HK40005464A - Fgfr inhibitor - Google Patents

Description

FGFR inhibitor

Citation of related applications

This application claims the equity for No. 201611254119.7 Chinese invention patent application submitted on December 29th, 2016 to State Intellectual Property Office of the People's Republic of China, entire contents are integrally incorporated in a manner of quoting herein herein.

Technical field

The present invention relates to a kind of FGFR inhibitor, and its application in the drug of preparation treatment and FGFR related disease.More particularly to compound and its pharmaceutically acceptable salt shown in formula (I).

Background technique

Fibroblast growth factor acceptor (FGFR) is the receptor of fibroblast growth factor (FGF) signal transduction, its family is made of four members (FGFR1, FGFR2, FGFR3, FGFR4), for the glycoprotein as composed by extracellular immunoglobulin (Ig) spline structure domain, hydrophobic transmembrane domain and intracellular portion including tyrosine kinase domain.Fibroblast growth factor (FGF) is played a significant role in many physiology adjustment processes such as cell Proliferation, cell differentiation, cell migration and angiogenesis by these receptors (FGFR).There are many evidences to be directly associated FGF signal path abnormal (high expression, gene magnification, gene mutation, Chromosome recombination etc.) with many pathologic processes such as tumor cell proliferation, migration, invasion and vascularization.Therefore, FGFR becomes a kind of critical treatment target spot, has attracted extensive research and development interest.

Therefore, it is necessary to inhibit the appreciations illness such as the noval chemical compound of FGFR and method treating cancer.The present invention solves these demands.

The compound that a series of couples of FGFR have inhibitory activity, including reference compound 1 are reported in WO2015008844 patent.

Summary of the invention

The present invention provides compound shown in formula (I) or its pharmaceutically acceptable salt,

Wherein,

X, Y is separately selected from: H, F, C, Br, I；

R ₁Selected from C _1-3Alkyl；

R ₂Selected from C _1-3Alkyl.

In some schemes of the invention, above-mentioned R ₁Selected from Me or Et.

In some schemes of the invention, above-mentioned R ₂Selected from Me or Et.

In some schemes of the invention, above-mentioned X is selected from H, and Y is selected from H.

In some schemes of the invention, above-mentioned X is selected from F, and Y is selected from F.

In some schemes of the invention, above-mentioned X is selected from Cl, and Y is selected from Cl.

In some schemes of the invention, above-mentioned R ₁Selected from Me or Et, dependent variable is as defined above.

In some schemes of the invention, above-mentioned R ₂Selected from Me or Et, dependent variable is as defined above.

In some schemes of the invention, above-mentioned X is selected from H, and Y is selected from H, and dependent variable is as defined above.

In some schemes of the invention, above-mentioned X is selected from F, and Y is selected from F, and dependent variable is as defined above.

In some schemes of the invention, above-mentioned X is selected from Cl, and Y is selected from C, and dependent variable is as defined above.

In some schemes of the invention, above compound or its pharmaceutically acceptable salt are selected from:

Wherein, X, Y, R ₁、R ₂As defined herein.

The present invention is from above-mentioned each variable any combination there are also some schemes.

The present invention also provides compound described in following formula or its pharmaceutically acceptable salts, are selected from:

The present invention also provides compound described in following formula or its pharmaceutically acceptable salts, are selected from:

The present invention also provides a kind of pharmaceutical compositions, containing therapeutically effective amount according to compound described above or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.

The present invention also provides the application of above compound or its pharmaceutically acceptable salt or above-mentioned composition in preparation treatment FGFR related drugs.

The present invention also provides the application of above compound or its pharmaceutically acceptable salt or above-mentioned composition in preparation treatment FGFR related drugs.

In some schemes of the invention, the above-mentioned application stated, wherein the FGFR associated disease refers to solid tumor, including but not limited to gastric cancer, hepatocellular carcinoma, intrahepatic cholangiocarcinoma etc. caused by FGFR mutation or high expression.

