remington`s Pharmaceutical Sciences,Sixteenth Edition, E.W.Maetin (Mack Publishing Co., Easton, Pa., 1980) is disclosed for preparing pharmaceutically acceptable group Close the various carriers of object and the known technology for its preparation.In addition to any conventional carrier medium is incompatible with the compounds of this invention In addition, it such as generates any undesirable biological effect or pharmaceutically acceptable combination is interacting at harmful way Any other component of object, its use are covered within the scope of the invention.Potentially act as the material of pharmaceutically acceptable carrier Some examples of material include, but are not limited to ion-exchanger；Aluminium oxide；Aluminum stearate；Lecithin；Buffer substance, such as：Phosphorus Hydrochlorate；Glycine；Sorbic acid or potassium sorbate；The inclined glycosides glyceride mixtures of saturated vegetable fatty acid；Water；Salt or electrolyte, example Such as：Disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt；Colloidal silicon dioxide；Magnesium trisilicate；Polyvinylpyrrolidone；Poly- third Olefin(e) acid ester；Carbohydrate, such as lactose, dextrose and saccharose；Starch, such as cornstarch and potato starch；Cellulose and its spread out Biology, such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate；Gelatin；Talcum；Excipient, for example, cocoa butter and Suppository wax；Oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil；Glycol, such as Propylene glycol or polyethylene glycol；Esters, such as ethyl oleate and ethyl laurate；Agar；Pyrogen-free water；Isotonic saline solution；Ethyl alcohol； And other nontoxic compatible lubricants, such as NaLS and magnesium stearate；According to the judgement of formulation scientist, There may also be colorant, releasing agent, coating agent, sweetener, flavoring agent and fragrance, preservative and antioxidants in composition.
The present invention also provides a kind of pharmaceutical preparation, including compound of formula I or its pharmaceutically acceptable salt and optionally Pharmaceutically acceptable excipient or diluent, the compounds of this invention or its salt can be formulated as according to customary preparation methods Traditional drug formulations, such as capsule, tablet, pill, granule, emulsion, mixed floating agent, injection, drops etc..
The inventors discovered that compound of formula I and its pharmaceutically acceptable salt of the invention, which have, inhibits interleukin-17, especially It is the effect of the secretion of interleukin-17 F, and can prevent and treat tumour.The experimental results showed that there is portion in compound of formula I Point compound is in a concentration of 0.5 μM/L to the inhibiting rate of interleukin 17F close to 70%；To black under the dosage of 20mg/kg The tumours such as plain tumor, cancer of pancreas, colorectal cancer, lung cancer have good inhibiting effect, more than 50%.
Specific implementation mode
The technical scheme in the embodiments of the invention will be clearly and completely described below, it is clear that described implementation Example is only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, this field is common The every other embodiment that technical staff is obtained without making creative work belongs to the model that the present invention protects It encloses.
Embodiment 1：The preparation of compound 1-1
Step A：
By D- (-)-quininic acid (40.0g, 0.208mol, p-methyl benzenesulfonic acid monohydrate (0.8g, 4.16mmol), acetone In (200.0ml), 2,2-dimethoxypropane (75.8g, 0.728mol) input reaction mouth bottle, heating reflux reaction 4h.System Start when reaction to be solid-liquid mixed phase, with the continuous progress of reaction, all dissolve.Reaction finishes, 40 DEG C, is concentrated under reduced pressure and does, Ethyl acetate (300.0ml) is added in residue, 5%NaHCO is added3Aqueous solution (300.0ml) stirs, liquid separation, water phase second Acetoacetic ester (100.0ml) extracts, and merges organic phase, is washed with saturated sodium-chloride water solution, and anhydrous sodium sulfate drying, filtering is spin-dried for, Obtain light yellow solid.It is recrystallized with ethyl acetate/petroleum ether system, obtains 36.2g off-white powders 3,4- oxygen-isopropylidene quininic acid- 1,5- lactone (intermediate 1-1a), yield：81.2%.mp：131~133 DEG C；
Step B：
(E) -3 (3- pyridyl groups) allyl sour (20g, 0.134mol) is added in reaction bulb, dichloromethane is added (200.0ml), solid is not completely dissolved, and thionyl chloride (40.0ml), heating reflux reaction 3h is added.The reaction was complete for raw material, instead The direct vacuum rotary steam of system is answered to obtain off-white powder (E) -3- (3- pyridyl groups) acryloyl chloride hydrochloride (intermediate 1-1b), directly For reacting in next step.
