CN105198871A - Quinoxalinone compounds as well as preparation methods and applications of quinoxalinone compounds - Google Patents
Quinoxalinone compounds as well as preparation methods and applications of quinoxalinone compounds Download PDFInfo
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- CN105198871A CN105198871A CN201510759801.0A CN201510759801A CN105198871A CN 105198871 A CN105198871 A CN 105198871A CN 201510759801 A CN201510759801 A CN 201510759801A CN 105198871 A CN105198871 A CN 105198871A
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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
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses quinoxalinone compounds as well as preparation methods and applications of the quinoxalinone compounds and relates to compounds as shown in the general formula (I) and salts of the compounds. The compounds can be effectively combined with proteins with Bromodomain structural domains to further regulate a downstream signal channel so as to take a specific effect; and the activity of parts of the compounds is higher than (+)-JQ1, and the cell activity is relatively good. The invention also relates to the preparation methods of the compounds and pharmaceutical preparations containing the compounds. By using the preparation methods, a series of compounds as shown in the general formula (I) and pharmaceutically acceptable salts of the compounds are synthesized.
Description
Technical field
The present invention relates to a kind of new the research of quinoxalinone derivatives, its preparation method and this compounds, as Brd4 inhibitor, there is anti-tumor application.
Background technology
When epigenetics refers to that not relating to DNA sequence dna changes, gene function there occurs can hereditary change, finally causes the change of phenotype.Chromatin is by DNA, histone and nonhistonesly form.Nucleosome is that chromatinic substantially repetition forms unit, eight aggressiveness be made up of histone H 3, H4, H2A, H2B and the histone h1 being positioned at nucleosome outside and be wrapped in its outer DNA containing 146 base pairs and form.Chromatinic state is transcribed for regulatory gene has vital role.Epigenetics relates to DNA methylation, histone modification.Karyomit(e) is reinvented and genetic regulation by non-coding RNAs etc.; wherein histone modification comprise histone acetylize, phosphorylation, methylate, ubiquitination and ADP ribosylation etc.; the relation of these diversified modifications and their combinations over time and space and biological function can be used as again a kind of important apparent mark or language, is thus called as " Histone Code ".
Bromodomain structural domain is 110 amino acid whose protein function structural domains of high conservative in an evolution, can the terminated acetylated lysine sites of specific recognition histone, the gene transcription regulation of signal dependency, non-basic is participated in by chromatinic assembling and acetylize; Bromodomain is also by the processes such as wide participation cell cycle regulating, cytodifferentiation, signal transduction to nonhistones acetylation modifications such as transcription factors.As comprised four albumen (Brd2, Brd3, Brd4 and BRDT) containing the BET family of Bromodomain structural domain, each albumen comprise two independently Bromodomain structural domain be used for the lysine sites that identifies that histone is terminated acetylated.
Oncogene c-myc wide participation kinds of tumors generation evolution, and be closely related with tumor pharmacother reactivity.Research shows, c-myc is unconventionality expression in mankind's kinds of tumors, is transformed, differentiation and apoptosis plays important pushing effect to Zhong Liu Evil evolution by the growth metabolism of cell cycle regulation process, cell, genetic instability, promotion vasculogenesis, Xi Bao Evil; Suppress c-myc activity can significantly Tumor suppression increment grow.These find to show that c-myc is a potential antitumor target spot.
C-myc, as a transcription factor, is difficult to from himself structure, find suitable structural domain to carry out small molecules design, destroys the interaction of all the other DNA.Nearest research shows, before c-myc genetic transcription starts, its promoter region needs to carry out epigenetics modification.This region istone lysine residue is acetylation modification, thus raises the protein B rd4 with Bromodomain structural domain, the latter by and transcriptional elongation factor P-TEFb interacts, regulate and control the formation of c-myc transcription complex.Therefore, if the combination of design small molecules interference Brd4 and acetylated histones, transcribing of c-myc will likely be suppressed.Research proves, affects the micromolecular inhibitor JQ1 of Brd4 and acetylated histones combination, significantly can lower transcribing of c-myc target gene relevant with it.Adopt 3 kinds of tumor research model validations, JQ1 all can the propagation of effective inhibition tumor cell, points out the targeted inhibition agent for Brd4 to get a good chance of becoming effective medicine of c-myc high expression level tumour.