In some schemes of the invention, the above-mentioned application stated, wherein the FGFR associated disease refers to FGFR mutation or highly expressed caused gastric cancer, hepatocellular carcinoma, intrahepatic cholangiocarcinoma.

Technical effect:

Part of compounds shows the inhibitory activity of picomole quantities to FGFR1 and FGFR4 in the present invention, and part of compounds is suitable to the inhibitory activity of FGFR4 and FGFR1.

Related definition

Unless otherwise indicated, following term used herein and phrase are intended to following meanings.One specific term or phrase it is no especially define in the case where should not be considered as uncertain or unclear, and should go to understand according to common meaning.When herein presented trade name, it is intended that refer to its corresponding commodity or its active constituent.Term " pharmaceutically acceptable " adopted here, it is for those compounds, material, composition and/or dosage form, they are within the scope of reliable medical judgment, use is contacted suitable for the tissue with human and animal, without excessive toxicity, irritation, allergic reaction or other problems or complication, match with reasonable interests/Hazard ratio.

Term " pharmaceutically acceptable salt " refers to the salt of the compounds of this invention, by present invention discover that the compound and relative nontoxic with specified substituent acid or alkali prepare.When in the compound of the present invention containing relatively acid functional group, base addition salts can be obtained by way of being contacted with the alkali of sufficient amount with the neutral form of this kind of compound in pure solution or suitable atent solvent.Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salt.When in the compound of the present invention containing relatively alkaline functional group, acid-addition salts can be obtained by way of being contacted with the acid of sufficient amount with the neutral form of this kind of compound in pure solution or suitable atent solvent.The example of pharmaceutically acceptable acid-addition salts includes inorganic acid salt, and the inorganic acid includes such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, one hydrogen radical of phosphoric acid, dihydrogen phosphate, sulfuric acid, bisulfate ion, hydroiodic acid, phosphorous acid etc.；And acylate, the organic acid include the acid that such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, citric acid, tartaric acid are similar with methanesulfonic acid；It further include the salt of amino acid (such as arginine), and the salt of such as glucuronic acid organic acid is (referring to Berge et al., " Pharmaceutical Salts ", Journal of Pharmaceutical Science 66:1-19 (1977)).Certain specific compounds of the invention contain alkalinity and acid functional group, so as to be converted into any alkali or acid-addition salts.

Preferably, it contacts salt with alkali or acid in a usual manner, then separates parent compound, thus the neutral form of raw compounds again.The forms of the parent fo of compound and its various salt is the difference is that certain physical properties, such as the different solubility in polar solvent.

" pharmaceutically acceptable salt " used herein belongs to the derivative of the compounds of this invention, wherein with acid at salt or with alkali at salt by way of modify the parent compound.The example of pharmaceutically acceptable salt includes but is not limited to: the inorganic acid of base such as amine or the alkali metal of acylate, acid group such as carboxylic acid or organic salt etc..Pharmaceutically acceptable salt includes the quaternary ammonium salt of conventional avirulent salt or parent compound, such as nontoxic inorganic acid or organic acid are formed by salt.Conventional avirulent salt includes but is not limited to the salt that those are derived from inorganic acid and organic acid, the inorganic acid or organic acid is selected from Aspirin, 2- ethylenehydrinsulfonic acid, acetic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, bicarbonate radical, carbonic acid, citric acid, edetic acid(EDTA), ethane disulfonic acid, ethane sulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic, hydrobromic acid, hydrochloric acid, hydriodate, hydroxyl, hydroxyl naphthalene, isethionic acid, lactic acid, lactose, dodecyl sodium sulfonate, maleic acid, malic acid, mandelic acid, Loprazolam, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, poly galacturonic, propionic acid, salicylic acid, stearic acid, sub- acetic acid, succinic acid, sulfamic acid, p-aminobenzene sulfonic acid, sulfuric acid, tannin, tartaric acid and p-methyl benzenesulfonic acid.

Pharmaceutically acceptable salt of the invention can be synthesized by the parent compound containing acid group or base by conventional chemical processes.Under normal circumstances, the preparation method of such salt is: in the mixture of water or organic solvent or both, reacting via free acid or these compounds of alkali form with the alkali appropriate of stoichiometry or acid to prepare.It is generally preferable that the non-aqueous medias such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.

