CN108084193A - A kind of BRD4 protein inhibitors - Google Patents

A kind of BRD4 protein inhibitors Download PDF

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Publication number
CN108084193A
CN108084193A CN201711374153.2A CN201711374153A CN108084193A CN 108084193 A CN108084193 A CN 108084193A CN 201711374153 A CN201711374153 A CN 201711374153A CN 108084193 A CN108084193 A CN 108084193A
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alkyl
compound
pharmaceutically acceptable
ester
acceptable salt
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郭守东
袁清泉
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Individual
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • 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
    • C07D471/22—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 systems contains four or more hetero rings

Abstract

The invention belongs to pharmaceutical technology fields, and in particular to the BRD4 protein inhibitors shown in logical formula (I), pharmaceutically acceptable salt, the ester of its facile hydrolysis, its isomers and intermediate and these compounds and its preparation method of intermediate.The BRD4 protein inhibitors of the present invention can be used in preparing the drug for the treatment of and/or pre- preventing tumor.Wherein R1、R2、R3、R4、R5, A, B, C, D, Q, m and n be defined as in the description.

Description

A kind of BRD4 protein inhibitors
1st, technical field
The invention belongs to pharmaceutical technology field, specifically relate to a kind of BRD4 protein inhibitors, its pharmaceutically acceptable salt, its The ester of facile hydrolysis, its isomers and intermediate and these compounds and its preparation method of intermediate, contain these compounds Pharmaceutical preparation.The BRD4 protein inhibitors of the present invention, which can be used in Cancerous disease, includes lung cancer, breast cancer, leukaemia, skin Cancer and lymthoma etc. and autoimmune disease include rheumatoid arthritis, psoriasis, Crohn disease and ulcerative colitis Treatment and the prevention of these diseases.
2nd, background technology
Epigenetic is research hotspot in recent years.Epigenetic can be understood as in different environment and, go out Existing different gene expression, and different physiology phenotypes is finally achieved, but its basic gene composition does not have change.This choosing The mechanism of selecting property is to utilize gene methylation (methylation) and after gene translation to histone (histone) Improvement.It is this after gene translation to the improvement phenomenon of histone (histone), in exposed histone (histone) Methylated on lysine (methylation) and acetylization reaction (acetylation) based on.
Bromodomains (BRD) protein family is the transcription identifying system after an important histone improvement.It Groundwork is the transcription of lysine and then progress back segment of the identification after the acetylation of exposed histone, is divided greatly including albumen The transcription and assimilation of son, the transcription of translation factor (transcription factors) and the activation of RNA polymerase.
So-called " bromo-base structure domain (bromodomain) " means to identify one of the polypeptide of the lysine residue of acetylation Point.In one embodiment, the bromo-base structure domain of BET family members polypeptide includes about 110 amino acid and shared one The conservative folding of kind, the folding include a kind of left-handed bundle of the four α spirals connected by different ring regions, these ring regions are with dyeing Matter interacts.
So-called " BET family polypeptides (BET family polypeptide) " means to include two bromo-base structure domains and one The polypeptide or its segment of additional end (ET) structural domain of kind, live with transcriptional regulatory activity or the Lysine binding of acetylation Property, BET family members include BRD2, BRD3, BRD4 and BRDT.
More and more evidences show many disorders such as cancers now, in terms of pathogenesis may be genetic transcription Caused by imbalance, and simultaneously extragenic mutation institute extremely.Therefore as can effectively control genetic transcription mechanism, such as BRD inhibitor, it will It is to cancer and the very effective therapy of immunity disease.
In the protein family of BRD, BRD4 and the connection of cancer and immunity disease are particularly close.JQ1 is one and generally acknowledges Highly selective BRD4 inhibitor.Substantial amounts of article has recorded JQ1 in a variety of and cancer and the relevant animal mould of immunity disease There is good therapeutic effect in type.But since the drug metabolism of JQ1 compounds is out of condition, and patent protection period is shorter, Therefore it does not have into Human Clinical Study.BRD4 inhibitor Cs PI-0610 is used to treat myelodysplastic syndrome, bone Marrow and bone marrow increment are carrying out the clinical I phases and are studying.BRD (BRD2/3/4) inhibitor MK-8628 is used to treat recurrent glue Matter knurl, solid tumor are carrying out the clinical II phases and are studying.
3rd, the content of the invention
Technical scheme is as follows：
General formula (I) compound represented, its pharmaceutically acceptable salt, the ester or its isomers of its facile hydrolysis：
Wherein,
A, B, C and D represent C or N respectively；
R1And R2Halogen, C are represented respectively1-6Alkyl, C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Alkoxy C1-6Alcoxyl Base, halogenated C1-6Alkyl, halogenated C1-6Alkoxy, C1-6Alkyl amine group, two (C1-6Alkyl) amido, hydroxyl, hydroxyl C1-6Alkyl, carboxylic Base, carboxyl C1-6Alkyl, amino, amino C1-6Alkyl, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl oxy, C1-6Alkyloxycarbonyl, C1-6Alkane Base amide groups, carbamoyl, C1-6Alkyl amine group formoxyl, two (C1-6Alkyl) amido formacyl, amino-sulfonyl, C1-6Alkane Base amido sulfonyl, two (C1-6Alkyl) amido sulfonyl, amino-sulfonyl C1-6Alkyl, C1-6Alkyl sulphonyl or guanidine radicals；
Q represents saturation, fractional saturation, undersaturated has 1~4 selected from N, S, O and/or SO2Heteroatomic 3~14 The heterocycle of member；
R3、R4And R5Hydrogen atom, OH, OR are represented respectively6,-O- aryl ,-OCH2- aryl, C1-6Alkyl, 3~8 yuan of cycloalkanes Base ,-CF3、-OCHF2、-OCF3, halogen ,-CN ,-NR6aR6b, carbonyl ,-COOR6、-COOH、-COR6、-CH(OH)R6、-CH(OR6) R6、-CONR6a R6b、-NHCOR6、-NHSO2R6、-NHSO2- aryl, aryl ,-SR6、-SOR6、-SO2R6、-SO2Aryl contains 1 ~4 are N, O, S, SO and/or SO2Heteroatomic 3~14 yuan of heterocycle；
R6、R6aAnd R6bHydrogen atom or C are represented respectively1-6Alkyl；
M is 0,1 or 2；
N is 1 or 2.
