CN107286108A - A kind of fibroblast growth factor acceptor selective depressant - Google Patents
A kind of fibroblast growth factor acceptor selective depressant Download PDFInfo
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- CN107286108A CN107286108A CN201610575836.3A CN201610575836A CN107286108A CN 107286108 A CN107286108 A CN 107286108A CN 201610575836 A CN201610575836 A CN 201610575836A CN 107286108 A CN107286108 A CN 107286108A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
- C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
- C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
Abstract
A kind of fibroblast growth factor acceptor selective depressant.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.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 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 present invention discloses a kind of formula (I) compound, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt,
Wherein, when Y is nitrogen-atoms, A is aryl, heteroaryl, cycloalkyl, heterocyclic radical or cycloalkenyl group；
When Y is carbon atom, and R2During for hydrogen, A is heteroaryl, cycloalkyl, heterocyclic radical or cycloalkenyl group；
When Y is carbon atom, and R2When being not hydrogen, A is aryl, heteroaryl, cycloalkyl, heterocyclic radical or cycloalkenyl group；
X is oxygen atom or sulphur atom；
R1It is separately hydrogen, halogen, cyano group, amino, amide groups, hydroxyl, ester group, acyl group, acyloxy, sulfonyl,
Sulfinyl ,-NR9R10, alkyl, silicon substrate, alkoxy, aryl, cycloalkyl, heteroaryl or heterocyclic radical；
R2, R3, R4, R5, R6, R7And R8It is separately hydrogen, silicon substrate, halogen, cyano group, hydroxyl, amino, amide groups, acyl
Base, alkyl or alkoxy；
R9, R10It is separately hydrogen, acyl group, alkyl or cycloalkyl；
M is 0,1,2,3 or 4.
Formula (I) compound of the present invention, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt, its
Include the compound of logical formula (II),
Wherein, A is 6 to 8 yuan of aryl, 5 to 8 unit's heteroaryls, 3 to 8 yuan of cycloalkyl, 3 to 8 circle heterocycles bases or 3 to 8 yuan of cyclenes
Base；
X is oxygen atom or sulphur atom；
R1It is separately hydrogen, halogen, cyano group, amide groups, hydroxyl, ester group, acyl group, acyloxy, sulfonyl, sulfenyl
Base ,-NR9R10, C1-6Alkyl, silicon substrate, C1-6Alkoxy, 6 to 8 yuan of aryl, 3 to 8 yuan of cycloalkyl, 5 to 8 unit's heteroaryls, 3 to 8 yuan
Heterocyclic radical；
R2, R3, R4, R5, R6, R7And R8It is separately hydrogen, halogen, cyano group, hydroxyl, amino, amide groups, acyl group, C1-6
Alkyl or C1-6Alkoxy；
R9, R10It is separately hydrogen, acyl group, C1-8Alkyl or 3 to 6 yuan of cycloalkyl；
M is 0,1,2,3 or 4.
Formula (II) compound of the present invention, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt, its
Include the compound of logical formula (III),
Wherein, X is oxygen atom or sulphur atom；
R1It is separately hydrogen, halogen, cyano group, amide groups, hydroxyl, ester group, acyl group, acyloxy, sulfonyl, sulfenyl
Base ,-NR9R10, C1-6Alkyl, silicon substrate, C1-6Alkoxy, 6 to 8 yuan of aryl, 3 to 8 yuan of cycloalkyl, 5 to 8 unit's heteroaryls or 3 to 8 yuan
Heterocyclic radical；
R2, R3, R4, R5, R6, R7And R8It is separately hydrogen, halogen, cyano group, hydroxyl, amino, amide groups, acyl group, C1-6
Alkyl or C1-6Alkoxy；
R9, R10It is separately hydrogen, acyl group, C1-8Alkyl or 3 to 6 yuan of cycloalkyl；
M is 0,1,2,3 or 4.
Formula (III) compound of the present invention, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt,
Including the compound of logical formula (IV),
Wherein, X is oxygen atom or sulphur atom；Z is nitrogen-atoms or carbon atom；
R2, R3, R4, R5, R6, R7And R8It is separately hydrogen, halogen, cyano group, hydroxyl, amino, amide groups, acyl group, C1-6
Alkyl or C1-6Alkoxy；
R11It independently is hydrogen, acyl group, C1-8Alkyl or 3 to 6 yuan of cycloalkyl；
Formula (I) compound of the present invention, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt, its
Include the compound of logical formula (V),
Wherein, R is worked as2During for hydrogen, A is 5 to 8 unit's heteroaryls, 3 to 8 yuan of cycloalkyl, 3 to 8 circle heterocycles bases or 3 to 8 yuan of cyclenes
Base；
Work as R2When being not hydrogen, A is 6 to 8 yuan of aryl, 5 to 8 unit's heteroaryls, 3 to 8 yuan of cycloalkyl, 3 to 8 circle heterocycles bases or 3
To 8 member cycloalkenyls；
X is oxygen atom or sulphur atom；
R1It is separately hydrogen, halogen, cyano group, silicon substrate, amide groups, hydroxyl, ester group, acyl group, acyloxy, sulfonyl,
Sulfinyl ,-NR9R10, C1-6Alkyl, C1-6Alkoxy, 6 to 8 yuan of aryl, 3 to 8 yuan of cycloalkyl, 5 to 8 unit's heteroaryls or 3 to 8
Circle heterocycles base；
R2, R3, R4, R5, R6, R7And R8It is separately hydrogen, halogen, cyano group, hydroxyl, amino, amide groups, acyl group, C1-6
Alkyl or C1-6Alkoxy；
R9, R10It is separately hydrogen, acyl group, C1-8Alkyl or 3 to 6 yuan of cycloalkyl；
M is 0,1,2,3 or 4.
Formula (V) compound of the present invention, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt, its
Include the compound of logical formula (VI),
Wherein, Q is oxygen atom, carbon atom or nitrogen-atoms；
R2, R3, R4, R5, R6, R7And R8It is separately hydrogen, halogen, cyano group, hydroxyl, amino, amide groups, acyl group, C1-6
Alkyl or C1-6Alkoxy；
Q is 0,1,2,3 or 4；
R is 0,1,2,3 or 4.
Formula (I) of the present invention, (II), (III), (IV), (V), (VI) compound, its stereoisomer, mutually variation
Structure body or pharmaceutically acceptable salt, it is selected from following compounds：
Compound of the present invention, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt, is used as FGFR4
Kinase Selectivity inhibitor, is preparing treatment by the application in FGFR4 or FGF19 disease mediated medicine or pharmaceutical composition.