In addition to the form of salt, there is also prodrug forms for compound provided by the present invention.Chemical change easily occurs in physiological conditions for the prodrug of compounds described herein to be converted to the compound of the present invention.In addition, pro-drug can be switched to the compound of the present invention by chemistry or biochemical method in environment in vivo.

Certain compounds of the invention can exist with nonsolvated forms or solvation form, including hydrate form.In general, solvation form is suitable with non-solvated form, it is intended to be included within the scope.

Certain compounds of the invention can have asymmetric carbon atom (optical centre) or double bond.Racemic modification, diastereoisomer, geometric isomer and single isomers are included within the scope of the present invention.

Unless otherwise indicated, with wedge key and dotted line key The absolute configuration for indicating a Stereocenter, uses wave Indicate wedge key or dotted line key When compound described herein contains olefinic double bond or other geometry asymmetric centers, unless otherwise prescribed, they include E, Z geometric isomer.Similarly, all tautomeric forms are included within the scope of the present invention.

The compound of the present invention may exist specific geometry or stereoisomer form.It is contemplated by the invention that all this kind of compounds, including cis and trans isomer, (-)-with (+)-to enantiomer, (R)-and (S)-enantiomer, diastereoisomer, (D)-isomers, (L)-isomers, and its racemic mixture and other mixtures, such as enantiomter or the mixture of diastereomer enrichment, all these mixtures are within the scope of the present invention.Other asymmetric carbon atom may be present in the substituent groups such as alkyl.All these isomers and their mixture, are included within the scope of the present invention.

Can by chiral synthesis or chiral reagent or other routine techniques prepare optically active (R)-and (S)-isomers and D and L isomers., can be by asymmetric syntheses or prepared by the derivatization with chiral auxiliary if expect a kind of enantiomer of certain of the invention compound, wherein gained non-enantiomer mixture is separated, and auxiliary group splits to provide pure required enantiomter.Or, when containing basic functionality (such as amino) or acidic functionality (such as carboxyl) in molecule, the salt of diastereoisomer is formed with optically active acid appropriate or alkali, then diastereoisomer fractionation is carried out by conventional method known in the field, then recycling obtains pure enantiomer.In addition, the separation of enantiomter and diastereoisomer is usually to be completed by using chromatography, the chromatography uses chiral stationary phase, and (such as generating carbaminate by amine) is optionally combined with chemical derivatization.

The compound of the present invention can include the atom isotope of unnatural proportions on one or more atoms for constituting the compound.For example, radioisotope labeled compound can be used, such as tritium ( ³H), iodine-125 ( ¹²⁵I) or C-14 ( ¹⁴C).The transformation of all isotopics of the compound of the present invention, no matter radioactivity whether, be included within the scope of the present invention.

Term " pharmaceutically acceptable carrier " is that refer to deliver effective quantity active material of the present invention, any preparation for not interfering the bioactivity of active material and having no toxic side effect to host or patient or the representative carrier of mounting medium include water, oil, vegetables and minerals, cream base, lotion base, ointment bases etc..These matrix include suspending agent, tackifier, transdermal enhancer etc..Their preparation is well known to the technical staff in cosmetic field or topical remedy field.Other information about carrier, Remington:The Science and Practice of Pharmacy, 21st Ed., Lippincott can be referred to, Williams&Wilkins (2005), the content of the document are incorporated herein by reference.

Term " excipient " typically refers to carrier, diluent and/or medium required for preparing drug composition effective.

For drug or pharmacologically active agents, term " effective quantity " or " therapeutically effective amount " refer to enough dosages of drug that is nontoxic but can achieving the desired results or medicament.For the peroral dosage form in the present invention, in composition it is a kind of " effective quantity " of active material refer to when being combined with active material another in the composition for the required dosage that achieves the desired results.A effective amount of determination varies with each individual, age and ordinary circumstance depending on receptor, also depends on specific active material, and suitable effective quantity can be determined by those skilled in the art according to routine test in case.

