CN110054619A - Novel diketopiperazine histone deacetylases inhibitor - Google Patents

Novel diketopiperazine histone deacetylases inhibitor Download PDF

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Publication number
CN110054619A
CN110054619A CN201810049921.5A CN201810049921A CN110054619A CN 110054619 A CN110054619 A CN 110054619A CN 201810049921 A CN201810049921 A CN 201810049921A CN 110054619 A CN110054619 A CN 110054619A
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methyl
base
alkyl
carbon atom
diketopiperazine
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陈新
高锦明
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Northwest A&F University
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Northwest A&F University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The invention belongs to medicinal chemistry arts; preventing and/or treating and the purposes in the histone deacetylase activity drug out of control for there are related disorders more particularly to a kind of novel diketopiperazine histone deacetylases inhibitor, preparation method, the pharmaceutical composition containing the histon deacetylase (HDAC) inhibitor and such inhibitor.

Description

Novel diketopiperazine histone deacetylases inhibitor
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a kind of novel diketopiperazine histone deacetylases suppression Preparation, preparation method, the pharmaceutical composition containing the histon deacetylase (HDAC) inhibitor and such inhibitor prevent in preparation And/or treatment and the purposes in the drug of histone deacetylase activity related disease out of control.
Background technique
The orderly transcriptional control of gene is the premise that body cell maintains normal function, if gene transcription regulation function is disorderly Disorderly, canceration may occur for cell.The acetylation of core histones and deacetylation and gene regulation are closely related, and are responsible for group egg Baiyi is acylated and deacetylation be the mutual antagonism of a pair of of function protease-acetylation of histone transferase (HATs) and group Albumen deacetylase (HDACs).HDACs is one group and adjusts in cyto-chromatin level, by induction DNA methylase inhibitor Control includes a series of biological effects such as chromatin recombination, transcription activating or inhibition, cell cycle, cell differentiation and Apoptosis Enzyme, it is especially related with the gene transcript expression regulation after cell activation.Histon deacetylase (HDAC) inhibitor passes through inhibition The activity of HDACs induces cell apoptosis, breaks up simultaneously Inhibit proliferaton, it is considered to be the anticancer drug target with development prospect.Mesh The research of preceding HDACs inhibitor is related to numerous tumor areas, such as hematological system, melanoma, breast cancer, oophoroma, prostate Cancer, lung cancer and colon cancer etc..
HDACs target spot is a kind of antitumor target with application prospect, and novel, effective HDACs inhibitor is still deposited In unsatisfied clinical demand, it would be desirable to generate new, selectable HDACs inhibitor is used to prevent and/or treat and group Albumen deacetylation enzymatic activity related disease out of control, especially tumor disease.
Summary of the invention
The object of the present invention is to provide it is a kind of it is novel, effectively using HDAC1 and HDAC6 as the inhibitor of target spot.
Technical scheme is as follows:
1, lead to the compound or its pharmaceutically acceptable salt of formula (I):
(I)
Wherein R1、R2、R3、R4Each independently represent hydrogen, alkyl, alkenyl, alkynyl, aralkyl, aryl or Het；
R5Selected from hydroxyl, can be optionally by one or more R6Substituted 2- aminophenyl, R6Can be hydrogen, alkyl, cyano, halogen, Halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl, aralkyl, aryl or Het；
Q1It is selected from aryl or Het, wherein aryl or Het each independently can be optionally by one or more R7Replace, R7It can be Hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl, aralkyl, diaryl alkane Base, aryl or Het；
Q2It is selected from aryl or Het, wherein aryl or Het each independently can be optionally by one or more R7Replace, R8It can be with It is hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl, aralkyl, diaryl Alkyl, aryl or Het；
Alkyl is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom；It or is the cyclic saturated hydrocarbon with 3-6 carbon atom Base；Or to connect the cyclic saturated hydrocarbon with 3-6 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom Base；
Alkoxy is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom；It or is the cyclic annular saturation with 3-6 carbon atom Alkyl；Or to connect the cyclic saturated hydrocarbon with 3-6 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom Base；Wherein each carbon atom is optionally substituted with an oxygen；
Alkylamino is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom；It or is the cyclic annular saturation with 3-6 carbon atom Alkyl；Or to connect the cyclic saturated hydrocarbon with 3-6 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom Base；Wherein each carbon atom is optionally replaced by NH atomic group；
Alkoxyalkyl is that alkoxy as defined above is connect with alkyl；
Alkenyl, the unsaturated alkyl containing double or triple bonds that alkynyl is the linear chain or branched chain with 1-6 carbon atom；
Aryl is the carbocyclic ring selected from phenyl, naphthalene, acenaphthenyl or tetralyl, is respectively optionally replaced by 1,2 or 3 substituent group, Each substituent group is independently selected from hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxy alkane Base, aralkyl, alkyl diaryl, aryl or Het；
Aralkyl, alkyl diaryl are that aryl as defined above is connect with alkyl；
Het is selected from pyrrole radicals, pyrazolyl, imidazole radicals, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole Base, pyridyl group, pyrimidine radicals, pyrazinyl or pyridazinyl monocyclic heterocycles；Or it is selected from quinolyl, quinoxalinyl, indyl, benzo miaow Oxazolyl, benzoxazolyl, benzo isoxazolyl, benzothiazolyl, benzisothia oxazolyl, benzofuranyl, benzothienyl, 2, The bicyclic heterocycle of 3- dihydrobenzo [1,4] dioxine base or benzo [1,3] dioxa cyclopentenyl；Or selected from 3-6 The bicyclic saturated hydrocarbyl of the monocyclic saturated hydrocarbon group base of carbon atom, 6-12 carbon atom, the carbon atom in middle ring is individually optionally by 1 ~4 O, S, N or NH replace；Each monocycle or it is bicyclic optionally replaced by 1,2 or 3 substituent group, each substituent group be independently selected from halogen, Halogenated alkyl, hydroxyl, alkyl or alkoxy；
Halogen be selected from fluorine, chlorine, bromine or iodine substituent group；
Halogenated alkyl is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom, or is full with the ring-type of 3-6 carbon atom And alkyl, or the cyclic annular saturation with 3-6 carbon atom for linear chain or branched chain saturated hydrocarbyl of the connection with 1-6 carbon atom Alkyl；Wherein one or more carbon atoms are optionally substituted with one or more halogen atoms.
2, the compound of claim 1, it is characterised in that:
Wherein R2、R3、R4Each independently represent hydrogen, alkyl, aryl or Het；
R1For hydrogen, alkyl, aralkyl, aromatic radical or Het；
R5 Selected from hydroxyl, can be optionally by one or more R6Substituted 2- aminophenyl, R6It can be hydrogen, alkyl, cyano, halogen Element, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl；
Q1It is selected from aryl or Het, wherein aryl or Het each independently can be optionally by one or more R7Replace, R7It can be Hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl；
Q2It is selected from aryl, wherein aryl can be optionally by one or more R8Replace, R8It can be hydrogen, alkyl, cyano, halogen, halogen Substituted alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl.
