CN117603123A - Novel indole HDAC6 small molecule inhibitor, preparation method and application - Google Patents
Novel indole HDAC6 small molecule inhibitor, preparation method and application Download PDFInfo
- Publication number
- CN117603123A CN117603123A CN202311457833.6A CN202311457833A CN117603123A CN 117603123 A CN117603123 A CN 117603123A CN 202311457833 A CN202311457833 A CN 202311457833A CN 117603123 A CN117603123 A CN 117603123A
- Authority
- CN
- China
- Prior art keywords
- hdac6
- small molecule
- molecule inhibitor
- novel indole
- solvent
- 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.)
- Pending
Links
- 102100022537 Histone deacetylase 6 Human genes 0.000 title claims abstract description 128
- 101000899330 Homo sapiens Histone deacetylase 6 Proteins 0.000 title claims abstract description 128
- 239000003112 inhibitor Substances 0.000 title claims abstract description 110
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 104
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims abstract description 100
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims abstract description 100
- -1 indole HDAC6 small molecule Chemical class 0.000 title claims abstract description 98
- 238000002360 preparation method Methods 0.000 title claims abstract description 70
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- 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 claims abstract description 30
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 24
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 24
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 24
- 230000000694 effects Effects 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 15
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 12
- 238000011282 treatment Methods 0.000 claims abstract description 10
- 230000009702 cancer cell proliferation Effects 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 67
- 239000000126 substance Substances 0.000 claims description 58
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- 239000000243 solution Substances 0.000 claims description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 45
- 239000002904 solvent Substances 0.000 claims description 44
- 238000006243 chemical reaction Methods 0.000 claims description 42
- 238000003756 stirring Methods 0.000 claims description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 33
- 239000002994 raw material Substances 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 25
- 239000003795 chemical substances by application Substances 0.000 claims description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 16
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 13
- 206010028980 Neoplasm Diseases 0.000 claims description 12
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- 230000002378 acidificating effect Effects 0.000 claims description 10
- 238000006482 condensation reaction Methods 0.000 claims description 10
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 5
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 5
- 235000011009 potassium phosphates Nutrition 0.000 claims description 5
- KCZFBLNQOSFGSH-UHFFFAOYSA-N tert-butyl n-(2-aminophenyl)carbamate Chemical group CC(C)(C)OC(=O)NC1=CC=CC=C1N KCZFBLNQOSFGSH-UHFFFAOYSA-N 0.000 claims description 5
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- JRHPOFJADXHYBR-HTQZYQBOSA-N (1r,2r)-1-n,2-n-dimethylcyclohexane-1,2-diamine Chemical compound CN[C@@H]1CCCC[C@H]1NC JRHPOFJADXHYBR-HTQZYQBOSA-N 0.000 claims description 2
- POCUPXSSKQAQRY-UHFFFAOYSA-N hydroxylamine;hydrate Chemical compound O.ON POCUPXSSKQAQRY-UHFFFAOYSA-N 0.000 claims description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 abstract description 15
- 239000013641 positive control Substances 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 8
- 238000012360 testing method Methods 0.000 abstract description 7
- 230000001419 dependent effect Effects 0.000 abstract description 5
- 238000011160 research Methods 0.000 abstract description 4
- 230000000259 anti-tumor effect Effects 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 abstract description 3
- 238000012827 research and development Methods 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 216
- 238000005481 NMR spectroscopy Methods 0.000 description 103
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
- 239000007787 solid Substances 0.000 description 56
- 238000004896 high resolution mass spectrometry Methods 0.000 description 55
- 238000002844 melting Methods 0.000 description 55
- 230000008018 melting Effects 0.000 description 55
- KMAKOBLIOCQGJP-UHFFFAOYSA-N indole-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-N 0.000 description 50
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- 238000001035 drying Methods 0.000 description 24
- 238000001704 evaporation Methods 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 18
- 238000004090 dissolution Methods 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 18
- 238000004809 thin layer chromatography Methods 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 15
- 239000012071 phase Substances 0.000 description 15
- 238000001914 filtration Methods 0.000 description 12
- 238000011068 loading method Methods 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 10
- 230000001105 regulatory effect Effects 0.000 description 10
- AQBJGAUQEJFPKZ-UHFFFAOYSA-N methyl 4-(aminomethyl)benzoate Chemical compound COC(=O)C1=CC=C(CN)C=C1 AQBJGAUQEJFPKZ-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 238000012544 monitoring process Methods 0.000 description 9
- 102000003964 Histone deacetylase Human genes 0.000 description 8
- 108090000353 Histone deacetylase Proteins 0.000 description 8
- 230000035755 proliferation Effects 0.000 description 8
- 238000000926 separation method Methods 0.000 description 7
- INNZWYJJSSRJET-UHFFFAOYSA-N 6-bromo-1h-indole-3-carboxylic acid Chemical compound BrC1=CC=C2C(C(=O)O)=CNC2=C1 INNZWYJJSSRJET-UHFFFAOYSA-N 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- BHFYJMNOBRLYSC-UHFFFAOYSA-N 2-methyl-1h-indole-3-carboxylic acid Chemical compound C1=CC=C2C(C(O)=O)=C(C)NC2=C1 BHFYJMNOBRLYSC-UHFFFAOYSA-N 0.000 description 4
- PHHZCIOPSFQASN-UHFFFAOYSA-N 6-methyl-1h-indole-3-carboxylic acid Chemical compound CC1=CC=C2C(C(O)=O)=CNC2=C1 PHHZCIOPSFQASN-UHFFFAOYSA-N 0.000 description 4
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 4
- FRDZGSBXKJXGNR-HTQZYQBOSA-N (1r,2r)-2-n,2-n-dimethylcyclohexane-1,2-diamine Chemical compound CN(C)[C@@H]1CCCC[C@H]1N FRDZGSBXKJXGNR-HTQZYQBOSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- NVNPLEPBDPJYRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CBr)C=C1 NVNPLEPBDPJYRZ-UHFFFAOYSA-N 0.000 description 2
- JVZMBSGNSAHFCY-UHFFFAOYSA-N 5-bromo-1h-indole-3-carboxylic acid Chemical compound C1=C(Br)C=C2C(C(=O)O)=CNC2=C1 JVZMBSGNSAHFCY-UHFFFAOYSA-N 0.000 description 2
- RVVSEZGJCOAUED-UHFFFAOYSA-N 5-methoxy-1h-indole-3-carboxylic acid Chemical compound COC1=CC=C2NC=C(C(O)=O)C2=C1 RVVSEZGJCOAUED-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000003893 Histone acetyltransferases Human genes 0.000 description 2
- 108090000246 Histone acetyltransferases Proteins 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000006196 deacetylation Effects 0.000 description 2
- 238000003381 deacetylation reaction Methods 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- WGVYCXYGPNNUQA-UHFFFAOYSA-N 1-(bromomethyl)-2-methylbenzene Chemical compound CC1=CC=CC=C1CBr WGVYCXYGPNNUQA-UHFFFAOYSA-N 0.000 description 1
- HXBMIQJOSHZCFX-UHFFFAOYSA-N 1-(bromomethyl)-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1CBr HXBMIQJOSHZCFX-UHFFFAOYSA-N 0.000 description 1
- FWLWTILKTABGKQ-UHFFFAOYSA-N 1-(bromomethyl)-3-methylbenzene Chemical compound CC1=CC=CC(CBr)=C1 FWLWTILKTABGKQ-UHFFFAOYSA-N 0.000 description 1
- LNWXALCHPJANMJ-UHFFFAOYSA-N 1-(bromomethyl)-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(CBr)=C1 LNWXALCHPJANMJ-UHFFFAOYSA-N 0.000 description 1
- GIGRWGTZFONRKA-UHFFFAOYSA-N 1-(bromomethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CBr)C=C1 GIGRWGTZFONRKA-UHFFFAOYSA-N 0.000 description 1
- WZRKSPFYXUXINF-UHFFFAOYSA-N 1-(bromomethyl)-4-methylbenzene Chemical compound CC1=CC=C(CBr)C=C1 WZRKSPFYXUXINF-UHFFFAOYSA-N 0.000 description 1
- ORPVVAKYSXQCJI-UHFFFAOYSA-N 1-bromo-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Br ORPVVAKYSXQCJI-UHFFFAOYSA-N 0.000 description 1
- WJIFKOVZNJTSGO-UHFFFAOYSA-N 1-bromo-3-methylbenzene Chemical compound CC1=CC=CC(Br)=C1 WJIFKOVZNJTSGO-UHFFFAOYSA-N 0.000 description 1
- FWIROFMBWVMWLB-UHFFFAOYSA-N 1-bromo-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(Br)=C1 FWIROFMBWVMWLB-UHFFFAOYSA-N 0.000 description 1
- ZBTMRBYMKUEVEU-UHFFFAOYSA-N 1-bromo-4-methylbenzene Chemical compound CC1=CC=C(Br)C=C1 ZBTMRBYMKUEVEU-UHFFFAOYSA-N 0.000 description 1
- ZDFBKZUDCQQKAC-UHFFFAOYSA-N 1-bromo-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Br)C=C1 ZDFBKZUDCQQKAC-UHFFFAOYSA-N 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QGXNHCXKWFNKCG-UHFFFAOYSA-N 2-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=CC=C1C#N QGXNHCXKWFNKCG-UHFFFAOYSA-N 0.000 description 1
- AFMPMSCZPVNPEM-UHFFFAOYSA-N 2-bromobenzonitrile Chemical compound BrC1=CC=CC=C1C#N AFMPMSCZPVNPEM-UHFFFAOYSA-N 0.000 description 1
- CVKOOKPNCVYHNY-UHFFFAOYSA-N 3-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=CC(C#N)=C1 CVKOOKPNCVYHNY-UHFFFAOYSA-N 0.000 description 1
- STXAVEHFKAXGOX-UHFFFAOYSA-N 3-bromobenzonitrile Chemical compound BrC1=CC=CC(C#N)=C1 STXAVEHFKAXGOX-UHFFFAOYSA-N 0.000 description 1
- LXWLEQZDXOQZGW-UHFFFAOYSA-N 3-bromofuran Chemical compound BrC=1C=COC=1 LXWLEQZDXOQZGW-UHFFFAOYSA-N 0.000 description 1
- XCMISAPCWHTVNG-UHFFFAOYSA-N 3-bromothiophene Chemical compound BrC=1C=CSC=1 XCMISAPCWHTVNG-UHFFFAOYSA-N 0.000 description 1
- UMLFTCYAQPPZER-UHFFFAOYSA-N 4-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=C(C#N)C=C1 UMLFTCYAQPPZER-UHFFFAOYSA-N 0.000 description 1
- QJPJQTDYNZXKQF-UHFFFAOYSA-N 4-bromoanisole Chemical compound COC1=CC=C(Br)C=C1 QJPJQTDYNZXKQF-UHFFFAOYSA-N 0.000 description 1
- HQSCPPCMBMFJJN-UHFFFAOYSA-N 4-bromobenzonitrile Chemical compound BrC1=CC=C(C#N)C=C1 HQSCPPCMBMFJJN-UHFFFAOYSA-N 0.000 description 1
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical compound OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 description 1
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 1
- TZNAHYKFVSHGDA-UHFFFAOYSA-N 5-methyl-1h-indole-3-carboxylic acid Chemical compound CC1=CC=C2NC=C(C(O)=O)C2=C1 TZNAHYKFVSHGDA-UHFFFAOYSA-N 0.000 description 1
- LPBGVZVDBKMWFS-UHFFFAOYSA-N 6-methoxy-1h-indole-3-carboxylic acid Chemical compound COC1=CC=C2C(C(O)=O)=CNC2=C1 LPBGVZVDBKMWFS-UHFFFAOYSA-N 0.000 description 1
- SRYCADDCUWPWAE-UHFFFAOYSA-N 7-methyl-1h-indole-3-carboxylic acid Chemical compound CC1=CC=CC2=C1NC=C2C(O)=O SRYCADDCUWPWAE-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102100039996 Histone deacetylase 1 Human genes 0.000 description 1
- 102000006947 Histones Human genes 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 101001035024 Homo sapiens Histone deacetylase 1 Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- GQRWKSOCRPULQJ-UHFFFAOYSA-N [bromo(cyclopropyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(Br)C1CC1 GQRWKSOCRPULQJ-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 108020001778 catalytic domains Proteins 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000009982 effect on human Effects 0.000 description 1
- 230000004049 epigenetic modification Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000006195 histone acetylation Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000001282 iso-butane Substances 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- VEDDBHYQWFOITD-UHFFFAOYSA-N para-bromobenzyl alcohol Chemical compound OCC1=CC=C(Br)C=C1 VEDDBHYQWFOITD-UHFFFAOYSA-N 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Indole Compounds (AREA)
Abstract
The invention belongs to the technical field of compound synthesis, and particularly relates to a novel indole HDAC6 small molecule inhibitor, a preparation method and application. The novel indole HDAC6 small molecule inhibitor is a compound shown in a formula I or pharmaceutically acceptable salt thereof;
Description
Technical Field
The invention belongs to the technical field of compound synthesis, and particularly relates to a novel indole HDAC6 small molecule inhibitor, a preparation method and application.
Background
Worldwide, cancer is the second leading cause of death next to cardiovascular disease. The treatment modes aiming at cancer mainly comprise operation treatment, radiotherapy and chemotherapy. At present, molecular targeted drug treatment is to effectively interfere with signal paths closely related to occurrence and development of cancers by using targeted drugs by taking certain cancerogenic sites as targets on the cellular molecular level, so as to realize high-efficiency tumor treatment. Compared with the traditional anti-tumor chemotherapeutic drugs, the reasonable use of the targeting drugs can greatly reduce the side effects of chemotherapy so as to achieve better cancer treatment effect.
Numerous studies have shown that the epigenetic modification processes of acetylation and deacetylation of histones play an important role in many biological processes. The level of histone acetylation in humans is maintained in dynamic equilibrium throughout the regulation of Histone Acetyltransferases (HATs) and Histone Deacetylases (HDACs). However, HDAC was found to be highly expressed in numerous tumor cells. Therefore, HDAC has been one of the hot targets for tumor-targeted therapies.
HDAC6 as a member of the class IIb histone deacetylase family, compared to other Zn 2+ The dependent HDACs have more obvious uniqueness. HDAC6 is located in the cytoplasm, contains two catalytic domains (CD 1 and CD 2) and one ubiquitin-binding zinc finger domain in the structure, and plays an important role in cancer, neurological diseases, inflammation and other diseases. The prior study proves that the abnormal expression of HDAC6 is closely related to the occurrence and development of gastric cancer, the over-expression can induce the transformation of normal cells to gastric cancer cells, Causing cancer. Thus, the occurrence and development of gastric cancer can be prevented by inhibiting the HDAC6 activity. However, currently reported HDAC6 inhibitors have little research for the treatment of gastric cancer.