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,
Following examples are only to provide the method for the practice present invention, and scope of the invention is not limited in any way.
The compounds of this invention is prepared according to following preparation scheme：
Chemicals X1 commercially available first and monosubstituted amine carry out coupling reaction under certain condition, obtain compound X2, chemical combination
Thing X2 and compound X3 carries out coupling reaction, obtains compound X4, and compound X4 is further led to isocyanates X5 reactions
Formula compound X6, compound X6 obtain compound X7 by nitro reduction, and with acryloyl chloride acylation reaction occurs for the compound, obtains
To 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, the resistance to Jilin Chemical of peace, special (Chengdu) bio-pharmaceuticals of Ace 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 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 compounds of this invention 1 is implemented to prepare according to following scheme：
1B (300mg, 2.00mmol) is dissolved in anhydrous THF (60mL), stirred under ice bath；1A is slowly added in batches
(641mg, 2.00mmol), is warming up to room temperature and continues to react 30min.TLC monitoring reactions are completed, and revolving removes most of solvent,
30mL water will be added in residue, continue to stir 10min at room temperature, separated out solid filtering, solid is washed with a small amount of frozen water.Collect
Solid, vacuum drying, obtains 1C products 625mg.Yield 72%.1H NMR(400MHz,CDCl3)δ8.46(s,1H),7.64(s,
1H),7.44–7.29(m,1H),7.24(s,1H),6.80–6.54(m,2H),3.38–3.25(m,4H),2.75–2.64(m,
4H), 2.58 (q, 7.1Hz, 2H), 1.53 (s, 9H), 1.20 (t, J=7.2Hz, 3H) .MS (ESI) m/z [M+H]+,434.24。
By 1C (620mg, 1.43mmol), methylamine hydrochloride (193mg, 2.86mmol), DIPEA (0.71mL,
4.29mmol) sequentially add in absolute ethyl alcohol (40mL), N2Under the conditions of 80 DEG C reaction 2h, TLC monitoring reaction complete, stop reaction
And it is cooled to room temperature.Solvent is spin-dried for, saturated sodium bicarbonate aqueous solution is added, EA aqueous layer extracteds 3 times merge organic layer, washed, do
It is dry, except solvent, crude product column chromatography (DCM:MeOH=100:1).Product is obtained, is dried in vacuo, obtains 1D product 398mg, yield
65%.1H NMR(400MHz,CDCl3) δ 8.20 (s, 1H), 7.50 (s, 1H), 7.24-6.97 (m, 2H), 6.66 (d, J=
6.7Hz, 1H), 5.67 (s, 1H), 3.32-3.20 (m, 4H), 2.95 (d, J=16.4Hz, 3H), 2.67-2.52 (m, 4H),
(t, J=7.2Hz, the 3H) of 2.49 (q, J=7.2Hz, 2H), 1.51 (s, 9H), 1.15
By 1D (370mg, 0.86mmol), 1E (214mg, 0.86mmol) is dissolved in toluene (15mL), is placed in N2Protection
Lower agitating and heating, isothermal reaction 2h at 100 DEG C, TLC monitoring reactions are completed.Stop reaction, be cooled to room temperature, be spin-dried for solvent, it is residual
Stay the direct column chromatography (DCM of thing:MeOH=85:1).Obtain target compound 1F product 238mg, yield 41%.1H NMR
(400MHz,CDCl3)δ11.49(s,1H),8.51(s,1H),7.32(s,1H),7.26–7.16(m,1H),7.07(s,1H),
6.78–6.50(m,2H),6.41(s,1H),3.95(s,6H),3.65–3.27(m,4H),2.95(s,3H),2.65–2.35(m,
6H), 1.53 (s, 9H), 1.14 (t, J=7.1Hz, 3H)
1F (200mg, 0.296mmol) is dissolved in DCM (20mL), in being stirred under condition of ice bath, TFA (4mL) is added,
It is slowly increased to that 2h is stirred at room temperature.TLC monitoring reactions are completed.Solvent is spin-dried for, residue adds saturated aqueous sodium carbonate, EA extractions
Take, merge EA layers, washing, anhydrous sodium sulfate drying.Revolving removes solvent, obtains target compound 1G product 120mg, yield
71%.Products obtained therefrom is directly used in next step reaction.
1G (110mg, 0.19mmol) is dissolved in DCM (10mL), DIPEA (38 μ L, 0.229mmol), Yu Bing is added
Stirred under the conditions of bath, be slowly added to acryloyl chloride (21 μ L), be slowly increased to that 20min is stirred at room temperature.TLC monitoring reactions are completed.Instead
Liquid is answered to wash, anhydrous sodium sulfate drying is filtered to remove drier, and revolving removes solvent, the direct column chromatography (DCM of residue:MeOH=
60:1).Obtain target compound 1 and amount to 72mg, yield 61%.1H NMR(400MHz,CDCl3)δ12.11–11.55(m,1H),
8.48 (s, 1H), 7.91-7.47 (m, 2H), 7.32 (d, J=8.9Hz, 1H), 7.02-6.82 (m, 1H), 6.58-6.37 (m,
3H), 6.26-6.20 (m, 1H), 5.79 (d, J=10.2Hz, 1H), 3.94 (s, 6H), 3.50 (s, 3H), 3.27-2.96 (m,
4H), 2.65-2.40 (m, 6H), 1.14 (t, J=7.2Hz, 3H)；MS(ESI)m/z[M+H]+,630.32。
Embodiment 2
2B (496mg, 3.33mmol) is dissolved in anhydrous THF (60mL), stirred under ice bath；2A is slowly added in batches
(360mg, 3.33mmol), is warming up to room temperature and continues to react 30min.TLC monitoring reactions are completed, and revolving removes most of solvent,
30mL water will be added in residue, continue to stir 10min at room temperature, separated out solid filtering, solid is washed with a small amount of frozen water.Collect
Solid, vacuum drying, obtains 2C products 583mg.Yield 79%.
By 2C (570mg, 2.57mmol), methylamine hydrochloride (347mg, 5.12mmol), DIPEA (1.34mL,
7.71mmol) sequentially add in absolute ethyl alcohol (40mL), N2Under the conditions of 80 DEG C reaction 2h, TLC monitoring reaction complete, stop reaction
And it is cooled to room temperature.Solvent is spin-dried for, saturated sodium bicarbonate aqueous solution is added, ethyl acetate aqueous layer extracted 3 times merges organic layer,
Washing, is dried, except solvent, crude product column chromatography (DCM:MeOH=100:1).Product is obtained, is dried in vacuo.Obtain 2D products
339mg, yield 61%.