3, the compound of claim 2, it is characterised in that:
Wherein R2、R3、R4Each independently represent hydrogen, methyl, ethyl；
R1For hydrogen, alkyl, aralkyl；
R5Selected from hydroxyl, can be optionally by one or more R6Substituted 2- aminophenyl, R6It can be hydrogen, methyl, ethyl, 1~2 A halogen or trifluoromethyl；
Q1Selected from following aromatic rings or substituted aromatic rings: phenyl, naphthalene, pyrrole radicals, furyl, thienyl, pyridyl group, Pyrazinyl, pyrimidine radicals, substituent group can be methyl, ethyl, 1~2 halogen or trifluoromethyl；
Q2It is selected from phenyl.
4, the compound of claim 3, it is characterised in that:
Wherein R2、R3、R4Each independently represent hydrogen；
R1For hydrogen, methyl, allyl, Cvclopropvlmethvl, benzyl；
R5Selected from hydroxyl, can be optionally by one or more R6Substituted 2- aminophenyl, R6It can be hydrogen, fluorine atom；
Q1Be selected from following aromatic rings or substituted aromatic rings: phenyl, indyl, substituent group can be methyl, 1~2 halogen Element or trifluoromethyl；
Q2It is selected from phenyl.
5, the compound of claim 1, it is characterised in that be following compound:
(S)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -N(2- aminophenyl) benzene first Amide (I-1)
(S)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -N(2- amino -4- fluorobenzene Base) benzamide (I-2)
(R)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -N(2- aminophenyl) benzene Formamide (I-3)
(R)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -N(2- amino -4- fluorobenzene Base) benzamide (I-4)
(S)-N(2- aminophenyl) -4- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) benzamide (I-5)
(S)-N(2- amino -4- fluorophenyl) -4- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) benzamide (I-6)
(R)-N(2- aminophenyl) -4- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) benzamide (I-7)
(R)-N(2- amino -4- fluorophenyl) -4- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) benzamide (I-8)
(S)-N(2- aminophenyl) -3- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) benzamide (I-9)
(S)-N(2- amino -4- fluorophenyl) -3- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) benzamide (I-10)
(S)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -NHydroxybenzamide (I- 11)
(R)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -NHydroxybenzamide (I- 12)
(S) -4- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) -NHydroxybenzamide (I-13)
(R) -4- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) -NHydroxybenzamide (I-14)
(S) -3- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) -NHydroxybenzamide (I-15)
4- ((3- benzyl -4- methyl -2,5- diketopiperazine -1- base) methyl) -NHydroxybenzamide (I-16)
4- ((4- allyl -3- benzyl -2,5- diketopiperazine -1- base) methyl) -NHydroxybenzamide (I-17)
4- ((3,4- dibenzyl -2,5- dioxopiperazine -1- base) methyl) -NHydroxybenzamide (I-18)
4- ((3- benzyl -4- (Cvclopropvlmethvl) -2,5- dioxopiperazine -1- base) methyl) -NHydroxybenzamide (I-19)
The compound of the present invention the preparation method is as follows:
Route one
Route two
The compounds of this invention can be prepared with above-mentioned or similar above-mentioned preparation method, according to the difference of substituent group and be taken Corresponding raw material is selected for the difference of base location.
Pharmacology test result shows that compounds of formula I and its pharmaceutically acceptable salt have HDAC1 or HDAC6 There is excellent inhibitory activity, therefore, compound of Formula I and its pharmaceutically acceptable salt can be used for treating and above-mentioned target Related clinical disease.Disease related with HDAC1 and HDAC6 may be, but not limited to: lung cancer, melanoma, liver cancer, kidney Cancer, leukaemia, non-small cell lung cancer, prostate cancer, thyroid cancer, cutaneum carcinoma, cancer of pancreas, oophoroma, carcinoma of testis, breast cancer, Bladder cancer, gallbladder cancer, myelodysplastic syndrome, lymthoma, the cancer of the esophagus, thyroid follcular carcinoma, gastrointestinal cancer, maincenter or outer Tumour (such as astrocytoma, neuroblastoma, glioma or neurinoma), the celiothelioma, II of all nervous systems Type or Non-Insulin Dependent Diabetes Mellitus, autoimmune disease.
Here is partial pharmacologic test and result:
(1) target compound is to the measurement of HDAC inhibitory activity and result
Synthesized compound measures the inhibitory activity to HDAC, and and positive control with fluorescence resonance energy transfer (FRET) method Medicine compares, and filters out the preferable compound of activity.HDAC is obtained by purifying or directly purchase kit.
Specific method: enzyme is added in reacting hole, reaction buffer is added in control wells.It is added and is dissolved in reacting hole Sample in DMSO is incubated for using contactless nanoliter level sound wave liquor-transferring system.It is added in each reacting hole corresponding Fluorogenic substrate rotate concussion.30 °C of sealings are incubated for 1-2h.The color developing agent stopped reaction containing TMP26 is added, generates fluorescence.Make With EnVision multiple labeling micropore board detector (Perkin Elmer) fluorescence intensity (exciting light: 490nM, emit light: 520nM).Colour developing reads endpoint value after reaching stable.Using 4 software of GraphPad Prism carry out percentage (relative to DMSO control group) and half inhibiting rate calculating.
Inhibitory activity result of the part of compounds to HDAC1
Embodiment HDAC1(IC50, nM) Embodiment HDAC1(IC50, nM)
I-1 405 I-7 2850
I-3 219 chidamide 310
I-5 1500
Inhibitory activity result of the part of compounds to HDAC6
Embodiment HDAC6(IC50, nM) Embodiment HDAC6(IC50, nM)
I-11 6.64 I-16 4.56
I-12 5.58 I-17 9.23
I-13 17.5 I-18 8.25
I-14 8.62 I-19 6.21
I-15 4190 ACY-1215 6.84
(2) in vitro antitumor activity assay of target compound
This experiment is using CTG method measurement compound to the inhibiting effect of leukemia cell line HL60 and K562.
Experimental method: it collects the cell in exponential phase of growth and carries out viable count.Keynote is accordingly cultivated with each cell Whole concentration of cell suspension.Every hole adds 90 μ L cell suspensions in 96- porocyte culture plates.Dissolving each test compound with DMSO is 10mM or 5mM storing liquid.Then 10 times of solution, each 2 multiple holes are diluted to culture medium respectively.Every plant of cell per well is separately added into 10 The corresponding 10 times of solution of μ L, final drug concentration are 10 μM or 25 μM, and DMSO final concentration is respectively that 0.1% ~ 0.5%(is shown in compound Preparation method and sample-adding design: the design of experiment orifice plate sample-adding).It is placed in 37oC, 5% CO272h is cultivated in incubator.Drug-treated 72h Afterwards, 50 μ L(1/2 volume of culture are added in every hole) the CTG solution that melts and equilibrate in advance room temperature, it is mixed with microwell plate oscillator 2min measures fluorescence signal value with Envision2104 plate reader after being placed at room temperature for 10min.Cell inhibitory rate formula: (1- Vsample/Vvehicle control× 100%) it calculates.Wherein VsampleFor the average value of drug-treated group, Vvehicle controlFor solvent The average value of control group.