Therefore, more small molecule HDAC6 inhibitors with strong drug effect and high selectivity are developed, and the method has important research value and application significance for treating gastric cancer and prognosis thereof.
Disclosure of Invention
In order to solve the above problems, a first object of the present invention is to provide a novel indole HDAC6 small molecule inhibitor which not only has a superior selective inhibitory effect on HDAC6, but also can inhibit gastric cancer cell proliferation in a concentration-dependent manner.
The second object of the present invention is to provide a method for preparing the novel indole HDAC6 small molecule inhibitor. A third object of the present invention is to provide the use of the novel indole HDAC6 small molecule inhibitors described above.
In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:
a novel indole HDAC6 small molecule inhibitor, which is a compound shown in a formula I or pharmaceutically acceptable salt thereof;
in the formula I, R 1 Selected from H, 5-CH 3 、6-CH 3 、7-CH 3 、5-OCH 3 、5-Br、6-Br、6-OCH 3 One of the following;
R 2 selected from H, CH 3 、 One of the following;
R 3 is H or CH 3 ；R 4 Selected from the group consisting ofOne of OH.
In view of improving the inhibitory effect of the compound on HDAC6 and the inhibitory effect on gastric cancer cell proliferation, a preferable embodiment is selected from the group consisting of compounds having the following structures, which are sequentially designated as compounds Z-1 to Z-55:
The preparation method of the novel indole HDAC6 small molecule inhibitor is characterized by comprising the following steps of:
when R is 2 H, R of a shape of H, R 4 Is thatIn the process, the preparation method of the novel indole HDAC6 small molecule inhibitor comprises the following steps:
(1) The method comprises the steps of (1) carrying out condensation reaction on a raw material A, a raw material B, a condensing agent a and an alkaline substance a in a solvent a to obtain an intermediate C;
(2) Reacting the intermediate C with hydroxylamine water solution in a solvent b, adding an alkaline substance b for reaction, adding an acidic substance and water after the reaction is finished, and performing suction filtration to obtain a novel indole HDAC6 micromolecule inhibitor shown as a compound M;
when R is 2 H, R of a shape of H, R 4 In the case of OH, the preparation method of the novel indole HDAC6 small molecule inhibitor comprises the following steps:
s1, carrying out condensation reaction on a raw material A, a raw material B, a condensing agent a and an alkaline substance a in a solvent a to obtain an intermediate C;
s2, reacting the intermediate C and the alkaline substance b in a solvent C to obtain a novel indole HDAC6 small molecule inhibitor shown in the compound J;
when R is 2 Not H, R 4 Is thatIn the process, the preparation method of the novel indole HDAC6 small molecule inhibitor comprises the following steps:
(1) the method comprises the steps of (1) carrying out condensation reaction on a raw material A, a raw material B, a condensing agent a and an alkaline substance a in a solvent a to obtain an intermediate C;
(2) Reacting the intermediate C, an alkaline substance C and a raw material a in a solvent d to obtain an intermediate E;
(3) reacting the intermediate E with hydroxylamine aqueous solution in a solvent b, adding an alkaline substance b for reaction, adding an acidic substance and water after the reaction is finished, and performing suction filtration to obtain a novel indole HDAC6 micromolecule inhibitor shown as a compound F;
when R is 2 H, R of a shape of H, R 4 Is thatIn the process, the preparation method of the novel indole HDAC6 small molecule inhibitor comprises the following steps:
s1, carrying out condensation reaction on a raw material A, a raw material B, a condensing agent a and an alkaline substance a in a solvent a to obtain an intermediate C;
s2, reacting the intermediate C and the alkaline substance b in a solvent C to obtain a compound J;
s3, reacting the compound J, the condensing agent b and the amine substance in a solvent d to obtain an intermediate K;
s4, dissolving the intermediate K in a solvent f, and then adding an acidic substance in a stirring state to react to obtain a novel indole HDAC6 small molecule inhibitor shown in a compound L;
when R is 2 Not H, R 4 Is thatIn the process, the preparation method of the novel indole HDAC6 small molecule inhibitor comprises the following steps:
carrying out condensation reaction on a raw material A, a raw material B, a condensing agent a and an alkaline substance a in a solvent a to obtain an intermediate C;
(ii) reacting the intermediate compound C, cuI, the raw material b and the amine substance in the solvent E to obtain an intermediate E';
(iii) reacting intermediate E' with alkaline material b in solvent d to obtain intermediate G;
(iv) reacting the intermediate G, the condensing agent b and the amine substance in the solvent d to obtain an intermediate H;
(v) dissolving the intermediate H in the solvent f, and then adding an acidic substance under stirring to react to obtain the novel indole HDAC6 small molecule inhibitor shown in the compound I.
For the purpose of improving the solubility of the raw materials and the yield of the product, preferably, the solvent a is methylene dichloride, the solvent b is a mixed solution of methylene dichloride and methanol, the solvent c is a mixed solution of methanol and water, the solvent d is N, N-dimethylformamide, the solvent e is toluene, and the solvent f is 1, 4-dioxane.
As a preferable scheme, the alkaline substance a is triethylamine, the alkaline substance b is sodium hydroxide, and the alkaline substance c is potassium hydroxide; the acidic substance is hydrochloric acid.
Preferably, the condensing agent a is EDCI or HOBT; the condensing agent b is EDCI or DMAP; the amine substance is N-Boc phenylenediamine.
Preferably, the raw material a is a bromo compound; the raw material b is trans (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexanediamine and anhydrous potassium phosphate.
The invention discloses application of novel indole HDAC6 small molecule inhibitors, in particular application in preparation of inhibitors based on HDAC6 targets or application in preparation of medicaments for targeted treatment of cancers based on the HDAC6 targets.
Further, the medicine comprises at least one of the novel indole HDAC6 small molecule inhibitors and pharmaceutically acceptable auxiliary materials; the mass content of the novel indole HDAC6 small molecule inhibitor is preferably 90% -98%; the present invention is not particularly limited to the auxiliary materials, and pharmaceutically acceptable auxiliary materials well known to those skilled in the art may be used.
Preferably, the cancer is gastric cancer. Further, the medicine is a medicine for inhibiting the proliferation activity of gastric cancer cells. The gastric cancer cell is MGC-803.
The novel indole HDAC6 small molecule inhibitor provided by the invention has a novel structure, has a good inhibiting effect on HDAC6, and can be used as an inhibitor of HDAC 6. And the compound can inhibit the proliferation activity of gastric cancer cells by chelating with metal ions in gastric cancer cells to form a stable complex. The preparation method of the compound provided by the invention has the characteristics of mild synthesis conditions, easiness in realization, and high yield and purity of the compound obtained by the method. Compared with a positive control vorinostat (SAHA), the novel indole HDAC6 small molecule inhibitor provided by the invention has a better selective inhibition effect on HDAC6 protein, and can inhibit gastric cancer cell (MGC-803) proliferation in a concentration dependent manner. Therefore, the compound has good application prospect in preparing inhibitors based on HDAC6 targets and medicines for inhibiting gastric cancer cell proliferation activity, and has important significance in research and development of inhibitors based on HDAC6 targets and antitumor medicines and research and treatment of related diseases.
Detailed Description
The invention is further described in connection with the following detailed description, which is not intended to be limiting.
Example 1
Novel indole HDAC6 small molecule inhibitor Z-1The preparation process is as follows:
(1) 1mmol of indole-3-carboxylic acid and 1.1mmol of methyl 4-aminomethylbenzoate are placed in a 250mL round bottom flask, methylene dichloride is added for dissolution, 2mmol of EDCI and 0.2mmol of HOBT are added sequentially while stirring at room temperature, then 1.1mmol of triethylamine is added, and the mixture is monitored by thin layer chromatography under normal temperature for 4 hours. Extracting with dichloromethane and water for 3 times, washing the lower organic phase with saturated NaCl solution, drying with anhydrous sodium sulfate, evaporating to dryness, parching with (100-200 mesh) silica gel, loading with 200-300 mesh silica gel on a separation column, and separating and purifying with (petroleum ether/ethyl acetate) solution of a certain proportion as mobile phase to obtain intermediate with 93% yield and 97% purity.
(2) Dissolving 1mmol of the intermediate obtained in the step (1) in DCM (MeOH=2:1), adding 30mmol of hydroxylamine aqueous solution (50% water) under stirring at room temperature of 650rpm, stirring at room temperature for 0.5h, adding 10mmol of sodium hydroxide for reaction for 10-30min, evaporating the organic solvent after the reaction of the raw materials is completed, adding a water dissolution system, then placing the organic solvent into an ice bath, adding dilute hydrochloric acid for regulating the pH value to 3-4, standing and suction filtering, pulping the obtained solid by using ethyl acetate, and finally drying to obtain the target compound Z-1, wherein the yield is 85%, the purity is 97%, the white solid has a melting point of 199.9-201.2 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.58(s,1H),11.17(s,1H),9.00(s,1H),8.49(d,J＝6.1Hz,1H),8.22-8.12(m,1H),8.08(d,J＝2.8Hz,1H),7.77-7.67(m,2H),7.42(dd,J＝12.1,8.1Hz,3H),7.19-7.04(m,2H),4.52(d,J＝6.0Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ165.12,164.64,144.28,136.62,131.60,128.35,127.49,127.35,126.62,122.37,121.47,120.85,112.30,110.84,42.14.HR-MS(ESI):calcd.C 17 H 15 N 3 O 3 ,[M+H]+m/z:310.1191,found:310.1194.
Example 2
Novel indole HDAC6 small molecule inhibitor Z-2The preparation process is as follows:
(1) 1mmol of indole-3-carboxylic acid and 1.1mmol of methyl 4-aminomethylbenzoate are placed in a 250mL round bottom flask, methylene chloride is added for dissolution, 2mmol of EDCI and 0.2mmol of HOBT are added sequentially while stirring at room temperature, then 1.1mmol of triethylamine is added, and the mixture is monitored by thin layer chromatography at normal temperature for 4 hours. Extracting with dichloromethane and water for 3 times, washing the lower organic phase with saturated NaCl solution, drying with anhydrous sodium sulfate, evaporating to dryness, adding (100-200 mesh) silica gel, parching, loading on column (200-300 mesh), and separating and purifying with (petroleum ether/ethyl acetate) solution of a certain proportion as mobile phase to obtain intermediate; the yield was 93% and the purity was 97%.
(2) 1mmol of the substance obtained in the step (1) is dissolved in DMF, and 3mmol of potassium hydroxide and 2mmol of bromomethane are added to react for 3-4 hours under the stirring condition of 650rpm at room temperature. After the TLC monitoring reaction is completed, ethyl acetate and water are used for extraction for 3 times, an upper organic phase is washed by saturated NaCl solution, dried by anhydrous sodium sulfate, evaporated to dryness, added with silica gel for stir-frying, packed into a column, and petroleum ether/ethyl acetate is used as a mobile phase for separation and purification to obtain an intermediate; the yield was 93% and the purity was 97%.
(3) Dissolving 1mmol of the substance obtained in the step (2) in DCM (MeOH=2:1), adding 30mmol of hydroxylamine aqueous solution (50% water) under stirring at room temperature of 650rpm, stirring at room temperature for 0.5h, adding 10mmol of sodium hydroxide, reacting for 10-30min, evaporating the organic solvent after the reaction of the raw materials is detected to be complete, adding the water dissolution system, then placing the organic solvent in an ice bath, adding dilute hydrochloric acid to adjust the pH value to 3-4, standing, suction filtering, pulping the obtained solid by ethyl acetate, and finally drying to obtain the target compound, wherein the yield is 75%, the purity is 97% of a white solid, and the melting point is 193.0-193.2 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.17(s,1H),8.50(t,J＝6.0Hz,1H),8.15(d,J＝7.8Hz,1H),8.05(s,1H),7.71(d,J＝8.0Hz,2H),7.49(d,J＝8.2Hz,1H),7.39(d,J＝8.0Hz,2H),7.22(t,J＝7.6Hz,1H),7.15(t,J＝7.5Hz,1H),4.50(d,J＝5.8Hz,2H),3.83(s,3H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.75,164.66,144.23,137.22,132.36,131.62,127.49,127.35,126.93,122.46,121.60,121.12,110.70,109.89,42.17,33.45.HR-MS(ESI):calcd.C 18 H 17 N 3 O 3 ,[M+H]+m/z:324.1348,found:324.1349.
Example 3
Novel indole HDAC6 small molecule inhibitor Z-3 with structural formula as followsThe preparation process differs from example 2 in that: the bromomethane in the step (2) was adjusted to bromoethane, and the rest was the same as in example 2. The compound of the structure shown in the formula Z-3 is obtained in 80% yield and is white solid, and the melting point is 207.0-207.3 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.38-11.02(m,1H),9.00(s,1H),8.49(dt,J＝6.2,3.7Hz,1H),8.20-8.08(m,2H),7.71(dd,J＝8.3,2.1Hz,2H),7.54(d,J＝8.2Hz,1H),7.40(dd,J＝8.3,2.1Hz,2H),7.17(dt,J＝26.7,7.0Hz,2H),4.52(dd,J＝14.2,5.8Hz,2H),4.24(qd,J＝7.3,2.1Hz,2H),1.41(td,J＝7.3,2.1Hz,3H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.79,164.65,144.22,136.29,131.63,130.64,127.70,127.56,127.36,127.10,122.41,121.73,121.11,110.71,110.03,42.18,41.21,15.59.HR-MS(ESI):calcd.C 19 H 19 N 3 O 3 ,[M+H]+m/z:338.1504,found:338.1507.
Example 4
Novel indole HDAC6 small molecule inhibitor Z-4 with structural formula as followsThe preparation process differs from example 2 in that: the bromomethane in the step (2) was adjusted to bromopropane, and the rest was the same as in example 2. The yield of the structure of formula Z-4 is 78%, white solid, melting point 203.0-203.4 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.16(s,1H),8.97(s,1H),8.46(d,J＝6.1Hz,1H),8.16(d,J＝7.8Hz,1H),8.10(s,1H),7.75-7.67(m,2H),7.54(d,J＝8.1Hz,1H),7.41(d,J＝8.0Hz,2H),7.17(dt,J＝25.7,7.3Hz,2H),4.51(d,J＝6.0Hz,2H),4.17(t,J＝6.9Hz,2H),1.81(h,J＝7.2Hz,2H),0.87(t,J＝7.3Hz,3H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.79,164.64,144.20,136.63,131.64,131.37,127.58,127.35,127.01,122.40,121.71,121.05,110.82,109.93,47.94,42.20,23.37,11.6.HR-MS(ESI):calcd.C 20 H 21 N 3 O 3 ,[M+H]+m/z:352.1661,found:352.1662.
