CN110627801A - 一类hdac抑制剂及其用途 - Google Patents
一类hdac抑制剂及其用途 Download PDFInfo
- Publication number
- CN110627801A CN110627801A CN201910992789.6A CN201910992789A CN110627801A CN 110627801 A CN110627801 A CN 110627801A CN 201910992789 A CN201910992789 A CN 201910992789A CN 110627801 A CN110627801 A CN 110627801A
- Authority
- CN
- China
- Prior art keywords
- hdac
- inhibitor
- dioxa
- benzo
- substituted
- 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.)
- Granted
Links
- 239000003276 histone deacetylase inhibitor Substances 0.000 title claims abstract description 35
- 229940121372 histone deacetylase inhibitor Drugs 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- 102000003964 Histone deacetylase Human genes 0.000 claims abstract description 38
- 108090000353 Histone deacetylase Proteins 0.000 claims abstract description 38
- 239000003112 inhibitor Substances 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 14
- JMZOMFYRADAWOG-UHFFFAOYSA-N methyl 7-methoxy-4-(7-methoxy-5-methoxycarbonyl-1,3-benzodioxol-4-yl)-1,3-benzodioxole-5-carboxylate Chemical class COC(=O)C1=CC(OC)=C2OCOC2=C1C1=C2OCOC2=C(OC)C=C1C(=O)OC JMZOMFYRADAWOG-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 9
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 8
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 8
- 206010061218 Inflammation Diseases 0.000 claims abstract description 8
- 230000004054 inflammatory process Effects 0.000 claims abstract description 8
- 229940079593 drug Drugs 0.000 claims abstract description 5
- -1 hydroxy, cyano, carbamoyl Chemical group 0.000 claims description 35
- 102100039996 Histone deacetylase 1 Human genes 0.000 claims description 22
- 101001035024 Homo sapiens Histone deacetylase 1 Proteins 0.000 claims description 22
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 17
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 6
- 239000002552 dosage form Substances 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 22
- 206010028980 Neoplasm Diseases 0.000 abstract description 13
- 238000002474 experimental method Methods 0.000 abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 230000003285 pharmacodynamic effect Effects 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 230000015572 biosynthetic process Effects 0.000 description 35
- 238000003786 synthesis reaction Methods 0.000 description 35
- ANSXAPJVJOKRDJ-UHFFFAOYSA-N furo[3,4-f][2]benzofuran-1,3,5,7-tetrone Chemical compound C1=C2C(=O)OC(=O)C2=CC2=C1C(=O)OC2=O ANSXAPJVJOKRDJ-UHFFFAOYSA-N 0.000 description 33
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 30
- UEGLMSYFPSTPHJ-UHFFFAOYSA-N 6H-2-benzazepine-7-carboxamide Chemical compound C1=NC=CC=C2C1=CC=C(C2)C(=O)N UEGLMSYFPSTPHJ-UHFFFAOYSA-N 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 102100022537 Histone deacetylase 6 Human genes 0.000 description 15
- 101000899330 Homo sapiens Histone deacetylase 6 Proteins 0.000 description 15
- WWGBHDIHIVGYLZ-UHFFFAOYSA-N N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]-oxomethyl]-5-isoxazolyl]phenyl]carbamic acid tert-butyl ester Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1C1=CC(C(=O)NCCCCCCC(=O)NO)=NO1 WWGBHDIHIVGYLZ-UHFFFAOYSA-N 0.000 description 15