Antiproliferative activity result (IC of the part of compounds to two kinds of tumor cell lines50, μM)
Embodiment HL60 K562
I-1 4.156 4.227
I-3 2.743 2.884
I-11 2.753 2.593
I-12 0.254 0.452
I-16 0.163 0.487
Chidamide 3.684 4.252
Specific embodiment:
Embodiment 1
(S)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -N(2- aminophenyl) benzene first Amide
Step a:4- ((3- ((1HIndol-3-yl) methyl) -2,5- dioxopiperazine -1- base) methyl) methyl benzoate system It is standby
It is sequentially added in 500mL eggplant-shape bottleLTryptophan methyl ester hydrochloride (25.47g, 0.1mol), di-tert-butyl dicarbonate (13.1g, 60mmol), acetonitrile 250mL, ice bath are cooled to 0 DEG C, and chloracetyl chloride (8mL, 0.1mol) is slowly added portionwise, finishes, The reaction was continued 1h, TLC detect fully reacting, add paraaminomethyl benzoic acid methyl ester hydrochloride (20.17 g, 0.1 mol), It is heated to reflux 6h, TLC detects fully reacting.It is concentrated under reduced pressure, is added 10% column chromatography silica gel (5.5 g), 200mL acetonitrile flowed back Night.Fully reacting, decompression boil off solvent, and residue separates (petroleum ether: ethyl acetate=1:4) with silica gel column chromatography, obtains white Solid (31.5g, 80.5%).1H-NMR (500 MHz, DMSO-d 6) δ: 10.98 (s, 1H), 8.40 (s, 1H), 7.78 (d, J = 8.22 Hz, 2H), 7.56 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.11 (t, J = 7.2 Hz, 1H), 7.06 (s, 1 H), 7.00 (t, J = 7.1 Hz, 1H), 6.96 (d, J = 8.1 Hz, 2H), 4.44 (d, J = 15.2 Hz, 1H), 4.28 (d, J = 15.2 Hz 2H), 3.87 (s, 3H), 3.50 – 3.36 (m, 2H), 3.07 (dd, J = 14.4, 4.1 Hz, 1H), 2.75 (t,J = 13.6 Hz, 1H).
Step b:(S)-4-((3-((1HIndol-3-yl) methyl) -2,5- dioxopiperazine -1- base) methyl) benzoic acid system It is standby
4- ((3- ((1 is added in the mono- neck bottle of 100mLHIndol-3-yl) methyl) -2,5- dioxopiperazine -1- base) methyl) benzene Methyl formate (391.4 mg, 1mmol), sodium hydroxide (160mg, 4mmol), water 1mL, methanol 25mL, tetrahydrofuran 25mL, often Temperature is stirred overnight, and TLC tracks fully reacting, stops heating, PH is adjusted under condition of ice bath to neutrality, suction filtration dries to obtain white solid 310.6mg yield 82.3%.ESI-MS m/z: 400.4 [M+Na]+.
Step c:(S)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -N(2- aminobenzene Base) benzamide preparation
Sequentially added in the mono- neck bottle of 50mL (S)-4-((3-((1HIndol-3-yl) methyl) -2,5- dioxopiperazine -1- base) Methyl) benzoic acid (100 mg, 0.265 mmol), HATU(93.6 mg, 0.292 mmol), DIPEA(0.184 mL, 1.06 mmol), 1,2- phenylenediamine (28.66 mg, 0.265 mmol) is added after stirring 30min under room temperature in DMF 25mL, Continue to stir 6h to fully reacting, water 100mL is added in reaction solution, is extracted with ethyl acetate (100mL × 3), collects organic Phase, anhydrous magnesium sulfate dry, filter, and obtain filtrate, and silica gel column chromatography (EA:MeOH=50:3) obtains 70 mg of white solid, yield 56.5%, m.p.: 145~147 °C. 1H-NMR (500 MHz, DMSO-d 6) δ:10.98 (s, 1H), 9.60 (s, 1H), 8.38 (s, 1H), 7.82 (d, J = 7.9 Hz, 2H), 7.57 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H), 7.07 (d, J = 1.7 Hz, 1H), 7.05 – 6.94 (m, 4H), 6.80 (d, J = 7.2 Hz, 1H), 6.62 (t,J = 7.3 Hz, 1H), 4.92 (s, 2H), 4.35 (dd, J = 34.5, 16.4 Hz, 3H), 3.45 – 3.38 (m, 2H), 3.08 (dd, J = 14.4, 4.0 Hz, 1H), 2.76 (d, J = 17.1 Hz, 1H). 13C NMR (126 MHz, DMSO-d 6) δ: 166.69, 165.60, 165.17, 143.54, 139.73, 136.52, 134.24, 128.45, 127.99, 127.93, 127.09, 126.95, 125.20, 123.84, 121.54, 119.22, 119.03, 116.78, 116.63, 111.82, 108.60, 56.18, 49.01, 48.49, 30.09.
Embodiment 2
(S)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -N(2- amino -4- fluorobenzene Base) benzamide
WithLTryptophan methyl ester hydrochloride, fluoro- 1, the 2- phenylenediamine of 4- are raw material, and target is made with the method for being similar to embodiment 1 Compound, obtain white solid (S)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -N- (2- amino -4- fluorophenyl) benzamide, yield 61.2%; m.p.: 198~200 °C. 1H-NMR (500 MHz, DMSO-d 6) δ: 10.99 (s, 1H), 9.54 (s, 1H), 8.39 (s, 1H), 7.82 (d, J = 7.9 Hz, 2H), 7.57 (d, J = 7.9, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.12 (dd, J 14.8, 7.7 Hz, 2H), 7.07 (d, J = 1.6 Hz, 1H), 7.02 (t, J = 7.7 Hz, 3H), 6.56 (dd, J = 11.2, 2.6 Hz, 1H), 6.45 – 6.32 (m, 1H), 5.25 (s, 2H), 4.39 (d, J = 15.0 Hz, 1H), 4.31 (d, J = 14.9 Hz, 2H), 4.06 (m, 1H), 3.43 – 3.38 (m, 1H), 3.08 (dd, J = 14.4, 4.1 Hz, 1H), 2.75 (d, J = 17.1 Hz, 1H). 13C NMR (126 MHz, DMSO-d 6) δ: 166.69, 165.85, 165.17, 160.58, 145.90, 139.75, 136.51, 134.10, 128.97, 128.47, 127.97, 127.92, 125.21, 121.54, 119.76, 119.21, 119.02, 111.82, 108.58, 102.53, 101.96, 56.17, 48.98, 48.17, 30.09.
Embodiment 3
(R)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -N(2- aminophenyl) benzene first Amide
WithRTryptophan methyl ester hydrochloride, 1,2- phenylenediamine are raw material, and preparation method such as embodiment 1 obtains white solid, yield 71.6%。Mp: 210-212°C;1H-NMR (500 MHz, DMSO-d 6) δ:10.98 (s, 1H), 9.60 (s, 1H), 8.38 (s, 1H), 7.82 (d, J = 7.9 Hz, 2H), 7.57 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H), 7.07 (d, J = 1.7 Hz, 1H), 7.05 – 6.94 (m, 4H), 6.80 (d, J = 7.2 Hz, 1H), 6.62 (t, J = 7.3 Hz, 1H), 4.92 (s, 2H), 4.35 (dd, J = 34.5, 16.4 Hz, 3H), 3.45 – 3.38 (m, 2H), 3.08 (dd, J = 14.4, 4.0 Hz, 1H), 2.76 (d, J = 17.1 Hz, 1H). 13C NMR (126 MHz, DMSO-d 6) δ: 166.69, 165.60, 165.17, 143.54, 139.73, 136.52, 134.24, 128.45, 127.99, 127.93, 127.09, 126.95, 125.20, 123.84, 121.54, 119.22, 119.03, 116.78, 116.63, 111.82, 108.60, 56.18, 49.01, 48.49, 30.09.
