CN110204543A - A kind of pyrrolopyridine ketone bifunctional molecule compound based on the induction BET degradation of Cereblon ligand - Google Patents

A kind of pyrrolopyridine ketone bifunctional molecule compound based on the induction BET degradation of Cereblon ligand Download PDF

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CN110204543A
CN110204543A CN201910570916.3A CN201910570916A CN110204543A CN 110204543 A CN110204543 A CN 110204543A CN 201910570916 A CN201910570916 A CN 201910570916A CN 110204543 A CN110204543 A CN 110204543A
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compound
pyrrolopyridine
ketone
alkyl
bifunctional molecule
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CN110204543B (en
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曹鹏
张惠斌
张剑
魏清筠
周金培
郑培源
朱佩钰
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China Pharmaceutical University
Jiangsu Provincial Insititute of Traditional Chinese Medicine
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Jiangsu Provincial Insititute of Traditional Chinese Medicine
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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Abstract

The present invention relates to a new class of pyrrolopyridine ketone bifunctional molecule and its pharmaceutically acceptable salt, hydrate, prodrugs and using the compound as the pharmaceutical composition of active constituent, and are preparing these compounds and its Pharmaceutical composition and its for treating or preventing the application in the diseases such as tumour, inflammation, immune.Bifunctional molecule of the present invention is a kind of protein degradation targeting association (PROTAC), preparation method is mature, BET protein micromolecular inhibitor is connected with Cereblon protein ligands in E3 ubiquitin ligase complex by using linking arm and obtains bifunctional molecule, gained compound can selective induction BET protein degradation, antitumor action is significant.

Description

A kind of double function of pyrrolopyridine ketone based on the induction BET degradation of Cereblon ligand It can molecular compound
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of pyrroles based on the induction BET degradation of Cereblon ligand And the difunctional PROTAC molecular compound of pyridinone and its pharmaceutically acceptable salt, hydrate, prodrug and with the compound For the pharmaceutical composition of active constituent, and prepare these compounds and its Pharmaceutical composition and its for treating or preventing it is swollen Application in the diseases such as tumor, inflammation, metabolism.
Background technique
Istone lysine acetyl modifies power formula after turning to the important genetic transcription and translation of one kind.BET albumen is tied by it Bromine structural domain (Bromodomain) identification acetyl-l-lysine (KAc) in structure plays a role, BET dysfunction and tumour, inflammation A variety of diseases such as disease, metabolism are related.The combination for inhibiting BET albumen and KAc, can effectively inhibit a variety of diseases such as tumour and inflammation Disease.
BET family protein includes tetra- kinds of hypotypes of BRD2, BRD3, BRD4 and BRDT, wherein studying the most in-depth is BRD4 Albumen promotes the carcinogenophores such as c-MYC, Bcl-X1 and BCL-6 research shows that BRD4 is raised the super enhancer region for arriving target gene The transcription of cause.Since BRD4 is adjusting the key effect in oncogene transcription, potential anti-tumor target is become.In recent years Carry out BET inhibitor to quickly grow, have a inhibitor more than ten be in early clinic research, such as IBET-762, OTX-015 and ABBV-075 etc..The kinds of tumors such as BET inhibitor center line cancer, acute myeloid leukaemia, prostate cancer show good efficacy.
Research find inhibit BRD4 albumen generally require to maintain drug into higher concentration for a long time, high dose administration can because Negative-feedback and lead to BRD4 protein enrichment so that the inhibitory effect to it weakens significantly；In addition, in BET inhibitor to certain It observed apparent drug resistance phenomenon in (such as three negative breast cancer) in the research of a little tumours.Above-mentioned for BET protein drug is asked Topic, more effective newtype drug need further to be developed.
Proteolysis targets chimera PROTAC (Proteolytic Targeting Chimera) technology, will target egg White small-molecule drug and E3 ubiquitin ligase ligand is connected by linking arm segment, in combination in target protein and E3 Ubiquitin ligase makes target protein ubiquitination so that proteasome degradation target protein.Compared to traditional small molecule, PROTAC technology With can be used for difficult patent medicine protein degradation, overcome protein enrichment phenomenon and drug resistance after administration, degradation effect strong and low dense The advantages such as catalytic degradation effect can be kept when spending.PROTAC technology has been used for the transformation of a variety of target drugs, Arvinas company The androgen receptor protein degradation agent PROTAC (treatment prostate cancer) of exploitation has entered I phase clinical research.With PROTAC skill Art, which carries out the research and development of new drug molecule, very high advantage and feasibility, and PROTAC molecule is likely to become the novel of next-generation great future Drug.
Summary of the invention
The purpose of the present invention is to provide a kind of compound for targeting degradation BET albumen and its preparation and application, specially The difunctional PROTAC molecule of pyrrolopyridine ketone and preparation method thereof based on Cereblon E3 ubiquitin ligase ligand, with And such compound is treating or preventing the application in the diseases such as tumour, inflammation, metabolism as the agent of BET protein degradation.
The purpose of the present invention is to provide difunctional small point of some new pyrrolopyridine ketones in and its can pharmaceutically connect The salt received, hydrate, prodrug and using the compound as the pharmaceutical composition of active constituent.These compounds have induction BET albumen drop The function of solution can be used for preparing new type antineoplastic medicine.The tumour can be but be not limited to Huppert's disease, gastric cancer, lung cancer, Breast cancer, the cancer of the esophagus, colon cancer, medulloblastoma, acute myeloblastic leukemia, chronic leukemia, melanoma, prostate Cancer, hepatoma, renal cell carcinoma, cervical carcinoma, cutaneum carcinoma, oophoroma, colon cancer, glioma, thyroid cancer or cancer of pancreas.
The object of the invention is also to provide a kind of preparation sides for synthesizing the new difunctional small molecule of pyrrolopyridine ketone Method.
Another object of the present invention is to provide a kind of drugs containing the new difunctional small molecule of pyrrolopyridine ketone Preparation.
In order to solve the above technical problems, The technical solution adopted by the invention is as follows:
Pyrrolopyridine ketone bifunctional molecule compound shown in formula I or its pharmaceutically acceptable salt, hydrate Or prodrug,
A-L-B
I
Wherein:
The A is pyrrolopyridine ketone BET protein inhibitor or derivatives thereof；
The B is the smaller ligand of cereblon albumen in E3 ubiquitin ligase complex, is selected from amides Close object, phthalimide class compound, Thalidomide, thalidomide derivatives, lenalidomide, lenalidomide derivative, pool Horse degree amine or pomalidomide derivative；
The L is linking arm, and L is selected from aliphatic chain or fragrant chain；
Wherein, linking arm L is connected by covalent bond with A and B.
Wherein, the L is one of arbitrary structures shown in Formula II:
Wherein:
N is selected from the integer between 1-10.