Term " active constituent ", " therapeutic agent ", " active material " or " activating agent " refer to a kind of chemical entities, it can effectively treat target disorder, disease or illness.

When any variable (such as R) occurs more than once in the composition of compound or structure, definition at each occurrence is all independent.Thus, for example, the group can be optionally at most replaced two R, and R in each case has independent option if a group is replaced 0-2 R.In addition, the combination of substituent group and/or its variant is only just allowed in the case where such group of credit union generates stable compound.

Unless otherwise prescribed, term " alkyl " can be monosubstituted (such as-CH for indicating linear or branched saturated hydrocarbon base ₂F) or polysubstituted (such as-CF ₃), it can be monovalence (such as methyl), divalent (such as methylene) or multivalence (such as methine).The example of alkyl includes methyl (Me), and ethyl (Et), propyl (e.g., n- propyl and isopropyl), butyl is (such as, n- butyl, isobutyl group, s- butyl, t- butyl), amyl (e.g., n- amyl, isopentyl, neopentyl) etc..

Unless otherwise prescribed, term " halogenated element " or " halogen " indicate fluorine, chlorine, bromine or iodine atom in itself or as a part of of another substituent group.In addition, term " halogenated alkyl " is intended to include monohaloalkyl alkyl and multi-haloalkyl.For example, term " halogenated (C ₁-C ₄) alkyl " be intended to include but are not limited to trifluoromethyl, 2,2,2- trifluoroethyls, 4- chlorobutyl and 3- bromopropyl etc..Unless otherwise prescribed, the example of halogenated alkyl includes but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl group and five chloroethyls.

The compound of the present invention can be prepared by a variety of synthetic methods well-known to those skilled in the art, combination including the specific embodiment, itself and other chemical synthesis process that are set forth below is formed by embodiment and art technology equivalent replacement mode known to personnel, and preferred embodiment includes but is not limited to the embodiment of the present invention.

Solvent used in the present invention can be through commercially available acquisition.The present invention uses following initialisms: eq represents equivalent；Equivalent DMSO represents dimethyl sulfoxide.

Compound manually or Software name, commercial compound use supplier's directory name.

Specific embodiment

Below by embodiment, the present invention will be described in detail, but is not meant to any unfavorable limitation of the present invention.The present invention has been described in detail herein, wherein also disclose its specific embodiment mode, to those skilled in the art, carrying out various changes and modifications for the specific embodiment of the invention without departing from the spirit and scope of the present invention will be apparent.

Reference example 1:WXR1

Route synthesis of the compound WXR1 referring to patent WO2015008844 report. ¹H NMR (400MHz, DMSO-d ₆) δ 8.40 (d, J=3.0Hz, 1H), 6.93 (d, J=2.5Hz, 2H), 6.74-6.52 (m, 2H), 6.20-6.16 (m, 1H), 5.74-5.69 (m, 1H), 5.45-5.61 (m, 1H), 4.12-3.90 (m, 2H), 3.90-3.79 (m, 8H), 2.47-2.30 (m, 2H) .MS m/z:419.1 [M+H] ⁺

Intermediate A 1:

Synthetic route:

Step 1: the synthesis of compound A1-1

At room temperature, first by 4- amino -7- bromine pyrrolo- [2,1-f] [1,2,4] triazine (3.00g, 14.1mmol, 1.00eq) is dissolved in 1, in the mixed solution of 4- dioxane (40mL) and water (8mL), again successively by N-Boc-2, which alcohol ester (4.36g, 14.8mmol of 5- dihydro -1H- pyrroles's -1- boric acid Knit-the-brows, 1.05eq) potassium phosphate (8.97g, 42.2mmol, 3.00eq) and 1,1 '-bis- (diphenylphosphine) ferrocene palladium chloride (1.03g, 1.41mmol, 0.10eq) it is added in the mixed solution.Under nitrogen protection, reaction solution 80 DEG C are heated to stir 2 hours.After reaction, reaction solution is down to 25 DEG C, it pours into 20mL water, there is black solid generation, black solid is collected by filtration, is then dissolved in methylene chloride/methanol (100mL, 5/1) in mixed solution, it filters again, filtrate is dry with anhydrous sodium sulfate, removes organic solvent by vacuum rotary steam and obtains crude product.Crude product is beaten with ethyl acetate (30mL), filters to obtain compound A1-1 (2.50g, 8.30mmol, yield 59.0%).LCMS (ESI) m/z:302.1 [M+H] ⁺, ¹H NMR (400MHz, CHLOROFORM-d) δ: 8.05 (s, 1H), 6.84-6.98 (m, 1H), 6.54-6.72 (m, 2H), 4.49-4.67 (m, 2H), 4.30-4.44 (m, 2H)

