CN108503623A - A kind of compound and the preparation method and application thereof inhibiting PRMT7 - Google Patents

A kind of compound and the preparation method and application thereof inhibiting PRMT7 Download PDF

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CN108503623A
CN108503623A CN201810449994.3A CN201810449994A CN108503623A CN 108503623 A CN108503623 A CN 108503623A CN 201810449994 A CN201810449994 A CN 201810449994A CN 108503623 A CN108503623 A CN 108503623A
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compound
raw material
prmt7
follows
preparation
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杨胜勇
李琳丽
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Sichuan University
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Sichuan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention belongs to chemical medicines, and in particular to a kind of compound inhibiting PRMT7, general formula are as follows：

Description

A kind of compound and the preparation method and application thereof inhibiting PRMT7
Technical field
The present invention relates to chemical synthetic drug technical field, in particular to a kind of compound inhibiting PRMT7 and its preparations Method and application.
Background technology
It is a kind of irreversible modification that protein arginine, which methylates, wherein the guanidine group of arginine residues with S- adenosines Become to methylate in the reaction of methionine (AdoMet).This modification is related to signal transduction, and transcription, rna transport and RNA are cut It connects.Four kinds of different types of protein arginine transmethylases are had now been found that, they can methylate arginine guanidine The nitrogen-atoms of side chain.It has studied and has been found that 11 kinds of protein arginine methyltransferases, according to the arginine methyl of catalysis substrate The difference for changing type, is divided into three types, I types include PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, PRMT8；II types include PRMT5 and PRMT9；Type III is then PRMT7.
PRMT7 is as protein arginine transmethylase, and the function in cell is mainly by modifying substrate protein To complete.The enzyme of arginine methyltransferase family has a selection Preference to substrate protein decorating site, usually GRG, RGG or The sites R in GR amino acid sequences, these sites are appeared in mostly in histone and RNA shearing GAP-associated protein GAPs, therefore at present Until find that this two albuminoid is the main substrate of modification of being methylated by arginine in cell.Currently, having reported that PRMT7 can be modified The albumen such as H2A, H4R3, H3R2, Alba20, Sm and Dishevelled.By the end of current, it has been found that PRMT7 is in chromatin Structure Regulation and control, gene expression, cell signalling, the assembling of protein splicing body, migration, drug resistance, power of regeneration and versatility dimension Hold etc. is worked.Seen at present by PRMT7 for the application in terms for the treatment of of cancer, and there are no and inhibit PRMT7 related Substance, and inhibit PRMT7 roles in terms of relevant report.
Invention content
The purpose of the present invention is to provide one kind capable of inhibiting the active compounds of PRMT7.
It is another object of the present invention to provide a kind of preparation methods of the above-mentioned active compounds of inhibition PRMT7.
It is also an object of the present invention to provide a kind of activity is higher, selectivity is strong, and quasi-medicated property significantly organizes PRMT7 suppressions The drug of preparation and corresponding treatment cancer.
It is also an object of the present invention to provide the concrete applications of the PRMT7 inhibitor.
The present invention provides a kind of compound inhibiting PRMT7, and general formula is as follows：
Wherein,
R1It is independent
R2It is independent
Its specific synthetic line is as follows：
Preparation method makes 2,4-, bis- chloro- 5-FUs successively with raw material A and raw material B condensations to get target product.
By this preparation method, following structural formula is obtained：
The acrylamide analog derivative being prepared has the effect of inhibition PRMT7, and PRMT7 is as protein arginine Transmethylase, the function in cell are mainly completed by modifying substrate protein, regulation and control, gene to chromatin Structure Expression, cell signalling, the assembling of protein splicing body, migration, drug resistance, power of regeneration and versatility maintenance etc. are played Important function, when PRMT7 is suppressed, endocellular chromosome structure can be then abnormal, cause cell can not proper splitting, There is apparent therapeutic effect to the infinite multiplication of tumour cell, therefore life can be added using the compound as main active Pharmaceutically the drug for the treatment of cancer is made in acceptable complementary ingredient to object.The cancer that emphasis is directed to have including prostate cancer, Chronic myelocytic leukemia, lung cancer, lymthoma, oophoroma.
Compared with prior art, the present invention haing the following advantages and advantageous effect：
The present invention synthesized it is a kind of it is new can inhibit the compound of PRMT7, and confirm some implementations of the compound In scheme, good inhibiting effect can be generated to PRMT7, while there is good inhibiting effect to tumour cell, had very Good pharmaceutical potential provides a kind of new potential selection for clinical application；Meanwhile the preparation of noval chemical compound provided by the invention Method is easy, and reaction condition is mild, and easy to operation and control, energy consumption is small, and yield is high, at low cost, can be suitble to industrialization production, makes Standby obtained chemical combination microbic activity is higher, and strong to the selectivity of tumour cell, quasi-medicated property is notable, before having a vast market Scape.
Specific implementation mode
The present invention is described in further detail with reference to embodiment, embodiments of the present invention are not limited thereto, Without departing from the idea case in the present invention described above, according to ordinary skill knowledge and customary means, various replace is made It changes and changes, should all be included within the scope of the invention.
To make the purpose of the present invention, process conditions and advantage effect be more clearly understood, in conjunction with following embodiment, to this Invention is described in further detail, and specific implementation example described herein only to explain the present invention, is not used to limit this Invention.
The specific synthetic route of given the included compound of general formula of the invention is as follows：
Embodiment 1：
Compound 1：N6- (the fluoro- 2- of 5- (4- methoxyl groups) pyrimidine-4-yl) -2- methyl-quinoxaline -4,6- diamines)
It is using raw material A(raw material A 1), raw material B are(raw material B1)
Synthetic route is as follows：
Specifically synthetic method is：
350mg raw material As 1 and 0.4mL n,N-diisopropylethylamine are dissolved in 15mL ethyl alcohol, 335mg 2,4- is then added Two chloro- 5-FUs；Reaction system stirs 12 hours in 85 DEG C, has white is fixed to generate, and after reaction, solid filters, uses 10mL ethyl alcohol and the washing of 10mL methanol, intermediate compound I is obtained after dry.
150mg intermediate compound Is and 152mg 4- methoxy-benzene boronic acid pinacol esters (raw material B1) are dissolved in 15mL (dioxies six Ring：Water=5:1) in system, 350mg cesium carbonates and 37mg [1,1 '-bis- (diphenylphosphino) ferrocene] palladium chloride is added.
