CN109593065A - A kind of bis- target spot inhibitor of HDAC/ALK and the preparation method and application thereof - Google Patents

A kind of bis- target spot inhibitor of HDAC/ALK and the preparation method and application thereof Download PDF

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CN109593065A
CN109593065A CN201811466331.9A CN201811466331A CN109593065A CN 109593065 A CN109593065 A CN 109593065A CN 201811466331 A CN201811466331 A CN 201811466331A CN 109593065 A CN109593065 A CN 109593065A
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alkyl
aryl
alkoxy
hydroxyl
amino
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甘宗捷
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Chongqing Medical University
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Chongqing Medical University
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Priority to CN201911175286.6A priority patent/CN111039875A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention belongs to field of medicinal chemistry, more particularly to bis- target spot inhibitor of a kind of HDAC/ALK and the preparation method and application thereof, the bis- target spot inhibitor structures of HDAC/ALK are shown in formula I, the bis- target spot inhibitor of HDAC/ALK have good inhibitory activity to HDAC and ALK kinases, the inhibitory activity of HepG2 liver cancer cells is better than suitable with current conventional medicines resistant to liver cancer Sorafenib, is in micromole's rank.

Description

A kind of bis- target spot inhibitor of HDAC/ALK and the preparation method and application thereof
Technical field
The invention belongs to field of medicinal chemistry, and in particular to a kind of bis- target spot inhibitor of HDAC/ALK and preparation method thereof with Using.
Technical background
Histon deacetylase (HDAC) (Histone deacetylases, HDACs) is to be catalyzed histone amino terminal spy Acetyl group removes on fixed lysine residue, so that chromatin densification crimps, a histone enzyme of suppressor transcription.Research is aobvious Showing, the occurrence and development of tumour and HDACs are closely related, and the full-length genome protein acetylation level of tumour cell generally reduces, and one As in the case of, positive correlation is presented in acetylation of histone level and Gene Transcription in vitro.Histon deacetylase (HDAC) inhibitor By the degree of acetylation of the intracellular histone of increase, chromatin acetylation can be caused, promote the gene activation of cancer cell, Lead to cell differentiation or death, tumor cell migration, invasion, the inhibiting effect of transfer and Antineoplastic angiogenesis are acted on It is proved.
Anaplastic lymphoma kinase (ALK) is that a receptor type protein tyrosine phosphoric acid of insulin receptor superfamily swashs Enzyme, it is closely related with tumor development.The fusion form for having now been found that 21 kinds of EML4-ALK is organized including systematicness Paraplasm, inflammatory myofibroblasts tumor, non-small cell lung cancer etc. (Biochem J, 2008,416 (2): 153-159).ALK melts The incidence closed in non-small cell type lung cancer (NSCLC) is about 3%~7%, and prominent without EGFR mutation or KRas Expression rate in the adenocarcinoma patients of change is about 42.8%.Mutation and abnormal activity of the ALK in kinds cancer, have become one The drug target of a treatment ALK positive cancer.
It is the new direction of oncotherapy and drug development that multiple target point, which inhibits tumor signal transduction, and multinomial result of study shows The bis- target spot inhibitor of HDAC and ALK, which share, to include the lung cancer that there is BAF to be mutated, advanced stage neuroblast to treatment kinds of tumors Tumor, Ceritinib drug resistant non-small cell lung etc. have remarkable result.And there has been no the bis- target spot inhibitor of HDAC/ALK at present Report therefore research and develop the bis- target spot inhibitor of novel HDAC/ALK, with important application prospects and meaning.
Summary of the invention
It is an object of the present invention to provide one kind can inhibit simultaneously HDAC target spot and ALK target spot compound or its Pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, general formula are shown in formula I:
Second object of the present invention, which is to provide, prepares compounds of formula I of the invention or its is pharmaceutically acceptable The method of salt, isomers, solvate, crystallization or prodrug.
Third object of the present invention is to provide comprising compounds of formula I of the invention or its is pharmaceutically acceptable The composition of salt, isomers, solvate, crystallization or prodrug and pharmaceutically acceptable carrier, and include general formula I of the invention Compound or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug and one or more antineoplastic combinations Object.
Fourth object of the present invention is to provide compounds of formula I or its pharmaceutically acceptable salt of the invention, different Structure body, solvate, crystallization or prodrug are preparing the application in the drug for preventing and/or treating tumour.
For achieving the above object, the present invention the following technical schemes are provided:
In a first aspect, the present invention provides compounds of formula I or its pharmaceutically acceptable salt, isomers, solvate, knot Brilliant or prodrug,
Wherein,
R1Selected from alkyl, naphthenic base, Heterocyclylalkyl, alkoxy and halogenated alkyl；
R2Selected from halogen, alkyl, alkoxy, alkoxyalkyl, hydroxyl, amino, carboxyl, cyano, nitro, naphthenic base, miscellaneous Naphthenic base；
M is selected from 0,1,2,3 and 4；
R3aAnd R3bIndependently selected from hydrogen, halogen, alkyl, alkoxy, alkoxyalkyl, hydroxyl, amino, carboxyl, cyano, Nitro, naphthenic base, Heterocyclylalkyl；
R4Selected from halogen, alkyl, alkoxy, alkoxyalkyl, hydroxyl, amino, carboxyl, cyano, nitro, naphthenic base, miscellaneous Naphthenic base；
N is selected from 0,1,2,3 and 4；
L is selected from key and alkylidene；
K is selected from key, alkylidene, alkenylene ,-NH-C (O)-(CH2)p-、-C(O)-NH-(CH2) p-, aryl and heteroaryl, The alkylidene, alkenylene ,-NH-C (O)-(CH2)p-、-C(O)-NH-(CH2) p-, aryl and heteroaryl can by one or Multiple alkyl, halogen, alkoxy, hydroxyl, amino, carboxyl, cyano and nitro replace, and the p is selected from the integer of 1-8；
R5And R6Independently selected from hydrogen, hydroxyl, aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, the aryl, heteroaryl, Naphthenic base, Heterocyclylalkyl can be by one or more amino, hydroxyl, carboxyl, alkyl, alkoxy, alkoxyalkyl, halogen, halogenated Alkyl, alkylamino, alkyl amide, amide groups, ester group, acyl group, alkanoyl, alkane aminoacyl, aryl, heteroaryl replace.