Embodiment 4
(R)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -N(2- amino -4- fluorobenzene Base) benzamide
WithRTryptophan methyl ester hydrochloride, fluoro- 1, the 2- phenylenediamine of 4- are raw material, and preparation method such as embodiment 1 obtains white solid, Yield 60.5%; Mp: 214-216°C;1H-NMR (500 MHz, DMSO-d 6) δ: 10.99 (s, 1H), 9.54 (s, 1H), 8.39 (s, 1H), 7.82 (d, J = 7.9 Hz, 2H), 7.57 (d, J = 7.9, 1H), 7.40 (d,J = 8.1 Hz, 1H), 7.12 (dd, J 14.8, 7.7 Hz, 2H), 7.07 (d, J = 1.6 Hz, 1H), 7.02 (t, J = 7.7 Hz, 3H), 6.56 (dd, J = 11.2, 2.6 Hz, 1H), 6.45 – 6.32 (m, 1H), 5.25 (s, 2H), 4.39 (d, J = 15.0 Hz, 1H), 4.31 (d, J = 14.9 Hz, 2H), 4.06 (m, 1H), 3.43 – 3.38 (m, 1H), 3.08 (dd, J = 14.4, 4.1 Hz, 1H), 2.75 (d, J = 17.1 Hz, 1H). 13C NMR (126 MHz, DMSO-d 6) δ: 166.69, 165.85, 165.17, 160.58, 145.90, 139.75, 136.51, 134.10, 128.97, 128.47, 127.97, 127.92, 125.21, 121.54, 119.76, 119.21, 119.02, 111.82, 108.58, 102.53, 101.96, 56.17, 48.98, 48.17, 30.09.
Embodiment 5
(S)-N(2- aminophenyl) -4- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) benzamide
WithLPhenylalanine methyl ester hydrochloride, 1,2- phenylenediamine, paraaminomethyl benzoic acid methyl ester hydrochloride are raw material, preparation method As embodiment 1 obtains white solid, yield 75.3%; Mp: 203-205°C; m.p.: 172~174 °C. 1H-NMR (500 MHz, DMSO-d 6) δ: 9.70 (s, 1H), 8.40 (s, 1H), 7.96 (d, J = 6.8 Hz, 2H), 7.31 – 7.18 (m, 6H), 7.14 (d, J = 6.3 Hz, 2H), 7.01 (t, J = 6.9 Hz, 1H), 6.83 (d, J = 7.1 Hz, 1H), 6.64 (t, J = 6.7, 1H), 4.94 (s, 2H), 4.66 (d, J = 14.8 Hz, 1H), 4.33 (d, J = 6.1 Hz, 2H), 3.54 (d, J = 17.2 Hz, 1H), 3.21 (d, J = 13.3 Hz, 1H), 3.06 – 2.89 (m, 1H), 2.80 (d, J = 17.2 Hz, 1H). 13C NMR (126 MHz, DMSO-d 6) δ: 166.04, 165.51, 165.28, 143.66, 139.69, 136.11, 134.32, 130.57, 128.62, 128.45, 127.32, 127.23, 127.01, 123.77, 116.75, 116.61, 56.06, 48.94, 48.67, 39.53.
Embodiment 6
(S)-N(2- amino -4- fluorophenyl) -4- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) benzamide
WithLPhenylalanine methyl ester hydrochloride, fluoro- 1, the 2- phenylenediamine of 4- are raw material, and preparation method such as embodiment 1 obtains white solid Body, yield 66.8%; m.p.: 175~177 °C. 1H-NMR (500 MHz, DMSO-d 6) δ: 9.62 (s, 1H), 8.40 (s, 1H), 7.95 (d, J = 6.1 Hz, 2H), 7.33 – 7.19 (m, 5H), 7.15 (s, 3H), 6.58 (d, J = 10.9 Hz, 1H), 6.39 (s, 1H), 5.26 (s, 2H), 4.65 (d, J = 14.7 Hz, 1H), 4.34 (d, J = 12.9 Hz, 2H), 3.53 (d, J = 17.2 Hz, 1H), 3.21 (d, J = 13.1 Hz, 1H), 2.96 (d, J = 13.0 Hz, 1H), 2.80 (d, J = 17.2 Hz, 1H). 13C NMR (126 MHz, DMSO-d 6) δ: 166.03, 165.78, 165.27, 160.60, 146.00, 139.72, 136.12, 134.20, 130.56, 129.08, 128.62, 128.48, 128.40, 127.33, 119.72, 102.52, 101.94, 56.06, 48.94, 48.66, 39.53.
Embodiment 7
(R)-N(2- aminophenyl) -4- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) benzamide
WithRPhenylalanine methyl ester hydrochloride, 1,2- phenylenediamine, paraaminomethyl benzoic acid methyl ester hydrochloride are raw material, preparation method Such as embodiment 1, white solid, yield 85.7% are obtained.m.p.: 168~170 °C. 1H-NMR (500 MHz, DMSO-d 6) δ: 9.69 (s, 1H), 8.40 (s, 1H), 7.96 (d, J = 6.9 Hz, 2H), 7.35 – 7.18 (m, 6H), 7.14 (d, J = 6.3 Hz, 2H), 7.01 (t, J = 7.0 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.65 (d, J = 6.9 Hz, 1H), 4.93 (s, 2H), 4.66 (d, J = 14.7 Hz, 1H), 4.33 (d, J = 4.4 Hz, 2H), 3.54 (d, J = 17.2 Hz, 1H), 3.28 – 3.11 (m, 1H), 3.07 – 2.87 (m, 1H), 2.80 (d, J = 17.2 Hz, 1H). 13C NMR (126 MHz, DMSO-d 6) δ: 166.03, 165.51, 165.28, 143.66, 139.69, 136.11, 134.32, 130.57, 128.62, 128.45, 127.32, 127.23, 123.77, 116.74, 116.61, 56.06, 48.94, 48.67, 39.53.