Reaction system is reacted 6 hours in 90 DEG C under protection of argon gas, is cooled to room temperature, is spin-dried for solvent, is added into mixture Enter 20mL purified waters, is extracted 3 times with 20mL ethyl acetate 20.It mixes, is spin-dried for by organic, then column chromatography (dichloromethane：First Alcohol=20:1), then compound 1 is recrystallized to give with ethyl acetate and petroleum ether.
The yield of the compound 1 is 90%.
Its1H NMR datas are as follows：
1H NMR(400MHz,DMSO-d6) 1H NMR (400MHz, DMSO) δ 10.07 (s, 1H), 8.69 (d, J=1.9Hz, 3H), 8.51 (d, J=3.5Hz, 1H), 8.17 (d, J=8.9Hz, 2H), 8.15-8.09 (m, 1H), 8.04 (d, J=9.1Hz, 1H), 6.98 (d, J=8.9Hz, 2H), 6.66 (s, 1H), 3.80 (s, 3H), 2.63 (s, 3H) .LC-MS:m/z 375.1[M+H ]+.
Wherein, raw material A 1 is not the Conventional compounds that can be bought, therefore the specific synthetic route of raw material A 1 is as follows：
Specific preparation method is as follows：
First, by 3.2g2- cyano-4-nitroanilines, 30mL acetone, 100mL toluene is placed in the round-bottomed flask of 250ml, It is cooled to 0 DEG C, 3.0mL SnCl are then slowly added dropwise4.Then, reaction system is flowed back 4h, is then cooled to room temperature, solid is taken out Filter obtains intermediate a.2.0g intermediates a and 540mg ammonium chlorides are mixed in 50mL (ethyl alcohol：Water=2:1) in system, 60 DEG C add Enter 2.6g reduced iron powders.It then heats to 85 DEG C to react 2 hours, is cooled to room temperature and is spin-dried for solvent, then filter mixture, The slag blanket that filtrate is spin-dried for acquisitions recrystallizes in petroleum ether and ethyl acetate mixtures to get raw material A 1.
Embodiment 2：
The present embodiment has replaced raw material B on the basis of above compound, specific as follows：
Compound 2：N6- (the fluoro- 2- of 5- (4- (trifluoromethyl) phenyl) pyrimidine-4-yl) -2- methyl-quinoxaline -4,6- diamines
It is using raw material A(raw material A 1), raw material B are(raw material B2)
Synthetic route is as follows：
Specific preparation method is same as the previously described embodiments, and which is not described herein again.
The yield of the compound 2 is 88%.
Its1H NMR datas are as follows：
1H NMR(400MHz,DMSO-d6) δ 10.25 (s, 1H), 8.68 (d, J=43.4Hz, 4H), 8.42 (d, J= 7.3Hz, 2H), 8.24-7.94 (m, 2H), 7.81 (d, J=7.3Hz, 2H), 6.65 (s, 1H), 2.63 (s, 3H) .LC-MS:m/z 413.1[M+H]+.
Embodiment 3：
The present embodiment has replaced raw material B on the basis of above compound, specific as follows：
Compound 3：N6- (the fluoro- 2- of 5- (4- nitrobenzophenones) pyrimidine-4-yl) -2- methyl-quinoxaline -4,6- diamines
It is using raw material A(raw material A 1), raw material B are(raw material B3)
Synthetic route is as follows：
Specific preparation method is same as the previously described embodiments, and which is not described herein again.
The yield of the compound 3 is 86%.
Its1H NMR datas are as follows：
1H NMR(400MHz,DMSO-d6) δ 10.29 (s, 1H), 8.74 (d, J=1.7Hz, 1H), 8.74-8.57 (m, 3H), 8.45 (d, J=8.9Hz, 2H), 8.29 (d, J=8.9Hz, 2H), 8.12 (dd, J=9.1,1.8Hz, 1H), 8.00 (d, J =9.0Hz, 1H), 6.65 (s, 1H), 2.63 (s, 3H) .LC-MS:m/z 390.1[M+H]+.
Embodiment 4：
The present embodiment has replaced raw material B on the basis of above compound, specific as follows：
Compound 4：4- (4- ((4- amino-2-methyl quinoline -6- bases) amino) -5- fluorinated pyrimidine -2- bases) benzonitrile
It is using raw material A(raw material A 1), raw material B are(raw material B4)
Synthetic route is as follows：
Specific preparation method is same as the previously described embodiments, and which is not described herein again.
The yield of the compound 4 is 82%.
Its1H NMR datas are as follows：
1H NMR(400MHz,DMSO-d6) δ 10.26 (s, 1H), 8.68 (s, 1H), 8.64 (d, J=3.3Hz, 3H), 8.36 (d, J=8.3Hz, 2H), 8.11 (d, J=8.9Hz, 1H), 7.97 (d, J=9.1Hz, 1H), 7.92 (d, J=8.3Hz, 2H), 6.64(s,1H),2.62(s,3H).LC-MS:m/z 370.1[M+H]+.
Embodiment 5：
The present embodiment has replaced raw material B on the basis of above compound, specific as follows：
Compound 5：4- (4- ((4- amino-2-methyl quinoline -6- bases) amino) -5- fluorinated pyrimidine -2- bases) benzamide
It is using raw material A(raw material A 1), raw material B are(raw material B5)
Synthetic route is as follows：
Specific preparation method is same as the previously described embodiments, and which is not described herein again.
The yield of the compound 5 is 86%.
Its1H NMR datas are as follows：
1H NMR(400MHz,DMSO-d6) δ 10.26 (s, 1H), 8.68 (s, 1H), 8.64 (d, J=3.3Hz, 3H), 8.36 (d, J=8.3Hz, 2H), 8.11 (d, J=8.9Hz, 1H), 7.97 (d, J=9.1Hz, 1H), 7.92 (d, J=8.3Hz, 2H), 6.64(s,1H),2.62(s,3H).LC-MS:m/z 388.1[M+H]+.
Embodiment 6：
The present embodiment has replaced raw material B on the basis of above compound, specific as follows：
Compound 6：N6- (2- (4- (tertiary butyl) phenyl) -5- fluorinated pyrimidine -4- bases) -2- methyl-quinoxaline -4,6- diamines
It is using raw material A(raw material A 1), raw material B are(raw material B6)
Synthetic route is as follows：
Specific preparation method is same as the previously described embodiments, and which is not described herein again.
