CN107304201A - A kind of deuterated Kinase Selectivity inhibitor - Google Patents
A kind of deuterated Kinase Selectivity inhibitor Download PDFInfo
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- CN107304201A CN107304201A CN201610247898.1A CN201610247898A CN107304201A CN 107304201 A CN107304201 A CN 107304201A CN 201610247898 A CN201610247898 A CN 201610247898A CN 107304201 A CN107304201 A CN 107304201A
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- 0 Cc1c(*)cc(*)c(Cl)c1-c(cc1)cc2c1nc(NC([C@@]1[C@](*)CCCC1)=C)nc2 Chemical compound Cc1c(*)cc(*)c(Cl)c1-c(cc1)cc2c1nc(NC([C@@]1[C@](*)CCCC1)=C)nc2 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N C1CCCCC1 Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/84—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The present invention is a kind of deuterated Kinase Selectivity inhibitor, offer formula (I) compound, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt, it is as FGFR4 Kinase Selectivities inhibitor and its is preparing treatment by the application in the medicine or pharmaceutical composition of FGFR4 or FGF19 associated diseases, compound disclosed by the invention is with a wide range of applications to the selective remarkable inhibiting activities of FGFR4 in therapeutic field of tumor.
Description
Technical field
The present invention relates to formula (I) compound as FGFR4 Kinase Selectivity inhibitor, and preparation method thereof, drug regimen
Thing and the method using the compound and composition to suppress kinase activity.
Background technology
It is close that fibroblast growth factor (Fibroblast growth factor, FGF) family includes 22 structures
Polypeptide, FGF and receptor tyrosine kinase FGFR1-4 (Fibroblast growth factor receptor, FGFR) are mutually
Effect makes acceptor occur homodimerization and autophosphorylation, then recruits embrane-associated protein and kytoplasm auxilin, activates many
Weight signal cascade reaction (Lin, B.C., Desnoyers, L.R.FGF19and cancer.Adv.Exp.Med.Biol.2012；
728:183–94；Powers, C.J. etc., Endocr.Relat.Cancer, 2000,7:165-197).In normal physiological conditions
Under, FGF19 is important cell metabolism regulatory factors；Under pathological conditions, FGF19 may be related to the generation development of kinds cancer.
It is now recognized that FGFR4, which is FGF19, uniquely shows specific acceptor, FGF19 by combined and activated with FGFR4 FGFR4 come
Play activity.FGFR4 in embryonic development, nervous centralis control, tissue repair, or even is swelling as one of FGFR family members
Played an important role during knurl invasion and attack and angiogenesis etc. (Ho, H.K. etc., Journal of Hepatology,
2009,50:118–127).Research find FGFR4 in kinds cancer exist be overexpressed phenomenon, such as liver cancer (Ho, H.K. etc.,
Journal of Hepatology,2009,50:118–127；Sawey, E.T. etc., Cancer Cell, 2011,19:347-
358), stomach cancer (Ye, Y.W. etc., Cancer, 2011,117:5304-5313；Ye, Y. etc., Ann.Surg.Oncol.2010,17:
3354-3361), cancer of pancreas (Leung, H.Y. etc., Int.J.Cancer, 1994,59:667-675), clear-cell carcinoma
(Takahashi, A. etc., Biochem.Biophys.Res.Commun.1999,257:855-859), rhabdomyosarcoma
(Taylor VI, J.G. etc., J.Clin.Invest.Doi:1o.1172/JCI39703), cholangiocarcinoma (Xu, Y.-F. etc.,
Biochem.Biophys.Res.Commun.2014,446:54-60), colon cancer (Barderas, R. etc., J.Proteomics,
2012,75:4647-4655；A.,PLos ONE,2012,8(5):E63695), prostate cancer (Xu, B. etc.,
BMC cancer 2011,11:84), oophoroma (Zaid, T.M. etc., Clin.Cancer Res.2013,19 (4):809-820)
Deng.Therefore, FGF19-FGFR4 signal paths play an important role in the generation evolution of mankind's kinds cancer.
Research finds that PD173074 is a kind of FGFR4 micromolecular inhibitors, can suppress the growth of human rhabdomyosarcoma cells
And with internal antitumor activity (Crose, L.E.S. etc., Clin.Cancer Res.2012,18 (14):1-11).
