[go: up one dir, main page]

CN106977425B - Hydroxamic acid derivs and the preparation method and application thereof with dnmt rna and histon deacetylase (HDAC) inhibitory activity - Google Patents

Hydroxamic acid derivs and the preparation method and application thereof with dnmt rna and histon deacetylase (HDAC) inhibitory activity Download PDF

Info

Publication number
CN106977425B
CN106977425B CN201710212240.1A CN201710212240A CN106977425B CN 106977425 B CN106977425 B CN 106977425B CN 201710212240 A CN201710212240 A CN 201710212240A CN 106977425 B CN106977425 B CN 106977425B
Authority
CN
China
Prior art keywords
cell
cancer
formula
acid
cancer cell
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201710212240.1A
Other languages
Chinese (zh)
Other versions
CN106977425A (en
Inventor
蒋宇扬
袁梓高
高春梅
孙钦升
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Graduate School Tsinghua University
Original Assignee
Shenzhen Graduate School Tsinghua University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenzhen Graduate School Tsinghua University filed Critical Shenzhen Graduate School Tsinghua University
Priority to CN201710212240.1A priority Critical patent/CN106977425B/en
Publication of CN106977425A publication Critical patent/CN106977425A/en
Application granted granted Critical
Publication of CN106977425B publication Critical patent/CN106977425B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a kind of hydroxamic acid derivs and the preparation method and application thereof with dnmt rna and histon deacetylase (HDAC) inhibitory activity; a kind of hydroxamic acid derivs or its pharmaceutically acceptable salt, hydroxamic acid derivs structural formula is as shown in formula I:Wherein, Ar is aromatic group, the aromatic group is selected from replace or non-substituted phenyl ring, replace or non-substituted aromatic heterocycle, replace or non-substituted benzheterocycle；Aromatic heterocycle replace or non-substituted and heterocycle；N=1,2,3,4,5 or 6；L1Link position be phenyl ring ortho position, meta or para position；L1For saturation or unsaturated carbon chains.