Step 2: the synthesis of compound A1-2

At room temperature, palladium dydroxide (615mg, 438 μm of ol) is added in methanol (30mL) solution of A1-1 (1.20g, 3.98mmol, 1.00eq).It is replaced 3 times with hydrogen, reaction solution is heated to 50 DEG C, under 50psi hydrogen atmosphere, after stirring 2 hours, reaction solution is cooled to room temperature, Filtration of catalyst, filtrate removes solvent by vacuum rotary steam and obtains A1-2 (1.21g, 3.99mmol, yield 99.5%). ¹H NMR (400MHz, METHANOL-d4) δ: 7.80 (s, 1H), 6.86 (d, J=4.4Hz, 1H), 6.53 (d, J=4.4Hz, 1H), 3.96-3.79 (m, 2H), 3.60-3.51 (m, 1H), 3.49-3.38 (m, 2H), 2.39-2.36 (m, 1H), 2.192.13 (m, 1H), 1.49 (d, J=3.6Hz, 9H)

Step 3: the synthesis of compound A1

At room temperature, N-iodosuccinimide (26.7g, 119mmol, 3.00eq) is added portionwise in n,N dimethylformamide (150mL) solution of A1-2 (12.0g, 39.6mmol, 1.00eq).After reaction solution is stirred at room temperature 1 hour, reaction solution is slowly added in ice water (200mL), there is solid generation, is filtered to remove solvent, obtain compound A1 after filter cake vacuum rotary steam is dry.Chiral fractionation (the pillar: IC (250mm*50mm, 10um) of compound A1；Mobile phase: [0.1% ammonium hydroxide/ethyl alcohol]；B%:30%-30%, min) obtain compound A1-A (retention time 2.947 minutes, 3.00g, 6.99mmol, yield 17.7%) and compound A1-B (retention time 3.280 minutes, 3.00g, 6.99mmol, yield 17.7%).

Intermediate B 1

CAS:1453211-48-7

Intermediate B 2

Synthetic route:

Step 1: the synthesis of compound B2-1

At 0 DEG C, by 1- chloromethyl -4- fluoro- 1, two (tetrafluoro boric acid) salt (512g of 4- diazabicyclo octane, 1.44mol, it 2.00eq) is added portionwise to 3, in acetonitrile (3.50L) solution of 5- dimethoxy benzaldehyde (120g, 722mmol, 1.00eq).At room temperature, stirring is filtered after 48 hours, filtrate decompression revolving removes solvent, residue is diluted with 1L ethyl acetate, then it is washed with 2L saturated sodium bicarbonate aqueous solution, after liquid separation, water phase is extracted three times with ethyl acetate (600mL), merges organic phase, with 2L saturated common salt water washing, anhydrous sodium sulfate dries, filters, and vacuum rotary steam removes solvent afforded crude material, crude product chromatographs (silica gel by column, petroleum ether is to petrol ether/ethyl acetate=3/1) purify to obtain compound B2-1 (45.5g, 225mmol, yield 31.2%).LCMS (ESI) m/z:203.0 [M+H] ⁺, ¹H NMR (400MHz, CHLOROFORM-d) δ: 10.29 (s, 1H), 6.84-6.80 (m, 1H), 3.84 (s, 6H).