Embodiment 8
(R)-N(2- amino -4- fluorophenyl) -4- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) benzamide
WithRPhenylalanine methyl ester hydrochloride, fluoro- 1, the 2- phenylenediamine of 4- are raw material, and preparation method such as embodiment 1 obtains white solid Body, yield 77.2%.M.p.: 155~157 °C. 1H-NMR (500 MHz, DMSO-d 6) δ: 9.69 (s, 1H), 8.40 (s, 1H), 7.96 (d, J = 6.9 Hz, 2H), 7.35 – 7.18 (m, 6H), 7.14 (d, J = 6.3 Hz, 2H), 7.01 (t, J = 7.0 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.65 (d, J = 6.9 Hz, 1H), 4.93 (s, 2H), 4.66 (d, J = 14.7 Hz, 1H), 4.33 (d, J = 4.4 Hz, 2H), 3.54 (d, J = 17.2 Hz, 1H), 3.28 – 3.11 (m, 1H), 3.07 – 2.87 (m, 1H), 2.80 (d, J = 17.2 Hz, 1H). 13C NMR (126 MHz, DMSO-d 6) δ: 166.04, 165.78, 165.26, 160.60, 145.98, 139.72, 136.13, 134.20, 130.56, 129.06, 128.61, 128.47, 128.40, 127.32, 119.73, 102.52, 101.94, 56.07, 48.94, 48.67, 39.54.
Embodiment 9
(S)-N(2- aminophenyl) -3- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) benzamide
WithLPhenylalanine methyl ester hydrochloride, 1,2- phenylenediamine, amino-methyl benzoic acid methyl ester hydrochloride are method for preparing raw material Such as embodiment 1, white solid, yield 56.3% are obtained.M.p.: 174~176 °C. 1H-NMR (500 MHz, DMSO-d6) δ: 9.74 (s, 1H), 8.37 (s, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.86 (s, 1H), 7.49 (t,J = 7.6 Hz, 1H), 7.34 (d, J = 7.4 Hz, 1H), 7.28 – 7.12 (m, 4H), 7.09 (d, J = 7.1 Hz, 2H), 7.01 (t, J = 7.3 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 6.63 (t, J = 7.3 Hz, 1H), 4.93 (s, 2H), 4.66 (d, J = 14.4 Hz, 1H), 4.31 (d, J = 14.1, 2H), 3.53 (d, J = 17.2, 1H), 3.19 (dd, J = 13.4, 3.6 Hz, 1H), 2.94 (d, J = 4.9 Hz, 1H), 2.70 (d, J = 17.3 Hz, 1H). 13C NMR (126 MHz, DMSO-d 6) δ: 166.00, 165.70, 165.39, 143.69, 136.50, 135.98, 131.81, 130.53, 128.94, 128.59, 128.54, 127.42, 127.24, 127.21, 127.05, 123.73, 116.76, 116.63, 60.25, 56.02, 48.82, 36.27.
Embodiment 10
(S)-N(2- amino -4- fluorophenyl) -3- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) benzamide
Preparation method such as embodiment 1, obtains white solid, yield 71.6%.M.p.: 123~125 °C. 1H-NMR (500 MHz, DMSO-d6) δ: 9.69 (s, 1H), 8.40 (s, 1H), 7.96 (d, J = 6.9 Hz, 2H), 7.35 – 7.18 (m, 6H), 7.14 (d, J = 6.3 Hz, 2H), 7.01 (t, J = 7.0 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.65 (d, J = 6.9 Hz, 1H), 4.93 (s, 2H), 4.66 (d, J = 14.7 Hz, 1H), 4.33 (d, J = 4.4 Hz, 2H), 3.54 (d, J = 17.2 Hz, 1H), 3.28 – 3.11 (m, 1H), 3.07 – 2.87 (m, 1H), 2.80 (d, J = 17.2 Hz, 1H). 13C NMR (126 MHz, DMSO-d 6) δ: 166.00, 165.39, 162.80, 160.63, 146.00, 136.47, 135.98, 135.28, 131.81, 130.53, 129.05, 128.92, 128.58, 128.54, 127.45, 127.24, 119.68, 102.57, 101.97, 60.25, 56.02, 48.82, 36.27.
Embodiment 11
(S)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -NHydroxybenzamide
Sequentially added in the mono- neck bottle of 50mL (S)-4-((3-((1HIndol-3-yl) methyl) -2,5- dioxopiperazine -1- base) Methyl) benzoic acid (100 mg, 0.265 mmol), HATU(93.6 mg, 0.292 mmol), DIPEA(0.184 mL, 1.06 mmol), DMF 25mL is added under room temperature after stirring 30minO-(oxinane -2- base) azanol (31 mg, 0.265 Mmol), continue to stir 6h to fully reacting, water 100mL is added in reaction solution, is extracted with ethyl acetate (100mL × 3), receives Collect organic phase, be concentrated under reduced pressure, direct plunges into next step.Concentrate obtained by previous step is added in 25mL eggplant-shape bottle, is added to first Benzene sulfonic acid sulfuric monohydrate (10mg, 0.05mmol), is stirred overnight, and silica gel column chromatography obtains 70 mg of white solid, and two steps are always received Rate 56.4%,1H-NMR (500 MHz, DMSO-d 6) δ: 11.32 (s, 1H), 9.12 (s, 1H), 8.40 (s, 1H), 7.71 (d, J = 7.0 Hz, 1H), 7.66 (s, 1H), 7.53 (d, J = 7.1 Hz, 2H), 7.41 (t, J = 7.1 Hz, 1H), 7.28 (d, J = 6.5 Hz, 1H), 7.15 (s, 1H), 7.10 (s, 1H), 7.06 (s, 1H), 4.61 (d, J = 14.4 Hz, 1H), 4.26 (d, J 15.2 Hz, 2H), 3.50 (d, J = 17.2 Hz, 1H), 3.17 (d, J = 13.1 Hz, 1H), 2.93 (d, J = 13.4 Hz, 1H), 2.65 (d, J = 17.2 Hz, 1H). 13C NMR (126 MHz, DMSO-d 6) δ: 166.64, 165.11, 145.91, 138.30, 136.48, 128.60, 127.97, 127.57, 126.01, 125.19, 121.48, 119.20, 118.97, 111.83, 108.50, 56.14, 49.01, 48.42, 30.05.
Embodiment 12
(R)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -NHydroxybenzamide
With (R)-4-((3-((1HIndol-3-yl) methyl) -2,5- dioxopiperazine -1- base) methyl) benzoic acid be raw material, use White solid, yield 48% is made similar to the method for embodiment 11;1H-NMR (500 MHz, DMSO-d 6) δ: 11.36 (s, 1H), 9.12 (s, 1H), 8.50 (s, 1H), 7.81 (d, J = 7.0 Hz, 1H), 7.66 (s, 1H), 7.55 (d, J = 7.1 Hz, 2H), 7.41 (t, J = 7.1 Hz, 1H), 7.38 (d, J = 6.5 Hz, 1H), 7.15 (s, 1H), 7.10 (s, 1H), 7.06 (s, 1H), 4.71 (d, J = 14.4 Hz, 1H), 4.26 (d,J 15.2 Hz, 2H), 3.50 (d, J = 17.2 Hz, 1H), 3.27 (d, J = 13.1 Hz, 1H), 2.93 (d, J = 13.4 Hz, 1H), 2.65 (d, J = 17.2 Hz, 1H). 13C NMR (126 MHz, DMSO-d 6) δ: 166.64, 165.11, 145.91, 137.30, 135.48, 129.60, 128.97, 127.57, 126.01, 125.19, 121.48, 119.20, 118.97, 111.83, 107.50, 55.14, 49.01, 48.42, 30.05.