Description

Different hydroxyl oxime with dnmt rna and histon deacetylase (HDAC) inhibitory activity Acid derivative and the preparation method and application thereof
Technical field
The invention belongs to field of medicaments, and in particular to there is one kind dnmt rna and histon deacetylase (HDAC) to press down Make active hydroxamic acid derivs and the preparation method and application thereof.
Background technique
Cancer is to cause first cause of disease of human death now, and the anti-tumor drug for researching and developing high-efficiency low-toxicity is extremely urgent.It is swollen The occurrence and development of tumor were both closely related with gene unconventionality, also had close relationship with epigenetic change.With gene unconventionality (amplification, transposition, deletion and the point mutation of such as oncogene or tumor suppressor gene) is different, and the change of epigenetic is not related to DNA sequence dna Variation, the hereditary information of parent can be kept in cell division, but can take a turn for the worse under certain condition, make malignant cell group Body is changed into normal cell.Therefore the enzyme that regulating and controlling effect is played in epigenetic is considered as new the one of anti-tumor drug research and development For target spot.
Dnmt rna (DNA methyltransferases, DNMTs) and histon deacetylase (HDAC) (Histone Deacetylases, HDACs) distinguish the methylation of catalytic dna and the deacetylation of histone, it is the important regulating and controlling of epigenetic Mode.DNMTs and HDACs high expression energy silencing tumor suppressor gene in cell, promotes the occurrence and development of tumour.Largely DNMTs inhibitor and HDACs inhibitor are developed to treat tumour, and some DNMTs inhibitor and HDACs inhibitor are facing Good antitumous effect is shown in bed, there are two DNMTs inhibitor (azacitidine, Decitabine) and five at present HDACs inhibitor (Vorinostat, Romidepsin, Belinostat, Panobinostat, Chidamide) listing.
DNA methylation, DNA methylase inhibitor and chromatin remodeling have closely connection in physiological function, together shadow Ring the expression of tumor suppressor gene.DNMTs and HDACs can also be influenced each other by direct or indirect mode.On the one hand, research is found When the inhibitor of DNMTs or HDACs is applied alone, the high expression of another enzyme may still lead to the silencing of tumour tumor suppressor gene, such Compensatory mechanism makes tumour cell generate drug resistance, reduces therapeutic effect.On the other hand, clinical research shows low dosage DNMT inhibitor and hdac inhibitor drug combination have apparent synergistic effect.Therefore the suppression of DNMTs and HDACs are targeted simultaneously Preparation can may more effectively be such that the tumor suppressor gene of silencing expresses again, and tumour cell is made to be more difficult to generate drug resistance, but mesh The report of preceding this respect not yet.
Summary of the invention
An object of the present invention is to provide a kind of hydroxamic acid multiple target point with DNMTs and HDACs inhibitory activity Inhibitor and preparation method thereof.
Hydroxamic acid multiple target point inhibitor provided by the present invention, structural formula is as shown in formula I.
In above-mentioned Formulas I, Ar is aromatic group, the aromatic group is selected from replace or non-substituted phenyl ring, replace or Non-substituted aromatic heterocycle, replace or non-substituted benzheterocycle, replace or non-substituted aromatic heterocycle and heterocycle；
Preferably, the heteroaromatic is selected from 4 yuan, 5 yuan, 6 yuan or 7 yuan heteroaromatics, includes 1,2 or 3 hetero atom on heterocycle, Hetero atom is independently selected from N, S, O；
The heteroaromatic is selected from pyridyl group, pyridinyl-N-oxide, pyrimidine radicals, pyridazinyl, furyl, thienyl, thiazole Base, imidazole radicals, pyranose, pyrroles；
The benzheterocycle is selected from quinoline, isoquinolyl, purine radicals, indyl, benzimidazole, pyrrolopyridine, dihydro Benzo dioxin, benzodioxole；
Substituent group on aromatic group is 1-5, preferably 1,2,3,4 or 5；Substituent group be selected from C1-C6 alkyl, The alkenyl of C1-C6, the alkynyl of C1-C6, hydroxyl, nitro, methoxyl group, trifluoromethyl, trifluoromethoxy, amino, acrylamido, Cyano, fluorine-based, chloro, bromo, iodo；
Preferably, the aromatic group is selected from
N=1,2,3,4,5 or 6；
L1Link position be phenyl ring ortho position, meta or para position；L1For carbon key or alkyl chain, including but not limited to methylene Base, ethylene group, vinyl, acetenyl.
Compound pharmaceutically acceptable salt shown in above-mentioned Formulas I also belongs to protection scope of the present invention.
Wherein, the pharmaceutically acceptable salt is inorganic acid salt or acylate.
The inorganic acid salt is selected from the salt that any one following inorganic acid are formed: hydrochloric acid, sulfuric acid or phosphoric acid.
The acylate is selected from the salt that any one following organic acid are formed: acetic acid, trifluoroacetic acid, malonic acid, lemon Acid and p-methyl benzenesulfonic acid.
Hydroxamic acid derivs shown in above-mentioned Formulas I be preferably it is following any one:
Hydroxamic acid compound shown in above-mentioned Formulas I is prepared by the method comprising the following steps；
1) under condensing agent effect, Formula II compound represented is reacted to obtain formula with formula III compound represented IV compound represented；Or Formula II compound represented is prepared into corresponding acyl with thionyl chloride, oxalyl chloride or phosphorus oxychloride It is reacted to obtain formula IV compound represented with formula III compound represented after chlorine derivative；
Ar, n or L in Formula II, III or IV1Ar, n or L corresponding with Formulas I1Definition it is identical；
In formula III, R is the alkyl of C1-C4.
2) compound shown in formula IV is reacted in alkaline solution with azanol or hydroxylamine hydrochloride, obtains compound shown in Formulas I.
In above method step 1), the condensing agent is selected from following at least one: benzotriazole-N, N, N', N'- tetramethyl Base urea hexafluorophosphoric acid ester N, N'- carbonyl dimidazoles, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3- dimethylamino Propyl) -3- ethyl carbodiimide etc..
The reaction of the step 1) carries out in organic solvent, and the organic solvent is selected from dimethylformamide, dimethyl One of acetamide, chloroform, methylene chloride, acetone, tetrahydrofuran, acetonitrile etc. are a variety of.
Step 1) the condensing agent and Formula II compound represented, the molar ratio of formula III compound represented can be successively For 1-4:1-2:1-4, concretely 1.5:1:1.1.
The reaction temperature of the reaction of the step 1) is 20-80 DEG C, and the reaction time is 3-12 hours.
In above method step 2), the alkali is selected from ammonium hydroxide, triethylamine, diisopropyl ethyl amine, sodium hydroxide, hydroxide One of potassium, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide etc. are a variety of.
The reaction of the step 2) carries out in aqueous solution or organic solvent, and organic solvent is selected from dimethylformamide, chlorine One of imitative, methylene chloride, methanol, ethyl alcohol, acetone, tetrahydrofuran, acetonitrile etc. are a variety of.
The molar ratio that compound shown in formula IV is reacted with azanol or hydroxylamine hydrochloride, alkali is 1:1-10:1-20, concretely 1: 5:5。
The reaction temperature of the step 2) reaction is 20-80 DEG C, and the reaction time is 0.5-10 hours；
Compound prepared by the present invention passes through high resolution mass spectrum, nuclear magnetic resonance, the test such as fusing point, it was demonstrated that prepared chemical combination Object is correct, is compound shown in general formula I.
It is also another object of the present invention to provide the applications of compound shown in formula I and its pharmaceutically acceptable salt.
The purposes of compound shown in formula I or its pharmaceutically acceptable salt is its application in the following aspects:
1) application in dnmt rna and/or histon deacetylase (HDAC) inhibitor is being prepared；