- 125000005605 benzo group Chemical group 0.000 description 15
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 14
- 230000000694 effects Effects 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- GIZCKBSSWNIUMZ-UHFFFAOYSA-N methyl 4-(aminomethyl)benzoate;hydrochloride Chemical compound Cl.COC(=O)C1=CC=C(CN)C=C1 GIZCKBSSWNIUMZ-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 230000014509 gene expression Effects 0.000 description 7
- HYHZGBOWRWIEGW-UHFFFAOYSA-N 5-methoxycarbonylthiophene-2-carboxylic acid Chemical group COC(=O)C1=CC=C(C(O)=O)S1 HYHZGBOWRWIEGW-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- XUUSYXJGMRQBKQ-UHFFFAOYSA-N 2h-2-benzazepine Chemical compound N1C=CC=C2C=CC=CC2=C1 XUUSYXJGMRQBKQ-UHFFFAOYSA-N 0.000 description 5
- HSSYVKMJJLDTKZ-UHFFFAOYSA-N 3-phenylphthalic acid Chemical compound OC(=O)C1=CC=CC(C=2C=CC=CC=2)=C1C(O)=O HSSYVKMJJLDTKZ-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- IEMKQRSOAOPKRJ-UHFFFAOYSA-N ethyl 2-chloropyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(Cl)N=C1 IEMKQRSOAOPKRJ-UHFFFAOYSA-N 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- BXGYYDRIMBPOMN-UHFFFAOYSA-N 2-(hydroxymethoxy)ethoxymethanol Chemical compound OCOCCOCO BXGYYDRIMBPOMN-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 108010033040 Histones Proteins 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical group CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- SATDLKYRVXFXRE-UHFFFAOYSA-N methyl 4-(chloromethyl)benzoate Chemical compound COC(=O)C1=CC=C(CCl)C=C1 SATDLKYRVXFXRE-UHFFFAOYSA-N 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- VPVXHAANQNHFSF-UHFFFAOYSA-N 1,4-dioxan-2-one Chemical compound O=C1COCCO1 VPVXHAANQNHFSF-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 229910010084 LiAlH4 Inorganic materials 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229940124639 Selective inhibitor Drugs 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- HTBWBWWADZJXID-TXEJJXNPSA-N Wuweizisu C Chemical compound COC1=C2C=3C(OC)=C4OCOC4=CC=3C[C@H](C)[C@H](C)CC2=CC2=C1OCO2 HTBWBWWADZJXID-TXEJJXNPSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- MJBWDEQAUQTVKK-IAGOWNOFSA-N aflatoxin M1 Chemical compound C=1([C@]2(O)C=CO[C@@H]2OC=1C=C(C1=2)OC)C=2OC(=O)C2=C1CCC2=O MJBWDEQAUQTVKK-IAGOWNOFSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical group [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- JXHYCCGOZUGBFD-UHFFFAOYSA-N benzoic acid;hydrochloride Chemical compound Cl.OC(=O)C1=CC=CC=C1 JXHYCCGOZUGBFD-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000011161 development Methods 0.000 description 2
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- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- DNMCSEZPFDMEHC-UHFFFAOYSA-N methyl 8-aminooctanoate;hydrochloride Chemical compound Cl.COC(=O)CCCCCCCN DNMCSEZPFDMEHC-UHFFFAOYSA-N 0.000 description 2
- IQLZWWDXNXZGPK-UHFFFAOYSA-N methylsulfonyloxymethyl methanesulfonate Chemical compound CS(=O)(=O)OCOS(C)(=O)=O IQLZWWDXNXZGPK-UHFFFAOYSA-N 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- RVWMQSODNUSUBL-UHFFFAOYSA-N potassium;oxidoamine Chemical compound [K+].[O-]N RVWMQSODNUSUBL-UHFFFAOYSA-N 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- QERYCTSHXKAMIS-UHFFFAOYSA-M thiophene-2-carboxylate Chemical compound [O-]C(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-M 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