Embodiment 13
(S) -4- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) -NHydroxybenzamide
With (S) -4- ((3- benzyl -2,5- dioxopiperazine -1- base) methyl) benzoic acid is raw material, with being similar to embodiment 11 Method obtains white solid, yield 57.1%; m.p.: 224~226°C. 1H-NMR (500 MHz, DMSO-d 6) δ: 11.28 (s, 1H), 9.09 (s, 1H), 8.41 (s, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.16 (m, 5H), 7.09 (d, J = 7.2 Hz, 2H), 4.65 (d, J = 14.7 Hz, 1H), 4.31 (d, J = 2.2 Hz, 1H), 4.23 (d, J = 14.7 Hz, 1H), 3.51 (d, J = 17.2 Hz, 1H), 3.17 (d, J = 3.9 Hz, 1H), 2.94 (dd, J = 13.5, 4.8 Hz, 1H), 2.70 (d,J 17.2 Hz, 1H). 13C NMR (126 MHz, DMSO-d 6) δ: 166.00, 165.27, 145.98, 138.25, 136.03, 130.55, 128.57, 128.54, 127.46, 127.26, 126.01, 56.01, 49.08, 48.91, 48.67。
Embodiment 14
(R) -4- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) -NHydroxybenzamide
With (S) -4- ((3- benzyl -2,5- dioxopiperazine -1- base) methyl) benzoic acid is raw material, with being similar to embodiment 11 Method obtains white solid, yield 55%; m.p.: 205~207 °C. 1H-NMR (500 MHz, DMSO-d 6) δ: 11.32 (s, 1H), 9.12 (s, 1H), 8.40 (s, 1H), 7.71 (d, J = 7.0 Hz, 1H), 7.66 (s, 1H), 7.53 (d, J = 7.1 Hz, 2H), 7.41 (t, J = 7.1 Hz, 1H), 7.28 (d, J = 6.5 Hz, 1H), 7.15 (s, 1H), 7.10 (s, 1H), 7.06 (s, 1H), 4.61 (d, J = 14.4 Hz, 1H), 4.26 (d,J = 15.2 Hz, 2H), 3.50 (d, J = 17.2 Hz, 1H), 3.17 (d, J = 13.1 Hz, 1H), 2.93 (d, J = 13.4 Hz, 1H), 2.65 (d, J = 17.2 Hz, 1H). 13C NMR (126 MHz, DMSO-d 6) δ: 165.99, 165.28, 164.44, 139.40, 136.02, 132.43, 130.55, 128.58, 128.55, 127.53, 127.27, 56.01, 49.09, 48.93, 48.68.
Embodiment 15
(S) -3- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) -NHydroxybenzamide
With (S) -3- ((3- benzyl -2,5- dioxopiperazine -1- base) methyl) benzoic acid is raw material, with being similar to embodiment 11 White solid, yield 49% is made in method; m.p.: 215~217 °C. 1H-NMR (500 MHz, DMSO-d 6) δ: 11.28 (s, 1H), 9.09 (s, 1H), 8.41 (s, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.16 (m, 5H), 7.09 (d, J = 7.2 Hz, 2H), 4.65 (d, J = 14.7 Hz, 1H), 4.31 (d, J = 2.2 Hz, 1H), 4.23 (d, J = 14.7 Hz, 1H), 3.51 (d, J = 17.2 Hz, 1H), 3.17 (d, J = 3.9 Hz, 1H), 2.94 (dd, J = 13.5, 4.8 Hz, 1H), 2.70 (d,J 17.2 Hz, 1H). 13C NMR (126 MHz, DMSO-d 6) δ: 166.00, 165.27, 145.98, 138.25, 136.03, 130.55, 128.57, 128.54, 127.46, 127.26, 126.01, 56.01, 49.08, 48.91, 48.67。
Embodiment 16
4- ((3- benzyl -2,5- dioxopiperazine -1- base) methyl) -NHydroxybenzamide
The preparation of step a:4- ((3- benzyl -4- methyl -2,5- dioxopiperazine -1- base) methyl) methyl benzoate
Be added in 100mL eggplant-shape bottle (S) -4- ((3- benzyl -2,5- dioxopiperazine -1- base) methyl) methyl benzoate (352.39mg, 1mmol), ice bath are cooled to 0 DEG C, are slowly added to sodium hydrogen (24mg, 1mmol), and after stirring 15min, iodine is added Methane (141.94mg, 1mmol), is refluxed overnight.TLC detects fully reacting, and ethyl alcohol quenching reaction is added, and silica gel column chromatography obtains White solid, yield 67%;1H NMR (500 MHz, DMSO) δ 7.96 (d, J = 7.0 Hz, 2H), 7.36 (d,J = 7.1 Hz, 2H), 7.20 (d, J = 6.8 Hz, 1H), 7.07 (t, J = 6.7 Hz, 2H), 6.97 (d,J = 6.8 Hz, 2H), 4.58 (d, J = 14.6 Hz, 1H), 4.41 (s, 1H), 4.33 (d, J = 14.5 Hz, 1H), 3.89 (s, 3H), 3.47 (d, J = 17.1 Hz, 1H), 3.18 (d, J = 12.9 Hz, 1H), 3.10 (d, J = 12.9 Hz, 1H), 2.96 (s, 3H), 2.35 (d, J = 17.1 Hz, 1H)。
The preparation of step b:4- ((3- benzyl -2,5- dioxopiperazine -1- base) methyl) benzoic acid
It is real with being similar to 4- ((3- benzyl -4- methyl -2,5- dioxopiperazine -1- base) methyl) methyl benzoate for raw material White solid, yield 91% is made in the method applied in 1 step b of example; ESIMS: [M+Na]+ : 375.4。
Step c:4- ((3- benzyl -2,5- dioxopiperazine -1- base) methyl) -NThe preparation of hydroxybenzamide
With 4- ((3- benzyl -2,5- dioxopiperazine -1- base) methyl) benzoic acid,O-(oxinane -2- base) azanol (31 Mg, 0.265 mmol) it is raw material, it is prepared with the method being similar in embodiment 11, obtains white solid, yield 56.1H NMR (500 MHz, DMSO) δ 7.96 (d, J = 7.0 Hz, 2H), 7.36 (d, J = 7.1 Hz, 2H), 7.20 (d, J = 6.8 Hz, 1H), 7.07 (t, J = 6.7 Hz, 2H), 6.97 (d, J = 6.8 Hz, 2H), 4.58 (d, J = 14.6 Hz, 1H), 4.41 (s, 1H), 4.33 (d, J = 14.5 Hz, 1H), 3.89 (s, 3H), 3.47 (d, J = 17.1 Hz, 1H), 3.18 (d, J = 12.9 Hz, 1H), 3.10 (d, J = 12.9 Hz, 1H), 2.96 (s, 3H), 2.35 (d, J = 17.1 Hz, 1H)。13C NMR (126 MHz, DMSO-d 6) δ: 165.49, 165.27, 145.98, 138.25, 136.03, 130.55, 128.57, 127.84, 127.46, 127.26, 125.01, 55.01, 48.08, 47.91, 47.67。
Embodiment 17
4- ((4- allyl -3- benzyl -2,5- dioxopiperazine -1- base) methyl) -NHydroxybenzamide
With (S) -4- ((3- benzyl -2,5- dioxopiperazine -1- base) methyl) methyl benzoate, 3- bromopropene is raw material, uses class The method for being similar to embodiment 16 obtains white solid, yield 48%;1H NMR (500 MHz, DMSO) δ 7.97 (d, J = 7.2 Hz, 2H), 7.38 (d, J = 7.0 Hz, 2H), 7.20 (d, J = 6.2 Hz, 1H), 7.05 (d, J = 6.0 Hz, 2H), 6.98 (d, J = 6.0 Hz, 2H), 5.84 (d, J = 5.5 Hz, 1H), 5.32 – 5.20 (m, 2H), 4.64 (t, J = 18.6 Hz, 1H), 4.52 (d, J = 15.1 Hz, 1H), 4.29 (d, J = 20.0 Hz, 2H), 3.67 – 3.46 (m, 2H), 3.36 (s, 1H), 3.20 (d, J = 12.4 Hz, 1H), 3.08 (d, J = 13.7 Hz, 1H), 2.39 (t, J = 27.4 Hz, 1H).
