CN108033957A - A kind of quinolines BET bromodomain inhibitor and its preparation method and application - Google Patents
A kind of quinolines BET bromodomain inhibitor and its preparation method and application Download PDFInfo
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- CN108033957A CN108033957A CN201810024854.1A CN201810024854A CN108033957A CN 108033957 A CN108033957 A CN 108033957A CN 201810024854 A CN201810024854 A CN 201810024854A CN 108033957 A CN108033957 A CN 108033957A
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The present invention relates to a kind of quinolines, their preparation method and their medical application, especially as the purposes of BET bromodomain inhibitor in the treatment of cancer.
Description
Technical field
The present invention relates to a kind of quinolines, their preparation method.The invention further relates to it as BET
The medical application of bromodomain inhibitor in the treatment of cancer.
Background technology
Body is tackling physiology and during environmental stimulus, the chemical modification of DNA (such as cytimidine methylate) and chromosome
DNA- packaging histone modifications (for example, acetylation, methylates, phosphorylation and ubiquitination) determine that epigenetic adjusts swashing for gene
Living and silence.Histone modification, covalent posttranslational modification (PTM) are close with adjusting the various normal or relevant processes of disease of body
Cut phase is closed, and the acetylation of istone lysine residue is considered as the mark of transcriptional activity gene.On the one hand, lysine acetyl
Its positive charge can be neutralized by, which changing, causes histone to be reduced with negatively charged DNA affinity, or destroys nucleosome packaging, produces
Addressable chromatin Structure, can recruit transcription mechanism.Another aspect acetylated lysine provides for protein identification module
Binding site.Bromodomain (BRD) be one kind can in specific recognition histone acetylated lysine (KAc) it is conservative
Protein structure domain, promotes the GAP-associated protein GAPs such as chromatin remodeling factors and transcription factor to be enriched in by being combined with acetylated lysine
Specific gene transcription start site, changes the activity of rna plymerase ii, adjusts the transcriptional expression of gene.61 kinds found in human body
BRD domains are present in 46 kinds of albumen, according to the difference of its female protein structure/sequence, can be divided into 8 large families, its
Middle BET protein families are the 2nd classes of BRD protein families, including BRD2, BRD3, BRD4 and BRDT.BET families bromine domain is known
Acetylated lysine residue in other histone H 3 and H4, is adjusted and cell cycle and the relevant gene of cell growth.Research card
Real, the generation of many diseases of the mankind all has close relationship, such as the B cell lymphoma of lymphocyte induction with BET albumen
Middle BRD2 is over-expressed, BRD code areas and NUT (nucleoprotein in testis) gene chromosomal translocation shape of BRD3/BRD4
Center line cancer is caused to be fallen ill into BRD-NUT pattern of fusion proto-oncogenes；At the same time study discoverys, hematopoietic system cancer including AML,
In the model of Burkitt lymthomas, Huppert's disease and B cell acute lymphatic leukemia, by disturbing BRD4 and cancer
The combination of gene M YC can suppress the expression of MYC.
We, which design, in the present invention has synthesized a kind of quinolines as BET bromodomain inhibitor, is used for
Treating cancer.
The content of the invention
The invention discloses quinolines shown in formula I or its pharmaceutically acceptable salt, the compound of formula I
With such as lower structure：
Wherein R1Straight or branched alkane, the ring of non-substituted or substitution 3~6 carbon for non-substituted or substitution 1~6 carbon
Various substituted benzyls, the heterocycle or various substituted of armaticity on alkyl, phenyl, various substituted phenyl, benzyl or phenyl ring
The heterocycle of armaticity；R2For hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino or alkoxy；R3For hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, ammonia
Various substituted benzyls on base, alkoxy, phenyl, various substituted phenyl, benzyl or phenyl ring, armaticity heterocycle or various take
The heterocycle of the armaticity in generation；R4Or R5The alkane or hydrogen of 1~3 carbon are expressed as independently of one another；X is oxygen or sulphur；N is 1,2 or 3.
The preferred R of compound of formula I of the present invention1For methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, sec-butyl,
The tert-butyl group, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, various substituted phenyl or benzyl；It is preferred that R2For hydrogen, hydroxyl
Or amino；It is preferred that R3For hydrogen, hydroxyl or alkoxy；It is preferred that R4Or R5Methyl, ethyl or hydrogen are expressed as independently of one another；It is preferred that X is
Oxygen or sulphur；It is preferred that n is 1 or 2.
The compound of formula I more preferably R of the present invention1For methyl, isopropyl, cyclopropyl, phenyl, 2- aminomethyl phenyls, 3- methyl
Phenyl, 4- aminomethyl phenyls, 2- methoxyphenyls, 3- methoxyphenyls, 4- methoxyphenyls, 4- phenyls, 3- fluorophenyls, 4-
Fluorophenyl, 3- chlorphenyls, 4- chlorphenyls or benzyl；More preferably R2For hydrogen or hydroxyl；More preferably R3For methoxyl group；More preferably R4Or
R5Methyl is expressed as independently of one another；More preferably X is oxygen；More preferably n is 1.
Currently preferred compound of formula I is as follows：
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- benzyls -8,9- dihydro -7H- cyclopentas [f] quinoline
Quinoline -9- alcohol (I-1)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- phenyl -8,9- dihydro -7H- cyclopentas [f] quinoline
Quinoline -9- alcohol (I-2)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (2- tolyls) -8,9- dihydro -7H- cyclopentas
[f] quinoline -9- alcohol (I-3)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (3- tolyls) -8,9- dihydro -7H- cyclopentas
[f] quinoline -9- alcohol (I-4)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (4- tolyls) -8,9- dihydro -7H- cyclopentas
[f] quinoline -9- alcohol (I-5)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (2- methoxyphenyls) -8,9- dihydro -7H- rings penta
Alkene simultaneously [f] quinoline -9- alcohol (I-6)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (3- methoxyphenyls) -8,9- dihydro -7H- rings penta
Alkene simultaneously [f] quinoline -9- alcohol (I-7)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (4- methoxyphenyls) -8,9- dihydro -7H- rings penta
Alkene simultaneously [f] quinoline -9- alcohol (I-8)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (3- fluorophenyls) -8,9- dihydro -7H- cyclopentas
[f] quinoline -9- alcohol (I-9)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (4- fluorophenyls) -8,9- dihydro -7H- cyclopentas
[f] quinoline -9- alcohol (I-10)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (3- chlorphenyls) -8,9- dihydro -7H- cyclopentas
[f] quinoline -9- alcohol (I-11)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (4- chlorphenyls) -8,9- dihydro -7H- cyclopentas
[f] quinoline -9- alcohol (I-12)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- ([1,1 '-biphenyl] -4- bases) -8,9- dihydros -7H-
Cyclopenta [f] quinoline -9- alcohol (I-13)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- methyl -8,9- dihydro -7H- cyclopentas [f] quinoline
Quinoline -9- alcohol (I-14)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- isopropyls -8,9- dihydro -7H- cyclopentas [f] quinoline
Quinoline -9- alcohol (I-15)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- cyclopropyl -8,9- dihydro -7H- cyclopentas [f] quinoline
Quinoline -9- alcohol (I-16)；
4- (2- methoxyl group -9- phenyl -8,9- dihydro -7H- cyclopentas [f] quinoline -6- bases) -3,5- dimethyl isoxazoles
(I-17)。
Another object of the present invention is to provide the preparation method of quinolines shown in formula I, following reaction equation：
Specifically include following steps：
(1) compound 2 is made with hydroxylamine hydrochloride, anhydrous sodium sulfate and chloraldurate in compound 1 in acid condition；
(2) compound 2 issues raw molecule inner ring condensation in sulfuric acid heating condition, and compound 3 is made；
(3) 4- quinoline carboxylic acid's intermediates are made with bromo acetone acid in compound 3 in alkaline conditions, then by decarboxylation system
Obtain compound 4；
(4) compound 4 is through the obtained compound 5 that methylates；
(5) compound 6 is made by bromo in compound 5；
(6) compound 7 is made with dimethyl malenate in compound 6；
(7) compound 8 is made through ester hydrolysis in compound 7；
(8) compound 9 is made through decarboxylation in compound 8；
(9) compound 10 is made through molecule inner ring condensation in compound 9；
(10) compound 11 is made through coupling reaction in compound 10；
(11) corresponding compound I-1 to I-16 is made with different grignard reagent reactions in compound 11；
(12) compound I-2 is dehydrated under sour environment is made compound 12；
(13) compound I-17 is made in the hydrogenated reduction of compound 12.