2) application in preparation eucaryote tumor cell proliferation inhibitor；
3) application in preparation prevention and/or tumor.
The dnmt rna (DNMTs) include in mammalian cells known hypotype (DNMT1, DNMT3A, DNMT3B)；The histon deacetylase (HDAC) (HDACs) includes known hypotype in mammalian cells, mainly include but It is not limited to HDAC1, HDAC2, HDAC3, HDAC8, HDAC4, HDAC5, HDAC7, HDAC9, HDAC6, HDAC10, HDAC11.
The eucaryote is mammal；The tumour cell is cancer cell；The cancer cell be leukaemia cancer cell, Breast cancer cell, liver cancer cells, pancreatic cancer cell, lung carcinoma cell, brain cancer cell, ovarian cancer cell, uterine cancer cells, carcinoma of testis Cell, skin cancer cell, stomach cancer cell, nasopharyngeal carcinoma cell, colon cancer cell, bladder cancer cell or rectum cancer cell；Preferably For the chronic marrow original leukaemia cell of people and human tissue cell's lymphoma cell.
The leukaemia cancer cell is specially human chronic myelogenous leukemia (CML) cell line k562, and the lymthoma is thin Born of the same parents are specially human tissue cell lymphoma cell U937, and the lung carcinoma cell is specially human lung carcinoma cell NCI-H520, the people Brain glioblastoma cell is specially U251, and the black cancer cell is specially A375, and the glioblastoma cells are specially People's glioblastoma cells A172 and human brain astrocytes blastoma cell U-118MG, the cervical cancer cell are specially Human cervical cancer cell lines Hela, the nasopharyngeal carcinoma cell are specially human nasopharyngeal epithelioma 1 CNE-2, and the liver cancer cells are specifically people Hepatoma H22 cells, the breast cancer cell are specially human breast cancer cell line Bcap-37 and MDA-MB-231.
The tumour is cancer；The cancer be leukaemia, lymthoma, lung cancer, black cancer, glioblastoma, cervical carcinoma, Nasopharyngeal carcinoma, liver cancer, breast cancer, the cancer of the brain, cancer of pancreas, oophoroma, uterine cancer, carcinoma of testis, cutaneum carcinoma, gastric cancer, colon cancer, bladder cancer Or the carcinoma of the rectum.
Compound shown in formula I or its pharmaceutically acceptable salt can also be used for preparation prevention and/or treatment tumour Drug.
The prevention and/or treatment prepared using I compound represented of formula or its pharmaceutically acceptable salt as effective component is swollen The drug of tumor, also belongs to protection scope of the present invention.
The dnmt rna and/or histone of the compound shown in formula I or the preparation of its pharmaceutically acceptable salt go second Deacerylase inhibitors, eucaryote tumor cell proliferation inhibitor and prevention and/or treat tumour drug can by injection, Injection, collunarium, eye drip, infiltration, absorption, the method physically or chemically mediated import body such as muscle, intradermal, subcutaneous, vein, glue Membrane tissue；Or body is imported after other material mixings or package.
When needs, one or more pharmaceutically acceptable carriers can also be added in said medicine.The load Body includes diluent, excipient, filler, adhesive, wetting agent, disintegrating agent, the sorbefacient, surface of pharmaceutical field routine Activating agent, absorption carrier, lubricant etc..
The prevention and/or tumor of the compound shown in formula I or the preparation of its pharmaceutically acceptable salt can make At diversified forms such as injection, tablet, pulvis, granule, capsule, oral solution, paste, cremes.The drug of above-mentioned various dosage forms It can be prepared according to the conventional method of pharmaceutical field.
Compound provided by the invention is by kinds of tumor cells system test (including leukaemia cell, lymphoma cell etc.) And dnmt rna, histon deacetylase (HDAC) inhibitory activity test, it was demonstrated that compound shown in formula I is a kind of potential There is the anti-tumor drug of inhibitory activity to dnmt rna and histon deacetylase (HDAC).Compound provided by the invention is former Material is easy to get, and preparation method is simple, experiments have shown that it has good anticancer effect, has in anti-tumor drug design research and development field good Good application prospect.
Specific embodiment
The present invention will be described below by way of specific embodiments, but it's not limited to that for the scope of the present invention.
Experimental method described in following embodiments is unless otherwise specified the conventional method of organic synthesis；The reagent And biomaterial obtains from commercial channels unless otherwise specified.
Embodiment 1
The chloro- N- of 5- (4- (3- (azanol base) -3- propionyl) phenethyl) -2- methoxy benzamide (compound 1)
Embodiment 1a
Tert-butyl (4- bromophenylethyl) carbamate
4- Bretylium Tosylate (10g, 50mmol) is dissolved in 250 milliliters of methylene chloride, addition di-tert-butyl dicarbonate (12g, 55mmol), it stirs 3 hours at room temperature, successively with saturated aqueous ammonium chloride, saturated sodium bicarbonate aqueous solution, water, saturated common salt Water washing reaction solution, organic phase are spin-dried for obtaining crude product after anhydrous magnesium sulfate is dry.Crystallization obtains title compound (white in ether Solid, 14.70g, 98% yield).1HNMR (400MHz, Chloroform-d) δ 7.42 (d, J=8.4Hz, 2H), 7.07 (d, J =8.3Hz, 2H), 4.51 (s, 1H), 3.35 (br, 2H), 2.75 (t, J=7.0Hz, 2H), 1.43 (s, 9H)
Embodiment 1b
(E) -3- (4- (2- ((tertbutyloxycarbonyl) amino) ethyl) phenyl) methyl acrylate
By embodiment 1a (3.0g, 10mmol), Anhydrous potassium carbonate (2.764g, 20mmol), two triphenylphosphine two of catalytic amount Palladium chloride is placed in 50ml round-bottomed flask, and dimethylformamide (DMF) 30ml is added, and deaeration in condenser is simultaneously added after being replaced with nitrogen Methyl acrylate (1.8ml, 20mmol).Overnight in 120~130 DEG C of reactions.Water is added after reaction and is extracted with ethyl acetate It takes.Organic phase is spin-dried for after anhydrous magnesium sulfate is dry, and obtained after being washed with deionized water title compound (white solid, 2.53g, 83% yield).1H NMR (400MHz, Chloroform-d) δ 7.68 (d, J=16.0Hz, 1H), 7.47 (d, J= 7.8Hz, 2H), 7.22 (d, J=7.8Hz, 2H), 6.42 (d, J=16.1Hz, 1H), 4.59 (s, 1H), 3.81 (s, 3H), 3.43-3.31 (m, 2H), 2.82 (t, J=7.0Hz, 2H), 1.34 (s, 9H)
Embodiment 1c
3- (4- (2- ((tertbutyloxycarbonyl) amino) ethyl) phenyl) methyl propionate
Embodiment 1b (3.05g, 10mmol) is dissolved in 200ml methanol, the palladium carbon of 10% mass fraction of 300mg is added, Flow back in autoclave 3h under the hydrogen of 2 atmospheric pressure.It filters later, rotation is (white except title compound is obtained after filtrate Color solid, 3.00g, 98% yield).1H NMR(400MHz,Chloroform-d)δ7.24–6.96(m,4H),4.54(s, 1H), 3.67 (s, 3H), 3.36 (d, J=6.3Hz, 2H), 2.93 (t, J=7.8Hz, 2H), 2.76 (t, J=7.0Hz, 2H), 2.70–2.55(m,2H),1.43(s,9H).
Embodiment 1d
3- (4- (2- aminoethyl) phenyl) methyl propionate
Embodiment 1c (2.54g, 8.28mmol) is dissolved in methylene chloride (40ml), trifluoroacetic acid is added dropwise under ice bath (12ml, 165mmol), reacts at room temperature 3h later.Liquid is removed with Rotary Evaporators rotation, sodium bicarbonate aqueous solution is added and with acetic acid Ethyl ester extraction.Organic phase removes ethyl acetate after being dried over anhydrous sodium sulfate, crude product is recrystallized to give title compound in ether Object (faint yellow solid, 1.42g, 83% yield).1H NMR(400MHz,Chloroform-d)δ7.16–7.08(m,4H), 3.67 (s, 3H), 2.99-2.88 (m, 4H), 2.72 (t, J=6.9Hz, 2H), 2.64-2.60 (m, 2H)
Embodiment 1e
3- (4- (2- (the chloro- 2- methoxy benzamide base of 5-) ethyl) phenyl) methyl propionate
By embodiment 1d (621mg, 3mmol), the chloro- benzoic acid of 2- methoxyl group -5- (839mg, 4.5mmol), condensing agent HBTU (2.56g, 6.75mmol) and DMAP (73mg, 0.6mmol) are dissolved in DMF, and room temperature reaction is overnight.Silicon after reaction Rubber column gel column chromatographic isolation obtains title compound (white solid, 844mg, 75% yield).1H NMR(400MHz,Chloroform-d) δ 8.17 (d, J=2.8Hz, 1H), 7.81 (s, 1H), 7.36 (dd, J=8.8,2.8Hz, 1H), 7.18 (s, 4H), 6.85 (d, J =8.8Hz, 1H), 3.75 (s, 3H), 3.72 (t, J=6.8Hz, 3H), 3.67 (s, 3H), 2.95 (t, J=7.8Hz, 2H), 2.89 (t, J=6.8Hz, 2H), 2.63 (t, J=7.8Hz, 2H)；13C NMR(101MHz,CDCl3)δ172.71,163.27, 155.35,138.12,136.56,131.60,131.40,128.46,127.91,126.15,122.42,112.19,55.49, 51.06,40.34,35.11,34.54,29.94.