In some preferred embodiments, the present invention provides compounds of formula I or its pharmaceutically acceptable salt, isomery Body, solvate, crystallization or prodrug, wherein R1Selected from C1-6Alkyl, C3-8Naphthenic base, C3-8Heterocyclylalkyl and halogenated C1-6Alkyl； It is further preferred that R1Selected from methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, first Oxygroup, ethyoxyl, propoxyl group, isopropoxy, trichloromethyl, trifluoromethyl；It is further preferred that R1For isopropyl.
In some preferred embodiments, the present invention provides compounds of formula I or its pharmaceutically acceptable salt, isomery Body, solvate, crystallization or prodrug, wherein R2Selected from halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, hydroxyl Base, amino, carboxyl, cyano, nitro, C3-8Naphthenic base, C3-8Heterocyclylalkyl, m are selected from 0,1,2,3 and 4；It is further preferred that R2 Selected from halogen, C1-3Alkyl, C1-3Alkoxy, C1-3Alkoxy C1-3Alkyl, hydroxyl, amino, carboxyl, cyano, nitro, m be selected from 0, 1,2 and 3；It is further preferred that R2For halogen, m is selected from 0 and 1；It is further preferred that m is 0.
In some preferred embodiments, the present invention provides compounds of formula I or its pharmaceutically acceptable salt, isomery Body, solvate, crystallization or prodrug, wherein R3aAnd R3bIndependently selected from hydrogen, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Alcoxyl Base C1-6Alkyl, hydroxyl, amino, carboxyl, cyano, nitro, C3-8Naphthenic base, C3-8Heterocyclylalkyl；It is further preferred that R3aAnd R3b Independently selected from hydrogen, halogen, C1-3Alkyl, C1-3Alkoxy, C1-3Alkoxy C1-3Alkyl, hydroxyl, amino, carboxyl, cyano, nitre Base, C3-8Naphthenic base, C3-8Heterocyclylalkyl；It is further preferred that R3aAnd R3bIndependently selected from hydrogen, fluorine, chlorine, bromine and iodine.
In some preferred embodiments, the present invention provides compounds of formula I or its pharmaceutically acceptable salt, isomery Body, solvate, crystallization or prodrug, wherein R4Selected from halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, hydroxyl Base, amino, carboxyl, cyano, nitro, C3-8Naphthenic base, C3-8Heterocyclylalkyl, n are selected from 0 and 1；It is further preferred that R4Selected from halogen Element, C1-3Alkyl, C1-3Alkoxy, C1-3Alkoxy C1-3Alkyl, hydroxyl, amino, carboxyl, cyano, nitro, C3-8Naphthenic base, C3-8 Heterocyclylalkyl, n are selected from 0 and 1, it is further preferred that n is 0.
In some preferred embodiments, the present invention provides compounds of formula I or its pharmaceutically acceptable salt, isomery Body, solvate, crystallization or prodrug, wherein L is selected from key, methylene, ethylidene, propylidene, isopropylidene；Further preferably Ground, L are selected from key and methylene.