Step C：
Sequentially add intermediate 1-1a (23.6g, 0.11mol) into reaction bulb, anhydrous methylene chloride (240.0ml), N, N- diisopropylethylamine (56.9g, 0.44mol), 4-dimethylaminopyridine (4.0g, 0.033mol), system cools to 0 with ice bath DEG C, the N of (E) -3- (3- pyridyl groups) acryloyl chloride hydrochlorides (intermediate 1-1b) (27.3g, 0.134mol), N- dimethyl is added dropwise Acetamide (110.0ml) solution, drips, and system is warming up to 25 DEG C of reaction 1h, and the reaction was complete for raw material.Water is added into system, Liquid separation, water phase are extracted twice with dichloromethane, are merged organic phase and are washed with water, 1N HCl respectively, then washed with saturated sodium-chloride, Anhydrous sodium sulfate is dried, and is filtered, and filtrate decompression revolving removes solvent, obtains pale yellow oil.With dichloromethane/petroleum ether knot Faint yellow solid 31.5g (intermediate 1-1c), yield is obtained by filtration in crystalline substance：82.8%.MS(ESI+)：M/z=345.2
Step D：
Intermediate 1-1c (4.0g, 11.58mmol) is added into reaction bulb, tetrahydrofuran (80.0ml), H is added2O (20.0ml), stirs dissolved clarification at room temperature.System cools to 0 DEG C with ice bath, be added dropwise 1mol/L LiOH aqueous solutions (17.4ml, 17.4mmol), it is added dropwise, reaction 1h is stirred at room temperature.TLC(PE:EA=1:1) the reaction was complete for display raw material, system 0.5N Aqueous citric acid solution tune pH value is concentrated to dryness to 6 or so, is obtained solid tetrahydrofuran (60.0ml × 3) extraction, is merged Organic phase is dried with anhydrous sodium sulfate, and filtering, filtrate rotates to obtain 2.41g solids (intermediate 1-1d), yield：57.3%.MS (ESI+)：M/z=363.1
Step E：
Intermediate 1-1d (1.0g, 2.75mmol) is added in reaction bulb, dichloromethane (20.0ml) is added and dissolves, adds Enter water (1.0ml), system cools to 0 DEG C with ice bath, and trifluoroacetic acid (2.0ml) is added dropwise, is added dropwise, and system is warming up to 25 DEG C instead 0.5h is answered, the reaction was complete for raw material, and system is directly concentrated under reduced pressure, and obtains off-white powder (compound 1-1) 0.77g, yield： 86.5%.MS(ESI+)：M/z=323.3.
Embodiment 2：The preparation of compound 1-5
Step E：
Intermediate 1-1c (10.0g, 28.96mmol), DCM (100.0ml) are sequentially added into there-necked flask, stir dissolved clarification, Add H2O (10.0ml), system cool to 0 DEG C with ice bath, and trifluoroacetic acid (20.0ml) is slowly added dropwise, and drop finishes, system heating To 25 DEG C of reaction 0.5h, the reaction was complete for raw material, and reaction system is concentrated under reduced pressure with oil pump at room temperature, obtains 7.2g off-white color foam-likes Solid 1-5e, yield：81.5%.MS(ESI+)：M/z=305.1.
Step F：
Under nitrogen protection, intermediate 1-5e (5.0g, 16.38mmol) is added in reaction bulb, anhydrous DMF is added (50.0ml) dissolves, and system is cooled to 0 DEG C, sodium hydride (1.64g, 40.95mmol, 60% mineral oil) is added portionwise, and stirs The DMF solution (10.0ml) containing bromoethane (3.9g, 35.79mmol) is slowly added dropwise in 30min, is warmed to room temperature reaction 2h naturally. Saturated aqueous ammonium chloride is added into reaction system, is extracted with ethyl acetate three times, merges organic phase, it is molten with saturated sodium-chloride Liquid washs, and anhydrous sodium sulfate drying filters, crude product rotated to obtain under decompression, crude product is purified through column chromatography, obtains 1.3g title compounds 1-5f, yield：22.0%.MS(ESI+)：M/z=361.2.