The yield of the compound 6 is 86%.
Its1H NMR datas are as follows：
1H NMR(400MHz,DMSO-d6)1H NMR(400MHz,DMSO)δ10.12(s,1H),8.71(s,3H),8.54 (s, 1H), 8.16 (d, J=7.0Hz, 3H), 8.07 (d, J=8.5Hz, 1H), 7.46 (d, J=7.4Hz, 2H), 6.67 (s, 1H),2.64(s,3H),1.30(s,9H).LC-MS:m/z 401.2[M+H]+.
Embodiment 7：
The present embodiment has replaced raw material B on the basis of above compound, specific as follows：
Compound 7：N6- (the fluoro- 2- of 5- (furans -3- bases) pyrimidine-4-yl) -2- methyl-quinoxaline -4,6- diamines
It is using raw material A(raw material A 1), raw material B are(raw material B7)
Synthetic route is as follows：
Specific preparation method is same as the previously described embodiments, and which is not described herein again.
The yield of the compound 7 is 91%.
Its1H NMR datas are as follows：
1H NMR (400MHz, DMSO) δ 10.07 (s, 1H), 8.67 (s, 3H), 8.47 (d, J=3.3Hz, 1H), 8.19 (s, 1H), 8.13 (d, J=8.9Hz, 1H), 7.98 (d, J=9.0Hz, 1H), 7.75 (s, 1H), 6.87 (s, 1H), 6.64 (s, 1H),2.62(s,3H).LC-MS:m/z 336.1[M+H]+.
Embodiment 8：
The present embodiment has replaced raw material B on the basis of above compound, specific as follows：
Compound 8：N6- (the fluoro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases) pyrimidine-4-yl) -2- methyl-quinoxalines -4,6- Diamines
It is using raw material A(raw material A 1), raw material B are(raw material B8)
Synthetic route is as follows：
Specific preparation method is same as the previously described embodiments, and which is not described herein again.
The yield of the compound 8 is 90%.
Its1H NMR datas are as follows：
1H NMR (400MHz, DMSO) δ 9.98 (s, 1H), 8.66 (d, J=1.8Hz, 3H), 8.41 (d, J=3.7Hz, 1H), 8.13 (dd, J=7.5,3.3Hz, 2H), 7.96 (d, J=9.1Hz, 1H), 7.84 (s, 1H), 6.64 (s, 1H), 3.87 (s,3H),2.62(s,3H).LC-MS:m/z 350.2[M+H]+.
Embodiment 9：
The present embodiment has replaced raw material B on the basis of above compound, specific as follows：
Compound 9：N6- (the fluoro- 2- of 5- (4- phenyls) pyrimidine-4-yl) -2- methyl-quinoxaline -4,6- diamines
It is using raw material A(raw material A 1), raw material B are(raw material B9)
Synthetic route is as follows：
Specific preparation method is same as the previously described embodiments, and which is not described herein again.
The yield of the compound 9 is 86%.
Its1H NMR datas are as follows：
1H NMR(400MHz,DMSO-d6) δ 10.12 (s, 1H), 8.69 (d, J=1.8Hz, 1H), 8.64 (s, 2H), 8.54 (d, J=3.5Hz, 1H), 8.23 (d, J=8.8Hz, 2H), 8.12 (dd, J=9.1,2.0Hz, 1H), 8.01 (d, J=9.1Hz, 1H), 7.43 (t, J=8.0Hz, 2H), 7.20 (t, J=7.4Hz, 1H), 7.08 (d, J=7.7Hz, 2H), 7.01 (d, J= 8.8Hz,2H),6.63(s,1H),2.61(s,3H).LC-MS:m/z 437.1[M+H]+.
Embodiment 10：
The present embodiment has replaced raw material B on the basis of above compound, specific as follows：
Compound 10：N6- (2- (2- (benzyloxy) phenyl) 5) -5- fluorinated pyrimidine -4- bases) -2- methyl-quinoxalines -4,6- Diamines
It is using raw material A(raw material A 1), raw material B are(raw material B10)
Synthetic route is as follows：
Specific preparation method is same as the previously described embodiments, and which is not described herein again.
The yield of the compound 10 is 95%.
Its1H NMR datas are as follows：
1H NMR(400MHz,DMSO-d6) δ 10.04 (s, 1H), 8.54 (dd, J=29.3,2.8Hz, 4H), 8.13 (dd, J =9.1,2.1Hz, 1H), 7.83 (d, J=9.1Hz, 1H), 7.68 (dd, J=7.6,1.7Hz, 1H), 7.48-7.32 (m, 1H), 7.25 (dd, J=7.7,1.5Hz, 2H), 7.23-7.16 (m, 3H), 7.14 (d, J=8.1Hz, 1H), 7.02 (t, J=7.4Hz, 1H),6.57(s,1H),5.10(s,2H),2.57(s,3H).LC-MS:m/z 451.1[M+H]+.
Embodiment 11：
The present embodiment has replaced raw material B on the basis of above compound, specific as follows：
Compound 11：N6- (2- (3,4- dimethoxys) -5-FU -4- bases) -2- methyl-quinoxaline -4,6- diamines
It is using raw material A(raw material A 1), raw material B are(raw material B11)
Synthetic route is as follows：
Specific preparation method is same as the previously described embodiments, and which is not described herein again.
The yield of the compound 11 is 90%.
Its1H NMR datas are as follows：
1H NMR(400MHz,DMSO-d6) δ 10.08 (s, 1H), 8.69 (s, 3H), 8.51 (d, J=3.2Hz, 1H), 8.12 (d, J=8.9Hz, 1H), 8.01 (d, J=9.0Hz, 1H), 7.93-7.74 (m, 2H), 7.01 (d, J=8.5Hz, 1H), 6.64 (s,1H),3.80(s,3H),3.75(s,3H),2.62(s,3H).LC-MS:m/z 405.1[M+H]+.
Embodiment 12：
The present embodiment has replaced raw material B on the basis of above compound, specific as follows：
Compound 12：N6- (2- (benzo [d] [1,3] dioxy-5- bases)-5-FU-4- bases) methyl-quinoxaline-4-2-, 6- diamines
It is using raw material A(raw material A 1), raw material B are(raw material B12)
Synthetic route is as follows：
Specific preparation method is same as the previously described embodiments, and which is not described herein again.
The yield of the compound 12 is 86%.