Example 5
Novel indole HDAC6 small molecule inhibitor Z-5 with structural formula as follows The preparation process differs from example 2 in that: the bromomethane in the step (2) was adjusted to be isobromopropane, and the rest was the same as in example 2. The yield of the structure of formula Z-5 was 76%, a white solid, melting point 189.9-191.2 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ8.49(d,J＝6.1Hz,1H),8.33-8.10(m,2H),7.73(d,J＝7.9Hz,2H),7.56(d,J＝8.2Hz,1H),7.42(d,J＝7.9Hz,2H),7.17(dt,J＝25.7,7.4Hz,2H),4.78(h,J＝6.8Hz,1H),4.52(d,J＝5.9Hz,2H),1.48(d,J＝6.6Hz,6H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.90,164.60,144.13,136.09,131.64,127.65,127.35,127.13,122.38,121.75,121.19,110.82,110.07,47.41,42.19,22.89.HR-MS(ESI):calcd.C 20 H 21 N 3 O 3 ,[M+H]+m/z:352.1661,found:352.1666.
Example 6
Novel indole HDAC6 small molecule inhibitor Z-6 with structural formula as followsThe preparation process differs from example 2 in that: the bromomethane in the step (2) was adjusted to isobutane, and the rest was the same as in example 2. The yield of the structure of formula Z-6 was 69%, a white solid, melting point 177.8-178.5 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ8.49(d,J＝6.2Hz,1H),8.17(d,J＝7.9Hz,1H),8.10(s,1H),7.72(d,J＝7.9Hz,2H),7.53(d,J＝8.2Hz,1H),7.40(d,J＝7.9Hz,2H),7.17(dt,J＝26.6,7.3Hz,2H),4.51(d,J＝5.8Hz,2H),4.20(t,J＝7.0Hz,2H),1.77(p,J＝7.2Hz,2H),1.33-1.22(m,3H),0.90(t,J＝7.4Hz,3H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.82,164.45,144.04,136.58,131.72,131.31,127.57,127.28,127.00,122.43,121.71,121.07,110.78,109.92,46.06,42.19,32.08,19.92,13.98.HR-MS(ESI):calcd.C 21 H 23 N 3 O 3 ,[M+H]+m/z:366.1817,found:366.1818.
Example 7
Novel indole HDAC6 small molecule inhibitor Z-7 with structural formula as followsThe preparation process differs from example 2 in that: the bromomethane in the step (2) was adjusted to bromomethyl cyclopropane, and the rest was the same as in example 2. The structure of formula Z-7 was obtained in 67% yield as a white solid with a melting point of 177.7-178.7deg.C. 1 H NMR(400MHz,DMSO-d6,ppm)δ8.51(t,J＝6.0Hz,1H),8.23-8.13(m,2H),7.72(d,J＝7.9Hz,2H),7.57(d,J＝8.2Hz,1H),7.40(d,J＝7.9Hz,2H),7.17(dt,J＝26.0,7.3Hz,2H),4.51(d,J＝5.8Hz,2H),4.08(d,J＝7.0Hz,2H),1.27(dd,J＝15.9,6.8 Hz,1H),0.57(q,J＝5.4,4.9 Hz,2H),0.42(t,J＝5.0 Hz,2H). 13 C NMR(101 MHz,DMSO-d6,ppm)δ164.82,164.54,144.20,136.67,131.65,131.07,127.56,127.33,126.99,122.40,121.66,121.08,110.86,110.01,50.52,42.18,31.62,30.31,11.68,4.33.HR-MS(ESI):calcd.C 21 H 21 N 3 O 3 ,[M+H]+m/z:364.1661,found:364.1666.
Example 8
Novel indole HDAC6 small molecule inhibitor Z-8 with structural formula as followsThe preparation process differs from example 2 in that: the bromomethane in the step (2) was adjusted to benzyl bromide, and the rest was the same as in example 2. The yield of the structure of formula Z-8 was 87%, a white solid, melting point 137.1-137.9 ℃. 1 H NMR(400 MHz,DMSO-d6,ppm)δ11.20(s,1H),9.01(s,1H),8.58(t,J＝6.0 Hz,1H),8.23-8.15(m,2H),7.72(d,J＝7.9 Hz,2H),7.54(d,J＝8.0 Hz,1H),7.40(d,J＝8.0 Hz,2H),7.34(t,J＝7.2 Hz,2H),7.27(t,J＝8.3 Hz,3H),7.21-7.10(m,2H),5.47(s,2H),4.50(d,J＝5.7 Hz,2H). 13 C NMR(101 MHz,DMSO-d6,ppm)δ164.71,164.65,144.15,137.90,136.65,131.71,131.65,129.16,128.11,127.73,127.60,127.37,127.12,122.65,121.77,121.26,111.12,110.59,49.95,42.23.HR-MS(ESI):calcd.C 24 H 21 N 3 O 3 ,[M+H]+m/z:400.1661,found:400.1666.
Example 9
Novel indole HDAC6 small molecule inhibitor Z-9 with structural formula as follows The preparation process differs from example 2 in that: the bromomethane in the step (2) was adjusted to 4-methoxybenzyl bromide, and the rest was the same as in example 2. The yield of the structure of formula Z-9 was 72%, a white solid, melting point 146.7-147.6 ℃. 1 H NMR(400 MHz,DMSO-d6,ppm)δ11.20(s,1H),9.06(d,J＝13.2 Hz,1H),8.55(t,J＝6.0 Hz,1H),8.16(d,J＝8.3 Hz,2H),7.72(d,J＝7.8 Hz,2H),7.56(d,J＝8.0 Hz,1H),7.41(d,J＝8.0 Hz,2H),7.30-7.10(m,4H),6.90(d,J＝8.2 Hz,2H),5.37(s,2H),4.51(d,J＝6.0 Hz,2H),3.71(s,3H). 13 C NMR(101 MHz,DMSO-d6,ppm)δ164.79,159.25,144.15,136.54,131.59,131.50,129.65,129.32,127.60,127.35,127.13,122.59,121.71,121.24,114.53,111.16,110.39,55.55,49.47,42.21.HR-MS(ESI):calcd.C 25 H 23 N 3 O 4 ,[M+H]+m/z:430.1767,found:430.1768.
Example 10
Novel indole HDAC6 small molecule inhibitor Z-10 with structural formula as followsThe preparation process differs from example 2 in that: and (3) adjusting the bromomethane in the step (2) to be 4-methylbenzyl bromide. Compound Z-10 is produced in 66% yield as a white solid with a melting point of 131.6-132.0deg.C. 1 H NMR(400 MHz,DMSO-d6,ppm)δ11.19(s,1H),9.01(s,1H),8.55(t,J＝6.0 Hz,1H),8.27-8.04(m,2H),7.71(d,J＝8.0 Hz,2H),7.53(d,J＝8.0 Hz,1H),7.40(d,J＝8.0 Hz,2H),7.14(p,J＝7.3,6.6 Hz,7H),5.41(s,2H),4.52(dd,J＝13.8,5.9 Hz,2H),2.25(s,3H). 13 C NMR(101 MHz,DMSO-d6,ppm)δ164.72,144.15,137.36,136.61,134.80,131.64,129.68,127.81,127.59,127.35,127.15,122.57,121.75,121.21,111.13,110.48,49.77,42.21,21.13.HR-MS(ESI):calcd.C 25 H 23 N 3 O 3 ,[M+H]+m/z:414.1817,found:414.1818.
Example 11
Novel indole HDAC6 small molecule inhibitor Z-11 with structural formula as followsThe preparation process differs from example 2 in that: the bromomethane in the step (2) was adjusted to 2-methylbenzyl bromide, and the rest was the same as in example 2. The yield of the structure of formula Z-11 was 55%, a white solid, melting point 189.5-190.7 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ8.57(d,J＝6.3Hz,1H),8.17(d,J＝7.5Hz,1H),7.97(s,1H),7.68(d,J＝7.8Hz,2H),7.46(d,J＝7.6Hz,1H),7.38(d,J＝7.9Hz,2H),7.18(dq,J＝13.4,7.8,7.0Hz,4H),7.09(t,J＝7.5Hz,1H),6.73(d,J＝7.7Hz,1H),5.43(s,2H),4.48(d,J＝5.9Hz,2H),2.27(s,3H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.68,164.49,144.08,136.97,136.37,135.68,131.70,131.44,130.83,128.15,127.71,127.56,127.30,127.03,126.63,122.67,121.86,121.30,111.05,110.60,48.07,42.18,19.24.HR-MS(ESI):calcd.C 25 H 23 N 3 O 3 ,[M+H]+m/z:414.1817,found:414.1822.
Example 12
Novel indole HDAC6 small molecule inhibitor Z-12 has a structural formula ofThe preparation process differs from example 2 in that: and (3) adjusting the bromomethane in the step (2) to be 3-methylbenzyl bromide. The yield of the structure of formula Z-12 was 67%, a white solid, melting point 110.0-111.3 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.18(s,1H),8.99(s,1H),8.56(t,J＝6.0Hz,1H),8.17(d,J＝7.9Hz,2H),7.77-7.68(m,2H),7.53(d,J＝8.0Hz,1H),7.41(d,J＝7.9Hz,2H),7.26-7.01(m,6H),5.42(s,2H),4.50(d,J＝5.8Hz,2H),2.26(s,3H). 13 CNMR(101MHz,DMSO-d6,ppm)δ164.71,144.14,138.34,137.81,136.67,131.69,129.08,128.80,128.32,127.59,127.35,127.10,124.90,122.63,121.75,121.24,111.11,110.53,49.96,42.22,21.47.HR-MS(ESI):calcd.C 25 H 23 N 3 O 3, [M+H]+m/z:414.1817,found:414.1823./>
Example 13
Novel indole HDAC6 small molecule inhibitor Z-13 with structural formula as followsThe preparation process differs from example 2 in that: the bromomethane in the step (2) was adjusted to 4-fluorobenzyl bromide, and the rest was the same as in example 2. The yield of the structure of formula Z-13 was 69%, white solid, melting point 141.1-142.2 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.43-10.89(m,1H),9.05(s,1H),8.57(t,J＝5.9Hz,1H),8.17(d,J＝8.9Hz,2H),7.72(d,J＝7.8Hz,2H),7.55(d,J＝8.0Hz,1H),7.40(d,J＝7.9Hz,2H),7.32(dd,J＝8.4,5.5Hz,2H),7.17(td,J＝8.3,7.5,3.3Hz,4H),5.46(s,2H),4.50(d,J＝5.9Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.68,163.28,160.85,144.14,136.55,134.09,134.06,131.65,131.59,129.95,129.87,127.60,127.37,127.14,122.68,121.78,121.30,116.07,115.86,111.08,110.69,49.17,42.22.HR-MS(ESI):calcd.C 24 H 20 FN 3 O 3 ,[M+H]+m/z:418.1567,found:418.1573.
Example 14
Novel indole HDAC6 small molecule inhibitor Z-14 with structural formula as followsThe preparation process differs from example 2 in that: the bromomethane in the step (2) was adjusted to 4-cyanobenzyl bromide, and the rest was the same as in example 2. The yield of the structure shown in Z-14 is 59%, the white solid, the melting point is 198.9-201.3 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.58(s,1H),9.00(s,1H),8.52(dt,J＝19.4,5.9Hz,1H),8.18(d,J＝8.7Hz,1H),7.83(d,J＝7.9Hz,1H),7.72(d,J＝7.9Hz,2H),7.63(d,J＝7.9Hz,1H),7.52(t,J＝7.5Hz,1H),7.41(d,J＝8.2Hz,2H),7.31(t,J＝8.8Hz,1H),7.25(d,J＝7.8Hz,1H),7.21-7.07(m,2H),5.50(d,J＝18.5Hz,2H),4.52(t,J＝5.0Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ168.00,165.12,164.69,144.28,141.00,136.62,133.27,133.14,131.73,128.44,128.35,127.61,127.49,127.35,127.13,126.62,126.19,122.71,122.36,121.78,121.47,121.33,120.84,112.30,111.12,110.83,42.24,42.14.HR-MS(ESI):calcd.C 25 H 20 N 4 O 3 ,[M+H]+m/z:425.1613,found:425.1614.
Example 15
Novel indole HDAC6 small molecule inhibitor Z-15 with structural formula as followsThe preparation process differs from example 2 in that: and (3) adjusting the bromomethane in the step (2) to 3-cyanobenzyl bromide. The yield of the structure shown in Z-15 is 56%, white solid, melting point 155.7-156.6 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.17(s,1H),8.98(s,1H),8.57(t,J＝6.2Hz,1H),8.26-8.14(m,2H),7.79(d,J＝7.6Hz,1H),7.71(d,J＝8.0Hz,2H),7.62-7.49(m,2H),7.39(dd,J＝13.4,7.4Hz,4H),7.16(p,J＝7.2Hz,2H),5.50(d,J＝8.1Hz,2H),4.50(d,J＝5.7Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ168.05,164.69,144.13,138.05,136.63,135.18,131.81,131.73,131.65,130.56,129.84,129.19,129.09,127.63,127.60,127.37,127.21,127.14,127.06,122.70,121.79,121.31,111.10,110.70,110.66,49.85,42.23.HR-MS(ESI):calcd.C 25 H 20 N 4 O 3 ,[M+H]+m/z:425.1613,found:425.1614.
Example 16
Novel indole HDAC6 small molecule inhibitor Z-16 with structural formula as followsThe preparation process differs from example 2 in that: the bromomethane in the step (2) was adjusted to 2-cyanobenzyl bromide, and the rest was the same as in example 2. The yield of the structure of formula Z-16 was 45%, a white solid, melting point 149.1-151.7 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.18(s,1H),8.99(s,1H),8.58(dd,J＝15.4,9.5Hz,1H),8.17(dd,J＝27.1,6.2Hz,2H),7.93(d,J＝7.8Hz,1H),7.68(dd,J＝31.0,7.7Hz,3H),7.52(t,J＝7.3Hz,1H),7.44-7.36(m,2H),7.36-7.31(m,1H),7.24-7.11(m,2H),7.06(d,J＝7.9Hz,1H),5.68(d,J＝16.3Hz,2H),4.50(d,J＝5.9Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ170.84,164.73,164.65,144.15,136.79,135.88,135.81,133.88,132.20,131.64,130.57,129.84,128.56,128.26,128.01,127.92,127.74,127.60,127.49,127.36,127.10,122.69,121.75,121.28,111.01,110.58,47.61,42.24.HR-MS(ESI):calcd.C 25 H 20 N 4 O 3 ,[M+H]+m/z:425.1613,found:425.1616.
