CN107304211A - A kind of selective FGFR4 kinase inhibitors - Google Patents
A kind of selective FGFR4 kinase inhibitors Download PDFInfo
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- CN107304211A CN107304211A CN201610581171.7A CN201610581171A CN107304211A CN 107304211 A CN107304211 A CN 107304211A CN 201610581171 A CN201610581171 A CN 201610581171A CN 107304211 A CN107304211 A CN 107304211A
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- 0 CC(C)(C)CNCCN(*)CC(C)=S Chemical compound CC(C)(C)CNCCN(*)CC(C)=S 0.000 description 5
- VYGOKPFOEDPIIZ-UHFFFAOYSA-N CN(CCC=O)c1cc(NC(N2c3nc(C=O)c(CN(CCN(C)C4)C4=S)cc3CCC2)=O)ncc1C#N Chemical compound CN(CCC=O)c1cc(NC(N2c3nc(C=O)c(CN(CCN(C)C4)C4=S)cc3CCC2)=O)ncc1C#N VYGOKPFOEDPIIZ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
Offer formula (I) compound of the present invention, 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.FGF19 and 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 is as one of FGFR family members, in embryonic development, nervous centralis control, tissue repair, or even swollen
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 1. formula (I) compounds, its stereoisomer, dynamic isomer or pharmaceutically acceptable
Salt,
Wherein, Y is carbon atom or nitrogen-atoms；
R1Selected from following group：
R2, R3, R4It independently is N or C (RX)；
R5Selected from-NRY1RY2,-O- (CH2)0-3-RY1,
R6Selected from hydrogen, halogen, cyano group, amino, amide groups, hydroxyl, ester group, acyl group, acyloxy, sulfonyl, sulfinyl,
Alkyl, alkoxy, aryl, cycloalkyl, heteroaryl, heterocyclic radical, cycloheteroalkylalkyl；
R7, R8, R9It independently is N or C (RX)；
RXIt independently is hydrogen, halogen, cyano group, amino, amide groups, hydroxyl, ester group, acyl group, acyloxy, sulfonyl, sub- sulphur
Acyl group, alkyl, alkoxy, aryl, cycloalkyl, heteroaryl or heterocyclic radical；
When Z oxygen atoms；RY1, RY2It independently is alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, silicon substrate；
When Z sulphur atoms；RY1, RY2It independently is hydrogen, alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, silicon substrate.
Formula (I) compound of the present invention, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt, its
Include logical formula (II) compound
Wherein, R5Selected from-NRY1RY2,-O- (CH2)0-3-RY1,
R6Selected from hydrogen, halogen, cyano group, amino, amide groups, hydroxyl, ester group, acyl group, acyloxy, sulfonyl, sulfinyl,
Alkyl, alkoxy, aryl, cycloalkyl, heteroaryl, heterocyclic radical, cycloheteroalkylalkyl；
RY1, RY2It independently is alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, silicon substrate.
Formula (II) compound of the present invention, it is characterised in that R5Selected from following group：
R6Selected from hydrogen, and following group：
Formula (I) compound of the present invention, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt, its
Include logical formula (III) compound
Wherein, R5Selected from-NRY1RY2,-O- (CH2)0-3-RY1,
R6Selected from hydrogen, halogen, cyano group, amino, amide groups, hydroxyl, ester group, acyl group, acyloxy, sulfonyl, sulfinyl,
Alkyl, alkoxy, aryl, cycloalkyl, heteroaryl, heterocyclic radical, cycloheteroalkylalkyl；
RY1, RY2It independently is hydrogen, alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, silicon substrate.
Formula (III) compound of the present invention, it is characterised in that R5Selected from following group：
R6Selected from hydrogen, and following group：
Formula (III) compound of the present invention, it is characterised in that R5Selected from following group：
Formula (I) of the present invention, (II), (III) compound, its stereoisomer or pharmaceutically may be used at dynamic isomer
The salt of receiving, it is selected from following compounds：
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.
Detailed description of the invention
Term " hydrogen " in this article refers to-H.
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 " cyano group " in this article refers to-CN.
Term " amino " in this article refers to-NH2。
Term " hydroxyl " in this article refers to-OH.
Term " aryl " in this article refers to that 6 to 10 yuan of full carbon are monocyclic or fused polycycle (shares adjacent carbon atom pair
Ring) group, polycyclic (i.e. the ring with the adjacent carbon atom pair) group of the pi-electron system with conjugation.Aryl can produced
It is covalently attached on any carbon atom of rock-steady structure with defined chemical constitution.Aryl described herein can be optionally by one
Or multiple substituents are replaced：Fluorine, chlorine, bromine, iodine, cyano group, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl group,
Amide groups, ester group, amido, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl group, Heterocyclylalkyl, alkenyl, alkynyl and cycloalkyloxy.
It is that term " heteroaryl " in this article refers to be made up of 5 to 10 atoms and be selected from N, O containing at least one
Or the heteroatomic aromatic group such as S.The term can have single ring (non-limiting examples include furans, thiophene, imidazoles,
Pyrazoles, pyridine, pyrazine, oxazole, thiazole etc.) or multiple condensed ring (non-limiting examples include benzothiophene, benzofuran, indoles,
Iso-indoles etc.), wherein condensed ring can be or can not be comprising heteroatomic aromatic group, it is assumed that tie point is by virtue
The atom of race's heteroaryl groups.Heteroaryl described herein optionally can be replaced by one or more substituents：Fluorine,
Chlorine, bromine, iodine, cyano group, nitro, hydroxyl, amino, alkyl, alkoxy, acyl group, acyloxy, amide groups, ester group, amido, sulfonyl,
Sulfinyl, cycloalkyl, cycloalkenyl group, Heterocyclylalkyl, alkenyl, alkynyl and cycloalkyloxy.
Term " cycloalkyl " in this article refers to have 3 to 10 carbon atoms, with monocyclic or polycyclic (including condensed ring, bridge
Ring and spiral ring system) cyclic alkyl.The non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl
Deng.Cycloalkyl described herein optionally can be replaced by one or more substituents：Fluorine, chlorine, bromine, iodine, cyano group, nitre
Base, hydroxyl, carboxyl, amino, alkyl, oxo, alkoxy, acyl group, acyloxy, amide groups, ester group, amido, cycloalkyl, cyclenes
Base, Heterocyclylalkyl, alkenyl, alkenyloxy group, alkynyl, cycloalkyloxy, aryl or heteroaryl.