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- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
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Abstract
本发明公开了一类HDAC抑制剂，所述抑制剂为如通式（I）–（IV）所示的联苯双酯衍生物及其药学上可接受的盐或氘代物，以及含有它们的药物组合物，用于制备抗肿瘤、自身免疫性疾病、炎症或阿尔兹海默症药物的用途。本发明制备的联苯双酯衍生物均具有HDAC抑制活性，经药效学实验表明，本发明所涉及的化合物可用作肿瘤、自身免疫性疾病、炎症或阿尔兹海默症的治疗药物。
Description
技术领域
本发明涉及药物化学领域，具体涉及一类具有HDAC抑制活性的联苯双酯衍生物及其制备方法与用途。
背景技术
组蛋白去乙酰化酶(Histone deacetylase，HDACs)在表观遗传调控中发挥着重要作用，可通过催化组蛋白或非组蛋白的去乙酰化过程调控基因表达。在HDACs的四个亚类中，I类HDACs与肿瘤发生及发展的关系较为密切，其广泛存在于人体的各种器官。研究证实，I类HDACs中的HDAC1亚型在多种恶性肿瘤，如子宫内膜癌、肺癌、前列腺癌、乳腺癌、结肠癌、胰腺癌、血癌等中均呈现高表达(Zhu S,et al.Mir-548an,TranscriptionallyDownregulated by HIF1α/HDAC1,Suppresses Tumorigenesis of Pancreatic Cancer byTargeting Vimentin Expression.Mol Cancer Ther,2016,15(9):2209-2219；Zhao R,etal.DNA damage-binding complex recruits HDAC1to repress Bcl-2transcription inhuman ovarian cancer cells.Mol Cancer Res,2014,12(3):370-380.)。HDAC1的高表达可导致组蛋白乙酰化异常，与肿瘤的发生、发展密切相关，故通过抑制HDAC1可达到治疗肿瘤的目的(Stubbs,M.C,et al.Selective Inhibition of HDAC1 and HDAC2 as aPotential Therapeutic Option for B-ALL.Clin Cancer Res,2015,21(10):2348–2358.)。
II类HDACs中的HDAC6亚型具有独特的结构和底物特异性，其表达和功能的改变与多种疾病密切相关。研究表明，HDAC6的异常表达可通过调控Ras、EGFR等信号通路，促进细胞癌变以及肿瘤细胞的生长、增殖、血管生成；此外，其高表达还可增强肿瘤细胞的转移性与侵袭性(Lee YS,et al.The cytoplasmic deacetylase HDAC6is required forefficient oncogenic tumorigenesis.Cancer Res,2008,68:7561-7569)。与此同时，HDAC6亦与神经退行性疾病(如阿尔兹海默症)、炎症、自身免疫疾病等的病理进程密切相关(Selenica M L,et al.Histone deacetylase 6inhibition improves memory andreduces total tau levels in a mouse model of tau deposition.Alzheimers ResTher,2014,6(1):12；de Zoeten E F,et al.Histone deacetylase 6and heat shockprotein 90control the functions of Foxp3(+)T-regulatory cells.Mol Cell Biol,2011,31(10):2066-2078；Regna N L et al.Specific HDAC6 inhibition by ACY-738reduces SLE pathogenesis in NZB/W mice.Clin Immunol,2016,162:58-73)。
现获批上市的HDACs抑制剂主要为广谱的HDACs抑制剂，包括vorinostat(SAHA)、belinostat和panobinostat。但它们存在恶心、呕吐、骨髓抑制及致QT间期延长等毒副作用，应用范围受限，故亟需发现新型HDAC抑制剂以改善该类药物的安全性(Balasubramanian S,et al.Isoform-specific histone deacetylase inhibitors:thenext step？Cancer Lett,2009,280:211-221.)。亚型选择性HDAC抑制剂是当前研究热点，其中HDAC6选择性抑制剂的研究备受关注，但尚未有药物上市，仅ACY-1215处于临床研究中。除直接干预肿瘤细胞的生命活动外，HDAC6选择性抑制剂还可下调程序性死亡配体(Programmed Death-Ligand 1,PD-L1)，发挥免疫治疗作用。因此，新型HDAC6选择性抑制剂的发现可为HDAC6选择性抑制剂的临床实验和肿瘤免疫治疗提供更多选择。此外，临床用药显示，除HDAC6选择性抑制剂外，仅作用于少数几种HDAC亚型(如HDAC1、HDAC2、HDAC3)的抑制剂，可在一定程度上降低SAHA等广谱HDACs抑制剂抑制所有HDAC亚型产生的毒副作用。
联苯双酯是中药单体五味子丙素的结构类似物，在临床上用作保肝药物。近年来亦有研究探索其在抗肿瘤领域的用途。然而迄今，尚无基于联苯双酯母核发现的HDAC抑制剂的报道。
发明内容
针对现有技术的不足，本发明提供了一类HDAC抑制剂及其用途。
本发明的技术方案如下：
一类HDAC抑制剂，所述抑制剂为如通式(I)–(IV)所示的联苯双酯衍生物及其药学上可接受的盐或氘代物：
其中，通式(I)、(II)中W是(CH2)n1或至少被1个R1取代的C6-14芳基、C5-14芳杂基、C7-12芳烷基、C6-12芳杂烷基；
通式(III)中X是至少被1个R2取代的C6-14芳基、C5-14芳杂基、C7-12芳烷基、C6-12芳杂烷基或其中Y是至少被1个R3取代的C6-14芳基、C5-14芳杂基；
通式(IV)中Z是至少被1个R4取代的C6-14芳基、C5-14芳杂基；
n1＝1-9；R1、R2、R3、R4分别独立地选自氢、卤素、羟基、氰基、氨甲酰基、C1-6烷基、C1-6烷氧基、C2-6不饱和脂链烃基；R5是氢、C1-6烷基或n2＝1-4。
进一步方案，所述通式(I)–(IV)所示的联苯双酯衍生物选自以下化合物：
进一步方案，所述HDAC抑制剂为选择性的HDAC6抑制剂，所述选择性的HDAC6抑制剂为如下列通式(I)、(Ⅲ)所示的联苯双酯衍生物及其药学上可接受的盐或氘代物，