Example 17
Novel indole HDAC6 small molecule inhibitor Z-17 with structural formula as followsThe preparation process differs from example 2 in that: the bromomethane in the step (2) was adjusted to 2-nitrobenzyl bromide, and the rest was the same as in example 2. The yield of the structure shown in Z-17 is 43%, and the melting point is 157.8-158.1 ℃ as a light yellow solid. 1 H NMR(400 MHz,DMSO-d6,ppm)δ11.19(s,1H),9.01(s,1H),8.60(t,J＝5.8 Hz,1H),8.25-8.14(m,2H),8.11(s,1H),7.72(d,J＝7.9 Hz,2H),7.60(dt,J＝22.1,7.5 Hz,2H),7.44(dd,J＝23.7,6.5 Hz,3H),7.23-7.13(m,2H),6.62(d,J＝7.6 Hz,1H),5.88(s,2H),4.51(d,J＝5.8 Hz,2H). 13 C NMR(101 MHz,DMSO-d6,ppm)δ164.65,147.77,144.08,136.89,134.85,133.44,132.00,131.61,129.43,128.74,127.62,127.35,126.99,125.65,123.01,121.85,121.60,111.20,111.14,47.52,42.23.HR-MS(ESI):calcd.C 24 H 20 N 4 O 5 ,[M+H]+m/z:445.1512,found:445.1515.
Example 18
Novel indole HDAC6 small molecule inhibitor Z-18 with structural formula as followsThe preparation process differs from example 2 in that: the bromomethane in the step (2) was adjusted to 3-nitrobenzyl bromide, and the rest was the same as in example 2. The yield of the structure of formula Z-18 was 57%, a pale yellow solid, melting point 165.9-167.3 ℃. 1 H NMR(400 MHz,DMSO-d 6 ,ppm)δ11.18(s,1H),8.99(s,1H),8.57(t,J＝6.1 Hz,1H),8.28-8.11(m,4H),7.73(d,J＝8.0 Hz,2H),7.68-7.61(m,2H),7.57(d,J＝8.1 Hz,1H),7.44(dd,J＝20.5,7.9 Hz,2H),7.18(p,J＝7.0Hz,2H),5.66(s,2H),4.52(d,J＝6.1 Hz,2H). 13 C NMR(101 MHz,DMSO-d 6 ,ppm)δ164.63,148.43,144.08,140.24,136.56,134.34,131.69,130.83,129.84,127.74,127.60,127.37,127.12,123.15,122.90,122.42,121.85,121.48,111.05,49.03,42.24.HR-MS(ESI):calcd.C 24 H 20 N 4 O 5 ,[M+H] + m/z:445.1512,found:445.1513.
Example 19
Novel indole HDAC6 small molecule inhibitor Z-19 with structural formula as followsThe preparation process differs from example 2 in that: the bromomethane in the step (2) was adjusted to 4-nitrobenzyl bromide, and the rest was the same as in example 2. The yield of the structure of formula Z-19 was 62%, as a pale yellow solid, melting point 172.9-174.1 ℃. 1 H NMR(400 MHz,DMSO-d6,ppm)δ8.58(dq,J＝12.3,6.2 Hz,1H),8.31-8.15(m,3H),7.92(d,J＝7.9 Hz,1H),7.72(d,J＝7.8Hz,1H),7.61-7.37(m,4H),7.37-7.24(m,2H),7.15(ddt,J＝22.3,14.7,6.4 Hz,2H),5.81-5.39(m,2H),4.57-4.48(m,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ167.70,164.61,147.45,146.01,145.67,137.90,136.60,131.81,131.64,129.84,129.63,129.54,129.15,128.71,128.11,127.76,127.73,127.62,127.36,127.14,124.37,122.89,122.64,121.87,121.77,121.48,119.89,111.03,49.95,49.26,42.26.HR-MS(ESI):calcd.C 24 H 20 N 4 O 5 ,[M+H]+m/z:445.1512,found:445.1513.
Example 20
Novel indole HDAC6 small molecule inhibitor Z-20The preparation process is as follows:
(1) 1mmol of indole-3-carboxylic acid and 1.1mmol of methyl 4-aminomethylbenzoate are placed in a 250mL round bottom flask, methylene dichloride is added for dissolution, 2mmol of EDCI and 0.2mmol of HOBT are added sequentially while stirring at room temperature, then 1.1mmol of triethylamine is added, and the mixture is monitored by thin layer chromatography under normal temperature for 4 hours. Extracting with dichloromethane and water for 3 times, washing the lower organic phase with saturated NaCl solution, drying with anhydrous sodium sulfate, evaporating to dryness, adding (100-200 mesh) silica gel, parching, loading onto column (200-300 mesh), and separating and purifying with (petroleum ether/ethyl acetate) solution as mobile phase to obtain intermediate; the yield was 93% and the purity was 97%.
(2) 1mmol of the substance obtained in the step (1) and 0.6mmol of anhydrous potassium phosphate are dissolved in toluene, and then 1.2mmol of bromobenzene, 0.3mmol of CuI as a catalyst and 2.1mmol of trans (1R, 2R) -N, N-dimethyl-1, 2-cyclohexanediamine are added under stirring at room temperature of 650rpm, and reacted for 4 to 5 hours in an oil bath at 110 ℃. After the reaction is monitored, the system is extracted for 3 times by ethyl acetate and water, the upper organic phase is washed by saturated NaCl solution, dried by anhydrous sodium sulfate and evaporated to dryness, a silica gel stir-fried sample is added, a column is packed, petroleum ether/ethyl acetate is used as a mobile phase for separation and purification, and the yield of the intermediate is 93%, and the purity is 97%.
(3) Dissolving 1mmol of the substance obtained in the step (2) in DCM (MeOH=2:1), adding 30mmol of hydroxylamine aqueous solution (50% water) into the solution at a stirring state of 650rpm at room temperature, stirring the solution for 0.5h at room temperature, adding 10mmol of sodium hydroxide to react for 10-30min, evaporating the organic solvent after the reaction of the raw materials is completed, adding a water dissolution system, then placing the organic solvent into an ice bath, adding dilute hydrochloric acid to adjust the pH value to 3-4, standing and suction-filtering, pulping the obtained solid by using ethyl acetate, and finally drying to obtain the target compound Z-20, wherein the yield is 73%, white solid, and the melting point is 129.8-131.2 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.21(s,1H),9.02(s,1H),8.72(t,J＝6.0Hz,1H),8.42(s,1H),8.36-8.14(m,1H),7.73(d,J＝8.0Hz,2H),7.68-7.60(m,4H),7.57-7.52(m,1H),7.49(dp,J＝5.3,2.4Hz,1H),7.44(d,J＝8.0Hz,2H),7.26(tt,J＝7.7,5.8Hz,2H),4.55(d,J＝5.8Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ167.69,164.51,145.87,143.93,138.80,136.05,131.69,131.15,130.48,129.86,129.70,127.88,127.80,127.76,127.61,127.39,124.70,123.64,122.19,122.13,112.33,111.17,42.24.HR-MS(ESI):calcd.C 23 H 19 N 3 O 3 ,[M+H]+m/z:386.1504,found:386.1515.
Example 21
Novel indole HDAC6 small molecule inhibitor Z-21 with structural formula as followsThe preparation process differs from example 20 in that: the bromobenzene in the step (2) was adjusted to 4-methoxybromobenzene, and the rest was the same as in example 2. The structure of formula Z-21 is produced in 75% yield as a white solid with a melting point of 177.8-179.3 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ8.65(t,J＝6.1Hz,1H),8.36-8.22(m,2H),7.73(d,J＝8.0Hz,2H),7.60-7.50(m,2H),7.47-7.38(m,3H),7.29-7.11(m,4H),4.54(d,J＝5.7Hz,2H),3.85(s,3H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.57,158.90,143.80,136.52,131.64,131.34,127.57,127.49,127.32,126.34,123.44,122.08,121.90,115.53,111.77,111.06,55.99,42.23.HR-MS(ESI):calcd.C 24 H 21 N 3 O 4 ,[M+H]+m/z:416.1610,found:416.1619.
Example 22
Novel indole HDAC6 small molecule inhibitor Z-22 with structural formula as followsThe preparation process differs from example 20 in that: the bromobenzene in the step (2) was adjusted to 4-methyl bromobenzene, and the rest was the same as in example 2. The yield of the structure of formula Z-22 was 68%, a white solid, melting point 121.4-122.8 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.19(s,1H),8.98(s,1H),8.69(t,J＝6.1Hz,1H),8.38(s,1H),8.31-8.22(m,1H),7.73(d,J＝8.0Hz,2H),7.51(t,J＝7.2Hz,3H),7.43(d,J＝7.9Hz,4H),7.24(tt,J＝7.7,5.8Hz,2H),4.54(d,J＝5.8Hz,2H),2.41(s,3H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.63,164.54,143.95,137.40,136.31,136.18,131.71,131.10,130.86,129.87,127.69,127.60,127.40,124.59,123.54,122.14,122.02,112.08,111.16,42.25,21.09.HR-MS(ESI):calcd.C 24 H 21 N 3 O 3 ,[M+H]+m/z:400.1661,found:400.1668.
Example 23
Novel indole HDAC6 small molecule inhibitor Z-23, structural formulaIs thatThe preparation process differs from example 20 in that: the bromobenzene in the step (2) was adjusted to 3-methyl bromobenzene, and the rest was the same as in example 2. The yield of the structure of formula Z-23 was 46%, a white solid, melting point 159.6-161.7 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ8.69(t,J＝6.0Hz,1H),8.39(s,1H),8.33-8.24(m,1H),7.74(d,J＝7.9Hz,2H),7.56(d,J＝7.8Hz,1H),7.51(t,J＝7.7Hz,1H),7.44(t,J＝7.9Hz,4H),7.26(dq,J＝13.2,7.0Hz,3H),4.55(d,J＝5.9Hz,2H),2.43(s,3H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.54,143.79,140.22,138.73,136.03,131.05,130.23,128.52,127.75,127.60,127.33,125.10,123.62,122.15,122.10,121.68,112.19,111.27,42.25,21.39.HR-MS(ESI):calcd.C 24 H 21 N 3 O 3 ,[M+H]+m/z:400.1661,found:400.1668.
Example 24
Novel indole HDAC6 small molecule inhibitor Z-24 with structural formula as followsThe preparation process differs from example 20 in that: the bromobenzene in the step (2) was adjusted to 3-cyanobromobenzene, and the rest was the same as in example 2. The structure of formula Z-24 has a yield of 67%, a white solid, a melting point of 190.5-191.3 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.22(s,1H),8.75(q,J＝6.2Hz,1H),8.47(d,J＝5.5Hz,1H),8.29(d,J＝7.5Hz,1H),8.19-8.09(m,2H),7.94(t,J＝9.3Hz,1H),7.84-7.69(m,3H),7.64(d,J＝7.7Hz,1H),7.54-7.47(m,1H),7.44(d,J＝7.9Hz,1H),7.29(p,J＝7.0Hz,2H),4.57(dd,J＝13.8,5.7Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ167.56,164.44,143.84,141.11,135.80,133.18,131.67,130.89,129.88,129.81,127.95,127.77,127.63,127.39,124.34,123.99,122.43,122.24,112.87,111.35,42.26.HR-MS(ESI):calcd.C 24 H 18 N 4 O 3 ,[M+H]+m/z:411.1457,found:411.1458.
Example 25
Novel indole HDAC6 small molecule inhibitor Z-25 with structural formula as followsThe preparation process differs from example 20 in that: the bromobenzene in the step (2) was adjusted to 4-cyanobromobenzene, and the rest was the same as in example 2. The yield of the structure of formula Z-25 was 61%, a white solid, melting point 197.7-198.3 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ8.74(q,J＝6.6Hz,1H),8.44(d,J＝5.5Hz,1H),8.29(d,J＝7.5Hz,1H),7.96(d,J＝24.8Hz,1H),7.88-7.76(m,1H),7.73(d,J＝7.9Hz,2H),7.68-7.57(m,2H),7.44(d,J＝7.9Hz,2H),7.27(q,J＝7.2Hz,2H),6.00(s,1H),4.56(d,J＝5.9Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.54,150.64,143.84,138.69,135.97,135.62,131.69,131.05,130.37,127.77,127.62,127.37,124.95,124.73,123.85,123.76,122.20,121.40,112.46,111.23,42.27.HR-MS(ESI):calcd.C 24 H 18 N 4 O 3 ,[M+H]+m/z:411.1457,found:411.1458.
Example 26
Novel indole HDAC6 small molecule inhibitor Z-26 with structural formula as followsThe preparation process differs from example 20 in that: the bromobenzene in the step (2) was adjusted to 2-cyanobromobenzene, and the rest was the same as in example 2. The yield of the obtained structure represented by the formula Z-26 is 57%, and the melting point is 178.9-180.3 ℃ as a white solid. 1 H NMR(400MHz,DMSO-d6,ppm)δ8.83-8.49(m,1H),8.44-8.27(m,1H),8.15(d,J＝7.2Hz,1H),7.95(d,J＝7.8Hz,1H),7.82-7.63(m,4H),7.43-7.10(m,6H),4.53(d,J＝10.7Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.21,140.53,136.95,135.54,135.09,131.57,129.80,128.89,127.44,127.25,126.99,123.94,122.50,122.25,116.56,113.26,111.14,110.09,42.33.HR-MS(ESI):calcd.C 24 H 18 N 4 O 3 ,[M+H]+m/z:411.1457,found:411.1458.
Example 27
Novel indole HDAC6 small molecule inhibitor Z-27 with structural formula as followsThe preparation process differs from example 20 in that: the bromobenzene in the step (2) was adjusted to 2-nitrobromobenzene, and the rest was the same as in example 2. The yield of the structure of formula Z-27 was 35%, a tan solid, melting point 159.7-161.2 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.19(s,1H),9.03(s,1H),8.67(dt,J＝20.9,6.3Hz,1H),8.40(s,1H),8.28(t,J＝6.8Hz,1H),8.21-8.12(m,1H),7.89(dd,J＝28.7,8.0Hz,1H),7.73(d,J＝7.9Hz,2H),7.64(d,J＝4.4Hz,2H),7.55(d,J＝7.4Hz,1H),7.52-7.39(m,2H),7.24(dp,J＝15.7,6.2,5.4Hz,2H),4.55(p,J＝9.5,7.6Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.54,143.91,138.76,136.05,131.66,131.08,130.49,127.91,127.74,127.61,127.38,124.70,123.69,122.16,112.30,111.18,42.25.HR-MS(ESI):calcd.C 23 H 18 N 4 O 5 ,[M+H]+m/z:431.1355,found:431.1358.