Step 2: the synthesis of compound B2

At room temperature, 2, 6- bis- fluoro- 3, 5- dimethoxy benzaldehyde (8.30g, 41.1mmol, 1.00eq), (1- diazo -2- oxopropyl) dimethyl phosphonate (9.5g, 49.3mmol, 1.20eq) and potassium carbonate (11.4g, 82.1mmol, after 2.00eq) being stirred 16 hours in 20mL methanol, filtering reacting liquid, filtrate is diluted with 50mL methylene chloride, it is washed again with 20mL saturated sodium bicarbonate aqueous solution, after anhydrous sodium sulfate drying, filtering, filtrate removes solvent by vacuum rotary steam and obtains compound B2 (3.50g, 17.7mmol, yield 43.0%). ¹HNMR (400MHz, CHLOROFORM-d) δ: 6.68-6.47 (m, 1H), 3.81 (s, 6H), 3.45 (s, 1H)

Intermediate B 3

CAS:1453211-48-7

Examples 1 and 2: the synthesis of compound WX001A, WX001B

Step 1: the synthesis of compound WX001-1

At room temperature, by B1 (341mg, 2.10mmol, 1.50eq), triethylamine (425mg, 4.20mmol, 582uL, 3.00eq) and, 1 '-bis- (diphenylphosphine) ferrocene palladium chloride (102mg, 140 μm of ol, 0.10eq) it is added sequentially to A1 (600mg, 1.40mmol, N 1.00eq), in the solution of dinethylformamide (10mL), after nitrogen displacement three times, it is heated to 90 DEG C.After stirring 1 hour, reaction solution is cooled to room temperature, it pours into 20mL water, three times with ethyl acetate (8mL) extraction, merge organic phase, after organic phase washed once with saturated salt solution (15mL), it is dry with anhydrous sodium sulfate, filtering, filtrate decompression revolving removes solvent afforded crude material, and crude product obtains compound WX001-1 (390mg by column chromatography (100-200 mesh silica gel, petrol ether/ethyl acetate=50/1 to 1/1) purifying, 841 μm of ol, yield 60.1%).LCMS (ESI) m/z:464.2 [M+H] ⁺, ¹H NMR (400MHz, CHLOROFORM-d) δ: 8.03 (s, 1H), 7.94 (s, 1H), 6.65 (d, J=2.0Hz, 2H), 6.49-6.48 (m, 1H), 3.55-3.28 (m, 4H), 2.96 (s, 3H), 2.89 (s, 3H), 2.35-2.23 (m, 1H), 2.08-1.95 (m, 1H), 1.67-1.54 (m, 2H), 1.49 (s, 9H).

Step 2: the synthesis of compound WX001-2

At room temperature, by hydrochloric ethyl acetate solution (4M, 2.00mL, 9.51eq) it is slowly dropped to WX001-1 (390mg, 841 μm of ol, in ethyl acetate (2mL) solution 1.00eq), after stirring 1 hour, the solid was filtered, the hydrochloride (200mg of solid dry compound WX001-2 at reduced pressure conditions, 500 μm of ol, yield 59.45%).LCMS (ESI) m/z:364.2 [M+H] ⁺, ¹H NMR (400MHz, METHANOL-d4) δ: 8.13 (s, 1H), 7.11 (s, 1H), 6.79 (d, J=2.0Hz, 2H), 6.61 (t, J=2.0Hz, 1H), 4.18-4.07 (m, 1H), 3.91-3.79 (m, 7H), 3.68-3.55 (m, 1H), 3.52-3.41 (m, 2H), 2.67-2.55 (m, 1H), 2.40-2.28 (m, 1H).