2D (330mg, 1.53mmol) is dissolved in mixed solution (THF:H2O=1:1) 20mL, adds sodium acid carbonate
(193mg, 2.30mmol), stirs 5 minutes, is subsequently added into benzyl chloroformate (215 μ L, 1.53mmol) and 12h, TLC is stirred at room temperature
Monitoring reaction is completed.It is spin-dried for removing most of THF, residue adds the appropriate aqueous solution, and EA is extracted three times, washes 2 times, EA layers of rotation
Dry, column chromatography (pure DCM) obtains 2E products 381mg.Yield 71%.1H NMR(400MHz,CDCl3)δ8.07(s,1H),7.99–
7.63(m,2H),7.47–7.30(m,6H),7.28–7.05(m,2H),6.22(s,1H),5.50(s,1H),5.20(s,2H),
2.93–2.83(m,3H).MS(ESI)m/z[M+H]+,351.1。
By 2E (370mg, 1.06mmol), 2F (263mg, 1.06mmol) is dissolved in toluene (15mL), is placed in N2Protection
Lower agitating and heating, isothermal reaction 2h at 100 DEG C, TLC monitoring reactions are completed.Stop reaction, be cooled to room temperature, be spin-dried for solvent, it is residual
Stay the direct column chromatography (DCM of thing:MeOH=85:1).Obtain target compound 2G and amount to 222mg, yield 35%.1H NMR
(400MHz,CDCl3)δ12.23–11.45(m,1H),8.49(s,1H),7.81–7.45(m,3H),7.44–7.32(m,5H),
7.13–6.85(m,2H),6.55(s,1H),5.22(s,2H),3.94(s,6H),3.49(s,3H).MS(ESI)m/z[M+H]+,
598.0。
2G (210mg, 0.351mmol) is dissolved in MeOH (20mL), in being stirred under room temperature condition, Pd/C is added
80mg, is passed through hydrogen, persistently stirs 6h.TLC monitoring reactions are completed.Solid catalyst is filtered, solvent is spin-dried for, obtains target chemical combination
Thing 2H 130mg, yield 80%.Products obtained therefrom is directly used in next step reaction.
2H (130mg, 0.281mmol) is dissolved in DCM (10mL), DIPEA (59 μ L, 0.337mmol), Yu Bing is added
Stirred under the conditions of bath, be slowly added to acryloyl chloride (23 μ L), be slowly increased to that 20min is stirred at room temperature.TLC monitoring reactions are completed.Instead
Liquid is answered to wash, anhydrous sodium sulfate drying is filtered to remove drier, and revolving removes solvent, the direct column chromatography (DCM of residue:MeOH=
60:1).Obtain the product 87mg of target compound 2, yield 60%.1H NMR(400MHz,CDCl3)δ11.77(s,1H),8.47(s,
1H),8.24(s,1H),7.76(s,1H),7.58(s,1H),7.35(s,1H),7.18-7.00(m,2H),6.51(s,1H),
(s, the 3H) .MS of 6.47-6.43 (m, 1H), 6.27-6.20 (m, 1H), 5.78 (d, J=10.3Hz, 1H), 3.91 (s, 6H), 3.49
(ESI)m/z[M+H]+,517.92。
Embodiment 3
The compounds of this invention 3 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 3, ESI-MS m/
z：617.2[M+H]+。
Embodiment 4
The compounds of this invention 4 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 4, ESI-MS m/
z：630.3[M+H]+。
Embodiment 5
The compounds of this invention 5 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 5, ESI-MS m/
z：629.5[M+H]+。
Embodiment 6
The compounds of this invention 6 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 6, ESI-MS m/
z：631.4[M+H]+。
Embodiment 7
The compounds of this invention 7 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 7, ESI-MS m/
z：645.2[M+H]+。
Embodiment 8
The compounds of this invention 8 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 8, ESI-MS m/
z：631.3[M+H]+。
Embodiment 9
The compounds of this invention 9 is implemented to prepare according to the similar scheme of embodiment 1, prepare compound 9, ESI-MS m/
z：533.4[M+H]+。
Embodiment 10
Addition 10A (200mg, 1.38mmol) in 50mL round-bottomed flasks, 10B (420mg, 2.08mmol), ethanol (20mL),
DIPEA (362 μ L, 2.08mmol), reacts 4h under nitrogen protection, reaction solution is spin-dried in 60 DEG C of oil baths, adds dichloromethane, take out
Filter, collects filtrate, the residue obtained after being spin-dried for is through silica gel column chromatography (dichloromethane：Methanol 50:1) white solid 10C is purified to obtain
(328mg, yield 76.6%).
10C (150mg, 0.483mmol), 10D (144mg, 0.580mmol), toluene are added in 50mL round-bottomed flasks
(20mL), TEA (67 μ L, 0.483mmol) reacts 8h in 100 DEG C of oil baths under nitrogen protection, reaction solution suction filtration collects filtrate,
It is spin-dried for, obtained residue is through silica gel column chromatography (dichloromethane：Methanol 100:1) white solid 10E (97mg, yield are purified to obtain
36.0%).