It is a further object to provide compound of formula I or its pharmaceutically acceptable salt as BET
The purposes of bromodomain inhibitor in the treatment of cancer.
Embodiment
Present disclosure is illustrated below by embodiment.In the present invention, embodiments discussed below be in order to
Preferably illustrate the present invention, be not for limiting the scope of the invention.
Embodiment 1
The preparation of N- (the bromo- 4- aminomethyl phenyls of 3-) -2- (oximido) acetamide (2)
Under the conditions of 35 DEG C, chloraldurate (12.5g, 75.9mmol) and sodium sulphate (87.5g, 612.7mmol) are dissolved in
In 170mL water.The lower warmed aqueous solution (50ml) for adding the bromo- 4- methylanilines (1) of 3- (12.84g, 69mmol) of stirring, adds
Dense HCl (7.5ml), forms white insoluble matter, the aqueous solution (15.25g, 219.4mmol) of hydroxylamine hydrochloride is then added, at 85 DEG C
It is lower stirring 2 it is small when, then cool down, filtered after temperature is down to 50 DEG C, use 10ml water washing filter cakes.Obtained solid is placed in 40
It is dried in vacuum overnight at DEG C, obtains yellow solid (15.20g), yield：85.69%.mp.156-159℃；1H NMR
(300MHz, DMSO-d6) δ 12.24 (s, 1H), 10.27 (s, 1H), 8.05 (d, J=2.0Hz, 1H), 7.64 (s, 1H), 7.55
(dd, J=8.4,2.0Hz, 1H), 7.29 (d, J=8.2Hz, 1H), 2.29 (s, 3H)
Embodiment 2
The preparation of bromo- 5- Methvl-indoles -2, the 3- diketone (3) of 6-
The 250mL concentrated sulfuric acids are poured into oil bath heating in round-bottomed flask and, to 60 DEG C, round-bottomed flask are then removed into oil bath.30
Dry N- (the bromo- 4- aminomethyl phenyls of 3-) -2- (oximido) acetamide (2) (15.2g, 59.12mmol) is added portionwise in minute,
Temperature is controlled to be no more than 65 DEG C.Then 80 DEG C are heated the mixture to, after stirring 15 minutes, frozen water is cooled to 70 DEG C.Then will
Trash ice add solution left standstill 1 it is small when, filter, washing filter cake obtains crude product, and it is water-soluble that crude product is dissolved at 60 DEG C to 2.5N NaOH
In liquid (50mL), then it is acidified with acetic acid (12mL).After when standing 0.5 is small, 35 DEG C are cooled to, is filtered, abandons filter cake.Will filter
Liquid and cleaning solution merge, and are acidified using dense HCl (12mL), placed under the conditions of 5 DEG C 2 it is small when after, filter, wash filter cake, it is dry,
Obtain Orange red solid product (3.75g), yield：26.42%.mp.250-253℃；1H NMR (300MHz, DMSO-d6) δ
11.17 (s, 1H), 7.49 (s, 1H), 7.11 (s, 1H), 2.29 (s, 3H)
Embodiment 3
The preparation of 6- methyl -3- hydroxyl -7- bromoquinolines (4)
Under the conditions of 50 DEG C, 6- bromine 5- Methvl-indoles -2,3- diketone (3) (10.61g, 44.20mmol) is added portionwise
In potassium hydroxide aqueous solution (200mL, 3.535mol/L), continue after the completion of charging stirring 1.5 it is small when, be then cooled to room
Temperature.Bromo acetone acid (20.66g, 123.75mmol) is added, and is stirred at room temperature 6 days.Then with concentrated hydrochloric acid tune pH to 4, this
When separate out precipitation, filter, using frozen water wash filter cake, dry (40 DEG C) using vacuum drying chamber, obtain yellow solid intermediate
(11.6g)。
Gained yellow solid intermediate (11.6g, 41.12mmol) is added portionwise and has been heated to 200 DEG C of diphenyl ether
In (200mL), stir 10 minutes, it was observed that carbon dioxide is released rapidly.Solution is filtered while hot miscellaneous to remove sepia solid
Matter.Then filtrate is cooled to 20 DEG C, there is solid precipitation.Filter, filter cake is washed with n-hexane, it is dry, obtain light tan solid
(4.33g), yield：41.15%.mp.228-231℃；1H NMR (300MHz, DMSO-d6) δ 10.45 (s, 1H), 8.54 (d, J
=2.6Hz, 1H), 8.11 (s, 1H), 7.74 (s, 1H), 7.42 (d, J=2.6Hz, 1H), 2.46 (s, 3H)
Embodiment 4
The preparation of 6- methyl -3- methoxyl group -7- bromoquinolines (5)
6- methyl -3- hydroxyl -7- bromoquinolines (4) (5g, 21.00mmol) are dissolved in dimethyl sulfoxide (DMSO) (50ml), 10
Potassium carbonate (5.8g, 42mmol) is added at DEG C, iodomethane (5.96g, 42mmol) is then added dropwise, after being added dropwise to complete, is warmed to room temperature
Stir 3 it is small when, TLC show reaction be basically completed, add water (200ml) dilution, use ethyl acetate (100ml × 2) extract, receive
Collect organic phase, anhydrous sodium sulfate drying, filtering, removes solvent under reduced pressure, column chromatography purifies to obtain light yellow solid (3.7g), yield：
69.88%.mp.119-122℃；1H NMR (300MHz, Chloroform-d) δ 8.59 (d, J=2.8Hz, 1H), 8.24 (s,
1H), 7.54 (s, 1H), 7.23 (d, J=2.7Hz, 1H), 3.92 (s, 3H), 2.54 (s, 3H)
Embodiment 5
The preparation of 6- bromomethyl -3- methoxyl group -7- bromoquinolines (6)
6- methyl -3- methoxyl group -7- bromoquinolines (5) (2.7g, 10.71mmol) are dissolved in 30ml tetrahydrofurans and are stirred,
Argon gas protect, be heated to 85 DEG C reflux, then be spaced 3 it is small when add in three batches bromo-succinimide (2.09g,
11.78mmol) with benzoyl peroxide (518.84mg, 2.14mmol), 9 it is small when after TLC show reaction be basically completed, question response
Temperature is down to room temperature, is filtered using diatomite, washs filtrate with saturation sodium hydrogensulfite, then washed through saturation NaCl, anhydrous sulphur
Sour sodium drying, filters, removes solvent under reduced pressure, white solid (2.11g), yield are purified to obtain through column chromatography：59.52%.mp.121-
124℃；1H NMR (300MHz, Chloroform-d) δ 8.65 (d, J=2.9Hz, 1H), 8.29 (s, 1H), 7.83 (s, 1H),
7.30 (d, J=2.9Hz, 1H), 4.76 (s, 2H), 3.94 (s, 3H)
Embodiment 6
The preparation of 2- ((the bromo- 3- methoxy quinolines -6- bases of 7-) methyl) dimethyl malenate (7)
Sodium hydride (0.317g, 7.93mmol) is added in anhydrous tetrahydro furan (20ml), under ice bath, is slowly added dropwise third
Acid dimethyl (1.02g, 6.34mmol), after being added dropwise to complete, continues after stirring 45min, and addition 6- bromomethyl -3- methoxyl groups -
7- bromoquinolines (6) (1.75g, 5.29mmol), continue to stir 3h, TLC shows that reaction is basically completed, then under being then warmed to room temperature
40ml water is added thereto, is extracted using ethyl acetate (30ml × 2), is collected organic phase and is dried using anhydrous sodium sulfate, is depressurized
Solvent is evaporated off, white solid product (1.35g), yield are purified to obtain through column chromatography：66.81%.mp.108-110℃；1H NMR
(300MHz, Chloroform-d) δ 8.63 (d, J=2.9Hz, 1H), 8.27 (s, 1H), 7.62 (s, 1H), 7.29 (d, J=
2.8Hz, 1H), 3.99 (t, J=7.7Hz, 1H), 3.94 (s, 3H), 3.70 (s, 6H), 3.51 (d, J=7.7Hz, 2H)
Embodiment 7
The preparation of 2- ((the bromo- 3- methoxy quinolines -6- bases of 7-) methyl) malonic acid (8)
2- ((the bromo- 3- methoxy quinolines -6- bases of 7-) methyl) dimethyl malenate (7) (1.35g, 3.53mmol) is dissolved in
In methanol (15ml), KOH (0.793g, 0.0141mol) is added, flow back 12h, treats that temperature is cooled to room temperature and removes solvent under reduced pressure,
15ml water dissolving obtained solid is added, then with dense HCl tune PH to 2, is filtered, washs filter cake, it is dry, obtain light yellow solid
(1.21g), yield：96.73%.1H NMR (300MHz, DMSO-d6) δ 8.62 (d, J=2.8Hz, 1H), 8.20 (s, 1H),
7.79 (s, 1H), 7.72 (d, J=2.9Hz, 1H), 3.92 (s, 3H), 3.74 (t, J=7.5Hz, 1H), 3.33 (d, J=
7.6Hz, 2H)
Embodiment 8
The preparation of 3- (3- methoxyl group -7- bromoquinolines -6-)-propionic acid (9)
2- ((the bromo- 3- methoxy quinolines -6- bases of 7-) methyl) malonic acid (8) (1.21g, 3.42mmol) is added into flask
In, 150 DEG C are warming up to, stir about 15h, TLC display reaction is basically completed, and obtains gray solid (0.92g), yield：
86.82%.mp.238-240℃；1H NMR (300MHz, DMSO-d6) δ 8.51 (d, J=2.7Hz, 1H), 8.09 (s, 1H),
7.73 (s, 1H), 7.61 (d, J=2.9Hz, 1H), 3.83 (s, 3H), 2.99 (t, J=7.6Hz, 2H), 2.57 (t, J=
7.6Hz, 2H)
Embodiment 9
The preparation of bromo- 2- methoxyl groups -7,8- dihydro -9H- cyclopentas [f] quinoline -9- ketone (10) of 6-
Polyphosphoric acids (20g) and 3- (3- methoxyl group -7- bromoquinolines -6-)-propionic acid (9) (1g, 3.22mmol) are added and burnt
In bottle, 110 DEG C are heated to, is stirred overnight.TLC shows that reaction is basically completed, and adds frozen water (40ml) and is quenched, uses ethyl acetate
(20ml × 2) extract, and gained organic phase is dried using anhydrous sodium sulfate, filter, remove solvent under reduced pressure, purify shallow through column chromatography
Yellow solid (0.233g), yield：24.74%.mp.148-152℃；1H NMR (300MHz, Chloroform-d) δ 8.69
(d, J=1.2Hz, 2H), 8.44 (s, 1H), 4.01 (s, 3H), 3.29-3.11 (m, 2H), 2.92-2.81 (m, 2H)
Embodiment 10
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -7,8- dihydro -9H- cyclopentas [f] quinoline -9- ketone
(11) preparation
By bromo- 2- methoxyl groups -7,8- dihydro -9H- cyclopentas [f] quinoline -9- ketone (10) of 6- (65mg,
0.222mmol), 3,5- dimethyl isoxazoles -4- boric acid (47.04mg, 0.334mmol) and cesium carbonate (144.99mg,
0.445mmol) it is dissolved in 5ml mixed solvents and (glycol dimethyl ether: water=4: in 1), under nitrogen protection, adds four triphenylphosphines
Palladium (25.71mg, 022mmol), is heated to 80 DEG C, overnight.TLC shows that reaction is basically completed, and cools the temperature to room temperature, and decompression is steamed
Except solvent, light yellow solid (37.22mg), yield are purified to obtain through column chromatography：54.25%.mp.202-204℃；1H NMR
(300MHz, Chloroform-d) δ 8.79 (d, J=3.0Hz, 1H), 8.71 (d, J=3.0Hz, 1H), 8.06 (s, 1H), 4.02
(s, 3H), 3.02-2.91 (m, 2H), 2.88-2.73 (m, 2H), 2.34 (s, 3H), 2.18 (s, 3H)；13C NMR (75MHz,
Chloroform-d) δ 206.95,166.25,159.05,158.35,155.61,145.51,142.49,137.54,130.98,
126.30,125.76,113.47,108.31,55.87,36.94,25.44,11.70,10.67.MS (ESI) m/z：309.0[M+
H]+。
Embodiment 11
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- benzyls -8,9- dihydro -7H- cyclopentas [f] quinoline
The preparation of quinoline -9- alcohol (I-1)
Under -78 DEG C, nitrogen protection, by compound 6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -7,8- bis-
Hydrogen -9H- cyclopentas [f] quinoline -9- ketone (11) (30mg, 0.097mmol) is dissolved in tetrahydrofuran, and grignard examination is then added dropwise