Embodiment 1f
The chloro- N- of 5- (4- (3- (azanol base) -3- propionyl) phenethyl) -2- methoxy benzamide
Embodiment 1e (100mg, 0.26mmol) is added in methanol (2ml), be subsequently added into hydroxylamine hydrochloride (180mg, 2.6mmol) with sodium tert-butoxide (375mg, 3.9mmol), reaction is stayed overnight at room temperature.Reaction dissolvent and column color are removed after reaction Spectrum separates to obtain title compound (faint yellow solid, 31mg, 32% yield).170~172 DEG C of fusing point,1H NMR(400MHz, DMSO-d6) δ 10.36 (s, 1H), 8.70 (s, 1H), 8.23 (t, J=5.6Hz, 1H), 7.66 (d, J=2.8Hz, 1H), 7.50 (dd, J=8.9,2.8Hz, 1H), 7.20-7.11 (m, 5H), 3.81 (s, 3H), 3.48 (q, J=6.8Hz, 2H), 2.78 (t, J =7.5Hz, 4H), 2.25 (t, J=7.7Hz, 2H)；13C NMR(101MHz,DMSO)δ168.15,163.33,155.63, 138.77,136.79,131.42,129.48,128.51,128.14,124.61,124.24,114.09,56.18,40.67, 34.40,33.76,30.36.HRMS (ESI) m/z calculated value [M-H] -375.1112, measured value 375.1122.
Embodiment 2
(E) the chloro- N- of -5- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -2- methoxy benzamide (compound 2)
Embodiment 2a
(E) -3- (4- (2- aminoethyl) phenyl) methyl acrylate
Embodiment 1b (2.53g, 8.28mmol) is dissolved in methylene chloride (40ml), trifluoroacetic acid is added dropwise under ice bath (12ml, 165mmol), reacts at room temperature 3h later.Liquid is removed with Rotary Evaporators rotation, sodium bicarbonate aqueous solution is added and with acetic acid Ethyl ester extraction.Organic phase removes ethyl acetate after being dried over anhydrous sodium sulfate, crude product is recrystallized to give title compound in ether Object (faint yellow solid, 1.15g, 67% yield).1H NMR(400MHz,DMSO-d6)δ7.75(br,2H),7.74–7.60(m, 3H), 7.32 (d, J=8.0Hz, 2H), 6.64 (d, J=16.0Hz, 1H), 3.73 (s, 3H), 3.06 (t, J=7.8Hz, 1H), 2.88 (t, J=7.9Hz, 2H)；13C NMR(101MHz,DMSO)δ166.57,144.11,139.98,132.49,129.19, 128.52,117.37,51.34,33.12,33.05.
Embodiment 2b
(E) -3- (4- (2- (the chloro- 2- methoxy benzamide of 5-) ethyl) phenyl) methyl acrylate
By embodiment 2a (615mg, 3mmol), the chloro- benzoic acid of 2- methoxyl group -5- (839mg, 4.5mmol), condensing agent HBTU (2.56g, 6.75mmol) and DMAP (73mg, 0.6mmol) are dissolved in DMF, and room temperature reaction is overnight.Silicon after reaction Rubber column gel column chromatographic isolation obtains title compound (white solid, 908mg, 81% yield).1H NMR(400MHz,DMSO-d6)δ8.26 (t, J=5.6Hz, 1H), 7.73-7.57 (m, 4H), 7.50 (dd, J=8.8,2.8Hz, 1H), 7.32 (d, J=8.0Hz, 2H), 7.15 (d, J=8.9Hz, 1H), 6.62 (d, J=16.1Hz, 1H), 3.81 (s, 3H), 3.72 (s, 3H), 3.52 (dt, J= 5.6,7.1Hz, 2H), 2.87 (t, J=7.1Hz, 2H)；13C NMR(101MHz,DMSO)δ166.62,163.44,155.61, 144.31,142.20,131.96,131.37,129.43,129.22,128.32,124.73,124.24,117.01,114.08, 56.17,51.29,40.29,34.65.
Embodiment 2c
(E) the chloro- N- of -5- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -2- methoxy benzamide
Embodiment 1e (100mg, 0.27mmol) is added in methanol (2ml), be subsequently added into hydroxylamine hydrochloride (180mg, 2.6mmol) with sodium tert-butoxide (375mg, 3.9mmol), reaction is stayed overnight at room temperature.Reaction dissolvent and column color are removed after reaction Spectrum separates to obtain title compound (faint yellow solid, 37mg, 37% yield).158~160 DEG C of fusing point,1H NMR(400MHz, DMSO-d6) δ 10.74 (s, 1H), 9.04 (s, 1H), 8.26 (t, J=5.6Hz, 1H), 7.63 (d, J=2.8Hz, 1H), 7.56- 7.48 (m, 3H), 7.44 (d, J=15.7Hz, 1H), 7.30 (d, J=7.8Hz, 2H), 7.15 (d, J=8.9Hz, 1H), 6.43 (d, J=15.8Hz, 1H), 3.82 (s, 3H), 3.51 (q, J=6.7Hz, 2H), 2.85 (t, J=7.1Hz, 2H)；13C NMR (101MHz,DMSO)δ163.43,155.62,140.93,132.82,131.37,129.44,129.19,127.41,124.77, 124.26,118.37,114.11,56.18,40.36,34.61.HRMS (ESI) m/z calculated value [M+H]+375.1112, actual measurement Value 375.1122.
Embodiment 3
(E) the chloro- N- of -5- (3- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -2- methoxy benzamide (compound 3)
Embodiment 3a
Tert-butyl (3- bromophenylethyl) carbamate
Using Bretylium Tosylate as raw material, the preparation method is the same as that of Example 1 a.Yield is 97%.1H NMR(400MHz, Chloroform-d) δ 7.36 (dd, J=7.5,1.4Hz, 2H), 7.21-7.15 (m, 1H), 7.12 (d, J=7.7Hz, 1H), 4.55 (s, 1H), 3.36 (q, J=6.8Hz, 2H), 2.77 (t, J=7.1Hz, 2H), 1.44 (s, 9H)
Embodiment 3b
(E) -3- (3- (2- ((tertbutyloxycarbonyl) amino) ethyl) phenyl) methyl acrylate
Using embodiment 3a as raw material, the preparation method is the same as that of Example 1 b.Yield is 86%.1H NMR(400MHz,DMSO-d6)δ 7.64 (d, J=16.1Hz, 1H), 7.58-7.48 (m, 2H), 7.34 (t, J=7.8Hz, 1H), 7.26 (d, J=7.6Hz, 1H), 6.92 (t, J=5.6Hz, 1H), 6.63 (d, J=16.0Hz, 1H), 3.73 (s, 3H), 3.26-3.04 (m, 2H), 2.72 (t, J =7.3Hz, 2H), 1.36 (s, 9H)；13C NMR(101MHz,DMSO)δ166.54,155.41,144.55,140.14, 133.84,130.83,128.72,128.34,126.10,117.56,77.38,54.78,51.34,40.97,34.99, 28.13.
Embodiment 3c
(E) -3- (3- (2- aminoethyl) phenyl) methyl acrylate
Using embodiment 3b as raw material, preparation method is the same as embodiment 2a.Yield is 72%.1H NMR(400MHz,DMSO-d6)δ 7.98 (br, 2H), 7.72-7.56 (m, 3H), 7.39 (t, J=7.6Hz, 1H), 7.33 (d, J=7.6Hz, 1H), 6.68 (d, J =16.1Hz, 1H), 3.73 (s, 1H), 3.07 (t, J=7.9Hz, 1H), 2.91 (br, 1H)；13C NMR(101MHz,DMSO)δ 166.52,144.31,138.12,134.19,130.78,129.07,128.39,126.74,117.94,51.39,32.84.
Embodiment 3d
(E) -3- (3- (2- (the chloro- 2- methoxy benzamide base of 5-) ethyl) phenyl) methyl acrylate
Using embodiment 3c as raw material, preparation method is the same as embodiment 2b.Yield is 77%.1H NMR(400MHz,DMSO-d6)δ 8.26 (t, J=5.7Hz, 1H), 7.69-7.56 (m, 4H), 7.50 (dd, J=8.8,2.8Hz, 1H), 7.38 (t, J=7.5Hz, 1H), 7.33 (t, J=7.6Hz, 1H), 7.15 (d, J=8.9Hz, 1H), 6.65 (d, J=16.0Hz, 1H), 3.79 (s, 3H), 3.73 (s, 3H), 3.54 (dt, J=5.7,7.1Hz, 2H), 2.86 (t, J=7.1Hz, 2H)；13C NMR(101MHz,DMSO)δ 166.54,163.49,155.56,144.48,140.10,133.94,131.32,130.88,129.36,128.84,128.45, 126.28,124.88,124.22,117.67,114.05,56.14,51.36,40.23,34.45.
Embodiment 3e
(E) the chloro- N- of -5- (3- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -2- methoxy benzamide
Using embodiment 3d as raw material, preparation method is the same as embodiment 2c.Yield is 35%.124~126 DEG C of fusing point,1H NMR (400MHz,DMSO-d6) δ 8.27 (t, J=5.6Hz, 1H), 7.63 (d, J=2.8Hz, 1H), 7.50 (dd, J=8.8, 2.8Hz, 1H), 7.48-7.38 (m, 3H), 7.36 (t, J=7.5Hz, 1H), 7.27 (d, J=7.5Hz, 1H), 7.15 (d, J= 8.9Hz, 1H), 6.47 (d, J=15.8Hz, 1H), 3.80 (s, 3H), 3.53 (q, J=6.7Hz, 2H), 2.85 (t, J= 7.1Hz,2H)；13C NMR(101MHz,DMSO)δ163.45,162.59,155.59,139.98,137.80,134.92, 131.36,129.71,129.41,128.85,127.56,125.38,124.76,124.24,119.25,114.07,56.15, 40.44,34.63.HRMS (ESI) m/z calculated value [M-H] -373.0955, measured value 373.0954.
Embodiment 4
(E) the chloro- N- of -2- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -5- (trifluoromethyl) benzene first Amide (is changed
Close object 4)
Embodiment 4a
(E) -3- (4- (2- (2- chloro- 5- (trifluoromethyl) benzamido) ethyl) phenyl) methyl acrylate
Using the chloro- 5- of 2- (trifluoromethyl) benzoic acid and embodiment 2a as raw material, preparation method is the same as embodiment 2b.Yield is 65%.1H NMR(400MHz,DMSO-d6) δ 8.70 (t, J=5.6Hz, 1H), 7.81 (dd, J=8.5,2.2Hz, 1H), 7.74 (d, J=8.4Hz, 1H), 7.70-7.56 (m, 4H), 7.33 (d, J=7.9Hz, 2H), 6.61 (d, J=16.1Hz, 1H), 3.72 (s, 3H), 3.51 (td, J=5.6,7.1Hz, 2H), 2.88 (t, J=7.1Hz, 2H)；19F NMR(376MHz,DMSO)δ- 61.17；13C NMR(101MHz,DMSO)δ166.61,164.75,144.30,142.00,137.68,134.33,131.98, 130.73,129.30,128.25,127.74,127.22,125.49,124.77,116.98,51.30,40.05,34.49.
Embodiment 4b
(E) the chloro- N- of -2- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -5- (trifluoromethyl) benzene first Amide
Using embodiment 4a as raw material, preparation method is the same as embodiment 2c.Yield is 29%.162~163 DEG C of fusing point,1H NMR (400MHz,DMSO-d6) δ 10.72 (s, 1H), 9.03 (s, 1H), 8.69 (t, J=5.6Hz, 1H), 7.81 (dd, J=8.4, 2.3Hz, 1H), 7.74 (d, J=8.4Hz, 1H), 7.63 (d, J=2.2Hz, 1H), 7.50 (d, J=7.8Hz, 2H), 7.43 (d, J=15.7Hz, 1H), 7.31 (d, J=7.8Hz, 2H), 6.43 (d, J=15.8Hz, 1H), 3.50 (q, J=6.7Hz, 2H), 2.87 (t, J=7.2Hz, 2H)；13C NMR(101MHz,DMSO)δ164.74,140.73,137.98,137.70,134.32, 132.82,130.72,129.28,127.75,127.42,127.33,125.50,125.46,124.78,122.07,118.31, (39.15,38.97,34.45.HRMS ESI) m/z calculated value [M-H]-411.0723 measured value 411.0717.