Its1H NMR datas are as follows：
1H NMR(400MHz,DMSO-d6) δ 110.09 (s, 1H), 8.59 (d, J=68.0Hz, 4H), 8.04 (d, J= 28.0Hz,2H),7.82(s,1H),7.66(s,1H),6.97(s,1H),6.64(s,1H),6.08(s,2H),2.62(s,3H) .LC-MS:m/z 389.1[M+H]+.
Embodiment 13：
The present embodiment has replaced raw material B on the basis of above compound, specific as follows：
Compound 13：N6- (2- (2,3 dihydrobenzos [b] [1,4] dioxy -6- bases) -5-FU -4- bases) -2- methyl quinolines Quinoline -4,6- diamines
It is using raw material A(raw material A 1), raw material B are(raw material B13)
Synthetic route is as follows：
Specific preparation method is same as the previously described embodiments, and which is not described herein again.
The yield of the compound 13 is 92%.
Its1H NMR datas are as follows：
1H NMR(400MHz,DMSO-d6) δ 10.07 (s, 1H), 8.64 (d, J=1.4Hz, 3H), 8.50 (d, J= 3.4Hz, 1H), 8.10 (d, J=9.0Hz, 1H), 7.99 (d, J=9.0Hz, 1H), 7.72 (dd, J=8.5,1.8Hz, 1H), 7.67 (d, J=1.7Hz, 1H), 6.89 (d, J=8.5Hz, 1H), 6.64 (s, 1H), 4.27 (d, J=4.6Hz, 4H), 2.62 (s,3H).LC-MS:m/z 403.1[M+H]+.
Embodiment 14：
The present embodiment has replaced raw material B on the basis of above compound, specific as follows：
Compound 14：N6- (the fluoro- 2- of 5- (3,4,5- trimethoxyphenyls) pyrimidine-4-yl) -2- methyl-quinoxalines -4,6- Diamines
It is using raw material A(raw material A 1), raw material B are(raw material B14)
Synthetic route is as follows：
Specific preparation method is same as the previously described embodiments, and which is not described herein again.
The yield of the compound 14 is 86%.
Its1H NMR datas are as follows：
1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.97–8.40(m,4H),8.09(s,1H),8.00(s, 1H),7.57(s,2H),6.63(s,1H),3.78(s,5H),3.70(s,3H),2.61(s,3H).LC-MS:m/z 435.1[M+ H]+.
Embodiment 15：
The present embodiment has replaced raw material B on the basis of above compound, specific as follows：
Compound 15：
It is using raw material A(raw material A 1), raw material B are(raw material B15)
Synthetic route is as follows：
Specific preparation method is same as the previously described embodiments, and which is not described herein again.
The yield of the compound 15 is 86%.
Its1H NMR datas are as follows：
1H NMR(400MHz,DMSO-d6) δ 10.15 (s, 1H), 8.81 (d, J=1.7Hz, 1H), 8.79 (t, J= 15.5Hz, 2H), 8.57 (d, J=3.4Hz, 2H), 8.24 (dd, J=8.7,1.5Hz, 1H), 8.14 (dd, J=9.1,1.9Hz, 1H), 8.06 (dd, J=5.5,3.3Hz, 2H), 7.63 (d, J=8.7Hz, 1H), 7.02 (d, J=1.4Hz, 1H), 6.69 (s, 1H),2.64(s,3H).LC-MS:m/z 385.1[M+H]+.
Embodiment 16：
The present embodiment has replaced raw material B on the basis of above compound, specific as follows：
Compound 16：N6- (5- fluoro- 2- (quinolyl-4) pyrimidine-4-yl) -2- methyl-quinoxaline -4,6- diamines
It is using raw material A(raw material A 1), raw material B are(raw material B16)
Synthetic route is as follows：
Specific preparation method is same as the previously described embodiments, and which is not described herein again.
The yield of the compound 16 is 96%.
Its1H NMR datas are as follows：
1H NMR(400MHz,DMSO-d6) δ 10.35 (s, 1H), 8.98 (s, 1H), 8.70 (d, J=32.3Hz, 5H), 8.32–7.88(m,4H),7.77(s,1H),7.56(s,1H),6.64(s,1H),2.61(s,3H).LC-MS:m/z 396.1[M +H]+.
Embodiment 17：
The present embodiment has replaced raw material B on the basis of above compound, specific as follows：
Compound 17：N6- (2- (benzofuran -2- bases) -5-FU -4- bases) -2- methyl-quinoxaline -4,6- diamines
It is using raw material A(raw material A 1), raw material B are(raw material B17)
Synthetic route is as follows：
Specific preparation method is same as the previously described embodiments, and which is not described herein again.
The yield of the compound 17 is 86%.
Its1H NMR datas are as follows：
1H NMR(400MHz,DMSO-d6) δ 10.26 (s, 1H), 8.85 (d, J=1.5Hz, 1H), 8.58 (t, J= 5.7Hz, 3H), 8.25-8.09 (m, 1H), 8.02 (d, J=9.0Hz, 1H), 7.74 (d, J=7.7Hz, 1H), 7.65 (d, J= 8.3Hz, 1H), 7.53 (s, 1H), 7.42 (t, J=7.7Hz, 1H), 7.31 (t, J=7.5Hz, 1H), 6.67 (s, 1H), 2.63 (s,3H).LC-MS:m/z 385.1[M+H]+.
Embodiment 18：
The present embodiment has replaced raw material B on the basis of above compound, specific as follows：
Compound 18：N6- (the fluoro- 2- of 5- (3,4,5- trimethoxyphenyls) pyrimidine-4-yl) -2- methyl-quinoxalines -4,6- Diamines
It is using raw material A(raw material A 1), raw material B are(raw material B18)
Synthetic route is as follows：
Specifically synthetic method is：
Same above-described embodiment method, is prepared intermediate compound I, and 150mg intermediate compound Is and 300mg raw materials B18 are dissolved in 15mL (dioxane：Water=5:1) in system, 350mg cesium carbonates and 37mg [1,1 '-bis- (diphenylphosphino) ferrocene] dichloro is added Change palladium.Reaction system is reacted 6 hours in 90 DEG C under protection of argon gas, is cooled to room temperature.It is spin-dried for solvent, is added into mixture 20mL water three times with the extraction of 20mL ethyl acetate merges organic layer and is spin-dried for, cross column chromatography (dichloromethane：Methanol=20:1), It recrystallizes up to compound 18.
The yield of the compound 18 is 85%.