其中，通式(I)中W为至少被1个R1取代的C6-14芳基、C5-14芳杂基；通式(III)中X为至少被1个R2取代的C6-14芳基、C5-14芳杂基或而Y是至少被1个R3取代的C6-14芳基、C5-14芳杂基；R1、R2、R3分别独立地选自氢、卤素、羟基、氰基、氨甲酰基、C1-6烷基、C1-6烷氧基、C2-6不饱和脂链烃基；R5是氢、C1-6烷基或n2＝1-4。
进一步方案，所述HDAC抑制剂为选择性的HDAC1/2/3抑制剂，所述HDAC1/2/3抑制剂为如通式(IV)所示的联苯双酯衍生物及其药学上可接受的盐或氘代物，
其中，通式(IV)中Z是至少被1个R4取代的C6-14芳基、C5-14芳杂基；R4独立地选自氢、卤素、羟基、氰基、氨甲酰基、C1-6烷基、C1-6烷氧基、C2-6不饱和脂链烃基。
本发明还提供一种HDAC抑制剂组合物，包括上述的HDAC抑制剂以及至少一种药用载体或赋形剂。
进一步方案，所述HDAC抑制剂组合物还包括至少一种其它治疗剂。
所述HDAC抑制剂组合物的剂型为临床上或药学上可接受的任一剂型。
本发明的另一个技术方案是提供上述一类HDAC抑制剂的用途，所述HDAC抑制剂在制备抗肿瘤、自身免疫性疾病、炎症或阿尔兹海默症药物中的应用。
另外，本发明还提供一种药物组合物的用途，所述药物组合物或HDAC抑制剂组合物在制备抗肿瘤、自身免疫性疾病、炎症或阿尔兹海默症药物中的应用。
本发明化合物的用药剂量为1mg-1000mg/天，也可根据病情的轻重或剂型的不同偏离此范围。
除非另外定义，所有本文使用的科技术语都具有与要求保护的主题所属领域的技术人员一般理解相同的含义。
其中“卤素”指氟、氯、溴或碘。
“C6-14芳基”是指6-14个碳原子的全碳单环或稠合多环基团，具有完全共轭的π电子系统。其非限制性实例有：苯环、萘环、蒽环。
“C5-14芳杂基”是指5-14个环原子的非全碳单环或稠合多环基团，具有完全共轭的π电子系统。其非限制性实例有：吡啶、咪唑、噻吩、呋喃、噻唑、嘌呤、吲哚、氮杂吲哚。
“C6-12芳杂烷基”是指含6-12个碳原子的芳杂基上连有烷基的基团；
“C7-12芳烷基”是指含7-12个碳原子的芳基上连有烷基的基团；
“C1-6烷基”指1到6个碳原子的烷基；
“C1-6烷氧基”指1到6个碳原子的烷烃中一个氢原子被氧原子取代。如甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、叔丁氧基、正戊氧基、新戊氧基和正己氧基等；
“C2-6不饱和脂链烃基”指含有双键或者三键的碳原子数为2-6个的直链或者支链的烯基或者炔基。不饱和脂链烃基的非限制性实例有：乙烯基、1-丙烯基、2-丙烯基、乙炔基等。
本发明的化合物或其药学上可接受的盐或氘代物具有同样的功效，其中药学上可接受的盐是上述通式(I)、(II)、(III)或(IV)的盐，其中药学上可接受的盐是盐酸盐、硫酸盐、磷酸盐、马来酸盐、富马酸盐、枸橼酸盐、甲磺酸盐、酒石酸盐、钠盐或钾盐。
所述“药用载体”是指药学领域常规的药物载体，包括药学领域的常规稀释剂、赋形剂(如水等)、填充剂(如淀粉等)、粘合剂(如纤维素衍生物、明胶等)、湿润剂(如甘油等)、崩解剂(如琼脂、碳酸钙等)、吸收促进剂(如季铵化合物等)、表面活性剂(如十六烷醇等)、吸附载体(如高龄土和皂黏土等)、润滑剂(如滑石粉等)，必要时还可以加入香味剂、甜味剂等。
所述的“药学上可接受的任一剂型”适用于通过任何适当途径给药，如口服(包括含服或舌下给药)、直肠给药、经鼻给药、局部给药(包括含服、舌下给药或经皮给药)、阴道给药或胃肠外给药(包括皮下注射、肌内注射、静脉注射或皮内注射)途径。这些制剂可由药剂学领域中已知的任何方法制备。例如，通过将活性成分与载体或赋形剂混在一起的方法。
本发明的HDAC抑制剂为具有HDAC抑制活性的联苯双酯衍生物及其药学上可接受的盐或氘代物。联苯双酯是合成中药单体五味子丙素的关键中间体，在结构上可看作五味子丙素类似物，是临床中缓解病毒性肝炎和药物性肝损伤所致转氨酶升高的常用药物，具有优良的安全性。近来研究表明，联苯双酯在肿瘤治疗中亦有潜在的应用价值，但尚未见基于联苯双酯的基本骨架进行HDAC抑制剂发现的研究。
通过多次实验证实，本发明制备的联苯双酯衍生物均具有HDAC抑制活性，其中大部分化合物可高强度地抑制HDAC1或/和HDAC6。部分化合物在高强度抑制HDAC1的同时，呈现出显著的抗肿瘤细胞增殖活性，且对HDAC1/2/3选择性优良。另有部分化合物在高强度抑制HDAC6的同时，呈现出优良的HDAC6选择性。药效学实验表明，本发明所涉及的化合物可用作肿瘤、自身免疫性疾病、炎症或阿尔兹海默症的治疗药物。
具体实施方式
以化合物1(路线I)、化合物2、9、12、21(路线II)为例，本发明的化合物制备方法如下：
另外，化合物3-6参考路线I制备；化合物7、8、10、11、13-20参考路线II制备。需要指出的是，以下包含的特定实施例是为了举例说明，不应被理解为对本发明范围的限制。此外应理解，在阅读了本发明涉及的内容以后，本领域的技术人员可以对本发明作各种改动或修改，这种等价形式同样落于本申请所附权利要求书所限定的范围。
路线I中：a为LiAlH4(氢化铝锂)，THF(四氢呋喃)，0℃；
b为MsCl(甲磺酰氯)，TEA(三乙胺)，DCM(二氯甲烷)，rt(室温)；
c为Methyl-8-aminooctanoate hydrochloride(8-氨基辛酸甲酯盐酸盐)，TEA,CH3CN(乙腈)，40℃；
d为NH2OK(羟胺钾)，CH3OH(甲醇)，rt。
路线II中：a为Benzylamine(苄胺)，TEA，CH3CN，40℃；
b为HCOONH4(甲酸铵)，Pd/C(10％)(10％钯碳)，CH3OH,N2(氮气保护)，50℃；
c为methyl 4-(chloromethyl)benzoate(4-氯甲基苯甲酸甲酯)，Cs2CO3(碳酸铯),KI(碘化钾)，CH3CN，N2，80℃；
d为NH2OK，CH3OH，rt；
e为5-(methoxycarbonyl)thiophene-2-carboxylic acid(5-甲氧羰基噻吩-2-羧酸)，EDC·HCl(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐)，HOBT(1-羟基苯并三氮唑),DIPEA(N,N-二异丙基乙胺)，DCM，rt；
f为methyl 4-(aminomethyl)benzoate hydrochloride(4-氨甲基苯甲酸甲酯盐酸盐)，triphosgene(三光气)，TEA,DCM，0℃-rt；
g为ethyl 2-chloropyrimidine-5-carboxylate(2-氯嘧啶-5-甲酸乙酯)，Cs2CO3,KI(碘化钾)，CH3CN,N2，80℃。
实施例1：
8-(4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-)-N-羟基辛酰胺(1)的合成
(1)、(7,7'-二甲氧基-[4,4'-二苯并[d][1,3]二恶茂]-5,5'-)二甲醇(23)的合成
在圆底烧瓶中加入联苯双酯(10.0g,23.9mmol,1eq)，以无水THF(150mL)溶解，冰浴下分批加入LiAlH4(2.72g,71.7mmol,3eq)，加入完毕后，转移至室温反应4h。冰浴下，加冰水除去多余的LiAlH4，抽滤，DCM润洗，滤液浓缩，依次以饱和NaHCO3溶液、水、饱和食盐水洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，得白色固体8.33g。