10E (97mg, 0.174mmol), trifluoroacetic acid (1mL), dichloromethane (2mL), room are added in 50mL round-bottomed flasks
The lower stirring reaction 4h of temperature, reaction solution is spin-dried for, and saturated sodium carbonate and ethyl acetate are added in residue, and extracting and demixing collects organic phase,
Anhydrous sodium sulfate drying, is spin-dried for obtaining 10F.10F is dissolved in dichloromethane (10mL), is placed in ice bath and stirs, and adds DIPEA (33 μ
L, 0.187mmol), acryloyl chloride (15 μ L, 0.187mmol) is added dropwise, 1h is reacted, reaction solution is spin-dried for, add saturated sodium carbonate and
Ethyl acetate, extracting and demixing collects organic phase, and saturated sodium carbonate washing, anhydrous sodium sulfate drying is spin-dried for obtained residue through silicon
Plastic column chromatography (dichloromethane：Methanol 50:1) compound as white solid 10 (37mg, yield 41.5%) is purified to obtain.1H NMR
(400MHz,CDCl3)δ12.11(s,1H),8.44–8.29(m,1H),6.57–6.49(m,1H),6.48–6.24(m,2H),
6.24-5.99 (m, 2H), 5.66 (d, J=10.2Hz, 1H), 4.88-4.68 (m, 2H), 4.24-4.05 (m, 2H), 3.92 (s,
6H),3.82–3.61(m,2H),3.56–3.43(m,3H).MS(ESI)m/z[M+H]+,512.01。
Embodiment 11
The compounds of this invention 11 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 11, ESI-MS
m/z：549.4[M+H]+。
Embodiment 12
The compounds of this invention 12 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 12, ESI-MS
m/z：533.1[M+H]+。
Embodiment 13
The compounds of this invention 13 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 13, ESI-MS
m/z：526.1[M+H]+。
Embodiment 14
The compounds of this invention 14 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 14, ESI-MS
m/z：512.1[M+H]+。
Embodiment 15
The compounds of this invention 15 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 15, ESI-MS
m/z：524.2[M+H]+。
Embodiment 16
The compounds of this invention 16 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 16, ESI-MS
m/z：527.1[M+H]+。
Embodiment 17
The compounds of this invention 17 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 17, ESI-MS
m/z：550.1[M+H]+。
Embodiment 18
The compounds of this invention 18 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 18, ESI-MS
m/z：534.2[M+H]+。
Embodiment 19
The compounds of this invention 19 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 19, ESI-MS
m/z：647.3[M+H]+。
Embodiment 20
The compounds of this invention 20 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 20, ESI-MS
m/z：646.2[M+H]+。
Embodiment 21
The compounds of this invention 21 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 21, ESI-MS
m/z：535.3[M+H]+。
Embodiment 22
The compounds of this invention 22 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 22, ESI-MS
m/z：534.2[M+H]+。
Embodiment 23
The compounds of this invention 23 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 23, ESI-MS
m/z：529.1[M+H]+。
Embodiment 24
The compounds of this invention 24 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 24, ESI-MS
m/z：528.2[M+H]+。
Embodiment 25
The compounds of this invention 25 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 25, ESI-MS
m/z：543.3[M+H]+。
Embodiment 26
The compounds of this invention 26 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 26, ESI-MS
m/z：542.1[M+H]+。
Embodiment 27
The compounds of this invention 27 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 27, ESI-MS
m/z：556.2[M+H]+。
Embodiment 28
28A (210mg, 0.810mmol), 28B (241mg, 0.971mmol), toluene are added in 50mL round-bottomed flasks
(30mL), 4h is reacted under nitrogen protection in 100 DEG C of oil baths, is cooled to room temperature, and reaction solution suction filtration, toluene washing is collected filter cake, done
It is dry to obtain yellow solid 28C (271mg, yield 65.9%).
28C (271mg, 0.534mmol), palladium carbon (100mg), THF (30mL), ethanol are added in 250mL round-bottomed flasks
(30mL), is passed through under hydrogen, normal temperature and pressure and reacts 3h, reaction solution suction filtration, ethanol washing, and merging filtrate is spin-dried for obtaining white admittedly
Body 28D, 28D are dissolved in DMF (5mL), are placed in ice bath, add DIPEA (93 μ L, 0.534mmol), be added dropwise acryloyl chloride (44 μ L,
0.534mmol), drip and finish, reacted under ice bath and water is added in 30min, reaction solution, ethyl acetate, extracting and demixing collects organic phase,
Water is used successively, and saturated aqueous sodium carbonate washing, anhydrous sodium sulfate drying is spin-dried for, and residue is through silica gel column chromatography (dichloromethane：
Methanol 100:1) compound as white solid 28 (102mg, yield 35.9%) is purified to obtain.1H NMR(400MHz,DMSO-d6)δ
12.56(s,1H),9.69(s,1H),8.95(s,1H),7.76–7.62(m,1H),7.62–7.47(m,1H),7.25–7.17
(m, 2H), 6.87 (s, 1H), 6.49 (dd, J=17.0,10.2Hz, 1H), 6.24 (dd, J=17.0,2.0Hz, 1H), 6.10
(s, 1H), 5.73 (dd, J=10.2,1.9Hz, 1H), 3.93 (s, 6H), 3.21 (s, 3H), 2.37 (s, 3H) .MS (ESI) m/z
[M+H]+,530.88。
Embodiment 29
29A (197mg, 1.25mmol), 29B (600mg, 1.87mmol), Pd are added in 100mL round-bottomed flasks2(dba)3
(114mg, 0.125mmol), X-phos (119mg, 0.250mmol), cesium carbonate (815mg, 2.50mmol), toluene (15mL),
Nitrogen bubble 15min is used, 8h is reacted in 110 DEG C of oil baths under nitrogen protection, is cooled to room temperature, suction filtration, with dichloromethane and first
Alcohol (5:1) mixed solvent is washed, and solvent is evaporated off in merging filtrate, and obtained residue is through column chromatography (dichloromethane：Methanol 20:1) divide
Off-white powder 29C (151mg, yield 27.4%) is obtained from purifying.
29C (151mg, 0.342mmol), 29D (102mg, 0.410mmol), toluene are added in 100mL round-bottomed flasks
(15mL), reacts 4h, reaction solution is spin-dried for, and residue is through silica gel column chromatography (dichloromethane under nitrogen protection in 100 DEG C of oil baths：First
Alcohol 50:1) white solid 29E (105mg, yield 44.5%) is purified to obtain.