Disclose the patent application of a series of Brd4 inhibitor at present, comprising WO2013184878, WO2014076237, WO2014128655, WO2014134232, WO2014154762, WO2014128070, WO2011054553, WO2011054846, WO2011054848 etc.
The present invention relates to a kind of new the research of quinoxalinone derivatives, it has anti-tumor application as Brd4 inhibitor.Therefore described general formula (I) compound and its pharmaceutical salts potential for antitumor and relative disease.
Summary of the invention
The object of the present invention is to provide that a class is novel has the inhibiting new antitumoral molecule of Brd4.This compounds has quinazolinone structure, can disturb and have the Brd4 of Bromodomain structural domain and the combination of acetylated histones, and then lowers transcribing of oncogene c-myc target gene relevant with it, therefore can become effective medicine of tumour.
The present invention also aims to the preparation method that a class Quinoxalinone Brd4 inhibitor is provided.
Detailed description content is as follows:
The present invention has synthesized a series of general formula (I) compound and pharmacy acceptable salt thereof:
Wherein R
1be selected from cycloalkyl, aromatic heterocyclic, substituted or unsubstituted aromatic base, substituted or unsubstituted benzyl;
Wherein R
2represent H, alkyl, alkoxyl group, substituted or unsubstituted aromatic base, substituted or unsubstituted benzyl, cycloalkyl or hydroxyl;
Wherein R
3represent H, methyl or ethyl;
Preferred compound of the present invention includes, but are not limited to:
(R)-4-benzyl-6-(3,5-dimethyl isoxazole-4-base)-3-ethyl-3,4-dihydro-quinoxaline-2 (1H)-one;
(R)-6-(3,5-dimethyl isoxazole-4-base)-4-(4-methoxybenzyl)-3-methyl-3,4-dihydro-quinoxaline-2 (1H)-one;
(R)-4-(4-methoxybenzyl)-6-(3,5-dimethyl isoxazole-4-base)-3-methyl-3,4-dihydro-quinoxaline-2 (1H)-one;
(R)-4-cyclopentyl-6-(3,5-dimethyl isoxazole-4-base)-3-methyl-3,4-dihydro-quinoxaline-2 (1H)-one;
(R)-4-cyclohexyl-6-(3,5-dimethyl isoxazole-4-base)-3-methyl-3,4-dihydro-quinoxaline-2 (1H)-one;
(S)-6-(3,5-dimethyl isoxazole-4-base)-4-(4-methoxybenzyl)-3-methyl-3,4-dihydro-quinoxaline-2 (1H)-one;
(S)-4-cyclopentyl-6-(3,5-dimethyl isoxazole-4-base)-3-methyl-3,4-dihydro-quinoxaline-2 (1H)-one;
1 '-benzyl-7 '-(3,5-dimethyl isoxazole-4-base)-1 ', 4 '-dihydro-3 ' and H-spiral shell [pentamethylene-1,2 '-quinoxaline]-3 '-one;
4-(4-chlorobenzyl)-6-(3,5-dimethyl isoxazole-4-base)-3,4-dihydro-quinoxaline-2 (1H)-one;
(R)-3,4-dibenzyl-6-(3,5-dimethyl isoxazole-4-base)-3,4-dihydro-quinoxaline-2 (1H)-one;
(R)-6-(3,5-dimethyl isoxazole-4-base)-4-(4-methoxybenzyl)-1,3-dimethyl-3,4-dihydro-quinoxaline-2 (1H)-one;
4-(5-benzyl-4-methylene radical-4,5-dihydro tetrazole [1,5-a] quinoxaline-7-base)-3,5-dimethyl isoxazoles.
The structure of compound is:
Compound shown in general formula (I) can contain asymmetric or chiral centre, therefore can exist with different stereoisomeric forms in any ratio.All stereoisomeric forms in any ratio of the compounds of this invention, include but not limited to diastereomer.Enantiomer and atropisomer and their mixture (as racemic mixture), include within the scope of the invention.
Compound shown in general formula (I) can also exist with different tautomeric form, and all these forms includes within the scope of the present invention.Term " tautomer " or " tautomeric form " refer to the constitutional isomer of the different-energy mutually transformed via low energy barrier.
According to the present invention, pharmacy acceptable salt comprises the additive salt formed with following acid: the salt that hydrochloric acid, Hydrogen bromide, sulfuric acid, citric acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, toxilic acid, Phenylsulfonic acid, succsinic acid and similar known acceptable acid become.
