CN109111426A - A kind of fused bicyclic heteroaryl group or aryl compound, and application thereof - Google Patents

A kind of fused bicyclic heteroaryl group or aryl compound, and application thereof Download PDF

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CN109111426A
CN109111426A CN201710486439.3A CN201710486439A CN109111426A CN 109111426 A CN109111426 A CN 109111426A CN 201710486439 A CN201710486439 A CN 201710486439A CN 109111426 A CN109111426 A CN 109111426A
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alkyl
amino
alkoxy
hydroxyl
substituted
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CN109111426B (en
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罗成
姚志艺
郑明月
谢轶谦
张元元
邢婧
乔刚
梅良和
蒋昊
蒋华良
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Suzhou Suplead Life Sciences Co ltd
Shanghai Institute of Materia Medica of CAS
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Suzhou Suplead Life Sciences Co ltd
Shanghai Institute of Materia Medica of CAS
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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Abstract

The present invention provides a kind of formula (I) compounds represented logical as follows, or its pharmaceutically acceptable salt, isomers, racemic modification, crystalline hydrate, solvate or their mixture, comprising its pharmaceutical composition and its preparation for treat disease relevant to BRD4 drug application.

Description

A kind of fused bicyclic heteroaryl group or aryl compound, and application thereof
Technical field
The invention belongs to pharmaceutical technology fields.More particularly to a kind of fused bicyclic heteroaryl group or aryl compound or its pharmacy Acceptable salt or its isomers, racemic modification, crystalline hydrate, solvate or their mixture, include its medicine Compositions and its drug for preparing and treating relevant to BRD4 disease application.
Background technique
In recent years, containing bromine structural proteins 4 (Bromodomain-containing protein 4, BRD4) be found with Heart failure is closely related, and BRD4 inhibitor alleviates cardiac myocyte hypertrophy symptom by the expression of the excessively plump gene of reduction, this Drug for research and development treatment heart failure provides new direction.In addition, BRD4 is confirmed as kinds cancer (including in NUT- Line cancer, Huppert's disease, acute lymphatic leukaemia etc.) target, main mechanism is: in center line cancer, chromosome translocation is led Cause forms BRD4 albumen and NUT fusion protein, and cell is promoted to generate dysdifferentiation and malignant proliferation, so as to cause associated cancer hair It is raw.In the tumour that c-myc is relied on, BRD4 identifies the lysine of acetylation on histone, starts the transcription of downstream c-myc, leads Cause associated cancer.
Cardiomegaly includes caused by primary myocardial hypertrophy and other factors (such as hypertension) for resistance high load capacity The main reason for compensatory myocardial hypertrophy is heart failure.Such as there is oedema, cannot lie down at the symptoms in patient, seriously affects life Quality.Heart failure mostly occurs in the middle-aged and the old, but in recent years since life stress is big, and many young men heart also occur and decline The symptom exhausted.Current treatment method be using cardiotonic drug increase myocardial contractive power, but this kind of drug there are therapeutic window it is narrow or The problems such as poor selectivity, and have ignored the processing to hypertrophic cardiomyocytes.And 8-hydroxyquinoline class drug passes through inhibition BRD4, Mitigate myocardial hypertrophy, cooperates other drugs lightening heart load, be likely to become the new treatment of heart failure.
NUT- center line cancer (NUT-midline carcinoma) is a kind of pernicious the swelling of aggressive high mortality of rare height Tumor is apt to occur in children, youth, is typically less than 1 year by discovery to death.Pathogenesis is since chromosome translocation leads to testis Nucleoprotein (NUT) and BRD4 protein fusion, make BRD4 lose PID structural domain in conjunction with transcription factor and can not activated transcription, carefully Born of the same parents' differentiation is unable to complete, and then is evolved into canceration.NUT- center line cancer there is no at present specificity active drug, to patient vitals with To seriously threaten.
In addition, BRD4 is confirmed the targets for being overexpressed relevant cancer to c-myc for many, these cancers include acute Leukemic lymphoblastoid, mixed lineage leukemia, Huppert's disease, Burkitt ' s lymthoma, hepatocellular carcinoma, triple negative breast cancer, Non-small cell lung cancer, prostate cancer, cancer of pancreas, neuroblastoma etc., treatment guidelines or existing drug currently without special efficacy Toxicity is big, easy to recur.Therefore need to research and develop the anticarcinogen of new mother nucleus structure.
Summary of the invention
It is an object of the present invention to provide a kind of fused bicyclic heteroaryl group or aryl compound or its can pharmaceutically connect Salt, isomers, racemic modification, crystalline hydrate, solvate or their mixture received.
A further object of the present invention is to provide a kind of pharmaceutical composition, described pharmaceutical composition includes to be used as effective component The fused bicyclic heteroaryl group or aryl compound or its pharmaceutically acceptable salt, isomers, racemic modification, the crystallization water Close object, solvate or their mixture and pharmaceutically acceptable carrier.
Another object of the present invention is to provide the fused bicyclic heteroaryl group or aryl compound or its can pharmaceutically connect Salt, isomers, racemic modification, crystalline hydrate, solvate or their mixture received are preparing disease relevant to BRD4 Purposes in the drug of disease.Such targeting compounds bromine domain protein (BRD4), can be used for preventing or treating cardiovascular disease Or tumour.
A further object of the present invention is to provide the fused bicyclic heteroaryl group or aryl compound or its can pharmaceutically connect Salt, isomers, racemic modification, crystalline hydrate, solvate or their mixture received are in the relevant disease for the treatment of BRD4 In purposes.
The present inventor's in-depth study by long-term, it was found that one kind has the compound as led to structure shown in formula (I) With the active effect of BRD4 is inhibited, it can be used for preparing the drug for the treatment of or prevention mammalian diseases relevant to BRD4. Based on above-mentioned discovery, inventor completes the present invention.
According to an aspect of the invention, there is provided a kind of such as logical formula (I) compound represented or its is pharmaceutically acceptable Salt, isomers, racemic modification, crystalline hydrate, solvate or their mixture:
Wherein,
W be N, O or S,
X is C or N；
For aromatic heterocycle；
When W is O or S, R1It is not present；
When W is N, R1It is not present or R1Selected from H, C1~C10 alkyl, C1~C10 alkoxy, it is preferable that R1It is not present Or R1Selected from H, methyl, ethyl, propyl, butyl, methoxyl group, ethyoxyl or propoxyl group；
R2It is selected from:
H；
Oxo group；
The C that unsubstituted or hydroxyl replaces1-C10Alkyl；
C1-C10Alkoxy；
Halogen；
Nitro；
Cyano；
C1-C10Acyl group；
C1-C10Alkoxy C1-C10Alkanoyl；
Sulfonic group；
Substituted or unsubstituted 5 to 8 yuan of aryl, wherein the substituent group in 5 to 8 yuan of substituted aryl is selected from halogen, oxygen For group, amino, hydroxyl, C1-C10Alkyl or C1-C10One or more of alkoxy (preferably one to three)；
Substituted or unsubstituted 3 to 8 yuan of naphthenic base, wherein the substituent group in 3 to 8 yuan of substituted naphthenic base is selected from halogen Element, amino, hydroxyl, C1-C10Alkyl or C1-C10One or more of alkoxy (preferably one to three)；
Substituted or unsubstituted amino, wherein the substituent group in the amino replaced is selected from the one or more of following group: Halogen, C1-C10Alkyl, C1-C10Alkanoyl, C1-C10Alkoxy, hydroxyl, C1-C10Alkyl sulphonyl, it is unsubstituted or be selected from C1-C10Alkoxy, C1-C10One or more of alkyl, halogen, amino, hydroxyl, nitro or oxo group (preferably one to three It is a) group replace 5 to 8 yuan of aryl, it is unsubstituted or by be selected from C1-C10Alkoxy, C1-C10Alkyl, halogen, amino, hydroxyl, 5 to 8 yuan of aryl C that one or more of nitro or oxo group (preferably one to three) group replace1-C10Alkyl does not take Generation or by be selected from C1-C10Alkoxy, C1-C10One or more of alkyl, halogen, amino, hydroxyl, nitro or oxo group (preferably one to three) group replace 5 to 8 unit's heteroaryls, it is unsubstituted or by be selected from C1-C10Alkoxy, C1-C10Alkyl, halogen 5 to 8 unit's heteroaryls that one or more of element, amino, hydroxyl, nitro or oxo group (preferably one to three) group replace C1-C10Alkyl；
Substituted or unsubstituted 5 to 8 unit's heteroaryl, wherein the substituent group in 5 to 8 substituted unit's heteroaryls is selected from halogen Element, amino, hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy；
Substituted or unsubstituted 5 to 8 unit's heteroaryl C1-C10Alkyl, wherein 5 to 8 substituted unit's heteroaryl C1-C10Alkyl In substituent group be selected from halogen, amino, hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10One or more in alkoxy It is a；
Substituted or unsubstituted 5 to 8 yuan of aryl, wherein the substituent group in 5 to 8 yuan of substituted aryl is selected from halogen, ammonia Base, hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy；
Substituted or unsubstituted 5 to 8 yuan of aryl C1-C10Alkyl, wherein 5 to 8 yuan of substituted aryl C1-C10In alkyl Substituent group is selected from halogen, amino, hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy；
Substituted or unsubstituted 5 to 8 yuan of aryl C2-C10Alkenyl, wherein 5 to 8 yuan of substituted aryl C2-C10Alkenyl In substituent group be selected from halogen, oxo group, amino, hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10In alkoxy One or more (preferably one to three)；
Wherein, Y O, S or NH,
R9Are as follows: H；Hydroxyl；Amino；C1-C10Alkyl amino；Substituted or unsubstituted C1-C10Alkyl, wherein substituted C1- C10Substituent group in alkyl is selected from amino, hydroxyl, sulfydryl or C1-C10One to three in alkylthio group；It is substituted or unsubstituted C1-C10Alkoxy, wherein substituted C1-C10Substituent group in alkoxy is selected from amino, hydroxyl, sulfydryl or C1-C10Alkylthio group； Substituted or unsubstituted 5 to 8 unit's heteroaryl, wherein substituent group in 5 to 8 substituted unit's heteroaryls be selected from halogen, amino, Hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy；Substituted or unsubstituted 5 to 8 yuan of heteroaryls Base C1-C10Alkyl, wherein 5 to 8 substituted unit's heteroaryl C1-C10Substituent group in alkyl is selected from halogen, amino, hydroxyl, nitre Base, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy；Substituted or unsubstituted 5 to 8 yuan of aryl, wherein take Substituent group in 5 to 8 yuan of aryl in generation is selected from halogen, amino, hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10Alkoxy One or more of；Substituted or unsubstituted 5 to 8 yuan of aryl C1-C10Alkyl, wherein 5 to 8 yuan of substituted aryl C1-C10Alkane Substituent group in base is selected from halogen, amino, hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10One or more in alkoxy It is a；Substituted or unsubstituted 5 to 8 yuan of aryl C2-C10Alkenyl, wherein 5 to 8 yuan of substituted aryl C2-C10Taking in alkenyl Dai Jiwei is selected from halogen, amino, hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy；