Example 28
Novel indole HDAC6 small molecule inhibitor Z-28 with structural formula as followsThe preparation process differs from example 20 in that: the bromobenzene in the step (2) was adjusted to 3-nitrobromobenzene, and the rest was the same as in example 2. The yield of the structure of formula Z-28 is 58%, a pale yellow solid, and the melting point is 176.8-178.3 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.21(s,1H),9.06(s,1H),8.73(d,J＝24.9Hz,1H),8.51(s,1H),8.42(d,J＝9.9Hz,1H),8.30(d,J＝8.1Hz,2H),8.17(d,J＝8.1Hz,1H),7.93(d,J＝8.0Hz,1H),7.74(d,J＝7.8Hz,2H),7.66(d,J＝8.4Hz,1H),7.45(d,J＝7.9Hz,2H),7.29(dt,J＝17.2,8.8Hz,2H),4.68-4.40(m,2H). 13 CNMR(101MHz,DMSO-d6,ppm)δ164.58,164.46,164.34,143.77,141.69,139.67,135.80,131.99,131.71,130.94,130.78,127.96,127.63,127.40,124.69,124.17,122.67,122.33,122.28,121.08,119.12,115.30,113.31,111.07,42.27.HR-MS(ESI):calcd.C 23 H 18 N 4 O 5 ,[M+H]+m/z:431.1355,found:431.1358.
Example 29
Novel indole HDAC6 small molecule inhibitor Z-29 with structural formula as followsThe preparation process differs from example 20 in that: the bromobenzene in the step (2) was adjusted to 4-nitrobromobenzene, and the rest was the same as in example 2. The yield of the structure of formula Z-29 is 60%, a yellow solid, melting point 179.5-180.0deg.C. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.19(s,1H),8.99(s,1H),8.77(q,J＝5.6Hz,1H),8.51(s,1H),8.35-8.27(m,1H),8.16(d,J＝8.7Hz,1H),7.92-7.81(d,J＝7.9Hz,2H),7.76-7.71(m,1H),7.65(d,J＝7.9Hz,1H),7.55-7.47(m,1H),7.44(dd,J＝8.0,3.4Hz,1H),7.30(tp,J＝14.2,7.1Hz,2H),4.57(dd,J＝11.8,7.8Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.51,164.17,145.82,144.23,143.70,135.56,131.77,130.74,130.48,129.84,128.33,127.64,127.41,126.33,126.08,124.67,124.34,122.93,122.44,121.07,113.98,111.50,42.31.HR-MS(ESI):calcd.C 23 H 18 N 4 O 5 ,[M+H]+m/z:431.1355,found:431.1358.
Example 30
Novel indole HDAC6 small molecule inhibitor Z-30 with structural formula as followsThe preparation process differs from example 20 in that: the bromobenzene in the step (2) was adjusted to 4-bromophenol, and the other components were the same as in example 2. The yield of the structure of formula Z-30 was 20%, the melting point was 160.5-161.2 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.21(s,1H),9.91(s,1H),9.04(s,1H),8.65(t,J＝6.0Hz,1H),8.27(d,J＝11.2Hz,2H),7.73(d,J＝7.8Hz,2H),7.42(t,J＝7.3Hz,5H),7.28-7.16(m,2H),6.99(d,J＝8.2Hz,2H),4.54(d,J＝5.8Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.65,157.30,144.00,136.61,131.64,131.39,130.14,127.59,127.37,126.44,123.34,122.00,121.81,116.74,111.47,111.11,42.21.HR-MS(ESI):calcd.C 23 H 19 N 3 O 4 ,[M+H]+m/z:402.1454,found:402.1460.
Example 31
Novel indole HDAC6 small molecule inhibitor Z-31 with structural formula as followsThe preparation process differs from example 20 in that: the bromobenzene in the step (2) was adjusted to 4-bromobenzyl alcohol, and the rest was the same as in example 2. The yield of Z-31 is 66%, a white solid, melting point 164.9-165.6 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.25(s,1H),9.09(s,1H),8.73(t,J＝6.2Hz,1H),8.34(s,1H),8.26(d,J＝7.5Hz,1H),7.71(d,J＝8.0Hz,2H),7.54(dd,J＝18.8,5.3Hz,5H),7.43(d,J＝7.9Hz,2H),7.25(p,J＝7.0Hz,2H),5.50(d,J＝5.8Hz,1H),4.57(dd,J＝24.7,5.0Hz,4H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.65,157.30,144.00,136.61,131.64,131.39,130.14,127.59,127.37,126.44,123.34,122.00,121.81,116.74,111.47,111.11,45.77,42.21.HR-MS(ESI):calcd.C 24 H 21 N 3 O 4 ,[M+H]+m/z:416.1610,found:416.1615.
Example 32
Novel indole HDAC6 small molecule inhibitor Z-32 with structural formula as followsThe preparation process differs from example 20 in that: the bromobenzene in the step (2) was adjusted to 3-bromofuran, and the rest was the same as in example 2. The yield of the structure of formula-32 is 77%, white solid, melting point 185.9-187.4 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ8.65(d,J＝6.1Hz,1H),8.36(s,2H),8.26(d,J＝7.8Hz,1H),7.90(d,J＝1.9Hz,1H),7.74(d,J＝8.0Hz,2H),7.61(d,J＝8.2Hz,1H),7.43(d,J＝8.0Hz,2H),7.28(dt,J＝21.2,7.3Hz,2H),7.03(d,J＝1.9Hz,1H),4.55(d,J＝5.8Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.46,164.35,144.75,143.78,136.04,135.26,131.80,130.79,127.60,127.49,127.35,126.76,123.77,122.18,122.05,112.24,111.59,107.69,42.26.HR-MS(ESI):calcd.C 21 H 17 N 3 O 4 ,[M+H]+m/z:376.1297,found:376.1298.
Example 33
Novel indole HDAC6 small molecule inhibitor Z-33 with structural formula as followsThe preparation process differs from example 20 in that: will step by stepThe bromobenzene in step (2) was adjusted to 3-bromothiophene, and the rest was the same as in example 2. The compound of formula Z-33 is produced in 70% yield as a white solid with a melting point of 188.4-189.3 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.22(s,1H),8.74(t,J＝6.0Hz,1H),8.43(s,1H),8.26(d,J＝7.7Hz,1H),7.83(d,J＝4.9Hz,2H),7.73(d,J＝8.0Hz,2H),7.62(d,J＝8.1Hz,1H),7.49(d,J＝4.9Hz,1H),7.43(d,J＝7.9Hz,2H),7.27(dt,J＝19.9,7.2Hz,2H),4.54(d,J＝5.9Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.50,143.92,137.18,136.13,131.63,131.12,128.15,127.62,127.44,127.38,123.94,123.76,122.18,122.04,116.88,111.95,111.48,42.24.HR-MS(ESI):calcd.C 21 H 17 N 3 O 3 S,[M+H]+m/z:392.1069,found:392.1075./>
Example 34
Novel indole HDAC6 small molecule inhibitor Z-34 with structural formula as followsThe preparation process differs from example 1 in that: the indole-3-carboxylic acid in step (1) was adjusted to 5-methylindole-3-carboxylic acid, and the remainder was the same as in example 1. Z-34 yield 68%, white solid, melting point 186.8-187.7deg.C. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.49(d,J＝2.9Hz,1H),11.19(s,1H),9.03(s,1H),8.48(t,J＝6.0Hz,1H),8.02(d,J＝2.8Hz,1H),7.96(s,1H),7.72(d,J＝7.9Hz,2H),7.40(d,J＝7.9Hz,2H),7.32(d,J＝8.3Hz,1H),7.01-6.95(m,1H),4.51(d,J＝5.9Hz,2H),2.39(s,3H). 13 C NMR(101MHz,DMSO-d6,ppm)δ165.24,144.35,134.97,131.54,129.44,128.36,127.50,127.33,126.83,123.91,121.11,111.94,110.32,42.13,21.80.HR-MS(ESI):calcd.C 18 H 17 N 3 O 3 ,[M+H]+m/z:324.1348,found:324.1349.
Example 35
Novel indole HDAC6 small molecule inhibitor Z-35 with structural formula as followsThe preparation process differs from example 1 in that: the indole-3-carboxylic acid in step (1) was adjusted to 6-methylindole-3-carboxylic acid, and the remainder was the same as in example 1.The yield of Z-35 is 66%, a white solid, and the melting point is 171.5-172.0 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.57-11.32(m,1H),11.19(s,1H),9.16-8.87(m,1H),8.48(t,J＝6.2Hz,1H),8.06-7.93(m,2H),7.71(d,J＝7.9Hz,2H),7.39(d,J＝7.9Hz,2H),7.22(s,1H),6.93(d,J＝8.1Hz,1H),4.50(d,J＝5.9Hz,2H),2.39(s,3H). 13 C NMR(101MHz,DMSO-d6,ppm)δ165.17,164.56,144.24,137.06,131.69,131.45,127.76,127.48,127.31,124.49,122.61,121.15,112.04,110.74,42.13,21.77.HR-MS(ESI):calcd.C 18 H 17 N 3 O 3 ,[M+H]+m/z:324.1348,found:324.1350.
Example 36
Novel indole HDAC6 small molecule inhibitor Z-36 with structural formula as followsThe preparation process differs from example 2 in that: the indole-3-carboxylic acid in step (1) was adjusted to 6-methylindole-3-carboxylic acid, and bromobenzene in step (2) was adjusted to benzyl bromide, and the other components were the same as in example 2. Yield of Z-36 was 72%, white solid, melting point 184.1-184.3 ℃. 1 H NMR(600MHz,DMSO-d6,ppm)δ11.16(s,1H),8.98(s,1H),8.48(t,J＝6.1Hz,1H),8.08(d,J＝1.4Hz,1H),8.04(d,J＝8.0Hz,1H),7.72-7.68(m,2H),7.39(d,J＝8.0Hz,2H),7.36-7.32(m,3H),7.29-7.25(m,1H),7.25-7.21(m,2H),6.97(dd,J＝8.2,1.4Hz,1H),5.42(s,2H),4.49(d,J＝6.0Hz,2H),2.38(s,3H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.76,164.65,144.18,138.01,137.09,131.92,131.64,131.13,129.16,128.06,127.61,127.36,124.98,123.02,121.49,110.76,110.56,49.76,42.22,21.91.HR-MS(ESI):calcd.C 25 H 23 N 3 O 3 ,[M+H]+m/z:414.1817,found:414.1828.
Example 37
Novel indole HDAC6 small molecule inhibitor Z-37 with structural formula as followsThe preparation process differs from example 1 in that: the indole-3-carboxylic acid in step (1) was adjusted to 7-methylindole-3-carboxylic acid, and the procedure of example 1 was followed. Z-37 yield 60%, whiteSolid, melting point 157.8-158.6 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.59(d,J＝3.0Hz,1H),11.17(s,1H),8.98(s,1H),8.50(t,J＝6.0Hz,1H),8.10(d,J＝2.9Hz,1H),7.97(d,J＝7.9Hz,1H),7.72(d,J＝8.0Hz,2H),7.40(d,J＝8.0Hz,2H),7.00(t,J＝7.5Hz,1H),6.94(d,J＝7.0Hz,1H),4.51(d,J＝5.9Hz,2H),2.47(s,3H). 13 C NMR(101MHz,DMSO-d6,ppm)δ165.18,144.29,136.16,131.61,129.80,128.07,127.51,127.35,126.36,122.84,121.39,121.05,119.09,111.19,42.14,17.12.HR-MS(ESI):calcd.C 18 H 17 N 3 O 3 ,[M+H]+m/z:324.1348,found:324.1355.
Example 38
Novel indole HDAC6 small molecule inhibitor Z-38 with structural formula as followsThe preparation process differs from example 1 in that: the indole-3-carboxylic acid in step (1) was adjusted to 5-methoxyindole-3-carboxylic acid, and the remainder was the same as in example 1. The yield obtained was 68% with the structure of formula Z-38, as a white solid with a melting point of 196.6-197.7 ℃.1H NMR (400 MHz, DMSO-d6, ppm) δ11.45 (s, 1H), 11.17 (s, 1H), 8.99 (s, 1H), 8.46 (d, J=5.7 Hz, 1H), 8.04 (d, J=3.2 Hz, 1H), 7.72 (dd, J=8.1, 2.3Hz, 2H), 7.68 (d, J=2.8 Hz, 1H), 7.43-7.37 (m, 2H), 7.32 (dd, J=8.9, 2.8Hz, 1H), 6.79 (dd, J=8.8, 2.8Hz, 1H), 4.51 (d, J=5.8 Hz, 2H), 3.76 (d, J=2.6 Hz, 3H). 13 C NMR(101MHz,DMSO-d6,ppm)δ165.26,164.67,154.84,144.36,131.60,128.60,127.47,127.36,112.97,112.64,110.45,103.00,55.67,42.12.HR-MS(ESI):calcd.C 18 H 17 N 3 O 4 ,[M+H]+m/z:340.1297,found:340.1298.
Example 39
Novel indole HDAC6 small molecule inhibitor Z-39 with structural formula as followsThe preparation process differs from example 1 in that: the indole-3-carboxylic acid in step (1) was adjusted to 5-bromoindole-3-carboxylic acid, and the remainder was the same as in example 1. The yield of the obtained structure of the formula Z-39 was 70%, a white solid, melting point 19 1.6-192.5℃。 1 H NMR(400MHz,DMSO-d6,ppm)δ11.80(s,1H),11.19(s,1H),9.01(s,1H),8.60(t,J＝5.5Hz,1H),8.33(t,J＝2.9Hz,1H),8.15(d,J＝3.2Hz,1H),7.74(dd,J＝8.1,3.8Hz,2H),7.42(td,J＝9.2,3.7Hz,3H),7.32-7.26(m,1H),4.53(t,J＝4.9Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.66,144.07,135.32,131.65,129.68,128.47,127.52,127.37,124.94,123.67,114.41,113.74,110.41,42.15.HR-MS(ESI):calcd.C 17 H 14 BrN 3 O 3 ,[M+H]+m/z:388.0297,found:388.0299.
Example 40
Novel indole HDAC6 small molecule inhibitor Z-40 with structural formula as followsThe preparation process differs from example 1 in that: the indole-3-carboxylic acid in step (1) was adjusted to 6-bromoindole-3-carboxylic acid, the remainder being as in example 1. The yield of the obtained structure represented by the formula Z-40 was 70%, a white solid, melting point 195.4-196.3 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.70(s,1H),11.17(s,1H),9.00(s,1H),8.59(t,J＝6.1Hz,1H),8.11(d,J＝8.3Hz,2H),7.76-7.68(m,2H),7.65(d,J＝1.7Hz,1H),7.41(d,J＝8.0Hz,2H),7.25(dd,J＝8.5,1.8Hz,1H),4.52(d,J＝5.9Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ164.69,144.08,137.48,131.64,129.20,127.61,127.52,127.37,125.75,123.81,123.22,115.11,114.96,111.00,42.15.HR-MS(ESI):calcd.C 17 H 14 BrN 3 O 3 ,[M+H]+m/z:388.0297,found:388.0299.