Embodiment 18
4- ((3,4- dibenzyl -2,5- dioxopiperazine -1- base) methyl) -NHydroxybenzamide
With (S) -4- ((3- benzyl -2,5- dioxopiperazine -1- base) methyl) methyl benzoate, bromobenzyl is raw material, with being similar to The method of embodiment 16 obtains white solid, yield 63%;1H NMR (500 MHz, DMSO) δ 7.98 (d, J = 6.9 Hz, 2H), 7.49 – 7.28 (m, 7H), 7.20 (s, 1H), 7.04 (s, 2H), 6.96 (d, J = 6.0 Hz, 2H), 5.17 (d, J = 15.1 Hz, 1H), 4.72 (d, J = 14.4 Hz, 1H), 4.24 (d, J = 14.5 Hz, 1H), 4.14 (d, J = 16.3 Hz, 2H), 3.90 (s, 3H), 3.61 (d, J = 17.0 Hz, 1H), 3.26 (d, J = 10.3 Hz, 1H), 3.07 (d, J = 13.5 Hz, 1H), 2.44 (t, J = 21.8 Hz, 1H).
Embodiment 19
4- ((3- benzyl -4- (Cvclopropvlmethvl) -2,5- dioxopiperazine -1- base) methyl) -NHydroxybenzamide
With (S) -4- ((3- benzyl -2,5- dioxopiperazine -1- base) methyl) methyl benzoate, Cvclopropvlmethvl chlorine is raw material, White solid, yield 72% are obtained with the method for being similar to embodiment 16;1H NMR (500 MHz, DMSO) δ 7.93 (d, J = 6.9 Hz, 2H), 7.45 – 7.28 (m, 2H), 7.20 (s, 1H), 7.02 (s, 2H), 6.95 (d, J = 6.0 Hz, 2H), 5.17 (d, J = 15.1 Hz, 1H), 4.72 (d, J = 14.4 Hz, 1H), 4.24 (d, J = 14.5 Hz, 1H), 4.14 (d, J = 16.3 Hz, 2H), 3.90 (s, 3H), 3.61 (d, J = 17.0 Hz, 1H), 3.26 (d, J = 10.3 Hz, 1H), 3.07 (d, J = 13.5 Hz, 1H), 2.44 (t, J = 21.8 Hz, 1H), 0.15-0.4 (m, 4H) . 13C NMR (126 MHz, DMSO-d 6) δ: 166.00, 165.27, 145.98, 132.25, 130.03, 129.25, 128.57, 127.54, 127.46, 127.16, 126.51, 56.21, 49.08, 48.91, 48.67。

Claims (9)

1. the compound of logical formula (I) or its pharmaceutically acceptable salt:
(I)
Wherein R1、R2、R3、R4Each independently represent hydrogen, alkyl, alkenyl, alkynyl, aralkyl, aryl or Het；
R5Selected from hydroxyl, can be optionally by one or more R6Substituted 2- aminophenyl, R6Can be hydrogen, alkyl, cyano, halogen, Halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl, aralkyl, aryl or Het；
Q1It is selected from aryl or Het, wherein aryl or Het each independently can be optionally by one or more R7Replace, R7It can be Hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl, aralkyl, diaryl alkane Base, aryl or Het；
Q2It is selected from aryl or Het, wherein aryl or Het each independently can be optionally by one or more R7Replace, R7It can be with It is hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl, aralkyl, diaryl Alkyl, aryl or Het；
Alkyl is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom；It or is the cyclic saturated hydrocarbon with 3-6 carbon atom Base；Or to connect the cyclic saturated hydrocarbon with 3-6 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom Base；
Alkoxy is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom；It or is the cyclic annular saturation with 3-6 carbon atom Alkyl；Or to connect the cyclic saturated hydrocarbon with 3-6 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom Base；Wherein each carbon atom is optionally substituted with an oxygen；
Alkylamino is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom；It or is the cyclic annular saturation with 3-6 carbon atom Alkyl；Or to connect the cyclic saturated hydrocarbon with 3-6 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom Base；Wherein each carbon atom is optionally replaced by NH atomic group；
Alkoxyalkyl is that alkoxy as defined above is connect with alkyl；
Alkenyl, the unsaturated alkyl containing double or triple bonds that alkynyl is the linear chain or branched chain with 1-6 carbon atom；
Aryl is the carbocyclic ring selected from phenyl, naphthalene, acenaphthenyl or tetralyl, is respectively optionally replaced by 1,2 or 3 substituent group, Each substituent group is independently selected from hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxy alkane Base, aralkyl, alkyl diaryl, aryl or Het；
Aralkyl, alkyl diaryl are that aryl as defined above is connect with alkyl；
Het is selected from pyrrole radicals, pyrazolyl, imidazole radicals, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole Base, pyridyl group, pyrimidine radicals, pyrazinyl or pyridazinyl monocyclic heterocycles；Or it is selected from quinolyl, quinoxalinyl, indyl, benzo miaow Oxazolyl, benzoxazolyl, benzo isoxazolyl, benzothiazolyl, benzisothia oxazolyl, benzofuranyl, benzothienyl, 2, The bicyclic heterocycle of 3- dihydrobenzo [1,4] dioxine base or benzo [1,3] dioxa cyclopentenyl；Or selected from 3-6 The bicyclic saturated hydrocarbyl of the monocyclic saturated hydrocarbon group base of carbon atom, 6-12 carbon atom, the carbon atom in middle ring is individually optionally by 1 ~4 O, S, N or NH replace；Each monocycle or it is bicyclic optionally replaced by 1,2 or 3 substituent group, each substituent group be independently selected from halogen, Halogenated alkyl, hydroxyl, alkyl or alkoxy；
Halogen be selected from fluorine, chlorine, bromine or iodine substituent group；
Halogenated alkyl is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom, or is full with the ring-type of 3-6 carbon atom And alkyl, or the cyclic annular saturation with 3-6 carbon atom for linear chain or branched chain saturated hydrocarbyl of the connection with 1-6 carbon atom Alkyl；Wherein one or more carbon atoms are optionally substituted with one or more halogen atoms.