Its1H NMR datas are as follows：
1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.97–8.40(m,4H),8.09(s,1H),8.00(s, 1H),7.57(s,2H),6.63(s,1H),3.78(s,6H),3.70(s,3H),2.61(s,3H).LC-MS:m/z 435.1[M+ H]+.
Wherein, raw material B18 is not the Conventional compounds that can be bought, therefore the specific synthetic route of raw material B1 is as follows：
The specific preparation method of raw material B18 is as follows：
By 2.5g5- bromo- 1,2,3- trimethoxy-benzenes and 3.0g connection boric acid pinacol esters are dissolved in 50mL dioxane, are added Enter 1.6g potassium acetates and 730mg [1,1 '-bis- (diphenylphosphino) ferrocene] palladium chloride.Reaction system is under protection of argon gas It reacts 4 hours, then cools to room temperature in 80 DEG C.It is spin-dried for solvent, 100mL water is added into mixture, with 60mL ethyl acetate Extraction is three times.Organic layer is mixed, is spin-dried for.Cross column chromatography (petroleum ether：Ethyl acetate=10:1), then in ethyl acetate and stone It is recrystallized in oily ether system up to raw material B18.
Embodiment 19：
The present embodiment has replaced raw material A on the basis of above compound, specific as follows：
Compound 19：N- (the fluoro- 2- of 5- (3,4,5- trimethoxies) pyrimidine-4-yl) -2- methyl-quinoxaline -6- amine
It is using raw material A(raw material A 2), raw material B are(raw material B18)
Synthetic route is as follows：
Specific intermediate II is identical with intermediate compound I preparation method, is specifically shown in the preparation method of intermediate compound I in embodiment 1, in The method that mesosome II reacts prepare compound 19 with raw material B18 is identical as compound 18, is specifically shown in compound 18 in embodiment 18 Synthesis.
The yield of the compound 19 is 87%.
Its1H NMR datas are as follows：
1HNMR(400MHz,DMSO-d6) δ 9.95 (s, 1H), 8.51 (d, J=3.4Hz, 1H), 8.47 (d, J=1.7Hz, 1H), 8.17 (d, J=8.4Hz, 1H), 8.12 (dd, J=9.1,2.1Hz, 1H), 7.93 (d, J=9.1Hz, 1H), 7.65 (s, 2H), 7.39 (d, J=8.4Hz, 1H), 3.86 (s, 6H), 3.73 (s, 3H), 2.65 (s, 3H) .LC-MS:m/z 420.1[M+H ]+.
Embodiment 20：
The present embodiment has replaced raw material A on the basis of above compound, specific as follows：
Compound 20：N- (the fluoro- 2- of 5- (3,4,5- trimethoxies) pyrimidine-4-yl) quinoline -6- amine
It is using raw material A(raw material A 3), raw material B are(raw material B18)
Synthetic route is as follows：
Specific intermediate III is identical with intermediate compound I preparation method, is specifically shown in the preparation method of intermediate compound I in embodiment 1, The method that intermediate III reacts prepare compound 20 with raw material B18 is identical as compound 18, is specifically shown in compound in embodiment 18 18 synthesis.
The yield of the compound 20 is 80%.
Its1H NMR datas are as follows：
1H NMR(400MHz,DMSO-d6) δ 10.02 (s, 1H), 8.81 (dd, J=4.1,1.5Hz, 1H), 8.59-8.49 (m, 2H), 8.29 (d, J=7.9Hz, 1H), 8.17 (dd, J=9.1,2.3Hz, 1H), 8.04 (d, J=9.1Hz, 1H), 7.66 (s, 2H), 7.51 (dd, J=8.3,4.2Hz, 1H), 3.86 (s, 6H), 3.73 (s, 3H) .LC-MS:m/z 406.1[M+H]+.
Embodiment 21：
The present embodiment has replaced raw material A on the basis of above compound, specific as follows：
Compound 21：N- (the fluoro- 2- of 5- (3,4,5- trimethoxies) pyrimidine-4-yl) quinoline -7- amine
It is using raw material A(raw material A 4), raw material B are(raw material B18)
Synthetic route is as follows：
Specific intermediate compound IV is identical with intermediate compound I preparation method, is specifically shown in the preparation method of intermediate compound I in embodiment 1, in The method that mesosome IV reacts prepare compound 21 with raw material B18 is identical as compound 18, is specifically shown in compound 18 in embodiment 18 Synthesis.
The yield of the compound 21 is 92%.
Its1H NMR datas are as follows：
1H NMR(400MHz,DMSO-d6) δ 10.07 (s, 1H), 9.05 (s, 1H), 8.84 (dd, J=4.2,1.7Hz, 1H), 8.56 (d, J=3.7Hz, 1H), 8.29 (dd, J=8.2,0.9Hz, 1H), 7.97 (s, 2H), 7.74 (s, 2H), 7.43 (dd, J=8.2,4.2Hz, 1H), 3.93 (s, 6H), 3.75 (s, 3H) .LC-MS:m/z 406.1[M+H]+.
Embodiment 22：
The present embodiment has replaced raw material A on the basis of above compound, specific as follows：
Compound 22：N- (the fluoro- 2- of 5- (3,4,5- trimethoxies) pyrimidine-4-yl) quinoxaline -6- amine
It is using raw material A(raw material A 5), raw material B are(raw material B18)
Synthetic route is as follows：
Specific intermediate V is identical with intermediate compound I preparation method, is specifically shown in the preparation method of intermediate compound I in embodiment 1, in The method that mesosome V reacts prepare compound 22 with raw material B18 is identical as compound 18, is specifically shown in compound 18 in embodiment 18 Synthesis.
The yield of the compound 22 is 90%.
Its1H NMR datas are as follows：
1HNMR(400MHz,DMSO-d6) δ 10.20 (s, 1H), 9.10 (d, J=1.9Hz, 1H), 8.86 (d, J=1.4Hz, 1H), 8.81 (s, 1H), 8.57 (d, J=3.5Hz, 1H), 8.20 (dd, J=9.1,2.1Hz, 1H), 8.07 (d, J=9.1Hz, 1H),7.71(s,2H),3.92(s,6H),3.75(s,3H).LC-MS:m/z407.1[M+H]+.