Desnoyers etc. has found that FGF19 monoclonal antibodies are capable of selective exclusion FGF19 and FGFR4 interaction, and the antibody can press down
Human Colonic Tumor in Nude Mice growth of transplanted human processed and can effectively prevent FGF19 transgenic mices suffering from hepatic cancer (Desnoyers, L.R. etc.,
Oncogene,2008,27:85-97).Sawey etc. has found that FGF19 monoclonal antibodies can significantly inhibit human liver cancer growth of transplanted human
(Sawey, E.T. etc., Cancer Cell, 2011,19,347-358).Ho etc. has found FGFR4 micromolecular inhibitor V4-015 energy
Inducing mammary cancer cell-apoptosis and suppress cancer cell migration (Ho, H.K. etc., Current Medicinal Chemistry,
2013,20:1203-1217).Selective FGFR4 micromolecular inhibitors BLU9931 can suppress hepatoma cell proliferation, while energy
Enough suppress human liver cancer xenograft tumor growth and in dose dependent (Hagel, M. etc., Cancer Discov.2015,5 (4):
1-14).These researchs show, by blocking FGF19 and FGFR4 interaction to suppress tumour growth, and this is tumour
Molecular targeted therapy provides effective target spot.Targeting FGFR4 selective micromolecular inhibitor is likely to become kinds of tumors
Medicine.
The content of the invention
The present invention relates to the selective molecule inhibitor compounds of new FGFR4 and its pharmaceutically acceptable salt.This
Invention is directed to these compounds at least one other therapeutic agent and optionally pharmaceutically acceptable load alone or in combination
The composition of agent.The present invention further relate to these compounds have alone or in combination at least one other therapeutic agent prevent or treat by
Application method in the disease of FGFR4 or FGF19 mediations.
The invention discloses a kind of formula (I) compound, its stereoisomer, dynamic isomer or pharmaceutically acceptable
Salt,
Wherein, R1, R2It is each independently selected from hydrogen, deuterium, methyl or one or many deuterated or complete deuterated C1-C4Alkane
Base；
R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18It is hydrogen, deuterium, or halogen；
Also, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18In at least one
It is deuterium, or one or many deuterated or complete deuterated C1-C4Alkyl；
X is selected from oxygen atom, carbon atom；
N=0,1.
Formula (I) compound of the present invention, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt, its
Include the compound of logical formula (II),
Wherein, R1, R2It is each independently selected from hydrogen, deuterium, methyl or one or many deuterated or complete deuterated C1-C4Alkane
Base；
R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18It is hydrogen, deuterium, or halogen；
Also, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18In at least one be deuterium,
Or R1, R2For one or many deuterated or complete deuterated C1-C4Alkyl.
Formula (II) compound of the present invention, it is characterised in that R1, R2Separately it is selected from：Hydrogen, deuterated methyl,
Or deuterated ethyl.
Formula (II) compound of the present invention, it is characterised in that R1, R2Separately it is selected from a deuterium methyl, two deuterium first
Base, three deuterium methyl, a deuterium ethyl, two deuterium ethyls, three deuterium ethyls, four deuterium ethyls, and five deuterium ethyls.
Formula (II) compound of the present invention, it is characterised in that R1, R2Separately it is selected from three deuterium methyl.
Formula (I) (II) compound of the present invention, it is characterised in that the compound is selected from：
The compound any one of of the invention, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt, as
FGFR4 Kinase Selectivity inhibitor, is preparing treatment in FGFR4 or FGF19 disease mediated medicine or pharmaceutical composition
Using.
Medicine of the present invention or pharmaceutical composition, it is used for the treatment of various cancers.
Of the present invention, the various cancers for the treatment of include：Liver cancer, stomach cancer, clear-cell carcinoma, sarcoma, cholangiocarcinoma, colon cancer,
Prostate cancer, oophoroma, breast cancer.
Embodiment
Relevant definition
Term " hydrogen " in this article refers to-H.
Term " deuterium " in this article refers to-D.
Term " halogen " in this article refers to-F ,-Cl ,-Br and-I.
Term " fluorine " in this article refers to-F.