Embodiment 5
(E) -4- hydroxy-n-(4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -3- methoxybenzoyl Amine (compound 5)
Embodiment 5a
(E) -3- (4- (2- (4- hydroxy 3-methoxybenzene formamido) ethyl) phenyl) methyl acrylate
Using vanillic acid and embodiment 2a as raw material, preparation method is the same as embodiment 2b.Yield is 69%.1H NMR(400MHz,DMSO-d6) δ 9.56 (s, 1H), 8.36 (t, J=5.6Hz, 1H), 7.77-7.55 (m, 3H), 7.47-7.21 (m, 4H), 6.80 (d, J=8.3Hz, 1H), 6.61 (d, J=16.0Hz, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 3.47 (dt, J=5.6,7.3Hz, 2H), 2.87 (t, J=7.3Hz, 2H)；13C NMR(101MHz,DMSO)δ166.63, 165.76,149.28,146.98,144.35,142.48,131.84,129.17,128.31,125.50,120.47,116.90, 114.67,111.18,55.54,51.30,40.40,35.01.
Embodiment 5b
(E) -4- hydroxy-n-(4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -3- methoxybenzoyl Amine
Using embodiment 5a as raw material, preparation method is the same as embodiment 2c.Yield is 34%.150~152 DEG C of fusing point,1H NMR (400MHz,DMSO-d6) δ 8.33 (s, 1H), 7.46 (d, J=7.8Hz, 2H), 7.42-7.13 (m, 5H), 6.78 (d, J= 8.2Hz, 1H), 6.39 (d, J=15.8Hz, 1H), 3.79 (s, 3H), 3.50-3.41 (m, 2H), 2.83 (t, J=7.4Hz, 2H)；13C NMR(101MHz,DMSO)δ165.82,162.81,149.88,147.10,140.93,137.03,132.94, 129.11,127.27,125.09,120.54,119.00,114.75,111.22,55.54,40.51,35.01.HRMS(ESI) M/z calculated value [M-H]-355.1294 measured value 355.1303.
Embodiment 6
(E) dioxane between-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) benzo [d] [1,3] Amylene -5- formamide (compound 6)
Embodiment 6a
(E) -3- (4- (2- (benzo [d] [1,3] dioxole -5- formamide) ethyl) phenyl) methyl acrylate
Using piperic acid and embodiment 2a as raw material, preparation method is the same as embodiment 2b.Yield is 73%.1H NMR(400MHz, DMSO-d6) δ 8.39 (t, J=5.6Hz, 1H), 7.75-7.54 (m, 3H), 7.40 (dd, J=8.2,1.7Hz, 1H), 7.34 (d, J=1.7Hz, 1H), 7.28 (d, J=7.9Hz, 2H), 6.97 (d, J=8.1Hz, 1H), 6.60 (d, J=16.1Hz, 1H), 6.08 (s, 2H), 3.72 (s, 3H), 3.47 (td, J=5.6,7.2Hz, 2H), 2.86 (t, J=7.2Hz, 2H)；13C NMR (101MHz,DMSO)δ166.64,165.14,149.46,147.15,144.35,142.40,131.85,129.17,128.43, 128.31,121.92,116.91,107.70,107.08,101.50,51.31,40.45,34.84.
Embodiment 6b
(E) dioxane between-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) benzo [d] [1,3] Diene -5-
Formamide
Using embodiment 6a as raw material, preparation method is the same as embodiment 2c.Yield is 41%.186~187 DEG C of fusing point,1H NMR (400MHz,DMSO-d6) δ 10.72 (s, 1H), 9.02 (s, 1H), 8.40 (t, J=5.6Hz, 1H), 7.52-7.37 (m, 4H), 7.35 (d, J=1.7Hz, 1H), 7.27 (d, J=7.8Hz, 2H), 6.97 (d, J=8.1Hz, 1H), 6.41 (d, J=15.8Hz, 1H), 6.09 (s, 2H), 3.46 (q, J=6.7Hz, 2H), 2.84 (t, J=7.3Hz, 2H)；13C NMR(101MHz,DMSO)δ 165.16,162.76,149.45,147.16,141.15,138.08,132.68,129.14,128.50,127.39,121.92, (118.29,107.69,107.09,101.49,40.53,34.82.HRMS ESI) m/z calculated value [M-H]-353.1137, actual measurement Value 353.1129.
Embodiment 7
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -2,3- dihydrobenzo [b] [1,4] two It dislikes English -6- formamide (compound 7)
Embodiment 7a
(E) -3- (4- (2- (2,3- dihydrobenzo [b] [1,4] dioxin -6- formamide) ethyl) phenyl) methyl acrylate
With 2,3- dihydro-Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid and embodiment 2a for raw material, preparation method is the same as embodiment 2b.? Rate is 69%.1H NMR(400MHz,DMSO-d6) δ 8.37 (t, J=5.6Hz, 1H), 7.76-7.56 (m, 3H), 7.46-7.18 (m, 4H), 6.90 (d, J=8.1Hz, 1H), 6.59 (d, J=16.1Hz, 1H), 4.40-4.13 (m, 4H), 3.72 (s, 3H), 3.46 (td, J=5.6,7.2Hz, 2H), 2.85 (t, J=7.2Hz, 2H)；13C NMR(101MHz,DMSO)δ166.62, 165.21,145.79,144.33,142.76,142.43,131.85,129.16,128.28,127.52,120.42,116.93, 116.56,116.02,64.21,63.90,51.28,40.36,34.85.
Embodiment 7b
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -2,3- dihydrobenzo [b] [1,4] two Dislike English -6-
Formamide
Using embodiment 7a as raw material, preparation method is the same as embodiment 2c.Yield is 35%.187~189 DEG C of fusing point,1H NMR (400MHz,DMSO-d6) δ 8.39 (t, J=5.6Hz, 1H), 7.48 (d, J=7.9Hz, 2H), 7.42 (d, J=15.7Hz, 1H), 7.37-7.30 (m, 2H), 7.26 (d, J=7.9Hz, 2H), 6.90 (d, J=8.1Hz, 1H), 6.42 (d, J=15.8Hz, 1H), 4.32-4.23 (m, 4H), 3.45 (q, J=6.7Hz, 2H), 2.84 (t, J=7.3Hz, 2H)；13C NMR(101MHz, DMSO)δ165.20,162.68,145.78,142.76,141.15,137.96,132.69,129.13,127.53,127.37, (120.42,118.32,116.56,116.02,64.21,63.90,40.45,34.82.HRMS ESI) m/z calculated value [M-H]- 367.1294 measured value 367.1302.
Embodiment 8
(E) the fluoro- N- of -5- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) niacinamide (compound 8)
Embodiment 8a
(E) -3- (4- (2- (5- fluoro niacinamide) ethyl) phenyl) methyl acrylate
Using 5- fluorine nicotinic acid and embodiment 2a as raw material, preparation method is the same as embodiment 2b.Yield is 65%.1H NMR (400MHz,DMSO-d6) δ 8.87 (t, J=5.6Hz, 1H), 8.84 (t, J=1.8Hz, 1H), 8.74 (d, J=2.8Hz, 1H), 8.03 (ddd, J=9.6,2.9,1.7Hz, 1H), 7.76-7.54 (m, 3H), 7.31 (d, J=8.1Hz, 2H), 6.61 (d, J= 16.0Hz, 1H), 3.72 (s, 3H), 3.53 (dt, J=5.6,7.2Hz, 2H), 2.89 (t, J=7.2Hz, 2H)；19F NMR (376MHz,DMSO)δ-126.86；13C NMR(101MHz,DMSO)δ167.18,163.86,160.49,157.96,145.00, 144.96,144.87,142.65,140.69,140.47,132.52,132.09,132.06,129.76,128.91,122.23, 122.03,117.56,51.87,41.08,35.19.
Embodiment 8b
(E) the fluoro- N- of -5- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) niacinamide
Using embodiment 8a as raw material, preparation method is the same as embodiment 2c.Yield is 33%.189~190 DEG C of fusing point,1H NMR (400MHz,DMSO-d6) δ 10.74 (s, 1H), 9.07 (s, 1H), 8.88 (t, J=5.6Hz, 1H), 8.85 (s, 1H), 8.74 (d, J=2.8Hz, 1H), 8.04 (d, J=9.4Hz, 1H), 7.50 (d, J=7.8Hz, 2H), 7.43 (d, J=15.8Hz, 1H), 7.29 (d, J=7.8Hz, 2H), 6.42 (d, J=15.8Hz, 1H), 3.52 (q, J=6.8Hz, 2H), 2.88 (t, J=7.2Hz, 2H).19F NMR(376MHz,DMSO)δ-126.86；13C NMR(101MHz,DMSO)δ163.28,162.66,159.93, 157.39,144.44,144.40,140.82,140.12,139.90,137.98,132.78,131.54,131.51,129.18, (127.42,121.67,121.48,118.34,40.60,34.59.HRMS ESI) m/z calculated value [M+H]+330.1254, actual measurement Value 330.1261.
Embodiment 9
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) quinoline -6- formamide (compound 9)
Embodiment 9a
(E) -3- (4- (2- (quinoline -6- formamide) ethyl) phenyl) methyl acrylate
Using QUINOLINE-6-CARBOXYLIC ACID and embodiment 2a as raw material, preparation method is the same as embodiment 2b.Yield is 71%.1HNMR (400MHz,DMSO-d6) δ 8.99 (dd, J=4.2,1.7Hz, 1H), 8.85 (t, J=5.5Hz, 1H), 8.47 (td, J=4.2, 1.7Hz, 2H), 8.14 (dd, J=8.8,2.0Hz, 1H), 8.08 (d, J=8.8Hz, 1H), 7.71-7.57 (m, 4H), 7.33 (d, J=8.1Hz, 2H), 6.61 (d, J=16.1Hz, 1H), 3.72 (s, 3H), 3.57 (td, J=5.5,7.2Hz, 2H), 2.93 (t, J=7.2Hz, 2H)；13C NMR(101MHz,DMSO)δ166.63,165.63,151.88,148.52,144.34, 142.32,136.94,132.28,131.91,129.20,128.87,128.35,127.67,127.54,126.98,122.04, 116.95,51.30,40.58,34.82.
Embodiment 9b
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) quinoline -6- formamide
Using embodiment 9a as raw material, preparation method is the same as embodiment 2c.Yield is 38%.186~188 DEG C of fusing point,1H NMR (400MHz,DMSO-d6) δ 8.98 (dd, J=4.2,1.7Hz, 1H), 8.83 (t, J=5.6Hz, 1H), 8.51-8.43 (m, 2H), 8.15 (dd, J=8.8,1.9Hz, 1H), 8.07 (d, J=8.8Hz, 1H), 7.61 (dd, J=8.3,4.2Hz, 1H), 7.50 (d, J=7.8Hz, 2H), 7.43 (d, J=15.8Hz, 1H), 7.32 (d, J=7.8Hz, 2H), 6.42 (d, J= 15.8Hz, 1H), 3.62-3.52 (m, 2H), 2.92 (t, J=7.3Hz, 2H)；13C NMR(101MHz,DMSO)δ165.64, 162.70,151.86,148.53,141.05,137.98,136.92,132.76,132.33,129.18,128.86,127.66, (127.55,127.42,126.99,122.03,118.35,40.66,34.80.HRMS ESI) m/z calculated value [M-H]- 360.1348 measured value 360.1350.
Embodiment 10
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -1H- benzo [d] imidazoles -5- formyl Amine (compound 10)
Embodiment 10a
(E) -3- (4- (2- (1H- benzo [d] imidazoles -5- formamido) ethyl) phenyl) methyl acrylate
Using 1H- benzimidazole-5-carboxylic acid and embodiment 2a as raw material, preparation method is the same as embodiment 2b.Yield is 76%.1H NMR(400MHz,DMSO-d6) δ 12.71 (s, 1H), 8.54 (t, J=5.6Hz, 1H), 8.33 (s, 1H), 8.20-8.07 (m, 1H), 7.75-7.56 (m, 5H), 7.32 (d, J=7.9Hz, 2H), 6.60 (d, J=16.1Hz, 1H), 3.72 (s, 3H), 3.53 (q, J=6.8Hz, 2H), 2.95-2.87 (m, 2H)；13C NMR(101MHz,DMSO)δ167.75,166.62,166.58, 144.34,143.62,142.52,131.84,129.18,128.29,127.07,124.31,121.18,118.99,116.92, 109.53,51.27,40.50,34.93.
Embodiment 10b
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -1H- benzo [d] imidazoles -5- formyl Amine