The research of quinoxalinone derivatives preparation method of the present invention is as follows:
Step a: compd A and corresponding amino acid are obtained by reacting compd B;
Step b, c: compd B is obtained by reacting Compound C in SODIUM HYDROSULPHITE sodium water solution;
Steps d: Compound C and iodomethane reaction obtain Compound D;
Step e: Compound D and corresponding phenyl aldehyde or naphthenone are obtained by reacting compd E;
Step f: compd E and 3,5-dimethyl isoxazole-4-pinacol borate are obtained by reacting the compound that general formula (I) represents;
Wherein, in step a, compd A and corresponding amino acid reflux to spend the night and obtain compd B, and operable solvent is ethanol, tetrahydrofuran (THF), DMF and water etc.;
In step b, c, compd B and V-Brite B at room temperature stir to spend the night and obtain Compound C, and operable solvent is water;
In steps d, Compound C and methyl iodide react and obtain Compound D in 4 hours under ice bath, and reaction solvent is DMF;
In step e, be obtained by reacting compd E under Compound D and corresponding phenyl aldehyde or naphthenone room temperature, reaction solvent is tetrahydrofuran (THF);
In step f, compd E and 3,5-dimethyl isoxazole-4-pinacol borate reflux under nitrogen protection to spend the night and obtain the compound that general formula (I) represents, solvent selects water, ethanol, toluene Mixed Solvent.
Below the pharmacological experiment data of part of compounds of the present invention:
Brd4 (BD1) the enzyme level determination of activity of the research of quinoxalinone derivatives
It is AlphaScreen detection technique that the binding activities of compound and BRD4 albumen bromodomain structural domain (hereinafter referred to as BRD4 (BD1)) tests what adopt.Compound primary dcreening operation inhibiting rate concentration is 1 μM, the IC of the active compound preferably of part of detecting primary dcreening operation
50.
Preparation HEPES damping fluid (50mMHEPES, 100mMNaCl, 0.1%BSA, 0.05%CHAPS, pH7.5) for the preparation of BRD4 (BD1) albumen, Biotin mark histone H 4, testing compound (DMSO0.1%), donorbeads and acceptorbeads solution.Get 384 orifice plate one piece, according to layout, point testing compound hole, blank control wells (min, max), positive drug control wells on plate.Add the compound solution 5 μ L of different concns respectively to testing compound hole and positive drug hole, blank adds damping fluid 5 μ L (DMSO0.1%).Continue to add BRD4 (BD1) protein solution 5 μ L to each hole except blank control wells (min), add damping fluid 5 μ L to blank control wells (min).Incubated at room temperature is after 15 minutes, every hole adds the histone H 4 solution 5 μ L of Biotin mark, after continuing at room temperature to hatch 1 hour, add donorbeads and acceptorbeads solution 15 μ L, lucifuge incubated at room uses the Alphamode (λ of EnSpire detector after 1 hour
ex=680, λ
em=570) fluorescence values is read.
Numerical value process: inhibiting rate=(Max-Signal)/(Max-Min) × 100%
Wherein: the histone H 4 that Max:Biotin marks and the value that albumen is combined completely
The histone H 4 background values of Min:Biotin mark
Signal: the value under compound respective concentration
S curve is done with compound concentration and corresponding inhibiting rate.Obtain the IC of respective compound
50.
Table 1 is compound pharmacological evaluation biological activity result
Table 1
Note: " NT " represents do not have test I C
50.
Part of compounds primary dcreening operation concentration listed by table 1 is show the inhibiting rate suitable with positive control (+)-JQ1 under 1 μM, part of compounds IC50 is better than (+)-JQ1, demonstrate stronger activity, show that compound of the present invention can effectively combine the albumen with bromodomian structural domain at enzyme level, therefore compound of the present invention can become effective medicine of tumour.
The restraining effect of MV-4-11 cell
Select embodiment 1 compound to carry out measuring its restraining effect to MV-4-11 cell, concrete operations are as follows:
1st day: plating cells
Cell plate trypsinized, and determine cell density.Diluting cells slurries obtain the volume needed for optimum density.Get 90 μ l/ porocyte slurries to test panel, (5%CO under 37 DEG C of humidified condition
2) hatch 24 hours.
2nd day: add compound
The DMSO solution of positive control and test compounds is prepared according to orifice plate (200 × ultimate density).7 μ l compounds are added to 133 μ l perfect medium (ultimate densities: 10 ×).10 μ l compounds are added to test panel (final concentration: 1 ×).(5%CO under 37 DEG C of humidified condition
2) hatch.