Term " Heterocyclylalkyl " in this article refers at least contain selected from the hetero atom such as O, N and S and optionally one containing one
The non aromatic cycloalkyl of bar or a plurality of double or triple bonds.Heterocyclylalkyl can have 3 to 10 annular atoms as overall.Heterocycle alkane
Base can be covalently attached in any heteroatom or carbon atom of generation rock-steady structure with defined chemical constitution.Heterocyclylalkyl
Non-limiting examples include：Pyrrolinyl, piperidyl, piperazinyl, tetrahydrofuran base, THP trtrahydropyranyl, morpholinyl, pyranose
Deng.One or more N or S atom on Heterocyclylalkyl can be oxidized (for example morpholine N-Oxide, thiomorpholine S- oxides,
Thiomorpholine S, S- dioxide).Heterocyclylalkyl can also contain one or more oxo groups, such as phthalimido group, piperazine
Pyridine ketone group, oxazolidine ketone group, 2,4 (1H, 3H)-dioxo-pyrimidine radicals, pyridine -2 (1H) -one base etc..Heterocyclylalkyl described herein
Optionally it can be replaced by one or more substituents：Fluorine, chlorine, bromine, iodine, cyano group, nitro, hydroxyl, carboxyl, amino,
Alkyl, alkoxy, oxo, acyl group, acyloxy, amide groups, ester group, amido, cycloalkyl, cycloalkenyl group, Heterocyclylalkyl, alkenyl, alkene
Epoxide, alkynyl, cycloalkyloxy, aryl or heteroaryl.
Term " alkenyl " in this article refers to have 2 to 8 carbon atoms and with the unsaturated site of at least one alkenyl
Alkenyl group.The non-limiting examples of alkenyl include vinyl, acrylic, pi-allyl, isopropenyl, cyclobutenyl, isobutene
Base etc..Alkenyl described herein optionally can be replaced by one or more substituents：Fluorine, chlorine, bromine, iodine, cyano group, nitre
Base, hydroxyl, carboxyl, amino, alkyl, alkoxy, oxo, acyl group, acyloxy, amide groups, ester group, amido, cycloalkyl, cyclenes
Base, Heterocyclylalkyl, alkenyl, alkenyloxy group, alkynyl, alkynyloxy group, cycloalkyloxy, aryl or heteroaryl.
Term " alkenyloxy group " in this article refers to alkenyl-O-, wherein the alkenyl is as defined herein.
Term " alkynyl " in this article refers to have 2 to 8 carbon atoms and with the unsaturated site of at least one alkynyl
Alkynyl group.The non-limiting examples of alkynyl include acetenyl, propargyl etc..Alkynyl described herein can be optionally by one
Or multiple substituents are replaced：Fluorine, chlorine, bromine, iodine, cyano group, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, oxo,
Acyl group, acyloxy, amide groups, ester group, amido, cycloalkyl, cycloalkenyl group, Heterocyclylalkyl, alkenyl, alkenyloxy group, alkynyl, alkynyloxy group,
Cycloalkyloxy, aryl or heteroaryl.
Term " cycloalkenyl group " in this article refers to the non-aromatic group of naphthene base with 3 to 10 carbon atoms, and it has
The ring (including fusion, bridged ring system and spiral ring system) of single or multiple ring-types and with least one carbon-carbon double bond
Unsaturation ring.The non-limiting examples of cycloalkenyl group include cyclopropanyl, cyclobutane base, cyclopentenyl, cyclopentadienyl group, cyclohexene
Base, cyclohexadienyl, cycloheptenyl, cyclo-octene base etc..Cycloalkenyl group 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, oxo, acyl group, acyloxy,
Amide groups, ester group, amido, cycloalkyl, cycloalkenyl group, Heterocyclylalkyl, alkenyl, cycloalkyloxy, aryl or heteroaryl.
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 " alkoxy " in this article refers to alkyl group and is connected by oxygen atom with molecule remainder (- O- alkane
Base), wherein the alkyl is as defined herein.The non-limiting examples of alkoxy include methoxyl group, ethyoxyl, trifluoro methoxy
Base, difluoro-methoxy, positive propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy etc..
Term " amide groups " in this article refers to-NR30- C (O)-alkyl ,-NR30- C (O)-cycloalkyl ,-NR30- C (O)-ring
Alkenyl ,-NR30- C (O)-aryl ,-NR30- C (O)-heteroaryl and-NR30- C (O)-Heterocyclylalkyl, wherein R30For hydrogen, cycloalkyl,
Cycloalkenyl group, aryl, heteroaryl, Heterocyclylalkyl and alkyl.Wherein described hydrogen, cycloalkyl, cycloalkenyl group, aryl, heteroaryl, heterocycle alkane
The group such as base and alkyl is as defined herein.
Term " acyl group " in this article refer to H-C (O)-, R31R32N-C (O)-, alkyl-C (O)-, cycloalkyl-C (O)-, ring
Alkenyl-C (O)-, Heterocyclylalkyl-C (O)-, aryl-C (O)-and heteroaryl-C (O)-, wherein the R31And R32Separately
Selected from hydrogen, hydroxyl, alkyl, Heterocyclylalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl group, acyl group or cycloalkyl.Its
Described in hydrogen, hydroxyl, alkyl, Heterocyclylalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl group, acyl group and cycloalkyl etc.
Group is as defined herein.
Term " sulfonyl " in this article refers to R33R34N-S(O)2-, cycloalkyl-S (O)2-, cycloalkenyl group-S (O)2-, virtue
Base-S (O)2-, heteroaryl-S (O)2-, Heterocyclylalkyl-S (O)2- and alkyl-S (O)2-, wherein the R33And R34Separately
Selected from hydrogen, hydroxyl, alkyl, Heterocyclylalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl group, acyl group or cycloalkyl.Its
Described in hydrogen, hydroxyl, alkyl, Heterocyclylalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl group, acyl group and cycloalkyl etc.
Group is as defined herein.
Term " sulfinyl " in this article refers to R35R36N-S (O)-, cycloalkyl-S (O)-, cycloalkenyl group-S (O)-, virtue
Base-S (O)-, heteroaryl-S (O)-, Heterocyclylalkyl-S (O)-or alkyl-S (O)-, wherein the R35And R36Separately select
From hydrogen, hydroxyl, alkyl, Heterocyclylalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl group, acyl group or cycloalkyl.Wherein
The bases such as the hydrogen, hydroxyl, alkyl, Heterocyclylalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl group, acyl group and cycloalkyl
Group is as defined herein.
Term " acyloxy " in this article refer to-O-C (O)-alkyl ,-O-C (O)-cycloalkyl ,-O-C (O)-cycloalkenyl group ,-
O-C (O)-aryl ,-O-C (O)-heteroaryl and-O-C (O)-Heterocyclylalkyl, wherein the alkyl, cycloalkyl, cycloalkenyl group, aryl,
The group such as heteroaryl and Heterocyclylalkyl is as defined herein.
Term " ester group " in this article refer to alkyl-O-C (O)-, cycloalkyl-O-C (O)-, cycloalkenyl group-O-C (O)-, heterocycle
Alkyl-O-C (O)-, aryl-O-C (O)-and heteroaryl-O-C (O)-, wherein the alkyl, cycloalkyl, cycloalkenyl group, heterocycle alkane
The groups such as base, aryl and heteroaryl are as defined herein.
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.
In each position of this specification, the substituent of the compounds of this invention is disclosed in the form of group or scope.
