CN109705071A - Hdac inhibitor and its preparation method and application - Google Patents

Hdac inhibitor and its preparation method and application Download PDF

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CN109705071A
CN109705071A CN201811247197.3A CN201811247197A CN109705071A CN 109705071 A CN109705071 A CN 109705071A CN 201811247197 A CN201811247197 A CN 201811247197A CN 109705071 A CN109705071 A CN 109705071A
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yuan
compound
formula
alkyl
hydrogen
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CN109705071B (en
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李进
吴波
张登友
尚巳耘
楚洪柱
王稚京
吕开智
梁秋香
农云宏
陈伟
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Chengdu Lead Drug Development Corp Ltd
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Abstract

The invention discloses a kind of formula (I) compounds represented.The invention further relates to the pharmaceutical compositions containing formula (I) compound and the compound to prepare the purposes in hdac inhibitor class drug.The compound of the present invention or its pharmaceutical composition can be used for treating cell breeding disease, autoimmune disease, inflammation, neurodegenerative disease or viral disease.

Description

Hdac inhibitor and its preparation method and application
Technical field
The present invention relates to hdac inhibitors and its preparation method and application.
Background technique
Tumour refers to body under the effect of the various tumorigenesis factors, and the cell of local organization loses at the genetic level gives birth to it Long normal regulation leads to clonal abnormality hyperplasia and the neoformation that is formed.The outer genetic mechanism for causing gene to inactivate mainly wraps DNA methylation is included, the modification of other compositions in acetylation of histone and chromatin higher order structure, these modifications change dyeing texture Type causes genetic transcription adjusting to change, and the imbalance of genetic transcription causes cell Proliferation not normal, so as to cause tumour generation.
Acetylation of histone plays the role of a nucleus for the transcriptional control of eukaryocyte.It is acted on by the mutual antagonism of a pair of of function Protease acetylation of histone transferase (HATs) and histon deacetylase (HDAC) (HDACs) regulation.In normal cell, this A pair of of enzyme is in dynamic balance state.Under normal circumstances, the enhancing of acetylation of histone level is related with Gene Transcription in vitro enhancing, And Acetylation Level is too low related with gene expression inhibition.The study found that HDAC over-expresses and be transcribed factor recruitment, cause The abnormal inhibition of specific gene, so as to cause tumour and other diseases；And inhibit the activity of HDAC that will cause many cancer cells Growth inhibition and apoptosis.Therefore, HDAC has become the newest and most popular target in current anti-tumor drug research and development field.
Hdac inhibitor has the function of interference and histon deacetylase (HDAC).It is commonly divided into two major classes: NAD+- dependence Enzyme and Zn2+ dependent enzyme.Zn2+ dependent protein enzyme includes HDACs I (including HDAC 1,2,3 and 8), II (including HDAC 4,5,6,7,9 and 11), IV (including HDAC 11) subtribe；NAD+- dependent enzyme is mainly HDACs III subtribe.HDAC inhibits Agent mechanism of action is to block gene expression caused by raising dysfunction due to HDAC suppressed, by changing by inhibiting HDAC Become the degree of acetylation of histone to change chromatin Structure, thus controlling gene expression treatment cancer.It passes through induction tumour Growth retardation, differentiation or the apoptosis of cell are significant in efficacy to treatment hematological system tumor and solid tumor.Hdac inhibitor has swollen Tumor specificity has cytotoxicity to proliferation and static mutant, and normal cell has 10 times or more of tolerance to it, It will not cause growth retardation and the apoptosis of normal cell.
There are five types of hdac inhibitors to list at present.The SAHA, action target spot Pan-HDAC of listing in 2006；2011 The FK-288, action target spot HDAC1, HDAC2 of year listing；The PXD101 of listing in 2014, action target spot HDAC1, HDAC2；The chidamide of listing in 2015, the target spot of effect are HDAC1, HDAC2, HDAC3, HDAC10；Listing in 2015 LBH589, the target spot of effect are HDAC (MOLT-4cells).This five kinds of hdac inhibitors are in anticancer activity, toxic side effect, hypotype Selectivity etc. has certain problems, and the target spot of this five kinds of hdac inhibitors effect is without HDAC6.
Therefore, it is badly in need of a kind of noval chemical compound with histon deacetylase (HDAC) inhibitory activity now.
Summary of the invention
To solve the above-mentioned problems, the present invention provides formula (I) compound represented or its crystal form or its hydrate or Its optical isomer or its solvate or its pharmaceutically acceptable salt:
Wherein, n is 0~10；
L1Indicate without or C1~C10Alkylidene or C1~C10Alkenyl；
Y is N or CR2, wherein R2Selected from hydrogen, halogen, hydroxyl, amino, trifluoromethyl, cyano, C1~C10Alkyl or C1~ C10Alkoxy；
X is O, S or NR3；Wherein R3Selected from hydrogen, C1~C10Alkyl or C1~C10Acyl group；
R1For hydrogen, C1~C10Alkyl, C3~C10Cycloalkane or heterocycloalkane；
Ring A indicates 3~10 yuan of cycloalkane, 3~10 yuan of heterocycloalkane, 5~10 yuan of aryl or 5~10 yuan of heteroaryl Base；Wherein A ring can be further by 0~5 R4Replace, wherein each R4It is independently chosen from halogen, cyano, nitro, fluoroform respectively Base, trifluoromethoxy ,-(CH2)qR5、–(CH2)qOR5、–(CH2)qOCOR5、–(CH2)qNR5R6、–(CH2)qNR5COR6、–(CH2)qCOR5、–(CH2)qCOOR5、–(CH2)qCONR5R6, q is 0~10；
R5、R6It is respectively selected from hydrogen, C1~C10Alkyl, 5~10 yuan of cycloalkane, 5~10 yuan of heterocycloalkane, 5~10 yuan Aryl or 5~10 yuan of heteroaryl, wherein R5、R6It can be further by R7Replace；
R7Selected from halogen, hydroxyl, amino, C1~C10Alkyl, C1~C10Alkoxy, C1~C10Alkylamino ,- (CH2)rOR8；Wherein r is 0~10；.
R8Selected from hydrogen, C1~C10Alkyl.
Further, the compound has the structure as shown in formula (I a) or formula (I b):
Further, formula (I a) compound has the structure as shown in formula (I a-1):
Wherein, L1It indicates without, C1~C5Alkylidene orWherein m is 0~3；
R1Indicate hydrogen, C1~C5Alkyl；
R2Indicate hydrogen, halogen, trifluoromethyl, trifluoromethoxy ,-(CH2)qR5、–(CH2)qOR5、–(CH2)qNR5R6、– (CH2)qCOR5, q is 0~5；
R5、R6It is respectively selected from hydrogen, C1~C5Alkyl, 5~10 yuan of cycloalkane, 5~10 yuan of heterocycloalkane, 5~10 yuan Aryl or 5~10 yuan of heteroaryl；, wherein R5、R6It can be further by R7Replace；
R7Selected from halogen, hydroxyl, amino, C1~C5Alkyl, C1~C5Alkoxy, C1~C5Alkylamino ,-
(CH2)rOR8；Wherein r is 0~5；.
R8Selected from hydrogen, C1~C5Alkyl；
Ring A indicates phenyl, 5 yuan of heteroaromatics, 6 yuan of heteroaromatics, 10 yuan of heteroaromatics.
Further, formula (I a) compound has the structure as shown in formula (I a-2):
Wherein, R1Indicate hydrogen, halogen；Ring A indicates phenyl, 5 yuan of heteroaromatics, 6 yuan of heteroaromatics.