5th day: cell imaging
Test agent is thawed before use 30 minutes.Add 30 μ l cell titer-Glo reagent in each hole, rock plate 10 minutes with inducing cell lysis.Plate is at room temperature hatched 2 minutes, with stabilized illumination signal.Envision is used to carry out measuring (timed interval: 0.5 second).
XLfit is used to carry out data processing.
%INH=(peak signal-compound signal)/(peak signal-minimum signal) × 100.
Peak signal is record in DMSO solution.
Minimum signal is record in substratum.
Table 2 is for measuring its restraining effect to MV-4-11 cell to compound 1.
Table 2
Experimental result shows that this compound has good cyto-inhibition.
The invention will be further described by the following examples.
Embodiment
Below in conjunction with embodiment, the invention will be further described.It should be noted that, following embodiment only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should in the protection domain required by the application's claim.
Raw material can obtain from commercial channels, or is prepared by methods known in the art, or prepares according to methods described herein.
The structure of compound by nucleus magnetic resonance (
1h-NMR) or mass spectrum (MS) determine.It is that mensuration solvent is deuterated dimethyl sulfoxide (DMSO-D6) or deuterochloroform (CDCl by BrukerAV-300 type nuclear magnetic resonance analyser that NMR measures
3), TMS is interior mark.
Preparation embodiment:
Embodiment 1:
Synthetic route is:
A) the fluoro-1-oil of mirbane of the bromo-2-of 4-(2.0g, 9.1mmol), D-2-aminobutyric acid (1.03g, 10.0mmol) with salt of wormwood (1.38g, 10.0mmol) be dissolved in the mixing solutions of ethanol (10mL) and water (3mL), reflux 8 hours.Be cooled to room temperature, 1M salt acid for adjusting pH to 2 ~ 3.Suction filtration, sherwood oil rinses separates out solid, dry, obtains R-2 ((the bromo-2-nitrophenyl of 5-)-amino) butyric acid 2.61g, yellow-brown solid, productive rate 94.7%.
1HNMR(300MHz，DMSO)：δ8.44(d，J＝7.3Hz，1H)，8.02(d，J＝9.1Hz，1H)，7.25(d，J＝1.9Hz，1H)，6.88(dd，J＝9.1，2.0Hz，1H)，4.54(dd，J＝12.5，5.3Hz，1H)，1.98-1.77(m，2H)，0.87(t，J＝7.4Hz，3H)。
B) (the bromo-2-nitrophenyl of 5-)-D-2-aminobutyric acid (1.20g, 4.0mmol) and salt of wormwood (1.09g, 8.0mmol) are added to the water (10mL), and stirring at room temperature is to all dissolving.
C) add V-Brite B (3.45g, 19.8mmol) in reaction flask, stirring at room temperature 10 hours in batches.Suction filtration, obtains (R)-6-bromo-3-ethyl-3,4-dihydro-quinoxaline-2 (1H)-one 0.41g, white solid, productive rate 40.6%.
1HNMR(300MHz，DMSO)：δ10.31(s，1H)，6.85(d，J＝2.1Hz，1H)，6.70(dd，J＝8.2，2.1Hz，1H)，6.61(d，J＝8.2Hz，1H)，6.29(s，1H)，3.76-3.66(m，1H)，1.72-1.52(m，2H)，0.91(t，J＝7.4Hz，3H)。
D) the bromo-3-ethyl-3 of (R)-6-, 4-dihydro-quinoxaline-2 (1H)-one (0.85g, 3.3mmol), phenylsilane (1.08g, 10.0mmol), phenyl aldehyde (1.06g, 10.0mmol) and dibutyl tin dichloride (1.11g, 3.7mmol) are dissolved in tetrahydrofuran (THF) (10mL).Stirring at room temperature 10 hours.Decompression revolves desolventizing, silica column purification, uses petrol ether/ethyl acetate wash-out (V/V=3/1).Obtain (R)-4-benzyl-6-bromo-3-ethyl-3,4-dihydro-quinoxaline-2 (1H)-one 0.93g, transparent oily liquid, productive rate 80.9%.