Preferably compound is：
Wherein,
A, B, C and D represent C or N respectively；
R1And R2Halogen, C are represented respectively1-6Alkyl, C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Alkoxy C1-6Alcoxyl Base, halogenated C1-6Alkyl, halogenated C1-6Alkoxy, C1-6Alkyl amine group, two (C1-6Alkyl) amido, hydroxyl, hydroxyl C1-6Alkyl, carboxylic Base, carboxyl C1-6Alkyl, amino, amino C1-6Alkyl, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl oxy, C1-6Alkyloxycarbonyl, C1-6Alkane Base amide groups, carbamoyl, C1-6Alkyl amine group formoxyl, two (C1-6Alkyl) amido formacyl, amino-sulfonyl, C1-6Alkane Base amido sulfonyl, two (C1-6Alkyl) amido sulfonyl, amino-sulfonyl C1-6Alkyl, C1-6Alkyl sulphonyl or guanidine radicals；
Q represents saturation, fractional saturation, undersaturated has 1~4 selected from N, S, O and/or SO2Heteroatomic 5~10 The heterocycle of member；
R3、R4And R5Hydrogen atom, OH, OR are represented respectively6、C1-6Alkyl ,-CF3、-OCHF2、-OCF3, halogen ,-CN ,- NR6aR6b, carbonyl ,-COOR6、-COOH、-COR6、-CH(OH)R6、-CH(OR6)R6、-CONR6a R6b、-NHCOR6、-NHSO2R6- SR6、-SOR6Or-SO2R6；
R6、R6aAnd R6bHydrogen atom or C are represented respectively1-6Alkyl；
M represents 1；
N represents 1.
Preferably compound is：
Wherein,
A, B, C and D represent C or N respectively；
R1And R2Halogen, C are represented respectively1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkyl amine group, hydroxyl, carboxyl, amino or ammonia Base C1-6Alkyl；
Q represent saturation, fractional saturation, it is undersaturated have 1~2 it is miscellaneous selected from heteroatomic 5~10 yuan of N, S or O Ring group；
R3、R4And R5Hydrogen atom, OH, C are represented respectively1-6Alkyl ,-CF3、-OCHF2、-OCF3, halogen ,-CN ,-NR6aR6b、 Carbonyl or-COOH；
R6aAnd R6bHydrogen atom is represented respectively；
M represents 1；
N represents 1.
Preferably compound is：
Wherein,
A, B, C and D represent C or N respectively；
R1And R2Halogen or C are represented respectively1-6Alkyl；
Q represent saturation, fractional saturation, it is undersaturated have 1~2 be selected from N 5~10 yuan of heterocycle；R3、R4And R5 Hydrogen atom or carbonyl are represented respectively；
M represents 1；
N represents 1.
Further preferred compound is：
A, B, C and D represent C or N respectively；
R1Represent halogen；
R2Represent C1-6Alkyl；
R3、R4And R5Hydrogen atom or carbonyl are represented respectively；
M represents 1；
N represents 1.
Particularly preferred compound is：
Detailed description of the invention
" halogen atom " of the present invention includes fluorine atom, chlorine atom, bromine atoms, preferably iodine atom, fluorine atom and chlorine Atom.
" C1-6 alkyl " of the present invention refers to the paraffin section containing 1~6 carbon atom and removes derived from a hydrogen atom The alkyl of linear chain or branch chain, such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tertiary butyl, positive penta Base, isopentyl, 2- methyl butyls, 3- methyl butyls, 1,1- dimethyl propyls, 1,2- dimethyl propyls, neopentyl, 1- ethyls third Base, n-hexyl, isohesyl, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 1,1- dimethylbutyls, 1,2- dimethyl butyrates Base, 1,3- dimethylbutyls, 2,2- dimethylbutyls, 2,3- dimethylbutyls, 3,3- dimethylbutyls, 1- ethyl-butyls, 2- Ethyl-butyl, 1,1,2- thmethylpropyls, 1,2,2- thmethylpropyls, 1- ethyl -1- methyl-propyls and 1- Ethyl-2-Methyls third Base.It is preferred that C1-4Alkyl, C1-3Alkyl.
" C of the present invention1-6Alkoxy " refers to term " C1-6The group that alkyl " is connected by oxygen atom with other structures, Such as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, amoxy, new penta Oxygroup, hexyloxy etc..
" C of the present invention1-6Alkyl-carbonyl " refers to term " C1-6The group that alkyl " is connected by carbonyl with other structures, Such as methyl carbonyl, ethylcarbonyl group, propyl carbonyl, Isopropylcarbonyl, butyl carbonyl, butylcarbonyl, tert-butyl carbonyl, sec-butyl Carbonyl, pentylcarbonyl, neopentyl carbonyl, hexyl carbonyl etc..
" C of the present invention1-6Alkoxy carbonyl group " is term " C1-6The base that alkoxy " is connected by carbonyl with other structures Group, such as methoxycarbonyl group, carbethoxyl group, propylene carbonyl oxygen, butyloxycarbonyl, butoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl, secondary Butoxy carbonyl, penta oxygen carbonyl, new penta oxygen carbonyl, own oxygen carbonyl etc..
" aryl " of the present invention refers to cyclic aromatic groups of the annular atom for 6~14 yuan of carbon atoms, including 6~8 yuan Monocyclic aryl and 8~14 yuan of fused ring aryls.6~8 unit monocycle aryl refer to all undersaturated aryl, such as phenyl, ring pungent four Alkenyl etc..8~14 yuan of fused ring aryls refer to share two adjacent carbon atom institutes each other by two or more cyclic structures It is formed, at least one ring is the cyclic group of all undersaturated aromatic rings, including 8~14 yuan of whole unsaturated condensed ring virtues Base, naphthalene, anthryl and phenanthryl etc. further includes 8~14 yuan of fractional saturation fused ring aryls, such as 3~8 yuan of monocyclic cycloalkanes of saturation of benzo 3~8 yuan of base, benzo fractional saturation monocyclic cycloalkyls, specific example such as 2,3- dihydro -1H- indenyls, 1H- indenyls, 1,2,3,4- tetra- Hydrogen naphthalene, DHN 1,4 dihydronaphthalene base etc..
It is described that there is 1~4 selected from N, S, O, SO and/or SO2Heteroatomic 3-14 circle heterocycles refer to single heterocycle, simultaneously Ring, loop coil or bridged ring, described and ring, loop coil or bridged ring refer to one of non-common carbon atom by N, S, O, SO and/or SO2 Hetero atom replacement formed and heterocycle, spiroheterocyclic, bridge heterocycle.
And heterocycle refers to containing 6~14 annular atoms (hetero atom there are one wherein at least containing) by two or more Cyclic structure shares two adjacent atoms and connects to be formed and ring structure each other, including 6~14 yuan of unsaturations and heterocycle Base, 6~14 yuan of fractional saturations and heterocycle, 6~10 yuan of saturations and heterocycle.6~14 yuan of unsaturations and heterocycle, refer to whole Ring be undersaturated condensed cyclic structure, such as the structure that the unsaturated single heterocycles of 3~8 yuan of benzo are formed, 3~8 yuan are unsaturated single Structure that heterocycle and 3~8 yuan of unsaturated single heterocycles are formed etc., specific example includes but not limited to：Benzofuranyl, benzo It is different furyl, benzothienyl, indyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazole base, quinolyl, different Quinolyl, acridinyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, phenol piperazine base, pteridine radicals, purine Base, naphthyridines base,Deng.6~14 yuan of fractional saturations and heterocycle, refer at least contain The condensed cyclic structure of one fractional saturation ring, such as the structure that 3~8 yuan of fractional saturation list heterocycles of benzo are formed, 3~8 yuan of parts are satisfied Structure formed with single heterocycle and 3~8 yuan of fractional saturation list heterocycles etc., specific example includes but not limited to：1,3- dihydros Benzofuranyl, benzo [d] [1.3] dioxa cyclopentenyl, isoindoline base, Chromanyl, 1,2,3,4- nafoxidines simultaneously [3, 4-c] pyrroles, Deng.6~10 yuan of saturations and heterocycle, it is the condensed cyclic structure of saturation to refer to whole rings, such as 3~8 yuan of saturation list heterocycles and 3 The structure that~8 yuan of saturation list heterocycles are formed, specific example include but are not limited to：Cyclobutane and nafoxidine base, ring penta Alkane and nafoxidine base, azetidine and imidazolidinyl,Deng.