29E (105mg, 0.152mmol), trifluoroacetic acid (1mL), dichloromethane (2mL), room are added in 50mL round-bottomed flasks
The lower stirring reaction 4h of temperature, reaction solution is spin-dried for, and saturated sodium carbonate and ethyl acetate are added in residue, and extracting and demixing collects organic phase,
Anhydrous sodium sulfate drying, is spin-dried for obtaining 29F.29F is dissolved in dichloromethane (10mL), is placed in ice bath and stirs, and adds DIPEA (30 μ
L, 0.173mmol), acryloyl chloride (14 μ L, 0.173mmol) is added dropwise, 1h is reacted, reaction solution is spin-dried for, add saturated sodium carbonate and
Ethyl acetate, extracting and demixing collects organic phase, and saturated sodium carbonate washing, anhydrous sodium sulfate drying is spin-dried for obtained residue through silicon
Plastic column chromatography (dichloromethane：Methanol 20:1) compound as white solid 29 (13mg, yield 13.3%) is purified to obtain.1H NMR
(400MHz,CDCl3) δ 12.97 (s, 1H), 7.86 (s, 2H), 7.15 (d, J=8.7Hz, 1H), 6.82-6.59 (m, 2H),
6.51 (s, 1H), 6.40 (d, J=16.4Hz, 1H), 6.18 (dd, J=16.7,10.3Hz, 1H), 5.75 (d, J=10.1Hz,
1H),5.66(s,1H),3.92(s,6H),3.35–3.24(m,4H),3.23(s,3H),2.68–2.55(m,4H),2.55–
2.39 (m, 5H), 1.14 (t, J=6.9Hz, 3H) .MS (ESI) m/z [M+H]+,643.15。
Embodiment 30
The compounds of this invention 30 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 30, ESI-MS
m/z：644.1[M+H]+。
Embodiment 31
The compounds of this invention 31 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 31, ESI-MS
m/z：577.4[M+H]+。
Embodiment 32
The compounds of this invention 32 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 32, ESI-MS
m/z：465.2[M+H]+。
Embodiment 33
The compounds of this invention 33 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 33, ESI-MS
m/z：590.0[M+H]+。
Embodiment 34
The compounds of this invention 34 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 34, ESI-MS
m/z：618.4[M+H]+。
Embodiment 35
The compounds of this invention 35 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 35, ESI-MS
m/z：648.1[M+H]+。
Embodiment 36
The compounds of this invention 36 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 36, ESI-MS
m/z：642.4[M+H]+。
Embodiment 37
The compounds of this invention 37 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 37, ESI-MS
m/z：618.1[M+H]+。
Embodiment 38
The compounds of this invention 38 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 38, ESI-MS
m/z：644.3[M+H]+。
Embodiment 39
The compounds of this invention 39 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 39, ESI-MS
m/z：645.0[M+H]+。
Embodiment 40
By 40A (406mg, 3.15mmol), 40B (1316mg, 4.09mmol), EDCI (910mg, 4.72mmol), HOBt
(640mg,4.72mmol),Et3N (653 μ L, 4.72mmol), sequentially adds dissolving stirring in DMF (35mL).N2The lower room temperature of protection
12h is stirred, TLC monitoring reactions are completed, and will stop reacting, reaction solution is poured into frozen water, is stirred vigorously, and are separated out a large amount of solid
Body, filtering, wash with a small amount of frozen water, vacuum drying, solid product 40C product 804mg, yield 59%.1H NMR
(400MHz,CDCl3) δ 10.27 (s, 1H), 8.17 (d, J=9.6Hz, 1H), 8.05 (d, J=2.7Hz, 1H), 6.50 (dd, J
=9.6,2.8Hz, 1H), 3.93-3.80 (m, 4H), 3.59-3.47 (m, 4H), 2.27 (s, 6H), 1.56 (s, 9H), 1.01-
0.94(m,2H),0.94–0.88(m,2H).MS(ESI)m/z[M+H]+,434.35。
40C (800mg, 1.85mmol) is dissolved in MeOH (20mL), in being stirred under room temperature condition, Pd/C is added
200mg, hydrogen is replaced and protected, and stirs 6h.TLC monitoring reactions are completed.Solid catalyst is filtered, solvent is spin-dried for, obtains target
Compound 40D product 596mg, yield 80%.Products obtained therefrom is directly used in next step reaction.
40E (220mg, 1.46mmol) is dissolved in anhydrous THF (60mL), stirred under ice bath；40D is slowly added in batches
(590mg, 1.46mmol), is warming up to room temperature and continues to react 30min.TLC monitoring reactions are completed, and revolving removes most of solvent,
30mL water will be added in residue, continue to stir 10min at room temperature, separated out solid filtering, solid is washed with a small amount of frozen water.Collect
Solid, vacuum drying, obtains product 40F products 597mg.Yield 79%.
By 40F (590mg, 1.15mmol), methylamine hydrochloride (156mg, 2.30mmol), DIPEA (0.57mL,
3.45mmol) sequentially add in absolute ethyl alcohol (40mL), N2Under the conditions of 80 DEG C reaction 2h, TLC monitoring reaction complete, stop reaction
And it is cooled to room temperature.Solvent is spin-dried for, saturated sodium bicarbonate aqueous solution is added, EA aqueous layer extracteds 3 times merge organic layer, washed, do
It is dry, except solvent, crude product column chromatography (DCM:MeOH=100:1).Product is obtained, is dried in vacuo.Product 40G product 362mg, yield
61%.
By 40G (350mg, 0.68mmol), 40H (168mg, 0.68mmol) is dissolved in toluene (15mL), is placed in N2Protect
Isothermal reaction 2h at lower agitating and heating, 100 DEG C is protected, TLC monitoring reactions are completed.Stop reaction, be cooled to room temperature, be spin-dried for solvent,
Direct column chromatography (the DCM of residue:MeOH=85:1).Obtain target compound 40I product 180mg, yield 35%.1H NMR
(400MHz,CDCl3)δ11.42(s,1H),8.52(s,1H),7.29–7.20(m,2H),6.63–6.41(m,4H),3.93(s,
6H),3.85–3.70(m,4H),3.51(s,3H),3.23–2.92(m,4H),2.31(s,6H),1.53(s,9H),1.01–
0.94(m,2H),0.94–0.87(m,2H).MS(ESI)m/z[M+H]+,759.20
40I (160mg, 0.21mmol) is dissolved in DCM (20mL), in being stirred under condition of ice bath, TFA (4mL) is added,
It is slowly increased to that 2h is stirred at room temperature.TLC monitoring reactions are completed.Solvent is spin-dried for, residue adds saturated aqueous sodium carbonate, EA extractions
Take, merge EA layers, washing, anhydrous sodium sulfate drying.Revolving removes solvent, obtains target compound 40J product 112mg, yield
81%.MS(ESI)m/z[M+H]+,659.21.Products obtained therefrom is directly used in next step reaction.