Wherein, the B is one of arbitrary structures shown in formula III:
Wherein:
W is selected from CH2, C=O, SO2, NH, N- alkyl；
X is selected from O, S；
Y is selected from NH, N- alkyl, N- aryl, N- heterocycle, N- naphthenic base, O, S；
Z is selected from-alkyl ,-naphthenic base ,-Cl ,-F ,-H；
G, G ' is selected from-H, alkyl ,-OH ,-CH2Heterocycle；
R1Selected from-H ,-D ,-F ,-Cl ,-Br ,-I ,-NO2、-CN、-NH2、-OH、-CH3、-CH2F、-CHF2、-CF3、- CH2D、-CHD2、-CD3、-CH2CH3；
Present invention is preferably related to the pyrrolopyridine ketone bifunctional molecule compound as shown in general formula IV or its pharmaceutically Acceptable salt, hydrate or prodrug:
Wherein:
R1、R2、R3、R4It is identical or different, separately it is selected from-H ,-D ,-F ,-Cl ,-Br ,-I ,-NO2、-CN、-NH2、- OH、-CH3、-CH2F、-CHF2、-CF3、-CH2D、-CHD2、-CD3、-CH2CH3；
R5Selected from C1-C6Alkyl ,-H ,-D ,-F ,-Cl ,-Br ,-l ,-NO2、-CN、-NH2、-OH、-CH2F、-CHF2、-CF3、- CH2D、-CHD2、-CD3、-NHSO2CH3、-NHSO2C2H5、-NHCO2CH3、-NHCO2C2H5、-NHCO2C3H7、-NHCO2C4H9、- NHCO2CH(CH3)2、-SO2CH3、-SO2C2H5；
M is selected from unsubstituted ,-CH2-、-CO-、-C(H)(OH)-、-(CH2)mO-、-(CH2)S(O)n、-(CH2)mN (Ra)-, Wherein m is independently 0 or 1, and n is independently 0,1 or 2, and wherein Ra is selected from H, C1-C3Alkyl, C1-C3Halogenated alkyl, (C2-C3Industry Alkyl)-OH or unsubstituted cyclopropyl；
R6Selected from C1-C6Alkyl, C1-C6Alkoxyalkyl, Rb or-(C1-C6Alkylidene)-Rb, wherein every Rb is independently Selected from aryl, heterocycle, naphthenic base or cycloalkenyl, and every Rb is independently selected from unsubstituted or replaced by 1-5 Rc, wherein Rc Independently selected from C1-C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Alkoxyalkyl, C2-C6Alkenyl, C2-C6Alkynes Base ,-F ,-C1 ,-Br ,-I ,-NO2、-CN、-NH2,-COOH ,-CO- replace monocyclic aryl ,-CO- replace monocyclic heterocycles base ,-replace Monocyclic aryl ,-replace monocyclic heterocycles base；
R7Selected from-H, C1-C6Alkyl；
L is any one in Formula V:
N is selected from the integer between 1-10.
The present invention is more preferably related to difunctional small molecule or its pharmaceutically acceptable salt, hydrate as shown in general formula VI Or prodrug:
Wherein:
R1、R2、R3、R4It is identical or different, separately it is selected from-H ,-F ,-Cl ,-Br ,-CH3、-CH2F、-CHF2、- CF3、-CH2D、-CHD2、-CD3；
R7Selected from-H ,-CH3、-CH2CH3；
L is any one in Formula VII:
N is selected from the integer between 1-6.
Preferred compounds of the invention includes, but are not limited to:
General formula VI compound represented can contain asymmetric or chiral centre, therefore can be with different stereoisomeric forms in any ratio In the presence of.All stereoisomeric forms in any ratio of the compounds of this invention, including but not limited to diastereoisomer, enantiomter and resistance turn Isomers and their mixture, such as racemate are included within the scope of the present invention.
General formula VI compound represented can also exist with different tautomeric forms, and all these forms are included in this In invention scope.Belong to " tautomer " or " tautomeric form " and refers to the different-energy mutually converted via low energy barrier Constitutional isomer.
According to the present invention, pharmaceutically acceptable salt include and it is following acid formed addition salts: hydrochloric acid, hydrobromic acid, sulfuric acid, Phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, Citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid etc..Hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, Pyruvic acid, acetic acid, trifluoroacetic acid, maleic acid, benzene sulfonic acid, succinic acid and similar known acceptable acid are at salt.
In addition, the invention also includes the prodrugs of derivative of the present invention.The prodrug of derivative of the present invention is the derivative of general formula VI Object, their own may have weaker activity even without activity, but upon administration, (such as pass through generation in physiological conditions Thank, solvolysis or other mode) it is converted to corresponding biologically active form.
Wherein, the pyrroles, which opens pyridinone bifunctional molecule compound, is prepared by intermediate VIII or IX,
Wherein, R2、R3、R4It is identical or different, separately it is selected from-H ,-F ,-Cl ,-Br ,-CH3、-CH2F、-CHF2、- CF3、-CH2D、-CHD2、-CD3；
R7Selected from-H ,-CH3、-CH2CH3。
Wherein, the pyrrolopyridine ketone bifunctional molecule compound the preparation method is as follows:
Wherein, step a is 1. 2. compound reacts to obtain with paratoluensulfonyl chloride compound；Step b be compound 2. with React to obtain compound 3. for nitrogen sodium；Step c is 3. 4. compound reacts to obtain with bromo-acetic acid tert-butyl compound；Step d is 4. 5. compound reacts to obtain with trifluoroacetic acid compound；Step e is 5. 6. compound reacts to obtain with thionyl chloride compound； Step f is 6. 7. compound reacts to obtain compound with the smaller ligand of cereblon albumen；Step g be compound 8. with 9. the smaller ligand of cereblon egg certainly reacts to obtain compound；Step h be compound 9. with trifluoroacetic acid reaction Close object 10.；Step j is 7. compound VIII reacts to obtain the compound of general formula VIa expression with compound；Step k is compound IX It 10. reacts to obtain the compound of general formula VIb expression with compound；
Wherein, VIa and VIb is two parts of general formula VI；
Wherein:
R1、R2、R3、R4It is identical or different, separately it is selected from-H ,-F ,-Cl ,-Br ,-CH3、-CH2F、-CHF2、- CF3、-CH2D、-CHD2、-CD3；
R7Selected from-H ,-CH3、-CH2CH3；
N is selected from the integer between 1-6.
Wherein, specific steps are as follows:
Step a: 1. compound being dissolved in appropriate pyridine, paratoluensulfonyl chloride is added portionwise, and a period of time is stirred at room temperature Afterwards, suitable aqueous hydrochloric acid solution is added, is extracted through ethyl acetate, saturated common salt is washed, collected organic layer, and anhydrous sodium sulfate is dry It is dry, it is concentrated under reduced pressure, residue is purified by silica gel column chromatography, affords compound 2..
Step b: by compound, 2. sharp sodium azide is dissolved in the mixed solution of proper amount of acetone and water, after being heated to reflux, is added Enter suitable quantity of water, extracted through ethyl acetate, saturated aqueous sodium carbonate is washed, saturated common salt washing, collected organic layer, anhydrous sodium sulfate It is dry, it is concentrated under reduced pressure, obtains compound 3..
Step c: 3. compound is dissolved in appropriate tetrahydrofuran with bromo-acetic acid tert-butyl, when stirring one section in ice-water bath Between, sodium hydride is added portionwise, continues after reacting a period of time in ice-water bath, then reacts at room temperature a period of time again, adds appropriate Methanol is quenched, and suitable quantity of water is added, extracts through ethyl acetate, and saturated common salt washing, collected organic layer, anhydrous sodium sulfate is dry, subtracts Pressure concentration, residue are purified by silica gel column chromatography, afford compound 4..
Step d: compound being dissolved in the dichloromethane solution of appropriate trifluoroacetic acid 4., after reacting at room temperature a period of time, It is concentrated under reduced pressure, obtains compound 5..
Step e: 5. compound being dissolved in q. s. methylene chloride, suitable thionyl chloride is added, then N is added dropwise, N- diformazan The catalysis of base formamide after being heated to reflux, is concentrated under reduced pressure, obtains compound 6..
Step f: the smaller ligand of cereblon albumen is dissolved in appropriate N-Methyl pyrrolidone, and compound is added 6. after reacting at room temperature a period of time, suitable quantity of water being added, there is solid precipitation, filter, dry crude product passes through silica gel column chromatography layer 7. analysis purifying, affords compound.
Step g: by the smaller ligand of cereblon albumen, 8. compound is dissolved in appropriate acetonitrile with pyridine, is slowly dripped The acetonitrile solution for adding phosphorus oxychloride after reacting at room temperature a period of time after dripping, is concentrated under reduced pressure, suitable quantity of water is added, through acetic acid second Ester extraction, saturated common salt washing, collected organic layer, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and residue passes through silica gel column chromatography layer 9. analysis purifying, affords compound.
Step h: compound being dissolved in the dichloromethane solution of appropriate trifluoroacetic acid 9., after reacting at room temperature a period of time, It is concentrated under reduced pressure, obtains compound 10..