Bridge heterocycle refers to the caged scaffold formed by 5~12 annular atoms (hetero atom there are one wherein at least containing).“5 ~12 yuan of bridge heterocycles " include 5~12 yuan of saturation bridge heterocycles, 5~12 yuan of fractional saturation bridge heterocycles.
5~12 yuan of saturation bridge heterocycles, it is the cyclic group of saturation to refer to all rings in the bridge heterocycle, is preferably 7~8 First saturation bridge heterocycle, specific example include but not limited to：
Deng.
5~12 yuan of fractional saturation bridge heterocycles, referring to has at least one ring in the bridge heterocycle be undersaturated cyclic group, Preferably 7~8 yuan of fractional saturation bridge heterocycles, specific example include but not limited to： Deng.
Spiro heterocyclic radical refers to the spirane structure formed by 5~12 annular atoms (hetero atom there are one wherein at least containing).5~ 12 yuan of spiroheterocyclics include 5~12 yuan of saturation spiroheterocyclics, 5~12 yuan of fractional saturation spiroheterocyclics.
5~12 yuan of saturation spiroheterocyclics refer to that all rings in the spiroheterocyclic are the cyclic group of saturation, specific example bag It includes but is not limited only to： Deng.
5~12 yuan of fractional saturation spiroheterocyclics refer to that at least one ring is undersaturated cyclic group in the spiroheterocyclic, is had Body example includes but are not limited to：、、、Deng.
Containing there are one the heterocyclic compounds of N：Such as aziridine (ethylene imine), azetidine, 1,2- diazacyclos Butane, pyrrolidines, 2,5- pyrrolin, 2H- pyrroles or 3H- pyrroles (different pyrroles), piperidines, dihydropyridine, tetrahydropyridine, a word used for translation heptan Because etc.；
Containing there are one the heterocyclic compounds of O：Such as ethylene oxide, propylene oxide (azetidine), tetrahydrofuran, dihydro Furans, 2H- pyrans, 4H- pyrans, oxinane, 3,4- dihydro -2H- pyrans,Heptan English etc.；
Containing there are one the heterocyclic compounds of S：Such as thiirane, Thietane, tiacyclopentane (thiophane), 2,5- dihydro-thiophenes base, thiophene alkane (hexahydro thiapyran), thia cyclohexyl, thia cycloheptane etc.；
Containing there are two the heterocyclic compounds of N：Such as imidazolidine, imidazoline (4,5- glyoxalidine), pyrazolidine, pyrazoline (4,5- pyrazolines), piperazine etc.；
Containing there are two the heterocyclic compounds of O：Such as dioxirane, 1,2- dioxetanes, dioxolanes (1,3- Dioxolanes), dioxane (1,3- dioxanes, 1,4- dioxanes), Dioxepane etc.；
Containing there are two the heterocyclic compounds of S：Such as 1,3- dithiolanes, 1,3- dithiane etc.；
Containing there are three the heterocyclic compounds of O：Such as three oxygen, six ring (threeAlkane) etc.；
Containing there are one the heterocyclic compounds of mono- O of N：Such as oxaza propane, tetrahydrochyseneAzoles, 4,5- dihydrosAzoles, four Hydrogen is differentAzoles, 4,5- dihydros are differentAzoles, 2,3- dihydros are differentAzoles, morpholine, tetrahydrochysenePiperazine, dihydroPiperazine,Piperazine, 5,6- dihydros- 4H-1,3-Piperazine etc.；
Containing there are one the heterocyclic compounds of mono- S of N：Such as thiazoline (4,5- thiazolines), thiazolidine, thiomorpholine, 2H-1,3- thiazines, 4H-1,3- thiazines, 5,6- dihydro -4H-1,3- thiazines, 6H-1,3- thiazines, 2H-1,4- thiazines, 4H-1,4- Thiazine etc.；
Containing there are one the heterocyclic compounds of mono- S of O：Such as oxathiolane, 1,3- thioxane, oxygen thia ring Hexane (thiopheneAlkane) etc.；
Containing there are two the heterocyclic compounds of mono- O of N：Such asDiazine (oxa- diazine) etc.；
Containing there are one the heterocyclic compounds of mono- O of N, mono- S：Such as N1O1S1：Thiazine etc..
The preparation method of further requirement protection general formula (I) described compound of the present invention.
The preparation method of general formula (I) compound of the present invention includes making compound shown in general formula (IV), its is pharmaceutically acceptable Salt or its facile hydrolysis ester, with compound shown in general formula (V), its pharmaceutically acceptable salt, its facile hydrolysis ester or its is different Structure body reacts,
Wherein, R1、R2、R3、R4、R5, A, B, C, D, Q, m and n as defined hereinabove.
Method described in following flows and/or those of ordinary skill in the art have may be employed in above-claimed cpd of the present invention Other technologies for knowing synthesize, but are not limited only to following methods.
When n is 1, reaction scheme is：
Reaction step：
The preparation of step 1 compound c
Raw material a is dissolved in acetonitrile, adds in calcium hydroxide, temperature control is less than 30 DEG C, and raw material b (210g, 1.2mol) is added dropwise, after Ambient temperature overnight.The reaction was complete for TLC monitoring.Filtering, filtrate are spin-dried for, and add in water, EA extractions afterwards, and organic phase is washed with saturated sodium bicarbonate It washs, dries to obtain yellow solid compound c, be directly used in next step.
The preparation of step 2 compound d
Compound c is added in phosphorus oxychloride, is refluxed overnight.The reaction was complete for TLC monitoring.It is spin-dried for most of trichlorine oxygen Phosphorus, remaining grease, which is poured into mixture of ice and water, to be stirred, and has yellow solid precipitation, and filtration drying obtains yellow solid compound d.
The preparation of step 3 compound e
Compound d is added in ammonium hydroxide, is stirred at room temperature, until solid all dissolves, is spin-dried for, is obtained brown solid, by solid It is beaten with EA, filters to obtain light tan solid compound e.
The preparation of step 4 compound g
Intermediate e is dissolved in dichloromethane, adds in triethylamine stirring.Raw material f is dissolved in dichloromethane, 30 DEG C of dropwise additions of temperature control It into above-mentioned mixed liquor, drips off and is refluxed overnight, TLC monitorings reaction is substantially completely.Filtering, filtrate are spin-dried for, and residue is added to second Acid：1,2- dichloroethanes=1:In 1 mixing liquid, it is refluxed overnight.Solution is spin-dried for, pours into saturated sodium carbonate solution, there is solid analysis Go out, filter, ethyl alcohol recrystallization obtains yellow solid compound g.
The preparation of step 5 compound h
Intermediate g is added in toluene, adds in HMPA, Lawesson ' s reagent, reflux is spin-dried for solvent column chromatography Obtain yellow solid compound h.
The preparation of step 6 compound of formula I
Intermediate h is taken to be dissolved in tetrahydrofuran, is cooled to 0 DEG C, adds in hydrazine hydrate stirring.Temperature is kept to add in triethylamine, after Continuous stirring, dropwise addition chloroacetic chloride, which is warming up to, to be stirred at room temperature, and is added in acetic acid, is warming up to and is refluxed overnight, and TLC monitoring reactions are basically completed, It is spin-dried for solvent column chromatography and obtains yellow solid formula (I) compound.
In reaction equation, R1、R2、R3、R4、R5, A, B, C, D, Q and m as defined hereinabove.
Intermediate of the compound in preparation process shown in further requirement protection general formula (I) of the present invention, i.e. general formula (II), (III) compound represented, its pharmaceutically acceptable salt, the ester or its isomers of its facile hydrolysis, wherein, R1、R2、R3、R4、R5、 A, B, C, D, Q, m and n be as defined hereinabove.
" pharmaceutically acceptable salt " of any of the above-described compound of the present invention includes alkali metal salt, such as sodium salt, sylvite, lithium salts Deng；Alkali salt, such as calcium salt, magnesium salts；Other metal salts, such as aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt；It is inorganic Alkali salt, such as ammonium salt；Organic alkali salt, such as t-octyl amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycine alkyl ester Salt, ethylenediamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexyl amine salt, N, N '-dibenzyl second Diamine salts, chloroprocanine salt, procaine salt, diethanolamine salt, N- benzyls-phenethyl amine salt, piperazine salt, tetramethyl amine Salt, three (methylol) aminomethane salt；Halogen acid salt, such as hydrofluoride, hydrochloride, hydrobromate, hydriodate；Inorganic acid Salt, such as nitrate, perchlorate, sulfate, phosphate；Rudimentary alkyl sulfonate, such as mesylate, fluoroform sulphonate, second Sulfonate etc.；Arylsulphonate, such as benzene sulfonate, P-TOLUENE SULFO ACID 99's salt；Acylate, such as acetate, malate, fumaric acid Salt, succinate, citrate, tartrate, oxalates, maleate etc.；Amino-acid salt, as glycinate, trimethyl are sweet Propylhomoserin salt, arginine salt, ornithine salt, glutamate, aspartate etc..
" ester of facile hydrolysis " of any of the above-described compound of the present invention refers to that those can hydrolyze generation parent in human body Close the pharmaceutically acceptable ester of object.It is readily apparent that the ester susceptible to hydrolysis of the compounds of this invention for those skilled in the art It can be formed, can be made by conventional method at the free carboxy or hydroxyl of the compound.
" isomers " of any of the above-described compound of the present invention includes all differences to alloisomerism, diastereo-isomerism and mutually variation Configuration formula.When a key is represented with a wedge, this shows that the key will come out from paper in three-dimensional, and when a key is shade When, this shows that the key will be returned in paper in three-dimensional.
Further requirement of the present invention protection includes any compound recited above, its pharmaceutically acceptable salt, it is easy The pharmaceutical composition of the ester of hydrolysis or its isomers and other medicinal active ingredients.
The present invention also includes any of the above-described compound, its pharmaceutically acceptable salt, the ester or its isomers of its facile hydrolysis, It can be configured to manner known in the art clinically or pharmaceutically acceptable any dosage form, with oral, parenteral, rectum Or the modes such as transpulmonary administration are applied to the patient for needing this treatment.During for being administered orally, conventional solid pharmaceutical preparation is can be made into, Such as tablet, capsule, pill, granule；Oral liquid is may be made as, such as oral solution, oral suspensions, syrup Agent etc..When oral formulations are made, suitable filler, adhesive, disintegrant, lubricant etc. can be added in.It is given for parenteral During medicine, injection is can be made into, including parenteral solution, injection sterile powder and concentrated solution for injection.When injection is made, it can be used Conventional method production in existing pharmaceutical field, when preparing injection, can be added without additives, also can be according to the property of drug Add in suitable additives.During for rectally, suppository etc. can be made into.During for transpulmonary administration, inhalant or spray can be made into Mist agent etc..Containing a effective amount of formula of physiology (I) compound represented 0.01g~10g in per unit preparation, can be 0.01g, 0.05g、0.1g、0.125g、0.2g、0.25g、0.3g、0.4g、0.5g、0.6g、0.75g、1g、1.25g、1.5g、1.75g、 2g, 2.5g, 3g, 4g, 5g, 10g etc..
The compounds of this invention, its pharmaceutically acceptable salt or its stereoisomer have preferable BRD4 inhibitory action, It is that preferably there is excellent antitumor action and the drug for the treatment of autoimmune diseases effect.Simultaneously the compounds of this invention, its Pharmaceutically acceptable salt or its stereoisomer are preparing treating cancer disease (including lung cancer, breast cancer, leukaemia, skin Cancer and lymthoma etc.) and autoimmune disease (including rheumatoid arthritis, psoriasis, Crohn disease and ulcerative colitis It is scorching) in play an important role.
The autoimmunity and/or inflammatory disease that can be influenced using compound according to the present invention and composition are included but not It is limited to：Psoriasis, allergy, regional enteritis, irritable bowel syndrome, sjogren disease, tissue graft rejection reaction and shifting The hyperacute rejection of organ is planted, asthma, systemic loupus erythematosus ＜ and relevant glomerulonephritis ＞, dermatomyositis are multiple Hardening, chorionitis, vasculitis (the relevant and other vasculitis ＞ of ANCA-, autoimmune haemolytic and thrombocytopenic disease Shape, Gourde(G) Paasche syndrome ＜ and relevant glomerulonephritis and empsyxis ＞, atherosclerosis, rheumatoid arthritis, slowly The Idiopathic Thrombocytopenic Purpura (ITP) of property, Addison disease, Parkinson's disease, Alzheimer disease, diabetes, septic Shock and myasthenia gravis.
What is included herein is therapy, wherein at least one chemical entities provided herein are combined with anti-inflammatory agent Administration.Anti-inflammatory agent includes but not limited to：NSAID, non-specific and COX-2 specificity cyclooxygenase enzyme inhibitors, gold compound, Cortical steroid, methotrexate (MTX), Tumor Necrosis Factor Receptors (TNF) receptor antagonist, immunosuppressor and methotrexate (MTX).
The example of NSAID includes but not limited to, brufen, Flurbiprofen, naproxen and naproxen sodium, and Diclofenac is double The combination of the fragrant sour sodium of chlorine and Misoprostol, sulindac, benzene daybreak propionic acid, Diflunisal, piroxicam, Indomethacin, support degree Acid, fenoprofen calcium, Ketoprofen, Nabumetone sodium, sulfasalazine, tolmetin sodium and hydroxychloroquine.The example of NSAID further includes COX-2 specific inhibitors such as celecoxib, valdecoxib, Lu meter Kao former times and/or etoricoxib.
In some embodiments, anti-inflammatory agent is salicylate or salt.Salicylate or salt include but not limited to acetyl group Salicylic acid or aspirin, sodium salicylate and Choline Salicylate and magnesium salicylate.
Anti-inflammatory agent can also be cortical steroid.For example, cortical steroid can be cortisone, and dexamethasone, first Prednisolone, prednisolone, Inflamase or prednisone.
In a further embodiment, anti-inflammatory agent is gold compound such as sodium aurothiomalate or Anranofin.
Present invention additionally comprises wherein anti-inflammatory agent be metabolic poison such as dihydrofolate reductase inhibitor such as methotrexate (MTX) or The embodiment of dihydrooratic acid salt dehydrogenase inhibitor such as leflunomide.
It is anti-monoclonal antibody (such as according to storehouse pearl that other embodiments of the present invention, which is related to wherein at least one anti-inflammatory compound, Monoclonal antibody or the combination for training gram pearl monoclonal antibody ＞, TNF antagonist such as Etanercept (entanercept) or infliximab, the English profit Former times monoclonal antibody is a kind of anti-TNF alpha monoclonal antibody.
It is that immunosuppressant compounds are such as selected from that other embodiments of the present invention, which are related to wherein at least one active drug, Methotrexate (MTX), leflunomide, ring born of the same parents are plain, tacrolimus, the immunosuppressant compounds in imuran and mycophenolate mofetil Combination.
The compounds of this invention has the following advantages compared with the immediate prior art：
(1) BRD4 protein inhibitors of the present invention have preferable BRD4 inhibitory action；
(2) BRD4 protein inhibitors preparation process of the present invention is simple, and drug purity is high, stable quality, is easy to be advised greatly Mould industrial production.
4th, specific embodiment
The specific embodiment of form by the following examples makees further specifically the above of the present invention It is bright.But the scope that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following embodiment.
Embodiment 1 6- (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3,4] [1,4]-diaza [5,6-b] -4- indyls) methyl) piperidines -2- ketone (compound 1) preparation
Step 1：The preparation of (4- chlorphenyls)-(2- hydroxyl -1H-3- indyls) methyl ketone (intermediate C)
Raw material A (133g, 1.0mol) is dissolved in acetonitrile 1L, adds in calcium hydroxide (148g, 2.0mol), temperature control is less than 30 Raw material B (210g, 1.2mol), rear ambient temperature overnight is added dropwise in degree.The reaction was complete for TLC monitoring.Filtering, filtrate are spin-dried for, and add in 2L afterwards Water, EA extractions (500ml*3), organic phase is washed with saturated sodium bicarbonate, dries to obtain yellow solid 210g, yield 77.8%, it is directly used in next step.
Step 2：The preparation of (4- chlorphenyls)-(the chloro- 1H-3- indyls of 2-) methyl ketone (intermediate D)
Intermediate C (210g, 0.78mol) is added in 1L phosphorus oxychloride, is refluxed overnight.The reaction was complete for TLC monitoring.Rotation Most of phosphorus oxychloride is killed, remaining grease pours into 2L mixture of ice and water and stirs 1h, there is yellow solid precipitation, filtration drying Obtain yellow solid 160g, yield 71%.
Step 3：The preparation of (4- chlorphenyls)-(2- amino -1H-3- indyls) methyl ketone (intermediate E)
Intermediate D (160g, 0.55mol) is added in ammonium hydroxide 800ml, is stirred at room temperature for 24 hours, until solid all dissolves, It is spin-dried for, obtains brown solid, solid is beaten with EA500ml, filter to obtain light tan solid 125g, yield 83%.
Step 4：(S) -5- (4- chlorphenyls) -3- (2- oxo-piperidine -1- methyl) -3,10- dihydros -1H- [1,4] azepine seven The preparation of ring simultaneously [5,6-b] indol-2-one (intermediate G)
Intermediate E (120g, 0.44mol) is dissolved in 600ml dichloromethane, is added in triethylamine (53g, 1.2mol) and is stirred. Raw material F (225g, 1.1mol) is dissolved in 100ml dichloromethane, 30 DEG C of temperature control is added drop-wise in above-mentioned mixed liquor, drips off and flowed back At night, TLC monitorings reaction is substantially completely.Filtering, filtrate are spin-dried for, and residue is added to acetic acid：1,2- dichloroethanes=1:1 mixed liquor In body 1L, it is refluxed overnight.Solution is spin-dried for, pours into saturated sodium carbonate solution, there is solid precipitation, is filtered, ethyl alcohol recrystallization obtains yellow Solid 51g.Yield 26%.
Step 5：(S) -5- (4- chlorphenyls) -3- (2- oxo-piperidine -1- methyl) -3,10- dihydros -1H- [1,4] azepine seven The preparation of ring simultaneously [5,6-b] indoles -2- thioketones (intermediate H)
Intermediate G (50g, 0.12mol) is added in toluene 500ml, adds in HMPA (24g, 0.14mol), Lawesson ' sreagent (59g, 0.14mol), flow back 3h, is spin-dried for solvent column chromatography and obtains yellow solid 41g, yield 79%. (eluant dichloromethane：Methanol=10:1)
Step 6：6- (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3,4] [1,4]-diaza [5,6-b] -4- indyls) methyl) piperidines -2- ketone (compound 1) preparation
Intermediate H (10g, 23mmol) is taken to be dissolved in tetrahydrofuran 100ml, is cooled to 0 DEG C, add in hydrazine hydrate (3.5g, 46mmol) stir 2h.Keep temperature add in triethylamine (4.6g, 46mmol), continue stir 1h, be added dropwise chloroacetic chloride (4g, It 46mmol) is warming up to and 3h is stirred at room temperature, add in acetic acid 50ml, be warming up to and be refluxed overnight, TLC monitoring reactions are basically completed, and are spin-dried for Solvent column chromatography obtains yellow solid 1.7g.Yield 12%.
Molecular formula：C25H23N6ClO molecular weight：458.16LC-MS(M+H)+:459
1H NMR(DMSO)δ1.51(2H,t),δ1.57(2H,m),δ2.18(2H,t),δ2.36-2.45(5H,m),δ 3.74 (1H, m), δ 4.41 (1H, t), δ 7.11-7.13 (2H, m) 7.30 (2H, s), δ 7.45 (2H, s), δ 7.89-7.93 (2H, m),δ9.59(1H,br),δ10.83(1H,br).