(2)、(7,7'-二甲氧基-[4,4'-二苯并[d][1,3]二恶茂]-5,5'-)双(亚甲基)二甲磺酸酯(24)的合成
在圆底烧瓶中加入中间体23(5.50g,15.2mmol,1eq)，以DCM溶解(50mL)，冰浴下依次加入TEA(6.33mL,45.5mmol,3eq)和MsCl(3.84mL,45.5mmol,3eq)，转移至室温反应8h。体系依次以饱和NaHCO3溶液、水、饱和食盐水洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，得黄色油状物7.57g，直接用于下一步反应。
(3)、8-(4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-)辛酸甲酯(25)的合成
在圆底烧瓶中依次加入中间体24(200mg,0.386mmol,1eq)、8-氨基辛酸甲酯盐酸盐(323mg,1.54mmol,4eq)、TEA(0.322mL,2.31mmol,6eq)及CH3CN(3mL)，40℃反应8h。旋去CH3CN，依次以饱和NaHCO3溶液、水、饱和食盐水洗涤，DCM萃取，无水Na2SO4干燥，过滤，滤液减压浓缩，经硅胶柱层析得淡黄色固体163mg。
(4)、8-(4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-)-N-羟基辛酰胺(1)的合成
NH2OK甲醇溶液的制备：称取KOH(9.70g,173mmol,1.5eq)置于圆底烧瓶中，甲醇(24mL)溶解；称取NH2OH·HCl(8.00g,115mmol,1eq)置于三颈瓶中，甲醇(40mL)溶解；冰浴下，将KOH甲醇溶液滴加至NH2OH·HCl甲醇溶液中，N2保护下反应1h，抽滤，滤液待用。
在圆底烧瓶中，依次加入中间体25(130mg，0.293mmol,1eq)、NH2OK甲醇溶液(4mL)，室温反应4h。用1N的HCl溶液调PH＝7，有固体析出，抽滤，滤饼水洗，干燥，经硅胶柱层析得黄色固体80mg；1H NMR(400MHz,DMSO-d6):δ10.38(s,1H),8.67(s,1H),6.98(s,2H),6.12(s,2H),6.07(s,2H),4.41-4.28(m,1H),4.14-4.00(m,1H),3.90(s,6H),3.78-3.66(m,1H),3.22-2.85(m,3H),1.96(t,J＝7.2Hz,2H),1.86-1.76(m,1H),1.75-1.65(m,1H),1.51(t,J＝6.8Hz,2H),1.37-1.27(m,6H)；ESI-MS:501.19[M+H]+。
实施例2：
4-((4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-)甲基)-N-羟基苯甲酰胺(2)的合成
(1)、7-苄基-4,10-二甲氧基-7,8-二氢-6H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓(25)的合成
在圆底烧瓶中依次加入中间体24(7.57g,14.6mmol,1eq)、CH3CN(50mL)、苄胺(6.38mL,58.4mmol,4eq)和TEA(8.12mL,58.4mmol,4eq)，40℃反应8h。旋去CH3CN，依次以饱和NaHCO3溶液、水、饱和食盐水洗涤，DCM萃取，无水Na2SO4干燥，过滤，滤液减压浓缩，乙酸乙酯重结晶，得白色固体5.01g。
(2)、4,10-二甲氧基-7,8-二氢-6H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓(26)的合成
在圆底烧瓶中依次加入中间体25(5.00g,11.5mmol,1eq)、HCOONH4(4.00g,63.4mmol,5.5eq)、10％Pd/C(1.10g)、甲醇(50mL)，N2保护，50℃搅拌反应10h。抽滤除去Pd/C，甲醇润洗，滤液减压浓缩，依次以饱和NaHCO3溶液、水、饱和食盐水洗涤，DCM萃取，无水Na2SO4干燥，过滤，滤液减压浓缩，经硅胶柱层析得淡黄色固体2.09g。
(3)、4-((4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-)甲基)苯甲酸甲酯(27)的合成
在圆底烧瓶中依次加入中间体26(150mg,0.437mmol,1eq)、4-氯甲基苯甲酸甲酯(96.8mg,0.524mmol,1.2eq)、Cs2CO3(185mg,0.524mmol,1.2eq)、KI(87mg,0.524mmol,1.2eq)和无水CH3CN(2mL)，N2保护，80℃反应9h。旋去CH3CN，依次以饱和NaHCO3溶液、水、饱和食盐水洗涤，DCM萃取，无水Na2SO4干燥，过滤，滤液减压浓缩，经硅胶柱层析得黄色固体206mg。
(4)、4-((4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-)甲基)-N-羟基苯甲酰胺(2)的合成
化合物2参考实施例1步骤(4)制备。
1H NMR(400MHz,DMSO-d6):δ11.20(s,1H),9.03(s,1H),7.76(d,J＝8.0Hz,2H),7.48(d,J＝8.0Hz,2H),6.65(s,2H),6.05(s,2H),6.00(s,2H),3.88(s,6H),3.72(d,J＝13.6Hz,1H),3.54(d,J＝13.6Hz,1H),3.44(d,J＝12.8Hz,2H),3.03(d,J＝12.4Hz,2H)；ESI-MS:493.24[M+H]+。
实施例3：
5-(4,10-二甲氧基-7,8-二氢-6H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-羰基)-N-羟基噻吩-2-甲酰胺(9)的合成
(1)、5-(4,10-二甲氧基-7,8-二氢-6H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-羰基)噻吩-2-羧酸甲酯(28)的合成
在圆底烧瓶中依次加入5-甲氧羰基噻吩-2-羧酸(89.5mg,0.481mmol,1.1eq)、EDC·HCl(92.1mg,0.481mmol,1.1eq)、HOBt(65.4mg,0.481mmol,1.1eq)、DIPEA(217μL,1.31mmol,3eq)和DCM(2mL)，室温搅拌1h。加入中间体26(150mg,0.437mmol,1eq)，继续室温反应4h。依次以饱和NaHCO3溶液、水、饱和食盐水洗涤，DCM萃取，无水Na2SO4干燥，过滤，滤液减压浓缩，经硅胶柱层析得黄色固体208mg。
(2)、5-(4,10-二甲氧基-7,8-二氢-6H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-羰基)-N-羟基噻吩-2-甲酰胺(9)的合成
化合物9参考实施例1中步骤(4)制备。
1H NMR(400MHz,DMSO-d6):δ11.41(s,1H),9.29(s,1H),7.59(d,2.8Hz,1H),7.53(d,4.0Hz,1H),6.88(s,1H),6.75(s,1H),6.09(s,2H),6.04(s,2H),5.17-4.71(m,2H),4.27-4.01(m,1H),3.85(s,6H),3.65-3.49(m,1H)；ESI-MS:513.08[M+H]+。