Example 41
Novel indole HDAC6 small molecule inhibitor Z-41 with structural formula as followsThe preparation process differs from example 1 in that: the indole-3-carboxylic acid in step (1) was adjusted to 6-methoxyindole-3-carboxylic acid, and the remainder was the same as in example 1. The yield of the obtained structure of the formula Z-41 was 72%, a white solid, melting point 170.8-171.2 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.39(d,J＝2.9Hz,1H),11.20(s,1H),9.04(s,1H),8.49(t,J＝6.1Hz,1H),8.00(d,J＝8.7Hz,1H),7.94(d,J＝2.8Hz,1H),7.72(d,J＝8.0Hz,2H),7.40(d,J＝7.9Hz,2H),6.94(d,J＝2.3Hz,1H),6.76(dd,J＝8.7,2.3Hz,1H),4.50(d,J＝5.9Hz,2H),3.77(s,3H). 13 C NMR(101MHz,DMSO-d6,ppm)δ165.20,164.72,156.32,144.30,137.39,131.55,127.50,127.34,127.08,122.04,120.73,111.05,110.84,95.18,55.63,42.12.HR-MS(ESI):calcd.C 18 H 17 N 3 O 4 ,[M+H]+m/z:340.1297,found:340.1298.
Example 42
Novel indole HDAC6 small molecule inhibitor Z-42 with structural formula as followsThe preparation process differs from example 2 in that: the indole-3-carboxylic acid in step (1) was adjusted to 2-methylindole-3-carboxylic acid, and the procedure of example 2 was followed. Yield of formula Z-42 38%, white solid, melting point 185.4-186.5 ℃. 1 H NMR(600MHz,DMSO-d6,ppm)δ11.16(s,1H),8.98(s,1H),8.25(t,J＝6.0Hz,1H),7.86-7.80(m,1H),7.72(d,J＝8.2Hz,2H),7.49-7.46(m,1H),7.44(d,J＝8.1Hz,2H),7.30(t,J＝7.5Hz,2H),7.24(d,J＝7.6Hz,1H),7.15-7.10(m,2H),7.02(d,J＝7.5Hz,2H),5.49(s,2H),4.54(d,J＝5.9Hz,2H),2.58(s,3H). 13 CNMR(101MHz,DMSO-d6,ppm)δ165.73,140.52,138.10,136.30,129.79,129.16,127.73,127.58,127.35,126.69,125.80,121.93,120.88,120.10,110.55,109.09,46.17,42.77,12.02.HR-MS(ESI):calcd.C 13 H 13 N 3 O 3 ,[M+H]+m/z:414.1817,found:414.1825.
Example 43
Novel indole HDAC6 small molecule inhibitor Z-43 with structural formula as followsThe preparation process differs from example 1 in that: the indole-3-carboxylic acid in the step (1) was adjusted to 2-methylindole-3-carboxylic acid, and the remainder was the same as in example 2. The yield of the obtained structure shown in the formula Z-43 is 50%, the white solid, and the melting point is 134.4-135.2 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.49(s,1H),11.17(s,1H),9.00(d,J＝11.1Hz,1H),7.99(t,J＝6.1Hz,1H),7.81(d,J＝7.3Hz,1H),7.72(d,J＝7.9Hz,2H),7.43(d,J＝7.8Hz,2H),7.36-7.30(m,1H),7.13-7.02(m,2H),4.53(d,J＝6.0Hz,2H),2.60(s,3H). 13 C NMR(101MHz,DMSO-d6,ppm)δ165.91,164.65,144.37,140.10,135.15,131.53,127.51,127.32,126.49,121.49,120.38,119.90,111.40,107.95,42.57,13.82.HR-MS(ESI):calcd.C 18 H 17 N 3 O 3 ,[M+H]+m/z:324.1348,found:324.1350.
Example 44
Novel indole HDAC6 small molecule inhibitor Z-44 with structural formula as followsThe preparation process differs from example 2 in that: the indole-3-carboxylic acid in step (1) was adjusted to 2-methylindole-3-carboxylic acid, and bromobenzene in step (2) was adjusted to cyclopropylbenzyl bromide, and the remainder was the same as in example 2. The yield of the obtained structure of formula Z-44 was 72%, a white solid, melting point 125.4-126.7 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.17(s,1H),8.98(s,1H),8.18(d,J＝6.2Hz,1H),7.79(d,J＝7.7Hz,1H),7.74(d,J＝8.0Hz,2H),7.51(d,J＝8.0Hz,1H),7.44(d,J＝8.0Hz,2H),7.12(dt,J＝18.6,7.1Hz,2H),4.54(d,J＝5.9Hz,2H),4.11(d,J＝6.7Hz,2H),2.65(s,3H),1.16(td,J＝8.0,4.0Hz,1H),0.52-0.31(m,4H). 13 C NMR(101MHz,DMSO-d6,ppm)δ165.86,164.63,144.25,140.19,136.12,131.56,127.54,127.36,125.70,121.63,120.59,119.91,110.55,108.65,46.61,42.67,12.06,11.78.HR-MS(ESI):calcd.C 22 H 23 N 3 O 3 ,[M+H]+m/z:378.1817,found:378.1832.
Example 45
Novel indole HDAC6 small molecule inhibitor Z-45 with structural formula as followsThe preparation process differs from example 2 in that: the indole-3-carboxylic acid in the step (1) is adjusted to 2-methylindole-3-carboxylic acid, and the bromobenzene in the step (2) is adjusted to 4-fluorobenzyl bromide. The yield of the formula Z-45 is 56%, the white solid has a melting point of 168.9-170.3 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.09(s,1H),9.25-8.81(m,1H),8.25(t,J＝6.1Hz,1H),7.86-7.79(m,1H),7.76-7.70(m,2H),7.50-7.42(m,3H),7.14(ddd,J＝8.9,6.9,2.1Hz,4H),7.07(dd,J＝8.4,5.6Hz,2H),5.47(s,2H),4.54(d,J＝5.9Hz,2H),2.59(s,3H). 13 C NMR(101MHz,DMSO-d6,ppm)δ165.68,163.01,160.60,144.15,140.40,136.18,134.30,134.27,131.61,129.80,128.80,128.72,127.60,127.36,125.82,121.99,120.93,120.12,116.07,115.86,110.52,109.20,45.47,42.69,12.00.HR-MS(ESI):calcd.C 25 H 22 FN 3 O 3 ,[M+H]+m/z:432.1723,found:432.1726.
Example 46
(1) 1mmol of indole-3-carboxylic acid and 1.1mmol of methyl 4-aminomethylbenzoate are placed in a 250mL round bottom flask, methylene chloride is added for dissolution, 2mmole of EDCI and 0.2 mmole of HOBT are added sequentially while stirring at room temperature, then 1.1mmol of triethylamine is added, and the mixture is monitored by thin layer chromatography at normal temperature for 4 hours. Extracting with dichloromethane and water for 3 times, washing the lower organic phase with saturated NaCl solution, drying with anhydrous sodium sulfate, evaporating to dryness, adding (100-200 mesh) silica gel, parching, loading onto column (200-300 mesh), and separating and purifying with (petroleum ether/ethyl acetate) solution as mobile phase to obtain intermediate; the yield was 93% and the purity was 97%.
(2) 1mmol of the substance obtained in the step (1) was dissolved in DMF, and 3mmol of potassium hydroxide and 2mmol of benzyl bromide were added with stirring at room temperature of 650rpm to react for 3-4 hours. After the TLC monitoring reaction is completed, ethyl acetate and water are used for extraction for 3 times, an upper organic phase is washed by saturated NaCl solution, dried by anhydrous sodium sulfate, evaporated to dryness, added with silica gel for stir-frying, packed into a column, and petroleum ether/ethyl acetate is used as a mobile phase for separation and purification to obtain an intermediate; the yield was 93% and the purity was 97%.
(3) Dissolving 1mmol of the substance obtained in the step (2) in methanol solution, adding 2-3mL of water, adding 10mmol of sodium hydroxide solution under the stirring condition of 650rpm at room temperature, stirring and dissolving, placing in an oil bath at 60 ℃ for reaction reflux for 4-5h, evaporating to remove methanol after TLC monitoring reaction is complete, adding a water dissolution system, placing in an ice bath, regulating the pH value to 3-4 by using concentrated hydrochloric acid, and finally standing, suction filtering and drying to obtain an intermediate. The yield was 95% and the purity was 97%.
(4) After 1mmol of step (3) was dissolved in DMF, 1.2mmol of EDCI and 0.5mmol of DMAP were added and stirred at room temperature for 0.5h, then 1.1mmol of N-Boc-1, 2-phenylenediamine was added and reacted at room temperature for 2-3h. After the reaction is completed, extracting the system for 3 times by using ethyl acetate and water, washing the upper layer by using saturated NaCl solution, drying by using anhydrous sodium sulfate, evaporating the organic phase, adding silica gel for stir-frying, loading into a column, and separating and purifying by using a column layer method to obtain an intermediate. The yield was 62% and the purity was 97%.
(5) 1mmol of step (4) is dissolved in 1, 4-dioxane, 100mmol of hydrochloric acid is added for reaction for 2.5 hours, and precipitation is formed in the reaction process. After the reaction is completed, distilling the 1, 4-dioxane solution under reduced pressure, adding water to dissolve the system, adding saturated sodium bicarbonate solution under ice bath condition, regulating the solution to be alkalescent, standing for 15min, suction filtering, and drying to obtain the compound Z-46 with the yield of 67% and the purity of 98%. The compound of formula Z-46 is produced in 67% yield as a white solid with a melting point of 210.3-211.1 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ9.96(s,1H),8.60(d,J＝5.9Hz,1H),8.24-8.14(m,2H),8.00(d,J＝8.0Hz,2H),7.51(dd,J＝21.8,7.9Hz,3H),7.37-7.23(m,6H),7.15(dq,J＝20.0,7.2Hz,3H),7.04(d,J＝7.9Hz,1H),6.91(t,J＝7.5Hz,1H),5.47(s,2H),4.56(d,J＝5.9Hz,2H),3.56(d,J＝2.2Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ165.86,164.74,144.77,137.91,136.66,133.07,131.75,129.16,128.39,128.12,127.73,127.53,127.31,127.14,126.98,122.65,121.77,121.26,119.53,111.13,110.63,49.97,42.26.HR-MS(ESI):calcd.C 30 H 26 N 4 O 2 ,[M+H]+m/z:475.2134,found:475.2137.
Example 47
(1) 1mmol of indole-3-carboxylic acid and 1.1mmol of methyl 4-aminomethylbenzoate are placed in a 250mL round bottom flask, methylene dichloride is added for dissolution, 2mmol of EDCI and 0.2mmol of HOBT are added sequentially while stirring at room temperature, then 1.1mmol of triethylamine is added, and the mixture is monitored by thin layer chromatography under normal temperature for 4 hours. Extracting with dichloromethane and water for 3 times, washing the lower organic phase with saturated NaCl solution, drying with anhydrous sodium sulfate, evaporating to dryness, adding (100-200 mesh) silica gel, parching, loading (200-300 mesh) on column, and separating and purifying with (petroleum ether/ethyl acetate) solution as mobile phase to obtain intermediate; the yield was 93% and the purity was 97%.
(2) 1mmol of the substance obtained in the step (1) was dissolved in DMF, and 3mmol of potassium hydroxide and 2mmol of benzyl bromide were added with stirring at room temperature of 650rpm to react for 3-4 hours. After the TLC monitoring reaction is completed, ethyl acetate and water are used for extraction for 3 times, an upper organic phase is washed by saturated NaCl solution, dried by anhydrous sodium sulfate, evaporated to dryness, added with silica gel for stir-frying, packed into a column, and petroleum ether/ethyl acetate is used as a mobile phase for separation and purification to obtain an intermediate; the yield was 93% and the purity was 97%.
(3) Dissolving 1mmol of the substance obtained in the step (2) in methanol solution, adding 2-3mL of water, adding 10mmol of sodium hydroxide solution under the stirring condition of 650rpm at room temperature, stirring and dissolving, placing in an oil bath at 60 ℃ for reaction and reflux for 4-5h, evaporating to remove methanol after TLC monitoring reaction is complete, adding a water dissolution system, placing in an ice bath, regulating the pH to 3-4 by using concentrated hydrochloric acid, and finally standing, suction filtering and drying to obtain the compound Z-47. The compound of formula Z-47 was produced in 83% yield as a white solid with a melting point of 284.6-285.4 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ8.61(t,J＝6.0Hz,1H),8.23-8.14(m,2H),7.91(d,J＝8.0Hz,2H),7.54(d,J＝8.0Hz,1H),7.45(d,J＝7.7Hz,2H),7.37-7.30(m,2H),7.30-7.23(m,3H),7.21-7.10(m,2H),5.47(s,2H),4.54(d,J＝5.8Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ167.85,164.79,145.87,137.85,136.63,131.74,129.98,129.84,129.16,128.13,127.72,127.70,127.10,122.68,121.76,121.30,111.13,110.50,49.96,42.28.HR-MS(ESI):calcd.C 24 H 2 N 2 O 3 ,[M+H]+m/z:385.1552,found:385.1559.
Example 48
(1) 1mmol of indole-3-carboxylic acid and 1.1mmol of methyl 4-aminomethylbenzoate are placed in a 250mL round bottom flask, methylene chloride is added for dissolution, 2mmole of EDCI and 0.2 mmole of HOBT are added sequentially while stirring at room temperature, then 1.1mmol of triethylamine is added, and the mixture is monitored by thin layer chromatography at normal temperature for 4 hours. Extracting with dichloromethane and water for 3 times, washing the lower organic phase with saturated NaCl solution, drying with anhydrous sodium sulfate, evaporating to dryness, adding (100-200 mesh) silica gel, parching, loading onto column (200-300 mesh), and separating and purifying with (petroleum ether/ethyl acetate) solution as mobile phase to obtain intermediate; the yield was 93% and the purity was 97%.