This specifically means that the present invention includes each individual sub-combination in such group and each member of scope or member.Such as
Term " C1-6Alkyl " specifically means to separately disclose methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
Term " the compounds of this invention " (unless otherwise particularly pointing out) in this article refers to formula (I) compound and its all pure
And the stereoisomer of mixing, 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.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, the derivative or prodrug for improving 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 acids 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, bromide and iodide of butyl；Such as dialkyl sulfate, including dimethyl, diethyl, dibutyl and diamyl
Sulfate；Such as long chain halide, including decyl, lauryl, chloride, bromide and the iodate of myristyl and stearyl
Thing；Such as aralkyl halide, the bromide of such as benzyl and phenethyl.
The protection group related to hydroxyl, amino, sulfydryl, carboxyl etc., refers to hydroxyl, amino, sulfydryl, carboxyl etc. by 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 includes 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..
Embodiment
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, implement below
Example is 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：
Intermediate X 1 commercially available first prepares compound X3, compound X3 reductionization with the coupling of commercially available intermediate X 2
Compound X4, compound X4 obtain compound X6 with compound X5 coupling reactions, and compound X6 is obtained with compound X7 exchange reactions
Final general formula compound X8.
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 Alfa TCI、Splendid remote chemistry, the resistance to Jilin Chemical of peace, special (Chengdu) bio-pharmaceuticals of Ace and the special reagent of Chengdu bass
It is commercially available, or is prepared by method well-known to those skilled in the art Deng company.
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 include 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 by precipitation, filtering, crystallization, evaporation, distill 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 bromo- PAs of the fluoro- 5- of compound 4- (7.64g, 40.0mmol) are dissolved in N-methyl pyrrolidones (180ml)
In, then add Zn (CN)2(2.47g, 21.0mmol) and tetrakis triphenylphosphine palladium (4.63g, 4.0mmol), in nitrogen protection
Lower 135 DEG C are reacted 5 hours, and cooling adds water, with ethyl acetate, merge organic phase, the N-methyl pyrrole in most organic phase is washed with water
Pyrrolidone, saturated common salt water washing, anhydrous sodium sulfate drying is filtered, and concentration is beaten, mistake with petrol ether/ethyl acetate (2/1)
Filter is dried to obtain compound 1A (4.8g).
By compound 1A (686mg, 5.0mmol), N- methyl -2- methoxy ethyls amine (1.074ml, 10.0mmol), N,
N- dimethyl acetamides (12ml) and diisopropyl ethyl amine (3.3ml, 20.0mmol) are placed in tube sealing, in 80 DEG C of reactions, warp
Thin-layer chromatography monitoring reaction is complete, is concentrated under reduced pressure at 75 DEG C, is beaten with petrol ether/ethyl acetate (2/1), and filtration drying is obtained
Compound 1B (508mg).
2- amino -3- pyridine carboxaldehydes (25.0g, 204.7mmol), 1,1- dimethoxy acetone are sequentially added into there-necked flask
(31.4g, 266.1mmol), ethanol (250ml) and water (50ml), under the conditions of 0-15 DEG C, are added dropwise sodium hydroxide
Water (25ml) solution of (10.2g, 255.9mmol), drop finishes, and continues stirring reaction.Complete, the concentration through thin-layer chromatography monitoring reaction
Ethanol is removed, is extracted with ethyl acetate, merges organic layer, anhydrous sodium sulfate drying is filtered and concentrated.Wash residual with n-hexane
Slag, is collected by filtration and obtains compound 1C (35.0g).
Compound 1C (35g, 171.4mmol) is dissolved in ethanol (400ml), palladium/carbon (4g, 10%) is added, in hydrogen
Under the conditions of react and stay overnight.Complete through thin-layer chromatography monitoring reaction, diatomite filtering, concentration filtrate obtains compound 1D (34.5g).
Compound 1D (400mg, 1.92mmol) is dissolved in dichloromethane (5ml), diisopropyl ethyl amine is then added
(476 μ l, 2.88mmol), is cooled to 0 DEG C, instills the dichloromethane of p-nitrophenyl chloroformate ester (427mg, 2.12mmol)
(2ml) solution, recovers to room temperature reaction.It is complete through thin-layer chromatography monitoring reaction, add saturated aqueous ammonium chloride, dichloromethane
Extraction, merges organic phase, uses saturated common salt water washing, and anhydrous sodium sulfate drying is filtered, concentration, silica gel column chromatography (acetic acid second
Ester：Acetone=50:1~10) obtain compound 1E (243mg).
Compound 1E (243mg, 0.65mmol) and compound 1B (149mg, 0.72mmol) are dissolved in anhydrous tetrahydro furan
In (5ml), be cooled to -15 DEG C, then in nitrogen protection under be slowly added to NaHMDS (1.0M in THF, 720 μ l,
0.72mmol), after reacting 0.5 hour, after addition saturated ammonium chloride solution is quenched, it is extracted with ethyl acetate, merges organic phase, use
Saturated common salt water washing, anhydrous sodium sulfate drying is filtered, concentration, silica gel column chromatography (petroleum ether：Ethyl acetate=1:1) obtain
White solid 1F (112mg).
Compound 1F (112mg) is dissolved in tetrahydrofuran (2ml) and water (2ml), concentrated hydrochloric acid (0.5ml) is then added,
After room temperature reaction 2 hours, after the sodium acid carbonate neutralization for adding saturation, it is extracted with ethyl acetate, merges organic phase, use saturated common salt
Water washing, anhydrous sodium sulfate drying is filtered, and concentration is beaten with petrol ether/ethyl acetate (5/1), and filtration drying obtains compound
1(88mg)。1H NMR(400MHz,CDCl3)δ13.58(s,1H),10.14(s,1H),8.27(s,1H),7.71–7.62(m,
3H), 4.15-4.09 (m, 2H), 3.88 (t, J=5.2Hz, 2H), 3.73 (t, J=5.2Hz, 2H), 3.40 (s, 3H), 3.30
(s, 3H), 2.98 (t, J=6.3Hz, 2H), 2.11-2.03 (m, 2H)；ESI-MS m/z：395.2[M+H]+。
Embodiment 2
Compound 1D (12.0g, 57.6mmol) is dissolved in acetonitrile (200ml), be added portionwise NBS (10.25g,
It is complete through thin-layer chromatography monitoring reaction 57.6mmol) and then in room temperature reaction, after being concentrated under reduced pressure, water is added, chloroform extraction is closed
And organic phase, saturated common salt water washing is used, anhydrous sodium sulfate drying is filtered, concentration, column chromatography (petroleum ether：Ethyl acetate=2:
1) compound 2A (9.37g) is obtained.1H NMR(400MHz,CDCl3)δ7.30(s,1H),5.58(s,1H),3.48(s,6H),
3.44-3.39 (m, 2H), 2.80 (s, 1H), 2.73 (t, J=6.3Hz, 2H), 1.95-1.86 (m, 2H).