Term " chlorine " in this article refers to-Cl.
Term " bromine " in this article refers to-Br.
Term " iodine " in this article refers to-I.
Term " deuterated " refers to one or more of compound or group hydrogen and replaced by deuterium.Deuterated can be a substitution,
Two substitutions, polysubstituted or full substitution.Term " one or more deuterated " is used interchangeably with " one or many deuterated ".Deuterium exists
The deuterium isotopic content of deuterium the position of substitution is greater than natural deuterium isotopic content (0.015%), and even more preferably greater than 50%, more preferably
More than 75%, even more preferably greater than 95%, even more preferably greater than 97%, even more preferably greater than 99%, even more preferably greater than 99.5%
Term " alkyl " in this article refers to the saturated aliphatic hydrocarbons group with 1 to 10 carbon atom, the term bag
Include straight chain and branched hydrocarbyl.The non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group,
Sec-butyl, the tert-butyl group, n-pentyl, neopentyl, n-hexyl etc..Alkyl described herein optionally following can be taken by one or more
Replaced for base：Fluorine, chlorine, bromine, iodine, cyano group, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl group, acyloxy, oxo,
Amide groups, ester group, amido, cycloalkyl, cycloalkenyl group, Heterocyclylalkyl, alkenyl, alkenyloxy group, alkynyl, cycloalkyloxy, Heterocyclylalkyl oxygen
Base, aryloxy group, heteroaryloxy, aryl or heteroaryl.
Term " optional " or " optionally " refer to the event or situation that then describe can with but not necessarily occur, and this is retouched
State situation about occurring including wherein described event or situation and the situation that wherein it is occurred without.
Term " optionally quilt ... replaces " refers to that the structure is unsubstituted or by one or more institutes of the present invention
The substituent substitution stated.Term " substitution " in this article refers to any group by specifying substituent monosubstituted or polysubstituted to this
The degree that monosubstituted or polysubstituted (the multiple substitution for being included in same section) allows in chemistry, each substituent can be located at
Any available position on the group, and can be connected by any available atom on the substituent." it is any can profit
The method that position " refers to by methods known in the art or instructed herein is chemically obtained, and is not produced excessively not
Any position on the group of stable molecule.When having two or more substituents on any group, each substitution
Base is defined independently of any other substituent, therefore can be identical or different.
Term " the compounds of this invention " (unless otherwise particularly pointing out) in this article refers to formula (I) compound and its all pure
And mixing stereoisomer, geometric isomer, dynamic isomer, solvate, the compound of prodrug and isotope marks
With any pharmaceutically acceptable salt.The solvate of the compounds of this invention refers to and stoichiometry and non-stoichiometric solvent
With reference to compound or its salt, such as hydrate, ethanolates, methanol solvate etc..Compound can also one or more crystalloids
State is present, i.e., as eutectic, polymorph, or it can exist with amorphous solid.All such form is by claim
Covered.
Term is " pharmaceutically acceptable " to represent that material or composition must be with constituting preparation in chemistry and/or in toxicology
Other compositions and/or with its treat mammal it is compatible.
Term " stereoisomer " in this article refers to the chiral different compound with one or more Stereocenters,
Including correspondence isomers and diastereoisomer.
Term " dynamic isomer " in this article refers to the structural isomerism with different-energy and carried that low energy can be crossed
Build, so that mutually inversion of phases.Such as proton tautomer includes carrying out change, such as enol-keto tautomerism by proton migration
Body and imine-enamine tautomers, or the heteroaryl containing the annular atom for being connected to ring-NH- parts and ring=N- parts
The tautomeric form of group, such as pyrazoles, imidazoles, benzimidazole, triazole and tetrazolium.Valence tautomers include some into
Bonding electron recombinates and carries out change.
Term " prodrug " is in this article referred to when to snibject, can directly or indirectly provide the change of the present invention
Any derivative of the compounds of this invention of compound, its active metabolite or residue.Especially preferably those can increase this hair
Bright compound bioavailability, improves the derivative or prodrug of metabolic stability and tissue-targeting.