In some preferred embodiments, the present invention provides compounds of formula I or its pharmaceutically acceptable salt, isomery Body, solvate, crystallization or prodrug, wherein K is selected from key, methylene, ethylidene, propylidene, isopropylidene, ethenylidene, Asia Acrylic, butenylidene ,-NH-C (O)-(CH2)p-、-C(O)-NH-(CH2) p-, phenyl and heteroaryl, the p is selected from 1-6 Integer, the methylene, ethylidene, propylidene, isopropylidene, ethenylidene, allylidene, butenylidene ,-NH-C (O)-(CH2)p-、-C(O)-NH-(CH2) p-, phenyl and heteroaryl can be by one or more C1-6Alkyl, halogen, C1-6Alcoxyl Base, hydroxyl, amino, carboxyl, cyano and nitro replace；It is further preferred that K is selected from key, methylene, ethylidene, sub- ethylene Base ,-NH-C (O)-(CH2)p-、-C(O)-NH-(CH2) p-, the p be selected from 1-6 integer, the methylene, ethylidene, Ethenylidene ,-NH-C (O)-(CH2)p-、-C(O)-NH-(CH2) p- can be by one or more C1-6Alkyl, halogen, C1-6Alcoxyl Base, hydroxyl, amino, carboxyl, cyano and nitro replace；It is further preferred that K is selected from key, ethenylidene ,-NH-C (O)- (CH2)6-、-C(O)-NH-(CH2)6-。
In some preferred embodiments, the present invention provides compounds of formula I or its pharmaceutically acceptable salt, isomery Body, solvate, crystallization or prodrug, wherein R5And R6Independently selected from hydrogen, hydroxyl, benzene, naphthalene, azepine aryl, thia aryl, oxygen Heteroaryl, nitrogen thia aryl, oxygen thia aryl, nitrogen oxa- aryl, C3-8Naphthenic base, miscellaneous C3-8Naphthenic base, the benzene, naphthalene, nitrogen Heteroaryl, thia aryl, oxa- aryl, nitrogen thia aryl, oxygen thia aryl, nitrogen oxa- aryl, C3-8Naphthenic base, miscellaneous C3-8Cycloalkanes Base can be by one or more amino, hydroxyl, carboxyl, C1-6Alkyl, C1-6Alkoxy, C1-6Alcoxyl C1-6It is alkyl, halogen, halogenated C1-6Alkyl, C1-6Alkylamino, C1-6Alkyl amide, amide groups, ester group, acyl group, C1-6Alkanoyl, C1-6It is alkane aminoacyl, aryl, miscellaneous Aryl replaces；It is further preferred that R5For hydrogen, R6Selected from hydroxyl, benzene, naphthalene, azepine aryl, thia aryl, oxa- aryl, nitrogen sulphur Heteroaryl, oxygen thia aryl, nitrogen oxa- aryl, the benzene, naphthalene, azepine aryl, thia aryl, oxa- aryl, nitrogen thia virtue Base, oxygen thia aryl, nitrogen oxa- aryl can be by one or more amino, hydroxyl, carboxyl, C1-6Alkyl, C1-6Alkoxy, C1-6 Alcoxyl C1-6Alkyl, halogen, halogenated C1-6Alkyl, C1-6Alkylamino, C1-6Alkyl amide, amide groups, ester group, acyl group, C1-6Alkane acyl Base, C1-6Alkane aminoacyl, aryl, heteroaryl replace；It is further preferred that R5For hydrogen, R6Selected from hydroxyl and benzene, the benzene can By one or more amino, hydroxyl, carboxyl, C1-3Alkyl, C1-3Alkoxy, C1-3Alcoxyl C1-3Alkyl, halogen, halogenated C1-3Alkane Base, C1-3Alkylamino, C1-3Alkyl amide, amide groups, ester group, acyl group, C1-3Alkanoyl, C1-3Alkane aminoacyl, aryl, heteroaryl take Generation.
In some specific embodiments, the present invention provides compounds of formula I or its pharmaceutically acceptable salt, isomery Body, solvate, crystallization or prodrug, wherein compounds of formula I structure is as shown in general formula Ia:
R1For isopropyl；
R3aSelected from fluorine, chlorine, bromine and iodine；
R3bFor hydrogen；
L is selected from key and methylene；
K is selected from key, ethenylidene ,-NH-C (O)-(CH2)6-、-C(O)-NH-(CH2)6-；
R5For hydrogen；
R6Selected from hydroxyl and benzene, the benzene can be by one or more amino, hydroxyl, carboxyl, C1-3Alkyl, C1-3Alcoxyl Base, C1-3Alcoxyl C1-3Alkyl, halogen, halogenated C1-3Alkyl, C1-3Alkylamino, C1-3Alkyl amide, amide groups, ester group, acyl group, C1-3 Alkanoyl, C1-3Alkane aminoacyl, aryl, heteroaryl replace.
The present invention provides compounds in detail below:
Second aspect, the present invention provide the preparation method of compounds of formula I of the invention.The system of compounds of formula I Preparation Method includes the following steps:
Step 1: the compound of formula A reacts the compound of production C with the compound of formula B；
Step 2: the compound of formula C reacts the compound of production I with substituted hydroxylamine；
Wherein, R1、R2、m、R3a、R3b、R4、n、L、K、R5And R6With meaning in I simultaneously.
The third aspect, the present invention provide pharmaceutical composition, it includes the compound of the present invention or its pharmaceutically acceptable salt, Isomers, solvate, crystallization or prodrug.
In some embodiments, the present invention provides pharmaceutical composition, and it includes the chemical combination of general formula I of the present invention or general formula Ia Object, isomers, solvate, crystallization or prodrug, also comprising one or more compounds selected from following composition: IDH1 inhibits Agent, IDH2 inhibitor, tyrosine protein enzyme inhibitor, EGFR inhibitor, VEGFR inhibitor, Bcr-Abl inhibitor, c-kit suppression Preparation, c-Met inhibitor, Raf inhibitor, mek inhibitor, inhibitors of histone deacetylase, VEGF antibody, EGF antibody, HIV kinases inhibitor, HMG-CoA reductase inhibitor etc..
Can by compound, isomers, solvate, crystallization or the prodrug of general formula I of the present invention or general formula Ia with pharmaceutically Acceptable carrier, diluent or excipient are prepared by mixing into pharmaceutical preparation, to be suitable for oral or parenteral.To prescription Method includes, but are not limited in intradermal, intramuscular, peritonaeum, intravenous, subcutaneous, intranasal and peroral route.The preparation can be by appointing What approach application, such as by being transfused or injecting, absorbed by transepithelial or mucocutaneous (such as oral mucosa or rectum etc.) Approach application.Administration can be whole body or local.The example of oral administration preparation includes solid or liquid dosage form, specifically For, including tablet, pill, granula, pulvis, capsule, syrup, emulsion, suspension etc..The preparation can be by this field The method preparation known, and include the conventional use of carrier of field of pharmaceutical preparations, diluent or excipient.