Compound 2A (9.37g, 32.6mmol) is dissolved in anhydrous tetrahydro furan (300ml), nitrogen protection, be cooled to-
78 DEG C, lithium methide (1.6M in Et are added dropwise2O, 20.4ml, 32.6mmol) stirring 5 minutes after, butyl lithium (1.6M is slowly added dropwise
In hexane, 57.1ml, 91.3mmol) stirring 1 hour after, add DMF (5.0ml, 65.2mmol) continue stir, through thin layer
Chromatography monitoring reaction is complete, instills after saturated aqueous ammonium chloride is quenched, adds ethyl acetate extraction, merge organic phase, with full
And brine It, anhydrous sodium sulfate drying, filter, concentration, silica gel column chromatography (petroleum ether：Ethyl acetate=2:1) changed
Compound 2B (5.5g).1H NMR(400MHz,CDCl3)δ10.33(s,1H),7.77(s,1H),5.64(s,1H),5.46(s,
1H), 3.56-3.44 (m, 8H), 2.78 (t, J=6.2Hz, 2H), 2.00-1.90 (m, 2H).
N- (tertbutyloxycarbonyl) monoethanolamine (1.62g, 10.0mmol) is dissolved in tetrahydrofuran (100ml), 0 DEG C is cooled to
Afterwards, sodium hydride (640mg, 16.0mmol) and KI (266mg, 1.6mmol) are added, bromoacetate is then added dropwise
(2.22ml, 20.0mmol), after reacting 5 hours, after being warmed to room temperature reaction 8 hours, concentration adds ammonium chloride solution, uses acetic acid
Ethyl ester is extracted, and merges organic phase, uses saturated common salt water washing, and anhydrous sodium sulfate drying is filtered, concentration, silica gel column chromatography (oil
Ether：Ethyl acetate=5:1) target product (467mg) is obtained.Target product is dissolved in dichloromethane (5ml), three are then added
Fluoroacetic acid (2ml), it is complete through thin-layer chromatography monitoring reaction, it is concentrated under reduced pressure and is dried to obtain compound 2C trifluoroacetate
(775mg)。
Compound 2B (472.5mg, 2.0mmol) and compound 2C trifluoroacetate (488mg, 2.0mmol) is dissolved in
In 1,2- dichloroethanes (10ml), triethylamine (836 μ l, 6.0mmol) is added, sodium triacetoxy borohydride is then added
(635.8mg, 3.0mmol), after reacting at room temperature 3 hours, adds water and is extracted 3 times with dichloromethane, anhydrous sodium sulfate drying, mistake
Filter, concentrates column chromatography (dichloromethane：Methanol=50:1) white solid 2D (585mg) is obtained.
Compound 2D (585mg, 1.82mmol) is dissolved in dichloromethane (10ml), then add DIPEA (451 μ l,
2.73mmol), 0 DEG C is cooled to, dichloromethane (5ml) solution of p-nitrophenyl chloroformate ester (551mg, 2.73mmol) is instilled,
Recover to room temperature reaction.It is complete through thin-layer chromatography monitoring reaction, saturated aqueous ammonium chloride is added, dichloromethane extraction merges
Organic phase, uses saturated common salt water washing, and anhydrous sodium sulfate drying is filtered, concentration, silica gel column chromatography (ethyl acetate：Acetone=
50:1~20) obtain compound 2E (825mg).
Compound 2E (825mg, 1.70mmol) and compound 1B (392mg, 1.9mmol) are dissolved in anhydrous tetrahydro furan
In (10ml), -15 DEG C are then cooled to, nitrogen protection is lower to be added dropwise LiHMDS (1.0M in THF, 1.9ml, 1.9mmol) in this
At a temperature of reaction 4 hours after, add aqueous ammonium chloride solution be quenched after reaction, be extracted with ethyl acetate, merge organic phase, use saturation
Brine It, anhydrous sodium sulfate drying is filtered, concentration, silica gel column chromatography (ethyl acetate：Methanol=500:1~10) obtain
Compound 2F (780mg).
Compound 2F (780mg) is dissolved in tetrahydrofuran (3ml) and water (3ml), the concentrated hydrochloric acid then added (0.7ml),
After room temperature reaction 2 hours, after the sodium acid carbonate neutralization for adding saturation, it is extracted with ethyl acetate, merges organic phase, use saturated common salt
Water washing, anhydrous sodium sulfate drying is filtered, and concentration is beaten with petrol ether/ethyl acetate (5/1), and filtration drying obtains compound
2(700mg)。1H NMR(400MHz,CDCl3)δ13.56(s,1H),10.26(s,1H),8.26(s,1H),7.69(s,1H),
7.68 (s, 1H), 5.14 (s, 2H), 4.28 (s, 2H), 4.14-4.07 (m, 2H), 3.93-3.86 (m, 4H), 3.73 (t, J=
5.2Hz, 2H), 3.46-3.41 (m, 2H), 3.40 (s, 3H), 3.30 (s, 3H), 2.96 (t, J=6.4Hz, 2H), 2.15-1.96
(m,2H)；ESI-MS m/z：508.0[M+H]+。
Embodiment 3
The compounds of this invention 3 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 3, ESI-MS m/z：524.1[M+
H]+。
Embodiment 4
The compounds of this invention 4 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 4, ESI-MS m/z：494.2[M+
H]+。
Embodiment 5
The compounds of this invention 5 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 5, ESI-MS m/z：522.4[M+
H]+。
Embodiment 6
The compounds of this invention 6 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 6, ESI-MS m/z：538.5[M+
H]+。
Embodiment 7
The compounds of this invention 7 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 7, ESI-MS m/z：397.1[M+
H]+。
Embodiment 8
The compounds of this invention 8 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 8, ESI-MS m/z：510.2[M+
H]+。
Embodiment 9
The compounds of this invention 9 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 9, ESI-MS m/z：526.3[M+
H]+。
Embodiment 10
The compounds of this invention 10 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 10, ESI-MS m/z：496.1
[M+H]+。
Embodiment 11
The compounds of this invention 12 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 11, ESI-MS m/z：510.0
[M+H]+。
Embodiment 12
The compounds of this invention 12 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 12, ESI-MS m/z：526.2
[M+H]+。
Embodiment 13
Compound N1- methyl-N2- tertbutyloxycarbonyl ethylenediamine (10.0g, 57.4mmol) is dissolved in tetrahydrofuran (100ml)
In, then add triethylamine (8.4ml, 60mmol), be cooled to 0 DEG C, then be added dropwise bromoacetate (6.31ml,
57.4mmol), continue to react after completion of dropping.Through thin-layer chromatography monitoring reaction, complete, concentration, adds water and is extracted with dichloromethane
Take twice, organic phase uses saturated aqueous ammonium chloride, water and saturated common salt water washing respectively, anhydrous sodium sulfate drying is filtered dense
Contracting, column chromatography (petroleum ether：Ethyl acetate=3:1) target product (13.4g) is obtained.Product is dissolved in dichloromethane (20ml)
In, trifluoroacetic acid (10ml) is added, after reacting at room temperature 8 hours, compound 13A trifluoroacetate is concentrated under reduced pressure to give
(20.5g)。
Compound 2B (4.73g, 20mmol) and compound 13A trifluoroacetate (5.43g, 20mmol) is dissolved in 1,2-
In dichloroethanes (50ml), after then adding triethylamine (8.36ml, 60mmol) stirring 0.5 hour, triacetyl oxygen is added portionwise
Base sodium borohydride (8.48g, 40mmol), continues stirring reaction.It is complete through thin-layer chromatography monitoring reaction, add saturated ammonium chloride water
Solution is quenched, and concentration removes organic solvent, and removing impurity is extracted with ethyl acetate, and extracts with water the target in ethyl acetate
Product, merges aqueous phase, and adding saturated sodium bicarbonate aqueous solution makes aqueous phase be adjusted to weak base, is extracted with dichloromethane, merges organic
Phase, anhydrous sodium sulfate drying, filtering is concentrated to give compound 13B (4.5g).