The compounds of this invention can be used in a salt form, such as derive from inorganic acid or organic acid obtain " pharmaceutically
Acceptable salt ".These include but is not limited to what follows：Acetate, adipate, alginates, citrate, asparagus fern ammonia
Hydrochlorate, benzoate, benzene sulfonate, disulfate, butyrate, camphor hydrochlorate, camsilate, digluconate, ring penta
Alkane propionate, lauryl sulfate, esilate, glucose enanthate, glycerophosphate, Hemisulphate, enanthate, caproic acid
Salt, fumarate, hydrochloride, hydrobromate, hydriodate, 2- isethionates, lactate, maleate, first sulphur
Hydrochlorate, hydrochloride, 2- naphthalene sulfonates, oxalates, pectinic acid salt, sulfate, 3- phenylpropionic acid salt, picrate, trimethyl
Acetate, propionate, succinate, tartrate, rhodanate, tosilate and caprate.In addition, alkaline nitrogenous base
Quaterisation generation quaternary ammonium salt can occur with following reagent for group：Such as low-carbon alkyl halide, including methyl, ethyl, propyl group
With the chloride of butyl, bromide and iodide；Such as dialkyl sulfate, including dimethyl, diethyl, dibutyl and diamyl
Sulfate；The chloride of such as long chain halide, including decyl, lauryl, myristyl and stearyl, bromide and iodate
Thing；Such as aralkyl halide, the bromide of such as benzyl and phenethyl.
With hydroxyl, amino, sulfydryl, the related protection group such as carboxyl refers to that by hydroxyl, amino, sulfydryl carboxyl etc. passes through official
Protection can be rolled into a ball, it is to avoid it occurs undesirable reaction, and protection group used is well-known to those skilled in the art, is such as existed
Protective Groups in Organic Synthesis (John Wiley＆Sons, New York, the third edition, 1999)
In those protection groups for referring to.
It is present invention additionally comprises the compounds of this invention of isotope marks, i.e., identical with above-mentioned disclosed structure, but the knot
One or more atoms are had identical proton number from it in structure but the atom of different neutron populations is substituted.With reference to chemical combination of the present invention
The isotope embodiment of thing include hydrogen, carbon, nitrogen, oxygen, sulphur, fluorine, chlorine, the isotope of iodine, respectively such as2H,3H,13C,14C,15N,18O
,17O,35S,18F,36Cl and131I etc..The compound of the present invention, its stereoisomer, dynamic isomer or pharmaceutically acceptable
Salt, and the above form containing above-mentioned isotope and/or other atom isotopes compound, in the scope of the invention
It is interior.The compounds of this invention of some isotope marks, such as quilt3H or14Those compounds that C is marked can be used for drug entities
In distribution experiment, therefore, these3H or14C isotopes are prepared because it is easy and detection is particularly preferred.In addition, heavier
Isotope such as2Some the compounds of this invention that H is substituted with more preferable metabolic stability due to having some treatments excellent
Gesture, can such as increase Half-life in vivo and less dosage, therefore,2H is also preferred in some cases.
The compounds of this invention has FGFR4 selective inhibitories, available for application and preparation in the medicine of the mankind or animal doctor
Or pharmaceutical composition, disease relevant disease such as cancer for treating FGFR4 or FGF19 mediations.Specifically, the chemical combination
Thing can be used for the cancer for treating the mankind or animal, including liver cancer, stomach cancer, cancer of pancreas, clear-cell carcinoma, sarcoma, cholangiocarcinoma, colon
Cancer, prostate cancer, oophoroma, breast cancer etc..
Through the application, multiple embodiments of the Compounds and methods for of the present invention are mentioned above.Described multiple embodiments
Multiple illustrative examples are aimed to provide, it should not be constructed as the description of substitute.Also, it is noted that reality discussed herein
Example (including various methods and parameter) is applied only for the explanation present invention, and is not in any way limit the scope of the present invention.
For the description present invention, specific embodiment is listed below.But it is to be understood that the invention is not restricted to these embodiments,
Following examples are only to provide the method for the practice present invention, and scope of the invention is not limited in any way.
Each general formula compound of the present invention is prepared according to following preparation scheme：
The preparation method of logical formula (I) compound is summarized as follows：
The coupling of intermediate A 1 commercially available first and commercially available intermediate A 2 prepares compound A-13, compound A-13 again with compound
A4 carries out further coupling reaction and obtains compound A-45, and the removing amido protecting group of compound A-45 obtains amino-compound A6,
Compound A6 and acryloyl chloride A7 reactions obtain target compound (I).