Using embodiment 10a as raw material, preparation method is the same as embodiment 2c.Yield is 32%.179~181 DEG C of fusing point,1H NMR (400MHz,DMSO-d6) δ 12.68 (s, 1H), 10.74 (s, 1H), 9.03 (s, 1H), 8.54 (t, J=5.5Hz, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.72 (br, 1H), 7.62 (br, 1H), 7.49 (d, J=7.8Hz, 2H), 7.42 (d, J= 15.8Hz, 1H), 7.30 (d, J=7.8Hz, 2H), 6.42 (d, J=15.8Hz, 1H), 3.57-3.47 (m, 2H), 2.89 (t, J =7.3Hz, 2H)；HRMS (ESI) m/z calculated value [M-H]-349.1301 measured value 349.1306.
Embodiment 11
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -1H- pyrrolo- [2,3-b] pyridine - 3- formyl
Amine (compound 11)
Embodiment 11a
(E) -3- (4- (2- (1H- pyrrolo- [2,3-b] pyridine-3-carboxamide base) ethyl) phenyl) methyl acrylate
Using 7- azaindole -3- carboxylic acid and embodiment 2a as raw material, preparation method is the same as embodiment 2b.Yield is 61%.1H NMR(400MHz,DMSO-d6) δ 12.13 (s, 1H), 8.47 (dd, J=8.0,1.6Hz, 1H), 8.29 (d, J=4.7Hz, 1H), 8.18 (t, J=5.7Hz, 1H), 8.14 (d, J=2.5Hz, 1H), 7.68-7.61 (m, 3H), 7.32 (d, J=8.1Hz, 2H), 7.19 (dd, J=7.9,4.7Hz, 1H), 6.60 (d, J=16.1Hz, 1H), 3.72 (s, 3H), 3.54-3.49 (m, 2H), 2.90 (t, J=7.3Hz, 2H)
Embodiment 11b
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -1H- pyrrolo- [2,3-b] pyridine - 3- formyl
Amine
Using embodiment 11a as raw material, preparation method is the same as embodiment 2c.Yield is 27%.196~198 DEG C of fusing point,1H NMR (400MHz,DMSO-d6) δ 12.06 (s, 1H), 10.73 (s, 1H), 9.04 (s, 1H), 8.43 (dd, J=7.9,1.7Hz, 1H), 8.26 (dd, J=4.7,1.7Hz, 1H), 8.15-8.08 (m, 2H), 7.49 (d, J=7.7Hz, 2H), 7.42 (d, J= 15.8Hz, 1H), 7.30 (d, J=7.7Hz, 2H), 7.16 (dd, J=7.9,4.7Hz, 1H), 6.42 (d, J=15.8Hz, 1H), 3.49 (q, J=6.8Hz, 2H), 2.87 (t, J=7.3Hz, 2H)；13C NMR(101MHz,DMSO)δ163.79,162.69, 148.27,143.29,141.27,137.99,132.69,129.16,129.07,127.72,127.40,118.31,116.68, 109.48,35.26.HRMS (ESI) m/z calculated value [M-H]-349.1301 measured value 349.1293.
Embodiment 12, mtt assay cell inhibitory effect active testing
Cell in vitro proliferation inhibition test uses mtt assay, using following two cell line: human chronic myelogenous leukemia (CML) cell line k562, human tissue cell lymphoma cell U937.
K562 and U937 be suspension cell, with containing volume fraction be 10% fetal calf serum RPIM-1640 culture solution, 37 DEG C, volume fraction be 5% CO2Under the conditions of routine culture.
Concrete operations are as follows:
Firstly, it is 5mM/L that the compound (i.e. sample) that embodiment 1-26 is prepared is configured to compound concentration respectively DMSO (dimethyl sulfoxide) solution, then by the solution of acquisition through gradient dilution, a series of sample for obtaining concentration gradients is molten Liquid.
Then, the K562 cell or U937 cell of logarithmic growth phase, with 1.5 × 105The cell density of a/mL connects Kind is in 96 orifice plates, 99 holes μ L/, and then 1 μ L of sample solution is added in every hole, and making sample effect final concentration is respectively 0.01,0.05, 0.1,0.5,1,5,10,25,50 μM.Every kind of sample, each concentration set three multiple holes, and it is right that positive controls, feminine gender is arranged According to group and blank control group, wherein positive controls are separately added into positive control medicine histon deacetylase (HDAC) inhibitor SAHA and dnmt rna inhibitor SGI-027, the DMSO of negative control group addition and sample solution with concentration, blank pair Cell is not added according to group.MTT solution is added after acting on 72h, 10 holes μ L/ are centrifuged at 2000rpm, 4 DEG C after continuing culture 4 hours 5 minutes, dimethyl sulfoxide (DMSO) is added after sucking supernatant, 100 holes μ L/ keep the temperature about 10 minutes in 37 DEG C, then with micro vibration It swings device to vibrate about 5 minutes, makes crystallization dissolution completely, measure OD value at 490nm with microplate reader.
Cell proliferation inhibition rate (Inhibition Rate, IR%) is calculated as follows:
IR%=(negative control OD- sample OD)/(negative control OD- blank control OD) × 100%,
By calculating, the cell in vitro proliferation inhibition activity of compound prepared by the present invention is obtained, the results are shown in Table 1.Its In, IC50It is indicated greater than 50 μM with "-", IC50It is indicated greater than 10 μM and less than 50 μM with "+", IC50Greater than 5 μM and less than 10 μM It is indicated with " ++ ", IC50It is indicated greater than 1 μM less than 5 μM with " +++ ", IC50It is indicated less than 1 μM with " ++++".Test result shows Majority of compounds shows good anti-K562 and U937 cultivation effect, wherein 2,3,6 pairs of U937 Proliferation Abilities of compound IC50Less than 1 μM.
The tumor cell in vitro proliferation inhibition activity of the compound of 1 embodiment 1~11 of table preparation
Note: IC50Indicate half-inhibitory concentration.
Embodiment 13, the test of dnmt rna inhibitory activity
Using isotope labelling S-adenosylmethionine (3H-SAM) test compound turns DNA methyl in 100mM The inhibitory activity of enzyme (DNMT1, DNMT3A, DNMT3B) is moved, and with the dnmt rna inhibitor of reported in literature NSC319745 is compareed.Compound and corresponding a certain amount of dnmt rna hypotype are mixed in advance, are incubated at room temperature After 15min, be added artificial synthesized biotin labeling oligonucleotides substrate and3H-SAM simultaneously reacts 4h at room temperature.Then will Reaction system is transferred in the coated high pass orifice of Streptavidin, reacts at room temperature 1h.Radioactive activity passes through liquid scintillation Counting method obtains.By comparing the inhibitory activity for obtaining compound to enzyme with negative control group (no inhibitor group).Compound pair The results are shown in Table 2 for the inhibition percentage (%Inhibition) of different subtype dnmt rna enzyme.Showing of test result Closing object has certain inhibitory activity to dnmt rna, and different to different subtype rejection ability.Majority of compounds pair The inhibitory activity of DNMT1 is suitable with NSC319745 activity, and DNMT3A/3B inhibitory activity is weaker.Compound 9 is to DNMT3B's Inhibitory activity is better than the inhibitory activity to DNMT1/3A.Compound 10 is all larger than 30% to the inhibiting rate of three hypotypes, and right The inhibitory activity of DNMT3B is similar to compound N SC319745.Compound 4 shows strongest in listed compound DNMT1 inhibitory activity (inhibiting rate be greater than 60%), and to DNMT3B inhibiting rate nearly 50%, and it is weaker to DNMT3A inhibitory activity (inhibiting rate 23%).
The dnmt rna inhibitory activity of the compound of 2 embodiment 1~11 of table preparation
Embodiment 14, the test of histon deacetylase (HDAC) inhibitory activity
Using two hypotype HDAC1 and HDAC6 of histon deacetylase (HDAC) family as research object, compound is tested to group The inhibitory activity of albumen deacetylase, each compound set ten concentration gradients, three multiple holes, and the HDAC suppression to have listed Preparation SAHA is compareed.Compound is dissolved into reaction buffer first, certain volume is added later goes second containing histone The peptide buffer solution of trypsase and acetylation is added as reaction substrate in the buffer solution of acylase after incubation at room temperature 15 minutes To start deacetylation, while compound concentration and enzyme content being made to reach setting value, is incubated at room temperature after being gently mixed 60 seconds, Record the kinetic parameter reacted under certain exciting light and wavelength of transmitted light in 1 hour.By with negative control group (no inhibitor Group) compare the inhibitory activity for obtaining compound to enzyme, and compound is calculated, the half of histon deacetylase (HDAC) is inhibited Concentration (IC50), the results are shown in Table 3, wherein IC50It is indicated greater than 10nM and less than 100nM with "+", IC50Less than 10nM with "+ + " indicate.Test result shows all compounds to the half-inhibitory concentration (IC of HDAC1/650) it is less than 100nM, it shows to have Good HDAC1/6 inhibitory activity.IC of the compound 5,6,7,9,10 to HDAC1/650Inhibitory activity less than 10nM, with SAHA Quite.
The histon deacetylase (HDAC) inhibitory activity of the compound of 3 embodiment 1~11 of table preparation