Step j: by compound VIII, 7. compound is dissolved in suitable methylene chloride, first alcohol and water with Salzburg vitriol Mixed solution in, be stirred at room temperature a period of time, be added sodium ascorbate, react at room temperature a period of time after, be added suitable quantity of water, warp Methylene chloride extraction, saturated common salt washing, collected organic layer, outstanding aqueous sodium persulfate is dry, is concentrated under reduced pressure, and residue passes through silicagel column Chromatographic purification affords compound VIa.
Step k: by compound IX, compound 10., 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, 1- Hydroxybenzotriazole and triethylamine are dissolved in appropriate anhydrous tetrahydro furan, after reacting at room temperature a period of time, are concentrated under reduced pressure, and are added suitable Water is measured, is extracted through ethyl acetate, saturated common salt washing, collected organic layer, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and residue is logical Silica gel column chromatography purifying is crossed, compound VIb is obtained.
Wherein:
R1、R2、R3、R4It is identical or different, separately it is selected from-H ,-F ,-Cl ,-Br ,-CH3、-CH2F、-CHF2、- CF3、-CH2D、-CHD2、-CD3；
R7Selected from-H ,-CH3、-CH2CH3；
N is selected from the integer between 1-6.
A kind of pharmaceutical composition contains the above compound or its stereoisomer, tautomer, medicine of therapeutically effective amount Acceptable salt, hydrate, prodrug and pharmaceutically acceptable carrier on, diluent, adjuvant, medium or they Combination.
Wherein, the dosage form is injection, any one in tablets and capsules.
Above-mentioned compound and its pharmaceutically acceptable salt or combinations of the above object treats or prevents tumour in preparation Application in drug.
Wherein, the tumour can be but be not limited to Huppert's disease, gastric cancer, lung cancer, breast cancer, the cancer of the esophagus, colon cancer, Medulloblastoma, acute myelocytic leukemia, chronic leukemia, melanoma, prostate cancer, hepatoma, renal cell carcinoma, Cervical carcinoma, cutaneum carcinoma, oophoroma, colon cancer, glioma, thyroid cancer, cancer of pancreas.
Detailed description of the invention
Fig. 1 is that compound of the embodiment of the present invention 1,2,9 and 10 is right in MV-4-11 cell line under the conditions of single concentration is administered The degradation of BET albumen and the expression inhibiting schematic diagram of c-MYC.
Fig. 2 be concentration gradient administration under the conditions of compound of the embodiment of the present invention 1 and 2 in MV-4-11 cell line to BET egg The expression inhibiting schematic diagram of white degradation and c-MYC.
Fig. 3 be concentration gradient administration under the conditions of compound of the embodiment of the present invention 9 and 10 in MV-4-11 cell line to BET The expression inhibiting schematic diagram of Chi white degradation and c-MYC.
Specific embodiment
According to following embodiments, the present invention may be better understood.However, as it will be easily appreciated by one skilled in the art that real It applies content described in example and is merely to illustrate the present invention, without sheet described in detail in claims should will not be limited Invention.
Raw material can obtain from commercial channels, or be prepared by methods known in the art, or according to side described herein Method preparation.
The structure of compound by nuclear magnetic resonance (1H-NMR) and/or mass spectrum (MS) determines.NMR measurement is to use ACF- 300BRUK type or AVANCE NEO 400MHZ Nuclear Magnetic Resonance, measurement solvent are deuterated chloroform (CDCl3) or deuterated diformazan Asia Sulfone (DMSO-D6), TMS are internal standard.The measurement of MS HP1100 type mass spectrograph.Column chromatography uses 200-300 mesh silica gel (Qing Daohai Foreignize plant produced).
Embodiment 1:
Prepare 4- (2- (2,4- difluoro phenoxy group) -5- (ethyl sulfonamide base) phenyl)-N- ((1- (2- (2- ((2- (2,6- Dioxopiperidine -3- base) -1- oxoisoindolines -4- base) amino) -2- oxoethoxy) ethyl) -1H-1,2,3- triazoles - 4- yl) methyl) -6- methyl -7- oxo -6,7- dihydro -1H- pyrrolo- [2,3-c] pyridine-2-carboxamide (1), structural formula is such as Under:
Step 1: preparation 2- hydroxyethyl -4- oluene sulfonic acides ester (1a)
By ethylene glycol (3.91g, 62.95mmol) bath in 5mL pyridine, be added portionwise paratoluensulfonyl chloride (6g, 31.47mmol), it after being stirred at room temperature 4 hours, is added 6mol/L hydrochloric acid (40mL), is extracted with ethyl acetate, saturated common salt washing, Collected organic layer, outstanding aqueous sodium persulfate is dry, and decompression boils off organic solvent, and residue is purified by silica gel column chromatography, uses Petrol ether/ethyl acetate (V/V=20/1-10/1) affords colourless liquid, weight 2g, yield 29.39%.
1H NMR (300MHz, CDCl3) δ (ppm): 7.81 (d, J=8.3Hz, 2H), 7.36 (d, J=8.0Hz, 2H), 4.16-4.12 (m, 2H), 3.85-3.78 (m, 2H), 2.45 (s, 3H), 2.01 (d, J=19.0Hz, 1H)
Step 2: preparation 2- hydroxyethyl nitrine (1b)
1a (1.2g, 5.55mmol) and sodium azide (0.72g, 11.1mmol) are dissolved in 5mL acetone and 5mL water mixed liquid In, it being heated to reflux 16 hours, 20mL water is added, is extracted with ethyl acetate, saturated aqueous sodium carbonate is washed, saturated common salt washing, Collected organic layer, anhydrous sodium sulfate is dry, and decompression boils off organic solvent, obtains colourless liquid, weight 0.41g, yield 84.85%.
1H NMR (300MHz, CDCl3) (s, the 1H) of δ (ppm): 3.82-3.74 (m, 2H), 3.49-3.39 (m, 2H), 2.01
Step 3: the preparation 2- nitrine ethoxyacetic acid tert-butyl ester (1c)
1b (0.41g, 4.71mmo1) and bromo-acetic acid tert-butyl (1.1g, 5.65mmol) are dissolved in 15mL tetrahydrofuran, It stirs 10 minutes, is added portionwise sodium hydride (0.38g, 9.42mmol) in ice-water bath, continuation is reacted 0.5 hour in ice-water bath Afterwards, it reacts at room temperature 3 hours, proper amount of methanol is added to be quenched, 30mL water is added, is extracted with ethyl acetate, saturated common salt washing, collection has Machine layer, anhydrous sodium sulfate are dry, and decompression boils off organic solvent, residue by silica gel column chromatography purifying, using petroleum ether/ Ethyl acetate (V/V=30/1-20/1) affords colourless liquid, weight 0.41g, yield 43.28%.
1H NMR (300MHz, CDCl3) δ (ppm): 4.06-4.00 (m, 2H), 3.76-3.70 (m, 2H), 3.48-3.41 (m, 2H), 1.49 (d, J=5.8Hz, 9H)
Step 4: preparation 2- nitrine ethoxyacetic acid (1d)
1c (0.41g, 2.04mmol) is dissolved in 4mL methylene chloride, 1mL trifluoroacetic acid is added, is reacted at room temperature 3 hours Afterwards, decompression boils off organic solvent, obtains brown liquid, weight 0.29g.
Step 5: preparation 2- nitrine Ethoxyacetyl chloride (1e)
1d (0.29g, 2.03mmol) is dissolved in 4mL methylene chloride, 1mL thionyl chloride is added, adds 2 drop DMF and urges Change, after being heated to reflux 4 hours, decompression boils off organic solvent, obtains brown liquid, weight 0.33g.
Step 6:2- (2- nitrine ethyoxyl)-N- (2- (2,6- dioxopiperidine -3- base) -1,3- dioxoisoindolin - 4- yl) acetamide (1f)
Meter Na Du amine (0.3g, 1.16mmol) is dissolved in 3mLN- methyl pyrrolidone, addition 1e (0.38g, 2.31mmol), after reacting at room temperature 4 hours, 20mL water is added, there is solid precipitation, filter, dry crude product passes through silicagel column color Chromatographic purifying is composed, affords yellow solid, weight 0.26g, yield using methylene chloride/methanol (V/V=150/1-100/1) 58.16%.