Agent Benzylphosphonium Bromide magnesium (0.195mmol), after being added dropwise to complete, be warmed to room temperature stirring 3 it is small when, then add saturated ammonium chloride solution quench
Go out reaction.Remove solvent under reduced pressure, white solid (22.1mg), yield are purified to obtain through column chromatography：56.97%.mp.120-123℃
；1H NMR (300MHz, Chloroform-d) δ 8.63 (d, J=2.9Hz, 1H), 8.19 (d, J=2.9Hz, 1H), 7.81 (s,
1H), 7.21-7.01 (m, 3H), 6.81 (d, J=6.9Hz, 2H), 3.95 (s, 3H), 3.46 (d, J=13.0Hz, 1H), 3.26
(d, J=12.9Hz, 1H), 2.79-2.61 (m, 2H), 2.55-2.36 (m, 1H), 2.29-2.12 (m, 3H), 2.10-2.05 (m,
1H), 2.02-1.89 (m, 3H) .MS (ESI) m/z：401.2[M+H]+。
Embodiment 12
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- phenyl -8,9- dihydro -7H- cyclopentas [f] quinoline
The preparation of quinoline -9- alcohol (I-2)
Concrete operations reference compound 6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl group -9- benzyls -8,9- dihydro -
The preparation of 7H- cyclopentas [f] quinoline -9- alcohol (I-1), puts into compound (11) 190mg, obtains white solid 183mg, yield：
76.85%.mp.90-92℃；1H NMR (300MHz, Chloroform-d) δ 8.43 (d, J=2.9Hz, 1H), 7.80 (s,
1H), 7.45-7.22 (m, 6H), 3.55 (s, 3H), 3.08-2.95 (m, 1H), 2.92-2.79 (m, 1H), 2.77-2.56 (m,
2H), 2.33 (s, 3H), 2.17 (s, 3H)；13C NMR (75MHz, Chloroform-d) δ 165.74,159.09,152.89,
146.65,143.95,143.48,142.91,141.46,131.73,128.40,127.00,125.50,125.17,125.06,
115.06,109.30,86.76,77.26,60.42,55.14,46.17,11.65,10.61.MS (ESI) m/z：387.2[M+H
]+。
Embodiment 13
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (2- tolyls) -8,9- dihydro -7H- cyclopentas
The preparation of [f] quinoline -9- alcohol (I-3)
Concrete operations reference compound 6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl group -9- benzyls -8,9- dihydro -
The preparation of 7H- cyclopentas [f] quinoline -9- alcohol (I-1), puts into compound (11) 30mg, obtains white solid 21mg, yield：
53.89%.mp.96-99℃；1H NMR (300MHz, Chloroform-d) δ 8.47 (d, J=2.9Hz, 1H), 7.80 (s,
1H), 7.27-7.10 (m, 5H), 3.49 (s, 3H), 3.13-3.03 (m, 1H), 2.92-2.79 (m, 2H), 2.60-2.50 (m,
1H), 2.32 (s, 3H), 2.16 (s, 3H), 1.98 (s, 3H)；13C NMR (75MHz, Chloroform-d) δ 165.73,
159.10,152.99,144.16,143.42,143.18,142.87,141.39,135.12,132.43,131.72,127.53,
125.78,125.66,125.14,115.08,108.66,86.95,77.26,55.11,42.80,29.84,20.86,11.65,
10.63.MS(ESI)m/z：401.2[M+H]+。
Embodiment 14
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (3- tolyls) -8,9- dihydro -7H- cyclopentas
The preparation of [f] quinoline -9- alcohol (I-4)
Concrete operations reference compound 6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl group -9- benzyls -8,9- dihydro -
The preparation of 7H- cyclopentas [f] quinoline -9- alcohol (I-1), puts into compound (11) 30mg, obtains white solid 25mg, yield：
64.16%.mp.93-95℃；1H NMR (300MHz, Chloroform-d) δ 8.39 (d, J=2.9Hz, 1H), 7.75 (s,
1H), 7.33 (d, J=2.9Hz, 1H), 7.27-7.05 (m, 4H), 3.55 (s, 3H), 3.05-2.92 (m, 1H), 2.91-2.79
(m, 1H), 2.76-2.56 (m, 2H), 2.33 (s, 3H), 2.31 (s, 3H), 2.14 (s, 3H)；13C NMR (75MHz,
Chloroform-d) δ 165.74,159.10,152.85,146.53,143.84,143.35,142.87,141.53,138.04,
131.57,128.27,127.74,125.68,125.53,125.20,122.14,115.05,109.43,86.75,77.26,
55.16,46.16,21.64,11.66,10.62.MS (ESI) m/z：401.2[M+H]+。
Embodiment 15
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (4- tolyls) -8,9- dihydro -7H- cyclopentas
The preparation of [f] quinoline -9- alcohol (I-5)
Concrete operations reference compound 6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl group -9- benzyls -8,9- dihydro -
The preparation of 7H- cyclopentas [f] quinoline -9- alcohol (I-1), puts into compound (11) 30mg, obtains white solid 20mg, yield：
51.33%.mp.91-94℃；1H NMR (300MHz, Chloroform-d) δ 8.45 (d, J=2.9Hz, 1H), 7.79 (s,
1H), 7.36 (d, J=2.9Hz, 1H), 7.25 (d, J=8.4Hz, 2H), 7.14 (d, J=7.9Hz, 2H), 3.58 (s, 3H),
3.03-2.92 (m, 1H), 2.88-2.77 (m, 1H), 2.70-2.57 (m, 2H), 2.34 (s, 3H), 2.32 (s, 3H), 2.17 (s,
3H)；13C NMR (75MHz, Chloroform-d) δ 165.78,159.13,152.87,143.79,143.45,143.27,
142.86,141.44,136.66,131.55,129.08,125.63,125.22,124.94,115.03,109.53,86.80,
77.24,55.23,46.29,21.03,11.71,10.69.MS (ESI) m/z：401.2[M+H]+。
Embodiment 16
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (2- methoxyphenyls) -8,9- dihydro -7H- rings penta
The preparation of alkene simultaneously [f] quinoline -9- alcohol (I-6)
Concrete operations reference compound 6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl group -9- benzyls -8,9- dihydro -
The preparation of 7H- cyclopentas [f] quinoline -9- alcohol (I-1), puts into compound (11) 30mg, obtains white solid 21mg, yield：
53.89%.mp.130-133℃；1H NMR (300MHz, Chloroform-d) δ 8.63 (s, 1H), 7.91 (s, 1H), 7.82
(d, J=3.0Hz, 1H), 7.28 (d, J=1.2Hz, 1H), 7.05 (d, J=8.2Hz, 1H), 6.74 (t, J=7.5Hz, 1H),
6.42 (d, J=7.6Hz, 1H), 4.96 (s, 1H), 4.01 (s, 3H), 3.74 (s, 3H), 2.90-2.73 (m, 2H), 2.73-
2.54 (m, 2H), 2.32 (s, 3H), 2.19 (s, 3H)；13C NMR (75MHz, Chloroform-d) δ 165.86,159.37,
156.57,153.02,143.73,143.39,139.40,132.78,131.26,128.88,126,97,126.31,125.73,
120.78,115.17,111.44,110.88,87.49,77.26,55.61,43.92,11.69,10.67.MS (ESI) m/z：
417.1[M+H]+。
Embodiment 17