(2) 1mmol of the substance obtained in the step (1) and 0.6mmol of anhydrous potassium phosphate are dissolved in toluene, and then 1.2mmol of bromobenzene, 0.3mmol of CuI as a catalyst and 2.1mmol of trans (1R, 2R) -N, N-dimethyl-1, 2-cyclohexanediamine are added under stirring at room temperature of 650rpm, and reacted for 4 to 5 hours in an oil bath at 110 ℃. After the reaction is monitored, the system is extracted for 3 times by ethyl acetate and water, the upper organic phase is washed by saturated NaCl solution, dried by anhydrous sodium sulfate and evaporated to dryness, a silica gel stir-fried sample is added, a column is packed, petroleum ether/ethyl acetate is used as a mobile phase for separation and purification, and the yield of the intermediate is 93%, and the purity is 97%.
(3) Dissolving 1mmol of the substance obtained in the step (2) in methanol solution, adding 2-3mL of water, adding 10mmol of sodium hydroxide solution under the stirring condition of 650rpm at room temperature, stirring and dissolving, placing in an oil bath at 60 ℃ for reaction reflux for 4-5h, evaporating to remove methanol after TLC monitoring reaction is complete, adding a water dissolution system, placing in an ice bath, regulating the pH value to 3-4 by using concentrated hydrochloric acid, and finally standing, suction filtering and drying to obtain an intermediate. The yield was 95% and the purity was 97%.
(4) After 1mmol of step (3) was dissolved in DMF, 1.2mmol of EDCI and 0.5mmol of DMAP as condensing agents were added and stirred at room temperature for 0.5h, then 1.1mmol of N-Boc-1, 2-phenylenediamine was added and reacted at room temperature for 2-3h. After the reaction is completed, extracting the system for 3 times by using ethyl acetate and water, washing the upper layer by using saturated NaCl solution, drying by using anhydrous sodium sulfate, evaporating the organic phase, adding silica gel for stir-frying, loading into a column, and separating and purifying by using a column layer method to obtain an intermediate. The yield was 62% and the purity was 97%.
(5) 1mmol of step (4) is dissolved in 1, 4-dioxane, 100mmol of hydrochloric acid is added for reaction for 2.5 hours, and precipitation is formed in the reaction process. After the reaction is completed, distilling the 1, 4-dioxane solution under reduced pressure, adding water to dissolve the system, adding saturated sodium bicarbonate solution under ice bath condition, regulating the solution to be alkalescent, standing for 15min, suction filtering, and drying to obtain the compound Z-48. The yield of the compound of formula Z-48 is 56%, the white solid, the melting point is 207.3-208.0 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ10.08(s,1H),8.78(d,J＝6.4Hz,1H),8.46(d,J＝2.3Hz,1H),8.35-8.26(m,1H),8.04(d,J＝7.9Hz,2H),7.69-7.60(m,4H),7.58-7.46(m,4H),7.38(d,J＝7.9Hz,1H),7.26(tt,J＝7.1,5.4Hz,2H),7.15(dd,J＝8.0,1.9Hz,2H),7.03-6.95(m,1H),4.60(d,J＝5.9Hz,2H),3.57(s,2H).13C NMR(101MHz,DMSO-d6,ppm)δ165.90,164.56,144.64,138.81,136.07,133.01,131.19,130.49,128.46,127.89,127.81,127.54,127.40,126.99,124.71,123.65,122.19,122.14,112.37,111.19,42.29.HR-MS(ESI):calcd.C 29 H 24 N 4 O 2 ,[M+H]+m/z:461.1977,found:461.1983.
Example 49
(1) 1mmol of indole-3-carboxylic acid and 1.1mmol of methyl 4-aminomethylbenzoate are placed in a 250mL round bottom flask, methylene chloride is added for dissolution, 2mmole of EDCI and 0.2 mmole of HOBT are added sequentially while stirring at room temperature, then 1.1mmol of triethylamine is added, and the mixture is monitored by thin layer chromatography at normal temperature for 4 hours. Extracting with dichloromethane and water for 3 times, washing the lower organic phase with saturated NaCl solution, drying with anhydrous sodium sulfate, evaporating to dryness, adding (100-200 mesh) silica gel, parching, loading onto column (200-300 mesh), and separating and purifying with (petroleum ether/ethyl acetate) solution as mobile phase to obtain intermediate; the yield was 93% and the purity was 97%.
(2) 1mmol of the substance obtained in the step (1) and 0.6mmol of anhydrous potassium phosphate are dissolved in toluene, and then 1.2mmol of bromobenzene, 0.3mmol of CuI as a catalyst and 2.1mmol of trans (1R, 2R) -N, N-dimethyl-1, 2-cyclohexanediamine are added under stirring at room temperature of 650rpm, and reacted for 4 to 5 hours in an oil bath at 110 ℃. After the reaction is monitored, the system is extracted for 3 times by ethyl acetate and water, the upper organic phase is washed by saturated NaCl solution, dried by anhydrous sodium sulfate and evaporated to dryness, a silica gel stir-fried sample is added, a column is packed, petroleum ether/ethyl acetate is used as a mobile phase for separation and purification, and the yield of the intermediate is 93%, and the purity is 97%.
(3) Dissolving 1mmol of the substance obtained in the step (2) in methanol solution, adding 2-3mL of water, adding 10mmol of sodium hydroxide solution under the stirring condition of 650rpm at room temperature, stirring and dissolving, placing in an oil bath at 60 ℃ for reaction and reflux for 4-5h, evaporating to remove methanol after TLC monitoring reaction is complete, adding a water dissolution system, placing in an ice bath, regulating the pH to 3-4 by using concentrated hydrochloric acid, and finally standing, suction filtering and drying to obtain the compound Z-49. The compound of the structure of formula Z-49 was produced in a yield of 72%, as a white solid, melting point 257.3-258.2 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ8.72(d,J＝6.2Hz,1H),8.41(s,1H),8.29(d,J＝7.3Hz,1H),7.92(d,J＝7.8Hz,2H),7.64(d,J＝4.5Hz,4H),7.55(d,J＝7.7Hz,1H),7.47(t,J＝7.4Hz,3H),7.26(p,J＝7.2Hz,2H),4.58(d,J＝5.8Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ167.74,164.54,145.80,138.80,136.07,131.13,130.48,129.88,129.81,127.90,127.79,127.75,124.71,123.66,122.19,122.14,112.32,111.18,42.31.HR-MS(ESI):calcd.C 23 H 18 N 2 O 3 ,[M+H]+m/z:371.1395,found:371.1398.
Example 50
(1) 1mmol of indole-3-carboxylic acid and 1.1mmol of methyl 4-aminomethylbenzoate are placed in a 250mL round bottom flask, methylene chloride is added for dissolution, 2mmole of EDCI and 0.2 mmole of HOBT are added sequentially while stirring at room temperature, then 1.1mmol of triethylamine is added, and the mixture is monitored by thin layer chromatography at normal temperature for 4 hours. Extracting with dichloromethane and water for 3 times, washing the lower organic phase with saturated NaCl solution, drying with anhydrous sodium sulfate, evaporating to dryness, adding (100-200 mesh) silica gel, parching, loading onto column (200-300 mesh), and separating and purifying with petroleum ether/ethyl acetate as mobile phase to obtain intermediate; the yield was 93% and the purity was 97%.
(2) Dissolving 1mmol of the substance obtained in the step (1) in methanol solution, adding 2-3mL of water, adding 10mmol of sodium hydroxide solution under the stirring condition of 650rpm at room temperature, stirring and dissolving, placing in an oil bath at 60 ℃ for reaction reflux for 4-5h, evaporating to remove methanol after TLC monitoring reaction is complete, adding a water dissolution system, placing in an ice bath, regulating the pH value to 3-4 by using concentrated hydrochloric acid, and finally standing, suction filtering and drying to obtain an intermediate. The yield was 95% and the purity was 97%.
(3) After 1mmol of step (2) was dissolved in DMF, 1.2mmol of EDCI and 0.5mmol of DMAP as condensing agents were added and stirred at room temperature for 0.5h, then 1.1mmol of N-Boc-1, 2-phenylenediamine was added and reacted at room temperature for 2-3h. After the reaction is completed, extracting the system for 3 times by using ethyl acetate and water, washing the upper layer by using saturated NaCl solution, drying by using anhydrous sodium sulfate, evaporating the organic phase, adding silica gel for stir-frying, loading into a column, and separating and purifying by using a column layer method to obtain an intermediate. The yield was 62% and the purity was 97%.
(4) 1mmol of step (3) is dissolved in 1, 4-dioxane, 100mmol of hydrochloric acid is added for reaction for 2.5 hours, and precipitation is formed in the reaction process. After the reaction is completed, distilling the 1, 4-dioxane solution under reduced pressure, adding water to dissolve the system, adding saturated sodium bicarbonate solution under ice bath condition, regulating the solution to be alkalescent, standing for 15min, suction filtering, and drying to obtain the compound Z-48. The compound of formula Z-50 is produced in 72% yield as a white solid with a melting point of 201.3-202.2 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.58(d,J＝3.0Hz,1H),9.63(s,1H),8.53(t,J＝6.1Hz,1H),8.16(d,J＝7.7Hz,1H),8.09(d,J＝2.9Hz,1H),7.95(d,J＝7.9Hz,2H),7.45(dd,J＝11.1,8.0Hz,3H),7.20-7.05(m,3H),6.97(td,J＝7.6,1.5Hz,1H),6.81-6.75(m,1H),6.61(t,J＝7.6Hz,1H),4.98(s,2H),4.56(d,J＝6.0Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ165.69,165.14,144.62,143.30,136.63,133.44,128.35,128.27,127.40,127.15,126.93,126.63,124.01,122.37,121.48,120.86,116.97,116.76,112.31,110.87,42.18.HR-MS(ESI):calcd.C 23 H 20 N 4 O 2 ,[M+H]+m/z:385.1664,found:385.1672.
Example 51
(1) 1mmol of indole-3-carboxylic acid and 1.1mmol of methyl 4-aminomethylbenzoate are placed in a 250mL round bottom flask, methylene chloride is added for dissolution, 2mmole of EDCI and 0.2 mmole of HOBT are added sequentially while stirring at room temperature, then 1.1mmol of triethylamine is added, and the mixture is monitored by thin layer chromatography at normal temperature for 4 hours. Extracting with dichloromethane and water for 3 times, washing the lower organic phase with saturated NaCl solution, drying with anhydrous sodium sulfate, evaporating to dryness, adding (100-200 mesh) silica gel, parching, loading onto column (200-300 mesh), and separating and purifying with petroleum ether/ethyl acetate as mobile phase to obtain intermediate; the yield was 93% and the purity was 97%.
(2) Dissolving 1mmol of the substance obtained in the step (1) in methanol solution, adding 2-3mL of water, adding 10mmol of sodium hydroxide solution under the stirring condition of 650rpm at room temperature, stirring and dissolving, placing in an oil bath at 60 ℃ for reaction reflux for 4-5h, evaporating to remove methanol after TLC monitoring reaction is complete, adding a water dissolution system, placing in an ice bath, regulating the pH value to 3-4 by using concentrated hydrochloric acid, and finally standing, suction filtering and drying to obtain Z-51. The compound of formula Z-51 is produced in 85% yield as a white solid with a melting point of 237.8-238.5 ℃. 1 HNMR(400MHz,DMSO-d6,ppm)δ12.85(s,1H),11.59(s,1H),8.53(d,J＝6.1Hz,1H),8.23-8.06(m,2H),7.95-7.89(m,2H),7.45(t,J＝7.7Hz,3H),7.19-7.07(m,2H),4.56(d,J＝5.9Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ167.74,165.14,146.20,136.62,129.85,129.66,128.38,127.63,126.62,122.38,121.48,120.86,112.30,110.79,42.19.HR-MS(ESI):calcd.C 17 H 14 N 2 O 3 ,[M+H]+m/z:295.1082,found:295.1087.
Example 52
Novel indole HDAC6 small molecule inhibitor Z-52 with structural formula as followsThe preparation process differs from example 50 in that: the indole-3-carboxylic acid in the step (1) is adjusted to 6-methylindole-3-carboxylic acid.The compound of formula Z-52 was produced in 73% yield as a white solid with a melting point of 223.7-224.6 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.45(s,1H),9.69(d,J＝3.9Hz,1H),8.50(d,J＝5.7Hz,1H),8.02(q,J＝4.0,3.3Hz,2H),7.96(dd,J＝8.3,3.1Hz,2H),7.46(dd,J＝8.4,3.1Hz,2H),7.25-7.15(m,2H),7.03-6.89(m,2H),6.83(dd,J＝8.1,3.5Hz,1H),6.69-6.60(m,1H),5.34(s,2H),4.55(d,J＝6.1Hz,2H),2.39(d,J＝2.9Hz,3H). 13 CNMR(101MHz,DMSO-d6,ppm)δ165.72,165.19,144.71,142.47,137.07,133.36,131.44,128.27,127.78,127.42,127.16,126.91,124.51,124.45,122.61,121.15,117.56,117.17,112.04,110.78,42.17,21.77.HR-MS(ESI):calcd.C 24 H 22 N 4 O 2 ,[M+H]+m/z:399.1821,found:399.1826.
Example 53
Novel indole HDAC6 small molecule inhibitor Z-53 with structural formula as followsThe preparation process differs from example 51 in that: the indole-3-carboxylic acid in step (1) was changed to 6-methylindole-3-carboxylic acid, and the other components were the same as in example 51. The resulting product had a structure of formula Z-53 in 78% yield, as a white solid with a melting point of 227.8-228.7 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.43(s,1H),8.45(d,J＝6.1Hz,1H),8.05-7.95(m,2H),7.94-7.87(m,2H),7.43(d,J＝8.0Hz,2H),7.21(s,1H),6.93(dd,J＝8.2,1.5Hz,1H),4.53(d,J＝5.9Hz,2H),2.39(s,3H). 13 C NMR(101MHz,DMSO-d6,ppm)δ167.93,165.16,145.88,137.05,131.44,129.79,127.76,127.54,124.50,122.60,121.15,112.02,110.72,42.18,21.76.HR-MS(ESI):calcd.C 18 H 16 N 2 O 3 ,[M+H]+m/z:309.1239,found:309.1244.
Example 54
Novel indole HDAC6 small molecule inhibitor Z-54 with structural formula as follows The preparation process differs from example 50 in that: the indole-3-carboxylic acid in step (1) was adjusted to 6-bromoindole-3-carboxylic acid, and the procedure of example 50 was followed. The compound of formula Z-54 is produced in 77% yield, whiteThe color solid, the melting point is 231.2-232.1 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.43(s,1H),9.67(d,J＝3.9Hz,1H),8.50(d,J＝5.7Hz,1H),8.01(q,J＝4.0,3.3Hz,2H),7.94(dd,J＝8.3,3.1Hz,2H),7.43(dd,J＝8.4,3.1Hz,2H),7.25-7.14(m,2H),7.03-6.89(m,2H),6.82(dd,J＝8.1,3.5Hz,1H),6.69-6.60(m,1H),5.35(s,2H),4.57(d,J＝6.1Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ165.72,165.19,144.71,142.47,137.07,133.36,131.44,128.27,127.78,127.42,127.16,126.91,124.51,124.45,122.61,121.15,117.56,117.17,112.04,110.78,42.17.HR-MS(ESI):calcd.C 23 H 19 BrN 4 O 2 ,[M+H]+m/z:463.0769,found:463.0772.