Step 7: preparation 4- (2- (2,4- difluoro phenoxy group) -5- (ethyl sulfonamide base) phenyl)-N- ((1- (2- (2- ((2- (2,6- dioxopiperidine -3- base) -1- oxoisoindolines -4- base) nitrogen base) -2- oxoethoxy) ethyl) -1H-1, 2,3- triazole-4-yls) methyl) -6- methyl -7- oxo -6,7- dihydro -1H- pyrrolo- [2,3-c] pyridine-2-carboxamide (1)
By 4- (2- (2,4- difluoro phenoxy group) -5- (ethyl sulfonamide base) phenyl) -6- methyl -7- oxo-N- (propyl- 2- Alkynes -1- base) -6,7- dihydro -1H- pyrrolo- [2,3-c] pyridine-2-carboxamide (0.06g, 0.111mmol), 1f (0.06g, 0.111mmol) and Salzburg vitriol (0.009g, 0.044mmol) is dissolved in 2mL methylene chloride, 2mL methanol and the mixing of 2mL water It in liquid, is stirred at room temperature 10 minutes, is added sodium ascorbate (0.006g, 0.022mmol), after room temperature reaction 4 hours, 20mL is added Water is extracted with dichloromethane, and saturated common salt washing, collected organic layer, anhydrous sodium sulfate is dry, and decompression boils off organic solvent, residual Object is stayed to purify by silica gel column chromatography, it is solid to afford yellow using methylene chloride/methanol (V/V=100/1-30/1) Body, weight 0.069g, yield 58.70%.
1H NMR (400MHz, DMSO) δ (ppm): 12.34 (s, 1H), 11.01 (s, 1H), 9.76 (d, J=51.5Hz, 2H), 8.88 (s, 1H), 8.07 (s, 1H), 7.74 (s, 1H), 7.51 (d, J=20.4Hz, 2H), 7.28 (d, J=48.0Hz, 4H), 6.97 (dd, J=40.7,23.7Hz, 4H), 5.14 (s, 1H), 4.61 (s, 2H), 4.50 (s, 2H), 4.38 (d, J= 12.0Hz, 2H), 4.14 (s, 2H), 3.96 (s, 2H), 3.53 (s, 3H), 3.10 (s, 2H), 2.91 (s, 1H), 2.58 (s, 1H), 2.42-2.32 (m, 1H), 2.02 (s, 1H), 1.22 (s, 3H)
MS (ESI, m/z): 925.00 [M-H]
Embodiment 2:
Prepare 4- (2- (2,4- difluoro phenoxy group) -5- (ethyl sulfonamide base) phenyl)-N- ((1- (2- (2- (2- ((2- (2,6- dioxopiperidine -3- base) -1- oxoisoindolines -4- base) amino) -2- oxoethoxy) ethyoxyl) ethyl) -1H- 1,2,3-triazoles -4- base) methyl) -6- methyl -7- oxo -6,7-- dihydro -1H- pyrrolo- [2,3-c] pyridine-2-carboxamide (2), structural formula is as follows:
Ethylene glycol in 1 step 1 of embodiment is changed to diglycol, synthetic method is the same as embodiment 1.
1H NMR (400MHz, DMSO) δ (ppm): 12.35 (s, 1H), 11.01 (s, 1H), 9.83 (s, 1H), 9.68 (s, 1H), 8.87 (s, 1H), 7.99 (s, 1H), 7.72 (d, J=7.9Hz, 1H), 7.54 (d, J=7.0Hz, 1H), 7.52-7.45 (m, 1H), 7.34 (d, J=6.6Hz, 3H), 7.22 (d, J=8.7Hz, 1H), 7.06 (d, J=6.0Hz, 1H), 7.00 (d, J= 7.8Hz, 1H), 6.95-6.81 (m, 2H), 5.13 (d, J=8.5Hz, 1H), 4.50 (d, J=12.7Hz, 4H), 4.43-4.30 (m, 2H), 4.09 (s, 2H), 3.84 (s, 2H), 3.62 (d, J=4.5Hz, 4H), 3.52 (s, 3H), 3.10 (d, J=7.1Hz, 2H), 2.89 (d, J=12.6Hz, 1H), 2.60 (s, 1H), 2.35 (d, J=13.8Hz, 1H), 2.00 (d, J=10.0Hz, 1H), 1.24-1.20 (t, 3H)
MS (ESI, m/z): 969.06 [M-H]-.
Embodiment 3:
Prepare 4- (2- (2,4- difluoro phenoxy group) -5- (ethyl sulfonamide base) phenyl)-N- ((1- (2- (2- (2- (2- ((2- (2,6- dioxopiperidine -3- base) -1- oxoisoindolines -4- base) amino) -2- oxoethoxy) ethyoxyl) ethoxy Base) ethyl) -1H-1,2,3- triazole-4-yls) methyl) -6- methyl -7- oxo -6,7- dihydro -1H- pyrrolo- [2,3-c] pyrrole Pyridine -2- formamide (3), structural formula is as follows:
Ethylene glycol in 1 step 1 of embodiment is changed to triethylene-glycol, synthetic method is the same as embodiment 1.
1H NMR (300MHz, DMSO) δ (ppm): 12.33 (s, 1H), 11.00 (s, 1H), 9.82 (s, 1H), 9.67 (s, 1H), 8.86 (s, 1H), 7.96 (s, 1H), 7.73 (d, J=7.5Hz, 1H), 7.52 (dt, J=15.0,7.5Hz, 2H), 7.40- 7.30 (m, 3H), 7.23 (dd, J=8.8,2.6Hz, 1H), 7.13-6.97 (m, 2H), 6.94 (d, J=8.7Hz, 1H), 6.89 (d, J=2.2Hz, 1H), 5.14 (dd, J=13.3,5.0Hz, 1H), 4.48 (dd, J=9.3,4.9Hz, 4H), 4.37 (d, J= 6.7Hz, 2H), 4.11 (s, 2H), 3.77 (t, J=5.0Hz, 2H), 3.64-3.61 (m, 2H), 3.54 (d, J=4.7Hz, 2H), 3.53 (s, 3H), 3.50 (s, 4H), 3.11 (d, J=7.4Hz, 2H), 2.96-2.86 (m, 1H), 2.59 (d, J=17.7Hz, 1H), 2.36 (d, J=9.1Hz, 1H), 2.02 (s, 1H), 1.22 (t, J=5.6Hz, 3H)
MS (ESI, m/z): 1013.05 [M-H]-.
Embodiment 4:
Prepare 4- (2- (2,4- difluoro phenoxy group) -5- (ethyl sulfonamide base) phenyl)-N- ((1- (14- ((2- (2,6- bis- Oxo-piperidine -3- base) -1- oxoisoindolines -- 4- yl) amino) -14- oxo -3,6,9,12- tetra- oxygen myristyls) -1H- 1,2,3-triazoles -4- base) methyl) -6- methyl -7- oxo -6,7-- dihydro -1H- pyrrolo- [2,3-c] pyridine-2-carboxamide (4), structural formula is as follows:
Ethylene glycol in embodiment 1 in step 1 is changed to tetraethylene-glycol, synthetic method is the same as embodiment 1.
1H NMR (300MHz, DMSO) δ (ppm): 12.34 (s, 1H), 11.00 (s, 1H), 9.82 (s, 1H), 9.67 (s, 1H), 8.86 (s, 1H), 7.95 (s, 1H), 7.72 (d, J=7.2Hz, 1H), 7.52 (dt, J=15.1,7.4Hz, 2H), 7.34 (s, 3H), 7.23 (d, J=8.9Hz, 1H), 7.03 (dd, J=17.9,8.3Hz, 2H), 6.96-6.87 (m, 2H), 5.14 (d, J =8.6Hz, 1H), 4.48 (s, 4H), 4.37 (d, J=6.4Hz, 2H), 4.12 (s, 2H), 3.77 (s, 2H), 3.65 (s, 2H), 3.54 (s, 2H), 3.53 (s, 3H), 3.43 (d, J=11.6Hz, 8H), 3.10 (d, J=7.4Hz, 2H), 2.91 (t, J= 12.9Hz, 1H), 2.59 (d, J=17.7Hz, 1H), 2.34 (t, J=13.6Hz, 1H), 1.99 (d, J=4.4Hz, 1H), (1.23-1.21 t, 3H)
MS (ESI, m/z): 1081.20 [M+Na]+.