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (3- methoxyphenyls) -8,9- dihydro -7H- rings penta
The preparation of alkene simultaneously [f] quinoline -9- alcohol (I-7)
Concrete operations reference compound 6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl group -9- benzyls -8,9- dihydro -
The preparation of 7H- cyclopentas [f] quinoline -9- alcohol (I-1), puts into compound (11) 30mg, obtains white solid 20mg, yield：
51.33%.mp.93-95℃；1H NMR (300MHz, Chloroform-d) δ 8.53 (s, 1H), 7.87 (s, 1H), 7.39 (s,
1H), 7.25 (d, J=8.2Hz, 1H), 7.02 (s, 1H), 6.92 (d, J=7.8Hz, 1H), 6.83 (d, J=8.7Hz, 1H),
3.80 (s, 3H), 3.63 (s, 3H), 3.09-2.97 (m, 1H), 2.95-2.84 (m, 1H), 2.76-2.58 (m, 2H), 2.37 (s,
3H), 2.22 (s, 3H)；13C NMR (75MHz, Chloroform-d) δ 165.76,159.73,159.10,152.90,148.40,
143.91,143.39,142.85,141.35,131.69,129.46,125.50,125.18,117.51,115.03,111.79,
111.32,109.35,86.69,77.26,55.22,46.09,11.67,10.64.MS (ESI) m/z：417.1[M+H]+。
Embodiment 18
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (4- methoxyphenyls) -8,9- dihydro -7H- rings penta
The preparation of alkene simultaneously [f] quinoline -9- alcohol (I-8)
Concrete operations reference compound 6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl group -9- benzyls -8,9- dihydro -
The preparation of 7H- cyclopentas [f] quinoline -9- alcohol (I-1), puts into compound (11) 30mg, obtains white solid 23mg, yield：
59.03%.mp.98-100℃；1H NMR (300MHz, Chloroform-d) δ 8.47 (d, J=2.9Hz, 1H), 7.82 (s,
1H), 7.41 (d, J=2.8Hz, 1H), 7.29-7.24 (m, 2H), 6.87 (d, J=8.4Hz, 2H), 3.80 (s, 3H), 3.62
(s, 3H), 3.03-2.91 (m, 1H), 2.88-2.76 (m, 1H), 2.72-2.56 (m, 2H), 2.33 (s, 3H), 2.18 (s, 3H)
；13C NMR (75MHz, Chloroform-d) δ 165.80,159.11,158.54,152.89,143.65,143.08,142.90,
141.40,138.49,131.40,126.26,125.76,125.26,114.98,113.70,109.74,86.66,77.24,
55.30,46.31,11.72,10.69.MS (ESI) m/z：417.1[M+H]+。
Embodiment 19
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (3- fluorophenyls) -8,9- dihydro -7H- cyclopentas
The preparation of [f] quinoline -9- alcohol (I-9) 1
Concrete operations reference compound 6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl group -9- benzyls -8,9- dihydro -
The preparation of 7H- cyclopentas [f] quinoline -9- alcohol (I-1), puts into compound (11) 30mg, obtains white solid 23mg, yield：
58.45%.mp.92-94℃；1H NMR (300MHz, Chloroform-d) δ 8.40 (d, J=2.9Hz, 1H), 7.77 (s,
1H), 7.34-7.24 (m, 2H), 7.19 (d, J=10.4Hz, 1H), 7.08 (d, J=7.8Hz, 1H), 6.96 (dd, J=2.7,
1.1Hz, 1H), 3.75-3.62 (m, 1H), 3.58 (s, 3H), 3.06-2.93 (m, 1H), 2.92-2.79 (m, 1H), 2.74-
2.56 (m, 2H), 2.31 (s, 3H), 2.14 (s, 3H)；13C NMR (75MHz, Chloroform-d) δ 165.79,164.63,
161.37,159.05,152.98,149.47,144.02,143.39,142.94,140.90,131.91,129.97,125.53,
125.04,120.72,114.93,113.84,112.26,109.10,86.39,55.20,46.02,11.67,10.62.MS
(ESI)m/z：405.0[M+H]+。
Embodiment 20
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (4- fluorophenyls) -8,9- dihydro -7H- cyclopentas
The preparation of [f] quinoline -9- alcohol (I-10)
Concrete operations reference compound 6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl group -9- benzyls -8,9- dihydro -
The preparation of 7H- cyclopentas [f] quinoline -9- alcohol (I-1), puts into compound (11) 30mg, obtains white solid 20mg, yield：
50.83%.mp.85-87℃；1H NMR (300MHz, Chloroform-d) δ 8.47 (d, J=2.9Hz, 1H), 7.82 (s,
1H), 7.41-7.30 (m, 3H), 7.03 (t, J=8.7Hz, 2H), 3.61 (s, 3H), 3.06-2.94 (m, 1H), 2.90-2.78
(m, 1H), 2.71-2.58 (m, 2H), 2.33 (s, 3H), 2.17 (s, 3H)；13C NMR (75MHz, Chloroform-d) δ
165.82,163.40,159.06,152.97,143.80,143.02,142.20,141.03,131.67,126.79,125.74,
125.09,115.35,115.07,114.90,109.45,86.52,55.27,46.27,29.53,11.72,10.68.MS
(ESI)m/z：405.0[M+H]+。
Embodiment 21
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (3- chlorphenyls) -8,9- dihydro -7H- cyclopentas
The preparation of [f] quinoline -9- alcohol (I-11)
Concrete operations reference compound 6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl group -9- benzyls -8,9- dihydro -
The preparation of 7H- cyclopentas [f] quinoline -9- alcohol (I-1), puts into compound (11) 30mg, obtains white solid 20mg, yield：
48.84%.mp.84-86℃；1H NMR (300MHz, Chloroform-d) δ 8.46 (d, J=2.8Hz, 1H), 7.80 (s,
1H), 7.50 (s, 1H), 7.32-7.22 (m, 3H), 7.20-7.13 (m, 1H), 3.61 (s, 3H), 3.07-2.94 (m, 1H),
2.93-2.79 (m, 1H), 2.73-2.58 (m, 2H), 2.33 (s, 3H), 2.17 (s, 3H)；13C NMR (75MHz,
Chloroform-d) δ 165.81,159.07,153.05,148.71,144.13,143.45,142.94,140.70,134.52,
132.07,129.74,127.18,125.56,125.34,125.01,123.29,114.92,109.02,86.44,55.26,
46.03,14.20,11.71,10.67.MS (ESI) m/z：421.0[M+H]+。
Embodiment 22
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (4- chlorphenyls) -8,9- dihydro -7H- cyclopentas
The preparation of [f] quinoline -9- alcohol (I-12)
Concrete operations reference compound 6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl group -9- benzyls -8,9- dihydro -
The preparation of 7H- cyclopentas [f] quinoline -9- alcohol (I-1), puts into compound (11) 30mg, obtains white solid 19mg, yield：
46.40%.mp.87-89℃；1H NMR (300MHz, Chloroform-d) δ 8.45 (d, J=2.9Hz, 1H), 7.80 (s,
1H), 7.31 (d, J=1.0Hz, 4H), 7.30-7.29 (m, 1H), 3.61 (s, 3H), 3.05-2.93 (m, 1H), 2.89-2.77
(m, 1H), 2.68-2.58 (m, 2H), 2.32 (s, 3H), 2.16 (s, 3H)；13C NMR (75MHz, Chloroform-d) δ