1HNMR(300MHz，DMSO)：δ10.56(s，1H)，7.35-7.25(m，5H)，6.77(ddd，J＝23.7，15.0，5.0Hz，3H)，4.69(d，J＝15.6Hz，1H)，4.36(d，J＝15.6Hz，1H)，3.78(dd，J＝7.4，5.4Hz，1H)，1.56(m，2H)，0.81(t，J＝7.5Hz，3H)。
E) the bromo-3-ethyl-3 of (R)-4-benzyl-6-; 4-dihydro-quinoxaline-2 (1H)-one (0.31g; 0.9mmol); 3; 5-dimethyl isoxazole-4-pinacol borate (0.20g; 0.9mmol); sodium carbonate (0.26g; 2.7mmol) with tetra-triphenylphosphine palladium (0.10g; 0.1mmol) water-soluble (3mL), ethanol (1mL), in the mixed solvent of toluene (3mL); nitrogen protection, heating reflux reaction 12 hours.Extraction into ethyl acetate, anhydrous sodium sulfate drying.Decompression is spin-dried for solvent, silica column purification, use petrol ether/ethyl acetate wash-out (V/V=3/1), obtain (R)-4-benzyl-6-(3,5-dimethyl isoxazole)-3-ethyl-3,4-dihydro-quinoxaline-2 (1H)-one, faint yellow solid 0.19g, productive rate 58.5%.MS(ES)：m/z361.2[M+H]
+；
1HNMR(300MHz，DMSO)：δ10.54(s，1H)，7.33(d，J＝4.3Hz，4H)，7.27-7.16(m，1H)，6.85(d，J＝7.9Hz，1H)，6.62(d，J＝7.9Hz，1H)，6.43(s，1H)，4.67(d，J＝15.7Hz，1H)，4.44(d，J＝15.7Hz，1H)，3.92-3.85(m，1H)，2.10(s，3H)，1.93(s，3H)，1.73-1.61(m，1H)，1.59-1.48(m，1H)，0.85(t，J＝7.5Hz，3H).
Lower 9 row compounds are prepared according to the method identical with preparing embodiment 1:
Embodiment 11:
Synthetic route is:
With reference to method implementation step a, b, c, e and f of preparing embodiment 1.The concrete steps of steps d are: under condition of ice bath, add hydrogenation in batches receive (0.3g, 12.6mmol) to DMF (4mL), stir 5 minutes.Add (R)-6-bromo-3-methyl-3,4-dihydro-quinoxaline-2 (1H)-one (1.52g, 6.3mmol), stir 20 minutes.Drip methyl iodide (1.34g, 9,5mmol), react 4 hours.Add water cancellation, extraction into ethyl acetate, anhydrous sodium sulfate drying.Decompression revolves desolventizing, silica column purification, uses petrol ether/ethyl acetate wash-out (V/V=3/1), obtains bromo-1,3-dimethyl-3,4-dihydro-quinoxaline-2 (1H) the-one 1.21g of (R)-6-, light yellow solid, productive rate 75.2%.
1HNMR(300MHz，DMSO)：δ6.89-6.86(m，2H)，6.36(s，1H)，3.85(q，J＝6.6Hz，1H)，3.21(s，3H)，1.25(d，J＝6.6Hz，3H).
Final obtained compound (R)-6-(3,5-dimethyl isoxazole-4-base)-4-(4-methoxybenzyl)-1,3-dimethyl-3,4-dihydro-quinoxaline-2 (1H)-one, faint yellow solid, productive rate is 68.8%.MS(ES)：m/z391.2[M+H]
+；
1HNMR(300MHz，DMSO)δ7.29(d，J＝8.3Hz，2H)，7.12(d，J＝8.1Hz，2H)，6.90(d，J＝8.3Hz，2H)，6.81(d，J＝7.4Hz，1H)，6.56(s，1H)，4.50(d，J＝14.7Hz，1H)，4.24(d，J＝14.7Hz，1H)，4.06-4.01(m，1H)，3.72(s，3H)，3.33(s，3H)，2.18(s，3H)，2.01(s，3H)，1.04(d，J＝7.0Hz，3H).
Embodiment 12:
Synthetic route is:
With reference to method implementation step a, b, c, d and g of preparing embodiment 1.The concrete steps of step e, f are:
E) (R)-4-benzyl-6-bromo-3-methyl-3,4-dihydro-quinoxaline-2 (1H)-one (0.62g, 1.9mmol) dissolves in phosphorus oxychloride (3mL), is heated to 50 DEG C, reacts 4 hours.Add water, extraction into ethyl acetate, dry.Decompression is spin-dried for solvent, silica column purification, uses petrol ether/ethyl acetate wash-out (V/V=40/1), obtains the bromo-3-of 1-benzyl-7-chloro-2-methylene radical-1,2-dihydro-quinoxaline 0.35g, yellow solid, productive rate 53.8%.