Embodiment 5:
Prepare 4- (2- (2,4- difluoro phenoxy group) -5- (ethyl sulfonamide base) phenyl)-N- (3- ((2- (2,6- dioxos Piperidines -3- base) -1- oxoisoindolines -4- base) amino) -3- oxopropyl) -6- methyl -7- oxo -6,7- dihydro -1H- pyrrole Simultaneously [2,3-c] pyridine-2-carboxamide (5) is coughed up, structural formula is as follows:
Step 1: preparation (3- ((2- (2,6- dioxopiperidine -3- base) -1- oxoisoindoline diindyl -4- base) amino) -3- Oxopropyl) t-butyl carbamate (5a)
By 3- (4- amino -1- oxoisoindolines -2- base) piperidines -2,6- diketone (0.3g, 1.16mmol), 3- ((tertiary fourth Epoxide carbonyl) amino) propionic acid (0.26g, 1.39mmol) and pyridine (0.27g, 3.47mmol) be dissolved in 5mL acetonitrile, slowly drip The acetonitrile solution for adding phosphorus oxychloride (0.21g, 1.39mmol), after reacting at room temperature 2 hours after dripping, decompression boils off organic molten Agent is added 20mL water, is extracted with ethyl acetate, and saturated common salt washing, collected organic layer, anhydrous sodium sulfate is dry, and decompression boils off Organic solvent, residue are purified by silica gel column chromatography, are eluted using methylene chloride/methanol (V/V=100/1-30/1) Obtain yellow solid, weight 0.28g, yield 56.21%.
Step 2: preparation 3- amino-N- (2- (2,6- dioxopiperidine -3- base) -1- oxoisoindolines -4- base) interior acyl Amine (5b)
5a is dissolved in 4mL methylene chloride and 1ml trifluoroacetic acid, after room temperature reaction 2 hours, decompression boils off solvent, obtains Faint yellow solid is trifluoroacetate, weight 0.23g, yield 79.57%.
1H NMR (400MHz, DMSO) δ (ppm): 11.04 (s, 1H), 10.08 (s, 1H), 7.83 (dd, J=9.8, 8.3Hz, 4H), 7.52 (q, J=7.4Hz, 2H), 5.17 (dd, J=13.3,5.1Hz, 1H), 4.38 (d, J=14.0Hz, 2H), 3.10 (s, 2H), 2.99-2.88 (m, 1H), 2.75 (s, 2H), 2.62 (d, J=17.4Hz, 1H), 2.31 (qd, J=13.1, 4.3Hz, 1H), 2.08-1.99 (m, 1H)
MS (ESI, m/z): 331 [M+H]+.
Step 3: preparation 4- (2- (2,4- difluoro phenoxy group) -5- (ethyl sulfonamide base) phenyl)-N- (3- ((2- (2,6- Dioxopiperidine -3.- base) -1- oxoisoindolines -4- base) amino) -3- oxopropyl) -6- methyl -7- oxo -6,7- bis- Hydrogen -1H- pyrrolo- [2,3-c] pyridine-2-carboxamide (5)
By 4- (2- (2,4- difluoro phenoxy group) -5- (ethyl sulfonamide base) phenyl) -6- methyl -7- oxo -6,7- dihydro - 1H- pyrrolo- [2,3-c] pyridine-2-carboxylic acids (0.06g, 0.119mmol), 5b (0.6g, 0.131mmol), 1- (3- dimethylamino Propyl) -3- ethyl-carbodiimide hydrochloride EDCI (0.03g, 0.143mmol), I-hydroxybenzotriazole HOBT (0.02g, It 0.143mmol) is dissolved in 5ml anhydrous tetrahydro furan with triethylamine (0.02g, 0.238mmol), reacts at room temperature 3h, decompression boils off Tetrahydrofuran is added 20ml water, is extracted with ethyl acetate, and saturated common salt washing, collected organic layer, anhydrous sodium sulfate is dry, subtracts Pressure boils off organic solvent, and residue is purified by silica gel column chromatography, used methylene chloride/methanol (V/V=50/1-20/1) Afford faint yellow solid, weight 0.05g, yield 51.43%.
1H NMR (400MHz, DMSO) δ (ppm): 12.33 (s, 1H), 10.96 (s, 1H), 9.85 (d, J=40.3Hz, 2H), 8.53 (s, 1H), 7.82 (d, J=5.5Hz, 1H), 7.50 (d, J=7.4Hz, 2H), 7.35 (s, 3H), 7.24 (d, J= 8.1Hz, 1H), 7.07 (d, J=5.3Hz, 1H), 7.02-6.89 (m, 2H), 6.87 (s, 1H), 5.09 (d, J=8.4Hz, 1H), 4.34 (s, 2H), 3.58 (s, 2H), 3.55 (s, 3H), 3.11 (d, J=6.9Hz, 2H), 2.87 (d, J=12.5Hz, 1H), 2.68 (s, 2H), 2.56 (s, 1H), 2.23 (dd, J=27.0,13.4Hz, 1H), 1.96 (dd, J=15.4,9.6Hz, 1H), 1.22 (t, J=1.7Hz, 3H)
MS (ESI, m/z): 813.85 [M-H]-.
Embodiment 6:
Prepare 4- (2- (2,4- difluoro phenoxy group) -5- (ethyl sulfonamide base) phenyl)-N- (4- ((2- (2,6- dioxos Piperidines -3- base) -1- oxoisoindolines -4- base) amino) -4- oxo butyl) -6- methyl -7- oxo -6,7- dihydro -1H- pyrrole Simultaneously [2,3-c] pyridine-2-carboxamide (6) is coughed up, structural formula is as follows:
3- ((tert-butoxycarbonyl) amino) propionic acid in 5 step 1 of embodiment is changed to 4- ((tert-butoxycarbonyl) ammonia Base) butyric acid, synthetic method is the same as embodiment 5.
1H NMR (400MHz, DMSO) δ 12.23 (s, 1H), 10.98 (s, 1H), 9.80 (s, 2H), 8.38 (s, 1H), 7.80 (d, J=6.6Hz, 1H), 7.48 (d, J=10.2Hz, 2H), 7.34 (s, 3H), 7.23 (d, J=8.5Hz, 1H), 7.06 (d, J=5.1Hz, 1H), 7.02-6.92 (m, 2H), 6.85 (s, 1H), 5.13 (d, J=12.8Hz, 1H), 4.37 (d, J= 5.2Hz, 2H), 3.54 (s, 3H), 3.32 (s, 2H), 3.11 (d, J=6.9Hz, 2H), 2.89 (d, J=12.9Hz, 1H), 2.60 (d, J=17.5Hz, 1H), 2.44 (s, 2H), 2.34 (d, J=12.8Hz, 1H), 2.03 (s, 1H), 1.86 (s, 2H), 1.23 (s, 3H)
MS (ESI, m/z): 827.90 [M-H]-.
Embodiment 7:
Prepare 4- (2- (2,4- difluoro phenoxy group) -5- (ethyl sulfonamide base) phenyl)-N- (5- ((2- (2,6- dioxos Piperidines -3- base) -1- oxoisoindolines -4- base) amino) -5- oxopentyl) -6- methyl -7- oxo -6,7- dihydro -1H- pyrrole Simultaneously [2,3-c] pyridine-2-carboxamide (7) is coughed up, structural formula is as follows:
3- ((tert-butoxycarbonyl) amino) propionic acid in 5 step 1 of embodiment is changed to 5- ((tert-butoxycarbonyl) ammonia Base) valeric acid, synthetic method is the same as embodiment 5.