Compound 13B (1.0g, 3.0mmol) is dissolved in dichloromethane (10ml), then add DIPEA (744 μ l,
4.5mmol), 0 DEG C is cooled to, dichloromethane (5ml) solution of p-nitrophenyl chloroformate ester (907mg, 4.5mmol) is instilled, it is extensive
It is multiple extremely to react at room temperature.It is complete through thin-layer chromatography monitoring reaction, saturated aqueous ammonium chloride is added, dichloromethane extraction is associated with
Machine phase, uses saturated common salt water washing, and anhydrous sodium sulfate drying is filtered, concentration, silica gel column chromatography (dichloromethane：Methanol=30:
1) compound 13C (989mg) is obtained.
Compound 13C (100mg, 0.2mmol) and compound 13I (62mg, 0.3mmol) are dissolved in anhydrous tetrahydro furan
In (10ml), -15 DEG C are cooled to, then in the lower dropwise addition LiHMDS (1.0M in THF, 300 μ l, 0.3mmol) of nitrogen protection, in
React at this temperature, it is complete through thin-layer chromatography monitoring reaction, add aqueous ammonium chloride solution and be quenched after reaction, extracted with ethyl acetate
Take, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying is filtered, concentration, silica gel column chromatography (ethyl acetate：
Methanol=500:1~50) obtain compound 13D (75mg).
Compound 13D (75mg) is dissolved in tetrahydrofuran (2ml) and water (2ml), concentrated hydrochloric acid (0.4ml) is then added,
After room temperature reaction 2 hours, after the sodium acid carbonate neutralization for adding saturation, it is extracted with ethyl acetate, merges organic phase, use saturated common salt
Water washing, anhydrous sodium sulfate drying is filtered, and concentration is beaten with petrol ether/ethyl acetate (2/1), and filtration drying obtains compound
13(65mg)。1H NMR(400MHz,CDCl3)δ13.57(s,1H),10.25(s,1H),8.25(s,1H),7.68(s,1H),
7.64 (s, 1H), 5.11 (s, 2H), 4.15-4.05 (m, 2H), 3.88 (t, J=5.2Hz, 2H), 3.73 (t, J=5.2Hz,
2H), 3.39 (s, 3H), 3.39-3.35 (m, 2H), 3.29 (s, 3H), 3.21 (s, 2H), 2.94 (t, J=6.2Hz, 2H), 2.67
(t, J=5.5Hz, 2H), 2.37 (s, 3H), 2.11-1.99 (m, 2H)；ESI-MS m/z：521.3[M+H]+。
Embodiment 14
The compounds of this invention 14 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 14, ESI-MS m/z：575.4
[M+H]+。
Embodiment 15
The compounds of this invention 15 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 15, ESI-MS m/z：535.1
[M+H]+。
Embodiment 16
Compound 1B (200mg, 1.04mmol) is dissolved in chloroform (6ml) and water (2ml), sodium acid carbonate is then added
(175mg, 2.08mmol) is cooled to after 0 DEG C, is slowly added to thiophosgene (95 μ l, 1.25mmol), after reacting 3 hours, separates chlorine
Imitative layer, water layer is extracted twice with dichloromethane, merges organic phase, silica gel column chromatography (petroleum ether after being concentrated under reduced pressure：Ethyl acetate=
4:1) compound 16A (54mg) is obtained.
Compound 16A (54mg, 0.23mmol) and compound 13B (115mg, 0.345mmol) are dissolved in tetrahydrofuran
In (5ml), be heated to 40 DEG C reaction 24 hours after, silica gel column chromatography (dichloromethane：Methanol=30:1) compound 16B is obtained
(110mg)。
Compound 16B (110mg) is dissolved in tetrahydrofuran (2ml) and water (2ml), concentrated hydrochloric acid (0.5ml) is then added,
After room temperature reaction 2 hours, add after saturated sodium bicarbonate neutralization, white solid is filtrated to get after the removing tetrahydrofuran that is concentrated under reduced pressure
Compound 16 (48mg).1H NMR(400MHz,CDCl3)δ15.52(s,1H),10.28(s,1H),8.66(s,1H),8.23(s,
1H), 7.71 (s, 1H), 5.37 (t, J=4.9Hz, 1H), 5.12 (s, 2H), 4.65-4.53 (m, 2H), 3.68 (t, J=
5.1Hz, 2H), 3.52 (dd, J=10.3,5.1Hz, 2H), 3.44 (s, 3H), 3.38 (t, J=5.4Hz, 2H), 3.22 (s,
2H), 2.96 (t, J=6.4Hz, 2H), 2.68 (t, J=5.4Hz, 2H), 2.37 (s, 3H), 2.16-2.05 (m, 2H)；ESI-MS
m/z：523.3[M+H]+。
Embodiment 17
The compounds of this invention 17 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 17, ESI-MS m/z：536.2
[M+H]+。
Embodiment 18
The compounds of this invention 18 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 18, ESI-MS m/z：551.1
[M+H]+。
Embodiment 19
The compounds of this invention 19 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 19, ESI-MS m/z：523.0
[M+H]+。
Embodiment 20
The compounds of this invention 20 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 20, ESI-MS m/z：537.2
[M+H]+。
Embodiment 21
The compounds of this invention 21 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 21, ESI-MS m/z：539.0
[M+H]+。
Embodiment 22
The compounds of this invention 22 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 22, ESI-MS m/z：520.4
[M+H]+。
Embodiment 23
The compounds of this invention 23 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 23, ESI-MS m/z：533.3
[M+H]+。
Embodiment 24
The compounds of this invention 24 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 24, ESI-MS m/z：564.0
[M+H]+。
Embodiment 25
The compounds of this invention 25 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 25, ESI-MS m/z：551.1
[M+H]+。
Embodiment 26
The compounds of this invention 26 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 26, ESI-MS m/z：550.4
[M+H]+。
Embodiment 27
1- 1-aminocyclopropane-1-carboxylic acids (4.0g, 39.6mmol) are dissolved in water (160ml), addition formalin (6ml,
37%) with palladium/carbon (2.0g, 10%), reacted under hydrogen atmosphere.Through thin-layer chromatography monitoring reaction, complete, diatomite filtering, dense
Contracting filtrate, methanol is added into residue, and return stirring 1 hour stands cooling, is collected by filtration and obtains compound 27B (2.3g).