实施例4：
N-(4-(羟基氨基甲酰基)苄基)-4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-甲酰胺(12)的合成
(1)、4-((4,10-二甲氧基-7,8-二氢-6H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-甲酰胺基)甲基)苯甲酸甲酯(29)的合成
在圆底烧瓶中加入4-氨甲基苯甲酸甲酯盐酸盐(150mg,0.744mmol,1eq)，以DCM/饱和碳酸氢钠溶液体系(V:V＝1:1,4mL)溶解，冰浴下加入三光气(73.6mg,0.248mmol,0.33eq)，搅拌反应0.5h。加入中间体26(255mg,0.744mmol,1eq)和TEA(310μL,2.23mmol,3eq)后转移至室温反应6h。依次以饱和NaHCO3溶液、水、饱和食盐水洗涤，DCM萃取，无水Na2SO4干燥，过滤，滤液减压浓缩，经硅胶柱层析得黄色固体145mg。
(2)、N-(4-(羟基氨基甲酰基)苄基)-4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-甲酰胺(12)的合成
化合物12参考实施例1中步骤(4)制备。
1H NMR(400MHz,DMSO-d6):δ11.18(s,1H),9.01(s,1H),7.70(d,8.0Hz,2H),7.35(d,8.0Hz,2H),7.22(t,4.8Hz,1H),6.78(s,2H),6.07(s,2H),6.02(s,2H),4.74(d,J＝13.2Hz,2H),4.36(dd,J＝15.2,4.8Hz,1H),4.28(dd,J＝15.2,4.8Hz,1H),3.87(s,6H),3.47(d,J＝13.2Hz,2H)；ESI-MS:536.12[M+H]+。
实施例5：
2-(4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-)-N-羟基嘧啶-5-甲酰胺(21)的合成
(1)、2-(4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-)嘧啶-5-羧酸乙酯(30)的合成
中间体30参考实施例2步骤(3)制备，仅将4-氯甲基苯甲酸甲酯替换为2-氯-5-嘧啶羧酸乙酯。
(2)、2-(4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-基)-N-羟基嘧啶-5-甲酰胺(21)的合成
化合物21参考实施例1中步骤(4)制备。
1H NMR(400MHz,DMSO)δ11.13(s,1H),9.04(s,1H),8.76(s,2H),6.81(s,2H),6.08(s,2H),6.03(s,2H),5.43(d,J＝13.6Hz,2H),3.85(s,6H),3.67(d,J＝13.6Hz,2H)；ESI-MS:481.10[M+H]+。
实施例6：
5-((4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-)甲基)-N-羟基噻吩-2-甲酰胺(3)的合成
化合物3参考实施例5制备，仅将2-氯-5-嘧啶羧酸乙酯替换为5-(溴甲基)噻吩-2-羧酸甲酯。
1H NMR(400MHz,DMSO-d6):δ11.15(s,1H),9.09(s,1H),7.50(s,1H),7.08(s,1H),6.67(s,2H),6.05(s,2H),6.01(s,2H),4.12-4.01(m,1H),3.89(s,6H),3.70(d,12.4Hz,1H),3.54(d,11.6Hz,2H),3.04(d,11.2Hz,2H)；ESI-MS:498.94[M+H]+。
实施例7：
5-((4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-)甲基)-N-羟基呋喃-2-甲酰胺(4)的合成
化合物4参考实施例5制备，仅将2-氯-5-嘧啶羧酸乙酯替换为5-(氯甲基)呋喃-2-羧酸乙酯。
1H NMR(400MHz,DMSO-d6):δ11.11(s,1H),9.04(s,1H),7.02(d,2.8Hz,1H),6.72(s,2H),6.55(d,J＝3.2Hz,1H),6.04(s,2H),6.00(s,2H),3.88(s,6H),3.69(d,J＝14.0Hz,1H),3.52(d,J＝14.4Hz,1H),3.47(d,J＝12.8Hz,2H),3.04(d,J＝12.4Hz,2H)；ESI-HRMS:483.1338[M+H]+。
实施例8：
2-((4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-)甲基)-N-羟基嘧啶-5-甲酰胺(5)的合成
化合物5参考实施例5制备，仅将2-氯-5-嘧啶羧酸乙酯替换为2-(溴甲基)嘧啶-5-羧酸甲酯。ESI-MS:495.15[M+H]+。
实施例9：
6-((4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-)甲基)-N-羟基烟酰胺(6)的合成
化合物6参考实施例5制备，仅将2-氯-5-嘧啶羧酸乙酯替换为2-(溴甲基)吡啶-5-羧酸甲酯。
1H NMR(400MHz,DMSO-d6):δ11.35(s,1H),9.16(s,1H),8.87(d,J＝1.6Hz,1H),8.13(dd,J＝8.0,1.6Hz,1H),7.64(d,J＝8.0Hz,1H),6.71(s,2H),6.05(s,2H),6.01(s,2H),3.93-3.83(m,7H),3.65(d,J＝14.0Hz,1H),3.48(d,J＝12.4Hz,2H),3.09(d,J＝12.4Hz,2H)；ESI-HRMS:494.1547[M+H]+。
实施例10：
8-(4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-)-N-羟基-8-氧代辛酰胺(7)的合成
化合物7参考实施例3制备，仅将5-甲氧羰基噻吩-2-羧酸替换为辛二酸单甲酯。
1H NMR(400MHz,DMSO-d6):δ10.33(s,1H),8.66(s,1H),6.97(s,1H),6.75(s,1H),6.06(s,2H),6.01(s,2H),5.11(d,J＝13.6Hz,1H),4.65(d,J＝13.2Hz,1H),3.88(s,3H),3.86(s,3H),3.72(d,J＝13.2Hz,1H),3.27(d,J＝13.6Hz,1H),2.58-2.54(m,1H),2.44-2.37(m,1H),1.94(t,J＝7.2Hz,2H),1.56-1.46(m,4H),1.35-1.27(m,4H)；ESI-MS:515.09[M+H]+。
实施例11：
4-(4,10-二甲氧基-7,8-二氢-6H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-羰基)-N-羟基苯甲酰胺(8)的合成
化合物8参考实施例3制备，仅将5-甲氧羰基噻吩-2-羧酸替换为对苯二甲酸单甲酯。