Further, formula (I a) compound has the structure as shown in formula (I a-3):
Wherein, n=0,1,2,3；X indicates hydrogen, halogen；
R1Indicate hydrogen, C1~C5Alkyl, 6 yuan of aryl or heteroaryl；
R3Indicate hydrogen, C1~C5Alkyl；
R2Indicate hydrogen, halogen, trifluoromethyl, methoxyl group ,-(CH2)qR5、–(CH2)qNR5R6、–(CH2)qCOR5, q is 0~5；
R5、R6It is respectively selected from hydrogen, C1~C5Alkyl, 5~6 yuan of cycloalkane, 5~6 circle heterocyclic ring alkane, 5~6 yuan of heteroaromatics, Phenyl；
Ring A indicates phenyl, hexamethylene, 5~6 circle heterocyclic ring alkane, 5~6 yuan of heteroaromatics or 10 yuan of heteroaromatics.
Further, formula (I a) compound has the structure as shown in formula (I a-4):
Wherein, X indicates O, S, N；Ring A indicates phenyl, 5~6 yuan of heteroaromatics or 10 yuan of heteroaromatics.
Further, the formula (I a) is one of following compound:
Further, formula (I b) compound has the structure as shown in formula (I b-1):
Wherein, L1It indicates without, C1~C5Alkylidene orWherein m is 0~3；R1Indicate hydrogen, C1~C5Alkane Base；
R2Indicate hydrogen, halogen, trifluoromethyl, trifluoromethoxy ,-(CH2)qR5、–(CH2)qOR5、–(CH2)qNR5R6、– (CH2)qCOR5, q is 0~5；
R5、R6It is respectively selected from hydrogen, C1~C5Alkyl, 5~10 yuan of 5~10 yuan of cycloalkane of heterocycloalkane, 5~10 yuan Aryl or 5~10 yuan of heteroaryl；Wherein R5、R6It can be further by R7Replace；
R7Selected from halogen, hydroxyl, amino, C1~C5Alkyl, C1~C5Alkoxy, C1~C5Alkylamino ,-(CH2)rOR8；Wherein r is 0~5；
R8Selected from hydrogen, C1~C5Alkyl；
Ring A indicates phenyl, 5~6 yuan of heteroaromatics or 10 yuan of heteroaromatics.
Further, formula (I b) compound has the structure as shown in formula (I b-2):
Wherein, R1Indicate hydrogen, halogen；Ring A indicates phenyl, 5 yuan of heteroaromatics, 6 yuan of heteroaromatics.
Further, formula (I b) compound has the structure as shown in formula (I b-3):
Wherein, n=0,1,2,3；X indicates hydrogen, halogen；
R1Indicate hydrogen, C1~C5Alkyl, 6 yuan of aryl or heteroaryl；
R3Indicate hydrogen, C1~C5Alkyl；
R2Indicate hydrogen, halogen, trifluoromethyl, methoxyl group ,-(CH2)qR5、–(CH2)qNR5R6、–(CH2)qCOR5, q is 0~5；
R5、R6It is respectively selected from hydrogen, C1~C5Alkyl, 5~6 yuan of cycloalkane, 5~6 circle heterocyclic ring alkane, 5~6 yuan of heteroaromatics, Phenyl；
Ring A indicates phenyl, hexamethylene, 5~6 circle heterocyclic ring alkane, 5~6 yuan of heteroaromatics or 10 yuan of heteroaromatics.
Further, formula (I b) compound has the structure as shown in formula (I b-4):
Wherein, X indicates O, S, N；Ring A indicates phenyl, 5~6 yuan of heteroaromatics or 10 yuan of heteroaromatics.
Further, the formula (I b) is one of following compound:
The present invention also provides compound above-mentioned or its crystal form or its hydrate or its optical isomer or its is molten Object is closed in agent or its pharmaceutically acceptable salt is preparing the purposes in hdac inhibitor class drug.
Further, the drug be treatment cell breeding disease, autoimmune disease, inflammation, neurodegenerative disease or The drug of viral disease.
Further, the cell breeding disease is cancer.
Further, the cancer includes colon cancer, lung cancer, breast cancer, prostate cancer, the cancer of the brain, oophoroma, thyroid gland Cancer.
Further, the HDAC is HDAC6.
The present invention also provides a kind of pharmaceutical composition, it be with the described in any item compounds of claim 1-12 or Its crystal form or its hydrate or its optical isomer or its solvate or its pharmaceutically acceptable salt are active constituent, In addition the preparation that pharmaceutically acceptable auxiliary material is prepared.
Further, the preparation is oral preparation, transdermal absorption formulation or ejection preparation.
The present invention also provides pharmaceutical compositions above-mentioned to prepare the purposes in hdac inhibitor class drug.
Further, the drug be treatment cell breeding disease, autoimmune disease, inflammation, neurodegenerative disease or The drug of viral disease.
Further, the cell breeding disease is cancer.
Further, the cancer includes colon cancer, lung cancer, breast cancer, prostate cancer, the cancer of the brain, oophoroma, thyroid gland Cancer.
Further, the HDAC is HDAC6.
In some embodiments, in formula (I) compound represented, n 0,1,2 or 3, L1For nothing, C1~C3Alkylidene OrY is N or CR2, R2Selected from hydrogen, halogen, hydroxyl, amino, trifluoromethyl, cyano, C1~C3Alkyl or C1~ C3Alkoxy, X O, S or NR3, R3Selected from hydrogen, C1~C3Alkyl or C1~C3Acyl group, R1For hydrogen, C1~C3Alkyl, C3 ~C6Cycloalkane or 3~6 yuan of heterocycloalkane, ring A be 3~10 yuan of cycloalkane, 3~10 yuan of heterocycloalkane, 5~10 yuan Aryl or 5~10 yuan of heteroaryl, wherein A ring can be further by 1~3 R4Replace, wherein each R4It is independently chosen from halogen respectively Element, cyano, nitro, trifluoromethyl, trifluoromethoxy ,-(CH2)qR5、–(CH2)qOR5、–(CH2)qOCOR5、–(CH2)qNR5R6、– (CH2)qNR5COR6、–(CH2)qCOR5、–(CH2)qCOOR5、–(CH2)qCONR5R6, q 0,1,2 or 3, R5、R6Be respectively selected from hydrogen, C1~C3Alkyl, 5~6 yuan of cycloalkane, 5~6 yuan of heterocycloalkane, 5~6 yuan of aryl or 5~6 yuan of heteroaryl, wherein R5、R6It can be further by R7Replace, R7Selected from halogen, hydroxyl, amino, C1~C3Alkyl, C1~C3Alkoxy, C1~C3's Alkylamino ,-(CH2)rOR8, r 0,1,2 or 3, R8Selected from hydrogen, C1~C10Alkyl.
In some embodiments, in formula (I) compound represented, n 0, L1For without orY is N or CR2, R2Selected from hydrogen, halogen, trifluoromethyl, cyano, methyl, ethyl or methoxyl group, X O, S or NR3, R3Selected from hydrogen, methyl, ethyl, Formoxyl or acetyl group, R1For hydrogen, methyl, ethyl, ring A is the cycloalkane of 5-6 member, 5~6 yuan of heterocycloalkane, 5~6 yuan Aryl, 9~10 yuan of aryl, 5~6 yuan of heteroaryl, 9~10 yuan of heteroaryl, wherein A ring can be further by 1~3 R4It takes Generation, wherein each R4It is independently chosen from halogen, cyano, trifluoromethyl, trifluoromethoxy ,-(CH respectively2)qR5、–(CH2)qOR5、– (CH2)qNR5R6、–(CH2)qCOR5、–(CH2)qCOOR5、–(CH2)qCONR5R6, q 0,1,2 or 3, R5、R6It is respectively selected from hydrogen, C1 ~C3Alkyl, 5~6 yuan of cycloalkane, 5~6 yuan of heterocycloalkane, 5~6 yuan of aryl or 5~6 yuan of heteroaryl, wherein R5、R6It can be further by R7Replace, R7Selected from halogen, hydroxyl, amino, C1~C3Alkyl, C1~C3Alkoxy, C1~C3's Alkylamino ,-(CH2)rOR8, r 0,1,2 or 3, R8Selected from hydrogen, C1~C10Alkyl.