Compound 2B (5.9g, 25.0mmol) is dissolved in 1,2- dichloroethanes (100ml), methylamine (2.0M is then added
In THF, 50ml, 100.0mmol), in sodium triacetoxy borohydride (10.6g, 50.0mmol) is added portionwise at 0 DEG C, recover
It is complete through thin-layer chromatography monitoring reaction to reacting at room temperature, add saturated aqueous ammonium chloride and be quenched, concentration removes organic solvent,
Removing impurity is extracted with ethyl acetate, and the target product in ethyl acetate is extracted with water, merges aqueous phase, and add saturated carbon
Sour hydrogen sodium water solution makes aqueous phase be adjusted to weak base, is extracted three times with dichloromethane, merges organic phase, uses saturated common salt water washing, nothing
Aqueous sodium persulfate is dried, filtering, is concentrated to give compound 27A (5.63g).
Compound 27A (4.46g, 17.8mmol) and 27B (2.30g, 17.8mmol) are dissolved in dichloromethane (50ml),
In be separately added at 0 DEG C EDCI (3.41g, 17.8mmol), HOBt (2.41g, 17.8mmol) and triethylamine (3.72ml,
26.7mmol), it is warmed to room temperature reaction.It is complete through thin-layer chromatography monitoring reaction, it is concentrated under reduced pressure, adds saturated sodium bicarbonate water molten
Liquid, is extracted with ethyl acetate, anhydrous sodium sulfate drying, filtering, is concentrated to give compound 27C crude products.
Compound 27C is dissolved in dichloromethane (50ml), DIPEA (3.54ml, 21.4mmol) is then added, is cooled to
0 DEG C, dichloromethane (20ml) solution of p-nitrophenyl chloroformate ester (4.31g, 21.4mmol) is instilled, is recovered to room temperature reaction.
It is complete through thin-layer chromatography monitoring reaction, saturated aqueous ammonium chloride is added, dichloromethane extraction merges organic phase, eaten with saturation
Salt water washing, anhydrous sodium sulfate drying is filtered, concentration, silica gel column chromatography (ethyl acetate：Acetone=50:1) compound is obtained
27D(5.2g)。
By compound 1A (2.5g, 18.2mmol), 2- methoxy ethyls amine (4.75ml, 54.6mmol), N, N- dimethyl
Acetamide (40ml) and diisopropyl ethyl amine (9.02ml, 54.6mmol) are placed in tube sealing, are stayed overnight in 50 DEG C of reactions, through thin layer
Chromatography monitoring reaction is complete, is concentrated under reduced pressure at 75 DEG C, is beaten with petrol ether/ethyl acetate (1/1), and filtration drying obtains chemical combination
Thing 27E (2.2g).
Compound 27D (4.2g, 7.96mmol) and compound 27E (1.68g, 8.76mmol) are dissolved in anhydrous tetrahydro furan
In (150ml), be cooled to -15 DEG C, then in nitrogen protection it is lower be added dropwise LiHMDS (1.0M in THF, 17.5ml,
17.5mmol), it is complete through thin-layer chromatography monitoring reaction in reacting at this temperature, add aqueous ammonium chloride solution and be quenched after reaction, use
Ethyl acetate is extracted, and merges organic phase, uses saturated common salt water washing, and anhydrous sodium sulfate drying is filtered, concentration, silica gel column chromatography
(ethyl acetate：Methanol=500:1~10) obtain compound 27F (3.8g).
Compound 27F (3.8g) is dissolved in tetrahydrofuran (42ml) and water (14ml), concentrated hydrochloric acid is then added
(4.5ml), after reacting at room temperature 2 hours, after the sodium acid carbonate neutralization for adding saturation, is extracted with ethyl acetate, merges organic phase, use
Saturated common salt water washing, anhydrous sodium sulfate drying is filtered, and concentration is beaten with petrol ether/ethyl acetate (3/1), and filtration drying is obtained
To compound 27 (3.2g).1H NMR(400MHz,CDCl3)δ13.64(s,1H),10.28(s,1H),8.21(s,1H),7.60
(s, 1H), 7.52 (s, 1H), 5.32 (t, J=5.1Hz, 1H), 5.09 (s, 2H), 4.15-4.08 (m, 2H), 3.70-3.61 (m,
2H), 3.55-3.48 (m, 2H), 3.44 (s, 3H), 3.10 (s, 3H), 2.94 (t, J=6.2Hz, 2H), 2.31-1.94 (m,
8H),1.01-0.88(m,4H)；ESI-MS m/z：535.2[M+H]+。
Embodiment 28
The compounds of this invention 28 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 28, ESI-MS m/z：506.3
[M+H]+。
Embodiment 29
The compounds of this invention 29 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 29, ESI-MS m/z：520.4
[M+H]+。
Embodiment 30
The compounds of this invention 30 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 30, ESI-MS m/z：534.3
[M+H]+。
Embodiment 31
The compounds of this invention 31 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 31, ESI-MS m/z：550.2
[M+H]+。
Embodiment 32
The compounds of this invention 32 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 32, ESI-MS m/z：510.4
[M+H]+。
Embodiment 33
The compounds of this invention 33 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 33, ESI-MS m/z：466.0
[M+H]+。
Embodiment 34
The compounds of this invention 34 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 34, ESI-MS m/z：551.2
[M+H]+。
Embodiment 35
The compounds of this invention 35 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 35, ESI-MS m/z：492.3
[M+H]+。
Embodiment 36
The compounds of this invention 36 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 36, ESI-MS m/z：549.4
[M+H]+。
Embodiment 37
The compounds of this invention 37 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 37, ESI-MS m/z：551.2
[M+H]+。
Embodiment 38
The compounds of this invention 38 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 38, ESI-MS m/z：537.4
[M+H]+。
Embodiment 39
The compounds of this invention 39 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 39, ESI-MS m/z：539.2
[M+H]+。
Embodiment 40
The compounds of this invention 40 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 40, ESI-MS m/z：506.3
[M+H]+。
Embodiment 41
The compounds of this invention 41 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 41, ESI-MS m/z：550.4
[M+H]+。
Embodiment 42
The compounds of this invention 42 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 42, ESI-MS m/z：510.1
[M+H]+。
Embodiment 43
The compounds of this invention 43 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 43, ESI-MS m/z：534.2
[M+H]+。
Embodiment 44
By trimethylsilylethanol (2.0g, 16.9mmol), phthalimide (2.74g, 18.6mmol) and triphenyl
Phosphine (4.88g, 18.6mmol) is dissolved in anhydrous tetrahydro furan (60ml), in the lower dropwise addition azo-2-carboxylic acid's diisopropyl of nitrogen protection
Ester (3.76g, 18.6mmol), after reacting at room temperature 24 hours, concentration of reaction solution, adds ether and petroleum ether and stirring separates out solid,
Suction filtration, collects filtrate and concentrates silica gel column chromatography (petroleum ether：Ethyl acetate=5:1) compound 44A (2.2g) is obtained.
Compound 44A (2.2g, 8.89mmol) is dissolved in ethanol (40ml), then be added dropwise hydrazine hydrate (3.34ml,
53.4mmol), reaction 2 hours is then refluxed for, room temperature is cooled to, suction filtration removes the white solid separated out, filtrate acidic alcohol
PH=6 is modulated, dichloromethane suction filtration again is added after filtrate is concentrated, filtrate, column chromatography (dichloromethane after concentration is collected：First
Alcohol=20:1) compound 44B hydrochloride (860mg) is obtained.
By compound 1A (548.5mg, 4.0mmol), 44B hydrochloride (860mg, 5.6mmol), N, N- dimethylacetamides
Amine (12ml) and diisopropyl ethyl amine (1.983ml, 12.0mmol) are placed in tube sealing, are reacted 40 hours in 65 DEG C, through thin layer
Chromatography monitoring reaction is complete, cooling, adds water and is extracted with ethyl acetate, merges organic phase, the N in most organic phase is washed with water,
N- dimethyl acetamides, saturated common salt washing, anhydrous sodium sulfate drying is filtered, and concentration is beaten with petrol ether/ethyl acetate (3/1)
Slurry, filtration drying obtains compound 44C (495mg).
Compound 13C (100mg, 0.2mmol) and compound 44C (70mg, 0.3mmol) are dissolved in anhydrous tetrahydro furan
In (5ml), -15 DEG C are cooled to, then in the lower dropwise addition LiHMDS (1.0M in THF, 300 μ l, 0.3mmol) of nitrogen protection, in
React at this temperature, it is complete through thin-layer chromatography monitoring reaction, add aqueous ammonium chloride solution and be quenched after reaction, extracted with ethyl acetate
Take, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying is filtered, concentration, silica gel column chromatography (ethyl acetate：
Methanol=500:1~10) obtain compound 44D (75mg).
Compound 44D (75mg) is dissolved in tetrahydrofuran (2ml) and water (2ml), concentrated hydrochloric acid (0.4ml) is then added,
After room temperature reaction 2 hours, after the sodium acid carbonate neutralization for adding saturation, it is extracted with ethyl acetate, merges organic phase, use saturated common salt
Water washing, anhydrous sodium sulfate drying is filtered, and concentration is beaten with petrol ether/ethyl acetate (3/1), and filtration drying obtains compound
44(65mg)。1H NMR(400MHz,CDCl3)δ13.60(s,1H),10.25(s,1H),8.18(s,1H),7.64(s,1H),
7.54 (s, 1H), 5.11 (s, 2H), 4.86 (t, J=4.4Hz, 1H), 4.13-4.08 (m, 2H), 3.40-3.32 (m, 4H),
3.22 (s, 2H), 2.94 (t, J=6.2Hz, 2H), 2.67 (t, J=5.4Hz, 2H), 2.37 (s, 3H), 2.06-2.01 (m,
2H),1.07–0.99(m,2H),0.13(s,9H)；ESI-MS m/z：549.4[M+H]+。
Embodiment 45
The compounds of this invention 45 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 45, ESI-MS m/z：526.1
[M+H]+。
Embodiment 46
The compounds of this invention 46 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 46, ESI-MS m/z：550.0
[M+H]+。
Embodiment 47
The compounds of this invention 47 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 47, ESI-MS m/z：565.2
[M+H]+。
Embodiment 48
The compounds of this invention 48 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 48, ESI-MS m/z：527.0
[M+H]+。
Embodiment 49
The compounds of this invention 49 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 49, ESI-MS m/z：577.2
[M+H]+。
Embodiment 50
The compounds of this invention 50 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 50, ESI-MS m/z：574.1
[M+H]+。
Embodiment 51
The compounds of this invention 51 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 51, ESI-MS m/z：546.3
[M+H]+。
Embodiment 52
The compounds of this invention 52 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 52, ESI-MS m/z：562.3
[M+H]+。
Embodiment 53
The compounds of this invention 53 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 53, ESI-MS m/z：593.1
[M+H]+。
Embodiment 54
The compounds of this invention 54 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 54, ESI-MS m/z：551.2
[M+H]+。
Embodiment 55
Compound 16A (36mg, 0.154mmol) and intermediate 27C (84mg, 0.23mmol) are dissolved in tetrahydrofuran
In (5ml), be heated to 40 DEG C reaction 24 hours after, the silica gel column chromatography that is concentrated under reduced pressure obtains compound 55A (87mg).
Compound 55A (87mg) is dissolved in tetrahydrofuran (2ml), water (2ml) and concentrated hydrochloric acid (0.4ml) is then added,
After room temperature reaction 2 hours, add saturated sodium bicarbonate and neutralize, there is white solid to separate out after the removing tetrahydrofuran that is concentrated under reduced pressure
Filter, is washed with water after once drying afterwards and obtains compound 55 (33mg).1H NMR(400MHz,CDCl3)δ15.55(s,1H),
10.30 (s, 1H), 8.67 (s, 1H), 8.24 (s, 1H), 7.58 (s, 1H), 5.37 (t, J=4.7Hz, 1H), 5.09 (s, 2H),
4.67-4.54 (m, 2H), 3.68 (t, J=5.1Hz, 2H), 3.52 (dd, J=10.3,5.1Hz, 2H), 3.44 (s, 3H), 3.12
(s, 3H), 2.96 (t, J=6.2Hz, 2H), 2.37-1.93 (m, 8H), 0.96 (d, J=8.1Hz, 4H)；ESI-MS m/z：
551.4[M+H]+。
Embodiment 56
The compounds of this invention 56 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 56, ESI-MS m/z：554.3
[M+H]+。
Embodiment 57
The compounds of this invention 57 is implemented to prepare according to above-mentioned preparation scheme, obtains compound 57, ESI-MS m/z：563.4
[M+H]+。
Biological test
1. external biological chemokinases are tested
FGFR4 (being purchased from Promega) and substrate Poly (Glu4, Tyr1) will be recombinated in 1 × buffer (40mM Tris, pH
=7.5；20mM MgCl2；0.1mg/ml BSA；2mM MnCl2；50 μM of DTT) middle mixing.Compound is added into enzyme/substrate
In mixed system, mix and incubate in advance, be subsequently added into ATP and start reaction.React at room temperature after 60min, according to 1:1 volume ratio is added
ADP-Glo Reagent；Then 40min is reacted at 23 DEG C, according to 1:1 volume ratio adds Kinase Detection Reagent
Continue to react 30min.Detect the fluorescent value of each reacting hole.According to chemiluminescence intensity L values calculate inhibiting rate, inhibiting rate=
[1- (L sample-L blank)/(L feminine gender-L blank)] × 100%.According to sample inhibiting rate, using in XLfit softwares
4Parameter Logistic Model calculate the IC of compound50。
| Compound number | FGFR4(IC50)(nM) | FGFR1(IC50)(μM) |
| 1 | 0.08 | >10 |
| 2 | 0.07 | >10 |
| 3 | 1.2 | >10 |
| 4 | 2.5 | >10 |
| 5 | 3.6 | >10 |
| 6 | 1.7 | >10 |
| 7 | 0.05 | >10 |
| 8 | 0.06 | >10 |
Data above shows that the compounds of this invention has significant inhibitory action to FGFR4, to FGFR1 inhibitory activity
Not high, can be seen that the compounds of this invention from FGFR1 (IC50) numerical value and FGFR4 (IC50) inatheadearomatizationazone has choosing to FGFR4
Selecting property ground remarkable inhibiting activity.