The compound that the present invention is provided can be prepared by Standard synthetic methods well known in the art, and this specification is provided
Prepare the conventional method of the compounds of this invention.Initiation material can generally be obtained by being commercialized, for example, pass through AlfaTCI,Splendid remote chemistry, pacifies resistance to Jilin Chemical, Ace spy's (Chengdu) bio-pharmaceuticals and Chengdu shellfish
The companies such as this special reagent are commercially available, or are prepared by method well-known to those skilled in the art.
Following reaction methods and synthesis step provide the possibility for being used for synthesizing the compounds of this invention and key intermediate
Approach.On being described in more detail for indivedual reactions steps, referring to following embodiments.It will be understood by those skilled in the art that of the invention
Compound can also be obtained by other route of synthesis.Although hereafter having used specific initiation material and examination in reaction process
Agent, but these initiation materials can be replaced with reagent by other similar initiation materials or reagent place, to provide various derivatives
Thing.In addition, under the guidance of this specification, those skilled in the art can be passed through by many compounds made from following methods
Known conventional chemical processes are further modified.
In the preparation of the compounds of this invention, it may be necessary to protect intermediate some interference functional groups (for example, primary amine or
Secondary amine).Requirement for such protection group changes depending on the property of specific functional group and the condition of preparation method.Appropriate amino
Protection group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group (Cbz), 9- fluorenes methylene oxygen carbonyls
(Fmoc) etc..Appropriate hydroxyl protecting group includes pi-allyl, acetyl group, silylation, benzyl, trityl, to methoxybenzene
Methyl etc..It can be easily determined by (specifically referring to Protective Groups by those skilled in the art for such protection group
In Organic Synthesis, John Wiley＆Sons, New York, the third edition, 1999).
Hereafter it is explained further by embodiment with preparation and enumerates the compounds of this invention and corresponding preparation method.Ying Liao
Solution, although given in specific embodiment typical or preferred reaction condition (such as reaction temperature, the time, the mol ratio of reactant,
Reaction dissolvent and pressure etc.), but those skilled in the art can also use other reaction conditions.Optimum reaction condition can be with
Specific reaction substrate used or solvent and change, but the condition can be passed through by those skilled in the art it is conventional excellent
Change and determine.
The structure of following embodiment compounds is characterized by nuclear magnetic resonance (NMR) and/or mass spectrum (MS).Use Bruker
Ascend 400MHz NMR spectra instrument, compound is dissolved in appropriate deuterated reagent, entered under environment temperature by internal standard of TMS
OK1H-NMR is analyzed.Nmr chemical displacement (δ) is used hereinafter referred to as in units of ppm：S, it is unimodal；D, doublet；T, it is triple
Peak；Q, quartet；M, multiplet；Brs, width unimodal.MS passes through Waters UPLC-VevoTMTQ MS mass spectrographs (ESI) are determined.
React initiation material, intermediate and embodiment compound can be filtered by precipitation, crystallized, evaporation, distillation with
And the routine techniques such as chromatography (such as column chromatography, TLC is isolated and purified) carries out isolation and purification.
TLC uses Yantai Huanghai Sea HSGF254 tlc silica gels plate (0.2 ± 0.03mm), and TLC, which is isolated and purified, uses Yantai
Huanghai Sea HSGF254 thin-layer chromatography thickness prepares plate (0.9~1mm), is purchased from Haiyang Chemical Plant, Qingdao.
Column chromatography is using the mesh silica gel of the Yantai Huanghai Sea 300~400 as carrier, purchased from Haiyang Chemical Plant, Qingdao.
The commercialization solvent and reagent used in experiment unless otherwise specified, need not be further purified or handle after purchase
Directly use.During with reference to other embodiments or synthetic method, reaction condition (reaction temperature, reaction dissolvent, reactant molar ratio
Or/and duration of the reaction) may be different.In general, reaction process can be monitored by TLC, the suitable time is selected accordingly
Terminating reaction is simultaneously post-processed.The purification condition of compound is it can also happen that change, it is however generally that, the R according to TLCfValue choosing
Suitable column chromatography eluant, eluent is selected, or respective compound is isolated and purified by preparing TLC.