1HNMR(300MHz，DMSO)：δ7.37(t，J＝7.3Hz，2H)，7.32-7.23(m，2H)，7.19(d，J＝7.3Hz，2H)，7.14-7.02(m，2H)，5.00(s，2H)，4.77(d，J＝2.9Hz，1H)，4.28(d，J＝2.9Hz，1H)。
F) 1-benzyl-7-bromo-3-chloro-2-methylene radical-1,2-dihydro-quinoxaline (0.32g, 0.9mmol) and sodium azide (0.07g, 1.1mmol) are dissolved in acetic acid (4mL), reflux 8 hours.Saturated sodium carbonate solution adjusts pH to neutral, and extraction into ethyl acetate is dry.Decompression is spin-dried for solvent, obtains 5-benzyl-7-bromo-4-methylene radical-4,5-dihydro tetrazole [1,5-a] quinoxaline 0.14g, light tan solid, productive rate 42.9%.
1HNMR(300MHz，DMSO)：δ7.94(d，J＝8.3Hz，1H)，7.43-7.19(m，7H)，5.22(d，J＝2.4Hz，1H)，5.18(s，2H)，4.58(d，J＝2.4Hz，1H)。
Final obtained compound 4-(5-benzyl-4-methylene radical-4,5-dihydro tetrazole [1,5-a] quinoxaline-7-base)-3,5-dimethyl isoxazoles, faint yellow solid, productive rate 40.9%.MS(ES)：m/z370.2[M+H]
+；
1HNMR(300MHz，DMSO)δ8.08(d，J＝8.2Hz，1H)，7.36(d，J＝4.4Hz，4H)，7.31-7.23(m，1H)，7.13(dd，J＝8.2，1.5Hz，1H)，6.95(d，J＝1.4Hz，1H)，5.24(d，J＝2.4Hz，1H)，5.21(s，2H)，4.70(d，J＝2.4Hz，1H)，2.18(s，3H)，1.99(s，3H).
Embodiment 13
Tablet containing compound 1:
According to a conventional method supplementary material is mixed, granulate, dry, compressing tablet.
Claims (5)
1. the compound shown in claim general formula (I) and pharmacologically acceptable salt thereof:
Wherein R
1be selected from: cycloalkyl, aromatic heterocyclic, substituted or unsubstituted aromatic base, substituted or unsubstituted benzyl;
Wherein R
2be selected from: H, alkyl, alkoxyl group, substituted or unsubstituted aromatic base, substituted or unsubstituted benzyl, cycloalkyl or hydroxyl;
Wherein R
3be selected from: H, methyl or ethyl.
2. the compound of claim 1 can be following arbitrary compound or pharmaceutically acceptable salt thereof:
(R)-4-benzyl-6-(3,5-dimethyl isoxazole-4-base)-3-ethyl-3,4-dihydro-quinoxaline-2 (1H)-one;
(R)-6-(3,5-dimethyl isoxazole-4-base)-4-(4-methoxybenzyl)-3-methyl-3,4-dihydro-quinoxaline-2 (1H)-one;
(R)-4-(4-methoxybenzyl)-6-(3,5-dimethyl isoxazole-4-base)-3-methyl-3,4-dihydro-quinoxaline-2 (1H)-one;
(R)-4-cyclopentyl-6-(3,5-dimethyl isoxazole-4-base)-3-methyl-3,4-dihydro-quinoxaline-2 (1H)-one;
(R)-4-cyclohexyl-6-(3,5-dimethyl isoxazole-4-base)-3-methyl-3,4-dihydro-quinoxaline-2 (1H)-one;
(S)-6-(3,5-dimethyl isoxazole-4-base)-4-(4-methoxybenzyl)-3-methyl-3,4-dihydro-quinoxaline-2 (1H)-one;
(S)-4-cyclopentyl-6-(3,5-dimethyl isoxazole-4-base)-3-methyl-3,4-dihydro-quinoxaline-2 (1H)-one;
1 '-benzyl-7 '-(3,5-dimethyl isoxazole-4-base)-1 ', 4 '-dihydro-3 ' and H-spiral shell [pentamethylene-1,2 '-quinoxaline]-3 '-one;
4-(4-chlorobenzyl)-6-(3,5-dimethyl isoxazole-4-base)-3,4-dihydro-quinoxaline-2 (1H)-one;
(R)-3,4-dibenzyl-6-(3,5-dimethyl isoxazole-4-base)-3,4-dihydro-quinoxaline-2 (1H)-one;
(R)-6-(3,5-dimethyl isoxazole-4-base)-4-(4-methoxybenzyl)-1,3-dimethyl-3,4-dihydro-quinoxaline-2 (1H)-one;
4-(5-benzyl-4-methylene radical-4,5-dihydro tetrazole [1,5-a] quinoxaline-7-base)-3,5-dimethyl isoxazoles.