Preferably, R2Be selected from: oxo group, H, methyl, ethyl, propyl, butyl, fluorine, chlorine, bromine, iodine, formoxyl (- CHO), acetyl group, propiono, bytyry ,-SO3H, methoxy methyl acyl group, ethoxy acetyl, butoxy formoxyl, propoxyl group Formoxyl, methylol, ethoxy, hydroxypropyl, hydroxyl butyl, phenyl, amino, formamido, acetamido, propionamido-, butyryl Amido, methylamino, dimethylamino, ethylamino-, methylethylamine, Propylamino, butylamine base, sulfonyloxy methyl amido, ethyl sulphonyl Amido, sulfonyl propyl amido, butyl sulfonamide base,
Or R1、R2And atom in connection is formed together imidazole ring；
R3It is selected from: H；Nitro；Amino；Hydroxyl；C1-C10Alkyl；C1-C10Alkoxy；Hydroxyl C1-C10Alkyl；Amino C1-C10 Alkyl；Amino C1-C10Acyl group；Substituted or unsubstituted 5 to 8 unit's heteroaryl (preferably 5 to 6 unit's heteroaryls), wherein substituted 5 Substituent group into 8 unit's heteroaryls (preferably 5 to 6 unit's heteroaryls) is selected from halogen, amino, hydroxyl, nitro, cyano, C1-C10Alkyl Or C1-C10One or more of alkoxy；Substituted or unsubstituted 5 to 8 yuan of aryl, wherein in 5 to 8 yuan of substituted aryl Substituent group be selected from halogen, amino, hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy；
Preferably, R3Selected from H, nitro, amino, methylol, ethoxy, hydroxypropyl, amino methyl, amino-ethyl, amino Propyl, aminobutyl,Carbamoyl, glycyl or aminobutanonyl；
R4It is selected from: H；Oxo group；C1-C10Alkyl；C1-C10Alkoxy；Substituted or unsubstituted 5 to 8 unit's heteroaryl is (excellent Select 5 to 6 unit's heteroaryls), wherein substituent group in substituted 5 to 8 unit's heteroaryls (preferably 5 to 6 unit's heteroaryls) be selected from halogen, Amino, hydroxyl, oxo group, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy (preferably one, two or Three)；Substituted or unsubstituted 5 to 8 unit's heteroaryl C1-C10Alkyl (preferably 5 to 6 unit's heteroaryl C1-C10Alkyl), wherein it takes 5 to the 8 unit's heteroaryl C in generation1-C10Alkyl (preferably 5 to 6 unit's heteroaryl C1-C10Alkyl) in substituent group be selected from halogen, amino, Hydroxyl, oxo group, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy (preferably one, two or three It is a)；Substituted or unsubstituted 5 to 8 yuan of aryl, wherein the substituent group in 5 to 8 yuan of substituted aryl is selected from halogen, amino, hydroxyl Base, oxo group, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy；Substituted or unsubstituted 3 to 8 First saturated heterocyclyl, wherein the substituent group in 3 to 8 yuan of substituted saturated heterocyclyls is selected from halogen, amino, hydroxyl, oxo base Group, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy；Hydroxyl C1-C10Alkoxy；C1-C10Alkoxy C1-C10Alkoxy；Substituted or unsubstituted 3 to 8 yuan of saturated heterocyclyls oxygen groups, wherein 3 to 8 yuan of substituted saturated heterocyclyls Substituent group in oxygen groups is selected from halogen, amino, hydroxyl, oxo group, nitro, cyano, C1-C10Alkyl or C1-C10Alkoxy One or more of；Substituted or unsubstituted amino or substituted or unsubstituted amino C1-C10Alkyl, wherein substituted Amino or substituted amino C1-C10Substituent group in alkyl is selected from halogen, amino, hydroxyl, hydroxyl C1-C10Alkyl, oxo group, Nitro, cyano, C1-C10Alkyl, C1-C10Alkoxy, substituted or unsubstituted 3 to 8 yuan of naphthenic base, substituted or unsubstituted 5 to 8 Unit's heteroaryl (preferably 5 to 6 unit's heteroaryls), substituted or unsubstituted 5 to 8 unit's heteroaryl C1-C10Alkyl (preferably 5 to 6 yuan of heteroaryls Base C1-C10Alkyl), One or more of, wherein 3 to 8 yuan of substituted cycloalkanes Base, 5 to 8 unit's heteroaryls (preferably 5 to 6 unit's heteroaryls) replaced, and 5 to the 8 unit's heteroaryl C replaced1-C10Alkyl (preferably 5 To 6 unit's heteroaryl C1-C10Alkyl) in substituent group be selected from halogen, amino, hydroxyl, oxo group, nitro, cyano, C1-C10Alkane Base or C1-C10One or more of alkoxy；
Preferably, R4Selected from H, oxo group (=O),
R5To R8It is identical or different respectively, it is each independently selected from:
H；
Halogen；
Hydroxyl；
Nitro；
Sulfydryl；
C1-C10Alkylthio group；
Trifluoromethyl；
Trifluoroethyl；
Cyano；
Substituted or unsubstituted 3 to 8 yuan of saturated heterocyclyls, wherein the substituent group in 3 to 8 yuan of substituted saturated heterocyclyls Selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, Hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy or halogen；
Substituted or unsubstituted 5 to 8 yuan of aryl, wherein the substituent group in 5 to 8 yuan of substituted aryl is selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkane Base, C1-C10Alkyl, C1-C10Alkoxy or halogen；
Substituted or unsubstituted 5 to 8 unit's heteroaryl (preferably 5 to 6 unit's heteroaryls), wherein 5 to 8 substituted unit's heteroaryls Substituent group in (preferably 5 to 6 unit's heteroaryls) is selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, Cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy or halogen；
-NR10R12；
-NCOR13；
Substituted or unsubstituted C1-C10Alkyl, wherein substituted C1-C10Substituent group in alkyl is selected from: hydroxyl； Nitro；Cyano；Amino；Trifluoromethyl；Trifluoroethyl；Sulfydryl；C1-C10Alkoxy；C1-C10Alkyl amino；C1-C10Alkane Base aminoacyl amido；Aminoacyl amido；-NR10R12； It is unsubstituted or by be selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkane Base, C1-C10Alkyl, C1-C10Nafoxidine base, amino-sulfonyl, halogen and the C that alkoxy, tertbutyloxycarbonyl replace1-C10Alkane 5 to 8 unit's heteroaryls that one or more substituent groups in oxygroup formoxyl replace；It is unsubstituted or by be selected from amino, amino C1-C10 Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1- C10Alkyl, C1-C10Nafoxidine base, amino-sulfonyl, halogen and the C that alkoxy, tertbutyloxycarbonyl replace1-C10Alkoxy first 5 to 8 yuan of aryl that one or more substituent groups in acyl group replace；
Amino C1-C10Acyl group；
C1-C10Alkyl amino C1-C10Acyl group；
-OCOR14；
Substituted or unsubstituted C1-C10Alkoxy, wherein substituted C1-C10Substituent group in alkoxy is selected from hydroxyl, ammonia Base, C1-C10One in alkoxy, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, 3 to 8 yuan of saturated heterocyclyls and halogen or It is multiple；
Substituted or unsubstituted 3 to 8 yuan of naphthenic base, wherein substituent group in 3 to 8 yuan of substituted naphthenic base be selected from hydroxyl, Amino, C1-C10Alkoxy, C1-C10One or more in alkyl, hydroxyl, cyano, trifluoromethyl, trifluoroethyl, sulfydryl and halogen It is a；
-OR15,R15Selected from substituted or unsubstituted 3 to 8 yuan of naphthenic base or substituted or unsubstituted 3 to 8 yuan of saturated heterocyclics Base, wherein the substituent group in 3 to the 8 yuan of naphthenic base replaced or 3 to 8 yuan of substituted saturated heterocyclyls is selected from hydroxyl, amino, C1- C10Alkoxy, C1-C10One or more of alkyl, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, halogen；Replace or does not take 3 to 8 yuan of naphthenic base C in generation1-C10Alkyl, wherein 3 to 8 yuan of substituted naphthenic base C1-C10Substituent group in alkyl be selected from hydroxyl, Amino, C1-C10Alkoxy, C1-C10One or more in alkyl, hydroxyl, cyano, trifluoromethyl, trifluoroethyl, sulfydryl and halogen It is a；
Substituted or unsubstituted 3 to 8 yuan of saturated heterocyclyls C1-C10Alkyl, wherein 3 to 8 yuan of substituted saturated heterocyclyls C1-C10Substituent group in alkyl is selected from hydroxyl, amino, C1-C10Alkoxy, C1-C10Alkyl, hydroxyl, cyano, trifluoromethyl, three One or more of fluoro ethyl, sulfydryl and halogen；
Preferably, R5To R8It is identical or different respectively, it is each independently selected from: H；Fluorine；Chlorine；Bromine；Iodine；Hydroxyl；Ammonia Base；Nitro；Methyl；Ethyl；Propyl；Butyl；Methoxyl group；Ethyoxyl；Propoxyl group；Butoxy；C1-C10Alkyl；C1-C10 Alkoxy；Methoxybenzene；Ethoxybenzene；Propoxyl group benzene； -NHMe；
R10And R12It is identical or different, it is each independently selected from H；Hydroxyl；Nitro；Cyano；Trifluoromethyl；Trifluoroethyl；Mercapto Base；Hydroxyl C1-C10Alkyl；C1-C10Alkyl；C1-C10Alkoxy；C1-C10Alkoxy C1-C10Alkyl；C1-C10Alkyl amino C1- C10Alkyl；It is unsubstituted or by be selected from C1-C10It is alkyl-substitutedQuiltSubstituted C1-C10Alkyl；Not Replace or is selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoro second Base, sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy, halogen and C1-C10One in alkoxy formoxyl or 5 to 8 unit's heteroaryls that multiple substituent groups replace；It is unsubstituted or by be selected from amino, amino C1-C10Alkyl, amino C1-C10Alcoxyl Base, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy, Halogen and C1-C105 to the 8 unit's heteroaryl C that one or more substituent groups in alkoxy formoxyl replace1-C10Alkyl；It is unsubstituted Or it is selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, Sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy, halogen and C1-C10One or more in alkoxy formoxyl 5 to 8 yuan of aryl C that a substituent group replaces1-C10Alkyl；It is unsubstituted or by be selected from amino, amino C1-C10Alkyl, amino C1- C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10 Alkoxy, amino-sulfonyl, halogen and C1-C105 to 8 yuan of virtues that one or more substituent groups in alkoxy formoxyl replace Base；
Wherein, R11It indicates one or more substituent groups, and is each independently selected from H, halogen, hydroxyl, oxo group, nitre Base, amino, tertbutyloxycarbonyl, C1-C10Alkyl, C1-C10The nafoxidine base that alkoxy, trifluoromethyl, tertbutyloxycarbonyl replace Or amino-sulfonyl；
R13Selected from H；Hydroxyl；Nitro；Cyano；Trifluoromethyl；Trifluoroethyl；Sulfydryl；Hydroxyl C1-C10Alkyl；C1-C10Alkane Base；C1-C10Alkoxy；C1-C10Alkoxy C1-C10Alkyl；C1-C10Alkyl amino C1-C10Alkyl；C2-C10Alkenyl；It is unsubstituted Or it is selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, Sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy, halogen and C1-C10One or more in alkoxy formoxyl 5 to 8 unit's heteroaryls that a substituent group replaces；It is unsubstituted or by be selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, Hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy, halogen Element and C1-C105 to the 8 unit's heteroaryl C that one or more substituent groups in alkoxy formoxyl replace1-C10Alkyl；It is unsubstituted or It is selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, mercapto Base, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy, halogen and C1-C10One or more of alkoxy formoxyl 5 to the 8 unit's heteroaryl C that substituent group replaces2-C10Alkenyl；It is unsubstituted or by be selected from amino, amino C1-C10Alkyl, amino C1- C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10 Alkoxy, halogen and C1-C105 to 8 yuan of aryl C that one or more substituent groups in alkoxy formoxyl replace1-C10Alkyl； It is unsubstituted or by be selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoro Ethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy, halogen and C1-C10One in alkoxy formoxyl Or 5 to 8 yuan of aryl that multiple substituent groups replace；It is unsubstituted or by be selected from amino, amino C1-C10Alkyl, amino C1-C10Alcoxyl Base, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy, Halogen and C1-C105 to 8 yuan of aryl C that one or more substituent groups in alkoxy formoxyl replace2-C10Alkenyl；
R14Selected from C1-C10Alkyl, C1-C10Alkoxy, or it is selected from amino, amino C1-C10Alkoxy, hydroxyl, nitro, Cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy, tertbutyloxycarbonyl take The C that one or more substituent groups in the nafoxidine base in generation, amino-sulfonyl and halogen replace1-C10Alkyl.