1H NMR(400MHz,DMSO-d6):δ11.34(s,1H),9.16(s,1H),7.87(d,J＝8.0Hz,2H),7.56(d,J＝8.0Hz,2H),6.95(s,1H),6.41(s,1H),6.08(s,2H),6.03(s,2H)5.11(d,J＝13.6Hz,1H),4.27(d,J＝13.2Hz,1H),3.98-3.85(m,4H),3.81(s,3H),3.58(d,J＝13.6Hz,1H)；ESI-MS:506.99[M+H]+。
实施例12：
5-(4,10-二甲氧基-7,8-二氢-6H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-羰基)-N-羟基呋喃-2-甲酰胺(10)的合成
化合物10参考实施例3制备，仅将5-甲氧羰基噻吩-2-羧酸替换为5-甲氧羰基呋喃-2-羧酸。ESI-MS:497.11[M+H]+。
实施例13：
4-(2-(4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-)-2-氧代乙基)-N-羟基苯甲酰胺(11)的合成
化合物11参考实施例3制备，仅将5-甲氧羰基噻吩-2-羧酸替换为4-(甲氧羰基)苯乙酸。ESI-MS:521.16[M+H]+。
实施例14：
N-((5-(羟基氨基甲酰基)嘧啶-2-)甲基)-4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-甲酰胺(13)的合成
化合物13参考实施例4制备，仅将4-氨甲基苯甲酸甲酯盐酸盐替换为2-氨甲基嘧啶-5-甲酸甲酯盐酸盐。ESI-MS:538.16[M+H]+。
实施例15：
N-((5-(羟基氨基甲酰基)噻吩-2-)甲基)-4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-甲酰胺(14)的合成
化合物14参考实施例4制备，仅将4-氨甲基苯甲酸甲酯盐酸盐替换为5-氨甲基噻吩-2-羧酸甲酯盐酸盐。
1H NMR(400MHz,DMSO-d6):δ10.35(s,1H),9.10(s,0.7H),8.55(s,0.3H),7.51-7.40(m,1H),7.34(t,5.2Hz,1H),6.95(d,J＝2.8Hz,1H),6.78(s,2H),6.07(s,2H),6.02(s,2H),4.71(d,J＝13.2Hz,2H),4.48(dd,J＝15.6,5.2Hz,3H),4.37(dd,J＝15.6,5.2Hz,3H),3.88(s，6H)，3.46(d,J＝13.2Hz,2H)；ESI-HRMS:542.1226[M+H]+。
实施例16：
(E)-N-(4-(3-(羟基氨基)-3-氧代丙-1-烯-1-)苄基)-4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-甲酰胺(15)的合成
化合物15参考实施例4制备，仅将4-氨甲基苯甲酸甲酯盐酸盐替换为(E)-4-氨甲基苯丙烯酸甲酯盐酸盐。
1H NMR(400MHz,DMSO-d6):δ10.74(s,1H),9.03(s,1H),7.51(d,J＝7.6Hz,2H),7.44(d,J＝15.6Hz,1H),7.33(d,J＝8.0Hz,2H),7.18(t,J＝5.2Hz,1H),6.78(s,2H),6.44(d,J＝15.6Hz,1H),6.07(s,2H),6.02(s,2H),4.74(d,J＝13.2Hz,2H),4.36(dd,J＝15.6,5.2Hz,1H),4.25(dd,J＝15.6,5.2Hz,1H),3.87(s,6H),3.47(d,J＝13.2Hz,2H)；ESI-HRMS:562.1818[M+H]+。
实施例17：
N-(4-(羟基氨基甲酰基)苄基)-4,10-二甲氧基-N-甲基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-甲酰胺(16)的合成
化合物16参考实施例4制备，仅将4-氨甲基苯甲酸甲酯盐酸盐替换为4-((甲氨基)甲基)苯甲酸甲酯盐酸盐。
1H NMR(400MHz,DMSO-d6):δ11.20(s,1H),9.02(s,1H),7.76(d,J＝7.6Hz,2H),7.42(d,J＝7.2Hz,2H),6.75(s,2H),6.06(s,2H),6.01(s,2H),4.53(d,J＝15.2Hz,1H),4.28(d,J＝10.8Hz,1H),4.23(d,J＝12.8Hz,2H),3.87(s,6H),3.61(d,J＝12.8Hz,2H),2.79(s,3H)；ESI-MS:550.18[M+H]+。
实施例18：
N-(4-(羟基氨基甲酰基)苄基)-N-乙基-4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-甲酰胺(17)的合成
化合物17参考实施例4制备，仅将4-氨甲基苯甲酸甲酯盐酸盐替换为4-((乙氨基)甲基)苯甲酸甲酯盐酸盐。1H NMR(400MHz,DMSO-d6):δ11.20(s,1H),9.02(s,1H),7.75(d,J＝8.0Hz,2H),7.43(d,J＝7.6Hz,2H),6.73(s,2H),6.07(s,2H),6.01(s,2H),4.56(d,J＝15.6Hz,1H),4.32-4.17(m,3H),3.88(s,6H),3.62(d,J＝12.8Hz,2H),3.26–3.19(m,1H),3.16–3.04(m,1H),1.14(t,J＝6.4Hz,3H)；ESI-HRMS:564.1976[M+H]+。
实施例19：
N-(4-(羟基氨基甲酰基)苄基)-N-正丁基-4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-甲酰胺(18)的合成
化合物18参考实施例4制备，仅将4-氨甲基苯甲酸甲酯盐酸盐替换为4-((丁氨基)甲基)苯甲酸甲酯盐酸盐。
1H NMR(400MHz,DMSO-d6):δ11.21(s,1H),9.04(s,1H),7.74(d,J＝8.0Hz,2H),7.41(d,J＝8.0Hz,2H),6.69(s,2H),6.07(s,2H),6.01(s,2H),4.59(d,J＝15.6Hz,1H),4.24(d,J＝13.2Hz,2H),4.17(d,J＝16.0Hz,1H),3.87(s,6H),3.62(d,J＝13.2Hz,2H),3.28-3.20(m,1H),3.01-2.91(m,1H),1.61-1.51(m,2H),1.32-1.27(m,2H),0.87(t,J＝10.0Hz,3H)；ESI-MS:592.22[M+H]+。
实施例20：
N-(4-(羟基氨基甲酰基)苄基)-N-(3-羟基丙基)-4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-甲酰胺(19)的合成
化合物19参考实施例4制备，仅将4-氨甲基苯甲酸甲酯盐酸盐替换为4-(((3-羟丙基)氨基)甲基)苯甲酸甲酯盐酸盐。
1H NMR(400MHz,DMSO-d6):δ11.20(s,1H),9.03(s,1H),7.74(d,J＝8.4Hz,2H),7.39(d,J＝8.4Hz,2H),6.73(s,2H),6.06(s,2H),6.01(s,2H),4.58(d,J＝15.6Hz,1H),4.49(t,J＝5.2Hz,1H),4.29-4.19(m,3H),3.87(s,6H),3.61(d,J＝13.2Hz,2H),3.45-3.42(m,2H),3.30-3.23(m,1H),3.10-3.01(m,1H),1.79-1.70(m,2H)；ESI-HRMS:594.2084[M+H]+。