Embodiment 1
The compounds of this invention 1 is implemented to prepare according to above-mentioned preparation scheme.
1A (10g, 46.3mmol) is added in 500mL there-necked flasks, is dissolved under anhydrous THF (100mL), nitrogen protection, ice bath
Stirring, is added dropwise borine tetrahydrofuran solution (1M) (231mL, 231mmol), and drop finishes, is warmed to room temperature, is stirred overnight, and adds under ice bath
Water (150mL) is quenched, and ethyl acetate extraction, water washing, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, decompression is steamed
Except solvent, white solid 1B (9.7g, yield 100%) is obtained
1B (9.7g, 48.0mmol), manganese dioxide (29g, 336mmol), dichloromethane are added in 1L round-bottomed flasks
(400mL), stirs 3h at room temperature, and TLC detection reactions are complete.Suction filtration, dichloromethane washing, merging filtrate removes solvent under reduced pressure,
Obtain brown solid 1C (7.3g, yield 76.0%).
1C (3.7g, 18.5mmol), urea (16.6g, 277mmol), in 180 DEG C of oil baths are added in 250mL round-bottomed flasks
Middle stirring reaction 5h, is cooled to room temperature, and add water stirring, suction filtration, water washing, collects filter cake, and light yellow solid 1D is obtained after drying
(4g, yield 96.1%).
1D (4g, 17.8mmol) is added in 100mL round-bottomed flasks, POCl3 (25mL) flows back anti-in 110 DEG C of oil baths
5h is answered, reaction solution cooling removes excessive POCl3 under reduced pressure, is cooled to room temperature, water quenching on the rocks is gone out, saturated aqueous sodium carbonate is adjusted
PH to 8~9 is saved, the residue obtained after solvent is evaporated off through silica gel column layer in ethyl acetate extraction, water washing, anhydrous sodium sulfate drying
Analyse (petroleum ether：Ethyl acetate 5:1) isolate and purify and obtain light yellow solid 1E (2g, yield 46.1%).1H NMR(400MHz,
CDCl3) δ 9.24 (s, 1H), 8.13 (d, J=2.0Hz, 1H), 8.03 (dd, J=9.0,2.1Hz, 1H), 7.88 (d, J=
9.0Hz,1H).
1E (2g, 8.21mmol), 1F (1.49g, 7.92mmol), Pd (PPh are added in 250mL round-bottomed flasks3)2Cl2
(576mg, 0.821mmol), cesium carbonate (8.02g, 24.6mmol), THF (20mL), Isosorbide-5-Nitrae-dioxane (20mL), water
(4mL), reacts 3h in 80 DEG C of oil baths under nitrogen protection, adds water, and ethyl acetate extraction, washing, anhydrous sodium sulfate drying is evaporated off
Solvent, obtained residue is through silica gel column chromatography (petroleum ether：Ethyl acetate 5:1) isolate and purify light yellow solid 1G (1.93g,
Yield 78.2%).
1G (1.93g, 6.42mmol) is added in 250mL round-bottomed flasks, is dissolved with anhydrous THF (60mL), under nitrogen protection
Stirred at -20 DEG C, SO is added dropwise2Cl2(1.30mL, 16.0mmol), drop finishes, and continues to stir 1h, adds water (1mL) and is quenched
Reaction, reaction solution is spin-dried for, and adds acetonitrile, and stirring has solid precipitation, filter cake is collected in suction filtration, acetonitrile washing, light yellowly dry
Solid 1H (740mg, yield 31.2%).
1H (300mg, 0.812mmol), 1I (246mg, 1.22mmol), sodium acid carbonate are added in 50mL round-bottomed flasks
(171mg, 2.03mmol), NMP (12mL), the stirring reaction 10h in 95 DEG C of oil baths.Reaction solution is cooled to room temperature, adds water, acetic acid second
Ester is extracted, and solvent is evaporated off, and residue is through silica gel column chromatography (petroleum ether in water washing, anhydrous sodium sulfate drying：Ethyl acetate 2:1) divide
Off-white powder 1J (234mg, yield 53.8%) is obtained from purifying.