Preferably, the logical formula (I) compound represented, which has, is selected from structure shown in general formula (I-1) to general formula (I-5):
Wherein, R1To R8Substituent group definition as hereinbefore.
It is further preferred that the compound has the following structure:
Term definition
Wherein, in the present specification,
Halogen refers to fluorine, chlorine, bromine or iodine；
C1-C10Alkyl refers to straight chain or straight chained alkyl with 1 to 10 carbon atom, preferably, C1-C6Alkyl, C1-C10 The example of alkyl includes, but are not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, amyl, octyl；
C1-C10Alkoxy refers to straight chain or unbranched alkoxy with 1 to 10 carbon atom, preferably, C1-C6Alkoxy, C1-C10The example of alkoxy includes, but are not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutyl Oxygroup, amoxy, octyloxy；
C2-C10Alkenyl refers to the straight chain or straight chain with 2 to 10 carbon atoms and at least one carbon-carbon double bond Alkenyl, preferably, C2-C6Alkenyl；C2-C10The example of alkenyl include, but are not limited to vinyl, acrylic, cyclobutenyl, Pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, octenyl；
C1-C10Acyl group refers to 1 to 10 carbon atom and end group is the straight chain of carbonyl or the acyl group of straight chain, preferably For C1-C6Acyl group, C1-C10The example of acyl group include, but are not limited to formoxyl, acetyl group, propiono, bytyry, bytyry, Valeryl, caprylyl；
3 to 8 yuan of naphthenic base are 3 to 8 yuan of saturated cyclic alkyls, and the example includes, but are not limited to cyclopropyl alkyl, cyclobutane, ring Pentane, hexamethylene, cycloheptane and cyclooctane；
In the present invention, heterocycle includes 3 to 8 yuan of saturated heterocyclyls (preferably 3 yuan, 4 yuan, 5 yuan, 6 yuan of saturated heterocyclyls), It is comprising selected from one or more of N, O and S (including 1,2,3 or 4) heteroatomic 3 to 8 yuan of saturated heterocyclics Base, the example include, but are not limited to tetrahydrofuran base, nafoxidine base, tetrahydro-thienyl, tetrahydro-pyrazole base, imidazolidine base, Tetrahydro connects triazolyl, tetrahydro 1,2,4- triazolyl, tetrahydro 1,2,5- triazolyl, tetrahydro 1,3,4- triazolyl, tetrahydro 1,2,3,4- Tetrazole radical, tetrahydro 1,2,3,5- tetrazole radical, tetrahydro oxazolyl, tetrahydro isoxazolyl, tetrahydro isothiazolyl, THP trtrahydropyranyl, four Hydrogen thienyl, tetrahydro pyridyl, hexahydro-pyridazine base, hexahydropyrimidine base, morpholinyl, hexahydropyrazine base, piperidyl, Hexahydrotriazine Base, tetrahydro oxazines base；
The example of 5 to 8 yuan of aryl includes, but are not limited to benzene；
In the present invention, heteroaryl includes 5 to 8 unit's heteroaryls (preferably 5 to 6 unit's heteroaryls), for comprising selected from N, O and Heteroatomic 5 to 8 unit's heteroaryl (preferably 5 to 6 unit's heteroaryls) of one or more of S (including 1,2,3 or 4), The example include, but are not limited to furyl, thienyl, pyrazolyl, imidazole radicals, even triazolyl, 1,2,4- triazolyls, 1,2,5- tri- Oxazolyl, 1,3,4- triazolyl, 1,2,3,4- tetrazole radical, 1,2,3,5- tetrazole radical, oxazolyl, isoxazolyl, isothiazolyl, pyrans Base, thienyl, pyridyl group, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, oxazines base.
In the present invention, one or more may include 1,2,3 or 4.
According to another aspect of the present invention, a kind of pharmaceutical composition is provided, described pharmaceutical composition include as effectively at The logical formula (I) compound represented or its pharmaceutically acceptable salt, isomers, racemic modification, crystalline hydrate, solvent divided Close object or their mixture and pharmaceutically acceptable carrier.
Pharmaceutically acceptable carrier refers to: one or more biocompatible solids or liquid filler or gelatinous mass, They are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " referred to herein as composition Middle each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the drug effect of compound.Pharmacy Upper acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, fiber Plain acetic acid esters etc.), gelatin, talcum, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame Oil, peanut oil, olive oil etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbierite), emulsifier (such as), profit Humectant (such as lauryl sodium sulfate), colorant, flavoring agent, stabilizer, antioxidant, preservative, apirogen water.
Since the compounds of this invention is with excellent to BRD4 inhibitory activity, the compounds of this invention and its various crystalline substances Type, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and containing the compounds of this invention is chief active The pharmaceutical composition of ingredient can be used for treating, prevent and alleviate disease relevant to BRD4.According to the prior art, of the present inventionization Closing object can be used for treating following disease: cardiovascular disease and cancer etc..
Pharmaceutical composition of the invention include safe and effective amount within the scope of the compounds of this invention or its be pharmacologically subjected to Salt and pharmacologically acceptable excipient or carrier.Wherein " safe and effective amount " refers to: the amount of compound is enough obviously Improve the state of an illness, and is unlikely to generate serious side effect.In general, pharmaceutical composition contains 1-2000mg the compounds of this invention/agent, More preferably, containing 5-200mg the compounds of this invention/agent.Preferably, described is " one " for a capsule or tablet.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representative method of application includes (but being not limited to): in oral, tumor, rectum, parenteral (intravenous, intramuscular or subcutaneous) and local administration.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations In type, reactive compound is mixed at least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with Following compositions mixing: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) it bonds Agent, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；(c) moisturizer, example Such as, glycerol；(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates, And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti Pure and mild glycerin monostearate；(h) adsorbent, for example, kaolin；(i) lubricant, for example, talcum, calcium stearate, tristearin Or mixtures thereof sour magnesium, solid polyethylene glycol, lauryl sodium sulfate,.In capsule, tablet and pill, dosage form also may include Buffer.
Coating and shell material preparation can be used in solid dosage forms such as tablet, sugar-pill, capsule, pill and granule, such as casing and Other materials well known in the art.They may include opacifying agent, also, reactive compound or compound in this composition Release can discharge in certain a part in the digestive tract in a delayed fashion.The example of adoptable embedding component is polymeric material And wax material.When necessary, reactive compound can also be with one of above-mentioned excipient or a variety of formation microencapsulation forms.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture. In addition to active compounds, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, increase Solvent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethyl formyl The mixture of amine and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances Deng.
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste Agent, corrigent and fragrance.
In addition to active compounds, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene Sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or the mixture of these substances etc..
Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, Suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.It is suitable aqueous and Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
The dosage form of the compounds of this invention for local administration includes ointment, powder, patch, stock solution and inhalant. Active constituent aseptically with physiologically acceptable carrier and any preservative, buffer, or when necessary may need Propellant be mixed together.
The compounds of this invention can be administered alone, or be administered in combination with other pharmaceutically acceptable compounds.
It is the mammal that the compounds of this invention of safe and effective amount is applicable to treatment when using pharmaceutical composition (such as people), wherein dosage is the effective dosage pharmaceutically thought when application, for the people of 60kg weight, day is to medicament Amount is usually 1~2000mg, preferably 5~500mg.Certainly, specific dosage be also contemplated that administration route, patient health situation etc. because Element, within the scope of these are all skilled practitioners technical ability.
According to another aspect of the invention, provide logical formula (I) compound represented or its pharmaceutically acceptable salt or The use of isomers, racemic modification, crystalline hydrate, solvate in the drug that preparation is used to treat disease relevant to BRD4 On the way.
The relevant disease of the BRD4 includes, but are not limited to heart failure, cardiovascular disease, NUT- center line cancer, acute leaching It is bar leukaemia, mixed lineage leukemia, Huppert's disease, Burkitt ' s lymthoma, hepatocellular carcinoma, triple negative breast cancer, non- Small Cell Lung Cancer, prostate cancer, cancer of pancreas, neuroblastoma, lymthoma, tumor of kidney, retinoblastoma, osteosarcoma And chondrosarcoma, Posterior fossa medulloblastoma, nasopharyngeal carcinoma, thyroid papillary carcinoma, thymoma, pulmonary blastoma, pancreas mother cell Tumor, islet-cell tumour, ileocecus class cancer or celiothelioma etc., wherein the heart failure includes that myocardial hypertrophy disease and cardiac muscle are thin Born of the same parents' hypertrophy disease.