Fourth aspect, the present invention provide the compound of general formula I or general formula Ia of the present invention, isomers, solvate, crystallization or The method of prodrug or medicine composite for curing of the invention and/or pre- preventing tumor and in preparation treatment and/or prevention tumour medicine In application, including easily send out crowd to tumour or tumor patient applies the compound of the present invention, isomers, solvate, crystallization Or prodrug or the pharmaceutical composition comprising the compound of the present invention, isomers, solvate, crystallization or prodrug, effectively to drop Low Tumor incidence extends tumor patient life.
In some embodiments, the present invention provides compound, isomers, the solvent of general formula I or general formula Ia of the invention The method for closing the tumour of object, crystallization or prodrug or medicine composite for curing of the invention with drug resistance, including to anti-medicine Property tumor patient application therapeutically effective amount general formula I of the present invention or the compound of general formula Ia, isomers, solvate, crystallization Or prodrug or the pharmaceutical composition comprising the compound of the present invention, isomers, solvate, crystallization or prodrug.At other In embodiment, the present invention provides compound, isomers, solvate, crystallization or the prodrug of general formula I or general formula Ia of the invention Or the application of pharmaceutical composition of the invention in the drug that preparation treatment has the tumour of drug resistance.The tumour includes but not Be limited to solid tumor, preferably lung cancer, head and neck neoplasm, colorectal cancer, bladder cancer, cancer of pancreas, breast cancer, prostate cancer, gastric cancer, Carcinoma of mouth, liver cancer, oophoroma；It is further preferred that the tumour is Ceritinib non-small cell lung cancer.
Term explanation
" alkyl " of the invention refers to linear or branched saturated hydrocarbon base.Suitable alkyl is substituted or unsubstituted C1-10 Alkyl, such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, normal-butyl, sec-butyl, isobutyl group, tert-butyl, cyclobutyl, just Amyl, isopentyl, cyclopenta, cyclohexyl, n-hexyl etc..
" naphthenic base " of the invention refers to cricoid saturated hydrocarbyl.Suitable naphthenic base can be substituted or unsubstituted tool There are the monocyclic, bicyclic or tricyclic saturated hydrocarbyl of 3-10 carbon atom, such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl.
" alkoxy " of the invention refers to-O- alkyl.According to the present invention, suitable alkoxy is C1-10Alkoxy, such as C1-8 Alkoxy, C1-7Alkoxy, C1-6Alkoxy, C1-5Alkoxy, C1-4Alkoxy, C1-3Alkoxy, including methoxyl group, ethyoxyl, third Oxygroup, isopropoxy, isobutoxy, sec-butoxy etc..
" halogen " of the invention refers to fluorine, chlorine, bromine, iodine.
" halogenated alkyl " of the invention refers to the alkyl at least replaced by a halogen.
" aryl " of the invention, which refers to, may include monocycle or the multi-fused rings such as aromatic series of two rings or the aromatic rings of tricyclic, A part of wherein at least condensed ring forms the aromatic series of conjugation, contains 5 to 50 carbon atoms, and preferably from about 6 to about 14 Carbon atom.Suitable aryl includes but is not limited to phenyl, naphthalene, xenyl, anthryl, tetralyl, fluorenyl, indanyl, sub- connection Phenyl and acenaphthenyl.
" heteroaryl " of the invention refers at least one carbon atom quilt of aromatic monocyclic or multi-fused rings such as two rings or tricyclic The aromatic radical of hetero atom substitution, the hetero atom are O, S, N.Suitable heteroaryl includes but is not limited to imidazole radicals, benzene And imidazole radicals, imidazopyridyl, quinazoline ketone group, pyrrole radicals, imidazoles ketone group, furyl, thienyl, pyrazolyl, oxazolyl, Thiazolyl, isoxazolyl, isothiazolyl, oxadiazoles base, triazolyl etc..
" alkylidene " of the invention refers to the linear chain or branched chain bivalent group with 1 to 6 carbon atom.
" alkenylene " of the invention refers to the bilvalent radical of the linear chain or branched chain containing 2 to 6 carbon atoms and 1 to 3 double bonds Group.
" alkyl amide " of the invention refers to alkyl-C (O)-NH-.
" amide groups " of the invention refers to C (O) H-NH-.
" alkanoyl " of the invention refers to alkyl-C (O)-.
" alkane aminoacyl " of the invention refers to alkyl-NH-C (O)-or alkyl-N (alkyl)-C (O)-.
" solvate " of the invention refer in a conventional sense solute (such as salt of reactive compound, reactive compound) and The compound that solvent (such as water) combination is formed.Solvent refers to the solvent of known to those of skill in the art or easy determination.Such as Fruit is water, then solvate is commonly referred to as hydrate, such as monohydrate, dihydrate, trihydrate etc..
" crystallization " of the invention refers to that the various solid forms that compound of the present invention is formed, including crystal form, nothing are determined Shape.
" isomers " of the invention refers in molecule atom spatially stereoisomer caused by arrangement mode difference, Including enantiomter and diastereoisomer.
" prodrug " of the invention refer under the physiological condition of organism, due to reacting and conversion cost with enzyme, gastric acid etc. The compound of the compound of invention is converted to the compound of the compound of the present invention by the oxidation of enzyme, reduction, hydrolysis etc. And/or the compound of the compound of the present invention is converted to by the hydrolysis etc. of gastric acid etc..
" pharmaceutically acceptable salt " of the invention refers to the compound of the present invention and the pharmaceutically acceptable salt that acid is formed, The acid include but is not limited to phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, Fumaric acid, acetic acid, lactic acid, nitric acid etc..
" pharmaceutical composition " of the invention refer to comprising any compound as described herein, including isomers, prodrug, Solvate, the protection form of pharmaceutically acceptable salt or its chemistry and one or more pharmaceutically acceptable carriers it is mixed Close object.
" pharmaceutically acceptable carrier " of the invention refer to obvious irritation is not caused to organism and do not interfere to Give the bioactivity of compound and the carrier of property, comprising solvent, diluent or other excipient, dispersing agent, surfactant, Isotonic agent, thickener or emulsifier, preservative, solid binder, lubricant etc..Unless any conventional carrier medium and the present invention Compound is incompatible.The some examples that can be used as pharmaceutically acceptable carrier include, but are not limited to carbohydrate, such as lactose, Portugal Grape sugar and sucrose；Starch, such as cornstarch and potato starch；Cellulose and its derivates, such as sodium carboxymethylcellulose and Cellulose and cellulose acetate；Malt, gelatin etc..
" excipient " of the invention, which refers to, to be added in Pharmaceutical composition with the further inert substance for promoting to give compound. Excipient may include calcium carbonate, calcium phosphate, various saccharides and a plurality of types of starch, cellulose derivative, gelatin, plant Oil, polyethylene glycol.
The test of 1 HepG2 liver cancer cells inhibitory activity of experimental example
Experiment sets solvent control group and drug study group, and every group of drug study group sets 4 concentration, and each concentration divides into 3 Parallel hole.Each experiment is in triplicate.In 96 orifice plates, it is 1 × 10 that cell concentration, which is added, in every hole5The cell suspension 100 of a/mL μ L, i.e., every hole contain cell 1 × 104A, when inoculation, pays attention to being evenly distributed on cell in each hole.To prevent liquid evaporation, 96 holes A collar aperture not inoculating cell around plate, is added PBS moisturizing.After cell is adherent, in drug study group in every hole be added concentration be 0, 4, the 100 μ L of target compound of 8,12 and 16 μ g/mL makes its final concentration distinguish 0,2,4,6 and 8 μ g/mL.96 orifice plates are placed in 37 DEG C, 5%CO2Continue to cultivate in incubator, culture is terminated after 72h.After drug-treated cell 72h, 96 orifice plates are taken out, often 20 μ L of CCK-8 solution is added in hole, continues after being incubated for 0.5-4 hours in cell incubator, in automatic microplate reader at 450nm Measure every hole absorbance value (A).It is detected respectively with microplate reader after 0.5,1,2 and 4 hour when preliminary experiment, chooses range of absorbency Subsequent experimental is used for than a convenient time point (2h).
The growth inhibition effect of tumour cell is calculated as follows in different pharmaceutical concentration:
Linear regression analysis is made to drug concentration with inhibiting rate, is asked with linear equation and calculates IC50Value.Acquired results are detected with equal Number ± standard deviation indicates that experimental result is for statistical analysis using SPSS15.0 software, indicates that conspicuousness is poor with P < 0.05 Different, the result is shown in tables 1.
Inhibitory activity of 1. test-compound of table to HepG2 liver cancer cells
Table 1 the results show that compound I-1~I-3 to human hepatoma HepG2 cell have stronger inhibitory activity, be better than with Conventional medicines resistant to liver cancer Sorafenib is suitable at present, is in micromole's rank.
The test of 2 HDAC enzyme inhibition activity of experimental example
In 384 hole reaction plates, the compound and enzyme of various concentration is added in every hole, and 15min is incubated at room temperature after centrifugation, is used Synergy, which continuously reads fluorescence signal and chooses linear response section using Synergy, obtains slope (slope).And then calculate hundred Point than inhibiting rate, calculation formula is as follows: enzyme inhibition rate=Mean (maximum)-sample signal/Mean (maximum)-blank multiplied by 100%, using the log value of compound concentration as X-axis, corresponding percent inhibition is Y-axis, with analysis software GraphPad Prism 5 is fitted amount effect curve, to obtain the IC of each compound inhibitory enzyme activity50Value.ALK enzyme inhibition activity method with HDAC enzyme suppressing method is similar.Experimental result is shown in Table 2
2. test-compound of table is under 10nM and 1000nM concentration to the inhibiting rate of HDAC and ALK kinases
Table 2 is the results show that compound I-1~I-3 has inhibitory activity, surface compound I-1~I-3 to ALK and HDAC It is double target spot compounds.Wherein, compound I-1 has reached 81% in 10nM to the inhibiting rate of ALK, with positive drug gram azoles It is suitable for Buddhist nun.Under the concentration, I-2 and I-3 also show certain inhibitory activity.Suppression of the compound I-1 and I-3 to HDAC1 Rate processed is 4.8% and 20% in 10nM, though being weaker than positive control, still produces inhibitory activity to HDAC.
Specific embodiment
1 4- of embodiment [[the chloro- 4- of 5- [2- (isopropelsulfonyl) phenyl] amino] pyrimidine -2-base] amino]-N- hydroxyl The preparation of benzamide (I-1)
Step 1:4- [[the chloro- 4- of 5- [2- (isopropelsulfonyl) phenyl] amino] pyrimidine -2-base] amino] methyl benzoate Preparation
Weigh N- [(2- isopropelsulfonyl) phenyl] -2,5- Dichloro-pyrimidin -4- amine (1.0g) and 4-aminobenzoic acid first Ester (0.43g) adds 10ml isopropanol and 0.1mlHCl solution (37%) in 50ml eggplant type bottle, and 90 DEG C of heating stirrings are anti- It answers, TLC detects reaction process.TLC monitors raw material A and disappears.Stop reaction.It is down to room temperature, 30ml cold water is added, uses ethyl acetate Extraction merges organic layer, and with saturated common salt water washing 2 times, anhydrous sodium sulfate is dried overnight.Filtrate is collected in filtering, is depressurized dense Contract to obtain 1.12g crude product, and 0.83g white crystal, yield 72% is precipitated in methanol/water recrystallization.
Step 2:4- [[the chloro- 4- of 5- [2- (isopropelsulfonyl) phenyl] amino] pyrimidine -2-base] amino]-N- hydroxy benzenes The preparation of formamide (I-1)
Weigh 4- [[the chloro- 4- of 5- [2- (isopropelsulfonyl) phenyl] amino] pyrimidine -2-base] amino] methyl benzoate The freshly prepared azanol methanol solution of 20ml is added in 25ml eggplant type bottle in (0.2g), and stirring at normal temperature reacts 3h.TLC monitoring is former Expect that A disappears.Stop reaction.With saturated ammonium chloride solution tune pH to weakly acidic pH, there is white solid precipitation.Solid is filtered, filter cake is used Water washing obtains 0.19g crude product.Recrystallize to obtain 0.1g white powder, yield 50.5%.
2 4- of embodiment [[the chloro- 4- of 5- [2- (isopropelsulfonyl) phenyl] amino] pyrimidine -2-base] amino] methyl] N- It is prepared by (I-2) of hydroxybenzamide
Step 1:4- [[the chloro- 4- of 5- [2- (isopropelsulfonyl) phenyl] amino] pyrimidine -2-base] amino] methyl] benzene first The preparation of sour methyl esters
By N- [(2- isopropelsulfonyl) phenyl] -2,5- Dichloro-pyrimidin -4- amine (1.0g) and 4- aminomethyl benzoic acid Methyl esters (0.48g) is added in 50ml eggplant type bottle, adds 10ml isopropanol and 0.7g DIEA, and 90 DEG C of heating stirrings are reacted, TLC monitoring.After completion of the reaction, it is down to room temperature, 30ml cold water is added, is extracted with ethyl acetate, merges organic layer, and eaten with saturation Salt water washing 2 times, anhydrous sodium sulfate is dried overnight.Filtrate is collected in filtering, is concentrated under reduced pressure, and column chromatography obtains 0.45g white powder, Yield is 34.6%.
Step 2:4- [[the chloro- 4- of 5- [2- (isopropelsulfonyl) phenyl] amino] pyrimidine -2-base] amino] methyl] N- hydroxyl It is prepared by (I-2) of yl-benzamide
By 4- [[the chloro- 4- of 5- [2- (isopropelsulfonyl) phenyl] amino] pyrimidine -2-base] amino] methyl] benzoic acid first Ester (0.2g) is added in 25ml eggplant type bottle, and the freshly prepared azanol methanol solution of 20ml is added, and stirring at normal temperature reacts 3h.It is molten Liquid is become to clarify by muddiness.TLC monitors raw material A and disappears.With saturated ammonium chloride solution tune pH to weakly acidic pH, there is solid precipitation.It takes out Filter solid, filter cake are washed with water, and obtain 0.15g crude product.0.11g pink powder, yield 55.6% are recrystallized to obtain in methanol.
3 4- of embodiment [[the chloro- 4- of 5- [2- (isopropelsulfonyl) phenyl] amino] pyrimidine -2-base] amino] methyl] N- The preparation of hydroxy benzenes acrylamide (I-3)
The preparation of step 1:4- bromobenzyl carbamate
It weighs and bretylium tosylate 10g is added into 250ml single port bottle, 50ml methylene chloride is added, sequentially adds Et3N (5.98g) and (Boc)2O(12.9g).Stirring at normal temperature reacts 2h.200ml water is added into reaction system, uses methylene chloride (50ml × 3) extraction, merges dichloromethane layer, is successively washed with water, saturated salt solution 100ml, the anhydrous sulphur of dichloromethane layer Sour sodium is dry.It filters, concentration of organic layers obtains white solid.Dry to obtain solid 12.56g, yield 81.7%.
Step 2:(E) -3- [4- [(t-butoxycarbonyl amino) methyl] phenyl] methyl acrylate preparation
4- bromobenzyl carbamate 10g, methyl acrylate 9g, DIEA9g, palladium acetate 0.8g, three (2- are taken respectively Aminomethyl phenyl) phosphine 2g, acetonitrile 60ml, DMF30ml be added into 250ml eggplant type bottle, nitrogen protection, 90 DEG C of back flow reaction 6h.Drop Temperature is cooled to room temperature.200ml cold water is added into reaction system, filters.It takes mother liquor ethyl acetate (100ml × 2) to extract, closes And organic layer takes organic layer anhydrous sodium sulfate 30 minutes dry with saturated common salt water washing.It filters.Mother liquor is taken to add silicagel column Chromatography merges eluent, faint yellow solid 3.9g, yield 38.3% is concentrated under reduced pressure to obtain.
Step 3:(E) -3- [4- (aminomethyl) phenyl] methyl acrylate preparation
(E) -3- [4- [(t-butoxycarbonyl amino) methyl] phenyl] methyl acrylate 2.5g is added in 50ml eggplant type bottle, Trifluoracetic acid 6ml, methylene chloride 20ml, stirring at normal temperature react 2h.50ml water is added into reaction system, it is molten with saturated sodium carbonate Liquid tune pH is extracted with ethyl acetate (50ml × 3) to alkalescent, is merged organic layer, washed, taken with saturated salt solution (100ml) Organic layer is dry with anhydrous sodium sulfate.It filters, takes mother liquor that light yellow oil 1.21g, yield 73.8% is concentrated under reduced pressure to obtain.
Step 4:4- [[the chloro- 4- of 5- [2- (isopropelsulfonyl) phenyl] amino] pyrimidine -2-base] amino] methyl] benzene alkene Sour methyl esters preparation
Weigh N- [(2- isopropelsulfonyl) phenyl] -2,5- Dichloro-pyrimidin -4- amine (0.45g) and (E) -3- [4- (ammonia Methyl) phenyl] methyl acrylate (0.25g) in 50ml eggplant type bottle, adds 10ml isopropanol and 0.34g DIEA, 90 DEG C plus Thermal agitation reaction, TLC detect fully reacting.It is down to room temperature, 30ml cold water is added, is extracted with ethyl acetate, merges organic layer, and With saturated common salt water washing 2 times, anhydrous sodium sulfate is dried overnight.Filtering, collect filtrate, be concentrated under reduced pressure, column chromatograph 0.4g is white Color powder, yield 61.6%.
Step 5:4- [[the chloro- 4- of 5- [2- (isopropelsulfonyl) phenyl] amino] pyrimidine -2-base] amino] methyl] N- hydroxyl The preparation of base benzene acrylamide (I-3)
Weigh 4- [[the chloro- 4- of 5- [2- (isopropelsulfonyl) phenyl] amino] pyrimidine -2-base] amino] methyl] benzene olefin(e) acid The freshly prepared azanol methanol solution of 15ml is added in 25ml eggplant type bottle in methyl esters (0.15g), and stirring at normal temperature reacts 3h.Solution Become to clarify by muddiness.TLC monitors raw material A and disappears.Stop reaction.With saturated ammonium chloride solution tune pH to weakly acidic pH, there is solid It is precipitated.Solid is filtered, filter cake is washed with water, and obtains 0.12g crude product.Recrystallized in methanol 0.08g pink powder, yield are 46.7%.

Claims (10)

1. compounds of formula I or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug,
Wherein,
R1Selected from alkyl, naphthenic base, Heterocyclylalkyl, alkoxy and halogenated alkyl；
R2Selected from halogen, alkyl, alkoxy, alkoxyalkyl, hydroxyl, amino, carboxyl, cyano, nitro, naphthenic base, heterocycle alkane Base；
M is selected from 0,1,2,3 and 4；
R3aAnd R3bIndependently selected from hydrogen, halogen, alkyl, alkoxy, alkoxyalkyl, hydroxyl, amino, carboxyl, cyano, nitro, Naphthenic base, Heterocyclylalkyl；
R4Selected from halogen, alkyl, alkoxy, alkoxyalkyl, hydroxyl, amino, carboxyl, cyano, nitro, naphthenic base, heterocycle alkane Base；
N is selected from 0,1,2,3 and 4；
L is selected from key and alkylidene；
K is selected from key, alkylidene, alkenylene ,-NH-C (O)-(CH2)p-、-C(O)-NH-(CH2) p-, aryl and heteroaryl, it is described Alkylidene, alkenylene ,-NH-C (O)-(CH2)p-、-C(O)-NH-(CH2) p-, aryl and heteroaryl can be one or more Alkyl, halogen, alkoxy, hydroxyl, amino, carboxyl, cyano and nitro replace, and the p is selected from the integer of 1-8；
R5And R6Independently selected from hydrogen, hydroxyl, aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, the aryl, heteroaryl, cycloalkanes Base, Heterocyclylalkyl can by one or more amino, hydroxyl, carboxyl, alkyl, alkoxy, alkoxyalkyl, halogen, halogenated alkyl, Alkylamino, alkyl amide, amide groups, ester group, acyl group, alkanoyl, alkane aminoacyl, aryl, heteroaryl replace.
2. compound as described in claim 1 or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, It is characterized in that the R1Selected from C1-6Alkyl, C3-8Naphthenic base, C3-8Heterocyclylalkyl and halogenated C1-6Alkyl；It is further preferred that R1Choosing From methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, methoxyl group, ethyoxyl, the third oxygen Base, isopropoxy, trichloromethyl, trifluoromethyl；It is further preferred that R1For isopropyl.
3. compound as described in claim 1 or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, It is characterized in that the R2Selected from halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, hydroxyl, amino, carboxyl, cyanogen Base, nitro, C3-8Naphthenic base, C3-8Heterocyclylalkyl, m are selected from 0,1,2,3 and 4；It is further preferred that R2Selected from halogen, C1-3Alkane Base, C1-3Alkoxy, C1-3Alkoxy C1-3Alkyl, hydroxyl, amino, carboxyl, cyano, nitro, m are selected from 0,1,2 and 3；Further Preferably, R2For halogen, m is selected from 0 and 1；It is further preferred that m is 0.
4. compound as described in claim 1 or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, It is characterized in that the R3aAnd R3bIndependently selected from hydrogen, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, hydroxyl, Amino, carboxyl, cyano, nitro, C3-8Naphthenic base, C3-8Heterocyclylalkyl；It is further preferred that R3aAnd R3bIndependently selected from hydrogen, halogen Element, C1-3Alkyl, C1-3Alkoxy, C1-3Alkoxy C1-3Alkyl, hydroxyl, amino, carboxyl, cyano, nitro, C3-8Naphthenic base, C3-8 Heterocyclylalkyl；It is further preferred that R3aAnd R3bIndependently selected from hydrogen, fluorine, chlorine, bromine and iodine.
5. compound as described in claim 1 or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, It is characterized in that the R4Selected from halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, hydroxyl, amino, carboxyl, cyanogen Base, nitro, C3-8Naphthenic base, C3-8Heterocyclylalkyl, n are selected from 0 and 1；It is further preferred that R4Selected from halogen, C1-3Alkyl, C1-3Alkane Oxygroup, C1-3Alkoxy C1-3Alkyl, hydroxyl, amino, carboxyl, cyano, nitro, C3-8Naphthenic base, C3-8Heterocyclylalkyl, n are selected from 0 He 1, it is further preferred that n is 0.
6. compound as described in claim 1 or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, It is characterized in that the L is selected from key, methylene, ethylidene, propylidene, isopropylidene；It is further preferred that L is selected from key and methylene Base.
7. compound as described in claim 1 or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, It is characterized in that the K is selected from key, methylene, ethylidene, propylidene, isopropylidene, ethenylidene, allylidene, Aden's alkene Base ,-NH-C (O)-(CH2)p-、-C(O)-NH-(CH2) p-, phenyl and heteroaryl, the p is selected from the integer of 1-6, described Methylene, ethylidene, propylidene, isopropylidene, ethenylidene, allylidene, butenylidene ,-NH-C (O)-(CH2)p-、-C (O)-NH-(CH2) p-, phenyl and heteroaryl can be by one or more C1-6Alkyl, halogen, C1-6Alkoxy, hydroxyl, amino, Carboxyl, cyano and nitro replace；It is further preferred that K is selected from key, methylene, ethylidene, ethenylidene ,-NH-C (O)- (CH2)p-、-C(O)-NH-(CH2) p-, the p be selected from 1-6 integer, the methylene, ethylidene, ethenylidene ,- NH-C(O)-(CH2)p-、-C(O)-NH-(CH2) p- can be by one or more C1-6Alkyl, halogen, C1-6Alkoxy, hydroxyl, ammonia Base, carboxyl, cyano and nitro replace；It is further preferred that K is selected from key, ethenylidene ,-NH-C (O)-(CH2)6-、-C(O)- NH-(CH2)6-。
8. compound as described in claim 1 or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, It is characterized in that the R5And R6Independently selected from hydrogen, hydroxyl, benzene, naphthalene, azepine aryl, thia aryl, oxa- aryl, nitrogen thia virtue Base, oxygen thia aryl, nitrogen oxa- aryl, C3-8Naphthenic base, miscellaneous C3-8Naphthenic base, the benzene, naphthalene, azepine aryl, thia aryl, Oxa- aryl, nitrogen thia aryl, oxygen thia aryl, nitrogen oxa- aryl, C3-8Naphthenic base, miscellaneous C3-8Naphthenic base can be by one or more A amino, hydroxyl, carboxyl, C1-6Alkyl, C1-6Alkoxy, C1-6Alcoxyl C1-6Alkyl, halogen, halogenated C1-6Alkyl, C1-6Alkylamino, C1-6Alkyl amide, amide groups, ester group, acyl group, C1-6Alkanoyl, C1-6Alkane aminoacyl, aryl, heteroaryl replace；Further preferably Ground, R5For hydrogen, R6Selected from hydroxyl, benzene, naphthalene, azepine aryl, thia aryl, oxa- aryl, nitrogen thia aryl, oxygen thia aryl, nitrogen Oxa- aryl, the benzene, naphthalene, azepine aryl, thia aryl, oxa- aryl, nitrogen thia aryl, oxygen thia aryl, nitrogen oxa- Aryl can be by one or more amino, hydroxyl, carboxyl, C1-6Alkyl, C1-6Alkoxy, C1-6Alcoxyl C1-6It is alkyl, halogen, halogenated C1-6Alkyl, C1-6Alkylamino, C1-6Alkyl amide, amide groups, ester group, acyl group, C1-6Alkanoyl, C1-6It is alkane aminoacyl, aryl, miscellaneous Aryl replaces；It is further preferred that R5For hydrogen, R6Selected from hydroxyl and benzene, the benzene can be by one or more amino, hydroxyl Base, carboxyl, C1-3Alkyl, C1-3Alkoxy, C1-3Alcoxyl C1-3Alkyl, halogen, halogenated C1-3Alkyl, C1-3Alkylamino, C1-3Alkane amide Base, amide groups, ester group, acyl group, C1-3Alkanoyl, C1-3Alkane aminoacyl, aryl, heteroaryl replace.
9. compound as described in claim 1 or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, It is characterized in that compound compound selected from the following:
10. a kind of pharmaceutical composition, it includes described in any item compounds of claim 1 to 9 or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug.
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