3. the preparation method of the compound of claim 1-2, is prepared by following methods:
Wherein R
1be selected from: cycloalkyl, aromatic heterocyclic, substituted or unsubstituted aromatic base, substituted or unsubstituted benzyl;
Wherein R
2be selected from: H, alkyl, alkoxyl group, substituted or unsubstituted aromatic base, substituted or unsubstituted benzyl, cycloalkyl or hydroxyl;
Wherein R
3be selected from: H, methyl or ethyl.
4. the research of quinoxalinone derivatives shown in general formula (I) according to any one of claim 1-2 or its pharmacy acceptable salt are in preparation treatment and the purposes in the medicine of Bromodomain domain protein relative disease.
5. a pharmaceutical composition, is characterized in that, the research of quinoxalinone derivatives shown in general formula (I) described in right 1-2 any one containing treatment significant quantity or its pharmacy acceptable salt, and pharmaceutically acceptable auxiliary material.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108078822A (en) * | 2018-01-17 | 2018-05-29 | 山东大学 | A kind of morning-night special type toothpaste |
| CN110092782A (en) * | 2018-01-30 | 2019-08-06 | 中国科学院广州生物医药与健康研究院 | A kind of benzo six-membered heterocycle compound and its preparation method and application |
| JP2021512960A (en) * | 2018-02-06 | 2021-05-20 | シャンハイ ハイファ ファーマシューティカル カンパニー，リミティッド | Compounds with BET inhibitory activity and methods and uses thereof |
| CN113402515A (en) * | 2021-05-12 | 2021-09-17 | 四川大学华西医院 | Indole compound and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015002754A2 (en) * | 2013-06-21 | 2015-01-08 | Zenith Epigenetics Corp. | Novel bicyclic bromodomain inhibitors |
| WO2015104653A1 (en) * | 2014-01-09 | 2015-07-16 | Aurigene Discovery Technologies Limited | Bicyclic heterocyclic derivatives as bromodomain inhibitors |
| CN104995190A (en) * | 2012-12-20 | 2015-10-21 | 拜耳医药股份有限公司 | Bet-protein-inhibiting dihydroquinoxalinones |
-
2015
- 2015-11-06 CN CN201510759801.0A patent/CN105198871A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104995190A (en) * | 2012-12-20 | 2015-10-21 | 拜耳医药股份有限公司 | Bet-protein-inhibiting dihydroquinoxalinones |
| WO2015002754A2 (en) * | 2013-06-21 | 2015-01-08 | Zenith Epigenetics Corp. | Novel bicyclic bromodomain inhibitors |
| WO2015104653A1 (en) * | 2014-01-09 | 2015-07-16 | Aurigene Discovery Technologies Limited | Bicyclic heterocyclic derivatives as bromodomain inhibitors |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108078822A (en) * | 2018-01-17 | 2018-05-29 | 山东大学 | A kind of morning-night special type toothpaste |
| CN108078822B (en) * | 2018-01-17 | 2020-06-26 | 山东大学 | Special white and black toothpaste |
| CN110092782A (en) * | 2018-01-30 | 2019-08-06 | 中国科学院广州生物医药与健康研究院 | A kind of benzo six-membered heterocycle compound and its preparation method and application |
| JP2021512960A (en) * | 2018-02-06 | 2021-05-20 | シャンハイ ハイファ ファーマシューティカル カンパニー，リミティッド | Compounds with BET inhibitory activity and methods and uses thereof |
| CN113402515A (en) * | 2021-05-12 | 2021-09-17 | 四川大学华西医院 | Indole compound and preparation method and application thereof |
| CN113402515B (en) * | 2021-05-12 | 2022-05-27 | 四川大学华西医院 | Indole compound and preparation method and application thereof |
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