实施例21：
(E)-N-(4-(3-(羟基氨基)-3-氧代丙-1-烯-1-基)苄基)-N-甲基-4,10-二甲氧基-6,8-二氢-7H-[1,3]二恶茂[4',5':3,4]苯并[1,2-c][1,3]二恶茂[4',5':5,6]苯并[1,2-e]氮杂卓-7-甲酰胺(20)的合成
化合物20参考实施例4制备，仅将4-氨甲基苯甲酸甲酯盐酸盐替换为(E)-3-(4-((甲氨基)甲基)苯基)丙烯酸甲酯盐酸盐。ESI-HRMS:576.1980[M+H]+。
实施例22：本发明化合物的HDAC1酶抑制活性
本实施例以上市广谱HDACs抑制剂SAHA为阳性对照，采用Fluorescent-basedHDAC Activity Assay评价本发明化合物和SAHA的HDAC1酶抑制活性。本发明的其他化合物与以下所列举的化合物有类似的有益效果，但不应将此理解为本发明化合物仅具有以下有益效果。
HDAC1酶抑制活性的测试步骤为：配制待测化合物的DMSO溶液，并按试剂盒说明依次配制缓冲液、酶溶液以及相应的Substrate/Trypsin混合溶液；将梯度浓度的化合物溶液、酶溶液、Substrate/Trypsin混合溶液分别加入到384孔板中以配制催化反应体系(设无化合物对照、无酶对照孔)；室温孵育一定时间后，采用Synergy酶标仪连续读取荧光信号值，并选取线性反应段得到斜率(slope)，进而计算各浓度下的抑制率，IC50由GraphPadPrism 5软件拟合得到。
表1：化合物对HDAC1酶的抑制活性
上表中：“++++”代表0-20nM；“+++”代表20-100nM。
由表1中数据可知，所列举化合物均呈现出显著的HDAC1抑制活性，抑酶活性与SAHA相当或优于SAHA。
实施例22：本发明化合物的抗肿瘤细胞增殖活性
本实施例以SAHA为阳性对照，采用CCK-8法评价本发明化合物和SAHA对肺癌细胞株A549及结肠癌细胞株HCT116的抗增殖活性。本发明的其他化合物与以下所列举的化合物有类似的有益效果，但不应将此理解为本发明化合物仅具有以下有益效果。
抗肿瘤细胞增殖活性的测试步骤为：消化收集肿瘤细胞，以一定密度接种于96孔培养板，置于培养箱(37℃，5％CO2)中过夜。分别用不同浓度的化合物溶液处理细胞，化合物作用72h后，弃培养基，再用PBS轻轻洗涤细胞3次。随后，向培养板各孔中分别加入一定体积的培养基和CCK-8，继续培养一定时间。最后采用多功能酶标仪于570nm波长下测定吸光度OD值，计算抑制率，GI50值由GraphPad Prism 5软件拟合得到。
表2：化合物的抗肿瘤细胞增殖活性
上表中：“++++”代表＜0.1μM；“+++”代表0.1-1.0μM；“++”代表1.0-10μM；“+”代表10-50μM。
由表2中数据可知，所列举化合物均呈现出显著的抗肿瘤细胞增殖活性，抗增殖活性与SAHA相当或优于SAHA。
实施例23：本发明化合物的HDAC6选择性或I类HDACs选择性
文献表明，通过HDAC1、2、3、6、8、10、11酶抑制活性的测试可反映化合物对HDAC亚型抑制的选择性(Yu CW,et al.Quinazolin-2,4-dione-Based Hydroxamic Acids asSelective Histone Deacetylase-6Inhibitors for Treatment of Non-Small CellLung Cancer.J Med Chem,2019,62)
化合物对HDAC6和其他HDAC异构酶抑制活性的测试方法参考HDAC1抑制活性的测试方法，仅在测试相应酶抑制活性时更换催化反应体系底物。
以下通过本发明部分化合物对HDAC1、2、3、6、8、10、11的抑制活性数据，进一步阐述其对HDAC6或HDAC1/2/3的选择性。不应理解为本发明仅以下化合物具有HDAC6或HDAC1/2/3的选择性。
表3：化合物对HDAC1、2、3、6、8、10、11的抑制活性
上表中：“++++”代表0-10nM；“+++”代表10-100nM；“++”代表100-1000nM；“+”代表1000-10000nM。
由表3知，符合通式(I)的化合物3以及符合通式(III)的化合物12、19、20对HDAC6具有显著的抑酶活性，而对HDAC1、2、3、8、10、11的抑制活性则相对较弱，故为选择性的HDAC6抑制剂。化合物21具有显著的HDAC1、2、3抑制活性，而对HDAC6、8、10、11的抑制活性均相对较弱，故为选择性的HDAC1/2/3抑制剂。与广谱HDACs抑制剂SAHA相比，本发明化合物3、12、19、20、21在显著抑制剂相应HDAC亚型的同时，有利于降低SAHA对所有HDAC亚型抑制所产生的毒性。
综上，本发明制备的化合物具有良好的应用前景。
Claims (8)
1.一类HDAC抑制剂，其特征在于：所述抑制剂为如下列通式(I)–(IV)所示的联苯双酯衍生物及其药学上可接受的盐或氘代物：
上式中，W是(CH2)n1或至少被1个R1取代的C6-14芳基、C5-14芳杂基、C7-12芳烷基、C6-12芳杂烷基；
X是至少被1个R2取代的C6-14芳基、C5-14芳杂基、C7-12芳烷基、C6-12芳杂烷基或其中Y是至少被1个R3取代的C6-14芳基、C5-14芳杂基；
Z是至少被1个R4取代的C6-14芳基、C5-14芳杂基；
n1＝1-9；R1、R2、R3、R4分别独立地选自氢、卤素、羟基、氰基、氨甲酰基、C1-6烷基、C1-6烷氧基、C2-6不饱和脂链烃基；R5是氢、C1-6烷基或n2＝1-4。
2.根据权利要求1所述的一类HDAC抑制剂，其特征在于：所述联苯双酯衍生物选自以下化合物：
3.根据权利要求1所述的一类HDAC抑制剂，其特征在于：所述HDAC抑制剂为选择性的HDAC6抑制剂，所述选择性的HDAC6抑制剂为如通式(I)、(Ⅲ)所示的联苯双酯衍生物及其药学上可接受的盐或氘代物，
其中，通式(I)中W为至少被1个R1取代的C6-14芳基、C5-14芳杂基；
通式(III)中X为至少被1个R2取代的C6-14芳基、C5-14芳杂基或而Y是至少被1个R3取代的C6-14芳基、C5-14芳杂基；R1、R2、R3分别独立地选自氢、卤素、羟基、氰基、氨甲酰基、C1-6烷基、C1-6烷氧基、C2-6不饱和脂链烃基；R5是氢、C1-6烷基或n2＝1-4。
4.根据权利要求1所述的一类HDAC抑制剂，其特征在于：所述HDAC抑制剂为选择性的HDAC1/2/3抑制剂，所述HDAC1/2/3抑制剂为如通式(IV)所示的联苯双酯衍生物及其药学上可接受的盐或氘代物，
其中，通式(IV)中Z是至少被1个R4取代的C6-14芳基、C5-14芳杂基；R4独立地选自氢、卤素、羟基、氰基、氨甲酰基、C1-6烷基、C1-6烷氧基、C2-6不饱和脂链烃基。
5.一种HDAC抑制剂组合物，其特征在于：包括如权利要求1-4任一项所述的HDAC抑制剂以及至少一种药用载体或赋形剂。
6.根据权利要求5所述的一种HDAC抑制剂组合物，其特征在于：还包括至少一种其它治疗剂；所述HDAC抑制剂组合物的剂型为临床上或药学上可接受的任一剂型。
7.根据权利要求1-4任一项所述的一类HDAC抑制剂的用途，其特征在于：所述HDAC抑制剂在制备抗肿瘤、自身免疫性疾病、炎症或阿尔兹海默症药物中的应用。
8.根据权利要求5或6所述的组合物的用途，其特征在于：所述组合物在制备抗肿瘤、自身免疫性疾病、炎症或阿尔兹海默症药物中的应用。
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