Example 55
Novel indole HDAC6 small molecule inhibitor Z-55 with structural formula as followsThe preparation process differs from example 51 in that: the indole-3-carboxylic acid in step (1) is adjusted to 6-bromoindole-3-carboxylic acid. The yield of the formula Z-55 is 70%, the white solid has a melting point of 230.2-231.1 ℃. 1 H NMR(400MHz,DMSO-d6,ppm)δ11.43(s,1H),8.45(d,J＝6.1Hz,1H),8.05-7.95(m,2H),7.94-7.87(m,2H),7.43(d,J＝8.0Hz,2H),7.21(s,1H),6.93(dd,J＝8.2,1.5Hz,1H),4.53(d,J＝5.9Hz,2H). 13 C NMR(101MHz,DMSO-d6,ppm)δ167.93,165.16,145.88,137.05,131.44,129.79,127.76,127.54,124.50,122.60,121.15,112.02,110.72,42.18.HR-MS(ESI):calcd.C 17 H 13 BrN 2 O 3 ,[M+H]+m/z:373.0188,found:373.0189.
Test example 1
The in vitro enzyme activity of the compounds having the structures shown in the formulas Z-1 to Z-55 is measured as follows: by utilizing the deacetylation property of HDAC6, firstly, incubating the HDAC6 recombinant protein with the polypeptide with the acetylated lysine and the AMC fluorescent group at 37 ℃ for 20min to expose the AMC fluorescent group; and (3) adding pancreatin to hydrolyze the polypeptide, releasing a fluorescent group, measuring a fluorescence intensity change value at an excitation wavelength of 355nm and an emission wavelength of 460nm by using an enzyme-labeled instrument, and evaluating the inhibition rate of the target compound, wherein the positive control is vorinostat (SAHA). According to the concentration ladder that presumesThe degree of fluorescence intensity after the action of the compounds at different concentrations was measured, and the inhibition ratio was calculated. HDAC1 was tested as above. Calculation of fit using GraphPad prism8.0 software, calculation of compound IC 50 . Inhibition ratio = (positive control fluorescence intensity-compound fluorescence intensity)/(positive control fluorescence intensity-blank fluorescence intensity) ×100%. The results of the inhibition activity test are shown in Table 1.
TABLE 1 Selective inhibitory Activity of the inventive Compounds against HDAC6
Selecting compound with inhibition rate of over 60% on HDAC6 by using SAHA as positive control, and determining IC on HDAC6 50 Values, test results are shown in table 2.
TABLE 2 IC of some of the compounds of the invention on HDAC6 50 Value of
As shown in the experimental results of tables 1 and 2, compared with the positive control SAHA, the novel indole HDAC6 small molecule inhibitor provided by the invention has good selective inhibition effect on HDAC 6.
Test example 2
Selecting a compound Z-7 with high efficiency and high selectivity for inhibiting HDAC6, and testing proliferation inhibition effect on human gastric cancer cells MGC-803 cells by adopting an MTT method. The method comprises the following steps: culturing in 10% foetal calf serum high sugar culture medium at 37deg.C and 5% CO 2 Incubation was performed in an incubator. MGC-803 cells were treated with 2The density of 500 cells/well is inoculated on a 96-well plate, placed in an incubator for culturing for 12 hours, and after the cells are attached, 100 mu M of mother solution of the compound to be tested is prepared into gradient concentration, and 200 mu L of mother solution is added to the 96-well plate respectively. After 48h or 72h incubation, 20. Mu.L MTT solution with concentration of 5mg/mL is added to each well for further culture for 5h, then supernatant is sucked and removed, 150. Mu.L DMSO solution is added to each well, and a shaking table is oscillated at low speed for 15min to fully dissolve formazan crystals. Blank and negative control wells were simultaneously set, and absorbance values of each well were measured at 490nm using an enzyme-linked immunosorbent assay. Calculating inhibition rate, calculating with GraphPad prism8.0 software, fitting, and obtaining IC 50 Values. Inhibition (%) =1- (OD dosing group-OD blank)/(OD negative control group-OD blank) ×100%. The test results are shown in Table 3.
TABLE 3 proliferation inhibition comparison of Compounds Z-7 of the invention with SAHA
| Compounds of formula (I) | MGC-803IC 50 (μM) |
| Z-7 | 2.30±0.36 |
| SAHA | 6.02±0.79 |
The results in Table 3 show that the novel indole HDAC6 small molecule inhibitor Z-7 has good proliferation inhibition effect on MGC-803 cells, and the proliferation inhibition effect on MGC-803 cells is obviously better than that of positive control SAHA.
In conclusion, the novel indole HDAC6 small molecule inhibitor provided by the invention can effectively inhibit the proliferation activity of gastric cancer cells by chelating with metal ions in gastric cancer cells to form a stable complex. Compared with positive control SAHA, the novel indole HDAC6 small molecule inhibitor provided by the invention has a better selective inhibition effect on HDAC6, can inhibit gastric cancer cell proliferation in a concentration dependent manner, and has a good application prospect in preparing an HDAC6 target-based inhibitor and a drug for inhibiting gastric cancer cell proliferation activity.
Claims (10)
1. A novel indole HDAC6 small molecule inhibitor, which is characterized in that the novel indole HDAC6 small molecule inhibitor is a compound shown in a formula I or pharmaceutically acceptable salt thereof;
In the formula I, R 1 Selected from H, 5-CH 3 、6-CH 3 、7-CH 3 、5-OCH 3 、5-Br、6-Br、6-OCH 3 One of the following;
R 2 selected from H, CH 3 、 One of the following;
R 3 is H or CH 3 ；R 4 Selected from the group consisting ofOne of OH.
2. The novel indole HDAC6 small molecule inhibitor according to claim 1, characterized in that it is selected from the group consisting of compounds of the following structure, in turn denoted as compounds Z-1 to Z-55:
3. a method for preparing the novel indole HDAC6 small molecule inhibitor according to claim 1, wherein the technical route of the preparation method is as follows:
when R is 2 H, R of a shape of H, R 4 Is thatIn the process, the preparation method of the novel indole HDAC6 small molecule inhibitor comprises the following steps:
(1) The method comprises the steps of (1) carrying out condensation reaction on a raw material A, a raw material B, a condensing agent a and an alkaline substance a in a solvent a to obtain an intermediate C;
(2) Reacting the intermediate C with hydroxylamine water solution in a solvent b, adding an alkaline substance b for reaction, adding an acidic substance and water after the reaction is finished, and performing suction filtration to obtain a novel indole HDAC6 micromolecule inhibitor shown as a compound M;
when R is 2 H, R of a shape of H, R 4 Novel indole HDAC6 small molecule inhibitor when OHThe preparation method of (2) comprises the following steps:
s1, carrying out condensation reaction on a raw material A, a raw material B, a condensing agent a and an alkaline substance a in a solvent a to obtain an intermediate C;
S2, reacting the intermediate C and the alkaline substance b in a solvent C to obtain a novel indole HDAC6 small molecule inhibitor shown in the compound J;
when R is 2 Not H, R 4 Is thatIn the process, the preparation method of the novel indole HDAC6 small molecule inhibitor comprises the following steps:
(1) the method comprises the steps of (1) carrying out condensation reaction on a raw material A, a raw material B, a condensing agent a and an alkaline substance a in a solvent a to obtain an intermediate C;
(2) reacting the intermediate C, an alkaline substance C and a raw material a in a solvent d to obtain an intermediate E;
(3) reacting the intermediate E with hydroxylamine aqueous solution in a solvent b, adding an alkaline substance b for reaction, adding an acidic substance and water after the reaction is finished, and performing suction filtration to obtain a novel indole HDAC6 micromolecule inhibitor shown as a compound F;
when R is 2 H, R of a shape of H, R 4 Is thatIn the process, the preparation method of the novel indole HDAC6 small molecule inhibitor comprises the following steps:
s1, carrying out condensation reaction on a raw material A, a raw material B, a condensing agent a and an alkaline substance a in a solvent a to obtain an intermediate C;
s2, reacting the intermediate C and the alkaline substance b in a solvent C to obtain a compound J;
s3, reacting the compound J, the condensing agent b and the amine substance in a solvent d to obtain an intermediate K;
s4, dissolving the intermediate K in a solvent f, and then adding an acidic substance in a stirring state to react to obtain a novel indole HDAC6 small molecule inhibitor shown in a compound L;
When R is 2 Not H, R 4 Is thatIn the process, the preparation method of the novel indole HDAC6 small molecule inhibitor comprises the following steps:
carrying out condensation reaction on a raw material A, a raw material B, a condensing agent a and an alkaline substance a in a solvent a to obtain an intermediate C;
(ii) reacting the intermediate compound C, cuI, the raw material b and the amine substance in the solvent E to obtain an intermediate E';
(iii) reacting intermediate E' with alkaline material b in solvent d to obtain intermediate G;
(iv) reacting the intermediate G, the condensing agent b and the amine substance in the solvent d to obtain an intermediate H;
(v) dissolving the intermediate H in the solvent f, and then adding an acidic substance under stirring to react to obtain the novel indole HDAC6 small molecule inhibitor shown in the compound I.
4. The method for preparing the novel indole HDAC6 small molecule inhibitor according to claim 3, wherein the solvent a is dichloromethane, the solvent b is a mixed solution of dichloromethane and methanol, the solvent c is a mixed solution of methanol and water, the solvent d is N, N-dimethylformamide, the solvent e is toluene, and the solvent f is 1, 4-dioxane.
5. The method for preparing the novel indole HDAC6 small molecule inhibitor according to claim 3, wherein the basic substance a is triethylamine, the basic substance b is sodium hydroxide, and the basic substance c is potassium hydroxide; the acidic substance is hydrochloric acid.
6. The method for preparing a novel indole HDAC6 small molecule inhibitor according to claim 3, wherein the condensing agent a is EDCI or HOBt; the condensing agent b is EDCI or DMAP; the amine substance is N-Boc phenylenediamine.
7. The method for preparing a novel indole HDAC6 small molecule inhibitor according to claim 3, wherein the starting material a is a bromo compound; the raw material b is trans (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexanediamine and anhydrous potassium phosphate.
8. The use of a novel indole HDAC6 small molecule inhibitor according to claim 1 or 2, for the preparation of an inhibitor based on an HDAC6 target or for the preparation of a medicament for the targeted treatment of cancer based on an HDAC6 target.
9. The use of a novel indole HDAC6 small molecule inhibitor according to claim 8 wherein the cancer is gastric cancer.
10. The use of a novel indole HDAC6 small molecule inhibitor according to claim 8, wherein the medicament is a medicament for inhibiting gastric cancer cell proliferation activity; the gastric cancer cell is MGC-803.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311457833.6A CN117603123A (en) | 2023-11-04 | 2023-11-04 | Novel indole HDAC6 small molecule inhibitor, preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311457833.6A CN117603123A (en) | 2023-11-04 | 2023-11-04 | Novel indole HDAC6 small molecule inhibitor, preparation method and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117603123A true CN117603123A (en) | 2024-02-27 |
Family
ID=89950556
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311457833.6A Pending CN117603123A (en) | 2023-11-04 | 2023-11-04 | Novel indole HDAC6 small molecule inhibitor, preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117603123A (en) |
-
2023
- 2023-11-04 CN CN202311457833.6A patent/CN117603123A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP3342485B2 (en) | Aromatic sulfonamide hydroxamic acid derivatives | |
| KR100787131B1 (en) | Compounds that inhibit hif-1 activity the method for preparation thereof and the pharmaceutical composition containing them as an effective component | |
| JP4705756B2 (en) | Aromatic amino acid derivatives and pharmaceutical compositions | |
| CN103319466B (en) | Containing the 1,2,3-triazoles-dithiocarbamates compound of tonka bean camphor parent nucleus, preparation method and application thereof | |
| CN105566241B (en) | 1- sulfoamido -4- aryloxy group classes compound, preparation method and its medical usage | |
| CN110204487B (en) | Synthesis method of quinoline derivative | |
| CN109438264B (en) | Polysubstituted indenamine derivative and preparation method thereof | |
| CN113444038B (en) | 2-aryl isonicotinic acid amide LSD1/HDAC double-target inhibitor, and preparation method and application thereof | |
| CN105732468A (en) | N'-(2-(1H-indole-3-yl)acetyl)arylhydrazide compound and preparation method and application thereof | |
| KR100686531B1 (en) | Arylaminomethyl propenyl benzhydroxyamide derivatives with inhibitory activity against histone deacetylase and method for the preparation thereof | |
| WO2021012726A1 (en) | Method for synthesizing benzoimidazoquinazolinone compound | |
| CN113444069B (en) | 2-aryl-4- (1H-pyrazol-3-yl) pyridine LSD1/HDAC double-target inhibitor | |
| CN114014814A (en) | N-benzyl-4-phenylphthalazin-1-amine derivative, preparation method thereof and medicine for treating RECQL4 specific expression | |
| CN117603123A (en) | Novel indole HDAC6 small molecule inhibitor, preparation method and application | |
| WO2019165809A1 (en) | Method for preparing 2-nitroindole derivatives | |
| ES2238707T3 (en) | FLAVONA DERIVATIVES AND MEDICINES CONTAINING THEM. | |
| CN102775381A (en) | Substituted hydrazide compound, and its preparation method, medicinal compositions and application | |
| CN113563319B (en) | Indazole heterocyclic compounds having phosphodiesterase 4B inhibitory activity | |
| JP7359463B2 (en) | Benzoindazolone compounds and intermediates for their production | |
| CN112961117A (en) | Application and preparation method of oxadiazole hydroxamic acid compound | |
| KR100814100B1 (en) | Alkylcarbamoyl naphthalenyloxyprophenyl hydroxybenzamide derivatives having inhibitory activity against histone deacetylase, method for the preparation thereof, and anticancer composition comprising the same | |
| CN108586436A (en) | Bishydrazide derivative of one kind skeleton containing indoles and its preparation method and application | |
| CN108503600A (en) | A kind of polysubstituted quinoxaline derivant and preparation method thereof | |
| CN101434601B (en) | 2-furyl-1H-benzimidazole-4-acidamide type derivative | |
| CN107098861A (en) | Design, the synthesis of benzamide anti-tumor compounds of one class containing pyrazole ring |
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 |