2. the compound of claim 1, it is characterised in that:
Wherein R2、R3、R4Each independently represent hydrogen, alkyl, aryl or Het；
R1For hydrogen, alkyl, aralkyl, aromatic radical or Het；
R5 Selected from hydroxyl, can be optionally by one or more R6Substituted 2- aminophenyl, R6Can be hydrogen, alkyl, cyano, halogen, Halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl；
Q1It is selected from aryl or Het, wherein aryl or Het each independently can be optionally by one or more R6Replace, R6It can be Hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl；
Q2It is selected from aryl, wherein aryl can be optionally by one or more R7Replace, R7It can be hydrogen, alkyl, cyano, halogen, halogen Substituted alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl.
3. the compound of claim 2, it is characterised in that:
Wherein R2、R3、R4Each independently represent hydrogen, methyl, ethyl；
R1For hydrogen, alkyl, aralkyl；
R5Selected from can be optionally by one or more R6Substituted 2- aminophenyl, R6It can be hydrogen, methyl, ethyl, 1~2 halogen Or trifluoromethyl；
Q1Selected from following aromatic rings or substituted aromatic rings: phenyl, naphthalene, pyrrole radicals, furyl, thienyl, pyridyl group, Pyrazinyl, pyrimidine radicals, substituent group can be methyl, ethyl, 1~2 halogen or trifluoromethyl；
Q2It is selected from phenyl.
4. the compound of claim 3, it is characterised in that:
Wherein R2、R3、R4Each independently represent hydrogen；
R1For hydrogen, alkyl, benzyl；
R5Selected from can be optionally by one or more R5Substituted 2- aminophenyl, R6It can be hydrogen, methyl, 1~2 halogen；
Q1Be selected from following aromatic rings or substituted aromatic rings: phenyl, indyl, substituent group can be methyl, 1~2 halogen Or trifluoromethyl；
Q2It is selected from phenyl.
5. the compound of claim 1, it is characterised in that be following compound:
(S)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -N(2- aminophenyl) benzene first Amide (I-1)
(S)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -N(2- amino -4- fluorobenzene Base) benzamide (I-2)
(R)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -N(2- aminophenyl) benzene Formamide (I-3)
(R)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -N(2- amino -4- fluorobenzene Base) benzamide (I-4)
(S)-N(2- aminophenyl) -4- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) benzamide (I-5)
(S)-N(2- amino -4- fluorophenyl) -4- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) benzamide (I-6)
(R)-N(2- aminophenyl) -4- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) benzamide (I-7)
(R)-N(2- amino -4- fluorophenyl) -4- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) benzamide (I-8)
(S)-N(2- aminophenyl) -3- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) benzamide (I-9)
(S)-N(2- amino -4- fluorophenyl) -3- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) benzamide (I-10)
(S)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -NHydroxybenzamide (I- 11)
(R)-4-((3-((1HIndol-3-yl) methyl) -2,5- diketopiperazine -1- base) methyl) -NHydroxybenzamide (I- 12)
(S) -4- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) -NHydroxybenzamide (I-13)
(R) -4- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) -NHydroxybenzamide (I-14)
(S) -3- ((3- benzyl -2,5- diketopiperazine -1- base) methyl) -NHydroxybenzamide (I-15)
4- ((3- benzyl -4- methyl -2,5- diketopiperazine -1- base) methyl) -NHydroxybenzamide (I-16)
4- ((4- allyl -3- benzyl -2,5- diketopiperazine -1- base) methyl) -NHydroxybenzamide (I-17)
4- ((3,4- dibenzyl -2,5- dioxopiperazine -1- base) methyl) -NHydroxybenzamide (I-18)
4- ((3- benzyl -4- (Cvclopropvlmethvl) -2,5- dioxopiperazine -1- base) methyl) -NHydroxybenzamide (I-19).
6. compound according to any one of claims 1 to 5 or its pharmaceutically acceptable salt, wherein pharmaceutically acceptable salt includes The acid-addition salts that logical formula (I) compound and following acid are formed: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene sulfonic acid, to first Benzene sulfonic acid, naphthalene sulfonic acids, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, benzene Guanidine-acetic acid, tussol；Additionally include inorganic base acid salt, such as: containing alkali metal cations, alkaline earth metal cation, Ammonium cation salt.
7. a kind of pharmaceutical composition, wherein containing the described in any item compounds of claim 1-5 and pharmaceutically acceptable load Body.
8. the described in any item compounds of claim 1-5 are in preparation for preventing or treating clinical disease related with HDACs Drug in purposes.
9. the purposes of claim 8, wherein disease related with HDAC1 or HDAC6 can be lung cancer, melanoma, liver cancer, Kidney, leukaemia, prostate cancer, thyroid cancer, cutaneum carcinoma, cancer of pancreas, oophoroma, carcinoma of testis, breast cancer, bladder cancer, gall-bladder Cancer, myelodysplastic syndrome, lymthoma, the cancer of the esophagus, gastrointestinal cancer, astrocytoma, neuroblastoma, neuroglia Tumor, neurinoma, celiothelioma, Non-Insulin Dependent Diabetes Mellitus, autoimmune disease.
CN201810049921.5A 2018-01-18 2018-01-18 Novel diketopiperazine histone deacetylases inhibitor Pending CN110054619A (en)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994004513A1 (en) * 1992-08-14 1994-03-03 Xenova Limited Pharmaceutically active diketopiperazines
CN1112364A (en) * 1993-07-13 1995-11-22 大塚制药株式会社 Piperazine derivatives and salts thereof
CN1420882A (en) * 1999-07-28 2003-05-28 阿温蒂斯药物公司 Substd. oxoazaheterocyclyl compounds
WO2009051801A2 (en) * 2007-10-16 2009-04-23 Angiogenex Chemical inhibitors of inhibitors of differentiation
CN101511823A (en) * 2006-08-04 2009-08-19 麦那思制药（加拿大）有限公司 Multifunctional bioactive compounds
WO2015017546A1 (en) * 2013-07-30 2015-02-05 H. Lee Moffitt Cancer Center And Research Institute, Inc. Selective histone deactylase 6 inhibitors
CN105524043A (en) * 2016-01-05 2016-04-27 中国药科大学 Lactam histone deacetylase inhibitors

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994004513A1 (en) * 1992-08-14 1994-03-03 Xenova Limited Pharmaceutically active diketopiperazines
CN1112364A (en) * 1993-07-13 1995-11-22 大塚制药株式会社 Piperazine derivatives and salts thereof
CN1420882A (en) * 1999-07-28 2003-05-28 阿温蒂斯药物公司 Substd. oxoazaheterocyclyl compounds
CN101511823A (en) * 2006-08-04 2009-08-19 麦那思制药（加拿大）有限公司 Multifunctional bioactive compounds
WO2009051801A2 (en) * 2007-10-16 2009-04-23 Angiogenex Chemical inhibitors of inhibitors of differentiation
WO2015017546A1 (en) * 2013-07-30 2015-02-05 H. Lee Moffitt Cancer Center And Research Institute, Inc. Selective histone deactylase 6 inhibitors
CN105524043A (en) * 2016-01-05 2016-04-27 中国药科大学 Lactam histone deacetylase inhibitors

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