A further object of the present invention is to provide logical formula (I) compound represented or its pharmaceutically acceptable salt or Isomers, racemic modification, crystalline hydrate, solvate or their mixture are treating the use in disease relevant to BRD4 On the way comprising apply the logical formula (I) compound represented of therapeutically effective amount or its pharmaceutically acceptable salt, isomers, disappear outside Revolve body, crystalline hydrate, solvate or their mixture.
In the present invention, term " pharmaceutically acceptable " ingredient refers to suitable for people and/or animal and without excessive bad pair It reacts (such as toxicity, stimulation and allergy), that is, has the substance of reasonable benefit/risk ratio.
In the present invention, amount or table that term " effective quantity " refers to therapeutic agent treatment, alleviates or prevent target disease or situation Reveal the detectable amount for treating or preventing effect.The figure of the object is depended on for the accurate effective quantity of certain an object and is good for The combination of therapeutic agent and/or therapeutic agent that health situation, the property and degree of illness and selection are given.Therefore, standard is preassigned True effective quantity is useless.However, can determine the effective quantity with routine experiment for the situation that Mr. Yu gives, face Bed doctor can judge.
Unless stated otherwise, in the present invention, the compound occurred is intended to including all possible optical isomer, Such as the compound of single chiral or the mixture (i.e. racemic modification) of various different chipal compounds.All chemical combination of the invention Among object, each asymmetric carbon atom can be optionally the mixture of R configuration or S configuration or R configuration and S configuration.
As used herein, term " the compounds of this invention " refers to Formulas I compound represented.The term further includes and Formulas I chemical combination Various crystalline forms, pharmaceutically acceptable salt, hydrate or the solvate of object.
As used herein, term " pharmaceutically acceptable salt " refers to that the compounds of this invention and acid or alkali are formed by suitable use Make the salt of drug.Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferred salt is the compounds of this invention and acid The salt of formation.The acid for suitably forming salt includes but is not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid etc. are inorganic Acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, Picric acid, methanesulfonic acid, benzene methanesulfonic acid, the organic acids such as benzene sulfonic acid；And the acidic amino acids such as aspartic acid, glutamic acid.
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.
Nuclear magnetic resonance spectroscopy BrukerAMX-400 type, Gemini-300 type or AMX -600 type Nuclear Magnetic Resonance record, The unit of chemical shift δ is ppm.All solvents are analytical reagents.It is developed the color using the methods of iodine, Ultraluminescence.Decompression is steamed Except organic solvent carries out in Rotary Evaporators.The initial reactant used in the present invention is that business is purchased without illustrating It buys.
It should be noted that conventional post-processing approach is: after the reaction was completed, being added in reaction solution in following embodiments Suitable organic solvent and water separate organic phase and water phase, merge organic phase, and use NaSO4Decompression rotation after drying, filtering It is evaporated, obtains crude product, obtain final product later using column chromatographic isolation and purification.
Prepare embodiment:
Embodiment 1: the preparation (scheme referring to shown in following formulas) of compound 1
Step (i) compound a (500mg, 1eq) be dissolved in methylene chloride 5mL be added imidazoles (182mg, 1.2eq) and DIEA (483mg, 1.5eq), back flow reaction is overnight.TLC detects end of reaction, and solvent evaporated column chromatographs to obtain compound b (compound 1)(271mg)。
1H NMR (400MHz, DMSO-d6) δ 8.14 (s, 1H), 7.78 (dd, J=7.5,1.4Hz, 1H), 7.65 (dd, J =7.5,1.4Hz, 1H), 7.53 (td, J=7.5,1.5Hz, 1H), 7.46 (d, J=7.5Hz, 1H), 7.32 (td, J=7.5, 1.5Hz, 1H), 7.14 (d, J=7.5Hz, 1H), 6.92 (s, 1H)
Embodiment 2: the preparation (scheme referring to shown in following formulas) of compound 2
Step (i) compound a (500mg, 1eq) be dissolved in methylene chloride 5mL be added imidazoles (115mg, 1.2eq) and DIEA (305mg, 1.5eq), back flow reaction is overnight.TLC detects end of reaction, and solvent evaporated column chromatographs to obtain compound b (157mg)。
Step (ii) compound b (157mg, 1eq) is dissolved in THF (5mL), is added TBAF (132mg, 1.1eq), is heated to 50 Degree Celsius reaction 1h, TLC detect fully reacting.Solvent evaporated, residue are beaten with first alcohol and water, and compound c is obtained by filtration and (changes Close object 2) (35mg).
1H NMR (400MHz, DMSO-d6) δ 8.14 (s, 1H), 7.46 (d, J=15.0Hz, 1H), 7.36 (t, J= 14.9Hz,1H),7.25–7.08(m,3H),6.91(s,1H),5.03(s,1H).
Other than substrate a is different, preparation method phase of the compound synthesis method shown in following table with compound 1 or compound 2 Together.
Embodiment 3: the preparation (scheme referring to shown in following formulas) of compound 3
Step (i) compound a (500mg, 1eq) is dissolved in Isosorbide-5-Nitrae-dioxane solution 10mL, and isoxazole -4- boron is added Sour (239mg, 1.5eq) and potassium carbonate (390mg, 2eq) are added tetra-triphenylphosphine palladium (81mg, 0.05eq) after replacing nitrogen, return Stream reaction 6h.TLC detects end of reaction, and solvent evaporated column chromatographs to obtain compound b (259mg).
Step (ii) compound b (259mg) is dissolved in THF (10mL), is added TBAF (217mg, 1.1eq), is heated to 50 and takes the photograph Family name's degree reacts 1h, and TLC detects fully reacting.Solvent evaporated, residue are beaten with first alcohol and water, and compound c (chemical combination is obtained by filtration Object 3) (63mg).
1H NMR (400MHz, DMSO-d6) δ 8.42 (s, 1H), 7.36 (t, J=14.9Hz, 1H), 7.21 (dd, J= 15.0,3.1Hz, 1H), 7.12 (dd, J=14.7,3.2Hz, 1H), 6.69 (s, 1H), 5.04 (s, 1H)
Embodiment 4: the preparation (scheme referring to shown in following formulas) of compound 39
Step (i): compound a (500mg, 1eq) is dissolved in Isosorbide-5-Nitrae-dioxane 10mL, addition imidazoles (161mg, 1.2eq) with cesium carbonate (962mg, 1.5eq), Pd2 (dba) 3 (90mg, 0.05eq) and Xantphos is added after replacing nitrogen (114mg, 0.1eq), 110 DEG C of reaction 12h.End of reaction solvent evaporated column chromatographs to obtain compound b (230mg).
Step (ii): compound b (230mg, 1eq) is dissolved in 5mL methylene chloride, and Boron tribromide is added dropwise under ice bath (716mg, 3eq) drips and finishes ice bath reaction 8h.TLC detects end of reaction, pours into ice water, methylene chloride extraction, unsaturated carbonate hydrogen Sodium washing, the dry dry chromatography that steams of organic layer obtain compound c (compound 4) (33mg).
1H NMR (400MHz, DMSO-d6) δ 8.13 (s, 1H), 8.09 (s, 1H), 7.88 (d, J=15.0Hz, 2H), 7.44 (d, J=15.0Hz, 2H), 7.30-7.23 (m, 2H), 7.15 (s, 2H), 7.01 (d, J=15.0Hz, 2H), 6.49 (s, 1H),6.44(s,1H),5.07(s,2H).
Other than compound a is different, compounds process for production thereof shown in following table is identical with the preparation method of compound 39.
Embodiment 5: the preparation (scheme referring to shown in following formulas) of compound 49
Step (i): compound a (500mg, 1eq), imidazoles (115mg, 1.2eq) and cesium carbonate (690mg, 1.5eq) dissolution In 15mL toluene, palladium acetate (15.8mg, 0.05eq) and BINAP (88mg, 0.1eq), back flow reaction is added after replacing nitrogen 24h.End of reaction solvent evaporated column chromatographs to obtain target compound b (157mg).
Step (ii) compound b (157mg, 1eq) is dissolved in THF (6mL), is added TBAF (132mg, 1.1eq), is heated to 50 DEG C reaction 1h, TLC detect fully reacting.Solvent evaporated, residue are beaten with first alcohol and water, and compound c (compound is obtained by filtration 49)(35mg)。
1H NMR (400MHz, DMSO-d6) δ 9.31 (s, 1H), 9.26 (s, 1H), 7.74 (d, J=15.0Hz, 2H), 7.27 (d, J=15.0Hz, 2H), 7.19-7.06 (m, 6H), 6.86 (d, J=15.0Hz, 2H), 4.14 (s, 2H)
Other than compound a is different, compounds process for production thereof shown in following table is identical with the preparation method of compound 49.
Embodiment 6: the preparation (scheme referring to shown in following formulas) of compound 60
Under step (i) ice bath, compound a (1g, 1eq) is dissolved in 33% hydrobromic acid acetum of 10mL, and bromine is added dropwise (844mg, 1.1eq) drop finishes room temperature reaction overnight.End of reaction is poured into ice water, saturated sodium bicarbonate/saturation sodium hydrogensulfite Washing, ethyl acetate extraction, the dry dry chromatography that steams of organic layer obtain target compound b (193mg).
Step (ii) compound b (193mg, 1eq) is dissolved in methylene chloride 5mL, be added imidazoles (55mg, 1.2eq) and DIEA (174mg, 2eq) flows back for 24 hours.End of reaction solvent evaporated column chromatographs to obtain target compound c (131mg).
Step (iii) compound c (131mg, 1eq) is dissolved in methylene chloride 5mL, and Boron tribromide is added under ice bath (359mg, 3eq), ice bath react 6h.End of reaction is poured into ice water, saturated sodium bicarbonate washing, and ethyl acetate extraction is organic The dry dry chromatography that steams of layer obtains target compound d (compound 60) (25mg).
1H NMR (400MHz, DMSO-d6) δ 8.93 (s, 2H), 8.12 (s, 1H), 7.45 (dd, J=15.0,0.6Hz, 1H), 7.12 (dd, J=15.0,0.6Hz, 1H), 7.05 (dd, J=15.9,2.9Hz, 1H), 6.82 (dd, J=15.9, 2.9Hz,1H),4.25(s,1H).