1H NMR (400MHz, DMSO) δ (ppm): 12.25 (s, 1H), 10.98 (s, 1H), 9.78 (d, J=10.6Hz, 2H), 8.34 (s, 1H), 7.83 (d, J=7.0Hz, 1H), 7.48 (dd, J=11.7,4.6Hz, 2H), 7.34 (s, 3H), 7.28- 7.19 (m, 1H), 7.05 (dd, J=9.0,5.7Hz, 1H), 7.02-6.89 (m, 2H), 6.84 (s, 1H), 5.13 (dd, J= 13.1,4.7Hz, 1H), 4.37 (q, J=17.6Hz, 2H), 3.54 (s, 3H), 3.34-3.31 (m, 2H), 3.18-3.05 (m, 2H), 2.89 (d, J=13.1Hz, 1H), 2.59 (d, J=18.3Hz, 1H), 2.46-2.38 (m, 2H), 2.35 (d, J= 13.2Hz, 1H), 2.03 (s, 1H), 1.68 (s, 2H), 1.58 (d, J=5.3Hz, 2H), 1.23 (t, J=7.3Hz, 3H)
MS (ESI, m/z): 841.90 [M-H]-.
Embodiment 8:
Prepare 4- (2- (2,4- difluoro phenoxy group) -5- (ethyl sulfonamide base) phenyl)-N- (6- ((2- (2,6- dioxos Piperidines -3- base) -1- oxoisoindolines -4- base) amino) -6- oxo-hexyl) -6- methyl .7- oxo -6,7- dihydro -1H- pyrrole Simultaneously [2,3-c] pyridine-2-carboxamide (8) is coughed up, structural formula is as follows:
3- ((tert-butoxycarbonyl) amino) propionic acid in 5 step 1 of embodiment is changed to 6- ((tert-butoxycarbonyl) ammonia Base) caproic acid, synthetic method is the same as embodiment 5.
1H NMR (400MHz, DMSO) δ (ppm): 12.24 (s, 1H), 10.98 (s, 1H), 9.77 (d, J=25.4Hz, 2H), 8.31 (s, 1H), 7.80 (d, J=7.1Hz, 1H), 7.53-7.42 (m, 2H), 7.34 (s, 3H), 7.24 (d, J= 8.6Hz, 1H), 7.10-7.02 (m, 1H), 6.97 (dd, J=17.8,8.1Hz, 2H), 6.83 (s, 1H), 5.21-5.08 (m, 1H), 4.38 (t, J=12.2Hz, 2H), 3.54 (s, 3H), 3.31 (s, 2H), 3.11 (d, J=7.3Hz, 2H), 2.89 (d, J= 12.4Hz, 1H), 2.60 (d, J=17.4Hz, 1H), 2.37 (s, 2H), 2.34 (s, 1H), 2.02 (s, 1H), 1.65 (s, 2H), 1.56 (s, 2H), 1.38 (s, 2H), 1.22 (t, J=7.4Hz, 3H)
MS (ESI, m/z): 855.95 [M-H]-.
Embodiment 9:
Prepare 4- (2- (2,4- difluoro phenoxy group) -5- (ethyl sulfonamide base) phenyl)-N- (7- ((2- (2,6- dioxos Piperidines -3- base) -1- oxoisoindolines -4- base) amino) -7- oxo heptyl) -6- methyl -7- oxo -6,7- dihydro -1H- pyrrole Simultaneously [2,3-c] pyridine-2-carboxamide (9) is coughed up, structural formula is as follows:
3- ((tert-butoxycarbonyl) amino) propionic acid in 5 step 1 of embodiment is changed to 7- ((tert-butoxycarbonyl) ammonia Base) enanthic acid, synthetic method is the same as embodiment 5.
1H NMR (400MHz, DMSO) δ (ppm): 12.29 (s, 1H), 11.02 (s, 1H), 9.81 (d, J=24.8Hz, 2H), 8.32 (s, 1H), 7.81 (s, 1H), 7.49 (s, 2H), 7.35 (s, 3H), 7.22 (s, 1H), 7.06 (s, 1H), 7.02- 6.89 (m, 2H), 6.84 (s, 1H), 5.14 (d, J=10.8Hz, 1H), 4.36 (d, J=6.9Hz, 2H), 3.54 (s, 3H), 3.24 (s, 2H), 3.10 (s, 2H), 2.91 (s, 1H), 2.59 (d, J=15.8Hz, 1H), 2.36 (s, 2H), 2.18 (s, 1H), 2.01 (s, 1H), 1.62 (s, 2H), 1.52 (s, 2H), 1.35 (s, 4H), 1.23 (s, 3H)
MS (ESI, m/z): 869.95 [M-H]-.
Embodiment 10:
Prepare 4- (2- (2,4- difluoro phenoxy group) -5- (ethyl sulfonamide base) phenyl)-N- (8- ((2- (2,6- dioxos Piperidines -3- base) -1- oxoisoindolines -4- base) amino) -8- oxo octyl) -6- methyl -7- oxo -6,7- dihydro -1H- pyrrole Simultaneously [2,3-c] pyridine-2-carboxamide (10) is coughed up, structural formula is as follows:
3- ((tert-butoxycarbonyl) amino) propionic acid in 5 step 1 of embodiment is changed to 8- ((tert-butoxycarbonyl) ammonia Base) octanoic acid, synthetic method is the same as embodiment 5.
1H NMR (400MHz, DMSO) δ (ppm): 12.29 (s, 1H), 11.03 (s, 1H), 9.80 (d, J=29.2Hz, 2H), 8.31 (s, 1H), 7.81 (s, 1H), 7.49 (s, 2H), 7.34 (s, 3H), 7.23 (d, J=7.2Hz, 1H), 7.06 (s, 1H), 7.02-6.91 (m, 2H), 6.83 (s, 1H), 5.14 (d, J=12.6Hz, 1H), 4.36 (q, J=16.6Hz, 2H), 3.54 (s, 3H), 3.23 (s, 2H), 3.10 (s, 2H), 2.91 (s, 1H), 2.60 (d, J=16.8Hz, 1H), 2.35 (s, 2H), 2.34- 2.26 (m, 1H), 2.01 (s, 1H), 1.61 (s, 2H), 1.50 (s, 2H), 1.33 (s, 6H), 1.23 (s, 3H)
MS (ESI, m/z): 883.95 [M-H]-.
Embodiment 11: the protein level determination of activity of compound
The combination of first bromodomain structural domain of compound and BRD4 albumen n end (hereinafter referred to as BRD4 (BD1)) is living Property test using AlphaScreen detection technique.Compound primary dcreening operation concentration is 0.5 μM.
HEPES buffer solution (50mM HEPES, 100mM NaCl, 0.1%BSA, 0.05%CHAPS, pH7.5) is prepared to be used for Prepare BRD4 (BD1) albumen, Biotin label histone H 4, untested compound (DMSO 0.1%), donor beads and Acceptor beads solution.Take one piece of 384 orifice plate, according to arrangement, divide on plate untested compound hole, blank control wells (min, Max), positive drug control wells.The 5 μ L of compound solution of various concentration is separately added into untested compound hole and positive drug hole, it is empty White 5 μ L (DMSO0.1%) of addition buffer.Continue molten to each hole addition BRD4 (BD1) albumen in addition to blank control wells (min) 5 μ L of buffer is added to blank control wells (min) in 5 μ L of liquid.After being incubated for 15 minutes at room temperature, Biotin label is added in every hole 5 μ L of histone H 4 solution, continues after being incubated at room temperature 1 hour, and donor beads and acceptor beads solution 15 is added μ L reads fluorescence with the Alpha mode (λ ex=680, λ em=570) of EnSpire detector after being protected from light incubation at room temperature 1 hour Numerical value.