Step 3: the synthesis of compound WX001

At 0 DEG C, successively by diisopropylethylamine (259mg, 2.00mmol, 349 μ L, 4.00eq) and the dichloromethane solution (0.25M of acryloyl chloride, 1.80mL, 0.90eq) it is added to WX001-2 hydrochloride (200mg, 500 μm of ol, in methylene chloride (4.0mL) suspension 1.00eq), stirring is after five minutes, reaction solution is poured into 2mL water, after liquid separation, water phase is extracted three times with methylene chloride (1mL), merge organic phase, it is dry with anhydrous sodium sulfate, filtering, filtrate removes solvent afforded crude material by vacuum rotary steam, crude product prepares plate (methylene chloride/methanol=10/1) with thin layer and purifies to obtain compound WX001.Chiral fractionation (the pillar: AS (250mm*30mm, 5 μm) of compound WX001；Mobile phase: [0.1% ammonium hydroxide/ethyl alcohol]；B%:40%-40%, min) obtain WX001A (retention time 5.405 minutes, 65.0mg, 156 μm of ol, yield 31.13%) and WX001B (retention time 5.802 minutes, 65.0mg, 155 μm of ol, yield 31.13%).

WX001A, LCMS (ESI) m/z:418.1 [M+H] ⁺, ¹H NMR (400MHz, METHANOL-d4) δ: 7.73 (d, J=3.2Hz, 1H), 6.60-6.44 (m, 4H), 6.40-6.37 (m, 1H), 6.21-6.15 (m, 1H), 5.66-5.61 (m, 1H), 4.11-3.93 (m, 1H), 3.89-3.70 (m, 2H), 3.68 (s, 6H), 3.54-3.39 (m, 2H), 2.45-2.24 (m, 1H), 2.19-1.94 (m, 1H).

WX001B, LCMS (ESI) m/z:418.1 [M+H] ⁺, ¹H NMR (400MHz, METHANOL-d4) δ: 7.88 (d, J=2.0Hz, 1H), 6.75 (d, J=8.8Hz, 1H), 6.70 (d, J=2.0Hz, 2H), 6.68-6.59 (m, 1H), 6.54 (s, 1H), 6.41-6.18 (m, 1H), 5.87-5.65 (m, 1H), 4.27-4.06 (m, 1H), 4.05-3.91 (m, 1H), 3.90-3.83 (m, 1H), 3.82 (s, 6H), 3.79-3.69 (m, 1H), 3.67-3.55 (m, 1H), 2.58-2.40 (m, 1H), 2.36-2 .13 (m, 1H).

The synthesis of embodiment 3:WX002A

Step 1: the synthesis of compound WX002A-1

A1-B (900mg, 2.10mmol, 1.00eq), B2 (623mg, 3.14mmol, 1.50eq), triethylamine (636mg, 6.29mmol, 872 μ L, 3.00eq) and 1 '-bis- (diphenylphosphine) ferrocene palladium chloride (153mg, 210 μm of ol, 0.10eq) in 1.5mLN, dinethylformamide, after being replaced with nitrogen, it is stirred at room temperature 16 hours.Then, reaction solution is poured into 25mL water, is extracted 3 times with ethyl acetate (25mL), merge organic phase, it is dry with anhydrous sodium sulfate after 25mL saturated common salt water washing, after filtering, filtrate decompression revolving removes solvent and obtains WX002A-1 (850mg) crude product；

Step 2 and step 3 are referring to 1 synthetic method of embodiment.

WX002A, LCMS (ESI) m/z:454.1 [M+H] ⁺, 476.1 [M+Na] ⁺, ¹H NMR (400MHz, CHLOROFORM-d) δ: 7.87 (d, J=2.0Hz, 1H), 6.65 (d, J=7.2Hz, 1H), 6.58-6.54 (m, 1H), 6.45-6.24 (m, 2H), 5.66-5.61 (m, 1H), 4.15-4.00 (m, 1H), 3.97-3.76 (m, 7H), 3.71-3.44 (m, 3H), 2.52-2.27 (m, 1H), 2.19-2.03 (m, 1H)

Referring to method in embodiment 1-3, using intermediate A 1-A, A1-B and intermediate B 2, B3 as embodiment in Material synthesis following table

NMR the and MS data of each embodiment

Experimental example 1: in-vitro evaluation

Using ³³P isotope labelling kinase activity tests (Reaction Biology Corp) and measures IC ₅₀Value evaluates test-compound to the rejection ability of people FGFR1, FGFR4.