Embodiment 7: the preparation (scheme referring to shown in following formulas) of compound 63
Under step (i) ice bath, compound a (1g, 1eq) is dissolved in 33% hydrobromic acid acetum of 10mL, and bromine is added dropwise (844mg, 1.1eq) drop finishes room temperature reaction overnight.End of reaction is poured into ice water, saturated sodium bicarbonate/saturation sodium hydrogensulfite Washing, ethyl acetate extraction, the dry dry chromatography that steams of organic layer obtain target compound b (193mg).
Step (ii) compound b (193mg, 1eq), 3,5- dimethyl isoxazole -4- boric acid (142mg, 1.4eq) and carbonic acid Potassium (186mg, 2eq) is dissolved in Isosorbide-5-Nitrae-dioxane solution 8mL, replace nitrogen after be added tetra-triphenylphosphine palladium (39mg, 0.05eq), 110 DEG C of reaction 12h.End of reaction, solvent evaporated column chromatograph to obtain target compound c (119mg).
Step (iii) compound c (119mg, 1eq) is dissolved in methylene chloride 5mL, and Boron tribromide is added under ice bath (295mg, 3eq), ice bath react 3h.End of reaction is poured into ice water, saturated sodium bicarbonate washing, and ethyl acetate extraction is organic The dry dry chromatography that steams of layer obtains target compound d (compound 63) (45mg).
1H NMR (400MHz, DMSO-d6) δ 8.78 (s, 2H), 7.05 (dd, J=16.0,3.0Hz, 1H), 6.82 (dd, J =15.9,2.9Hz, 1H), 4.79 (s, 1H), 2.59 (s, 3H), 2.43 (s, 3H)
Other than substrate a is different, compounds process for production thereof shown in following table is identical with the preparation method of compound 63.
Embodiment 8: the preparation (scheme referring to shown in following formulas) of compound 81
Step (i): compound a (1.5g, 1.0eq) and imidazoles (1.2eq) are dissolved in DMF (10mL), under ice-water bath, in batches It is added sodium hydrogen (1.2eq), finishes, be slowly increased to room temperature reaction overnight, fully reacting.Water quenching is added to go out, EA is extracted twice, organic phase Dry with saturated common salt water washing 4 times, concentration, column chromatographic purifying obtains compound b (1.02mg).
Step (ii): compound b (500mg, 1.0eq) and 4-Methoxybenzylamine (4.0eq) are dissolved in heating in DMSO (5mL) Overnight to 95 DEG C of reactions.TLC detects fully reacting.It is cooling, add water quenching to go out, EA is extracted twice, and merges EA phase, saturated common salt washing It washs 3 times, dry, concentration, column chromatographic purifying obtains compound c (477mg).
Step (iii): compound c (477mg, 1.0eq) is dissolved in 33%HBr in HOAc solution, 95 DEG C of heating, reaction Complete EA extraction saturated sodium bicarbonate washing, dry crude product column chromatographs to obtain compound d (compound 81) (213mg).
1H NMR (400MHz, DMSO-d6) δ 8.47 (dd, J=14.9,3.0Hz, 1H), 8.10 (d, J=15.0Hz, 1H), 7.38 (t, J=14.9Hz, 1H), 7.27 (dd, J=15.0,0.6Hz, 1H), 7.15 (s, 1H), 7.08 (dd, J= 15.0,2.9Hz,1H),6.64(s,1H),1.97(s,2H).
Other than substrate a is different, preparation of the compounds process for production thereof shown in following table with compound 81.
Embodiment 9: the preparation (scheme referring to shown in following formulas) of compound 99
Step (i): compound a (1.2g, 1.0eq) and imidazoles (1.2eq) are dissolved in DMF (10mL), under ice-water bath, in batches It is added sodium hydrogen (1.2eq), finishes, be slowly increased to room temperature reaction overnight, fully reacting.Water quenching is added to go out, EA is extracted twice, organic phase Dry with saturated common salt water washing 4 times, concentration, column chromatographic purifying obtains compound b (674mg).
Step (ii): compound b (674mg, 1.0eq) and 4-Methoxybenzylamine (4.0eq) are dissolved in heating in DMSO (5mL) Overnight to 95 DEG C of reactions.TLC detects fully reacting.It is cooling, add water quenching to go out, EA is extracted twice, and merges EA phase, saturated common salt washing It washs 3 times, dry, concentration, column chromatographic purifying obtains compound c (650mg).
Step (iii): compound c (500mg, 1.0eq) is dissolved in 33%HBr in HOAc solution, 95 DEG C of heating, reaction Complete EA extraction saturated sodium bicarbonate washing, dry crude product column chromatographs to obtain compound d (compound 99) (330mg).
1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),8.06(s,1H),7.63(s,1H),7.21(s,1H), 6.89 (d, J=10.6Hz, 2H), 6.62 (s, 2H), 6.52 (d, J=10.0Hz, 1H)
Embodiment 10: the preparation (scheme referring to shown in following formulas) of compound 100
Step (i): compound a (145mg, 1.0eq) is dissolved in THF (5mL), is added TBAF (1.1eq), is heated to 50 DEG C instead 1h, TLC is answered to detect fully reacting.Post-processing: concentration, residue are beaten with first alcohol and water, and pale solid b is obtained by filtration and (changes Close object 100) (35mg).
1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.75(s,1H),8.30(s,1H),8.10(s,1H), 7.67 (s, 1H), 7.37 (d, J=6.3Hz, 1H), 7.25 (s, 1H), 7.17 (d, J=10.4Hz, 1H), 7.06 (s, 1H), 2.18(s,3H).
Other than substrate is different, preparation method of the compounds process for production thereof shown in following table with compound 99 or compound 100 It is identical.
Embodiment 11: the preparation (scheme referring to shown in following formulas) of compound 204
Step (i): compound a (237mg, 1eq.), 2- aminooimidazole (100mg, 2eq.), Pd2 (dba) 3 (50mg, 0.1eq.), Xphos (51mg, 0.2eq.) and potassium carbonate (240mg, 3eq.) are dissolved in the tert-butyl alcohol (10mL), 90 DEG C of reflux 7h, TLC Raw material fully reacting is monitored, solvent evaporated column chromatographs to obtain target product b (147mg).
Step (ii): compound b (116mg, 1eq.) and tetrabutyl ammonium fluoride (70mg, 1eq.) are in THF (10mL), and 50 DEG C 4h, fully reacting are stirred, Pre-HPLC separates to obtain target product c (compound 204) (20mg).
1H NMR(400MHz,cd3Od) δ 8.56 (s, 1H), 7.90 (s, 1H), 7.53 (d, J=30.0Hz, 2H), 7.29 (d, J=15.0Hz, 2H), 2.32 (s, 3H)
Other than substrate is different, compounds process for production thereof shown in following table is identical with the preparation method of compound 204.
Embodiment 12: the preparation (scheme referring to shown in following formulas) of compound 178
Step (i): compound a (240mg, 1eq.), 3,5- dimethyl isoxazole -4- boric acid (110mg, 1.5eq.), Pd2 (dba) 3 (46mg, 0.1eq.), Xphos (47mg, 0.2eq.) and potassium carbonate (210mg, 3eq.) are dissolved in the tert-butyl alcohol (10mL), and 90 DEG C reflux 7h, TLC monitor raw material fully reacting.Column chromatographs to obtain target product b (170mg).
Step (ii): compound b (170mg, 0.32mmol), TBAF (79mg, 0.3mmol) are stirred at 5mL THF, 50 DEG C Raw material fully reacting after 3h is mixed, abstraction solvent is filtered after ammonium chloride saturated solution stirring 1h is added, washed, EA mashing filtering Dry yellow solid c (compound 178) 45mg.
1H NMR (400MHz, MeOD) δ 8.21 (s, 1H), 7.38 (t, J=8.0Hz, 1H), 7.15 (d, J=6.8Hz, 1H), 7.04 (d, J=9.2Hz, 1H), 2.34 (s, 3H), 2.28 (s, 3H), 2.16 (s, 3H)
Other than substrate is different, compounds process for production thereof shown in following table is identical with the preparation method of compound 178.
Embodiment 13: the preparation ((scheme referring to shown in following formulas)) of compound 226
Step (i): compound a (1g, 1eq) is dissolved in DMF solution 10mL, is added imidazoles (275mg, 1.5eq), displacement Cuprous iodide (154mg, 0.3eq) and N, N- dimethylethanolamine (144mg, 0.6eq), 150 DEG C of reaction 6h are added after nitrogen.Instead It should finish, water quenching is gone out, ethyl acetate extraction, and the dry dry chromatography that steams of organic layer obtains target compound b (476mg).
Step (ii): compound b (476mg, 1eq) is dissolved in methanol 10mL, is added 10% palladium carbon (50mg), and hydrogen is replaced Gas reacts 3h.End of reaction, pad diatomite filtering, filtrate steam dry chromatography and obtain target compound c (319mg).
Step (iii): compound c (319mg, 1eq) is dissolved in ethanol/water (v:v=1:1) 10mL, and potassium carbonate is added (4eq) back flow reaction 12h.End of reaction, methylene chloride extraction, the dry dry chromatography that steams of organic layer obtain target compound d (chemical combination Object 226) (97mg).
Other than reaction substrate is different, preparation of the compounds process for production thereof shown in following table with compound 226.
Embodiment 14: the preparation (scheme referring to shown in following formulas) of compound 236
Step (i) compound a (378mg, 1eq) is dissolved in Isosorbide-5-Nitrae-dioxane solution 10mL, and isoxazole -4- boron is added Sour (239mg, 1.5eq) and potassium carbonate (390mg, 2eq) are added tetra-triphenylphosphine palladium (81mg, 0.05eq) after replacing nitrogen, return Stream reaction 6h.TLC detects end of reaction, and solvent evaporated column chromatographs to obtain compound b (259mg).
Step (ii) compound b (259mg) is dissolved in methanol hydrochloride solution, is heated to 50 DEG C of reaction 1h, TLC detection reactions Completely.Saturated sodium bicarbonate washing, ethyl acetate extraction, the dry dry chromatography that steams of organic layer obtain compound c (compound 236) (159mg)。
1H NMR(400MHz,DMSO-d6) δ 8.95 (dd, J=7.4,1.5Hz, 1H), 8.09 (dd, J=7.5,1.4Hz, 1H), 8.04 (s, 1H), 7.69 (d, J=7.5Hz, 1H), 7.36 (t, J=7.5Hz, 1H), 6.94 (d, J=7.5Hz, 1H), 6.78(s,1H).