Numerical value processing: inhibiting rate=(Max-Signal)/(Max-Min) × 100%
Wherein: the value that the histone H 4 and albumen of Max:Biotin label are completely combined
The histone H 4 background values of Min:Biotin label
Signal: the value under compound respective concentration
S curve is done with compound concentration and corresponding inhibiting rate.Obtain the IC of respective compound50。
The experimental result of compound is shown in Table 1:
Inhibitory activity result of 1 compound of table to BRD4 (BD1)
Compound number 0.5 μM of at of inhibiting rate (%) IC50(μM)
1 100 0.0027
2 100 0.0034
3 100 0.0037
4 100 0.0120
5 100 0.0084
6 100 0.0027
7 100 0.0023
8 100 0.0021
9 100 0.0030
10 100 0.0030
ABBV-075 100 0.0025
Compound of the embodiment of the present invention is as follows to the inhibiting effect of BET protein B RD4 (BD1):
As shown in table 1, embodiment compound and ABBV-075 reach the inhibiting rate of BRD4 (BD1) at 0.5 μM 100%, the IC of embodiment compound and ABBV-07550Quite, in nanomole rank, show that compound of the embodiment of the present invention is protected Potent BET protein inhibiting activity is held.
Embodiment 12:MTT method measures compound on tumor cell proliferation inhibition activity
It takes in exponential phase of growth in good condition one bottle of cell, 0.25% tryptic digestive juice is added, digestion makes to paste Parietal cell falls off, and counts 2~4 × 104A/ml, is made cell suspension.Take cell suspension inoculation on 96 orifice plates, 90 holes μ L/, Set constant temperature CO2It is cultivated 24 hours in incubator.Test medicine is added, 10 holes μ L/ are cultivated 72 hours.96 holes are added in MTT reagent In plate, 10 holes μ L/ react in incubator and suck within 4 hours supernatant, are added dimethyl sulfoxide, 100 holes μ L/, after dissolution to be crystallized, It is the light absorption value in the every hole of measurement at 570nm in wavelength with enzyme-linked immunosorbent assay instrument, and calculates cell inhibitory rate.With compound concentration S curve is done with corresponding inhibiting rate.Obtain the IC of respective compound50。
For 2 compound of table to people Acute Monocytic Leukemia Cell Line MV-4-11, human B lymphocyte oncocyte Ramos's is anti- Proliferation activity
For 3 compound of table to Human colorectal cancer cells DLD-1 and HCT-116, the antiproliferative of Non-small cell lung carcinoma A549 is living Property
N.D.=not determined, expression do not determine.
The proliferation inhibition activity of compound on tumor cell of the embodiment of the present invention is as follows:
As shown in table 2 and table 3, embodiment compound on tumor cell strain MV-4-11, Ramos, DLD-1, HCT-116 and A549 shows significant antiproliferative activity, and the antiproliferative activity of part of compounds is significantly better than ABBV-075.In MV4- 11, in Ramos, DLD-1 and HCT-116 cell strain, embodiment compound is suitable with the activity of ABBV-075；In A549 cell strain In, compared to ABBV-075, the antiproliferative activity of part of compounds is promoted from micromole's rank to nanomole rank, wherein implementing Example compound 3 improves 13 times to the antiproliferative activity of A549.To sum up, the effect of compound antitumor of the embodiment of the present invention is significant, Potent tumour cell antiproliferative activity is still maintained compared to ABBV-075.
Embodiment 13:Western-blot measures compound to the degradation of BET albumen and the expression inhibiting of c-MYC
The preparation of cell protein sample:
After people's Acute Monocytic Leukemia Cell Line MV-4-11 secondary culture, the good cell of growth conditions is taken, centrifugation is more Fresh medium is changed, is made 2 × 106A/ml cell suspension, is inoculated in 6 orifice plates, the hole 1mL/, in 37 DEG C, 5%CO2Cell incubation Overnight incubation in case.After test medicine is added, cell is received after cultivating the corresponding time.By treated, cell is transferred to new centrifuge tube In, it is collected after 1200rpm centrifugation 5min, after PBS washes one time, the RIPA lysate of 100 μ L is added in every a sample, is cracked on ice After 30min, 12000rpm is centrifuged 15min, and supernatant is transferred in new centrifuge tube, and 5 × SDS-PAGE albumen sample-loading buffer is added, 100 DEG C of denaturation 5min after mixing, -20 DEG C save or are directly used in Western-blot detection.
Specific step is as follows for protein immunoblot experiment (Western-blot, WB):
The SDS-PAGE glue of suitable concentration: resolving gel concentration 8% is prepared, concentration gum concentration is 5%.According to protein quantification As a result, adjustment loading volume.Protein sample concentration glue in voltage be 80V, into separation gel after voltage be adjusted to 120V.To bromine phenol Indigo plant stops electrophoresis when running out of PAGE glue completely.Membrane-transferring device is installed, is put into ice-water bath, 100V constant pressure transferring film 1.5 hours.It takes out Pvdf membrane is immersed in the TBST solution of 5% skim milk, is placed in shaking table room temperature and is closed 1 hour.TBST buffer washs 3 times, The primary antibody of corresponding dilution ratio is added, is placed in 4 DEG C of overnight incubations.TBST buffer washs 3 times, each 10min.It is added certain dilute The secondary antibody of ratio is released, is incubated at room temperature 1 hour.TBST buffer washs 3 times, each 10min.Use LI-COR company The double-colored laser imaging system exposure of Odyssey near-infrared.
Compound of the embodiment of the present invention is as follows to the degradation of BET albumen and the expression inhibiting situation of c-MYC:
As shown in Figure 1, when administration concentration is 100nmol/L, in MV-4-11 cell line, in Westem-blot reality It tests in result and 1,2,9 and 10 pair of BRD4 albumen of embodiment compound can be observed with apparent degradation, ABBV-075 pairs BRD4 albumen is without degradation；The expression inhibiting effect of 1,2,9 and 10 couple of c-MYC of embodiment compound is better than ABBV-075.This Inventive embodiments compound is as follows with the expression inhibiting situation of c-MYC to the degradation of BET albumen:
As shown in Figure 1, when administration concentration is 100nmol/L, in MV-4-11 cell line, in Western-blot It can be observed in experimental result, relative to blank control and ABBV-075 group, 1,2,9 and 10 pair of BRD4 albumen of embodiment compound There is apparent expression inhibiting effect with apparent degradation and to c-MYC, wherein embodiment compound 9 and 10 can be right BRD4 albumen reaches degradable, and ABBV-075 is to BRD4 albumen without degradation；1,2,9 and 10 couple of c- of embodiment compound The expression inhibiting effect of MYC is better than ABBV-075.
As shown in Fig. 2, when the administration concentration of embodiment compound 1 and 2 is 1,3,10,30,100nM/L, in MV-4-11 In cell line, compound 1 and 2 can be observed in Western-blot experimental result with the degradation and c- to BRD4 albumen The expression inhibiting of MYC is in concentration dependent.It is embodied in when administration concentration is 1nmol/L, compound 1 and 2 pair BRD4 egg The expression inhibiting effect of white degradation and c-MYC is weaker, without obvious phenomenon, as administration concentration increases, compound 1 and 2 pair The degradation of BRD4 albumen and the expression inhibiting effect of c-MYC gradually increase, and reach in 100nmol/L to the complete of BRD4 albumen Degradable and the complete inhibition that c-MYC is expressed.
As shown in figure 3, when the administration concentration of embodiment compound 9 and 10 is 1,3,10,30,100nM, in MV-4-11 In cell line, can be observed in Western-blot experimental result compound 9 and 10 with to BRD4 albumen degradation and The expression inhibiting of c-MYC is in concentration dependent.Specific manifestation increases with administration concentration, compound 9 and 10 pair BRD4 albumen The effect of the expression inhibiting of degradation and c-MYC gradually increases, and reaches in 100nmol/L to the efficient degradation of BRD4 albumen and right The complete inhibition of c-MYC expression.
In conclusion compound of the embodiment of the present invention has significant BET protein degradation and cell inhibitory effect effect, and Inhibitory effect is better than ABBV-075, illustrates that compound of the embodiment of the present invention can be prepared as anti-tumor drug, for oncotherapy or Prevention.
Embodiment 14: tablet
With compound (by taking 1 compound of embodiment as an example) 10g in claim 1 is contained, according to the general pressed disc method of pharmacy After adding auxiliary material 20g to mix, 100 are pressed into, every slice weight 300mg.