2. cell in vitro suppresses test
Human liver cancer cell：(FGFR4 dashes forward by HepG2, Bel-7402, Bel-7404, Hep3B (FGFR4 mutant strains) and HuH-7
Mutant), it is inoculated in 96 orifice plates, 37 DEG C, 5%CO2Under the conditions of cultivate.Next day, sample (T) is added, while being not added with sample controls
(C) and before dosing (T0) is compareed.The cell addition TCA that (T0) is compareed before dosing is fixed, and indwelling is stand-by.Add sample (T)
Continue to fix again after cultivating 48 hours with the cell for being not added with sample controls (C).All cells fixed are dyed with SRB dye liquors,
Free dyestuff is washed away with acetum again, Tris alkali is added after being air-dried, 490nm determines OD values after vibration dissolving is mixed.
Growth rate, if T >=T0, growth rate=(T-T0)/(C-T0) × 100% are calculated according to OD values；If T ＜ T0, (T-T0)/T0
×100.Each sample dilutes 8 concentration gradients, and duplicate hole is repeated twice, according to growth rate, using in Xlfit softwares
4Parameter Logistic Model calculate GI50 (μM).
Upper as shown by data, the compounds of this invention is to hepatoma cell strain Hep3B, and there is HuH-7 significant selective depression to make
With.
Claims (10)
1. a kind of formula (I) compound, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt,
Wherein, Y is carbon atom or nitrogen-atoms；
R1Selected from following group：
R2, R3, R4It independently is N or C (RX)；
R5Selected from-NRY1RY2,-O- (CH2)0-3-RY1,
R6Selected from hydrogen, halogen, cyano group, amino, amide groups, hydroxyl, ester group, acyl group, acyloxy, sulfonyl, sulfinyl, alkyl,
Alkoxy, aryl, cycloalkyl, heteroaryl, heterocyclic radical, cycloheteroalkylalkyl；
R7, R8, R9It independently is N or C (RX)；
RXIt independently is hydrogen, halogen, cyano group, amino, amide groups, hydroxyl, ester group, acyl group, acyloxy, sulfonyl, sulfinyl,
Alkyl, alkoxy, aryl, cycloalkyl, heteroaryl or heterocyclic radical；
When Z oxygen atoms；RY1, RY2It independently is alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, silicon substrate；
When Z sulphur atoms；RY1, RY2It independently is hydrogen, alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, silicon substrate.
2. formula (I) compound as claimed in claim 2, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt,
Including logical formula (II) compound
Wherein, R5Selected from-NRY1RY2,-O- (CH2)0-3-RY1,
R6Selected from hydrogen, halogen, cyano group, amino, amide groups, hydroxyl, ester group, acyl group, acyloxy, sulfonyl, sulfinyl, alkyl,
Alkoxy, aryl, cycloalkyl, heteroaryl, heterocyclic radical, cycloheteroalkylalkyl；
RY1, RY2It independently is alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, silicon substrate.
3. formula (II) compound as claimed in claim 2, it is characterised in that R5Selected from following group：
R6Selected from hydrogen, and following group：
4. formula (I) compound as claimed in claim 1, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt,
Including logical formula (III) compound
Wherein, R5Selected from-NRY1RY2,-O- (CH2)0-3-RY1,
R6Selected from hydrogen, halogen, cyano group, amino, amide groups, hydroxyl, ester group, acyl group, acyloxy, sulfonyl, sulfinyl, alkyl,
Alkoxy, aryl, cycloalkyl, heteroaryl, heterocyclic radical, cycloheteroalkylalkyl；
RY1, RY2It independently is hydrogen, alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, silicon substrate.
5. formula (III) compound as claimed in claim 4, it is characterised in that R5Selected from following group：
R6Selected from hydrogen, and following group：
6. formula (III) compound as claimed in claim 4, it is characterised in that R5Selected from following group：
7. the formula (I) as described in claim 1 to 6, (II), (III) compound, its stereoisomer, dynamic isomer or medicine
Acceptable salt on, it is selected from following compounds：
8. the compound as any one of claim 1 to 7, 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.
9. medicine as claimed in claim 8 or pharmaceutical composition, it is used for the treatment of various cancers.
10. as claimed in claim 9, 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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| WO2022089648A1 (en) * | 2020-11-02 | 2022-05-05 | Jacobio Pharmaceuticals Co., Ltd. | Crystalline forms of salts of fgfr4 inhibitor |
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| CN112759593A (en) * | 2019-11-01 | 2021-05-07 | 北京伯汇生物技术有限公司 | Bridged ring-fused aldehyde pyridine derivative and application thereof |
| CN113072550B (en) * | 2020-01-06 | 2023-08-08 | 周龙兴 | High-selectivity fibroblast growth factor receptor inhibitor and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020020377A1 (en) * | 2018-07-27 | 2020-01-30 | 北京加科思新药研发有限公司 | Fused ring derivative used as fgfr4 inhibitor |
| CN112513037A (en) * | 2018-07-27 | 2021-03-16 | 北京加科思新药研发有限公司 | Fused ring derivatives useful as FGFR4 inhibitors |
| US11136320B2 (en) | 2018-07-27 | 2021-10-05 | Jacobio Pharmaceuticals Co., Ltd. | Fused ring derivative used as FGFR4 inhibitor |
| JP2021532147A (en) * | 2018-07-27 | 2021-11-25 | ジャコバイオ ファーマスーティカルズ カンパニー リミテッドJacobio Pharmaceuticals Co., Ltd. | Fused ring derivative used as an FGFR4 inhibitor |
| JP7129728B2 (en) | 2018-07-27 | 2022-09-02 | ジャコバイオ ファーマスーティカルズ カンパニー リミテッド | Fused ring derivatives used as FGFR4 inhibitors |
| WO2022089648A1 (en) * | 2020-11-02 | 2022-05-05 | Jacobio Pharmaceuticals Co., Ltd. | Crystalline forms of salts of fgfr4 inhibitor |
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