In some embodiments, in formula (I) compound represented, A ring is
In some embodiments, in formula (I a-1) compound represented, L1Indicate without orR1For hydrogen, first Base, ethyl, ring A are phenyl, 5 yuan of nitrogenous heteroaromatics, 6 yuan of nitrogenous heteroaromatics, 10 yuan of nitrogenous heteroaromatics, R2For hydrogen, halogen, trifluoro Methyl, trifluoromethoxy ,-(CH2)qR5、–(CH2)qOR5、–(CH2)qNR5R6、–(CH2)qCOR5, q 0,1,2 or 3, R5、R6Point It Xuan Zi not hydrogen, C1~C3Alkyl, 5~6 yuan of cycloalkane, 5~6 yuan of heterocycloalkane, 5~6 yuan of aryl or 5~6 yuan it is miscellaneous Aryl, wherein R5、R6It can be further by R7Replace, R7Selected from halogen, hydroxyl, amino, C1~C3Alkyl, C1~C3Alkoxy, C1~C3Alkylamino ,-(CH2)rOR8, wherein r is 0,1,2 or 3, R8Selected from hydrogen, C1~C3Alkyl；
In some embodiments, in formula (I b-1) compound represented, L1Indicate without orR1For hydrogen, first Base, ethyl, ring A are phenyl, 5 yuan of nitrogenous heteroaromatics, 6 yuan of nitrogenous heteroaromatics, 10 yuan of nitrogenous heteroaromatics, R2For hydrogen, halogen, trifluoro Methyl, trifluoromethoxy ,-(CH2)qR5、–(CH2)qOR5、–(CH2)qNR5R6、–(CH2)qCOR5, q 0,1,2 or 3, R5、R6Point It Xuan Zi not hydrogen, C1~C3Alkyl, 5~6 yuan of cycloalkane, 5~6 yuan of heterocycloalkane, 5~6 yuan of aryl or 5~6 yuan it is miscellaneous Aryl, wherein R5、R6It can be further by R7Replace, R7Selected from halogen, hydroxyl, amino, C1~C3Alkyl, C1~C3Alkoxy, C1~C3Alkylamino ,-(CH2)rOR8, wherein r is 0,1,2 or 3, R8Selected from hydrogen, C1~C3Alkyl；
About the definition of the invention using term: unless otherwise indicated, group or term herein provide initial Definition is suitable for group or term of entire description；For the term being not specifically defined herein, it should according to open Content and context, their meaning can be given by providing those skilled in the art.
" substitution " refers to that the hydrogen atom in molecule is replaced by other different atoms or molecule.
The minimum value and maximum value of carbon content are indicated by prefix in hydrocarbon group, for example, prefix Ca~CbAlkyl table Bright any alkyl containing " a " to " b " a carbon atom, including straight chained alkyl and branched alkyl.Thus, for example, C1~C4Alkyl refers to Straight chained alkyl and branched alkyl comprising 1~4 carbon atom.
In the present invention, Ca~CbAlkoxy, Ca~CbAlkylamino radical, Ca~CbAcyl group etc. refers respectively to former containing " a " to " b " a carbon The group that alkyl and corresponding oxygen atom, amino, the acyl group etc. of son are connected to form.
In the present invention, halogen refers to fluorine atom, chlorine atom, bromine atom, iodine atom.
" naphthenic base ", " cycloalkane " refer to saturated rings or nonaromatic unsaturated ring that full carbon atom is formed in the present invention.
" heterocycle ", heterocycloalkane in the present invention ", Heterocyclylalkyl " refer to comprising at least one heteroatomic saturated rings or non- The unsaturated ring of armaticity；Wherein hetero atom refers to nitrogen-atoms, oxygen atom, sulphur atom.
" aryl ", " aromatic ring " refer to the unsaturated ring with armaticity that full carbon atom is formed in the present invention.
" heterocyclic base " in the present invention, heteroaromatic " refers to comprising at least one heteroatomic unsaturated ring with armaticity； Wherein hetero atom refers to nitrogen-atoms, oxygen atom, sulphur atom.
" alkylidene " refers to the hydrocarbon group being connected respectively with two atoms in the present invention；
Term " pharmaceutically acceptable " refers to certain carrier, load, diluent, auxiliary material, and/or to be formed by salt usual In chemistry or physically with constitute the other compatible at split-phase of certain pharmaceutical dosage form, and physiologically mutually compatible with receptor.
Term " salt " refers to above compound or its stereoisomer, the acid formed with inorganic and/or organic bronsted lowry acids and bases bronsted lowry And/or basic salt, also include amphoteric ion salt (inner salt), further includes quaternary ammonium salt, such as alkylammonium salt.These salt, which can be, to be changed Close being finally separating and directly obtaining in purifying for object.It is also possible to by by above compound or its stereoisomer, and it is certain The acid or alkali of quantity appropriate (such as equivalent) are obtained by mixing.These salt may be formed in the solution precipitating and with filtering Method is collected, or recycles obtain after the solvent evaporates, or is freeze-dried and is made after reacting in an aqueous medium.It is heretofore described Salt can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromate, hydrofluoride, phosphate, the acetic acid of compound Salt, propionate, succinate, oxalates, malate, succinate, fumarate, maleate, tartrate or trifluoro Acetate.
In certain embodiments of the invention, present invention comprises the compound of isotope labelling, the isotope labelling Compound refers to identical as listed compound herein, but one or more of atoms are replaced by another atom, should The atomic mass or mass number of atom are different from atomic mass or mass number common in nature.Formula (I) chemical combination can be introduced Isotope in object includes hydrogen, carbon, nitrogen, oxygen, sulphur, i.e. 2H, 3H, 13C, 14C, 15N, 17O, 18O, 35S.Contain above-mentioned isotope And/or the formula (I) of other atom isotopes compound and its stereoisomer and the compound, stereoisomer can Medicinal salt should be included within the scope of the invention.
In some embodiments, one or more compounds of the invention can be used in conjunction with one another.Also may be selected will The compound of the present invention is used in combination with any other active agent, is used to prepare regulating cell function or treats the medicine of disease Object or pharmaceutical composition.If using one group of compound, can by these compounds simultaneously, respectively or in an orderly manner to tested Object is administered.
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): oral, parenteral (intravenous, intramuscular or subcutaneous) and local administration.
Compound of the present invention has induction differentiation, immunological regulation, the block cell period, promotes Apoptosis Activity and well HDAC6 subtype-selective, it is intended to there is better curative effect to various cancers, while overcoming current HDAC The toxic side effect of inhibitor, such as the formation of anaemia, ishemic stroke, deep vein thrombosis, decrease of platelet and vomiting.
Compound of the present invention has HDAC inhibitory activity, can be used for treating disease extremely relevant to HDAC activity Disease.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention The technology realized all belongs to the scope of the present invention.
Specific embodiment
Raw material, equipment used in the specific embodiment of the invention are known product, are obtained by purchase commercial product.
The structure of the compounds of this invention be by nuclear magnetic resonance (NMR) or (and) mass spectrum (MS) is come what is determined.NMR displacement (δ) is with 10-6(ppm) unit provides.The measurement of NMR is with (Bruker AvanceIII 400 and Bruker Avance 300) nuclear magnetic resonance spectrometer, measurement solvent are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), Inside it is designated as tetramethylsilane (TMS).
The measurement of LC-MS is with Shimadzu LC-MS instrument (Shimadzu LC-MS 2020 (ESI)).
The measurement of HPLC uses Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A).
Reversed-phase preparative chromatography uses Gilson GX-281 reversed-phase preparative chromatography instrument.
Tlc silica gel plate isolates and purifies product with Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, thin-layer chromatography The specification of use is 0.4mm~0.5mm.
Column chromatography is generally carrier using 200~300 mesh silica gel of Yantai Huanghai Sea silica gel.
Known starting material of the invention can be used or be synthesized according to methods known in the art, or can purchase in Pacify the companies such as resistance to Jilin Chemical, Chengdu section Long Huagong, splendid remote chemical science and technology, lark prestige science and technology.