2 6- of embodiment (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3,4] [1,4]-diaza [5,6-b] -4- indyls) methyl) hexahydropyrimidine -2- ketone (compound 2) preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C24H22N7ClO molecular weight：459.16 LC-MS(M+H)+:460
1H NMR(DMSO)δ1.56(2H,t),δ1.70(2H,m),,δ2.39-2.57(5H,m),δ3.90(1H,m),δ 4.60 (1H, t), δ 7.32-7.67 (2H, m) 7.49 (2H, s), δ 7.79 (2H, s), δ 7.99-8.12 (2H, m), δ 9.01 (1H, br),δ10.32(2H,br).
3 6- of embodiment (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3,4] [1,4]-diaza [5,6-b] -4- indyls) methyl) pyrroline-2-one (compound 3) preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C24H21N6ClO molecular weight：444.15 LC-MS(M+H)+:445
1H NMR(DMSO)δ1.41-1.57(4H,m),,δ2.36-2.45(5H,m),δ3.74(1H,m),δ4.41(1H, T), δ 7.11-7.13 (2H, m) 7.30 (2H, s), δ 7.45 (2H, s), δ 7.89-7.93 (2H, m), δ 9.59 (1H, br), δ 10.83(1H,br).
4 6- of embodiment (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3,4] [1,4]-diaza [5,6-b] -4- indyls) methyl) imidazoline -2- ketone (compound 4) preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C23H20N7ClO molecular weight：445.14 LC-MS(M+H)+:446
1H NMR(DMSO)δ1.79(2H,d),δ2.22(3H,s),δ2.36-2.45(2H,m),δ3.41(1H,m),δ 4.01 (1H, t), δ 7.07-7.11 (2H, m) 7.25 (2H, s), δ 7.34 (2H, s), δ 7.66-7.69 (2H, m), δ 8.87 (1H, br),δ10.01(2H,br).
Embodiment 5 6- (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3,4] [1,4]-diaza [5,6-b] -4- indyls) methyl) pyrimid-2-one (compound 5) preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C25H19N6ClO molecular weight：454.13 LC-MS(M+H)+:455
1H NMR(DMSO)2.45(3H,s),δ3.41-3.57(3H,m),δ3.86(1H,m),δ7.07-7.11(2H,m) 7.25 (2H, s), δ 7.30 (1H, s) δ 7.34 (2H, s), (1H, t) the δ 7.66-7.69 of δ 7.50 (2H, m), δ 7.91 (1H, d) δ 9.45(1H,br),δ11.33(1H,br).
6 6- of embodiment (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3,4] [1,4]-diaza [5,6-b] -4- indyls) methyl) pyrimidine-2,4-dione (compound 6) preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C24H18N7ClO2Molecular weight：471.12 LC-MS(M+H)+:472
1H NMR (DMSO) 2.39 (3H, s), δ 3.12-3.35 (3H, m), δ 7.12 (2H, m) 7.25 (2H, s), δ 7.30 (1H,s)δ7.34(2H,s),δ7.66-7.69(2H,m),δ9.57(2H,br),δ12.33(1H,br).
7 8- of embodiment (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3,4] [1,4]-diaza [5,6-b] -4- indyls) methyl) -2- azaspiros [4,4] nonane -2- ketone (compound 7) preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C28H27N6ClO molecular weight：498.19 LC-MS(M+H)+:499
1H NMR(DMSO)δ1.51-1.70(4H,m),δ1.85-2.03(6H,m),δ3.33(3H,s),δ3.46-3.65 (3H, m), δ 4.65 (1H, t), δ 7.11-7.20 (4H, m), δ 7.45 (2H, s), δ 7.89-7.93 (2H, m), δ 10.34 (1H, br),δ12.87(1H,br).
8 eight 9- of embodiment (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3, 4] [1,4]-diaza [5,6-b] -4- indyls) methyl) -2- azaspiros [4,5] decane -2- ketone (compound 8) preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C29H29N6ClO molecular weight：512.21 LC-MS(M+H)+:513
1H NMR(DMSO)δ1.38(2H,m),δ1.55-1.83(8H,m),δ1.93(2H,d),δ(3.11,s)δ3.34 (2H, m) δ 3.65 (1H, m), δ 4.65 (1H, t), δ 7.11-7.20 (4H, m), δ 7.77 (2H, s), δ 7.83-7.91 (2H, m), δ 9.56(1H,br),δ11.87(1H,br).
9 9- of embodiment (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3,4] [1,4]-diaza [5,6-b] -4- indyls) methyl) -2- azaspiros [5,4] decane -2- ketone (compound 9) preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C29H29N6ClO molecular weight：512.21LC-MS(M+H)+:513
1H NMR(DMSO)δ1.40(4H,m),δ1.50-1.83(4H,m),δ1.93(2H,s),δ(2.01,s)δ(3.01, S) δ 3.44 (2H, m) δ 3.56 (1H, m), δ 4.24 (1H, t), δ 7.19 (2H, d), δ 7.67 (2H, d), δ 7.83-7.91 (4H, m),δ9.79(1H,br),δ11.56(1H,br).
10 6- of embodiment (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3, 4] [1,4]-diaza-[5,6-b] -4- [1,8a- dihydro-imidazols [1,2-a] pyridine) methyl) piperidines -2- ketone (compound 10) Preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C24H22N7ClO molecular weight：459.16 LC-MS(M+H)+:460
1H NMR(DMSO)δ1.51(2H,t),δ1.57(2H,m),δ2.18(2H,t),δ2.36-2.45(5H,m),δ 3.74 (1H, m), δ 4.41 (1H, t), δ 7.10-7.17 (2H, dd) 7.30 (2H, s), δ 7.45-7.60 (2H, m), δ 8.34- 8.40(2H,m),δ11.37(1H,br)
11 6- of embodiment (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3, 4] [1,4]-diaza-[5,6-b] -4- [1,8a- dihydro-imidazols [1,2-a] pyridine) methyl) pyrroles -2- ketone (compound 11) Preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C23H20N7ClO molecular weight：445.14 LC-MS(M+H)+:446
1H NMR(DMSO)δ1.45-1.52(2H,m),δ1.55-1.64(2H,m),δ2.44(2H,m),2.89(3H,s)δ 3.66 (1H, m), δ 4.05 (1H, t), δ 7.08-7.12 (2H, m) 7.30 (2H, s), δ 7.45 (2H, s), δ 7.89-7.93 (2H, m),δ11.63(1H,br).
12 6- of embodiment (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3, 4] [1,4]-diaza-[5,6-b] -4- [1,8a- dihydro-imidazols [1,2-a] pyridine) methyl) pyrimid-2-one (compound 12) Preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C24H18N7ClO molecular weight：455.13 LC-MS(M+H)+:456
1H NMR(DMSO)2.45(3H,s),δ3.41-3.47(2H,m),δ3.68,(1H,m)δ3.89(1H,m),δ 7.07-7.13 (2H, m) 7.25 (2H, s), δ 7.32-7.45 (3H, m) δ 7.34 (2H, s), δ 7.91-8.11 (2H, d) δ 8.17- 8.22(2H,m)δδ12.19(1H,br).