1J (234mg, 0.437mmol) is added in 100mL round-bottomed flasks, is dissolved with dichloromethane (3mL), trifluoro second is added
Sour (1.6mL, 21.9mmol), is stirred at room temperature 4h, reaction solution is spin-dried for, and is dissolved with ethyl acetate, 10% sodium hydrate aqueous solution is washed
Wash, anhydrous sodium sulfate drying is spin-dried for, obtain compound 1K, the solid is dissolved in dichloromethane (6mL), be placed in ice bath and stir, according to
Secondary addition DIPEA (67 μ L, 0.407mmol), acryloyl chloride (33 μ L, 0.407mmol) stirs 1h, and reaction solution is spin-dried for, and adds full
With sodium acid carbonate and ethyl acetate, extracting and demixing collects organic phase, and washing, anhydrous sodium sulfate drying is evaporated off solvent, obtained
Residue is through column chromatography (dichloromethane：Methanol 100:1) isolate and purify and obtain compound as white solid 1 (138mg, yield 64.5%)
Obtain compound 1, ESI-MS m/z：510.1[M+H]+。
Embodiment 2
The compounds of this invention 2 is implemented to prepare according to the similar approach of above-mentioned preparation scheme and embodiment 1, obtains compound 2,
ESI-MS m/z：507.4[M+H]+。
Embodiment 3
The compounds of this invention 3 is implemented to prepare according to the similar approach of above-mentioned preparation scheme and embodiment 1, obtains compound 3,
ESI-MS m/z：511.2[M+H]+。
Embodiment 4
The compounds of this invention 4 is implemented to prepare according to the similar approach of above-mentioned preparation scheme and embodiment 1, obtains compound 4,
ESI-MS m/z：496.3[M+H]+。
Embodiment 5
The compounds of this invention 5 is implemented to prepare according to the similar approach of above-mentioned preparation scheme and embodiment 1, obtains compound 5,
ESI-MS m/z：493.2[M+H]+。
Embodiment 6
The compounds of this invention 6 is implemented to prepare according to the similar approach of above-mentioned preparation scheme and embodiment 1, obtains compound 6,
ESI-MS m/z：497.4[M+H]+。
Embodiment 7
The compounds of this invention 7 is implemented to prepare according to the similar approach of above-mentioned preparation scheme and embodiment 1, obtains compound 7,
ESI-MS m/z：508.4[M+H]+。
Embodiment 8
The compounds of this invention 8 is implemented to prepare according to the similar approach of above-mentioned preparation scheme and embodiment 1, obtains compound 8,
ESI-MS m/z：505.1[M+H]+。
Embodiment 9
The compounds of this invention 9 is implemented to prepare according to the similar approach of above-mentioned preparation scheme and embodiment 1, obtains compound 9,
ESI-MS m/z：509.3[M+H]+。
Embodiment 10
The compounds of this invention 10 is implemented to prepare according to the similar approach of above-mentioned preparation scheme and embodiment 1, obtains compound
10, ESI-MS m/z：504.3[M+H]+。
Biological test
Pharmacokinetics in rats is evaluated
The internal pharmacokinetics behavior of this experimental evaluation compound 1 and compound 10.
Test compounding medicine：
When preparing intravenously administrable formulation, testing sample is weighed, 0.166mL100%DMSO shakings are added, ultrasound is until solid
It is completely dissolved, 0.160mL solution is taken out afterwards into the clean centrifuge tubes of 15mL, adds 0.32mLCremophorEL and fully vibrate,
Finally dropwise 2.72mL physiological saline simultaneously fully vibration obtain clear transparent solutions, final concentration of 1mg/mL, excipient respectively into
Point ratio is：5%DMSO+10%Cremophor EL+85% physiological saline.
When preparing oral administered dosage form, testing sample is weighed, first adds 0.026mLTween80 to be fully ground, is added dropwise
5.119mL0.5% sodium carboxymethylcelluloses (CMC-Na), final concentration of 2mg/mL, each component ratio of excipient is：0.5%
Tween 80+99.5% (0.5%CMC-Na).