Embodiment 23：
The present embodiment has replaced raw material A on the basis of above compound, specific as follows：
Compound 23：N- (5,6- dimethyl pyrazine -2- bases) the fluoro- 2- of -5- (3,4,5- trimethoxies) pyrimidine -4- amine
It is using raw material A(raw material A 6), raw material B are(raw material B18)
Synthetic route is as follows：
Specific intermediate VI is identical with intermediate compound I preparation method, is specifically shown in the preparation method of intermediate compound I in embodiment 1, in The method that mesosome VI reacts prepare compound 23 with raw material B18 is identical as compound 18, is specifically shown in compound 18 in embodiment 18 Synthesis.
The yield of the compound 23 is 95%.
Its1H NMR datas are as follows：
1H NMR(400MHz,DMSO-d6) δ 10.11 (s, 2H), 9.09 (d, J=2.1Hz, 1H), 8.57 (d, J= 3.7Hz, 1H), 8.02 (dd, J=9.2,2.2Hz, 1H), 7.94 (d, J=9.0Hz, 1H), 7.75 (s, 2H), 3.96 (s, 6H), 3.75 (s, 3H), 2.66 (d, J=4.1Hz, 6H) .LC-MS:m/z 385.1[M+H]+.
Embodiment 24：
The present embodiment has replaced raw material A on the basis of above compound, specific as follows：
Compound 24：N- (the fluoro- 2- of 5- (3,4,5- trimethoxies) pyrimidine-4-yl) -2- Methyl-1H-indole -5- amine
It is using raw material A(raw material A 7), raw material B are(raw material B18)
Synthetic route is as follows：
Specific intermediate VII is identical with intermediate compound I preparation method, is specifically shown in the preparation method of intermediate compound I in embodiment 1, The method that intermediate VII reacts prepare compound 24 with raw material B18 is identical as compound 18, is specifically shown in compound in embodiment 18 18 synthesis.
The yield of the compound 24 is 88%.
Its1H NMR datas are as follows：
1HNMR (400MHz, DMSO) δ 10.86 (s, 1H), 9.45 (s, 1H), 8.36 (d, J=3.9Hz, 1H), 7.99 (s, 1H), 7.63 (s, 2H), 7.37 (dd, J=8.6,1.8Hz, 1H), 7.26 (d, J=8.6Hz, 1H), 6.07 (s, 1H), 3.84 (s,6H),3.72(s,3H),2.38(s,3H).LC-MS:m/z 408.1[M+H]+.
Embodiment 25：
The present embodiment has replaced raw material A on the basis of above compound, specific as follows：
Compound 25：N- (the fluoro- 2- of 5- (3,4,5- trimethoxies) pyrimidine-4-yl) -1 hydrogen-indoles -5- amine
It is using raw material A(raw material A 8), raw material B are(raw material B18)
Synthetic route is as follows：
Specific intermediate VIII is identical with intermediate compound I preparation method, is specifically shown in the preparation method of intermediate compound I in embodiment 1, The method that intermediate VIII reacts prepare compound 25 with raw material B18 is identical as compound 18, is specifically shown in chemical combination in embodiment 18 The synthesis of object 18.
The yield of the compound 25 is 88%.
Its1H NMR datas are as follows：
1HNMR (400MHz, DMSO) δ 11.05 (s, 1H), 9.51 (s, 1H), 8.37 (d, J=3.9Hz, 1H), 8.15 (d, J=1.8Hz, 1H), 7.64 (s, 2H), 7.44 (d, J=2.0Hz, 1H), 7.39 (d, J=8.7Hz, 1H), 7.38-7.31 (m, 1H),6.41–6.35(m,1H),3.84(s,6H),3.72(s,3H).LC-MS:m/z 394.1[M+H]+.
Embodiment 26：
The present embodiment has replaced raw material A on the basis of above compound, specific as follows：
Compound 26：N- (the fluoro- 2- of 5- (3,4,5- trimethoxies) pyrimidine-4-yl) -1 hydrogen-indoles -6- amine
It is using raw material A(raw material A 9), raw material B are(raw material B18)
Synthetic route is as follows：
Specific intermediate compound I X is identical with intermediate compound I preparation method, is specifically shown in the preparation method of intermediate compound I in embodiment 1, in The method that mesosome IX reacts prepare compound 26 with raw material B18 is identical as compound 18, is specifically shown in compound 18 in embodiment 18 Synthesis.
The yield of the compound 26 is 88%.
Its1H NMR datas are as follows：
1HNMR (400MHz, DMSO) δ 11.05 (s, 1H), 9.59 (s, 1H), 8.40 (d, J=3.8Hz, 1H), 7.98 (s, 1H), 7.64 (s, 2H), 7.53 (d, J=8.5Hz, 1H), 7.45 (dd, J=8.5,1.6Hz, 1H), 7.38-7.26 (m, 1H), 6.41(s,1H),3.84(s,6H),3.73(s,3H).LC-MS:m/z 394.1[M+H]+.
Embodiment 27：
The present embodiment has replaced raw material A on the basis of above compound, specific as follows：
Compound 27：N- (the fluoro- 2- of 5- (3,4,5- trimethoxies) pyrimidine-4-yl) benzo [d] thiazole -6- amine
It is using raw material A(raw material A 10), raw material B are(raw material B18)
Synthetic route is as follows：
Specific intermediate X is identical with intermediate compound I preparation method, is specifically shown in the preparation method of intermediate compound I in embodiment 1, in The method that mesosome X reacts prepare compound 27 with raw material B18 is identical as compound 18, is specifically shown in compound 18 in embodiment 18 Synthesis.
The yield of the compound 27 is 88%.
Its1H NMR datas are as follows：
1HNMR (400MHz, DMSO) δ 9.96 (s, 1H), 9.29 (s, 1H), 8.93 (d, J=1.7Hz, 1H), 8.51 (t, J =3.4Hz, 1H), 8.09 (d, J=8.8Hz, 1H), 7.88 (dd, J=8.9,2.0Hz, 1H), 7.64 (s, 2H), 3.88 (s, 6H),3.73(s,3H).LC-MS:m/z 412.1[M+H]+.
Embodiment 28：
The present embodiment has replaced raw material A on the basis of above compound, specific as follows：
Compound 28：N- (the fluoro- 2- of 5- (3,4,5- trimethoxies) pyrimidine-4-yl) -1H- benzos [d] imidazoles -6- amine
It is using raw material A(raw material A 11), raw material B are(raw material B18)
Synthetic route is as follows：
Specific intermediate X I is identical with intermediate compound I preparation method, is specifically shown in the preparation method of intermediate compound I in embodiment 1, in The method that mesosome XI reacts prepare compound 28 with raw material B18 is identical as compound 18, is specifically shown in compound 18 in embodiment 18 Synthesis.