Step G：
Intermediate 1-5f (1.0g, 2.77mmol) is added in reaction bulb, methanol (10.0ml) is added, stirs at room temperature Dissolved clarification.Sodium methoxide (0.18g, 3.33mmol) is added in reaction system, reaction 1h is stirred at room temperature.The reaction was complete for raw material.To Saturated aqueous ammonium chloride (10.0ml) is added in reaction system, is concentrated under reduced pressure, residue is extracted with ethyl acetate three times, merges Organic phase is washed with saturated sodium-chloride, and anhydrous sodium sulfate drying filters, crude product rotated to obtain under decompression, crude product is pure through column chromatography Change, obtains 0.35g title compound 1-5, yield：32.1%.MS(ESI+)：M/z=393.3.
Embodiment 3：The preparation of compound 1-8
Step B：
(E) -3- (6- methyl -3- pyridyl groups) allyl sour (15g, 0.092mol) is added in reaction bulb, dichloro is added Methane (150.0ml), solid is not completely dissolved, and thionyl chloride (30.0ml), heating reflux reaction 3h is added.Raw material has reacted Entirely, it is (intermediate to obtain off-white powder (E) -3- (6- methyl -3- pyridyl groups) acryloyl chloride hydrochloride for the direct vacuum rotary steam of reaction system Body 1-8b), it is directly used in and reacts in next step.
Step C：
Sequentially add intermediate 1-1a (16.5g, 0.077mol) into reaction bulb, anhydrous methylene chloride (170.0ml), N, N- diisopropylethylamine (39.8g, 0.308mol), 4-dimethylaminopyridine (2.8g, 0.023mol), system is cooled to ice bath 0 DEG C, the N of (E) -3- (6- methyl -3- pyridyl groups) acryloyl chloride hydrochloride (intermediate 1-8b) (20.1g, 0.092mol) is added dropwise, N- dimethylacetylamides (80.0ml) solution, drips, and system is warming up to 25 DEG C of reaction 1h, and the reaction was complete for raw material.Into system Water is added, liquid separation, water phase is extracted twice with dichloromethane, merges organic phase and is washed respectively with water, 1N HCl, then with being saturated chlorination Sodium washs, and anhydrous sodium sulfate drying filters, and filtrate decompression revolving removes solvent, obtains pale yellow oil.With dichloromethane/stone Oily ether crystallization, is obtained by filtration faint yellow solid 21.80g (intermediate 1-8c), yield：78.8%.MS(ESI+)：M/z=359.2
Step D：
Intermediate 1-8c (10.0g, 0.028mol) is added into reaction bulb, tetrahydrofuran (200.0ml), H is added2O (50.0ml), stirs dissolved clarification at room temperature.System cools to 0 DEG C with ice bath, be added dropwise 1mol/L LiOH aqueous solutions (42.0ml, 0.042mol), it is added dropwise, reaction 1h is stirred at room temperature.TLC(PE:EA=1:1) the reaction was complete for display raw material, system 0.5N Aqueous citric acid solution tune pH value is concentrated to dryness to 6 or so, is obtained solid tetrahydrofuran (80.0ml × 3) extraction, is merged Organic phase is dried with anhydrous sodium sulfate, and filtering, filtrate rotates to obtain 6.48g solids (intermediate 1-8d), yield：61.7%.MS (ESI+)：M/z=377.1
Step E：
Intermediate 1-8d (1.0g, 2.65mmol) is added in reaction bulb, dichloromethane (20.0ml) is added and dissolves, adds Enter water (1.0ml), system cools to 0 DEG C with ice bath, and trifluoroacetic acid (2.0ml) is added dropwise, is added dropwise, and system is warming up to 25 DEG C instead 0.5h is answered, the reaction was complete for raw material, and system is directly concentrated under reduced pressure, and obtains off-white powder (compound 1-8) 0.69g, yield： 77.2%.MS(ESI+)：M/z=337.3.
Embodiment 4：The preparation of compound 1-9
It is prepared according to the operating condition of 1 technique of embodiment description, first, with (E) -3- (2- chloro-3-pyridyls base) allyl acid Instead of (E) -3- (3- pyridyl groups) allyl acid at acyl chlorides, intermediate 1-9b is obtained, then, intermediate 1-9b and 1-1a is in alkaline item Esterification under part, then through hydrolyzing, being deprotected to obtain title compound 1-9.MS(ESI+)：M/z=357.0.