Without specified otherwise in embodiment, reaction carries out under nitrogen atmosphere.
Without specified otherwise in embodiment, solution refers to aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature.
Without specified otherwise in embodiment, M is mole every liter.
Room temperature be optimum reaction temperature, usually 20 DEG C~30 DEG C.
It is overnight usually 12 ± 1 hours.
The synthesis of compound in 1 present invention of embodiment
General synthetic routes 1
(1.1) synthesis of intermediate 3a:
4-bromo- 2-fluorobenzaldehydes (100g, 493mmol) and 2-hydroxy methyl acetates (102g, 1.13mol) are dissolved in DMF In (1.0L), sodium hydrogen (59.2g, 1.48mol, 60%) is added at 0 DEG C, ice water (2.0L) is added after being stirred to react 1 hour, second Acetoacetic ester (1.0L) extracts 4 times, merges organic layer and is washed 1 time with saturated sodium chloride solution.Evaporating solvent under reduced pressure chromatographs pure through column Change to obtain intermediate 3a (22.0g, 86.3mmol, yield 18%).
(1.2) synthesis of intermediate 3b:
Using 5-bromo- 2-fluorobenzaldehydes and 2-hydroxy methyl acetates as raw material, according to the synthetic method of intermediate 3a, obtain Mesosome 3b (yield 42%).
(1.3) synthesis of intermediate 3c:
Using 4-bromo- 2-fluorobenzaldehydes and 2-methyl thioglycolates as raw material, according to the synthetic method of intermediate 3a, obtain Mesosome 3c (yield 94%).
(1.4) synthesis of intermediate 3d:
Using 5-bromo- 2-fluorobenzaldehydes and 2-methyl thioglycolates as raw material, according to the synthetic method of intermediate 3a, obtain Mesosome 3d (yield 87%).
(2.1) synthesis of intermediate 4a:
Intermediate 3a (38.20g, 151mmol) is dissolved in toluene (300mL), and addition benzyl mercaptan (24.50g, 197.00
Mmol), DIPEA (39.50g, 306.00mmol, 53.2mL), 4,5-bis- (diphenylphosphines)-9,9-dimethyl oxa-s Anthracene (8.90g, 15.40mmol) and tris(dibenzylideneacetone) dipalladium (6.89g, 7.53mmol), back flow reaction is overnight.After reaction It is added water (500mL), ethyl acetate (300mL) extracts 2 times, merges evaporating solvent under reduced pressure after organic layer.After column chromatographic purifying It obtains intermediate 4a (27.00g, 86.4mmol, yield 57%).
(2.2) synthesis of intermediate 4b:
Using intermediate 3b as raw material, according to the synthetic method of intermediate 4a, intermediate 4b (yield 91%) is obtained.
(2.3) synthesis of intermediate 4c:
Using intermediate 3c as raw material, according to the synthetic method of intermediate 4a, intermediate 4c (yield 89%) is obtained.
(2.4) synthesis of intermediate 4d:
Using intermediate 3d as raw material, according to the synthetic method of intermediate 4a, intermediate 4d (yield 76%) is obtained.
(3.1) synthesis of intermediate 6a1:
Intermediate 4a (600mg, 2.01mmol) is dissolved in acetic acid (15.0mL) and water (5.00mL), N-chlorine is added portionwise For succimide (1.07g, 8.00mmol).Water (20.0mL) is added after being stirred to react 2 hours.Ethyl acetate (30.0mL) extraction It takes 2 times, it is dry with anhydrous sodium sulfate after merging organic layer.After evaporating solvent under reduced pressure, methylene chloride is dissolved the residue in (10.0mL).Pyridine (470mg, 6.00mmol) is added, and room temperature is stirred to react 4 hours afterwards.Evaporating solvent under reduced pressure chromatographs pure through column Change to obtain intermediate 6a1 (410mg, 1.25mmol, yield 62%).
(3.2) synthesis of intermediate 6a2~6a60:
According to the synthetic method of intermediate 6a1, intermediate 6a2~6a60 is obtained.
1, the synthesis of compound 1
Intermediate 6a1 (3.70g, 11.20mmol) is dissolved in methylene chloride (15.0mL) and methanol (15.0mL), is added To be stirred to react 2 small for room temperature afterwards for aqueous hydroxylamine solution (22.2mL, 336.00mmol, 50%) and sodium hydroxide (1.34g, 33.5mmol) When.Finished product (3.20g, 9.15mmol, yield 82%) is purified to obtain through preparing HPLC after evaporating solvent under reduced pressure.1H NMR (400MHz, DMSO-d6) δ 10.94 (brs, 2H), 9.46 (s, 1H), 8.00-7.96 (m, 1H), 7.93 (d, J=8.4Hz, 1H), 7.71 (dd, J=8.4,1.6Hz, 1H), 7.58-7.53 (m, 1H), 7.26-7.19 (m, 2H), 7.15-7.09 (m, 2H), 7.05–6.99(m,1H)；MS(ESI)m/z 333(M+1)+。
2, the synthesis of compound 2~60
Using intermediate 6a2~6a60 as raw material, according to the synthetic method of compound 1, embodiment 2~60 in following table are obtained.
3, the synthesis of compound 61
(3.1) synthesis of intermediate 61a
Intermediate 6a1 (500mg, 1.51mmol) is dissolved in methanol (4.00mL) and water (4.00mL), hydroxide is added Room temperature is stirred to react 3 hours sodium (181mg, 4.53mmol) afterwards.Aqueous layer with ethyl acetate uses 1N hydrochloric acid to adjust pH=2 after washing 2 times, Then it is extracted with ethyl acetate again 2 times.Intermediate 61a crude product (500mg) is obtained after being associated with several layers of and evaporating solvent under reduced pressure.
(3.2) synthesis of intermediate 61b
Intermediate 61a (500mg, 1.58mmol) is dissolved in chloroform (10.0mL), oxalyl chloride is added at 0 DEG C Reaction 3.5 hours is stirred at room temperature in (401mg, 3.16mmol).After evaporating solvent under reduced pressure, residue is dissolved in tetrahydrofuran (4.92mL) and acetonitrile (5.0ml).At 0 DEG C be added trimethyl silicone hydride diazomethane cyclohexane solution (1.60mL, 3.20mmol, 2.0M) and be stirred to react 2 hours.Evaporating solvent under reduced pressure after the reaction was completed, residue are dissolved in dioxane In (5.37mL) and water (5.37mL), it is stirred to react at 60 DEG C 2 hours after silver carbonate (158mg, 948 μm of ol) are added.Reaction It cools down, is extracted with ethyl acetate 2 times after the completion, saturated sodium chloride solution is washed after merging organic layer, and it is dry to add anhydrous magnesium sulfate It is dry.Residue is dissolved in methanol (10.0mL) after evaporating solvent under reduced pressure, and trimethyl silicone hydride diazomethane cyclohexane solution is added A few drop acetic acid quenching reactions are added in (2.60mL, 5.21mmol, 2.0M) after being stirred to react 30 minutes.Ethyl acetate dilution is added It is washed after solution with saturated sodium chloride solution, it is dry to add anhydrous magnesium sulfate.Evaporating solvent under reduced pressure, after column chromatographic purifying in Mesosome 61b (160mg, 463 μm of ol, yield 29%).