40J (100mg, 0.15mmol) is dissolved in DCM (10mL), DIPEA (30 μ L, 0.182mmol), Yu Bing is added
Stirred under the conditions of bath, be slowly added to acryloyl chloride (15 μ L), be slowly increased to that 20min is stirred at room temperature.TLC monitoring reactions are completed.Instead
Liquid is answered to wash, anhydrous sodium sulfate drying is filtered to remove drier, and revolving removes solvent, the direct column chromatography (DCM of residue:MeOH=
60:1).Obtain the product 164mg of target compound 40, yield 60%.1H NMR(400MHz,DMSO)δ11.50(s,1H),9.38
(s,1H),8.51(s,1H),6.95–6.84(m,2H),6.44–6.35(m,1H),6.11(s,1H),5.77(s,2H),4.77
(s,2H),3.94(s,6H),3.70–3.59(m,4H),2.66(s,3H),2.21(s,6H),0.95–0.84(m,2H),0.79–
0.71(m,2H).MS(ESI)m/z[M+H]+,713.76。
Embodiment 41
By 41A (807mg, 2mmol), 41B (287mg, 2mmol), Cs2CO3(1303mg, 4mmol) is dissolved in toluene
In (25mL), N is passed through2After 5 minutes, Pd is added2(dba)3(183mg, 0.2mmol), XPhos (190mg, 0.4mmol), stirring
Under be passed through N25 minutes, it is placed in N2Isothermal reaction 8h at lower agitating and heating, 100 DEG C is protected, TLC monitoring reactions are completed.Stop anti-
Should, room temperature is cooled to, solvent, the direct column chromatography (DCM of residue is spin-dried for:MeOH=100:1).Obtain target compound 41C products
317mg, yield 31%.1H NMR(400MHz,CDCl3) δ 8.10 (s, 1H), 7.81 (d, J=2.2Hz, 1H), 7.11 (d, J=
8.7Hz, 1H), 7.06 (s, 1H), 6.92 (s, 1H), 6.61 (dd, J=8.7,2.7Hz, 1H), 5.30 (s, 1H), 5.12 (s,
1H), 3.90-3.78 (m, 4H), 3.29-3.18 (m, 4H), 2.76 (d, J=5.0Hz, 3H), 2.30 (s, 6H), 1.49 (s,
9H),0.98–0.93(m,2H),,0.92–0.85(m,2H).MS(ESI)m/z[M+H]+,511.44。
By 41C (310mg, 0.607mmol), 41D (211mg, 0.851mmol) is dissolved in toluene (15mL), is placed in N2
Isothermal reaction 2h at lower agitating and heating, 100 DEG C is protected, TLC monitoring reactions are completed.Stop reaction, be cooled to room temperature, be spin-dried for molten
Agent, the direct column chromatography (DCM of residue:MeOH=85:1).Obtain target compound 41E product 160mg, yield 21%.1H NMR
(400MHz,CDCl3) δ 12.58 (s, 1H), 8.39 (s, 1H), 7.74 (d, J=2.1Hz, 1H), 7.16 (d, J=8.7Hz,
1H), 6.87 (d, J=13.8Hz, 2H), 6.67 (dd, J=8.8,2.7Hz, 1H), 6.54 (s, 1H), 5.81 (s, 1H), 3.94
(s,6H),3.89–3.82(m,4H),3.62–3.52(m,4H),3.27(s,3H),2.34(s,6H),1.51(s,9H),1.07–
0.98(m,2H),0.95–0.88(m,2H).MS(ESI)m/z[M+H]+,758.42。
41E (160mg, 0.237mmol) is dissolved in DCM (20mL), in being stirred under condition of ice bath, TFA is added
(4mL), is slowly increased to that 2h is stirred at room temperature.TLC monitoring reactions are completed.Solvent is spin-dried for, residue adds saturated aqueous sodium carbonate,
EA is extracted, and merges EA layers, washing, anhydrous sodium sulfate drying.Revolving removes solvent, obtains target compound 41F products 130mg.Institute
Obtain product and be directly used in next step reaction.
41F (130mg, 0.197mmol) is dissolved in DCM (10mL), DIPEA (35 μ L, 0.209mmol) is added, in
Stirred under condition of ice bath, be slowly added to acryloyl chloride (13 μ L), be slowly increased to that 20min is stirred at room temperature.TLC monitoring reactions are completed.
Reaction solution is washed, anhydrous sodium sulfate drying, is filtered to remove drier, and revolving removes solvent, the direct column chromatography (DCM of residue:MeOH
=60:1).Obtain the product 138mg of target compound 41, yield 27%.1H NMR(400MHz,CDCl3)δ12.55(s,1H),8.41
(s, 1H), 7.90 (s, 1H), 7.82 (s, 1H), 7.26 (d, J=8.7Hz, 1H), 6.91 (s, 1H), 6.79 (d, J=7.9Hz,
1H), 6.54 (s, 1H), 6.45 (d, J=16.8Hz, 1H), 6.24 (dd, J=16.5,10.4Hz, 1H), 5.90 (s, 1H),
5.80 (d, J=10.3Hz, 1H), 3.94 (s, 6H), 3.90-3.81 (m, 4H), 3.37-3.21 (m, 7H), 2.36 (s, 6H),
1.13–0.98(m,2H),0.96–0.87(m,2H).MS(ESI)m/z[M+H]+,712.67。
Embodiment 42
The compounds of this invention 42 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 42, ESI-MS
m/z：630.1[M+H]+。
Embodiment 43
The compounds of this invention 43 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 43, ESI-MS
m/z：728.2[M+H]+。
Embodiment 44
By 44A (10g, 46.1mmol), DMAP (2.25g, 18.4mmol) is dissolved in THF (500mL), ice bath stirring
Under, it is slowly added dropwise (Boc)2O (20.1g, 92.2mmol), 30min is added dropwise to complete, and is gradually heating to react at room temperature 12h, TLC prisons
Reaction is surveyed to complete.Stop reaction, be spin-dried for solvent, the direct column chromatography (PE of residue:EA=100:1).Obtain target compound 44B
17.5g, yield 91%.
44B (17.5g, 42mmol) is dissolved in DCM (500mL), under condition of ice bath stir, add TFA (5.02g,
44mmol), it is slowly increased to that 20h is stirred at room temperature.TLC monitoring reactions are completed.Solvent is spin-dried for, it is water-soluble that residue adds saturated sodium carbonate
Liquid, EA extractions merge EA layers, washing, anhydrous sodium sulfate drying.Revolving removes solvent, obtains target compound 44C products
13.05g.Products obtained therefrom is directly used in next step reaction.