Embodiment 5：The preparation of compound 1-10
It is prepared according to the operating condition of 1 technique of embodiment description, first, with (E) -3- (5- nitro -3- pyridyl groups) allyl Acid replaces (E) -3- (3- pyridyl groups) allyl acid at acyl chlorides, obtains intermediate 1-10b, and then intermediate 1-10b and 1-1a is in alkali Esterification under the conditions of property, then through hydrolyzing, being deprotected to obtain title compound 1-10.MS(ESI+)：M/z=368.1.
Embodiment 6：The preparation of compound 1-11
It prepares according to the operating condition of 1 technique of embodiment description, first, is replaced with (E) -3- (2- pyridyl groups) acrylic acid (E) -3- (3- pyridyl groups) allyl acid obtains intermediate 1-11b at acyl chlorides, and then, intermediate 1-11b and 1-1a is in alkaline condition Lower esterification, then through hydrolyzing, being deprotected to obtain title compound 1-11.
MS(ESI+)：M/z=323.1.
Embodiment 7：The preparation of compound 1-14
Step B：
(2E) -3- (2- pyrimidine radicals) acrylic acid (18.0g, 0.12mol) is added in reaction bulb, dichloromethane is added (200.0ml), solid is not completely dissolved, and thionyl chloride (40.0ml), heating reflux reaction 3h is added.The reaction was complete for raw material, instead The direct vacuum rotary steam of system is answered to obtain off-white powder (2E) -3- (2- pyrimidine radicals) acryloyl chloride hydrochloride (intermediate 1-14b), directly It connects for reacting in next step.
Step C:
Intermediate 1-1a (21.4g, 0.1mol), anhydrous methylene chloride (220.0ml), N, N- are sequentially added into reaction bulb Diisopropylethylamine (51.7g, 0.4mol), 4-dimethylaminopyridine (3.7g, 0.03mol), system cool to 0 DEG C with ice bath, The N of (2E) -3- (2- pyrimidine radicals) acryloyl chloride hydrochlorides (intermediate 1-14b) (24.6g, 0.12mol), N- dimethyl second is added dropwise Amide (100.0ml) solution, drips, and system is warming up to 25 DEG C of reaction 1h, and the reaction was complete for raw material.Water is added into system, point Liquid, water phase are extracted twice with dichloromethane, are merged organic phase and are washed with water, 1N HCl respectively, then washed with saturated sodium-chloride, nothing Aqueous sodium persulfate is dried, and is filtered, and filtrate decompression revolving removes solvent, obtains pale yellow oil.It is crystallized with dichloromethane/petroleum ether, Faint yellow solid 24.2g (intermediate 1-14c), yield is obtained by filtration：69.9%.MS(ESI+)：M/z=346.2
Step E：
Intermediate 1-14c (10.0g, 28.87mmol), DCM (100.0ml) are sequentially added into there-necked flask, add H2O (10.0ml) trifluoroacetic acid (20.0ml) is slowly added dropwise in ice-water bath, and drop, which finishes, is stirred at room temperature 0.5h, and sampling TLC monitoring has been reacted Entirely.Reaction system is concentrated under reduced pressure with vacuum oil pump at room temperature, obtains 6.6g weak yellow foam shape solid 1-14e, yield： 74.6%.MS(ESI+)：M/z=306.0.
Step F：
Under nitrogen protection, intermediate 1-14e (6.0g, 19.59mmol) is added in reaction bulb, anhydrous DMF is added (60.0ml) dissolves, and system is cooled to 0 DEG C, sodium hydride (2.0g, 48.98mmol, 60% mineral oil) is added portionwise, and stirs 30min is slowly added dropwise containing iodomethane (6.2g, 43.68mmol), is warmed to room temperature reaction 1h naturally.It is added into reaction system 2N aqueous ammonium chloride solutions are extracted with ethyl acetate three times, merge organic phase, washed with saturated sodium-chloride, anhydrous sodium sulfate drying, It filters, rotates to obtain crude product under filtrate decompression, crude product is purified through column chromatography, obtains 2.4g title compound 1-14f, yield：36.6%. MS(ESI+)：M/z=334.2.
Step G：
Intermediate 1-14f (1.5g, 4.49mmol) is added in reaction bulb, methanol (15.0ml) is added, stirs at room temperature Mix dissolved clarification.Sodium methoxide (0.3g, 5.55mmol) is added in reaction system, reaction 0.5h is stirred at room temperature.The reaction was complete for raw material. Saturated aqueous ammonium chloride (15.0ml) is added into reaction system, is concentrated under reduced pressure, residue is extracted with ethyl acetate three times, closes And organic phase, it is washed with saturated sodium-chloride water solution, anhydrous sodium sulfate drying filters, crude product rotated to obtain under decompression, crude product is through column Chromatographic purifying obtains 0.57g title compound 1-14, yield：34.7%.MS(ESI+)：M/z=366.3.
Embodiment 8：The preparation of compound 2-1
Compound 1-5e, that is, compound 2-1 prepared by embodiment 2.
Embodiment 9：The preparation of compound 2-3
Step F：
Compound 2-3 is obtained according to the operation preparation of 2 step F descriptions of embodiment.MS(ESI+)：M/z=485.3.
Embodiment 10：Compound 1-1d, that is, compound 3-1 prepared by the preparation embodiment 1 of compound 3-1.
Embodiment 11：The preparation of compound 3-4
Step A：
It is different that D- (-)-quininic acid (20.0g, 0.10mol), toluene (120ml), methyl are sequentially added into 500ml single port bottles Butylene ketone (100.0ml), p-methyl benzenesulfonic acid monohydrate (2.0g, 0.01mol), finish and are warming up to reflux, frame water knockout drum, body System is in yellow turbid solution, and water 2h is divided after reflux, continues back flow reaction 2h.System becomes clarification, has a small amount of yellow insoluble matter to be affixed on bottle Wall, the reaction was complete for TLC monitoring.50 DEG C are concentrated under reduced pressure, and H is added in residue2O (80.0ml), with saturation NaHCO3Adjust pH be 7~ 8, water phase is extracted with dichloromethane (100.0ml × 2), is merged organic phase, is washed with brine (100.0ml), anhydrous Na2SO4It is dry Dry, filtering and concentrating obtains 23.70g yellow solids.With ethyl acetate petroleum ether system recrystallization, crystallization is overnight, 0 DEG C of crystallization 2h, It filters, filter cake is dried in vacuo to obtain 13.71g white crystals, i.e. intermediate 3-4a.Yield：53.92%.MS(ESI+)：M/z= 254.1。
Step C：
It is carried out according to the operation of step C in embodiment 1, wherein 1-1a is replaced with 3-4a.
Step D：
It is operated according to step D in embodiment 1, wherein replacing 1-1c with 3-4c.MS(ESI+)：M/z=403.2.
Embodiment 12：The preparation of compound 4-8
Step A：It is carried out according to the operation of step A in embodiment 11, wherein replacing methyl methacrylate ketone with cyclohexanone.
Step C：It is carried out according to the operation of step C in embodiment 1, wherein replacing 1-1b to be esterified in obtaining with 1-14b Mesosome 4-8c.
Step D：It is operated according to step D in embodiment 1, wherein replacing 1-1c with 4-8c.MS(ESI+)：M/z= 404.1。
Embodiment 13：The preparation of compound 5-1
Compound 1-1c, that is, compound 5-1 prepared by embodiment 1.
Embodiment 14：The preparation of compound 6-3
Step C：It is carried out according to the operation of step C in embodiment 1, wherein intermediate 1-1a is substituted with 4-8a.MS(ESI+)：M/z=385.4.
The biological activity test of 15 compound provided by the invention of embodiment
1, external activity is studied：Using interleukin-17 F (IL17F) detection kit, shown in ELISA method detection Formulas I The compound effects influence to U87-Luc cells IL17F secretion for 24 hours.
Operating procedure is as follows：
(1), it is loaded：Set respectively blank well (blank control wells in addition to being not added with sample and enzyme marking reagent, remaining each step operation with Gauge orifice is identical with sample to be tested hole), gauge orifice, sample to be tested hole.Standard items are accurately loaded on enzyme mark coating plate, wait for test sample First add sample diluting liquid in sample wells, then adds sample to be tested again.Sample is added on ELISA Plate hole bottom when sample-adding, is not touched as possible Hole wall gently shakes mixing.
(2), it incubates：It is incubated 30 minutes for 37 DEG C with sealing plate film sealing plate postposition.
(3), match liquid：It will be spare after 30 times of concentrated cleaning solutions, 30 times of dilutions of distilled water.
(4), it washs：It carefully takes sealing plate film off, discards liquid, dry, cleaning solution is filled it up with per hole, discarded after standing 30 seconds, ELISA Plate is patted on blotting paper to remove all liq in hole.It is so repeated 5 times, after last time is washed, draws or pour out Remaining washing buffer, ELISA Plate is tipped upside down on blotting paper, and the liquid remained in hole is all blotted.
(5), enzyme：Enzyme marking reagent is added per hole, except blank well.
(6), it develops the color：Color developing agent A is first added per hole, adds color developing agent B, gently shakes mixing, 37 DEG C are protected from light colour developing 10 Minute.
(7), it terminates：Add terminate liquid per hole, terminate reaction (blue is vertical at this time turns yellow).
(8), it measures：It is returned to zero with blank well, the absorbance (OD values) in each hole is sequentially measured under 450nm wavelength.Measurement is answered It is carried out within 15 minutes after adding terminate liquid.
Computational methods：
GI (growth inhibition ratio)=(1-ODMedicine group/ODControl group) × 100%.Test result is shown in Table 7, and table 7 provides for the present invention Compound external activity test result.
The external activity test result of 7 the compounds of this invention of table
2, internal effect research：
2.1 murine melanoma In vivo models
By 1 × 10 under aseptic condition7A B16-F10 cell inoculations are to C57BL/6 mouse oxter.After 10 days, aseptic condition Lower acquisition tumor tissues count after homogenate normal saline dilution, are made a concentration of 1 × 106The tumor cell suspension of a/mL, Only in right side of mice oxter inoculation 0.2mL/.Next day (after 24 hours) animal is grouped at random after inoculation, is administered after weighing, to be measuredization Close object 1 time a day, continuous intraperitoneal administration 13 times.Positive control Cytoxan intraperitoneal administration, is administered once.14th day Weighing body Weight puts to death animal, strips tumor tissues, weigh and take pictures.Tumor proliferation inhibiting rate is finally calculated, is commented with tumor control rate Valence antitumor action intensity.
2.2 mouse pancreas cancer PAN02 In vivo models
Mouse pancreas cancer PAN02 tumor liquid is inoculated into C57BL/6 right side of mice oxter under aseptic condition.It is sterile after 10 days Under the conditions of take well-grown tumor tissues, shred, grind, filtering, with being counted after normal saline dilution, be made a concentration of 1.2 ×107The tumor cell suspension of a/mL, only in C57BL/6 right side of mice oxter inoculation 0.2mL/.Next day, animal was random after inoculation Grouping, gives untested compound, successive administration 13 times by every group 6 after weighing.Positive control Cytoxan intraperitoneal administration, gives Medicine 1 time.It weighs within 14th day, puts to death animal, strip tumor tissues and weigh, take pictures.Tumor control rate is finally calculated, Antitumor action intensity is evaluated with tumor control rate.
2.3 mouse colorectal cancer MC38 In vivo models
Mouse colorectal cancer MC38 tumor liquid is inoculated into C57BL/6 right side of mice oxter under aseptic condition.It is sterile after 10 days Under the conditions of take well-grown tumor tissues, shred, grind, filtering, with being counted after normal saline dilution, be made a concentration of 1.2 The tumor cell suspension of × 107/mL, only in C57BL/6 right side of mice oxter inoculation 0.2mL/.Next day, animal was random after inoculation Grouping, gives untested compound, successive administration 13 times by every group 6 after weighing.Positive control Cytoxan intraperitoneal administration, gives Medicine 1 time.It weighs within 14th day, puts to death animal, strip tumor tissues and weigh, take pictures.Tumor control rate is finally calculated, Antitumor action intensity is evaluated with tumor control rate.
2.4 Mice Bearing Lewis Lung Cancer In vivo models
Mice Bearing Lewis Lung Cancer tumor liquid is inoculated into C57BL/6 right side of mice oxter under aseptic condition.After 10 days, sterile item Well-grown tumor tissues are taken under part, are shredded, and are ground, filtering, with being counted after normal saline dilution, it is made a concentration of 1.2 × 107The tumor cell suspension of a/mL, only in C57BL/6 right side of mice oxter inoculation 0.2mL/.Next day, animal was divided at random after inoculation Group, gives untested compound, successive administration 13 times by every group 6 after weighing.Cyclophosphamide intraperitoneal administration, is administered once.14th day It weighs in, puts to death animal, strip tumor tissues and weigh, take pictures.Tumor control rate is finally calculated, with tumor control rate Evaluate antitumor action intensity.
Computational methods：
Tumor proliferation inhibiting rate TGI (%)：TGI=(1-T/C) × 100.(T：Treatment group tumors weight；C：Negative control Group tumor weight).Test result is shown in Table 8.
The activity in vivo test result of 8 part of compounds of the present invention of table
As shown in Table 7, compound 1-1 is inhibited to interleukin 17F, and inhibiting rate is close to 70%；Compound 1-1 exists There is good inhibiting effect to tumours such as melanoma, cancer of pancreas, colorectal cancer, lung cancer under the dosage of 20mg/kg, is more than 50%.And its derivative also has good inhibiting effect to tumours such as melanoma, cancer of pancreas, colorectal cancer, lung cancer.
16 autoimmune disease animal model of embodiment
1. the mouse psoriasis model of imiquimod induction
1.1 animal packet
Imiquimod modeling Dosage Administering mode Animal number of elements
Control group - - - 10
Model group + - - 10
Imiquimod group + 1.5mg/kg Gavage 10
Compound 1-1 + 20mg/kg Tail vein injection 8
1.2 modelings and evaluation method
It is about 1.5 × 2cm to give mouse back unhairing, area with pet electric hair cutter and depilatory cream2.In addition to negative control group is dynamic Beyond the region of objective existence, every group of animal carry out modeling with imiquimod cream, that is, the dermal application at mouse back unhairing position are given once daily The imiquimod cream of 50mg is smeared 1 time, continuous 7 days daily.Compound is injected intraperitoneally on the day of modeling, 1 time a day, at the 8th day Manage animal.The next day of modeling for the first time start daily to animal carry out Pigs with Psoriasis area and disease severity (PASI, Psoriasis area and severity index) scoring.According to PASI standards of grading, to erythema, the scales of skin that peel off at mouse skin lesion And infiltration thickened degree gives the integral of 0-4 respectively, three, which is integrated addition, obtains total score.
PASI standards of grading：0, nothing；1, slightly；2, moderate；3, severe；4, pole severe.It, will when experiment terminates (the 7th day) Mouse cervical dislocation is put to death, and with vernier caliper measurement skin thickness, and the skin at back part of animal depilation is removed, with 4% poly Formaldehyde is fixed, and pathological analysis is carried out.PASI appraisal results are shown in following table 1 .3, are as a result indicated with mean+SD.
1.3 PASI score
Erythema
The scales of skin that peel off
Number of days Control group Modeling group MTX Compound 1-1
0 0±0 0±0 0±0 0±0
1 0±0 0±0 0±0 0±0
2 0±0 0.4±0.5 0.2±0.3 0.1±0
3 0±0 1.5±0.5 1.9±0.3 1.5±0.5
4 0±0 1.9±0.4 1.6±0.7 1.6±0.4
5 0±0 2.4±0.7 1.7±0.7 1.8±0.5
6 0±0 2.5±0.5 2.4±1.0 2.4±0.9
It thickens
Total score
Number of days Control group Modeling group MTX Compound 1-1
0 0±0 0±0 0±0 0±0
1 0±0 0±0 0±0 0±0
2 0±0 2.5±0.5 1.9±0.6 1.7±0.5
3 0±0 6±0.6 6.2±0.5 5.0±0.5
4 0±0 6.3±0.7 5.7±1.0 5.4±0.6
5 0±0 7.3±0.8 5.1±1.2 5.4±0.5
6 0±0 7.3±1.1 6.8±1.9 6.7±1.5
From PASI scorings, compound 1-1 is better than to the scales of skin that peel off and the improvement thickened the improvement degree of erythema pulicitiae. The different time of disease has some improvement to different pathological situation, substantially suitable with positive compound MTX.