Claims (13)

1. a kind of hydroxamic acid derivs or its pharmaceutically acceptable salt, hydroxamic acid derivs structural formula is as shown in formula I:
Wherein, Ar is aromatic group, and the aromatic group is selected from
N=1,2,3,4,5 or 6；
L1Link position be phenyl ring ortho position, meta or para position；L1It is straight for saturation or unsaturated carbon chains, the saturation selected from C1-C6 Alkane, the saturated alkane containing branch or substituent group of C1-C6, the unsaturated linear paraffin of C1-C6, C1-C6 containing branch or The unsaturated alkane of substituent group；
The compound of formula I is shown in following table:
2. hydroxamic acid derivs according to claim 1 or its pharmaceutically acceptable salt, wherein described pharmaceutically The salt of receiving is inorganic acid salt or acylate；
The inorganic acid salt is selected from the salt that any one following inorganic acid are formed: hydrochloric acid, sulfuric acid or phosphoric acid；
The acylate be selected from any one following organic acid formed salt: acetic acid, trifluoroacetic acid, malonic acid, citric acid and P-methyl benzenesulfonic acid.
3. the preparation side of -2 described in any item hydroxamic acid derivs or its pharmaceutically acceptable salt according to claim 1 Method comprising following steps:
1) under condensing agent effect, Formula II compound represented is reacted to obtain formula IV institute with formula III compound represented The compound shown；Or Formula II compound represented is prepared into corresponding acyl chlorides with thionyl chloride, oxalyl chloride or phosphorus oxychloride and is spread out It is reacted to obtain formula IV compound represented with formula III compound represented after biology；
Wherein, in, Ar is aromatic group, the aromatic group is selected from replace or non-substituted phenyl ring, replace or it is non-substituted Aromatic heterocycle, replace or non-substituted benzheterocycle, replace or non-substituted aromatic heterocycle and heterocycle；
N=1,2,3,4,5 or 6；
The link position of L1 is the ortho position of phenyl ring, meta or para position；L1 is saturation or unsaturated carbon chains；
R is the alkyl of C1-C4.
2) compound shown in formula IV is reacted in alkaline solution with azanol or hydroxylamine hydrochloride, obtains compound shown in Formulas I.
4. the preparation method according to requiring 3, in step 1), the condensing agent is selected from benzotriazole-N, N, N', N'- tetra- Methylurea hexafluorophosphoric acid ester N, N'- carbonyl dimidazoles, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3- dimethylamine Base propyl) one of -3- ethyl carbodiimide or a variety of.
5. the preparation method according to claim 4, wherein the step 1) condensing agent and Formula II compound represented, formula The molar ratio of III compound represented is followed successively by 1-4:1-2:1-4；
In above method step 2), the alkali be selected from ammonium hydroxide, triethylamine, diisopropyl ethyl amine, sodium hydroxide, potassium hydroxide, One of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide are a variety of；
The molar ratio that compound shown in formula IV is reacted with azanol or hydroxylamine hydrochloride, alkali is 1:1-10:1-20.
6. preparation method according to claim 5, wherein compound shown in formula IV is reacted with azanol or hydroxylamine hydrochloride, alkali Molar ratio be 1:5:5.
7. the purposes according to the power described in any item compounds of claim 1-2 or its pharmaceutically acceptable salt is it under State the application of aspect:
1) application in dnmt rna and/or histon deacetylase (HDAC) inhibitor is being prepared；
2) application in preparation eucaryote tumor cell proliferation inhibitor；Or
3) application in preparation prevention and/or tumor.
8. purposes according to claim 7, the dnmt rna includes hypotype in mammalian cells DNMT1, DNMT3A, DNMT3B；The histon deacetylase (HDAC) includes hypotype HDAC1 in mammalian cells, HDAC2, HDAC3, HDAC8, HDAC4, HDAC5, HDAC7, HDAC9, HDAC6, HDAC10, HDAC11；
The eucaryote is mammal；The tumour cell is cancer cell；The cancer cell is leukaemia cancer cell, mammary gland Cancer cell, liver cancer cells, pancreatic cancer cell, lung carcinoma cell, brain cancer cell, ovarian cancer cell, uterine cancer cells, carcinoma of testis are thin Born of the same parents, skin cancer cell, stomach cancer cell, nasopharyngeal carcinoma cell, colon cancer cell, bladder cancer cell or rectum cancer cell.
9. purposes according to claim 8, the cancer cell is that the chronic marrow original leukaemia cell of people and human tissue cell drench Bar oncocyte.
10. purposes according to claim 8, the leukaemia cancer cell is specially human chronic polymorpho nuclear leukemia cells system K562, the lymphoma cell are specially human tissue cell lymphoma cell U937, and the lung carcinoma cell is specially that human lung cancer is thin Born of the same parents NCI-H520, the human glioma cell are specially U251, and the black cancer cell is specially A375, and the colloid is female Cell carcinoma cells are specifically people's glioblastoma cells A172 and human brain astrocytes' blastoma cell U-118MG, described Cervical cancer cell is specially Human cervical cancer cell lines Hela, and the nasopharyngeal carcinoma cell is specially human nasopharyngeal epithelioma 1 CNE-2, described Liver cancer cells are specially HepG2 cell lines, and the breast cancer cell is specially human breast cancer cell line Bcap-37 and MDA- MB-231。
11. purposes according to claim 7, the tumour is cancer；The cancer is leukaemia, lymthoma, lung cancer, melanin Cancer, glioblastoma, cervical carcinoma, nasopharyngeal carcinoma, liver cancer, breast cancer, the cancer of the brain, cancer of pancreas, oophoroma, uterine cancer, carcinoma of testis, skin Skin cancer, gastric cancer, colon cancer, bladder cancer or the carcinoma of the rectum.
12. a kind of pharmaceutical composition, it comprises as the active constituent such as described in any item compounds of claim 1-2 or Its pharmaceutically acceptable salt and pharmaceutically acceptable auxiliaries.
13. pharmaceutical composition according to claim 12, dosage form be selected from injection, tablet, pulvis, granule, Capsule, oral solution, paste, creme.
CN201710212240.1A 2017-04-01 2017-04-01 Hydroxamic acid derivs and the preparation method and application thereof with dnmt rna and histon deacetylase (HDAC) inhibitory activity Active CN106977425B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710212240.1A CN106977425B (en) 2017-04-01 2017-04-01 Hydroxamic acid derivs and the preparation method and application thereof with dnmt rna and histon deacetylase (HDAC) inhibitory activity