By 44C (13.05g, 41.2mmol), homopiperazine (6.18g, 61.8mmol), Cs2CO3(33.6g, 103mmol) is molten
Solution is passed through N in toluene (250mL)2After 5 minutes, Pd is added2(dba)3(3.76g,4.1mmol),XPhos(3.91g,
8.2mmol), it is passed through N under stirring25 minutes, it is placed in N2Isothermal reaction 20h at lower agitating and heating, 100 DEG C is protected, TLC monitorings are anti-
It should complete.Stop reaction, be cooled to room temperature, be spin-dried for solvent, the direct column chromatography (DCM of residue:MeOH=100:1).Obtain target
Compound 44D product 4.29g, yield 31%.1H NMR(400MHz,CDCl3) δ 9.12 (s, 1H), 8.26 (d, J=9.4Hz,
1H), 7.37 (d, J=3.1Hz, 1H), 7.00 (dd, J=9.4,3.1Hz, 1H), 3.60-3.58 (m, 2H), 3.12-3.03 (m,
2H),2.77–2.67(m,2H),2.92–2.87(m,2H),2.02–1.93(m,2H),1.54(s,9H)。
By 44D (4.29g, 12.8mmol), m (2.46g, 19.2mmol), EDCI (2.96g, 15.4mmol), HOBt
(2.02g,15.4mmol),Et3N (1.94g, 19.2mmol), sequentially adds dissolving stirring in DCM (100mL).N2The lower room of protection
Temperature stirring 12h, TLC monitoring reaction is completed, and will stop reacting, reaction solution is poured into frozen water, is stirred vigorously, separate out a large amount of solid
Body, filtering, wash with a small amount of frozen water, vacuum drying, solid product 44E product 3.38g, yield 59%.1H NMR
(400MHz,CDCl3) δ 9.13 (s, 1H), 8.28 (d, J=9.4Hz, 1H), 7.40 (d, J=3.1Hz, 1H), 7.01 (dd, J=
9.4,3.1Hz,1H),3.85–3.53(m,8H),2.13(s,6H),2.08–1.98(m,2H),1.54(s,9H),0.95–0.87
(m,2H),0.83–0.75(m,2H).
44E (3.38g, 7.55mmol) is dissolved in DCM (100mL), in being stirred under condition of ice bath, TFA is added
(4mL), is slowly increased to that 2h is stirred at room temperature.TLC monitoring reactions are completed.Solvent is spin-dried for, residue adds saturated aqueous sodium carbonate,
EA is extracted, and merges EA layers, washing, anhydrous sodium sulfate drying.Revolving removes solvent, obtains target compound 44F products 2.62g.Institute
Obtain product and be directly used in next step reaction.
By 44F (694mg, 2mmol), 44N (287mg, 2mmol), Cs2CO3(1303mg, 4mmol) is dissolved in toluene
In (25mL), N is passed through2After 5 minutes, Pd is added2(dba)3(183mg, 0.2mmol), XPhos (190mg, 0.4mmol), stirring
Under be passed through N25 minutes, it is placed in N2Isothermal reaction 8h at lower agitating and heating, 100 DEG C is protected, TLC monitoring reactions are completed.Stop anti-
Should, room temperature is cooled to, solvent, the direct column chromatography (DCM of residue is spin-dried for:MeOH=100:1).Obtain target compound 44G products
277mg, yield 31%.1H NMR(400MHz,CDCl3) δ 9.12 (s, 1H), 8.34-8.23 (m, 2H), 7.41 (d, J=
3.1Hz, 1H), 7.05 (dd, J=9.4,3.1Hz, 1H), 5.71 (s, 1H), 5.24 (s, 1H), 3.93-3.51 (m, 8H), 2.93
(d, J=5.1Hz, 3H), 2.15 (s, 6H), 2.08-2.03 (m, 2H), 0.95-0.88 (m, 2H), 0.85-0.72 (m, 2H)；MS
(ESI)m/z[M+H]+,455.26。
By 44G (270mg, 0.607mmol), o (211mg, 0.851mmol) is dissolved in toluene (15mL), is placed in N2Protect
Isothermal reaction 2h at lower agitating and heating, 100 DEG C is protected, TLC monitoring reactions are completed.Stop reaction, be cooled to room temperature, be spin-dried for solvent,
Direct column chromatography (the DCM of residue:MeOH=85:1).Obtain target compound 44H product 175mg, yield 41%.1H NMR
(400MHz,CDCl3) δ 12.46 (s, 1H), 9.26 (s, 1H), 8.50 (s, 1H), 8.32 (d, J=9.3Hz, 1H), 7.44 (d, J
=3.0Hz, 1H), 7.07 (dd, J=9.4,3.1Hz, 1H), 6.56 (s, 1H), 6.31 (s, 1H), 3.95 (s, 6H), 3.89-
3.61(m,8H),3.47(s,3H),2.25–2.00(m,8H),0.98–0.90(m,2H),0.89–0.80(m,2H)；MS(ESI)
m/z[M+H]+,702.44。
44H (210mg, 0.351mmol) is dissolved in MeOH (20mL), in being stirred under room temperature condition, Pd/C is added
80mg, is passed through hydrogen, persistently stirs 6h.TLC monitoring reactions are completed.Solid catalyst is filtered, solvent is spin-dried for, obtains target chemical combination
Thing 44I products 132mg.Products obtained therefrom is directly used in next step reaction.
44I (132mg, 0.197mmol) is dissolved in DCM (10mL), DIPEA (35 μ L, 0.209mmol) is added, in
Stirred under condition of ice bath, be slowly added to acryloyl chloride (13 μ L), be slowly increased to that 20min is stirred at room temperature.TLC monitoring reactions are completed.
Reaction solution is washed, anhydrous sodium sulfate drying, is filtered to remove drier, and revolving removes solvent, the direct column chromatography (DCM of residue:MeOH
=60:1).Obtain the product 86mg of target compound 44, yield 60%.1H NMR(400MHz,CDCl3)δ12.59(s,1H),8.39
(s, 1H), 7.86 (s, 1H), 7.70 (s, 1H), 7.15 (d, J=8.8Hz, 1H), 6.80 (s, 1H), 6.60-6.52 (m, 2H),
6.42 (d, J=16.8Hz, 1H), 6.27-6.20 (m, 1H), 5.86 (s, 1H), 5.78 (d, J=10.3Hz, 1H), 3.94 (s,
6H),3.89–3.57(m,8H),3.28(s,3H),2.20–1.98(m,8H),0.91–0.77(m,4H)；MS(ESI)m/z[M+
H]+,726.50。
Embodiment 45
The compounds of this invention 45 is implemented to prepare according to the similar scheme of embodiment 1, prepares compound 45, ESI-MS
m/z：631.3[M+H]+。
D biological tests
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 | 0.07 | 10.1 |
| 2 | 0.09 | >50 |
| 3 | 1.2 | 12.3 |
| 4 | 1.5 | 22.4 |
| 5 | 1.8 | 15.6 |
| 6 | 1.7 | 11.2 |
| 7 | 1.5 | 24.6 |
| 8 | 0.9 | 33.1 |
| 9 | 0.2 | >50 |
| 10 | 0.1 | >50 |
| 11 | 1.2 | >50 |
| 12 | 1.7 | >50 |
| 13 | 0.5 | >50 |
| 14 | 0.1 | >50 |
| 15 | 1.8 | >50 |
| 16 | 0.8 | >50 |
| 17 | 1.9 | >50 |
| 18 | 2.2 | >50 |
| 19 | 0.05 | 44.3 |
| 20 | 0.08 | 10.4 |
| 21 | 0.6 | >50 |
| 22 | 0.1 | >50 |
| 23 | 0.3 | >50 |
| 24 | 0.6 | >50 |
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.