2. lupus erythematosus animal model
10 week old MRL/lpr spontaneous type lupus prone mouses, gavage or intraperitoneal injection compound, 1 time a day, continuous 3 months. During administration and experiment at the end of observe and detect dermal pathology, arthroncus degree and pathology, blood/urine creatinine urea nitrogen and Blood dsDNA and ANA antibody.The result shows that the compound of the present invention has clear improvement to lupus erythematosus.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered It is considered as protection scope of the present invention.

Claims (16)

1. Formulas I compound represented or its pharmaceutically acceptable salt：
Wherein, Q is selected from O and N；X, Y, Z are each independently selected from C, O, S and N；
R1And R2It is identical or different, independently selected from hydrogen, unsubstituted or substituted alkyl radical, unsubstituted or substituted alkenyl, unsubstituted Or the naphthenic base of substitution, unsubstituted or substituted aryl, unsubstituted or substituted aryl alkyl, unsubstituted or substituted acyl group； Alternatively, R1And R2Oxygen adjacent thereto forms acetal；
R3Selected from hydrogen, unsubstituted or substituted alkyl radical, unsubstituted or substituted alkenyl, unsubstituted or substituted naphthenic base, unsubstituted Or aryl, the unsubstituted or substituted acyl group of substitution；
R4Selected from hydrogen, unsubstituted or substituted alkyl radical, unsubstituted or substituted alkenyl, unsubstituted or substituted naphthenic base, unsubstituted Or aryl, the unsubstituted or substituted aryl alkyl of substitution；
R5Selected from hydrogen, halogen, cyano, nitro, unsubstituted or substituted hydroxyl, unsubstituted or substituted alkyl radical.
2. compound according to claim 1 or its pharmaceutically acceptable salt, wherein at least one in X, Y, Z are N, But it is asynchronously N.
3. compound according to claim 1 or 2 or its pharmaceutically acceptable salt, wherein Q is selected from O, R3And R4With its phase Adjacent oxygen forms lactone.
4. compound according to any one of claim 1 to 3 or its pharmaceutically acceptable salt, wherein R1And R2With it Adjacent oxygen forms acetal.
5. compound according to any one of claim 1 to 4 or its pharmaceutically acceptable salt, wherein R1And R2It is identical.
6. compound according to any one of claim 1 to 5 or its pharmaceutically acceptable salt, wherein R1And R2It is independent Ground is selected from hydrogen, C1-C3 alkyl and C1-C5 alkyl acyls.
7. compound according to any one of claim 1 to 6 or its pharmaceutically acceptable salt, wherein R1And R2With it Adjacent oxygen forms acetal shown in following formula：
Wherein, R6、R7Independently selected from hydrogen, C1-C5 alkyl, C2-C5 alkenyls, substituted or unsubstituted phenyl, phenyl C2-C5 alkene Base.
8. compound according to claim 7 or its pharmaceutically acceptable salt, wherein R6、R7C adjacent thereto forms 3 ~6 membered rings.
9. compound according to any one of claim 1 to 8 or its pharmaceutically acceptable salt, wherein R5Selected from hydrogen, first Base, ethyl, propyl, isopropyl, nitro, cyano, fluorine, chlorine, bromine and iodine.
10. compound according to any one of claim 1 to 9 or its pharmaceutically acceptable salt, wherein X, Y, Z C Or N.
11. compound according to claim 1 or its pharmaceutically acceptable salt, for selected from the compound of lower structure Or its pharmaceutically acceptable salt：
12. compound according to any one of claim 1 to 11 or its pharmaceutically acceptable salt, wherein the salt is The salt formed with alkali metal, alkaline-earth metal, transition metal or amine.
13. a kind of pharmaceutical composition, it includes described in any one of claim 1 to 12 compound or its is pharmaceutically acceptable Salt and optional pharmaceutically acceptable carrier or diluent.
14. the compound or its pharmaceutically acceptable salt described in any one of claim 1 to 12 are being prepared for inhibiting IL- Purposes in the secretion of 17F and active drug.
15. purposes according to claim 14, wherein the drug is for preventing or treating tumour.
16. purposes according to claim 14, wherein the drug is for preventing or treating inflammatory disease or autoimmune disease.
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