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710212240.1A CN106977425B (en) 2017-04-01 2017-04-01 Hydroxamic acid derivs and the preparation method and application thereof with dnmt rna and histon deacetylase (HDAC) inhibitory activity

Publications (2)

Publication Number Publication Date
CN106977425A CN106977425A (en) 2017-07-25
CN106977425B true CN106977425B (en) 2019-07-19

Family

ID=59343619

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710212240.1A Active CN106977425B (en) 2017-04-01 2017-04-01 Hydroxamic acid derivs and the preparation method and application thereof with dnmt rna and histon deacetylase (HDAC) inhibitory activity

Country Status (1)

Country Link
CN (1) CN106977425B (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112390791B (en) * 2019-08-14 2023-08-01 复旦大学 DNA methyltransferase 1 fluorescent probe and application thereof
CN112480078B (en) * 2020-11-10 2022-01-04 清华大学深圳国际研究生院 A kind of quinazoline hydroxamic acid derivative and its preparation method and application
CN113831338B (en) * 2021-09-20 2022-12-20 中国海洋大学 Histone deacetylase inhibitor and preparation method and application thereof
CN114292226B (en) * 2021-11-29 2023-04-18 沈阳药科大学 Compound with hydroxamic acid structure and preparation method and application thereof
CN114478509B (en) * 2022-01-14 2023-06-16 河北大学 Five-membered heterocycle substituted benzamide compound and preparation method and application thereof
CN114890989B (en) * 2022-05-25 2024-03-22 广东晨康生物科技有限公司 HDAC8 degradation agent with nitrogenous derivative as Linker, preparation method and application thereof
WO2024156288A1 (en) * 2023-01-29 2024-08-02 Shanghai Kygent Pharmaceutical Co., Ltd Dnmt1 inhibitors, pharmaceutical compositions, and therapeutic applications
CN119490449B (en) * 2023-08-16 2025-11-21 沈阳药科大学 Hydroxamic acid compound containing N-benzyl-2- (5-phenylpyridin-2-yl) acetamide and preparation method and application thereof
CN119019328B (en) * 2024-08-16 2025-09-19 成都理工大学 Quinoline derivative containing hydroxamic acid fragment, and preparation method and application thereof

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003219595A1 (en) * 2002-04-11 2003-10-27 In2Gen Co., Ltd. Alpha,Beta-UNSATURATED HYDROXAMIC ACID DERIVATIVES AND THEIR USE AS HISTONE DEACETYLASE INHIBITORS
US20070167499A1 (en) * 2003-10-27 2007-07-19 A*Bio Pte Ltd. Biaryl linked hydroxamates: preparation and pharmaceutical applications
EP1915141A1 (en) * 2005-08-10 2008-04-30 Novartis AG Method of use of deacetylase inhibitors
RU2453536C2 (en) * 2007-10-22 2012-06-20 Оркид Рисерч Лабораториз Лимитед Histone deacetylase inhibitors
CN102898378A (en) * 2012-11-16 2013-01-30 江苏先声药业有限公司 Phthalazinone derivatives and application thereof
KR20140118575A (en) * 2013-03-29 2014-10-08 한미약품 주식회사 Novel hydroxamate derivative
JP2016147807A (en) * 2013-06-04 2016-08-18 日本理化学工業株式会社 Hydroxamic acid derivative and salt thereof
CN105985335B (en) * 2015-01-28 2018-06-08 成都地奥九泓制药厂 Hydroxamic acid compound, preparation method and its usage
CN104610166B (en) * 2015-03-10 2017-06-13 山东大学 Pyrimidine benzyl hydroxamic acid histone deacetylases inhibitor and preparation method and application

Also Published As

Publication number Publication date
CN106977425A (en) 2017-07-25

Similar Documents

Publication Publication Date Title
CN106977425B (en) Hydroxamic acid derivs and the preparation method and application thereof with dnmt rna and histon deacetylase (HDAC) inhibitory activity
CN106946792B (en) A kind of hydroxamic acid derivs of phthalazone and the preparation method and application thereof
JP7293560B2 (en) Aromatic vinyl or aromatic ethyl derivative, its production method, intermediate, drug composition and use
JP7254028B2 (en) Histone deacetylase (HDACS) inhibitors
ES2452868T3 (en) New histone deacetylase inhibitors based simultaneously on 1H-trisubstituted pyrroles and aromatic and heteroaromatic spacers
CN105481789B (en) A kind of indoleamine-2,3-dioxygenase inhibitor and preparation method thereof
CN111875582B (en) Quinoline hydroxamic acid derivative and preparation method and application thereof
EP3088397A1 (en) Compounds that abrogate the cell cycle g2 checkpoint for use in the treatment of cancer
CN102099036A (en) Compounds and methods for treating inflammatory and fibrotic disorders
WO2008113255A1 (en) Benzamide derivatives with anti-proliferative activity, pharmaceutical preparations thereof
TW200808763A (en) Novel compounds I
TW201825473A (en) Selective hdac1,2 inhibitors
CN112480078B (en) A kind of quinazoline hydroxamic acid derivative and its preparation method and application
JP2008525409A (en) Pyrazine and pyridine and their derivatives as therapeutic compounds
CN106883217B (en) Nucleoside base hydroxamic acid derivative compound and preparation method and application thereof
KR102214225B1 (en) 5-membered heterocyclic amide type WNT pathway inhibitor
CN101687798A (en) Process for the preparation of compositions for modulating a kinase cascade and methods of use thereof
WO2017152857A1 (en) Indoleamine-2,3-dioxygenase inhibitor containing nitrogen alkylated and arylated sulphoxide imines
CN107879975A (en) Histon deacetylase (HDAC) inhibitor and its application
CA2892927A1 (en) Use of maleimide derivatives for preventing and treating leukemia
TWI904095B (en) Small molecule inhibitors of acetyl coenzyme a synthetase short chain 2 (acss2)
CN117069696A (en) Double-target small molecule inhibitor and preparation method and application thereof
KR20250013158A (en) Hydroxyamide derivatives and uses thereof
CN107056754B (en) Inhibitors of the WNT pathway with embedded urea-like structures
CN112250672B (en) Nucleoside base derivative and preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant