CN107721975A - BRD4 micromolecular inhibitors, synthetic method and its application with antitumor activity - Google Patents

BRD4 micromolecular inhibitors, synthetic method and its application with antitumor activity Download PDF

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CN107721975A
CN107721975A CN201711117562.4A CN201711117562A CN107721975A CN 107721975 A CN107721975 A CN 107721975A CN 201711117562 A CN201711117562 A CN 201711117562A CN 107721975 A CN107721975 A CN 107721975A
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brd4
dmso
nmr
micromolecular inhibitors
antitumor activity
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姚志艺
杨燕
夏晓明
舒启胜
薛楠楠
王庆宣
王东升
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Shanghai Institute of Technology
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Shanghai Institute of Technology
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
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    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Abstract

The invention belongs to field of pharmaceutical chemistry technology, specially a kind of BRD4 micromolecular inhibitors, synthetic method and its application with antitumor activity.The structural formula of the BRD4 micromolecular inhibitors of the present invention is represented with formula (I)：

Description

BRD4 micromolecular inhibitors, synthetic method and its application with antitumor activity
Technical field
The present invention relates to a kind of BRD4 micromolecular inhibitors, synthetic method and its application with antitumor activity, belong to Field of pharmaceutical chemistry technology.
Background technology
With the continuous development of medicine and pharmacology, treatment of the people for many diseases achieves achievement obvious to all.Cancer These diseases, nowadays it is a great problem for perplexing medical field.Research for antineoplastic is carried out in high gear.In recent years Come, clinically nearly 70 kinds conventional of antineoplastic, and due to its considerable prospect, in the antitumor of clinical experimental stage New drug has kind more than 300.Antineoplastic quantity is various, but preferably antineoplastic is rare.With to antineoplastic not Disconnected research and the rapid development of oncobiology, people gradually recognize the unlimited hyperplasia of cell.Focus is researched and developed also from traditional thin The special numerous targeting links during being directed to tumor development of cytotoxic drug.These target spot new drugs are directed to normal cell and tumour The difference of cell, can overcome that the poor selectivity of conventional cell cytotoxic drug, toxic side effect are strong, are also easy to produce the shortcomings of drug resistance, can Reach high selectivity and the therapeutic effect of hypotoxicity.
The content of the invention
For overcome the deficiencies in the prior art, the invention provides a kind of new amide-type with targeting anti-tumor activity Medicines structure, and with bromine domain protein 4 be the synthetic method of the compound for having bioactivity that target spot is screened and its Using.
Technical scheme is specifically described as follows.
The present invention provides the BRD4 micromolecular inhibitors with antitumor activity, and it has the structure shown in formula (I)：
Wherein：
R1、R2、R3It is any in halogen, hydrogen, alkoxy, aromatic radical or heterocycle；
R4Aryl, furans ring group, thiazolyl, triazol radical, piperazinyl or thienyl selected from unsubstituted either substitution, Substituent is monosubstituted, two substitutions or three substitutions.
In the present invention, R1、R2And R3Independently selected from halogen, hydrogen or C1~C14Any one in alkoxy.
In the present invention, R1、R2And R3It is any in methoxyl group or hydrogen.
In the present invention, R4Substituent is independently selected from halogen, nitro, amino, methoxyl group, alkyl, methoxy acyl group, ethoxy acyl One kind in base, acetamido or para hydroxybenzene.
The present invention also provides a kind of synthetic method of the above-mentioned BRD4 micromolecular inhibitors with antitumor activity, specific step It is rapid as follows：
Step 1：3,4,5- trimethoxybenzoic acids derivative and thionyl chloride reaction generation 3,4,5- trimethoxy-benzene first Chloride derivative 2a-2c；
Step 2：3,4,5- trimethoxy-benzoyl chlorides derivative 2a-2c) heterocycle reacts generation target in the basic conditions Compound 3a-3v；The chemical equation that it is synthesized is as follows：
In the present invention, in step 1,3,4,5- trimethoxybenzoic acid derivative equivalents are 1, and thionyl chloride equivalent is 4, Solvent is dry dichloromethane, is flowed back 2~5 hours；In step 2, acyl chlorides is added dropwise in ice bath, and heterocycle equivalent is 1, acid chloride equivalent weight For 1.5, solvent is dry dichloromethane, and alkali is selected from TEA or DIPEA one kind.
Further, the present invention provides a kind of above-mentioned BRD4 with antitumor activity inhibitor and treated, in advance in preparation Application in the antineoplastic of preventing tumor.Preferably, antineoplastic is treatment or prevention breast cancer, leukaemia or multiple The medicine of the diseases such as myeloma.
Compared to the prior art, it is the device have the advantages that as follows：Synthetic method of the present invention is simple, there is provided BRD4 Micromolecular inhibitor structure is novel, and part of compounds inhibitory activity is good, and antitumor activity can be good.
Embodiment
The BRD4 micromolecular inhibitors of the present invention are described further with reference to some embodiments, but this hair Bright protection domain is not limited to that.
Embodiment 1
100ml single port bottles are taken, sequentially add the 2- amino thiophenes of 10ml anhydrous methylene chlorides, 0.22g triethylamine and 0.10g Fen -3- carboxylate methyl esters, are stirred to dissolve, and the dichloromethane dissolved with the trimethoxy-benzoyl chlorides of 0.19g 3,4,5- is added dropwise under ice bath Alkane solution, room temperature magnetic stirrer over night.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration. Column chromatography obtains target compound 3a 0.11g (49%).1H NMR(500MHz,DMSO)δ11.63(s,1H),7.27–7.21(m, 3H), 7.11 (d, J=5.7Hz, 1H), 3.89 (s, 9H), 3.77 (s, 3H)13C NMR(125MHz,DMSO)δ165.58, 163.05,153.57,148.49,141.94,127.52,124.21,117.84,113.59,105.28,60.69,56.58, 52.46,40.35,40.19,40.02,39.85,39.69.HRMS(ESI):m/z calcd for C16H17NO6S[M+H]+ 352.0849；found 352.0848
Embodiment 2
100ml single port bottles are taken, sequentially add the 2- furans first of 10ml anhydrous methylene chlorides, 0.31g triethylamine and 0.10g Amine, it is stirred to dissolve, the dichloromethane solution dissolved with the trimethoxy-benzoyl chlorides of 0.36g 3,4,5-, room temperature is added dropwise under ice bath Magnetic stirrer over night.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration.Column chromatography obtains mesh Mark compound 3b 0.09g (30%).1H NMR (500MHz, DMSO) δ 8.93 (t, J=5.0Hz, 1H), 7.58 (s, 1H), 7.23 (s, 2H), 6.40 (s, 1H), 6.28 (s, 1H), 4.47 (d, J=5.4Hz, 2H), 3.82 (s, 6H), 3.70 (s, 3H) .13CNMR(125MHz,DMSO)δ165.88,153.04,152.91,142.50,129.69,110.95,107.42,105.33, 60.51,56.43,40.31,40.14,39.98,39.81,39.64,36.54.HRMS(ESI):m/z calcd for C15H17NO5[M+H]+292.1179；found 292.1192
Embodiment 3
100ml single port bottles are taken, sequentially add the 2- amino thiophenes of 10ml anhydrous methylene chlorides, 0.18g triethylamine and 0.10g Fen -3- carboxylic acid, ethyl esters, are stirred to dissolve, and the dichloromethane dissolved with the trimethoxy-benzoyl chlorides of 0.20g 3,4,5- is added dropwise under ice bath Alkane solution, room temperature magnetic stirrer over night.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration. Column chromatography obtains target compound 3c 0.10g (46%).1H NMR (500MHz, DMSO) δ 11.63 (s, 1H), 7.24 (d, J= 6.1Hz, 3H), 7.10 (d, J=5.7Hz, 1H), 4.35 (q, J=7.1Hz, 2H), 3.89 (s, 6H), 3.77 (s, 3H), 1.35- 1.30(m,3H).13C NMR(125MHz,DMSO)δ161.21,158.55,148.69,144.47,137.30,122.63, 119.21,111.38,108.58,100.18,72.56,72.31,72.05,56.21,56.04,51.62,9.62.HRMS (ESI):m/zcalcd for C17H19NO6S[M+H]+366.1006；found 366.1003
Embodiment 4
100ml single port bottles are taken, sequentially add the 2- amino thiophenes of 10ml anhydrous methylene chlorides, 0.19g triethylamine and 0.10g Azoles -4- methyl formates, are stirred to dissolve, and the dichloromethane dissolved with the trimethoxy-benzoyl chlorides of 0.22g 3,4,5- is added dropwise under ice bath Alkane solution, room temperature magnetic stirrer over night.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration. Column chromatography obtains target compound 3d 0.04g (16%).1H NMR(500MHz,DMSO)δ12.95(s,1H),8.11(s,1H), 7.51 (s, 2H), 3.86 (d, J=14.0Hz, 6H), 3.81 (d, J=15.4Hz, 3H), 3.74 (d, J=8.5Hz, 3H) .13CNMR(125MHz,DMSO)δ165.16,161.96,159.38,153.26,141.77,141.32,139.91,126.71, 123.57,106.26,60.59,56.58,52.32,40.48,40.31,40.15,39.98,39.81,39.65, 39.48.HRMS(ESI):m/z calcd for C15H16N2O6S[M+H]+353.0802；found 353.0800
Embodiment 5
100ml single port bottles are taken, sequentially add the 2- amino thiophenes of 10ml anhydrous methylene chlorides, 0.18g triethylamine and 0.10g Azoles -4- Ethyl formates, are stirred to dissolve, and the dichloromethane dissolved with the trimethoxy-benzoyl chlorides of 0.20g 3,4,5- is added dropwise under ice bath Alkane solution, room temperature magnetic stirrer over night.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration. Column chromatography obtains target compound 3e 0.06g (28%).1H NMR(500MHz,DMSO)δ12.94(s,1H),8.11(s,1H), 7.52 (s, 2H), 4.30 (q, J=7.1Hz, 2H), 3.88 (s, 6H), 3.75 (s, 3H), 1.31 (t, J=7.1Hz, 3H) .13CNMR(125MHz,DMSO)δ165.22,161.57,159.37,153.27,126.74,123.55,106.31,61.10, 60.61,56.60,40.52,40.36,40.19,40.02,39.86,39.69,39.53,14.68.HRMS(ESI):m/z calcd forC16H18N2O6S[M+H]+367.0958；found 367.0955
Embodiment 6
100ml single port bottles are taken, sequentially add amino second between 10ml anhydrous methylene chlorides, 0.20g triethylamine and 0.10g Anilide, it is stirred to dissolve, the dichloromethane solution dissolved with the trimethoxy-benzoyl chlorides of 0.23g 3,4,5- is added dropwise under ice bath, Room temperature magnetic stirrer over night.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration.Column chromatography Obtain target compound 3f 0.05g (21%).1H NMR(500MHz,DMSO)δ12.77(s,1H),8.11(s,1H),7.79(d, J=4.7Hz, 1H), 7.78 (d, J=3.3Hz, 1H), 7.77 (s, 1H), 7.11 (d, J=5.9Hz, 1H), 7.10 (s, 1H), 6.89 (d, J=8.6Hz, 1H), 3.85 (d, J=3.3Hz, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.80-3.75 (m, 3H).13C NMR(125MHz,CDCl3)δ169.22,166.09,153.11,141.11,138.57,130.05,129.31, 116.61,116.14,112.60,104.81,77.31,77.06,76.80,60.90,56.27,24.29.HRMS(ESI):m/z calcd forC18H20N2O5[M+H]+345.1444；found 345.1440
Embodiment 7
100ml single port bottles are taken, sequentially add 4- (the 1- piperazines of 10ml anhydrous methylene chlorides, 0.17g triethylamine and 0.1g Base) phenol, it is stirred to dissolve, dropwise addition is molten dissolved with the dichloromethane of the trimethoxy-benzoyl chlorides of 0.19g 3,4,5- under ice bath Liquid, it is stirred overnight at room temperature.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration.Column chromatography obtains Target compound 3g 0.07g (34%).1H NMR (500MHz, DMSO) δ 8.89 (s, 1H), 6.81 (d, J=8.8Hz, 2H), 6.70 (s, 2H), 6.66 (d, J=8.8Hz, 2H), 3.79 (s, 6H), 3.69 (s, 4H), 3.34 (s, 3H), 2.97 (s, 4H)13C NMR(125MHz,DMSO)δ169.13,153.29,151.87,144.38,138.83,131.75,118.97,115.97, 105.00,60.53,56.54,50.92,40.51,40.34,40.18,40.01,39.84,39.67,39.51.HRMS(ESI): m/zcalcd for C20H24N2O5[M+H]+373.1758；found 373.1797
Embodiment 8
100ml single port bottles are taken, sequentially add the fluoro- 5- ammonia of 2- of 10ml anhydrous methylene chlorides, 0.27g triethylamine and 0.1g Yl pyridines, it is stirred to dissolve, the dichloromethane solution dissolved with the trimethoxy-benzoyl chlorides of 0.31g 3,4,5- is added dropwise under ice bath, It is stirred overnight at room temperature.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration.Column chromatography obtains mesh Mark compound 3h 0.14g (51%).1H NMR(500MHz,DMSO)δ10.42(s,1H),8.55(s,1H),8.34–8.21 (m, 1H), 7.29 (s, 2H), 7.25-7.20 (m, 1H), 3.87 (s, 6H), 3.73 (d, J=8.0Hz, 3H)13C NMR (125MHz,DMSO)δ165.62,160.29,158.44,153.16,139.72,139.60,134.71,134.65,134.48, 129.66,109.86,109.54,105.88,60.61,56.61,40.48,40.31,40.15,39.98,39.81,39.65, 39.48.HRMS(ESI):m/z calcd for C15H15FN2O4[M+H]+307.1088；found 307.1100
Embodiment 9
100ml single port bottles are taken, sequentially add the 2- furans first of 10ml anhydrous methylene chlorides, 0.31g triethylamine and 0.1g Amine, it is stirred to dissolve, is added dropwise under ice bath and is stirred dissolved with 0.31g 3, the dichloromethane solution of 5- dimethoxy-benzoyl chlorides, room temperature Mix overnight.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration.Column chromatography obtains target chemical combination Thing 3i 0.03g (23%).1H NMR(500MHz,CDCl3) δ 7.38 (s, 1H), 6.91 (d, J=2.1Hz, 2H), 6.58 (d, J =2.1Hz, 1H), 6.47 (s, 1H), 6.37-6.32 (m, 1H), 6.30 (d, J=2.9Hz, 1H), 4.62 (d, J=5.4Hz, 2H),3.81(s,6H).13C NMR(125MHz,CDCl3)δ167.18,160.83,151.26,142.21,136.37, 110.48,107.61,105.01,103.73,77.38,77.12,76.87,55.50,37.01.HRMS(ESI):m/z calcd forC14H15NO4[M+H]+262.1074；found 262.1083
Embodiment 10
100ml single port bottles are taken, sequentially add the 2- amino thiophenes of 10ml anhydrous methylene chlorides, 0.19g triethylamine and 0.10g Azoles -4- methyl formates, are stirred to dissolve, and are added dropwise under ice bath dissolved with 0.19g 3, the dichloromethane of 5- dimethoxy-benzoyl chlorides Solution, it is stirred overnight at room temperature.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration.Column chromatography Obtain target compound 3j 0.03g (15%).1H NMR (500MHz, DMSO) δ 8.93 (t, J=5.0Hz, 1H), 7.58 (s, 1H), 7.23 (s, 2H), 6.40 (s, 1H), 6.28 (s, 1H), 4.47 (d, J=5.4Hz, 2H), 3.82 (s, 6H), 3.70 (s, 3H).13C NMR(125MHz,DMSO)δ165.42,161.94,160.97,159.21,141.34,133.81,123.64, 106.29,105.78,56.01,52.31,40.48,40.31,40.14,39.98,39.81,39.64,39.47.HRMS (ESI):m/z calcdfor C14H14N2O5S[M+H]+323.0696；found 323.0707
Embodiment 11
100ml single port bottles are taken, sequentially add the 2- amino thiophenes of 10ml anhydrous methylene chlorides, 0.17g triethylamine and 0.10g Azoles -4- Ethyl formates, are stirred to dissolve, and are added dropwise under ice bath dissolved with 0.17g 3, the dichloromethane of 5- dimethoxy-benzoyl chlorides Solution, it is stirred overnight at room temperature.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration.Column chromatography Obtain target compound 3k 0.04g (23%).1H NMR(500MHz,DMSO)δ13.06(s,1H),8.17(s,1H),7.37(d, J=2.2Hz, 2H), 6.79 (t, J=2.1Hz, 1H), 4.34 (q, J=7.1Hz, 2H), 3.86 (s, 6H), 1.37-1.29 (m, 3H).13C NMR(125MHz,DMSO)δ165.46,161.55,160.95,159.20,141.66,133.82,123.60, 106.29,105.76,61.11,56.01,40.43,40.26,40.09,39.93,39.76,39.59,39.43, 14.65.HRMS(ESI):m/z calcd for C15H16N2O5S[M+H]+337.0853；found 337.0854
Embodiment 12
100ml single port bottles are taken, sequentially add the 3- amino second of 10ml anhydrous methylene chlorides, 0.20g triethylamine and 0.10g Anilide, it is stirred to dissolve, is added dropwise under ice bath dissolved with 0.20g 3, the dichloromethane solution of 5- dimethoxy-benzoyl chlorides, room Temperature is stirred overnight.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration.Column chromatography obtains target Compound 3l 0.1g (50%).1H NMR(500MHz,DMSO)δ10.20(s,1H),9.98(s,1H),8.07(s,1H), 7.41 (d, J=8.0Hz, 1H), 7.34 (d, J=8.1Hz, 1H), 7.24 (dd, J=15.8,7.8Hz, 1H), 7.08 (dd, J= 19.5,2.2Hz,2H),6.71(s,1H),3.82(s,6H),2.05(s,3H).13C NMR(125MHz,DMSO)δ168.74, 165.50,160.81,139.96,139.69,129.06,116.03,115.19,112.11,106.15,103.77,55.95, 40.32,40.16,39.99,39.82,39.66,24.46.HRMS(ESI):m/z calcd for C17H18N2O4[M+H]+ 315.1339；found 315.1336
Embodiment 13
100ml single port bottles are taken, sequentially add the para hydroxybenzene of 10ml anhydrous methylene chlorides, 0.17g triethylamine and 0.1g Base piperazine, is stirred to dissolve, and is added dropwise under ice bath dissolved with 0.16g 3, the dichloromethane solution of 5- dimethoxy-benzoyl chlorides, room Temperature is stirred overnight.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration.Column chromatography obtains target Compound 3m 0.07g (36%).1H NMR (500MHz, DMSO) δ 8.89 (s, 1H), 6.80 (d, J=8.8Hz, 2H), 6.66 (d, J=8.8Hz, 2H), 6.54 (dd, J=20.0,2.1Hz, 3H), 3.86-3.61 (m, 8H), 3.39 (d, J=32.6Hz, 2H), 2.96 (d, J=46.5Hz, 4H)13C NMR(125MHz,DMSO)δ168.93,160.91,151.89,144.36, 138.50,119.00,115.97,105.15,101.63,55.88,50.81,40.37,40.20,40.03,39.87, 39.70.HRMS(ESI):m/z calcd for C19H22N2O4[M+H]+343.1652；found 343.1657
Embodiment 14
100ml single port bottles are taken, sequentially add the 2- amino thiophenes of 10ml anhydrous methylene chlorides, 0.19g triethylamine and 0.1g Fen -3- carboxylate methyl esters, are stirred to dissolve, and are added dropwise under ice bath dissolved with 0.19g 3, the dichloromethane of 4- dimethoxy-benzoyl chlorides Solution, it is stirred overnight at room temperature.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration.Column chromatography Obtain target compound 3n 0.03g (15%).1H NMR(500MHz,CDCl3) δ 11.96 (s, 1H), 7.65 (d, J=1.6Hz, 1H), 7.60 (d, J=8.3Hz, 1H), 7.26 (d, J=5.8Hz, 1H), 6.97 (d, J=8.4Hz, 1H), 6.78 (d, J= 5.7Hz, 1H), 3.99 (d, J=4.4Hz, 3H), 3.97 (s, 3H), 3.94 (s, 3H)13C NMR(125MHz,CDCl3)δ 166.43,163.26,152.87,149.71,149.37,124.71,123.78,120.27,116.08,112.62,110.94, 110.66,77.31,77.06,76.80,56.09,56.06,51.76.HRMS(ESI):m/z calcd for C15H15NO5S[M +H]+322.0743；found 322.0754
Embodiment 15
100ml single port bottles are taken, sequentially add the 2- furans first of 10ml anhydrous methylene chlorides, 0.31g triethylamine and 0.1g Amine, it is stirred to dissolve, is added dropwise under ice bath and is stirred dissolved with 0.31g 3, the dichloromethane solution of 4- dimethoxy-benzoyl chlorides, room temperature Mix overnight.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration.Column chromatography obtains target chemical combination Thing 3o 0.13g (50%).1H NMR (500MHz, DMSO) δ 8.84 (s, 1H), 7.51 (dd, J=30.6,22.2Hz, 3H), 7.01 (d, J=8.3Hz, 1H), 6.39 (s, 1H), 6.26 (s, 1H), 4.45 (d, J=5.3Hz, 2H), 3.79 (s, 6H) .13CNMR(125MHz,CDCl3)δ166.83,151.88,151.39,149.03,142.26,126.82,119.44,110.74, 110.52,110.28,107.65,77.30,77.05,76.79,56.03,56.01,37.03.HRMS(ESI):m/z calcd forC14H15NO4[M+H]+262.1074；found 262.1082
Embodiment 16
100ml single port bottles are taken, sequentially add the 2- amino thiophenes of 10ml anhydrous methylene chlorides, 0.17g triethylamine and 0.1g Fen -3- Ethyl formates, are stirred to dissolve, and are added dropwise under ice bath dissolved with 0.17g 3, the dichloromethane of 4- dimethoxy-benzoyl chlorides Solution, it is stirred overnight at room temperature.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration.Column chromatography Obtain target compound 3p 0.07g (36%).1H NMR (500MHz, DMSO) δ 11.71 (s, 1H), 7.51 (dd, J=11.2, 2.6Hz, 2H), 7.21 (dd, J=15.5,7.0Hz, 2H), 7.07 (d, J=5.7Hz, 1H), 4.36 (q, J=7.1Hz, 2H), 3.86 (d, J=3.1Hz, 6H), 1.33 (dd, J=18.4,11.4Hz, 3H)13C NMR(125MHz,CDCl3)δ166.07, 163.31,152.85,149.56,149.39,123.91,120.26,115.97,113.02,111.00,110.66,77.27, 77.02,76.77,60.78,56.11,56.08,14.38.HRMS(ESI):m/z calcd for C16H17NO5S[M+H]+ 336.0900；found 336.0903
Embodiment 17
100ml single port bottles are taken, sequentially add the 2- amino thiophenes of 10ml anhydrous methylene chlorides, 0.19g triethylamine and 0.1g Azoles -4- methyl formates, are stirred to dissolve, and are added dropwise under ice bath dissolved with 0.19g 3, the dichloromethane of 4- dimethoxy-benzoyl chlorides Solution, it is stirred overnight at room temperature.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration.Column chromatography Obtain target compound 3q 0.05 (25%).1H NMR(500MHz,DMSO)δ12.84(s,1H),8.09(s,1H),7.88– 7.67 (m, 2H), 7.10 (d, J=8.4Hz, 1H), 3.91-3.76 (m, 9H)13C NMR(125MHz,DMSO)δ165.27, 161.99,159.48,153.11,148.91,141.27,123.91,123.45,122.68,111.68,111.53,56.18, 56.14,52.30,40.49,40.33,40.16,39.99,39.83,39.66,39.49.HRMS(ESI):m/z calcd forC14H14N2O5S[M+H]+323.0696；found 323.0694
Embodiment 18
100ml single port bottles are taken, sequentially add the 2- amino thiophenes of 10ml anhydrous methylene chlorides, 0.18g triethylamine and 0.1g Azoles -4- Ethyl formates, are stirred to dissolve, and are added dropwise under ice bath dissolved with 0.17g 3, the dichloromethane of 4- dimethoxy-benzoyl chlorides Solution, it is stirred overnight at room temperature.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration.Column chromatography Obtain target compound 3r 0.04g (20%).1H NMR(500MHz,DMSO)δ12.75(s,1H),8.09(s,1H),7.79 (dd, J=11.1,2.6Hz, 2H), 7.10 (d, J=8.4Hz, 1H), 4.29 (q, J=7.1Hz, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 1.30 (t, J=7.1Hz, 3H)13C NMR(125MHz,DMSO)δ165.31,161.60,159.45,153.09, 148.88,141.59,123.91,123.40,122.69,111.69,111.54,61.08,56.19,56.14,40.47, 40.30,40.14,39.97,39.80,39.64,39.47,14.67.HRMS(ESI):m/z calcd for C15H16N2O5S[M +H]+337.0853；found 337.0854
Embodiment 19
100ml single port bottles are taken, sequentially add the 3- amino second of 10ml anhydrous methylene chlorides, 0.20g triethylamine and 0.1g Anilide, it is stirred to dissolve, is added dropwise under ice bath dissolved with 0.20g 3, the dichloromethane solution of 4- dimethoxy-benzoyl chlorides, room Temperature is stirred overnight.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration.Column chromatography obtains target Compound 3s 0.11g (52%).1H NMR(500MHz,DMSO)δ10.11(s,1H),10.00(s,1H),8.07(s,1H), 7.63 (d, J=7.3Hz, 1H), 7.54 (s, 1H), 7.42 (d, J=7.8Hz, 1H), 7.32 (d, J=7.9Hz, 1H), 7.24 (t, J=8.0Hz, 1H), 7.07 (d, J=8.4Hz, 1H), 3.84 (d, J=7.6Hz, 6H), 2.05 (s, 3H)13C NMR (125MHz,DMSO)δ168.77,165.39,152.12,148.76,139.94,129.02,127.51,116.08,115.01, 112.18,111.66,111.42,56.15,40.32,40.15,39.99,39.82,39.65,24.46.HRMS(ESI):m/z calcd forC17H18N2O4[M+H]+315.1339；found 315.1335
Embodiment 20
100ml single port bottles are taken, sequentially add the para hydroxybenzene of 10ml anhydrous methylene chlorides, 0.17g triethylamine and 0.1g Base piperazine, is stirred to dissolve, and is added dropwise under ice bath dissolved with 0.17g 3, the dichloromethane solution of 4- dimethoxy-benzoyl chlorides, room Temperature is stirred overnight.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration.Column chromatography obtains target Compound 3t 0.04g (20%).1H NMR (500MHz, DMSO) δ 8.92 (s, 1H), 6.98 (d, J=9.3Hz, 3H), 6.81 (d, J=8.9Hz, 2H), 6.66 (d, J=8.8Hz, 2H), 3.78 (d, J=4.5Hz, 3H), 3.77 (s, 3H), 3.62 (d, J= 5.9Hz,4H),3.06–2.73(m,4H).13C NMR(125MHz,DMSO)δ169.43,151.84,150.34,148.93, 144.39,128.40,120.48,118.96,115.97,111.67,111.54,56.06,50.92,40.29,40.12, 39.95,39.79,39.62.HRMS(ESI):m/z calcd for C19H22N2O4[M+H]+343.1652； found343.1659
Embodiment 21
100ml single port bottles are taken, sequentially add the 3- amino -5- of 10ml anhydrous methylene chlorides, 0.31g triethylamine and 0.1g Methylisoxazole, it is stirred to dissolve, is added dropwise under ice bath molten dissolved with 0.31g 3, the dichloromethane of 4- dimethoxy-benzoyl chlorides Liquid, it is stirred overnight at room temperature.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration.Column chromatography obtains Target compound 3u 0.06g (23%).1H NMR(500MHz,DMSO)δ11.15(s,1H),7.73–7.61(m,2H),7.06 (d, J=8.4Hz, 1H), 6.75 (s, 1H), 3.83 (d, J=4.7Hz, 6H), 2.41 (s, 3H)13C NMR(125MHz,DMSO) δ169.69,165.03,159.33,148.76,122.31,111.61,111.47,97.47,56.11,40.51,40.34, 40.17,40.01,39.84,39.67,39.51,12.58.HRMS(ESI):m/z calcd for C13H14N2O4[M+H]+ 263.1026；found 263.1035
Embodiment 22
100ml single port bottles are taken, sequentially add the fluoro- 5- of 2- of 10ml anhydrous methylene chlorides, 0.27g triethylamine and 0.10g Aminopyridine, it is stirred to dissolve, is added dropwise under ice bath dissolved with 0.27g 3, the dichloromethane solution of 5- dimethoxy-benzoyl chlorides, It is stirred overnight at room temperature.After reaction terminates, water quenching is added to go out, dichloromethane extraction, anhydrous sodium sulfate drying, concentration.Column chromatography obtains mesh Mark compound 3v 0.10g (41%).1H NMR (500MHz, DMSO) δ 8.89 (s, 1H), 6.80 (d, J=8.8Hz, 2H), 6.66 (d, J=8.8Hz, 2H), 6.54 (dd, J=20.0,2.1Hz, 3H), 3.86-3.61 (m, 8H), 3.39 (d, J= 32.6Hz, 2H), 2.96 (d, J=46.5Hz, 4H)13C NMR(125MHz,CDCl3)δ166.01,161.13,139.16, 139.04,136.11,133.76,133.70,133.03,132.91,132.73,109.62,109.31,105.17,104.21, 77.28,77.03,76.78,55.63.HRMS(ESI):m/z calcd for C14H13FN2O3[M+H]+277.0983； found277.0993
Cytoactive biological test is tested
Measuring principle：Compound, which suppresses growth of cancer cells detail, to be measured with through MTT methods.The original of mtt assay Reason is：Yellow Thiazolyl blue may pass through cell membrane and enter intracellular, and the succinate dehydrogenase in living cells mitochondria can allow external source Property MTT be reduced into the royal purple crystallization first a ceremonial jade-ladle, used in libation being deposited in cell, but dead cell is but without this function.Dimethyl sulfoxide (DMSO) is used again Dissolve first a ceremonial jade-ladle, used in libation.At 570nm wavelength, its light absorption value is determined with enzyme-linked immunosorbent assay instrument, obtains living cells quantity indirectly.
Experiment material：MCF-7 (human breast cancer cell), (people is multiple by K562 (human chronic polymorpho nuclear leukemia cells) KMS-1 Property myeloma cell), cultivated respectively with DMEM+10%FBS medium cultures or using 1640+10%FBS.
Test method and interpretation of result：
Experimental group：The medicine (final concentration of 10 of the μ l various concentrations of 190 μ l cell suspensions+10-5-10-10)
Blank control group：200μl PBS
Negative control group：μ l 2%DMSO (final concentration of 0.1%) of DMSO of 190 μ l cell suspensions+10
Positive controls：The compound of the μ l various concentrations of 190 μ l cell suspensions+10
MTT cell viability detecting steps
A) inoculating cell
In 37 DEG C, 5%CO2Under the conditions of, trained with the DMEM containing 10% hyclone, 1% penicillin and streptomysin Support cultured cell line in base.The upper strata culture medium in culture dish is discarded, cell is washed 2 times with PBS, adds pancreatin, be put into training Support in base and digest 1-2min, after cell takes off wall, add new culture medium, gently blow and beat, completely fall off cell, treat cell Enter the new culture mediums of 5ml, gently blow and beat, calculate cell concentration with cell counting, be then inoculated in 96 orifice plates.
B) cell culture
96 orifice plates being inoculated with are positioned over 37 DEG C, 5% CO2It is incubated overnight in incubator, next day cell can be adherent.
C) dosing
The medicine of various concentrations is added according to different experimental designs, every group sets 3~4 multiple holes, and 10 μ l phases are added per hole The medicine of concentration is answered, then 96 orifice plates are put into incubator and continue to cultivate.
D) MTT viability examinations
After being cultivated 24 hours, 48 hours, 72 hours after administration, 10 μ l 5mg/ml MTT is added per hole, after by 96 orifice plates It is positioned in incubator, is taken out after continuing culture 4 hours, the careful supernatant drawn per hole, every hole adds 100 μ l diformazan Base sulfoxide (DMSO) solution, place after being incubated 10min in incubator, concussion 40s or so, be completely dissolved first a ceremonial jade-ladle, used in libation crystal.
E) survey absorbance and calculate IC50Value
96 orifice plates are placed in ELIASA, Detection wavelength is the light absorption value at 570nm.With every 3~4 multiple holes absorbances Its relative inhibition of mean value calculation.The inhibiting rate of leukaemia, calculating half are effectively pressed down according under different pharmaceutical concentration Concentration (IC processed50).Every group of sample will do 3 parallel laboratory tests.
570nm readings, cell survival rate is calculated, IC is calculated according to result50, as a result such as table 1 below.
The structure and activity data (μm ol) of table 1.BRD4 micromolecular inhibitors

Claims (8)

1. the BRD4 micromolecular inhibitors with antitumor activity, it is characterised in that it has the structure shown in formula (I)：
Wherein：
R1、R2And R3It is any in halogen, hydrogen, alkoxy, aromatic radical or heterocycle；
R4Aryl, furans ring group, thiazolyl, triazol radical, piperazinyl or thienyl selected from unsubstituted either substitution, substitution Base is monosubstituted, two substitutions or three substitutions.
2. BRD4 micromolecular inhibitors as claimed in claim 1, it is characterised in that R1、R2And R3Independently selected from halogen, hydrogen Or C1~C14Any one in alkoxy.
3. BRD4 micromolecular inhibitors as claimed in claim 1, it is characterised in that R1、R2And R3Independently selected from methoxyl group or It is any in hydrogen.
4. BRD4 micromolecular inhibitors as claimed in claim 1, it is characterised in that R4Substituent is independently selected from halogen, nitre One kind in base, amino, methoxyl group, alkyl, methoxy acyl group, ethoxy acyl group, acetamido or para hydroxybenzene.
5. a kind of synthetic method of the BRD4 micromolecular inhibitors as claimed in claim 1 with antitumor activity, its feature It is, comprises the following steps that：
Step 1：3,4,5- trimethoxybenzoic acids derivative and thionyl chloride reaction generation 3,4,5- trimethoxy-benzoyl chlorides Derivative 2a-2c；
Step 2：3,4,5- trimethoxy-benzoyl chlorides derivative 2a-2c) heterocycle react in the basic conditions generation target chemical combination Thing 3a-3v；The chemical equation that it is synthesized is as follows：
6. synthetic method as claimed in claim 5, it is characterised in that：In step 1,3,4,5- trimethoxybenzoic acids derive Thing equivalent is 1, and thionyl chloride equivalent is 4, and solvent is dry dichloromethane, is flowed back 2~5 hours；In step 2, ice bath is added dropwise Acyl chlorides, heterocycle equivalent are 1, and acid chloride equivalent weight is 1.5~1.8, and solvent is dry dichloromethane, and alkali is selected from the one of TEA or DIPEA Kind.
7. the inhibitor of BRD4 with antitumor activity as described in one of claim 1-4 a kind of is preparing treatment, prevention Application in the antineoplastic of tumour.
8. application as claimed in claim 7, it is characterised in that antineoplastic for treat or prevent breast cancer, leukaemia or The medicine of the diseases such as Huppert's disease.
CN201711117562.4A 2017-11-13 2017-11-13 BRD4 micromolecular inhibitors, synthetic method and its application with antitumor activity Pending CN107721975A (en)

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