The yield of the compound 28 is 88%.
Its1H NMR datas are as follows：
1HNMR (400MHz, DMSO) δ 12.38 (s, 1H), 9.68 (d, J=11.8Hz, 1H), 8.43 (s, 1H), 8.19 (d, J=7.7Hz, 1H), 7.63 (t, J=11.8Hz, 4H), 7.53 (s, 1H), 3.85 (d, J=10.7Hz, 6H), 3.72 (s, 3H).LC-MS:m/z 395.1[M+H]+.
Embodiment 29：
The present embodiment has replaced raw material A on the basis of above compound, specific as follows：
Compound 29：N- (2,3- dihydrobenzos [b] [1,4] dioxin -6- bases) fluoro- 2- of -5- (3,4,5- trimethoxies) Pyrimidine -4- amine
It is using raw material A(raw material A 12), raw material B are(raw material B18)
Synthetic route is as follows：
Specific intermediate X II is identical with intermediate compound I preparation method, is specifically shown in the preparation method of intermediate compound I in embodiment 1, The method that intermediate X II reacts prepare compound 29 with raw material B18 is identical as compound 18, is specifically shown in compound in embodiment 18 18 synthesis.
The yield of the compound 29 is 88%.
Its1H NMR datas are as follows：
1HNMR (400MHz, DMSO) δ 9.55 (s, 1H), 8.40 (d, J=3.8Hz, 1H), 7.70 (d, J=2.4Hz, 1H), 7.61 (s, 2H), 7.21 (dd, J=8.8,2.4Hz, 1H), 6.86 (d, J=8.7Hz, 1H), 4.24 (s, 4H), 3.87 (s,6H),3.73(s,3H).LC-MS:m/z 413.1[M+H]+.
Embodiment 30：
The present embodiment is right based on the particular chemical for the acrylamide analog derivative that above-mentioned 29 embodiments provide It carries out the test experiments of the inhibition of external PRMT7 protein actives respectively.
Test method is as follows：
(1) experiment material：
It buys in the PRMT7 of Active Motif companies, product identification 31395；The SAM of Sigma companies, product identification A7007-100MG；The SAH of Sigma companies, product identification A9384-25MG；384 well culture plates of Perkin Elmer companies, Product identification SMP410A001PK；[3H]-SAM of PerkinElmer companies, product identification NET155V001MC.
(2) experiment content：
A. preparation
Prepare to measure buffer solution (the Tris buffer solutions of improvement)；
Series of compounds dilutes：Compound is transferred to assay plate by Echo in 100%DMSO；
Prepare enzyme solutions：Prepare enzyme solutions in measuring buffer solution；
Prepare substrate solution：Peptide and [3H]-SAM are added in measuring buffer solution to prepare substrate solution.
B. process
10 μ L enzyme solutions are transferred to assay plate or measure buffering for 10 μ L of low control transfer；It is incubated at room temperature 15 points Clock；Then substrate solution to every hole that 10 μ L are added starts to react, and is incubated at room temperature 240 minutes；Add to measuring in buffer solution Enter cold SAM so that termination mix is made, 10 μ L is added per hole to stop reacting, reaction turns the volume of 25 μ L of every hole after stopping It moves on on the Flash board in assay plate；It is at least incubated 1 hour at room temperature, uses ddH2O+0.1%Tween-20 washs Flash board Three times, it then measures.
C. curve matching：
In Excel tables 1. input data calculates inhibiting value with formula：
Formula is 1.:Inh%=(Max-Signal)/(Max-Min) * 100；
In GraphPad 2. input data calculates IC50 values with formula
Formula is 2.:Y=Bottom+ (Top-Bottom)/(1+10^ ((LogIC50-X) * HillSlope))
Wherein, Y is inhibiting rate, and X is compound concentration.
(3) experimental result：
By the above experimental method, the inhibitory activity that the compounds of this invention is directed to PRMT7 is tested, specific compound exists 10 μM, the inhibitory activity under 1 μM of concentration and part of compounds inhibit effective concentration (IC to the half of PRMT750) it is shown in Table one.
Inhibitory activity (Inh%) of one the compounds of this invention of table to PRMT7
As shown in Table 1,29 kinds provided by the invention specific compounds can have PRMT7 certain inhibiting effect, In, compound 1,11,12,13,14,15,17,18 has highly significant when measured concentration is 10 μM and 1 μM to PRMT7 Inhibition.Other group compounds also have preferable inhibition to PRMT7's.Thus provable chemical combination provided by the invention Object has remarkable inhibiting activity to PRMT7, there are no the technical field inhibited about PRMT7, the chemical combination synthesized in the present invention Object has made creative contribution.
Embodiment 31：
The present embodiment is right based on the particular chemical for the acrylamide analog derivative that above-mentioned 29 embodiments provide It is proliferated various tumor cell strains carries out Inhibition test respectively, verifies its inhibition to tumour cell.
(1) experiment material：
Main agents：RPMI-1640, fetal calf serum, pancreatin etc. are purchased from GibcoBRL companies (InvitrogenCorporation, USA), IMDM culture mediums are purchased from ATCC (AmericanTypeCultureCollection).Tetramethyl azo azoles salt (MTT), dimethyl sulfoxide (DMSO) (DMSO) are Sigma public Take charge of (USA) product.Human prostate cancer cell line (PC-3), human lung cancer cell line (H2228), human lung cancer cell line (NCI- H1975), human lung cancer cell line (PC-9), human lung cancer cell line (NCI-H358), human lung cancer cell line (Calu-1), lymthoma Cell line (Jeko-1), abortion syndrome (ES-2), abortion syndrome (HO8910), abortion syndrome (A2780S), abortion syndrome (A2780/T) etc. is purchased from U.S. ATCC (American Type Culture Collection), preserved by this laboratory.