All formulations Fresh and completion administration in 1 hour after preparing on the day of zoopery.It is accurate in preparation
After getting ready, three parts of samples are pipetted, each 0.02mL is used for the concentration for detecting determinand in preparation.
Administration：
6 rats are divided into two groups, every group 3.One of which is by intravenously administrable, and dosage is 2mg/kg；One group passes through mouth
Clothes administration, dosage is 10mg/kg.Each group upon administration 0,0.083,0.25,0.5,1,2,4,8,24h is quiet by eye socket respectively
Arteries and veins collects blood.
Blood specimen collection and analysis：
By way of eye socket is taken a blood sample by about 100 μ L blood collections into the clean EP pipes containing EDTA (EDTA final concentration
For 0.25mg/mL).It is rapid after the completion of collection to be inverted heparin tube at least 5 times, to ensure to be well mixed, it is then placed within ice
On.Each time point blood collected is at 4 DEG C, and 8000rpm centrifuges 5 minutes to obtain blood plasma.Separately 1.5mL centrifuge tubes are taken to mark
Compound name, number of animals at time point, blood plasma is transferred in the pipe.Blood plasma is stored in -80 DEG C until analysis.All matter
Analysis of spectrum data are collected by software Analyst1.5 (Applied Biosystems).All pharmacokinetic parameters are used
WinNonlin (version 6.1, Pharsight, Mountain View, CA) is analyzed.
Experimental result：
| Compound | Tmax(h) | Cmax(μg/mL) |
| 1 | 6 | 10.2 |
| 10 | 6 | 8.01 |
Analytical conclusions：
It can be seen from experimental result, the deuterated compound 1 of the present invention, compared with corresponding non-deuterated compound 16,
Cmax and AUC are significantly improved, and wherein Cmax improves at least 20%.
Claims (9)
1. a kind of formula (I) compound, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt,
Wherein, R1, R2It is each independently selected from hydrogen, deuterium, or one or many deuterated or complete deuterated C1-C4Alkyl；
R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18It is hydrogen, deuterium or halogen；
Also, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18In at least one be deuterium, or
R1, R2For one or many deuterated or complete deuterated C1-C4Alkyl；
X is selected from oxygen atom, carbon atom；
N=0,1.
2. formula (I) compound as claimed in claim 1, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt,
Including the compound of logical formula (II),
Wherein, R1, R2It is each independently selected from hydrogen, deuterium, or one or many deuterated or complete deuterated C1-C4Alkyl；
R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18It is hydrogen, deuterium or halogen；
Also, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18In at least one be deuterium, or
R1, R2For one or many deuterated or complete deuterated C1-C4Alkyl.
3. formula (II) compound as claimed in claim 2, it is characterised in that R1, R2Separately it is selected from：Hydrogen, deuterated first
Base, or deuterated ethyl.
4. formula (II) compound as claimed in claim 3, it is characterised in that R1, R2Separately it is selected from a deuterium methyl, two deuteriums
Methyl, three deuterium methyl, a deuterium ethyl, two deuterium ethyls, three deuterium ethyls, four deuterium ethyls, and five deuterium ethyls.
5. formula (II) compound as claimed in claim 4, it is characterised in that R1, R2Separately it is selected from three deuterium methyl.
6. such as claim 1, formula (I) (II) compound described in 2,3,4,5, it is characterised in that the compound is selected from：
7. the compound as any one of claim 1 to 6, its stereoisomer, dynamic isomer or pharmaceutically acceptable
Salt, as FGFR4 Kinase Selectivity inhibitor, preparing treatment by FGFR4 or FGF19 disease mediated medicine or medicine group
Application in compound.
8. medicine as claimed in claim 7 or pharmaceutical composition, it is used for the treatment of various cancers.
9. as claimed in claim 8, the various cancers for the treatment of include：Liver cancer, stomach cancer, clear-cell carcinoma, sarcoma, cholangiocarcinoma, colon
Cancer, prostate cancer, oophoroma, breast cancer.
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| CN201610247898.1A CN107304201A (en) | 2016-04-20 | 2016-04-20 | A kind of deuterated Kinase Selectivity inhibitor |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610247898.1A CN107304201A (en) | 2016-04-20 | 2016-04-20 | A kind of deuterated Kinase Selectivity inhibitor |
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2016
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