Embodiment 15: the preparation (scheme referring to shown in following formulas) of compound 237
Step (i): imidazoles (343mg, 3eq) is dissolved in anhydrous DMF (10ml) solution, add 60%NaH (168mg, 2.5eq), it stirs 5 minutes at room temperature.Compound a (500mg, 1eq) is added, stirs 1h at room temperature.Reaction solution slowly pours into ice In water, EA extraction, organic phase is washed 4 times, and salt washing is dry, is concentrated to get crude product b and is directly used in next step.
Step (ii): compound b (200mg) is dissolved in 10mL methanol hydrochloride solution, 50 DEG C of reaction 1h end of reaction.It is full It is washed with sodium bicarbonate solution, ethyl acetate extraction, the dry dry chromatography that steams of organic layer obtains target compound c (compound 237) (96mg)。
1H NMR(400MHz,DMSO-d6) δ 8.88 (dd, J=15.0,2.9Hz, 1H), 8.54 (dd, J=15.0, 2.9Hz, 1H), 7.74 (s, 1H), 7.60 (t, J=15.0Hz, 1H), 7.38 (d, J=15.0Hz, 1H), 7.09 (dd, J= 23.3,7.9Hz, 2H), 6.86 (d, J=15.0Hz, 1H), 6.54 (s, 1H), 5.57 (s, 2H)
Other than reaction substrate is different, compounds process for production thereof shown in following table is identical with the preparation method of compound 237.
Embodiment 16: the preparation (scheme referring to shown in following formulas) of compound 255
Step (i): compound a (500mg, 1eq) is dissolved in Isosorbide-5-Nitrae-dioxane solution 16mL, and 2- diuril azoles is added (286mg, 1.2eq) and sodium tert-butoxide (383mg, 2eq) replaces nitrogen, and Pd2 (dba) 3 (92mg, 0.05eq) and BINAP is added (125mg, 0.1eq), 110 DEG C of reaction 12h.End of reaction, solvent evaporated column chromatograph to obtain compound b (258mg).
Step (ii): compound b (258mg, 1eq) is dissolved in 33% hydrobromic acid acetum 10mL, 90 DEG C of reaction 5h. End of reaction, saturated sodium bicarbonate are quenched, and the dry dry chromatography that steams of ethyl acetate extraction organic layer obtains target compound c (chemical combination Object 255) (55mg).
1H NMR(400MHz,DMSO-d6) δ 9.01-8.86 (m, 2H), 8.19 (dd, J=15.0,2.9Hz, 1H), 7.91 (d, J=15.0Hz, 1H), 7.34 (d, J=15.0Hz, 1H), 7.21 (d, J=15.0Hz, 1H), 6.75 (dd, J=39.7, 15.0Hz,2H),6.59(s,1H).
Other than reaction substrate is different, compounds process for production thereof shown in following table is identical with the preparation method of compound 255.
Embodiment 17: the preparation (scheme referring to shown in following formulas) of compound 181
Step (i): imidazoles (0.36g, 3eq) is dissolved in anhydrous DMF (10ml) solution, adds 60%NaH (2.5eq), It stirs 5 minutes at room temperature.Raw material a is added, stirs 1h at room temperature.Reaction solution slowly pours into ice water, EA extraction, organic phase water It washes 4 times, salt washing is dry, is concentrated to get crude product b and is directly used in next step.
Step (ii): crude product b is dissolved in ethyl alcohol (10ml)/water (10ml), then weighs K2CO3(4eq) reacts reflux at 80 DEG C Overnight.Reaction solution is cooled to room temperature and pours into ice water, DCM extraction, organic phase washing, salt washing, dry, concentration, crude product column The isolated 250mg target product c of Chromatographic purification.
Step (iii): raw material c (250mg) is dissolved in saturation HCl (g)/MeOH (10ml), 3h is stirred at room temperature.It is precipitated solid Body filtering, filter residue methanolic ammonia solution 10mL dissolve, and stir 30min, solvent evaporated obtained solid washs to obtain target with water/methanol Compound d (compound 181) (92mg).
1HNMR(400MHz,CD3OD)δ9.16(s,1H),8.17(s,1H),7.52-7.80(m,2H),7.40-7.49(m, 2H), 7.25-7.27 (d, J=8.0Hz, 1H), 6.04 (s, 2H)
Other than substrate a is different, preparation method phase of the preparation method of compound 182-201 shown in following table with compound 181 Together.
Embodiment 18: the preparation (scheme referring to shown in following formulas) of compound 186
Step (i): acetylacetone,2,4-pentanedione (4.0eq) is dissolved in DMF (10ml), and 60%NaH (2.5eq) is added at -10 DEG C And be stirred at room temperature 10 minutes, raw material (400mg) reaction is added, TLC display reaction in 1 hour is stirred at room temperature seldom, heating To 55 DEG C and continuing stirring 1 hour, TLC shows that fully reacting reaction solution slowly pours into ice water, EA extraction, organic phase washing, Salt washing, it is dry, it is concentrated to get crude product, crude product is directly used in next step
Step (ii): previous step crude reaction is dissolved in ethyl alcohol (20ml), and it is anti-that hydroxylamine hydrochloride (2.0eq) is added in room temperature It should flow back 1 hour at 80 DEG C, TLC display generates a new point, and reaction solution pours into ice water, EA extraction, organic phase washing, salt Washing, dry, concentration, crude product column chromatography for separation obtains target product (300mg)；
Step (iii): raw material (300mg) is dissolved in HCl (g)/MeOH solution (20ml) of saturation, and reaction solution is in room temperature Then stirring 1 hour is warming up to 8 DEG C and reacts 2 hours, TLC shows that fundamental reaction is complete, and reaction solution pours into ice water, with saturation After sodium bicarbonate adjusts PH to alkalescent, solid is precipitated and filters, is washed 3 times with water and ether, drying obtains product d (compound 186)(200mg)。
1HNMR(CD3OD) 7.87 (br, 1H), 7.57-7.59 (br, 1H), 7.40-7.42 (br, 1H), 7.11-7.12 (br,1H),4.20(s,2H),2.31(s,3H),2.18(s,3H),2.11(s,3H).
Embodiment 19: the preparation (scheme referring to shown in following formulas) of compound 221
Step (i): compound a (500mg, 1.0eq) and imidazoles (2eq) are dissolved in DMF (10mL), under ice-water bath, in batches It is added sodium hydrogen (2.2eq), finishes, be slowly increased to room temperature reaction overnight, fully reacting.Water quenching is added to go out, EA is extracted twice, organic phase Dry with saturated common salt water washing 4 times, concentration, column chromatographic purifying obtains compound b (325mg).
Step (ii): compound b (300mg, 1.0eq) is dissolved in hydrochloric acid Isosorbide-5-Nitrae-dioxane solution, and room temperature reaction 2 is small When, end of reaction filters, and filter residue is washed with saturated sodium bicarbonate solution, filtered again, and filter residue washs to obtain chemical combination with methanol/water Object c (compound 221) (170mg).
1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),9.08(s,1H),8.53(s,1H),8.24(s,2H), 7.80 (s, 1H), 7.53 (t, J=8.1Hz, 1H), 7.26 (ddd, J=10.7,9.3,3.5Hz, 3H), 7.20 (s, 1H)
Other than substrate a is different, preparation method phase of the preparation method of compound 222-225 shown in following table with compound 221 Together.
Embodiment 20: the preparation (scheme referring to shown in following formulas) of compound 284
Step (i): compound a (140mg, 1.0eq) is dissolved in ethyl alcohol, and 40% chloroacetaldehyde (2.0eq) and carbon is added Sour hydrogen sodium (2.5eq), reaction solution are heated to reflux 30 minutes.TLC shows fully reacting, and reaction solution is directly concentrated, and column chromatography is pure Change to obtain compound b (120mg).
Step (ii): it disperses compound b (120mg, 1.0eq) in methanol hydrochloride solution (20mL), was stirred at room temperature Night.Fully reacting, concentration are added water dissolution, are adjusted to alkalescent with sodium bicarbonate aqueous solution, and solid, filtering, filter cake drying is precipitated It obtains compound c (compound 284) (80mg).
1HNMR(400MHz,DMSO-d6)br,1H),8.98(s,1H),7.85(s,1H),7.48-7.53(m,2H), 7.37 (t, J=8.0Hz, 1H), 7.23-7.28 (m, 2H), 7.08 (s, 1H), 6.97 (s, 1H), 5.59 (s, 2H)
Other than reaction substrate a is different, the preparation of compound shown in following table is identical with the preparation method of compound 284.
Embodiment 21: the preparation (scheme referring to shown in following formulas) of compound 283
Step (i): at -78 DEG C, compound a (230mg, 1.0eq) is dissolved in anhydrous tetrahydro furan 2mL, is added dropwise to In the anhydrous tetrahydro furan 6mL of Li-Al hydrogen (84mg, 3eq), 2h is reacted.TLC shows end of reaction, and saturated ammonium chloride solution is quenched It goes out, the dry dry chromatography that steams of ethyl acetate extraction organic layer obtains compound b (compound 283) (47mg).
1H NMR (400MHz, DMSO-d6) δ 8.40 (s, 1H), 8.33 (d, J=15.0Hz, 1H), 7.94 (dd, J= 15.0,3.1Hz, 1H), 7.73 (s, 1H), 7.64 (t, J=15.0Hz, 1H), 7.27 (dd, J=15.0,0.6Hz, 1H), 7.15 (s, 1H), 6.75 (dd, J=14.9,3.0Hz, 1H), 5.33 (s, 1H), 4.95 (s, 2H), 3.26 (s, 1H)
The test of Compound ira vitro BRD4 inhibitory activity
Molecular level experiment:
By constructing prokaryotic expression system, expression and purification includes the BRD4 albumen of BD1 structural domain, utilizes amplification chemistry Shine affine homogeneous detection (ALPHA) technology, establishes Screening Platform, using 5,8,12,16 acetylation modifications H4 polypeptide be substrate, be successfully established the Screening Platform of targeting BRD4_BD1 structural domain, and screening verification compound Inhibitory activity.Specific parcel received, under room temperature, in 20 μ lAlpha Screen reactants, the compound of 2.5 μ l and 2.5 μ l BRD4_BD1 albumen is incubated for 10min, and 5 μ l acetylation H are added4Polypeptide is incubated for 10min, and 10 μ l donor microballons and Acceptor beads are added Mixed liquor, be incubated for 60min, using Envision microplate reader read data.
Cellular level experiment:
Two plants of AML leukemia cell lines MV4.11, THP1 are cell model, examine or check compound to two plants of cell inhibitory effects IC50..10% fetal calf serum is added using 1640 culture mediums.After cell count, 96 holes are inoculated in every 104/100ul in hole In plate, at the same give compound processing, concentration gradient with 100 μM for initial concentration, twice of gradient dilution.Pass through alrma blue The variation of cell Proliferation after method detection administration 72 hours.Using cell survival rate as ordinate, drug concentration does figure for ordinate, and Compound is calculated to the IC of the Proliferation Ability of two kinds of cell strains50.Cell survival rate (%) calculation method are as follows: survival rate (%)= (dosing holes OD- blank well OD)/(control wells OD- blank well OD) × 100.The result shows that compound effectively inhibits leukaemia thin Born of the same parents' proliferation.