(2) experiment content：
It is 1~2 × 10 with complete cell culture fluid adjustment cell concentration4The cell suspension of a/mL is inoculated in 96 orifice plates, Per 200 μ l cell suspensions of hole, overnight incubation.Next day draws supernatant (drawing supernatant after suspension cell centrifugation), then uses ladder respectively The test-compound for spending concentration handles cell.The not negative control group of drug containing and isometric solvent control group are set simultaneously, DMSO a concentration of 0.1%, each dosage group set 3 multiple holes, at 37 DEG C, 5%CO2Under the conditions of cultivate.After 72 hours, it is added per hole The 20 μ l of MTT reagents of a concentration of 5mg/mL, after being further cultured for 2-4h, abandon supernatant, and 150 μ L of DMSO solution are added per hole, and oscillation is mixed Even 15min measures absorbance (A) value (A values are directly proportional to viable count) with microplate reader (λ=570nm), takes its average value.Phase Cell proliferation inhibiting rate=(negative control group A570Experimental group A570)/negative control group A570× 100%.Experiment at least repeats 3 times.Experimental data indicates that data statistics data is examined using t, P with mean<0.05 is statistically significant for difference.It is following Compound on intracellular inhibited proliferation uses IC50It indicates.
(3) experimental result：
Using above method, tests 14 equity of the compounds of this invention and carried out human prostate cancer cell line (PC-3), people Lung cancer cell line (H2228), human lung cancer cell line (NCI-H1975), human lung cancer cell line (PC-9), human lung cancer cell line (NCI-H358), human lung cancer cell line (Calu-1), lymphoma cell line (Jeko-1), abortion syndrome (ES-2), people Ovarian cancer cell line (HO8910), abortion syndrome (A2780S), the Proliferation Abilities such as abortion syndrome (A2780/T) Active testing, specific inhibitory activity effect are shown in Table two：
Proliferation inhibition activity (IC of two the compounds of this invention of table to different tumor cell lines50)
Cell line Cell type IC50(μM)
PC-3 Prostate cancer 1-3
H2228 Lung cancer 3-6
NCI-H1975 Lung cancer 2-7
PC-9 Lung cancer 1-3
NCI-H358 Lung cancer 1-3
Calu-1 Lung cancer 1-3
Jeko-1 Lymthoma 4.4
ES-2 Oophoroma 2.250
HO8910 Oophoroma 1
A2780S Oophoroma 1.267
A2780/T Oophoroma 3.342
By two content of table it is found that compound 14 is respectively less than 10 to IC50 (μM) numerical value of each tumour cell, inhibition Significantly, for tumour cell it is more polynary, the outer mutation of non-amount incurred has good pharmaceutical potential.It can be used for preparing treatment And/or the drug of pre- preventing tumor.
Although an embodiment of the present invention has been shown and described, it will be understood by those skilled in the art that：Not These embodiments can be carried out a variety of change, modification, replacement and modification by being detached under the principle of the present invention and objective, of the invention Range is limited by claim and its equivalent.

Claims (11)

1. a kind of compound inhibiting PRMT7, general formula are as follows：
Wherein,
R1It is independent
R2It is independent
2. a kind of compound inhibiting PRMT7 according to claim 1, which is characterized in that work as R2Structure beWhen, general structure is：
Then R1For with one kind in lower structure：
3. a kind of compound inhibiting PRMT7 according to claim 1, which is characterized in that work as R1Structure beWhen, general structure is：
Then, R2For with one kind in lower structure：
4. according to a kind of preparation method of the compound of inhibition PRMT7 of claims 1 to 3 any one of them, which is characterized in that Include the following steps：
(1) raw material A and n,N-diisopropylethylamine are dissolved in ethyl alcohol, and 2,4-, bis- chloro- 5-FUs is added, keep reaction temperature 70~95 DEG C of degree, and continue to stir, there is white is fixed to generate after reaction, white solid is filtered, washs, it is dry, it obtains Intermediate compound I；
(2) intermediate compound I and raw material B are dissolved in dioxane aqueous solution, cesium carbonate and [1,1 '-bis- (diphenylphosphinos) is added Ferrocene] palladium chloride, it reacts and is carried out in 80~100 DEG C of temperature environment under inert gas protection, waited for after completion of the reaction, It is cooled to room temperature, is spin-dried for solvent, purified water is added, is extracted using esters solvent, mix organic phase, be spin-dried for, into after column chromatography, weight Crystallization obtains purpose compound.
5. a kind of preparation method of the compound of inhibition PRMT7 according to claim 4, which is characterized in that the step (1) raw material A in is at least one of following substance：
6. a kind of preparation method of the compound of inhibition PRMT7 according to claim 5, which is characterized in that the raw material A OnlyWhen,Specific synthesis step it is as follows：
(A) 2 cyano 4 nitro aniline, acetone, toluene are mixed, 0 DEG C is cooled to, SnCl4 is then slowly added dropwise, then returns It after flowing reaction system, is cooled to room temperature, solid filters, and obtains intermediate a；
(B) intermediate compound I and ammonium chloride are mixed in ethanol water system, are heated to 40~60 DEG C, reduced iron powder is added, then 70~95 DEG C are warming up to, is reacted, waits for being cooled to room temperature after completion of the reaction, is spin-dried for solvent, mixture is filtered, and be spin-dried for filtering Liquid, the slag blanket of acquisition recrystallize to get.
7. a kind of preparation method of the compound of inhibition PRMT7 according to any one of claim 4 to 6, which is characterized in that Raw material B in the step (2) is at least one of following substance：
8. a kind of compound inhibiting PRMT7 according to claim 7, which is characterized in that the raw material B is onlyWhen,Building-up process it is as follows：
The bromo- 1,2,3- trimethoxy-benzenes of 5- and connection boric acid pinacol ester are dissolved in dioxane and are added potassium acetate and [1,1 '- Bis- (diphenylphosphino) ferrocene] palladium chloride, so that reaction system is reacted under 70~95 DEG C of environment under protection of argon gas, After completion of the reaction, it is cooled to room temperature；It is spin-dried for solvent, purified water is added, three times using esters solvent extraction, mixes organic layer, rotation It is dry, through column chromatography, recrystallize to obtain the final product.
9. a kind of PRMT7 inhibitor, which is characterized in that using any one of the claim 1-3 compounds as main active Biopharmacy on acceptable salt, crystal form, solvate.
10. a kind of drug for the treatment of cancer, which is characterized in that using the PRMT7 inhibitor described in claim 9 as main component, Acceptable complementary ingredient is prepared on addition biopharmacy.
11. the drug for the treatment of cancer according to claim 10, which is characterized in that the cancer for the treatment of includes prostate cancer, slow Property granulocytic leukemia, lung cancer, lymthoma, oophoroma.
CN201810449994.3A 2018-05-11 2018-05-11 A kind of compound and the preparation method and application thereof inhibiting PRMT7 Pending CN108503623A (en)

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