(3.3) synthesis of compound 61
Intermediate 61b (160mg, 463 μm of ol) is dissolved in methylene chloride (3.00mL) and methanol (3.00mL), hydroxyl is added It is stirred at room temperature 3 hours after amine aqueous solution (306mg, 9.27mmol) and sodium hydroxide (55.6mg, 1.39mmol).It removes under reduced pressure molten After agent, finished product (30.0mg, 83.2 μm of ol, yield 18%) are obtained after purification through MPLC.1H NMR(400MHz,DMSO–D6-d6)δ 10.69 (brs, 2H), 9.02 (s, 1H), 7.86 (s, 1H), 7.72 (d, J=8.4Hz, 1H), 7.60 (dd, J=8.4,1.6Hz, 1H), 7.22-7.20 (m, 2H), 7.09-7.07 (m, 2H), 6.98 (t, J=7.2Hz, 1H), 6.82 (s, 1H), 3.61 (s, 2H)；MS(ESI)m/z 347(M+1)+。
4, the synthesis of compound 62 and 63
(4.1) synthesis of intermediate 62a
Intermediate 6a1 (2.90g, 8.75mmol) is dissolved in dry tetrahydrofuran (25.0mL), is added in batches at 0 DEG C Enter Lithium Aluminium Hydride (365mg, 9.63mmol).Sal glauberi (3.00g) is added after being stirred to react 1 hour.Evaporating solvent under reduced pressure Intermediate 62a crude product (1.90g) is obtained afterwards.
(4.2) synthesis of intermediate 62b
Intermediate 62a (1.90g, 6.26mmol) is dissolved in methylene chloride (30.0mL), Dai Si-Martin's oxidant is added (3.72g, 8.77mmol) room temperature is stirred to react 4 hours afterwards.After evaporating solvent under reduced pressure, intermediate 62b is obtained through column chromatographic purifying (1.20g, 3.98mmol, yield 64%).
(4.3) synthesis of intermediate 46c
Sodium hydrogen (143mg, 5.97mmol) is dissolved in tetrahydrofuran (20.0mL), 2-(dimethoxy phosphorus are added at 0 DEG C Acyl group) it is stirred to react 1 hour after methyl acetate (1.34g, 5.97mmol).Be then slowly added into intermediate 62b (1.20g, Reaction 4 hours is stirred at room temperature in tetrahydrofuran (20.0mL) solution 3.98mmol).After evaporating solvent under reduced pressure, through column chromatographic purifying It obtains intermediate 62c (1.20g, 3.10mmol, yield 78%).
(4.4) synthesis of compound 62
Intermediate 62c (600mg, 1.62mmol) is dissolved in methylene chloride (10.0mL) and methanol (10.0mL), is added It is stirred at room temperature 2 hours after aqueous hydroxylamine solution (1.61g, 48.6mmol) and sodium hydroxide (194mg, 4.86mmol).With 1N hydrochloric acid PH is adjusted to acidity, obtains finished product (490mg, 1.34mmol, yield 83%) through column chromatographic purifying after evaporating solvent under reduced pressure.1H NMR (400MHz, DMSO-d6) δ 10.99 (s, 1H), 10.29 (s, 1H), 9.25 (s, 1H), 7.93 (s, 1H), 7.83 (d, J= 8.4Hz, 1H), 7.65 (dd, J=8.4,1.6Hz, 1H), 7.47 (d, J=15.6Hz, 1H), 7.31 (s, 1H), 7.23 (dd, J =8.4,7.2Hz, 2H), 7.14-7.09 (m, 2H), 7.05-6.99 (m, 1H), 6.61 (d, J=15.6Hz, 1H)；MS(ESI) m/z 359(M+1)+。
(4.5) synthesis of compound 63
62 compound of embodiment (173mg, 483 μm of ol) is dissolved in methanol (10.0mL), and addition palladium carbon (49.8mg, 410 μm ol) after reaction 2 hours is stirred at room temperature under hydrogen.After evaporating solvent under reduced pressure, through column chromatographic purifying obtain finished product (120mg, 333 μm of ol, yield 69%).1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),10.18(s,1H),8.78(s,1H), 7.90-7.84 (m, 1H), 7.70 (d, J=8.4Hz, 1H), 7.60 (dd, J=8.4,1.6Hz, 1H), 7.23-7.19 (m, 2H), 7.13-7.07 (m, 2H), 7.02-6.98 (m, 1H), 6.71 (d, J=0.8Hz, 1H), 3.04 (t, J=7.2Hz, 2H), 2.41 (t, J=7.2Hz, 2H)；MS(ESI)m/z 361(M+1)+。
The synthesis of compound in 2 present invention of embodiment
General synthetic routes 2:
(1.1) synthesis of intermediate 9a
By 5-bromobenzenes, simultaneously [d] thiazole (2.57g, 12.0mmol) is dissolved in dry tetrahydrofuran (75.0mL), at-78 DEG C Hexamethyldisilazide lithium (17.0mL) is added dropwise to continue to be stirred to react at -78 DEG C 30 minutes afterwards.Cyan carbonic acid acid second is added dropwise Ester (1.80g, 18.2mmol) continues to be stirred to react at -78 DEG C 30 minutes afterwards.Saturated ammonium chloride solution is added after the reaction was completed (50.0mL) is quenched and is warmed to room temperature.Ethyl acetate (30mL) extracts 3 times, merges evaporating solvent under reduced pressure after organic layer, through column layer Analysis purifies to obtain intermediate 9a (660mg, 2.31mmol, yield 19%).
(1.2) synthesis of intermediate 9b
Using 6-bromobenzenes, simultaneously [d] thiazole and cyan carbonic acid acetoacetic ester is raw materials, according to the synthetic method of intermediate 9a, obtain Mesosome 9b (yield 28%).
(1.3) synthesis of intermediate 9c
Using 5-bromobenzenes, simultaneously [d] oxazole and cyan carbonic acid acetoacetic ester is raw materials, according to the synthetic method of intermediate 9a, obtain Mesosome 9c (yield 25%).
(2.1) synthesis of intermediate 10a
By intermediate 9a (660mg, 2.31mmol), benzyl mercaptan (3434mg, 2.77mmol), DIPEA (894mg, 6.92mmol, 1.21mL), 4,5-bis- (diphenylphosphine)-9,9-xanthphos (267mg, 461 μm of ol) and three (two benzal Benzylacetone) two palladiums (211mg, 231 μm of ol) are dissolved in toluene (10.0mL), back flow reaction 5 hours under a nitrogen.It is cooled to room temperature Afterwards, ethyl acetate (250mL) and water (250mL) is added, is filtered to remove insoluble matter.It adds after ethyl acetate (250mL) successively It is washed with water, 0.2N hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution.Anhydrous sodium sulfate drying is added in organic layer, subtracts Pressure, which is evaporated off after solvent, obtains intermediate 10a (530mg, 1.61mmol, yield 70%) through column chromatographic purifying.
(2.2) synthesis of intermediate 10b
Using intermediate 9b as raw material, according to the synthetic method of intermediate 10a, intermediate 10b (yield 82%) is obtained.
(2.3) synthesis of intermediate 10c
Using intermediate 9c as raw material, according to the synthetic method of intermediate 10a, intermediate 10c (yield 71%) is obtained.
(2.4) synthesis of intermediate 11a1
Intermediate 10a (530mg, 1.61mmol) is dissolved in acetic acid (9.0mL) and water (3.0mL), N-is added at 0 DEG C Chlorosuccinimide (859mg, 6.44mmol) continues to be stirred to react at 0 DEG C 2 hours afterwards.Second is added after evaporating solvent under reduced pressure Acetoacetic ester and water are dried after separating organic layer with anhydrous magnesium sulfate, then evaporating solvent under reduced pressure.Dissolve the residue in methylene chloride In (10.0mL), room temperature is stirred afterwards for addition aniline (164mg, 1.76mmol) and pyridine (11.9g, 150mmol, 12.1mL) Night.Evaporating solvent under reduced pressure after the reaction was completed separates organic layer after methylene chloride and water is added, and anhydrous magnesium sulfate drying is added, then Intermediate 11a (480mg, 1.38mmol, yield 86%) is obtained through column chromatographic purifying after evaporating solvent under reduced pressure.
(2.5) synthesis of intermediate 11a2~11a7
It is raw material in following table, according to the synthetic method of intermediate 11a1, obtains intermediate 11a2~11a7.
1, the synthesis of compound 64
Intermediate 11a (480mg, 1.32mmol) is dissolved in methylene chloride (5.00mL) and methanol (5.00mL), is added Room temperature is stirred to react 3 hours afterwards for aqueous hydroxylamine solution (875mg, 26.5mmol) and sodium hydroxide (159mg, 3.97mmol).Decompression It is evaporated off after solvent and purifies to obtain finished product (364mg, 1.04mmol, yield 79%) through MPLC.1H NMR(400MHz,DMSO–d6)δ 12.08 (s, 1H), 10.46 (s, 1H), 9.61 (s, 1H), 8.42 (d, J=8.4Hz, 1H), 8.34 (d, J=2.0Hz, 1H), 7.90 (dd, J=8.4,2.0Hz, 1H), 7.30-7.19 (m, 2H), 7.18-7.10 (m, 2H), 7.06-7.01 (m, 1H)；MS (ESI)m/z 350(M+1)+。
2, the synthesis of compound 65~70
Using intermediate 11a2~11a7 as raw material, according to the synthetic method of compound 64, obtain compound 65 in following table~ 70。
The preparation of embodiment 3, the compounds of this invention
General synthetic routes 3:
(1.1) synthesis of intermediate 14a
Using 5-bromo- 1H-indoles-2-carboxylate methyl ester as raw material, according to the synthetic method of intermediate 4a, intermediate 14a is obtained (yield 60%).
(1.2) synthesis of intermediate 14b
Using 6-bromo- 1H-indoles-2-carboxylate methyl ester as raw material, according to the synthetic method of intermediate 4a, intermediate 14b is obtained (yield 72%).
(1.3) synthesis of intermediate 14c
Using 5-bromo- 1-methyl-1H-indoles-2-carboxylic acid, ethyl esters as raw material, according to the synthetic method of intermediate 4a, obtain Mesosome 14c (yield 71%).
(1.4) synthesis of intermediate 15a2~15a24
Raw material in following table obtains intermediate 15a1~15a24 according to the synthetic method of intermediate 6a1.
1, the synthesis of compound 71
Intermediate 15a1 (480mg, 1.28mmol) is dissolved in ethyl alcohol (10.0mL), 10% palladium carbon of addition (330mg, 2.74mmol) and after ammonium formate (806mg, 12.80mmol) it is stirred at reflux reaction 2 hours.It filters after the reaction was completed and depressurizes steaming Except solvent, residue is dissolved in methylene chloride (3.0mL) and methanol (3.0mL), is added sodium hydroxide (150mg, 3.84mmol) It is stirred at room temperature 2 hours with after aqueous hydroxylamine solution (1.32g, 40.0mmol).Evaporating solvent under reduced pressure after the reaction was completed is purified through MPLC It obtains finished product (123mg, 351 μm of ol, yield 29%).1H NMR(400MHz,DMSO-d6)δ12.17(s,1H),10.18(s, 1H), 9.25 (s, 1H), 8.09 (s, 1H), 7.59-7.47 (m, 2H), 7.17 (t, J=7.6Hz, 2H), 7.10-7.04 (m, 3H), 6.95 (t, J=7.2Hz, 1H)；MS(ESI)m/z 332(M+1)+。
2, the synthesis of compound 72~94
Using intermediate 15a2~15a24 as raw material, according to the synthetic method of compound 71, obtain compound 72 in following table~ 94。
3, the synthesis of compound 95
Intermediate 15a1 (210mg, 554 μm of ol) is dissolved in methylene chloride (3.00mL) and methanol (3.00mL), is added It is stirred at room temperature 3 hours after sodium hydroxide (66.5mg, 1.66mmol) and aqueous hydroxylamine solution (366mg, 11.1mmol).Reaction is completed Evaporating solvent under reduced pressure afterwards purifies to obtain finished product (62.0mg, 166.3 μm of ol, yield 30%) through preparative HPLC.1H NMR (400MHz,DMSO–d6)δ12.43(s,1H),10.99(s,1H),10.19(s,1H),9.41(s,1H),7.96(s,1H), 7.62 (d, J=8.8Hz, 1H), 7.54 (d, J=8.8Hz, 1H), 7.19 (t, J=7.6Hz, 2H), 7.08 (d, J=8.0Hz, 2H), 6.98 (t, J=7.6s Hz, 1H)；MS(ESI)m/z 366(M+1)+
4, the synthesis of compound 96~97
Using intermediate 15a8 and 15a18 as raw material, according to the synthetic method of compound 79, obtain compound 96 in following table~ 97。
The synthesis of embodiment 4, the compounds of this invention
General synthetic routes 4
(1.1) synthesis of intermediate 18a
1H-indoles-2-carboxylic acid, ethyl ester (1.89g, 9.99mmol) is dissolved in acetonitrile (200mL), 1-chloromethyl-4-is added Room temperature is stirred to react 24 hours bis- (tetrafluoro boric acid) salt (4.24g, 12.0mmol) of fluoro- 1,4-diazotising, two ring 2.2.2 octane afterwards. After evaporating solvent under reduced pressure, intermediate 18a (470mg, 2.27mmol, yield 22.71%) is obtained through column chromatographic purifying.
(1.2) synthesis of intermediate 19a
Intermediate 18a (470mg, 2.27mmol) is dissolved in tetrahydrofuran (10.0mL), addition trifluoroacetic acid (259mg, 2.27mmol, 320 μ L) and N-bromosuccinimide after room temperature be stirred to react 16 hours.After evaporating solvent under reduced pressure, chromatographed through column Purify to obtain intermediate 19a (640mg, 2.24mmol, yield 99%).
(1.3) synthesis of intermediate 20a
Using intermediate 19a as raw material, according to the synthetic method of intermediate 4a, intermediate 20a (yield 82%) is obtained.
(1.4) synthesis of intermediate 21a1 and 21a2
Raw material in following table obtains intermediate 21a1 and 21a2 according to the synthetic method of intermediate 6a1.
1, the synthesis of compound 82 and 83
Using intermediate 21a1 and 21a2 as raw material, according to the synthetic method of compound 79,82 He of compound in following table is obtained 83。
2, the synthesis of compound 100
(1) synthesis of intermediate 100a
2,2,2-tribromo-acetyl methyl ester imidates (6.60g, 37.4mmol) are added in acetic acid (50.0mL), at 0 DEG C Acetic acid (50.0mL) solution of 4-bromobenzenes-1,2-diamines (7.00g, 37.4mmol) is slowly added dropwise, is then stirred at room temperature anti- It should stay overnight.Water is added after the reaction was completed, is extracted with ethyl acetate 2 times, uses water and saturated sodium-chloride molten respectively after merging organic layer Liquid is washed, and it is dry that anhydrous sodium sulfate is added.Evaporating solvent under reduced pressure is stirred to react at 80 DEG C after residue is dissolved in methanol (100mL) 5 hours.Evaporating solvent under reduced pressure is added ethyl acetate dissolution, is successively washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, It is dry that anhydrous sodium sulfate is added.After evaporating solvent under reduced pressure, obtaining intermediate 100a through column chromatographic purifying, (3.00g, 11.8mmol are produced Rate 26%).
(2) synthesis of intermediate 100b
Using intermediate 100a as raw material, according to the synthetic method of intermediate 4a, intermediate 100b (yield 76%) is obtained.
(3) synthesis of intermediate 100c
Using intermediate 100b as raw material, according to the synthetic method of intermediate 6a1, intermediate 100c (yield 62%) is obtained.
(4) synthesis of compound 100
Using intermediate 100c as raw material, according to the synthetic method of compound 79, compound 84 (yield 43%) is obtained.1H NMR(400MHz,DMSO-d6)δ13.75(s,1H),11.91(s,1H),10.32(s,1H),9.42(s,1H),8.10–7.62 (m,3H),7.25–6.95(m,5H)；MS(ESI)m/z 333(M+1)+。
Beneficial effects of the present invention are illustrated below by way of test example:
1 HDAC1 and HDAC6 Enzyme Assay Method of test example
It is detected using HDAC inhibitory activity of homogeneous phase time discrimination fluorescence (HTRF) method to the compounds of this invention.
Use enzyme buffer liquid (50mM Tris-HCl pH 8.0,137mM NaCl, 2.7mM KCl, 1mM MgCl2, 0.01%Tween20) prepare the compound solution of various concentration.Use detection buffer (Cisbio Bioassays# 62SDBRDD) prepare Streptavidin XL-665 (Cisbio Bioassays#610SAXLA) and anti-H3K9me0-Eu (K) the detection mixture of (Cisbio Bioassays#61KB0KAE).
It takes 4 μ L compound solutions into reaction plate, 2 μ L HDAC solution (whole system HDAC1:30ng/ plates is added；HDAC6: 70ng/ plate), it is incubated at room temperature 10 minutes.4 μ L Histone H3 (1-21) lysine, 9 acetylated is added Biotinylated peptide (AnaSpec#AS-64361) is incubated for 60 minutes after pad pasting at 37 DEG C.10 μ L detection is added Mixture is incubated at room temperature 1 hour, reads fluorescence signal using multi-function microplate reader (Envision 2104).It is true from the data obtained Determine the inhibiting effect of compound and it maps with compound concentration, obtains concentration-response curve, be fitted according to four parameter model IC50Value.
The Enzyme assay of HDAC1, HDAC6, test are carried out to the compound of previous embodiment preparation according to the method described above It the results are shown in Table 1, wherein measuring the IC of each compound50According to illustrating to classify.
Table 1, compound are to the inhibitory activity of HDAC1 and HDAC6
Note:, "+" indicates IC50For greater than 500nM less than 10 μM；" ++ " indicates IC50It is less than 500nM greater than 100nM；"++ + " indicate IC50Less than 100nM.ND: data are testing and analyzing.
Test result show the compounds of this invention have good deacetylation enzyme inhibition activity, can effective for The treatment of histone deacetylase activity abnormal diseases.
2 cell growth inhibition assay of test example
By the HCT-116 cell inoculation of logarithmic growth phase in 12 well culture plates.After cell is adherent overnight, it is separately added into Compound is handled cell 24 hours.Cell is collected, SDS lysate cracks under ice bath.Above-mentioned cell pyrolysis liquid is taken to carry out SDS- PAGE electrophoresis, with it is wet transfer from one department to another system will be on protein delivery to pvdf membrane.TBST solution (100mM Tris-HCl pH=7.2- is added 7.4,0.9%NaCl, 0.2%Tween-20) prepare 5% skim milk confining liquid after, shaking table room temperature close 60 minutes.By film It is placed in antibody diluent (5% skim milk) diluted primary antibody, at 4 DEG C overnight.Three times with TBST solution room temperature washing, often Secondary 10 minutes.The secondary antibody of near-infrared label label is added, at room temperature in gently shaking on shaking table 1 hour.It is washed again with TBST solution After washing three times, fluorescence signal value is obtained in the double-colored fluoroscopic imaging systems of Odyssey CLx near-infrared.Chemical combination is determined from the data obtained The inhibiting effect of object simultaneously maps it with compound concentration, obtains concentration-response curve, is fitted EC according to four parameter model50Value.
Cell growth inhibition detection is carried out to the compound of previous embodiment preparation according to the method described above, test result is shown in Table 2, wherein measuring the EC of each compound50According to illustrating to classify.
Inhibitory activity of 2 compound of table to HCT-116 cell
Embodiment Activity Embodiment Activity Embodiment Activity Embodiment Activity
1 +++ 2 ++ 3 ++ 4 +++
5 +++ 6 ++ 7 ++ 8 +++
9 +++ 10 ++ 11 ++ 12 +++
13 +++ 14 ++ 15 +++ 16 +++
17 +++ 18 +++ 19 +++ 20 +++
21 +++ 22 ++ 23 ++ 24 +++
25 +++ 26 +++ 27 +++ 28 +++
29 +++ 30 ++ 31 ++ 32 ++
33 ++ 34 ++ 35 ++ 36 +++
37 ++ 38 ++ 39 ++ 40 ++
41 +++ 42 ++ 43 ++ 44 +++
45 ++ 46 +++ 47 ++ 48 ++
49 ++ 50 ++ 51 ++ 52 ++
53 ++ 54 ++ 55 ++ 56 ++
57 ++ 58 ++ 59 ++ 60 ++
61 +++ 62 +++ 63 +++ 64 ++
65 ++ 66 ++ 67 ++ 68 +
69 + 70 + 71 + 72 ++
73 + 74 + 75 + 76 ++
77 ++ 78 ++ 79 ++ 80 ++
81 ++ 82 ++ 83 ++ 84 ++
85 ++ 86 ++ 87 + 88 ++
89 ++ 90 + 91 ++ 92 ++
93 + 94 + 95 ++ 96 ++
97 ++ 98 ++ 99 ++ 100 ++
Note: "+" indicates EC50Greater than 50 μM；" ++ " indicates EC50Greater than 10 μM less than 50 μM；；" +++ " indicates EC50Small 10 μ M；ND: data are testing and analyzing.
Test result shows that the compounds of this invention has good inhibitory activity to HCT-116 cell.
In conclusion noval chemical compound shown in formula I disclosed by the invention, shows good deacetylase and inhibits to live Property, a kind of new medicinal possibility is provided for clinical treatment disease extremely relevant to histone deacetylase activity, is had Good application prospect.

Claims (24)

1. formula (I) compound represented or its crystal form or its hydrate or its optical isomer or its solvate or its Pharmaceutically acceptable salt:
Wherein, n is 0~10；
L1Indicate without or C1~C10Alkylidene or C1~C10Alkenyl；
Y is N or CR2, wherein R2Selected from hydrogen, halogen, hydroxyl, amino, trifluoromethyl, cyano, C1~C10Alkyl or C1~C10's Alkoxy；
X is O, S or NR3；Wherein R3Selected from hydrogen, C1~C10Alkyl or C1~C10Acyl group；
R1For hydrogen, C1~C10Alkyl, C3~C10Cycloalkane or 3~10 yuan of heterocycloalkane；
Ring A indicates 3~10 yuan of cycloalkane, 3~10 yuan of heterocycloalkane, 5~10 yuan of aryl or 5~10 yuan of heteroaryl； Wherein A ring can be further by 0~5 R4Replace, wherein each R4It is independently chosen from halogen, cyano, nitro, trifluoromethyl, three respectively Fluorine methoxyl group ,-(CH2)qR5、–(CH2)qOR5、–(CH2)qOCOR5、–(CH2)qNR5R6、–(CH2)qNR5COR6、–(CH2)qCOR5、– (CH2)qCOOR5、–(CH2)qCONR5R6, q is 0~10；
R5、R6It is respectively selected from hydrogen, C1~C10Alkyl, 5~10 yuan of cycloalkane, 5~10 yuan of heterocycloalkane, 5~10 yuan of virtue Base or 5~10 yuan of heteroaryl, wherein R5、R6It can be further by R7Replace；
R7Selected from halogen, hydroxyl, amino, C1~C10Alkyl, C1~C10Alkoxy, C1~C10Alkylamino ,-(CH2)rOR8； Wherein r is 0~10.
R8Selected from hydrogen, C1~C10Alkyl.
2. compound according to claim 1, it is characterised in that: formula (I) compound has such as formula (I a) or formula (I B) structure shown in:
3. compound according to claim 2, it is characterised in that: formula (I a) compound has as shown in formula (I a-1) Structure:
Wherein, L1It indicates without, C1~C5Alkylidene orWherein m is 0~3；
R1Indicate hydrogen, C1~C5Alkyl；
R2Indicate hydrogen, halogen, trifluoromethyl, trifluoromethoxy ,-(CH2)qR5、–(CH2)qOR5、–(CH2)qNR5R6、–(CH2)qCOR5, q is 0~5；
R5、R6It is respectively selected from hydrogen, C1~C5Alkyl, 5~10 yuan of cycloalkane, 5~10 yuan of heterocycloalkane, 5~10 yuan of virtue Base or 5~10 yuan of heteroaryl, wherein R5、R6It can be further by R7Replace；
R7Selected from halogen, hydroxyl, amino, C1~C5Alkyl, C1~C5Alkoxy, C1~C5Alkylamino ,-(CH2)rOR8；Its Middle r is 0~5；.
R8Selected from hydrogen, C1~C5Alkyl；
Ring A indicates phenyl, 5 yuan of heteroaromatics, 6 yuan of heteroaromatics, 10 yuan of heteroaromatics.
4. compound according to claim 2, it is characterised in that: formula (I a) compound has as shown in formula (I a-2) Structure:
Wherein, R1Indicate hydrogen, halogen；Ring A indicates phenyl, 5 yuan of heteroaromatics, 6 yuan of heteroaromatics.
5. compound according to claim 2, it is characterised in that: formula (I a) compound has as shown in formula (I a-3) Structure:
Wherein, n=0,1,2,3；X indicates hydrogen, halogen；
R1Indicate hydrogen, C1~C5Alkyl, 6 yuan of aryl or heteroaryl；
R3Indicate hydrogen, C1~C5Alkyl；
R2Indicate hydrogen, halogen, trifluoromethyl, methoxyl group ,-(CH2)qR5、–(CH2)qNR5R6、–(CH2)qCOR5, q is 0~5；
R5、R6It is respectively selected from hydrogen, C1~C5Alkyl, 5~6 yuan of cycloalkane, 5~6 circle heterocyclic ring alkane, 5~6 yuan of heteroaromatics, phenyl；
Ring A indicates phenyl, hexamethylene, 5~6 circle heterocyclic ring alkane, 5~6 yuan of heteroaromatics or 10 yuan of heteroaromatics.
6. compound according to claim 2, it is characterised in that: formula (I a) compound has as shown in formula (I a-4) Structure:
Wherein, X indicates O, S, N；Ring A indicates phenyl, 5~6 yuan of heteroaromatics or 10 yuan of heteroaromatics.
7. compound according to claim 2, it is characterised in that: the formula (I a) is one of following compound:
8. compound according to claim 2, it is characterised in that: formula (I b) compound has as shown in formula (I b-1) Structure:
Wherein, L1It indicates without, C1~C5Alkylidene orWherein m is 0~3；
R1Indicate hydrogen, C1~C5Alkyl；
R2Indicate hydrogen, halogen, trifluoromethyl, trifluoromethoxy ,-(CH2)qR5、–(CH2)qOR5、–(CH2)qNR5R6、–(CH2)qCOR5, q is 0~5；
R5、R6It is respectively selected from hydrogen, C1~C5Alkyl, 5~10 yuan of cycloalkane, 5~10 yuan of heterocycloalkane, 5~10 yuan of virtue Base or 5~10 yuan of heteroaryl；Wherein R5、R6It can be further by R7Replace；
R7Selected from halogen, hydroxyl, amino, C1~C5Alkyl, C1~C5Alkoxy, C1~C5Alkylamino ,-(CH2)rOR8；Its Middle r is 0~5；.
R8Selected from hydrogen, C1~C5Alkyl；
Ring A indicates phenyl, 5~6 yuan of heteroaromatics or 10 yuan of heteroaromatics.
9. compound according to claim 2, it is characterised in that: formula (I b) compound has as shown in formula (I b-2) Structure:
Wherein, R1Indicate hydrogen, halogen；Ring A indicates phenyl, 5 yuan of heteroaromatics, 6 yuan of heteroaromatics.
10. compound according to claim 2, it is characterised in that: formula (I b) compound has such as formula (I b-3) institute The structure shown:
Wherein, n=0,1,2,3；X indicates hydrogen, halogen；
R1Indicate hydrogen, C1~C5Alkyl, 6 yuan of aryl or heteroaryl；
R3Indicate hydrogen, C1~C5Alkyl；
R2Indicate hydrogen, halogen, trifluoromethyl, methoxyl group ,-(CH2)qR5、–(CH2)qNR5R6、–(CH2)qCOR5, q is 0~5；
R5、R6It is respectively selected from hydrogen, C1~C5Alkyl, 5~6 yuan of cycloalkane, 5~6 circle heterocyclic ring alkane, 5~6 yuan of heteroaromatics, phenyl；
Ring A indicates phenyl, hexamethylene, 5~6 circle heterocyclic ring alkane, 5~6 yuan of heteroaromatics or 10 yuan of heteroaromatics.
11. compound according to claim 2, it is characterised in that: formula (I b) compound has such as formula (I b-4) institute The structure shown:
Wherein, X indicates O, S, N；Ring A indicates phenyl, 5~6 yuan of heteroaromatics or 10 yuan of heteroaromatics.
12. compound object according to claim 2, it is characterised in that: the formula (I b) is one of following compound:
13. the described in any item compounds of claim 1-12 or its crystal form or its hydrate or its optical isomer or its Solvate or its pharmaceutically acceptable salt are preparing the purposes in hdac inhibitor class drug.
14. purposes according to claim 13, it is characterised in that: the drug is treatment cell breeding disease, itself exempts from The drug of epidemic disease, inflammation, neurodegenerative disease or viral disease.
15. purposes according to claim 14, it is characterised in that: the cell breeding disease is cancer.
16. purposes according to claim 15, it is characterised in that: the cancer includes colon cancer, lung cancer, breast cancer, preceding Column gland cancer, the cancer of the brain, oophoroma, thyroid cancer.
17. the described in any item purposes of 3-16 according to claim 1, it is characterised in that: the HDAC is HDAC6.
18. a kind of pharmaceutical composition, it is characterised in that: it is with the described in any item compounds of claim 1-12 or its crystalline substance Type or its hydrate or its optical isomer or its solvate or its pharmaceutically acceptable salt are active constituent, in addition The preparation that pharmaceutically acceptable auxiliary material is prepared.
19. composition according to claim 18, it is characterised in that: the preparation is oral preparation, transdermal absorption formulation Or ejection preparation.
20. pharmaceutical composition described in claim 18 or 19 is preparing the purposes in hdac inhibitor class drug.
21. purposes according to claim 20, it is characterised in that: the drug is treatment cell breeding disease, itself exempts from The drug of epidemic disease, inflammation, neurodegenerative disease or viral disease.
22. purposes according to claim 21, it is characterised in that: the cell breeding disease is cancer.
23. purposes according to claim 22, it is characterised in that: the cancer includes colon cancer, lung cancer, breast cancer, preceding Column gland cancer, the cancer of the brain, oophoroma, thyroid cancer.
24. according to the described in any item purposes of claim 20-23, it is characterised in that: the HDAC is HDAC6.
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CN110256416A (en) * 2019-05-13 2019-09-20 成都先导药物开发股份有限公司 Histon deacetylase (HDAC) inhibitor and preparation method thereof and purposes
CN110256416B (en) * 2019-05-13 2024-01-23 成都先导药物开发股份有限公司 Histone deacetylase inhibitor and preparation method and application thereof
CN110229146B (en) * 2019-05-13 2024-02-23 成都先导药物开发股份有限公司 Histone deacetylase inhibitor and preparation method and application thereof
WO2022218440A1 (en) * 2021-04-16 2022-10-20 青岛睿吉医疗技术有限公司 Fxr regulator, preparation method therefor, pharmaceutical composition thereof and use thereof
CN115215823A (en) * 2021-04-16 2022-10-21 青岛睿吉医疗技术有限公司 FXR (FXR) regulator and preparation method, pharmaceutical composition and application thereof
WO2023202578A1 (en) * 2022-04-18 2023-10-26 北京昌平实验室 Gpcr regulator and use thereof
WO2023202582A1 (en) * 2022-04-18 2023-10-26 北京昌平实验室 Gpcr regulator and use thereof

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