165.80,159.05,152.99,145.01,143.99,143.33,142.95,140.84,132.83,131.88,128.54,
126.55,125.60,125.05,114.90,109.22,86.47,55.26,46.18,29.69,11.71,10.67.MS
(ESI)m/z：421.0[M+H]+。
Embodiment 23
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- ([1,1 '-biphenyl] -4- bases) -8,9- dihydros -7H-
The preparation of cyclopenta [f] quinoline -9- alcohol (I-13)
Concrete operations reference compound 6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl group -9- benzyls -8,9- dihydro -
The preparation of 7H- cyclopentas [f] quinoline -9- alcohol (I-1), puts into compound (11) 30mg, obtains white solid 27mg, yield：
59.99%.mp.96-98℃；1H NMR (300MHz, Chloroform-d) δ 8.44 (d, J=2.8Hz, 1H), 7.82 (s,
1H), 7.63-7.55 (m, 4H), 7.50-7.42 (m, 4H), 7.40-7.35 (m, 2H), 3.57 (s, 3H), 3.11-2.98 (m,
1H), 2.96-2.84 (m, 1H), 2.80-2.62 (m, 2H), 2.34 (s, 3H), 2.18 (s, 3H)；13C NMR (75MHz,
Chloroform-d) δ 165.81,159.12,152.93,145.56,143.91,143.34,142.99,141.36,140.54,
139.87,131.70,128.84,128.74,127.40,127.09,126.97,126.56,125.57,125.20,115.03,
109.44,86.73,55.21,46.22,11.73,10.69.MS (ESI) m/z：463.1[M+H]+。
Embodiment 24
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- methyl -8,9- dihydro -7H- cyclopentas [f] quinoline
The preparation of quinoline -9- alcohol (I-14)
Concrete operations reference compound 6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl group -9- benzyls -8,9- dihydro -
The preparation of 7H- cyclopentas [f] quinoline -9- alcohol (I-1), puts into compound (11) 30mg, obtains white solid 15mg, yield：
47.53%.mp.95-97℃；1H NMR (300MHz, Chloroform-d) δ 8,60 (d, J=2.9Hz, 1H), 8.20 (d, J=
2.9Hz, 1H), 7.76 (s, 1H), 3.97 (s, 3H), 2.80-2.66 (m, 2H), 2.57-2.42 (m, 1H), 2.30 (s, 3H),
2.27-2.22 (m, 1H), 2.15 (s, 3H), 1.73 (s, 3H)；13C NMR (75MHz, Chloroform-d) δ 165.73,
159.17,153.04,144.13,143.35,142.00,140.08,131.05,125.64,125.03,114.95,108.78,
83.87,55.62,44.47,28.73,26.67,11.64,10.65.MS (ESI) m/z：325.1[M+H]+。
Embodiment 25
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- isopropyls -8,9- dihydro -7H- cyclopentas [f] quinoline
The preparation of quinoline -9- alcohol (I-15)
Concrete operations reference compound 6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl group -9- benzyls -8,9- dihydro -
The preparation of 7H- cyclopentas [f] quinoline -9- alcohol (I-1), puts into compound (11) 30mg, obtains white solid 16mg, yield：
46.66%.mp.71-74℃；1H NMR (300MHz, Chloroform-d) δ 8.61 (d, J=2.8Hz, 1H), 8.21 (d, J=
2.9Hz, 1H), 7.79 (s, 1H), 3.97 (s, 3H), 2.78-2.67 (m, 3H), 2.66-2.58 (m, 1H), 2.29 (s, 3H),
2.14 (s, 3H), 2.08-1.96 (m, 1H), 1.23 (d, J=6.6Hz, 3H), 0.67 (d, J=7.0Hz, 3H)；13C NMR
(75MHz, Chloroform-d) δ 165.68,159.15,152.89,143.68,143.25,141.71,140.82,131.14,
125.67,125.51,114.96,109.85,89.74,55.66,36.74,36.57,30.21,17.67,17.09,11.57,
10.58.MS(ESI)m/z：353.1[M+H]+。
Embodiment 26
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxies -9- cyclopropyl -8,9- dihydro -7H- cyclopentas [f] quinoline
The preparation of quinoline -9- alcohol (I-16)
Concrete operations reference compound 6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl group -9- benzyls -8,9- dihydro -
The preparation of 7H- cyclopentas [f] quinoline -9- alcohol (I-1), puts into compound (11) 30mg, obtains white solid 17mg, yield：
49.86%.mp.72-75℃；1H NMR (300MHz, Chloroform-d) δ 8.60 (d, J=3.0Hz, 1H), 8.32 (d, J=
2.9Hz, 1H), 7.80 (s, 1H), 3.97 (s, 3H), 2.78-2.70 (m, 2H), 2.57-2.48 (m, 1H), 2.30 (s, 3H),
2.26-2.19 (m, 1H), 2.15 (s, 3H), 1.52-1.40 (m, 1H), 0.68-0.57 (m, 2H), 0.56-0.46 (m, 2H)；13C
NMR (75MHz, Chloroform-d) δ 165.75,159.15,152.94,143.73,142.96,141.63,140.96,
130.90,125.70,110.15,85.51,55.62,42.18,37.30,29.22,20.37,12.38,10.64,6.91,
2.49,1.83.MS (ESI) m/z：351.1[M+H]+。
Embodiment 27
4- (2- methoxyl group -9- phenyl -7H- cyclopentas [f] quinoline -6- bases) -3,5- dimethyl isoxazoles (12)
Prepare
By 6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- phenyl -8,9- dihydro -7H- cyclopentas [f] quinoline
Quinoline -9- alcohol (I-2) (30mg, 0.077mmol) is dissolved in ethyl acetate (0.5ml), adds concentrated hydrochloric acid (0.05ml), at room temperature
Stir 3 it is small when, TLC show reaction be basically completed, remove solvent under reduced pressure, product (23.60mg), yield purified to obtain through column chromatography：
82.51%.mp.110-113℃；1H NMR (300MHz, Chloroform-d) δ 8.59 (d, J=2.9Hz, 1H), 7.80 (s,
1H), 7.54 (dt, J=4.5,0.8Hz, 4H), 7.52-7.44 (m, 1H), 7.26 (dd, J=2.9,0.8Hz, 1H), 6.64-
6.60 (m, 1H), 3.46 (s, 3H), 3.40 (d, J=2.1Hz, 2H), 2.37 (s, 3H), 2.23 (s, 3H) .MS (ESI) m/z：
369.5[M+H]+。
Embodiment 28
4- (2- methoxyl group -9- phenyl -8,9- dihydro -7H- cyclopentas [f] quinoline -6- bases) -3,5- dimethyl isoxazoles
(I-17) preparation
By 4- (2- methoxyl group -9- phenyl -7H- cyclopentas [f] quinoline -6- bases) -3,5- dimethyl isoxazoles (12)
(25mg, 0.068mmol) is dissolved in methanol (1ml), adds 1% palladium carbon, be stirred at room temperature under hydrogen shield 3 it is small when, TLC is shown
Show that reaction is basically completed, remove solvent under reduced pressure, white product (22.00mg), yield are purified to obtain through column chromatography：87.52%.