Claims (10)
1. a kind of formula (I) compound, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt,
Wherein, when Y is nitrogen-atoms, A is aryl, heteroaryl, cycloalkyl, heterocyclic radical or cycloalkenyl group；
When Y is carbon atom, and R2During for hydrogen, A is heteroaryl, cycloalkyl, heterocyclic radical or cycloalkenyl group；
When Y is carbon atom, and R2When being not hydrogen, A is aryl, heteroaryl, cycloalkyl, heterocyclic radical or cycloalkenyl group；
X is oxygen atom or sulphur atom；
R1It is separately hydrogen, halogen, cyano group, amino, amide groups, hydroxyl, ester group, acyl group, acyloxy, sulfonyl, sulfenyl
Base ,-NR9R10, alkyl, silicon substrate, alkoxy, aryl, cycloalkyl, heteroaryl or heterocyclic radical；
R2, R3, R4, R5, R6, R7And R8It is separately hydrogen, silicon substrate, halogen, cyano group, hydroxyl, amino, amide groups, acyl group, alkane
Base or alkoxy；
R9, R10It is separately hydrogen, acyl group, alkyl or cycloalkyl；
M is 0,1,2,3 or 4.
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, A is 6 to 8 yuan of aryl, 5 to 8 unit's heteroaryls, 3 to 8 yuan of cycloalkyl, 3 to 8 circle heterocycles bases or 3 to 8 member cycloalkenyls；
X is oxygen atom or sulphur atom；
R1It is separately hydrogen, halogen, cyano group, amide groups, hydroxyl, ester group, acyl group, acyloxy, sulfonyl, sulfinyl ,-
NR9R10, C1-6Alkyl, silicon substrate, C1-6Alkoxy, 6 to 8 yuan of aryl, 3 to 8 yuan of cycloalkyl, 5 to 8 unit's heteroaryls, 3 to 8 circle heterocycles
Base；
R2, R3, R4, R5, R6, R7And R8It is separately hydrogen, halogen, cyano group, hydroxyl, amino, amide groups, acyl group, C1-6Alkyl
Or C1-6Alkoxy；
R9, R10It is separately hydrogen, acyl group, C1-8Alkyl or 3 to 6 yuan of cycloalkyl；
M is 0,1,2,3 or 4.
3. formula (II) compound as claimed in claim 2, its stereoisomer, dynamic isomer or pharmaceutically acceptable
Salt, including the compound of logical formula (III),
Wherein, X is oxygen atom or sulphur atom；
R1It is separately hydrogen, halogen, cyano group, amide groups, hydroxyl, ester group, acyl group, acyloxy, sulfonyl, sulfinyl ,-
NR9R10, C1-6Alkyl, silicon substrate, C1-6Alkoxy, 6 to 8 yuan of aryl, 3 to 8 yuan of cycloalkyl, 5 to 8 unit's heteroaryls or 3 to 8 circle heterocycles
Base；
R2, R3, R4, R5, R6, R7And R8It is separately hydrogen, halogen, cyano group, hydroxyl, amino, amide groups, acyl group, C1-6Alkyl
Or C1-6Alkoxy；
R9, R10It is separately hydrogen, acyl group, C1-8Alkyl or 3 to 6 yuan of cycloalkyl；
M is 0,1,2,3 or 4.
4. formula (III) compound as claimed in claim 3, its stereoisomer, dynamic isomer or pharmaceutically acceptable
Salt, including the compound of logical formula (IV),
Wherein, X is oxygen atom or sulphur atom；Z is nitrogen-atoms or carbon atom；
R2, R3, R4, R5, R6, R7And R8It is separately hydrogen, halogen, cyano group, hydroxyl, amino, amide groups, acyl group, C1-6Alkyl
Or C1-6Alkoxy；
R11It independently is hydrogen, acyl group, C1-8Alkyl or 3 to 6 yuan of cycloalkyl.
5. formula (I) compound as claimed in claim 1, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt,
Including the compound of logical formula (V),
Wherein, R is worked as2During for hydrogen, A is 5 to 8 unit's heteroaryls, 3 to 8 yuan of cycloalkyl, 3 to 8 circle heterocycles bases or 3 to 8 member cycloalkenyls；
Work as R2When being not hydrogen, A is 6 to 8 yuan of aryl, 5 to 8 unit's heteroaryls, 3 to 8 yuan of cycloalkyl, 3 to 8 circle heterocycles bases or 3 to 8 yuan
Cycloalkenyl group；
X is oxygen atom or sulphur atom；
R1It is separately hydrogen, halogen, cyano group, silicon substrate, amide groups, hydroxyl, ester group, acyl group, acyloxy, sulfonyl, sulfenyl
Base ,-NR9R10, C1-6Alkyl, C1-6Alkoxy, 6 to 8 yuan of aryl, 3 to 8 yuan of cycloalkyl, 5 to 8 unit's heteroaryls or 3 to 8 circle heterocycles
Base；
R2, R3, R4, R5, R6, R7And R8It is separately hydrogen, halogen, cyano group, hydroxyl, amino, amide groups, acyl group, C1-6Alkyl
Or C1-6Alkoxy；
R9, R10It is separately hydrogen, acyl group, C1-8Alkyl or 3 to 6 yuan of cycloalkyl；
M is 0,1,2,3 or 4.
6. formula (V) compound as claimed in claim 5, its stereoisomer, dynamic isomer or pharmaceutically acceptable salt,
Including the compound of logical formula (VI),
Wherein, Q is oxygen atom, carbon atom or nitrogen-atoms；
R2, R3, R4, R5, R6, R7And R8It is separately hydrogen, halogen, cyano group, hydroxyl, amino, amide groups, acyl group, C1-6Alkyl
Or C1-6Alkoxy；
Q is 0,1,2,3 or 4；
R is 0,1,2,3 or 4.
7. the formula (I) as described in claim 1 to 6, (II), (III), (IV), (V), (VI) compound, its stereoisomer,
Dynamic isomer or pharmaceutically acceptable salt, 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
Application in composition.
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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