Table 1 inhibits BRD4 determination of activity result (IC50++++indicate < 0.1 μM；+++ indicate 0.1-1 μM；++ indicate 1-10 μ M；+ indicate > 10 μM；- indicate inactive)
It should be noted that the technical solution that the above embodiments are merely illustrative and not limiting of the present invention, any etc. Same replacement or change, should all be considered as and be included within the scope of the present invention.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims (10)

1. a kind of such as logical formula (I) compound represented or its pharmaceutically acceptable salt, isomers, racemic modification, crystalline hydrate Object, solvate or their mixture:
Wherein,
W be N, O or S,
X is C or N；
For aromatic heterocycle；
When W is O or S, R1It is not present；
When W is N, R1It is not present or R1Selected from H, C1~C10 alkyl, C1~C10 alkoxy；
R2It is selected from:
H；
Oxo group；
The C that unsubstituted or hydroxyl replaces1-C10Alkyl；
C1-C10Alkoxy；
Halogen；
Nitro；
Cyano；
C1-C10Acyl group；
C1-C10Alkoxy C1-C10Alkanoyl；
Sulfonic group；
Substituted or unsubstituted 5 to 8 yuan of aryl, wherein the substituent group in 5 to 8 yuan of substituted aryl is selected from halogen, oxo base Group, amino, hydroxyl, C1-C10Alkyl or C1-C10One or more of alkoxy (preferably one to three)；
Substituted or unsubstituted 3 to 8 yuan of naphthenic base, wherein the substituent group in 3 to 8 yuan of substituted naphthenic base is selected from halogen, ammonia Base, hydroxyl, C1-C10Alkyl or C1-C10One or more of alkoxy (preferably one to three)；
Substituted or unsubstituted amino, wherein the substituent group in the amino replaced is selected from the one or more of following group: halogen, C1-C10Alkyl, C1-C10Alkanoyl, C1-C10Alkoxy, hydroxyl, C1-C10Alkyl sulphonyl, it is unsubstituted or by be selected from C1-C10 Alkoxy, C1-C10One or more of alkyl, halogen, amino, hydroxyl, nitro or oxo group (preferably one to three) base Group replace 5 to 8 yuan of aryl, it is unsubstituted or by be selected from C1-C10Alkoxy, C1-C10Alkyl, halogen, amino, hydroxyl, nitro Or 5 to 8 yuan of aryl C that one or more of oxo group (preferably one to three) group replaces1-C10Alkyl, it is unsubstituted Or it is selected from C1-C10Alkoxy, C1-C10One or more of alkyl, halogen, amino, hydroxyl, nitro or oxo group are (excellent Select one to three) group replace 5 to 8 unit's heteroaryls, it is unsubstituted or by be selected from C1-C10Alkoxy, C1-C10Alkyl, halogen, 5 to the 8 unit's heteroaryl C that one or more of amino, hydroxyl, nitro or oxo group (preferably one to three) group replace1- C10Alkyl；
Substituted or unsubstituted 5 to 8 unit's heteroaryl, wherein the substituent group in 5 to 8 substituted unit's heteroaryls is selected from halogen, ammonia Base, hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy；
Substituted or unsubstituted 5 to 8 unit's heteroaryl C1-C10Alkyl, wherein 5 to 8 substituted unit's heteroaryl C1-C10In alkyl Substituent group is selected from halogen, amino, hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy；
Substituted or unsubstituted 5 to 8 yuan of aryl, wherein substituent group in 5 to 8 yuan of substituted aryl be selected from halogen, amino, Hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy；
Substituted or unsubstituted 5 to 8 yuan of aryl C1-C10Alkyl, wherein 5 to 8 yuan of substituted aryl C1-C10Substitution in alkyl Base is selected from halogen, amino, hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy；
Substituted or unsubstituted 5 to 8 yuan of aryl C2-C10Alkenyl, wherein 5 to 8 yuan of substituted aryl C2-C10In alkenyl Substituent group is selected from halogen, oxo group, amino, hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10One in alkoxy Or multiple (preferably one to three)；
Wherein, Y O, S or NH,
R9Are as follows: H；Hydroxyl；Amino；C1-C10Alkyl amino；Substituted or unsubstituted C1-C10Alkyl, wherein substituted C1-C10Alkane Substituent group in base is selected from amino, hydroxyl, sulfydryl or C1-C10One to three in alkylthio group；Substituted or unsubstituted C1-C10 Alkoxy, wherein substituted C1-C10Substituent group in alkoxy is selected from amino, hydroxyl, sulfydryl or C1-C10Alkylthio group；Replace or Unsubstituted 5 to 8 unit's heteroaryl, wherein the substituent group in 5 to 8 substituted unit's heteroaryls is selected from halogen, amino, hydroxyl, nitre Base, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy；Substituted or unsubstituted 5 to 8 unit's heteroaryl C1-C10 Alkyl, wherein 5 to 8 substituted unit's heteroaryl C1-C10Substituent group in alkyl is selected from halogen, amino, hydroxyl, nitro, cyanogen Base, C1-C10Alkyl or C1-C10One or more of alkoxy；Substituted or unsubstituted 5 to 8 yuan of aryl, wherein substituted 5 Substituent group into 8 yuan of aryl is selected from halogen, amino, hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10In alkoxy It is one or more；Substituted or unsubstituted 5 to 8 yuan of aryl C1-C10Alkyl, wherein 5 to 8 yuan of substituted aryl C1-C10In alkyl Substituent group be selected from halogen, amino, hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy； Substituted or unsubstituted 5 to 8 yuan of aryl C2-C10Alkenyl, wherein 5 to 8 yuan of substituted aryl C2-C10Substitution in alkenyl Base is selected from halogen, amino, hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy；
Or R1、R2And atom in connection is formed together imidazole ring；
R3It is selected from: H；Nitro；Amino；Hydroxyl；C1-C10Alkyl；C1-C10Alkoxy；Hydroxyl C1-C10Alkyl；Amino C1-C10Alkyl； Amino C1-C10Acyl group；Substituted or unsubstituted 5 to 8 unit's heteroaryl (preferably 5 to 6 unit's heteroaryls), wherein substituted 5 to 8 yuan Substituent group in heteroaryl (preferably 5 to 6 unit's heteroaryls) is selected from halogen, amino, hydroxyl, nitro, cyano, C1-C10Alkyl or C1- C10One or more of alkoxy；Substituted or unsubstituted 5 to 8 yuan of aryl, wherein the substitution in 5 to 8 yuan of substituted aryl Base is selected from halogen, amino, hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy；
R4It is selected from: H；Oxo group；C1-C10Alkyl；C1-C10Alkoxy；Substituted or unsubstituted 5 to 8 unit's heteroaryl (preferably 5 to 6 unit's heteroaryls), wherein substituent group in substituted 5 to 8 unit's heteroaryls (preferably 5 to 6 unit's heteroaryls) be selected from halogen, amino, Hydroxyl, oxo group, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy (preferably one, two or three It is a)；Substituted or unsubstituted 5 to 8 unit's heteroaryl C1-C10Alkyl (preferably 5 to 6 unit's heteroaryl C1-C10Alkyl), wherein replace 5 to 8 unit's heteroaryl C1-C10Alkyl (preferably 5 to 6 unit's heteroaryl C1-C10Alkyl) in substituent group be selected from halogen, amino, hydroxyl Base, oxo group, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy (preferably one, two or three)； Substituted or unsubstituted 5 to 8 yuan of aryl, wherein the substituent group in 5 to 8 yuan of substituted aryl is selected from halogen, amino, hydroxyl, oxygen For group, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy；Substituted or unsubstituted 3 to 8 yuan full And heterocycle, wherein the substituent group in 3 to 8 yuan of substituted saturated heterocyclyls is selected from halogen, amino, hydroxyl, oxo group, nitre Base, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy；Hydroxyl C1-C10Alkoxy；C1-C10Alkoxy C1-C10 Alkoxy；Substituted or unsubstituted 3 to 8 yuan of saturated heterocyclyls oxygen groups, wherein 3 to 8 yuan of substituted saturated heterocyclyl oxygen groups In substituent group be selected from halogen, amino, hydroxyl, oxo group, nitro, cyano, C1-C10Alkyl or C1-C10One in alkoxy It is a or multiple；Substituted or unsubstituted amino or substituted or unsubstituted amino C1-C10Alkyl, wherein substituted amino or Substituted amino C1-C10Substituent group in alkyl is selected from halogen, amino, hydroxyl, hydroxyl C1-C10Alkyl, oxo group, nitro, Cyano, C1-C10Alkyl, C1-C10Alkoxy, substituted or unsubstituted 3 to 8 yuan of naphthenic base, substituted or unsubstituted 5 to 8 yuan it is miscellaneous Aryl (preferably 5 to 6 unit's heteroaryls), substituted or unsubstituted 5 to 8 unit's heteroaryl C1-C10Alkyl (preferably 5 to 6 unit's heteroaryls C1-C10Alkyl), One or more of, wherein 3 to 8 yuan of substituted cycloalkanes Base, 5 to 8 unit's heteroaryls (preferably 5 to 6 unit's heteroaryls) replaced, and 5 to the 8 unit's heteroaryl C replaced1-C10Alkyl (preferably 5 To 6 unit's heteroaryl C1-C10Alkyl) in substituent group be selected from halogen, amino, hydroxyl, oxo group, nitro, cyano, C1-C10Alkane Base or C1-C10One or more of alkoxy；
R5To R8It is identical or different respectively, it is each independently selected from:
H；
Halogen；
Hydroxyl；
Nitro；
Sulfydryl；
C1-C10Alkylthio group；
Trifluoromethyl；
Trifluoroethyl；
Cyano；
Substituted or unsubstituted 3 to 8 yuan of saturated heterocyclyls, wherein the substituent group in 3 to 8 yuan of substituted saturated heterocyclyls is selected from Amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy or halogen；
Substituted or unsubstituted 5 to 8 yuan of aryl, wherein the substituent group in 5 to 8 yuan of substituted aryl is selected from amino, amino C1- C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy or halogen；
Substituted or unsubstituted 5 to 8 unit's heteroaryl (preferably 5 to 6 unit's heteroaryls), wherein 5 to 8 substituted unit's heteroaryls are (preferably 5 to 6 unit's heteroaryls) in substituent group be selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, cyano, Trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy or halogen；
-NR10R12；
-NCOR13；