mp.154-157℃；1H NMR (300MHz, Chloroform-d) δ 8.58 (d, J=2.9Hz, 1H), 7.80 (s, 1H), 7.36-
7.25 (m, 3H), 7.20-7.14 (m, 2H), 6.95 (d, J=2.9Hz, 1H), 4.84 (t, J=7.1Hz, 1H), 3.60 (s,
3H), 3.11-2.95 (m, 1H), 2.94-2.74 (m, 2H), 2.37 (s, 3H), 2.24 (s, 3H), 2.22-2.15 (m, 1H)；13C
NMR (75MHz, Chloroform-d) δ 165.65,159.25,152.92,145.38,143.74,143.33,143.28,
140.68,130.20,128.85,127.57,126.59,125.66,115.58,109.42,77.26,55.15,51.08,
36.33,31.67,11.73,10.75.MS (ESI) m/z：371.1[M+H]+。
Embodiment 29
Compound of formula I is evaluated as the BRD4-BD1 inhibitory activity of BET bromodomain inhibitor
Experimental method：BRD4 inhibitory activity tests, positive control drug are carried out using BRD4BD1 competitiveness fluorescents Polarization Detection
For PFI-1.
Experiment condition：
Test panel：Black, 96 orifice plate of round bottom (Thermo)
Test buffer solution：100mM potassium phosphates, pH value 6.5, along with 0.01% Triton X-100 (Sigma,
282103)。
Detection limit：100 μ L (a series of diluted protein solutions of 10 μ L mix 90 μ L probe solutions)
Incubation time：When 0.5-1 is small
Experimental procedure：
1st, the preparation of testing liquid：Prepare composite solution (albumen adds probe)
2nd, the ethylene glycol solution of test compound is prepared, is usually 10nM；(by these in addition to B1-B3 and B7-B9 holes
Leave blank in hole), 2 μ L ethylene glycol are added in other holes of 96 orifice plates；The working solution of 4 μ L compounds 1 is added in B1 to B3,
The working solution of compound 2 is added in B7 to B9, therefore, every kind of compound will all be tested three times, and can use one
Block plate tests two kinds of compounds；2 times of serial dilutions：From b rows 1-3 row and 7-9 be about to 2 μ L be transferred to C rows 1-3 row and
7-9 is arranged, and is continued in this order, to the last a H row, and again continues to carry out until H to B rows 4-6 and 10-12
OK, 2 μ L are discarded in being diluted from last time, prepare twice of dilution of test compound directly in assay plate by this way
Liquid, after completing this step, has 2 μ L in all 96 holes；Measure buffer solution (this some holes of 98 μ L is only added in A1-A2 holes
It is blank control, is used in assay plate), the positive control of 98 μ L is added into A7 holes in A3, A8 is added into A12 in hole
Composite solutions of the 98 μ L as negative control, the composite solution of 98 μ L is added in the remainder of tablet；Culture is covered with aluminium foil
Plate, be placed on shaking table be incubated 0.5-1 it is small when, polarization value is measured in plate reader：Excitation wavelength 485nm, launch wavelength 530nm.
50 μ L ethylene glycol are pipetted in 13 Eppendorf pipes, the change of 100 μ L maximum concentrations is shifted in another Eppendorf pipe
50 μ L compound solutions, are transferred in the first pipe, mix and proceed to last pipe by polymer solution with 50 μ L ethylene glycol, will be every
The solution transferase 12 μ 1 of kind dilution factor then shifts probe and probe/protein solution as described above to assay plate.
Determine that IC 50 is worth by the nonlinear regression and fitting (mP value vs log [compoound]) of competition curve, competition suppression
IC 50 value of the Ki values of preparation based on measurement calculates.
The BRD4-BD1 of compound suppresses efficiency
aIncome value is the average value of independent experiment three times, and standard deviation is within the 20% of report value.
bN.d.=not can determine that.
cAs positive control.
Embodiment 30
Compound of formula I comments the anticancer of cancer cell system MOLM-13 and MV4-11 as BET bromodomain inhibitor
Estimate
Cancer cell system：MOLM-13 and MV4-11
Experimental method：The cell in growth period of taking the logarithm is made into 4.5 × 105/mL cell suspensions, is seeded to 96 well culture plates
In, per 180 μ L of hole, every group sets 5 parallel holes, is separately added into each 20 μ L. of various concentrations tested material and is placed in constant temperature CO2 incubators
Cultivate 48 it is small when, add MTT tetramethyl nitrogen azoles is blue in 99 orifice plates, per 20 μ L of hole, continue culture 4 it is small when.Supernatant is sucked, is added
Enter DMSO, per 150 μ L of hole, shaken 5 minutes on plate shaker.In wavelength it is to be measured at 5770nm per hole with enzyme-linked immunosorbent assay instrument
Trap, the above experiment be respectively repeated 3 times.Cell proliferation inhibition rate is calculated, and then asks and calculates EC50。
The anticancer assessment of cancer cell system MOLM-13 and MV4-11
aIncome value is the average value of independent experiment three times, and standard deviation is within the 20% of report value.
bN.t.=is not measured.
Claims (6)
1. the compound or its pharmaceutically acceptable salt of a kind of logical formula (I)：
Wherein R1The cycloalkyl of straight or branched alkane, non-substituted or substitution 3~6 carbon for non-substituted or substitution 1~6 carbon,
Various substituted benzyls, the heterocycle of armaticity or various substituted armaticity on phenyl, various substituted phenyl, benzyl or phenyl ring
Heterocycle；R2For hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino or alkoxy；R3For hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, alcoxyl
Various substituted benzyls, the heterocycle of armaticity or various substituted virtues on base, phenyl, various substituted phenyl, benzyl or phenyl ring
The heterocycle of fragrance；R4Or R5The alkane or hydrogen of 1~3 carbon are expressed as independently of one another；X is oxygen or sulphur；N is 1,2 or 3.
2. compound of formula I according to claim 1, it is characterised in that in the compound of formula I：R1For methyl, ethyl,
It is propyl group, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, various
Substituted phenyl or benzyl；R2For hydrogen, hydroxyl or amino；R3For hydrogen, hydroxyl or alkoxy；R4Or R5It is expressed as independently of one another
Methyl, ethyl or hydrogen；X is oxygen or sulphur；N is 1 or 2.
3. compound of formula I according to claim 1, it is characterised in that in the compound of formula I：R1For methyl, isopropyl
Base, cyclopropyl, phenyl, 2- aminomethyl phenyls, 3- aminomethyl phenyls, 4- aminomethyl phenyls, 2- methoxyphenyls, 3- methoxyphenyls, 4-
Methoxyphenyl, 4- phenyls, 3- fluorophenyls, 4- fluorophenyls, 3- chlorphenyls, 4- chlorphenyls or benzyl；R2For hydrogen or hydroxyl；
R3For methoxyl group；R4Or R5Methyl is expressed as independently of one another；X is oxygen；N is 1.
4. compound of formula I according to claim 1, it is characterised in that the compound is preferably selected from：
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl group -9- benzyl -8,9- dihydro -7H- cyclopenta [f] quinoline -9-
Alcohol (I-1)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl group -9- phenyl -8,9- dihydro -7H- cyclopenta [f] quinoline -9-
Alcohol (I-2)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (2- tolyls) -8,9- dihydro -7H- cyclopentas [f] quinoline
Quinoline -9- alcohol (I-3)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (3- tolyls) -8,9- dihydro -7H- cyclopentas [f] quinoline
Quinoline -9- alcohol (I-4)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (4- tolyls) -8,9- dihydro -7H- cyclopentas [f] quinoline
Quinoline -9- alcohol (I-5)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (2- methoxyphenyls) -8,9- dihydro -7H- cyclopentas
[f] quinoline -9- alcohol (I-6)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (3- methoxyphenyls) -8,9- dihydro -7H- cyclopentas
[f] quinoline -9- alcohol (I-7)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (4- methoxyphenyls) -8,9- dihydro -7H- cyclopentas
[f] quinoline -9- alcohol (I-8)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (3- fluorophenyls) -8,9- dihydro -7H- cyclopentas [f] quinoline
Quinoline -9- alcohol (I-9)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (4- fluorophenyls) -8,9- dihydro -7H- cyclopentas [f] quinoline
Quinoline -9- alcohol (I-10)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (3- chlorphenyls) -8,9- dihydro -7H- cyclopentas [f] quinoline
Quinoline -9- alcohol (I-11)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- (4- chlorphenyls) -8,9- dihydro -7H- cyclopentas [f] quinoline
Quinoline -9- alcohol (I-12)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- ([1,1 '-biphenyl] -4- bases) -8,9- dihydro -7H- rings penta
Alkene simultaneously [f] quinoline -9- alcohol (I-13)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl group -9- methyl -8,9- dihydro -7H- cyclopenta [f] quinoline -9-
Alcohol (I-14)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxyl groups -9- isopropyls -8,9- dihydro -7H- cyclopentas [f] quinoline -
9- alcohol (I-15)；
6- (3,5- dimethyl isoxazole -4- bases) -2- methoxy -9- cyclopropyl -8,9- dihydro -7H- cyclopenta [f] quinoline -9-
Alcohol (I-16)；
4- (2- methoxyl group -9- phenyl -8,9- dihydro -7H- cyclopentas [f] quinoline -6- bases) -3,5- dimethyl isoxazoles (I-
17)。
5. the preparation method of compound of formula I according to claim 1, following reaction equation：
Specifically include following steps：
(1) compound 2 is made with hydroxylamine hydrochloride, anhydrous sodium sulfate and chloraldurate in compound 1 in acid condition；
(2) compound 2 issues raw molecule inner ring condensation in sulfuric acid heating condition, and compound 3 is made；
(3) 4- quinoline carboxylic acid intermediates are made with bromo acetone acid in compound 3 in alkaline conditions, then are made by decarboxylation
Compound 4；
(4) compound 4 is through the obtained compound 5 that methylates；
(5) compound 6 is made by bromo in compound 5；
(6) compound 7 is made with dimethyl malenate in compound 6；
(7) compound 8 is made through ester hydrolysis in compound 7；
(8) compound 9 is made through decarboxylation in compound 8；
(9) compound 10 is made through molecule inner ring condensation in compound 9；
(10) compound 11 is made through coupling reaction in compound 10；
(11) corresponding compound I-1 to I-16 is made with different grignard reagent reactions in compound 11；
(12) compound I-2 is dehydrated under sour environment is made compound 12；
(13) compound I-17 is made in the hydrogenated reduction of compound 12.
6. compound of formula I according to any one of claims 1 to 4, or its pharmaceutically acceptable salt are as BET
The purposes of bromodomain inhibitor in the treatment of cancer.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110627683A (en) * | 2018-06-25 | 2019-12-31 | 广东东阳光药业有限公司 | Preparation method of indanone intermediate |
| CN114276259A (en) * | 2022-01-04 | 2022-04-05 | 济川(上海)医学科技有限公司 | Preparation method of maleic acid dimethylindidine key intermediate |
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| US5475003A (en) * | 1994-03-03 | 1995-12-12 | Syntex (U.S.A.) Inc. | 8-phenylcyclopentenoquinoline and 8-phenylcyclohexenoquinoline derivatives |
| WO2013024104A1 (en) * | 2011-08-17 | 2013-02-21 | Glaxosmithkline Llc | 4-(8-methoxy-1-((1-methoxypropan-2-yl)-2-(tetrahydro-2h-pyran-4-yl)-1 h-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole and its use as bromodomain inhibitor |
| WO2016123709A1 (en) * | 2015-02-03 | 2016-08-11 | Trillium Therapeutics Inc. | Fluorinated imidazo[4,5-c]quinoline derivatives as inhibitors of bromodomain containing proteins |
| WO2016186453A1 (en) * | 2015-05-20 | 2016-11-24 | Kainos Medicine, Inc. | Quinoline derivatives as bromodomain inhibitors |
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2018
- 2018-01-09 CN CN201810024854.1A patent/CN108033957A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5475003A (en) * | 1994-03-03 | 1995-12-12 | Syntex (U.S.A.) Inc. | 8-phenylcyclopentenoquinoline and 8-phenylcyclohexenoquinoline derivatives |
| WO2013024104A1 (en) * | 2011-08-17 | 2013-02-21 | Glaxosmithkline Llc | 4-(8-methoxy-1-((1-methoxypropan-2-yl)-2-(tetrahydro-2h-pyran-4-yl)-1 h-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole and its use as bromodomain inhibitor |
| WO2016123709A1 (en) * | 2015-02-03 | 2016-08-11 | Trillium Therapeutics Inc. | Fluorinated imidazo[4,5-c]quinoline derivatives as inhibitors of bromodomain containing proteins |
| WO2016186453A1 (en) * | 2015-05-20 | 2016-11-24 | Kainos Medicine, Inc. | Quinoline derivatives as bromodomain inhibitors |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110627683A (en) * | 2018-06-25 | 2019-12-31 | 广东东阳光药业有限公司 | Preparation method of indanone intermediate |
| CN114276259A (en) * | 2022-01-04 | 2022-04-05 | 济川(上海)医学科技有限公司 | Preparation method of maleic acid dimethylindidine key intermediate |
| CN114276259B (en) * | 2022-01-04 | 2022-12-06 | 济川(上海)医学科技有限公司 | Preparation method of maleic acid dimethylindidine key intermediate |
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