13 6- of embodiment (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3, 4] [1,4]-diaza-[5,6-b] -4- [1,3a- dihydro-pyrroles [1,5-a] pyridine) methyl) piperidines -2- ketone (compound 13) Preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C24H22N7ClO molecular weight：459.16LC-MS(M+H)+:460
1H NMR(DMSO)δ1.53(2H,t),δ1.56(2H,m),δ2.32(2H,t),δ2.45-2.55(5H,m),δ 3.81 (1H, m), δ 4.32 (1H, t), δ 7.15-7.18 (2H, m) 7.31 (2H, s), δ 7.67 (2H, s), δ 8.11-8.32 (2H, m),δ11.83(1H,br).
14 6- of embodiment (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3, 4] [1,4]-diaza-[5,6-b] -4- [1,3a- dihydro-pyrroles [1,5-a] pyridine) methyl) pyrroles -2- ketone (compound 14) Preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C23H20N7ClO molecular weight：445.14 LC-MS(M+H)+:446
1H NMR(DMSO)δ1.59(2H,m),δ2.16(2H,m),,δ2.48-2.59(5H,m),δ3.86(1H,m),δ 4.37 (1H, t), δ 7.12-7.15 (2H, m) 7.35 (2H, s), δ 7.68 (2H, s), δ 8.12-8.22 (2H, m), δ 11.33 (1H, br).
15 6- of embodiment (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3, 4] [1,4]-diaza-[5,6-b] -4- [1,3a- dihydro-pyrroles [1,5-a] pyridine) methyl) pyrimid-2-one (compound 15) Preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C24H18N7ClO molecular weight：455.13 LC-MS(M+H)+:456
1H NMR(DMSO)2.49(3H,s),δ3.44-3.58(3H,m),δ3.94(1H,m),δ7.15-7.21(2H,m) 7.32 (2H, s), δ 7.39 (1H, s) δ 7.45 (2H, s), (1H, t) the δ 8.01-8.12 of δ 7.71 (2H, m), δ 8.23 (1H, d) δ 11.33(1H,br).
16 6- of embodiment (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3, 4] [1,4]-diaza-[5,6-b] -4- [1H- pyrroles [2,3-c] pyridine) methyl) piperidines -2- ketone (compound 16) preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C24H22N7ClO molecular weight：459.16 LC-MS(M+H)+:460
1H NMR(DMSO)δ1.53(2H,t),δ1.59(2H,m),δ2.16(2H,t),δ2.33-2.43(5H,m),δ 3.76 (1H, m), δ 4.42 (1H, t), δ 7.11-7.31 (4H, m), δ 7.45 (1H, s), δ 7.56 (1H, d), 7.77 (1H, d), δ 9.37(1H,br),δ10.61(1H,br).
17 6- of embodiment (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3, 4] [1,4]-diaza-[5,6-b] -4- [1H- pyrroles [2,3-c] pyridine) methyl) pyrroles -2- ketone (compound 17) preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C23H20N7ClO molecular weight：445.14 LC-MS(M+H)+:446
1H NMR(DMSO)δ1.50(2H,t),δ1.53(2H,m),δ2.11(2H,t),δ2.33(3H,d)δ2.46(2H, M), δ 3.78 (1H, m), δ 4.43 (1H, t), δ 7.14-7.36 (4H, m), δ 7.47 (1H, s), δ 7.57 (1H, d), 7.73 (1H, d),δ10.17(1H,br),δ11.61(1H,br).
18 6- of embodiment (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3, 4] [1,4]-diaza-[5,6-b] -4- [1H- pyrroles [2,3-c] pyridine) methyl) pyrimid-2-one (compound 18) preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C24H18N7ClO molecular weight：455.13 LC-MS(M+H)+:456
1H NMR(DMSO)δ2.53(3H,d)δ2.70(2H,m),δ3.58(1H,m),δ4.23(1H,t),δ7.14-7.36 (4H, m), δ 7.47-7.52 (3H, m), δ 7.60 (1H, d), δ 7.66 (1H.d) 7.75 (1H, d), δ 10.17 (1H, br), δ 11.61(1H,br).
19 6- of embodiment (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3, 4] [1,4]-diaza-[5,6-b] -4- [1H- pyrroles [3,2-c] pyridine) methyl) piperidines -2- ketone (compound 19) preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C24H22N7ClO molecular weight：459.16 LC-MS(M+H)+:460
1H NMR(DMSO)δ1.49(2H,t),δ1.64(2H,m),δ2.19(2H,t),δ2.31-2.42(5H,m),δ 3.73 (1H, m), δ 4.40 (1H, t), δ 7.11 (2H, d) 7.24 (2H, d), δ 7.69 (1H, s), δ 7.76 (1H, d), 7.89 (1H, d),δ10.17(1H,br),δ11.41(1H,br).
20 6- of embodiment (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3, 4] [1,4]-diaza-[5,6-b] -4- [1H- pyrroles [3,2-c] pyridine) methyl) pyrimid-2-one (compound 20) preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C24H18N7ClO molecular weight：455.13 LC-MS(M+H)+:456
1H NMR(DMSO)δ2.42(3H,s),δ3.53(1H,m),δ(2H,t)δ4.27(1H,t),δ7.08(2H,d)δ 7.14 (2H, d), δ 7.33-7.40 (3H, m) δ 7.59 (1H, s), δ 7.72 (1H, d), 7.89 (1H, d), δ 10.17 (1H, br), δ 11.41(1H,br).
21 6- of embodiment (((S) -6- (4- chlorphenyls) -1- methyl -4,11- dihydros-[1,2,4]-triazole [3', 4':3, 4] [1,4]-diaza-[5,6-b] -4- [1H- pyrroles [3,2-c] pyridine) methyl) pyrroles -2- ketone (compound 21) preparation
Synthetic method refers to reference implementation example 1.
Molecular formula：C23H20N7ClO molecular weight：445.14 LC-MS(M+H)+:446
1H NMR(DMSO)δ2.19-2.33(4H,m),δ2.42(3H,s),δ3.56-3.70(3H,m),δ4.26(1H, T), δ 7.12 (2H, d) 7.25 (2H, d), δ 7.39 (1H, s), δ 7.56 (1H, d), 7.69 (1H, d), δ 10.67 (1H, br), δ 11.48(1H,br).
External anti-bromo-base structure domain -4 (BRD4) determination of activity of 22 the compounds of this invention of embodiment
The binding ability of compound and BRD4 is measured using 384 hole AlphaScreen screening experiments.
Receptor：The recombinant human B RD4 albumen of Bacillus coli cells pNIC-28-Bsa4 expression adds in 6 histidine marks in N-terminal Label.It with histidine-tagged BRD4 is extracted from Bacillus coli cells, is purified by nickel chelate column affinity chromatography, 10- 500mM imidazoles carries out gradient elution, is carried out further with 75 size exclusion chromatographies of HiLoad 16/60Superdex (SEC) Purifying.It is measured with Agilent 1100LC/MSD TOF by polyacrylamide gel electrophoresis (SDS-PAGE) and electron spray mass spectrometry The integrality of albumen.PH 7.510mM 50mM 4- (2- the ethoxys) -1- piperazine ethanesulfonic acids (HEPES) of albumen after purification, - 80 DEG C of storages of 500mM NaCl and 5% glycerine.
Buffer solution：PH7.450mM HEPES, 0.1M NaCl, 0.05%3- [3- (courage amido propyl) dimethylamino] third sulphur Sour inner salt (Chaps).
Method：4 μ L of BRD4 albumen are added in dish, and dish includes compound/control, are then hatched 30min at room temperature, then are added Enter 4 μ L H4KAc4 peptides (peptide of self-defined mark), then hatch 30min again, it is rear to add in 8 μ L AlphaScreen pearls, per hole Beads is 0.064 μ g.Dish is placed on dark place 1h, then the reading on EnVision micropore board detectors.
Experimental result：It is as shown in table 1 below.
External anti-bromo-base structure domain -4 (BRD4) determination of activity of 1 the compounds of this invention of table
Wherein, +++ represent IC50(μM)<1μM；++ represent IC50(μM)<5μM；+ represent IC50(μM)<10μM
Experiment conclusion：
By table 1 as it can be seen that 1,3,7 pairs of BRD4 albumen of the compounds of this invention have stronger inhibitory activity, the compounds of this invention 2,4,5,10,11,16,17,21 pairs of BRD4 albumen have inhibitory activity.

Claims (10)

  1. The ester or its isomers of general formula 1. (I) compound represented, its pharmaceutically acceptable salt, its facile hydrolysis：
    Wherein,
    A, B, C and D represent C or N respectively；
    R1And R2Halogen, C are represented respectively1-6Alkyl, C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Alkoxy C1-6Alkoxy, Halogenated C1-6Alkyl, halogenated C1-6Alkoxy, C1-6Alkyl amine group, two (C1-6Alkyl) amido, hydroxyl, hydroxyl C1-6Alkyl, carboxyl, Carboxyl C1-6Alkyl, amino, amino C1-6Alkyl, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl oxy, C1-6Alkyloxycarbonyl, C1-6Alkyl Amide groups, carbamoyl, C1-6Alkyl amine group formoxyl, two (C1-6Alkyl) amido formacyl, amino-sulfonyl, C1-6Alkyl Amido sulfonyl, two (C1-6Alkyl) amido sulfonyl, amino-sulfonyl C1-6Alkyl, C1-6Alkyl sulphonyl or guanidine radicals；
    Q represents saturation, fractional saturation, undersaturated has 1~4 selected from N, S, O and/or SO2Heteroatomic 3~14 yuan Heterocycle；
    R3、R4And R5Hydrogen atom, OH, OR are represented respectively6,-O- aryl ,-OCH2- aryl, C1-6Alkyl, 3~8 yuan of cycloalkyl ,- CF3、-OCHF2、-OCF3, halogen ,-CN ,-NR6aR6b, carbonyl ,-COOR6、-COOH、-COR6、-CH(OH)R6、-CH(OR6)R6、- CONR6a R6b、-NHCOR6、-NHSO2R6、-NHSO2- aryl, aryl ,-SR6、-SOR6、-SO2R6、-SO2Aryl contains 1~4 A is N, O, S, SO and/or SO2Heteroatomic 3~14 yuan of heterocycle；
    R6、R6aAnd R6bHydrogen atom or C are represented respectively1-6Alkyl；
    M is 0,1 or 2；
    N is 1 or 2.
  2. 2. the ester or its isomers of compound as described in claim 1, its pharmaceutically acceptable salt, its facile hydrolysis：
    Wherein,
    Q represents saturation, fractional saturation, undersaturated has 1~4 selected from N, S, O and/or SO2Heteroatomic 5~10 yuan Heterocycle；
    R3、R4And R5Hydrogen atom, OH, OR are represented respectively6、C1-6Alkyl ,-CF3、-OCHF2、-OCF3, halogen ,-CN ,-NR6aR6b, carbonyl Base ,-COOR6、-COOH、-COR6、-CH(OH)R6、-CH(OR6)R6、-CONR6a R6b、-NHCOR6、-NHSO2R6-SR6、-SOR6 Or-SO2R6；
    M represents 1；
    N represents 1.
  3. 3. the ester or its isomers of compound as claimed in claim 2, its pharmaceutically acceptable salt, its facile hydrolysis：
    Wherein,
    R1And R2Halogen, C are represented respectively1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkyl amine group, hydroxyl, carboxyl, amino or amino C1-6 Alkyl；
    Q represent saturation, fractional saturation, it is undersaturated have 1~2 be selected from N, S or O heteroatomic 5~10 yuan of heterocycle；
    R3、R4And R5Hydrogen atom, OH, C are represented respectively1-6Alkyl ,-CF3、-OCHF2、-OCF3, halogen ,-CN ,-NR6aR6b, carbonyl Or-COOH；
    R6aAnd R6bHydrogen atom is represented respectively.
  4. 4. the ester or its isomers of compound as claimed in claim 3, its pharmaceutically acceptable salt, its facile hydrolysis：
    Wherein,
    R1And R2Halogen or C are represented respectively1-6Alkyl；
    Q represent saturation, fractional saturation, it is undersaturated have 1~2 be selected from N 5~10 yuan of heterocycle；
    R3、R4And R5Hydrogen atom or carbonyl are represented respectively.
  5. 5. the ester or its isomers of compound as claimed in claim 4, its pharmaceutically acceptable salt, its facile hydrolysis：
    Wherein,
    R1Represent halogen；
    R2Represent C1-6Alkyl；
    Q is represented
  6. 6. the ester or its isomers of compound as claimed in claim 5, its pharmaceutically acceptable salt, its facile hydrolysis：
  7. 7. intermediate of the compound in preparation process shown in further requirement protection general formula (I) of the present invention, i.e. general formula (II), (III) compound represented, its pharmaceutically acceptable salt, the ester or its isomers of its facile hydrolysis,
    Wherein, R1、R2、R3、R4、R5, A, B, C, D, Q, m and n it is as defined in claim 1.
  8. 8. the method for compound shown in general formula (I), its pharmaceutically acceptable salt, the ester of its facile hydrolysis or its isomers is prepared, This method includes making the ester of compound, its pharmaceutically acceptable salt or its facile hydrolysis shown in general formula (IV), with general formula (V) institute Show that compound, its pharmaceutically acceptable salt, the ester of its facile hydrolysis or its isomers react,
    Wherein, R1、R2、R3、R4、R5, A, B, C, D, Q, m and n it is as defined in claim 1.
  9. 9. including described in claim 1~6 any claim compound, its pharmaceutically acceptable salt, its facile hydrolysis The pharmaceutical composition of ester or its isomers and one or more pharmaceutical carriers and/or diluent is pharmaceutically acceptable any Dosage form.
  10. 10. compound, its pharmaceutically acceptable salt as described in claim 1~6 any claim, the ester of its facile hydrolysis Or application of its isomers in the drug for the treatment of and/or pre- preventing tumor is prepared.
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