Substituted or unsubstituted C1-C10Alkyl, wherein substituted C1-C10Substituent group in alkyl is selected from: hydroxyl；Nitre Base；Cyano；Amino；Trifluoromethyl；Trifluoroethyl；Sulfydryl；C1-C10Alkoxy；C1-C10Alkyl amino；C1-C10Alkyl Aminoacyl amido；Aminoacyl amido；-NR10R12； It is unsubstituted or by be selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkane Base, C1-C10Alkyl, C1-C10Nafoxidine base, amino-sulfonyl, halogen and the C that alkoxy, tertbutyloxycarbonyl replace1-C10Alkane 5 to 8 unit's heteroaryls that one or more substituent groups in oxygroup formoxyl replace；It is unsubstituted or by be selected from amino, amino C1-C10 Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1- C10Alkyl, C1-C10Nafoxidine base, amino-sulfonyl, halogen and the C that alkoxy, tertbutyloxycarbonyl replace1-C10Alkoxy first 5 to 8 yuan of aryl that one or more substituent groups in acyl group replace；
Amino C1-C10Acyl group；
C1-C10Alkyl amino C1-C10Acyl group；
-OCOR14；
Substituted or unsubstituted C1-C10Alkoxy, wherein substituted C1-C10Substituent group in alkoxy be selected from hydroxyl, amino, C1-C10One or more of alkoxy, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, 3 to 8 yuan of saturated heterocyclyls and halogen；
Substituted or unsubstituted 3 to 8 yuan of naphthenic base, wherein the substituent group in 3 to 8 yuan of substituted naphthenic base is selected from hydroxyl, ammonia Base, C1-C10Alkoxy, C1-C10One or more in alkyl, hydroxyl, cyano, trifluoromethyl, trifluoroethyl, sulfydryl and halogen It is a；
-OR15,R15Selected from substituted or unsubstituted 3 to 8 yuan of naphthenic base or substituted or unsubstituted 3 to 8 yuan of saturated heterocyclyls, Substituent group in middle 3 to 8 yuan of substituted naphthenic base or 3 to 8 yuan of substituted saturated heterocyclyls is selected from hydroxyl, amino, C1-C10Alcoxyl Base, C1-C10One or more of alkyl, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, halogen；
Substituted or unsubstituted 3 to 8 yuan of naphthenic base C1-C10Alkyl, wherein 3 to 8 yuan of substituted naphthenic base C1-C10In alkyl Substituent group is selected from hydroxyl, amino, C1-C10Alkoxy, C1-C10Alkyl, hydroxyl, cyano, trifluoromethyl, trifluoroethyl, sulfydryl and One or more of halogen；
Substituted or unsubstituted 3 to 8 yuan of saturated heterocyclyls C1-C10Alkyl, wherein 3 to 8 yuan of substituted saturated heterocyclyl C1-C10 Substituent group in alkyl is selected from hydroxyl, amino, C1-C10Alkoxy, C1-C10Alkyl, hydroxyl, cyano, trifluoromethyl, trifluoro second One or more of base, sulfydryl and halogen；
R10And R12It is identical or different, it is each independently selected from H；Hydroxyl；Nitro；Cyano；Trifluoromethyl；Trifluoroethyl；Sulfydryl；Hydroxyl Base C1-C10Alkyl；C1-C10Alkyl；C1-C10Alkoxy；C1-C10Alkoxy C1-C10Alkyl；C1-C10Alkyl amino C1-C10Alkane Base；It is unsubstituted or by be selected from C1-C10It is alkyl-substitutedQuiltSubstituted C1-C10Alkyl；It is unsubstituted Or it is selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, Sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy, halogen and C1-C10One or more in alkoxy formoxyl 5 to 8 unit's heteroaryls that a substituent group replaces；It is unsubstituted or by be selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, Hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy, halogen Element and C1-C105 to the 8 unit's heteroaryl C that one or more substituent groups in alkoxy formoxyl replace1-C10Alkyl；It is unsubstituted or It is selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, mercapto Base, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy, halogen and C1-C10One or more of alkoxy formoxyl 5 to 8 yuan of aryl C that substituent group replaces1-C10Alkyl；Or it is unsubstituted or by be selected from amino, amino C1-C10Alkyl, amino C1- C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10 Alkoxy, amino-sulfonyl, halogen and C1-C105 to 8 yuan of virtues that one or more substituent groups in alkoxy formoxyl replace Base；
Wherein, R11Indicate one or more substituent groups, and be each independently selected from H, halogen, hydroxyl, oxo group, nitro, Amino, tertbutyloxycarbonyl, C1-C10Alkyl, C1-C10The nafoxidine base or ammonia that alkoxy, trifluoromethyl, tertbutyloxycarbonyl replace Base sulfonyl；
R13Selected from H；Hydroxyl；Nitro；Cyano；Trifluoromethyl；Trifluoroethyl；Sulfydryl；Hydroxyl C1-C10Alkyl；C1-C10Alkyl；C1- C10Alkoxy；C1-C10Alkoxy C1-C10Alkyl；C1-C10Alkyl amino C1-C10Alkyl；C2-C10Alkenyl；It is unsubstituted or selected From amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl Base C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy, halogen and C1-C10One or more substituent groups in alkoxy formoxyl 5 to 8 unit's heteroaryls replaced；It is unsubstituted or by be selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitre Base, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy, halogen and C1- C105 to the 8 unit's heteroaryl C that one or more substituent groups in alkoxy formoxyl replace1-C10Alkyl；It is unsubstituted or be selected from Amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy, halogen and C1-C10One or more substituent groups in alkoxy formoxyl take 5 to the 8 unit's heteroaryl C in generation2-C10Alkenyl；It is unsubstituted or by be selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, Hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy, halogen Element and C1-C105 to 8 yuan of aryl C that one or more substituent groups in alkoxy formoxyl replace1-C10Alkyl；It is unsubstituted or by Selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitro, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, Hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy, halogen and C1-C10One or more substitutions in alkoxy formoxyl 5 to 8 yuan of aryl that base replaces；It is unsubstituted or by be selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxyl, nitre Base, cyano, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy, halogen and C1- C105 to 8 yuan of aryl C that one or more substituent groups in alkoxy formoxyl replace2-C10Alkenyl；
R14Selected from C1-C10Alkyl, C1-C10Alkoxy, or it is selected from amino, amino C1-C10Alkoxy, hydroxyl, nitro, cyanogen Base, trifluoromethyl, trifluoroethyl, sulfydryl, hydroxyl C1-C10Alkyl, C1-C10Alkyl, C1-C10Alkoxy, tertbutyloxycarbonyl replace Nafoxidine base, the C that replaces of one or more substituent groups in amino-sulfonyl and halogen1-C10Alkyl.
2. compound according to claim 1 or its pharmaceutically acceptable salt, isomers, racemic modification, crystalline hydrate Object, solvate or their mixture, wherein
R1It is not present or R1Selected from H, methyl, ethyl, propyl, butyl, methoxyl group, ethyoxyl or propoxyl group；
Preferably, R2It is selected from: oxo group, H, methyl, ethyl, propyl, butyl, fluorine, chlorine, bromine, iodine, formoxyl (- CHO), acetyl Base, propiono, bytyry ,-SO3H, methoxy methyl acyl group, ethoxy acetyl, butoxy formoxyl, propoxyl group formoxyl, hydroxyl Methyl, ethoxy, hydroxypropyl, hydroxyl butyl, phenyl, amino, formamido, acetamido, propionamido-, amide-based small, methylamino, Dimethylamino, ethylamino-, methylethylamine, Propylamino, butylamine base, sulfonyloxy methyl amido, ethyl sulfonamide base, sulfonyl propyl amine Base, butyl sulfonamide base,
3. compound according to claim 1 or 2 or its pharmaceutically acceptable salt, isomers, racemic modification, crystallization Hydrate, solvate or their mixture, wherein
R3Selected from H, nitro, amino, methylol, ethoxy, hydroxypropyl, amino methyl, amino-ethyl, aminopropyl, amino fourth Base,Carbamoyl, glycyl or aminobutanonyl；
Preferably, R4Selected from H, oxo group (=O),
4. compound according to any one of claims 1 to 3 or its pharmaceutically acceptable salt, isomers, racemic Body, crystalline hydrate, solvate or their mixture, wherein
R5To R8It is identical or different respectively, it is each independently selected from: H；Fluorine；Chlorine；Bromine；Iodine；Hydroxyl；Amino；Nitro； Methyl；Ethyl；Propyl；Butyl；Methoxyl group；Ethyoxyl；Propoxyl group；Butoxy；C1-C10Alkyl；C1-C10Alkoxy；Methoxybenzene；Ethoxybenzene；Propoxyl group benzene； -NHMe；
5. compound according to any one of claims 1 to 4 or its pharmaceutically acceptable salt, isomers, racemic Body, crystalline hydrate, solvate or their mixture, wherein
The logical formula (I) compound represented, which has, is selected from structure shown in general formula (I-1) to general formula (I-5):
Wherein, R1To R8Substituent group define it is identical as the definition in any one of Claims 1-4 respectively.
6. compound according to claim 1 or its pharmaceutically acceptable salt, isomers, racemic modification, crystalline hydrate Object, solvate or their mixture, wherein the logical formula (I) compound represented is selected from compound as described below:
7. a kind of pharmaceutical composition, it includes as effective component such as compound described in any one of claims 1 to 6, Or its pharmaceutically acceptable salt, isomers, racemic modification, crystalline hydrate, solvate or their mixture and medicine Acceptable carrier on.
8. compound according to any one of claim 1 to 6 or its pharmaceutically acceptable salt, isomers, racemic It is prepared by body, crystalline hydrate, solvate or their mixture or pharmaceutical composition according to claim 7 The purposes in drug for treating disease relevant to BRD4.
9. purposes according to claim 8, wherein the relevant disease of the BRD4 be selected from heart failure, cardiovascular disease, NUT- center line cancer, acute lymphatic leukaemia, mixed lineage leukemia, Huppert's disease, Burkitt ' s lymthoma, liver cell Cancer, triple negative breast cancer, non-small cell lung cancer, prostate cancer, cancer of pancreas and neuroblastoma, lymthoma, tumor of kidney, view Nethike embrane blastoma, osteosarcoma and chondrosarcoma, Posterior fossa medulloblastoma, nasopharyngeal carcinoma, thyroid papillary carcinoma, thymoma, Pulmonary blastoma, pancreatoblastoma, islet-cell tumour, ileocecus class cancer or celiothelioma.
10. purposes according to claim 9, wherein the heart failure is selected from myocardial hypertrophy disease and cardiac muscle cell's fertilizer Big disease.
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