Buffer conditions: 20mM Hepes (pH 7.5), 10mM MgCl2,1mM EGTA, 0.02%Brij35,0.02mg/ml BSA, 0.1mM Na3VO4.2mM DTT, 1%DMSO.

Test procedure: at room temperature, test-compound is dissolved in DMSO and is configured to 10mM solution for later use.Substrate is dissolved in the buffer newly prepared, tested kinases is added thereto and is uniformly mixed.It will be added in the reaction solution of above-mentioned mixing dissolved with the DMSO solution of test-compound using acoustic technique (Echo 550).In reaction solution compound concentration be 10 μM, 3.33 μM, 1.11 μM, 0.370 μM, 0.123 μM, 41.2nM, 13.7nM, 4.57nM, 1.52nM, 0.508nM, or be 10 μM, 2.50 μM, 0.62 μM, 0.156 μM, 39.1nM, 9.8nM, 2.4nM, 0.61nM, 0.15nM, 0.038nM.After hatching 15 minutes, it is added ³³P-ATP (0.01 μ Ci/ μ l of activity, respective concentration are listed in Table 1) starts to react.Supplier's article No. of FGFR1, FGFR4 and its substrate, lot number and the concentration information in reaction solution are listed in Table 1.After reaction carries out 120 minutes at room temperature, by reaction solution point on P81 ion exchange filter paper (Whatman#3698-915).After cleaning filter paper repeatedly with 0.75% phosphoric acid solution, the radioactivity of remaining phosphorylated substrate on filter paper is measured.The comparison of kinase activity of the kinase activity data containing test-compound and the kinase activity of blank group (only containing DMSO) indicates, it carries out curve fitting to obtain IC50 value by Prism4 software (GraphPad), experimental result is as shown in table 2.

Table 2: the compounds of this invention body outer screening test result

Conclusion: part of compounds shows the inhibitory activity of picomole quantities to FGFR in the present invention, and part of compounds is suitable to the inhibitory activity of FGFR4 and FGFR1.

Claims (14)

1. Compound shown in formula (I) or its pharmaceutically acceptable salt,

   Wherein,

   X, Y is separately selected from: H, F, C, Br, I；

   R ₁Selected from C _1-3Alkyl；

   R ₂Selected from C _1-3Alkyl.
2. Compound or its pharmaceutically acceptable salt according to claim 1, wherein R ₁Selected from Me or Et.
3. Compound according to claim 1 or claim 2 or its pharmaceutically acceptable salt, wherein R ₂Selected from Me or Et.
4. Compound according to claim 1 or claim 2 or its pharmaceutically acceptable salt, wherein X is selected from H, and Y is selected from H.
5. Compound according to claim 1 or claim 2 or its pharmaceutically acceptable salt, wherein X is selected from F, and Y is selected from F.
6. Compound according to claim 1 or claim 2 or its pharmaceutically acceptable salt, wherein X is selected from Cl, and Y is selected from Cl.
7. According to claim 1, compound or its pharmaceutically acceptable salt described in any one~6, be selected from:

   Wherein, X, Y, R ₁、R ₂As claim 1~6 defines.
8. Compound described in following formula or its pharmaceutically acceptable salt, are selected from:
9. Compound described in following formula or its pharmaceutically acceptable salt, are selected from:
10. A kind of pharmaceutical composition, compound or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier described in any one according to claim 1~9 containing therapeutically effective amount.
11. Compound or its pharmaceutically acceptable salt described in any one or according to claim 10 application of the composition in preparation treatment FGFR related disease drug according to claim 1~9.
12. Compound or its pharmaceutically acceptable salt described in any one or according to claim 10 application of the composition in preparation treatment FGFR related disease drug according to claim 1~9.
13. Application according to claim 11 or 12, wherein the FGFR associated disease refers to FGFR mutation or highly expressed caused solid tumor.
14. Application according to claim 11 or 12, wherein the FGFR associated disease refers to FGFR mutation or highly expressed caused gastric cancer, hepatocellular carcinoma, intrahepatic cholangiocarcinoma.