Embodiment 15: capsule
With compound (by taking 1 compound of embodiment as an example) 10g in claim 1 is contained, according to wanting for pharmacy capsule It asks after mixing auxiliary material 20g, is packed into Capsules, each capsule weight 300mg.
Embodiment 16: injection
With containing compound (by taking 1 compound of embodiment as an example) 10g in claim 1, according to pharmacy conventional method, into Row activated carbon adsorption, after 0.65 μm of filtering with microporous membrane, hydro-acupuncture preparation is made in filling nitrogen gas tank, and every dress 2mL is filling altogether 100 bottles.
Although describing the present invention by specific embodiment, modification and equivalent variations are for being proficient in this field It will be apparent from for technical staff, and they are included within the scope of the invention.

Claims (12)

1. a kind of pyrrolopyridine ketone bifunctional molecule based on the induction BET degradation of Cereblon ligand shown in formula I Object or its pharmaceutically acceptable salt, hydrate or prodrug are closed,
A-L-B
I
Wherein:
The A is pyrrolopyridine ketone BET protein inhibitor or derivatives thereof；
The B is the smaller ligand of cereblon albumen in E3 ubiquitin ligase complex, selected from amides compound, Phthalimide class compound, Thalidomide, thalidomide derivatives, lenalidomide, lenalidomide derivative, pomalidomide Or pomalidomide derivative；
The L is linking arm, and L is selected from aliphatic chain or fragrant chain；
Wherein, linking arm L is connected by covalent bond with A and B.
2. pyrrolopyridine ketone bifunctional molecule compound according to claim 1, which is characterized in that the L is One of arbitrary structures shown in Formula II:
Wherein:
N is selected from the integer between 1-10.
3. pyrrolopyridine ketone bifunctional molecule compound according to claim 1, which is characterized in that the B is One of arbitrary structures shown in formula III:
Wherein:
W is selected from CH2, C=O, SO2, NH, N- alkyl；
X is selected from O, S；
Y is selected from NH, N- alkyl, N- aryl, N- heterocycle, N- naphthenic base, O, S；
Z is selected from-alkyl ,-naphthenic base ,-Cl ,-F ,-H；
G, G ' is selected from-H, alkyl ,-OH ,-CH2Heterocycle；
R1Selected from-H ,-D ,-F ,-Cl ,-Br ,-I ,-NO2、-CN、-NH2、-OH、-CH3、-CH2F、-CHF2、-CF3、-CH2D、- CHD2、-CD3、-CH2CH3。
4. pyrrolopyridine ketone bifunctional molecule compound according to claim 1 is as shown in general formula IV,
Wherein:
R1、R2、R3、R4It is identical or different, separately it is selected from-H ,-D ,-F ,-Cl ,-Br ,-I ,-NO2、-CN、-NH2、-OH、- CH3、-CH2F、-CHF2、-CF3、-CH2D、-CHD2、-CD3、-CH2CH3；
R5Selected from C1-C6Alkyl ,-H ,-D ,-F ,-Cl ,-Br ,-I ,-NO2、-CN、-NH2、-OH、-CH2F、-CHF2、-CF3、- CH2D、-CHD2、-CD3、-NHSO2CH3、-NHSO2C2H5、-NHCO2CH3、-NHCO2C2H5、-NHCO2C3H7、-NHCO2C4H9、- NHCO2CH(CH3)2、-SO2CH3、-SO2C2H5；
M is selected from unsubstituted ,-CH2-、-CO-、-C(H)(OH)-、-(CH2)mO-、-(CH2)S(O)n、-(CH2)mN (Ra)-, wherein m It is independently 0 or 1, n is independently 0,1 or 2, and wherein Ra is selected from H, C1-C3Alkyl, C1-C3Halogenated alkyl, (C2-C3Alkylidene)- OH or unsubstituted cyclopropyl；
R6Selected from C1-C6Alkyl, C1-C6Alkoxyalkyl, Rb or-(C1-C6Alkylidene)-Rb, wherein every Rb is independently selected from virtue Base, heterocycle, naphthenic base or cycloalkenyl, and every Rb is independently selected from unsubstituted or replaced by 1-5 Rc, wherein Rc is independently Selected from C1-C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Alkoxyalkyl, C2-C6Alkenyl, C2-C6Alkynyl ,-F ,- Cl、-Br、-I、-NO2、-CN、-NH2,-COOH ,-CO- replace monocyclic aryl ,-CO- replace monocyclic heterocycles base ,-replace monocycle virtue Base ,-replace monocyclic heterocycles base；
R7Selected from-H, C1-C6Alkyl；
L is any one in Formula V:
N is selected from the integer between 1-10.
5. pyrrolopyridine ketone bifunctional molecule compound according to claim 4 is as shown in general formula VI:
Wherein:
R1、R2、R3、R4It is identical or different, separately it is selected from-H ,-F ,-Cl ,-Br ,-CH3、-CH2F、-CHF2、-CF3、- CH2D、-CHD2、-CD3；
R7Selected from-H ,-CH3、-CH2CH3；
L is any one in Formula VII:
N is selected from the integer between 1-6.
6. pyrrolopyridine ketone bifunctional molecule compound according to claim 5, which is characterized in that the compound For one of following compounds:
7. pyrrolopyridine ketone bifunctional molecule compound described in any one of claim 1~6, which is characterized in that The compound is prepared by intermediate VIII or IX,
Wherein, R2、R3、R4It is identical or different, separately it is selected from-H ,-F ,-Cl ,-Br ,-CH3、-CH2F、-CHF2、-CF3、- CH2D、-CHD2、-CD3；
R7Selected from-H ,-CH3、-CH2CH3。
8. the preparation method of pyrrolopyridine ketone bifunctional molecule compound described in any one of claim 1~6, Be characterized in that, should the preparation method is as follows:
Wherein, step a is 1. 2. compound reacts to obtain with paratoluensulfonyl chloride compound；Step b be compound 2. with nitrine 3. sodium reacts to obtain compound；Step c is 3. 4. compound reacts to obtain with bromo-acetic acid tert-butyl compound；Step d is chemical combination 4. 5. object reacts to obtain with trifluoroacetic acid compound；Step e is 5. 6. compound reacts to obtain with thionyl chloride compound；Step F is 6. 7. compound reacts to obtain compound with the smaller ligand of cereblon albumen；Step g be compound 8. with 9. the smaller ligand of cereblon albumen reacts to obtain compound；Step h be compound 9. with trifluoroacetic acid reaction Close object 10.；Step j is 7. compound VIII reacts to obtain the compound of general formula VIa expression with compound；Step k is compound IX It 10. reacts to obtain the compound of general formula VIb expression with compound；
Wherein, VIa and VIb is two parts of general formula VI；
Wherein:
R1、R2、R3、R4It is identical or different, separately it is selected from-H ,-F ,-Cl ,-Br ,-CH3、-CH2F、-CHF2、-CF3、- CH2D、-CHD2、-CD3；
R7Selected from-H ,-CH3、-CH2CH3；
N is selected from the integer between 1-6.
9. a kind of pharmaceutical composition, which is characterized in that described in claim 1~6 any one wherein containing therapeutically effective amount Compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, hydrate, prodrug and pharmaceutically acceptable Carrier, diluent, adjuvant, medium or their combination.
10. a kind of pharmaceutical composition according to claim 9, which is characterized in that the dosage form of the pharmaceutical composition is Any one in injection, tablets and capsules.
11. compound described in any one of claim 1~6 and its pharmaceutically acceptable salt or claim 9~10 Any one of described in composition preparation treat or prevent tumour drug in application.
12. application according to claim 11, which is characterized in that the tumour be Huppert's disease, gastric cancer, lung cancer, Breast cancer, the cancer of the esophagus, colon cancer, medulloblastoma, acute myelocytic leukemia, chronic leukemia, melanoma, prostate Cancer, hepatoma, renal cell carcinoma, cervical carcinoma, cutaneum carcinoma, oophoroma, colon cancer, glioma, thyroid cancer and cancer of pancreas Any one.
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