CN107151255A - Boric acid compound and its production and use - Google Patents
Boric acid compound and its production and use Download PDFInfo
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- CN107151255A CN107151255A CN201610125690.2A CN201610125690A CN107151255A CN 107151255 A CN107151255 A CN 107151255A CN 201610125690 A CN201610125690 A CN 201610125690A CN 107151255 A CN107151255 A CN 107151255A
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- Prior art keywords
- compound
- added
- solution
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- boric acid
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- 239000004327 boric acid Substances 0.000 title claims abstract description 84
- -1 Boric acid compound Chemical class 0.000 title claims abstract description 39
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 190
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 claims abstract description 14
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 5
- 125000005605 benzo group Chemical group 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 125000001188 haloalkyl group Chemical group 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 229940079156 Proteasome inhibitor Drugs 0.000 claims description 5
- 239000003207 proteasome inhibitor Substances 0.000 claims description 5
- 150000002431 hydrogen Chemical group 0.000 claims 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical group C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 54
- 230000005764 inhibitory process Effects 0.000 abstract description 6
- 108091005804 Peptidases Proteins 0.000 abstract description 4
- 239000004365 Protease Substances 0.000 abstract description 3
- 238000006467 substitution reaction Methods 0.000 abstract description 3
- 230000000079 pharmacotherapeutic effect Effects 0.000 abstract description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 abstract 1
- 238000012216 screening Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 219
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 204
- 238000006243 chemical reaction Methods 0.000 description 193
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 135
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 104
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 90
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 89
- 239000002904 solvent Substances 0.000 description 87
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 82
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 74
- 238000001035 drying Methods 0.000 description 74
- 238000001514 detection method Methods 0.000 description 69
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 66
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 66
- 238000003756 stirring Methods 0.000 description 63
- 239000007787 solid Substances 0.000 description 55
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 50
- 238000005160 1H NMR spectroscopy Methods 0.000 description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 46
- 238000004440 column chromatography Methods 0.000 description 42
- 229910052757 nitrogen Inorganic materials 0.000 description 41
- 239000012074 organic phase Substances 0.000 description 41
- 230000001681 protective effect Effects 0.000 description 41
- 238000000926 separation method Methods 0.000 description 41
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 37
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 37
- 239000000047 product Substances 0.000 description 37
- 238000005406 washing Methods 0.000 description 34
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 33
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 30
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 25
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 18
- 230000000694 effects Effects 0.000 description 17
- 238000010792 warming Methods 0.000 description 16
- 150000002148 esters Chemical group 0.000 description 14
- 235000019253 formic acid Nutrition 0.000 description 14
- 239000007788 liquid Substances 0.000 description 14
- 238000002390 rotary evaporation Methods 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical group [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000011592 zinc chloride Substances 0.000 description 10
- FIGYDZCRJFNSDZ-UHFFFAOYSA-N 2-methylpropylboron Chemical compound [B]CC(C)C FIGYDZCRJFNSDZ-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 0 CC(C)C[C@@](B(O)O)NC(C1N*CC1)=O Chemical compound CC(C)C[C@@](B(O)O)NC(C1N*CC1)=O 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 150000002240 furans Chemical class 0.000 description 8
- 229910052751 metal Inorganic materials 0.000 description 8
- 239000002184 metal Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 5
- 229960001467 bortezomib Drugs 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 150000003233 pyrroles Chemical class 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical group COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 5
- MOILFCKRQFQVFS-BDNRQGISSA-N (1r,3s,4r,5r)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1[C@@H]2C(C)(C)[C@H]1C[C@H](O)[C@@]2(O)C MOILFCKRQFQVFS-BDNRQGISSA-N 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical class C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 150000001642 boronic acid derivatives Chemical class 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 230000037012 chymotrypsin-like activity Effects 0.000 description 4
- 238000006482 condensation reaction Methods 0.000 description 4
- FNJVDWXUKLTFFL-UHFFFAOYSA-N diethyl 2-bromopropanedioate Chemical compound CCOC(=O)C(Br)C(=O)OCC FNJVDWXUKLTFFL-UHFFFAOYSA-N 0.000 description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 125000001979 organolithium group Chemical group 0.000 description 4
- 229910052710 silicon Inorganic materials 0.000 description 4
- 239000010703 silicon Substances 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 244000248349 Citrus limon Species 0.000 description 3
- 235000005979 Citrus limon Nutrition 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- KHIHBOPGYSBYJJ-UHFFFAOYSA-N azane;toluene Chemical compound N.CC1=CC=CC=C1 KHIHBOPGYSBYJJ-UHFFFAOYSA-N 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- JMVWCCOXRGFPJZ-UHFFFAOYSA-N propoxyboronic acid Chemical compound CCCOB(O)O JMVWCCOXRGFPJZ-UHFFFAOYSA-N 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- AKWIAIDKXNKXDI-UHFFFAOYSA-N 1h-pyrrole-3-carboxamide Chemical class NC(=O)C=1C=CNC=1 AKWIAIDKXNKXDI-UHFFFAOYSA-N 0.000 description 2
- JODRRPJMQDFCBJ-UHFFFAOYSA-N 2-Hydroxy-4-methylbenzaldehyde Chemical compound CC1=CC=C(C=O)C(O)=C1 JODRRPJMQDFCBJ-UHFFFAOYSA-N 0.000 description 2
- RNTYTQILDXWFLQ-UHFFFAOYSA-N 5-methyl-1-benzofuran-2-carboxylic acid Chemical compound CC1=CC=C2OC(C(O)=O)=CC2=C1 RNTYTQILDXWFLQ-UHFFFAOYSA-N 0.000 description 2
- YEQVNAGNEONSTR-UHFFFAOYSA-N 5-phenyl-1h-pyrrole-2-carboxylic acid Chemical compound N1C(C(=O)O)=CC=C1C1=CC=CC=C1 YEQVNAGNEONSTR-UHFFFAOYSA-N 0.000 description 2
- IIEBVSJZCPSSIK-UHFFFAOYSA-N 5-tert-butyl-1-benzofuran-2-carboxylic acid Chemical compound CC(C)(C)C1=CC=C2OC(C(O)=O)=CC2=C1 IIEBVSJZCPSSIK-UHFFFAOYSA-N 0.000 description 2
- STGSJLZWQHRTGE-UHFFFAOYSA-N 6-methyl-1-benzofuran-2-carboxylic acid Chemical compound CC1=CC=C2C=C(C(O)=O)OC2=C1 STGSJLZWQHRTGE-UHFFFAOYSA-N 0.000 description 2
- ZGVCUDGNUWNJDI-UHFFFAOYSA-N 7-methyl-1-benzofuran-2-carboxylic acid Chemical compound CC1=CC=CC2=C1OC(C(O)=O)=C2 ZGVCUDGNUWNJDI-UHFFFAOYSA-N 0.000 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 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- FIWNRHHXUSTNHD-UHFFFAOYSA-N [B]CC(C)CCCl Chemical compound [B]CC(C)CCCl FIWNRHHXUSTNHD-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- PFBUKDPBVNJDEW-UHFFFAOYSA-N dichlorocarbene Chemical group Cl[C]Cl PFBUKDPBVNJDEW-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000012285 osmium tetroxide Substances 0.000 description 2
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 235000019419 proteases Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 229910052711 selenium Inorganic materials 0.000 description 2
- 239000011669 selenium Substances 0.000 description 2
- 239000004575 stone Substances 0.000 description 2
- UVFAEQZFLBGVRM-MSMWPWNWSA-N succinyl-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)CCC(O)=O)CC(C)C)C(=O)NC=1C=C2OC(=O)C=C(C)C2=CC=1)C1=CC=C(O)C=C1 UVFAEQZFLBGVRM-MSMWPWNWSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 2
- YNVOMSDITJMNET-UHFFFAOYSA-N thiophene-3-carboxylic acid Chemical compound OC(=O)C=1C=CSC=1 YNVOMSDITJMNET-UHFFFAOYSA-N 0.000 description 2
- 230000001810 trypsinlike Effects 0.000 description 2
- QHKJIJXBJCOABP-UHFFFAOYSA-N 1-benzofuran-2-carboxamide Chemical class C1=CC=C2OC(C(=O)N)=CC2=C1 QHKJIJXBJCOABP-UHFFFAOYSA-N 0.000 description 1
- OFFSPAZVIVZPHU-UHFFFAOYSA-N 1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)=CC2=C1 OFFSPAZVIVZPHU-UHFFFAOYSA-N 0.000 description 1
- DYSJMQABFPKAQM-UHFFFAOYSA-N 1-benzothiophene-2-carboxylic acid Chemical compound C1=CC=C2SC(C(=O)O)=CC2=C1 DYSJMQABFPKAQM-UHFFFAOYSA-N 0.000 description 1
- VFHUJFBEFDVZPJ-UHFFFAOYSA-N 1h-indole-2-carboxamide Chemical class C1=CC=C2NC(C(=O)N)=CC2=C1 VFHUJFBEFDVZPJ-UHFFFAOYSA-N 0.000 description 1
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- YMZTUCZCQMQFMK-UHFFFAOYSA-N 3-methyl-1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2C(C)=C(C(O)=O)OC2=C1 YMZTUCZCQMQFMK-UHFFFAOYSA-N 0.000 description 1
- SNKGYZVEYQQMFY-UHFFFAOYSA-N 4-methyl-1-benzofuran-2-carboxylic acid Chemical compound CC1=CC=CC2=C1C=C(C(O)=O)O2 SNKGYZVEYQQMFY-UHFFFAOYSA-N 0.000 description 1
- BSOIGQKKGJNDJD-UHFFFAOYSA-N 5-(2-methylphenyl)thiophene-2-carboxylic acid Chemical compound CC1=CC=CC=C1C1=CC=C(C(O)=O)S1 BSOIGQKKGJNDJD-UHFFFAOYSA-N 0.000 description 1
- ZJBGVUBFQCFOSR-UHFFFAOYSA-N 5-ethyl-1-benzofuran Chemical compound CCC1=CC=C2OC=CC2=C1 ZJBGVUBFQCFOSR-UHFFFAOYSA-N 0.000 description 1
- GEMSHGKMBATUOL-UHFFFAOYSA-N 5-ethyl-1-benzofuran-2-carboxylic acid Chemical compound CCC1=CC=C2OC(C(O)=O)=CC2=C1 GEMSHGKMBATUOL-UHFFFAOYSA-N 0.000 description 1
- UFYABCWJPZTWHA-UHFFFAOYSA-N 5-methyl-1h-pyrrole-2-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)N1 UFYABCWJPZTWHA-UHFFFAOYSA-N 0.000 description 1
- PMZBHPUNQNKBOA-UHFFFAOYSA-N 5-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC(C(O)=O)=CC(C(O)=O)=C1 PMZBHPUNQNKBOA-UHFFFAOYSA-N 0.000 description 1
- OVOCLWJUABOAPL-UHFFFAOYSA-N 5-methylfuran-2-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)O1 OVOCLWJUABOAPL-UHFFFAOYSA-N 0.000 description 1
- VCNGNQLPFHVODE-UHFFFAOYSA-N 5-methylthiophene-2-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)S1 VCNGNQLPFHVODE-UHFFFAOYSA-N 0.000 description 1
- LZKWLHXJPIKJSJ-UHFFFAOYSA-N 5-nitrobenzofuran-2-carboxylic acid Chemical compound [O-][N+](=O)C1=CC=C2OC(C(=O)O)=CC2=C1 LZKWLHXJPIKJSJ-UHFFFAOYSA-N 0.000 description 1
- HOFDSZDCPNKUAK-UHFFFAOYSA-N 5-tert-butyl-1-benzofuran Chemical compound CC(C)(C)C1=CC=C2OC=CC2=C1 HOFDSZDCPNKUAK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- UVYHBXAZYDCMAO-MERQFXBCSA-N CB([C@H](CC(C)C)NC(c1ccc[o]1)=[U])O Chemical compound CB([C@H](CC(C)C)NC(c1ccc[o]1)=[U])O UVYHBXAZYDCMAO-MERQFXBCSA-N 0.000 description 1
- PYNZTRFUAXVQFM-AHGUJYFHSA-N CC(C)CC(B1O[C@](C)(CC2NC3C2)[C@H]3O1)Cl Chemical compound CC(C)CC(B1O[C@](C)(CC2NC3C2)[C@H]3O1)Cl PYNZTRFUAXVQFM-AHGUJYFHSA-N 0.000 description 1
- PIGGZRUXLYQORH-QJYWWFBJSA-N CC(C1[C@@]2(C)C1C2C1)[C@@H]1N Chemical compound CC(C1[C@@]2(C)C1C2C1)[C@@H]1N PIGGZRUXLYQORH-QJYWWFBJSA-N 0.000 description 1
- DDGXSYWLQZGUPN-UHFFFAOYSA-N CC1C(C([O]=C)=O)=CC=C1C Chemical compound CC1C(C([O]=C)=O)=CC=C1C DDGXSYWLQZGUPN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- UMSCPKPEJAYDKK-UHFFFAOYSA-N butan-1-amine;toluene Chemical compound CCCCN.CC1=CC=CC=C1 UMSCPKPEJAYDKK-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000004452 carbocyclyl group Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- UBKHHFOBCZFFKL-UHFFFAOYSA-N cyclopenta[c]pyran Chemical compound C1=COC=C2C=CC=C21 UBKHHFOBCZFFKL-UHFFFAOYSA-N 0.000 description 1
- 208000002925 dental caries Diseases 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- NYEFUKPRSIREFK-UHFFFAOYSA-N lithium;dichloromethane Chemical compound [Li+].Cl[CH-]Cl NYEFUKPRSIREFK-UHFFFAOYSA-N 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000002730 succinyl group Chemical group C(CCC(=O)*)(=O)* 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 230000006663 ubiquitin-proteasome pathway Effects 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field.Specifically related to new boric acid compound and its production and use, more particularly to new substituted five-membered heterocyclic boronic acids class and substitution benzo five-ring heterocycles boric acid compound and preparation method thereof, substituted five-membered heterocyclic boronic acids class and substitution benzo five-ring heterocycles boric acid compound produced by the present invention such as formula is tested through bioactivity screening, as a result show, described compound has the function of protease inhibition body, can be further used for preparing treatment and the medicine of proteasome relevant disease.
Description
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field.Specifically related to new boric acid compound and preparation method thereof and use
On the way, more particularly to new substituted five-membered heterocyclic boronic acids class and substitution benzo five-ring heterocycles boric acid compound and preparation method thereof and
Prepare treatment and the application in proteasome relevant disease medicine.
Background technology
It is that eucaryon is thin prior art discloses Ubiquitin-proteasome path (Ubiquitin-Proteasome Pathway, abbreviation UPP)
The main path of protein degradation in born of the same parents, can regulate and control to participate in the protein level of cell cycle control, maintain different cell processes
Biological homeostasis.Studies have shown that is in most of mammalian cell, and the path can recognize and degrade false folding
Protein；And it is demonstrated experimentally that cancer, the morbidity of cardiovascular and cerebrovascular disease and nerve degenerative diseases and Ubiquitin-proteasome
Path has important contact.
Research is disclosed in Ubiquitin-proteasome path, and the proteinase complex 26S proteasomes of multi-catalytic are hydrolysis eggs
White key component, is made up of two regulation particle 19S proteasomes and a cylindrical 20S proteasome；19S albumen
Enzyme body is located at the two ends of 20S proteasomes, is made up of 18 subunits, controls protein substrate to enter 20S proteasome cavitys
In identification, folding and transposition；20S proteasomes constitute 4 stacked rings by 28 subunits, wherein 7 different α are sub-
Base (α 1- α 7) two exterior chambers of formation, 7 different center cavities of β subunits (the β 1- β 7) formation with proteolytic active sites
Room；Three protein subunit hydrolysing activities in central lumen have been determined：There is the subunits of β 1 glutamy to turn hydrolase polypeptide activity
(PGPH), beta 2 subunit base has trypsin-like activity (T-L), and beta 5 subunit has chymotrypsinlike activity (CT-L).
Millennium Pharmaceuticals had listed first proteasome inhibitor bortezomib in the U.S. in success in 2003, and it is used to treat
Huppert's disease.The bortezomib is the reversible selective proteasome inhibitor of covalent type, main to suppress chymotrypsin sample
Activity.The suppression that the successful exploitation of bortezomib demonstrates proteasome is a kind of effective therapeutic strategy；However, clinical data
It has been shown that, bortezomib has more toxic side effect, for example, suffer from diarrhoea, vomit, Painful peripheral neuropathy becomes and blood platelet
Reduce disease etc..So far, the mechanism of these toxic side effects is unclear；In addition, the Clinical practice of bortezomib needs weekly
Intravenous injection twice or subcutaneous administrations scheme, great inconvenience is brought to patient.
Present situation based on prior art, present inventor intends providing new boric acid compound, further prepares toxic side effect
Low, administration flexibly, novel protease body inhibitor that can be oral.
The content of the invention
It is an object of the invention to provide a kind of structure is novel and new boric acid compound with protease inhibition body function.
Another object of the present invention is to provide the preparation method of above-mentioned new boric acid compound.
Further object of the present invention is to provide above-mentioned new boric acid compound for preparing treatment and proteasome relevant disease
Application in medicine.
In order to reach the purpose of the present invention, using following technical scheme：
The invention provides new boric acid compound, its structure shown in formula I,
Wherein：
X is C, O, S or NH；Y is CR, O, S or NH；
R is hydrogen, alkyl or aryl.
In some embodiments of the present invention, compound of formula I has following structure：
Wherein：
X is C, O, S or NH；Y is CR, O, S or NH；
R is hydrogen, alkyl or aryl.
In some embodiments of the present invention, compound is Formulas I-a S- enantiomters；
Wherein：
X is C, O, S or NH；Y is CR, O, S or NH；
R is hydrogen, alkyl or aryl.
In some embodiments of the present invention, Formulas I-a compounds have following structure：
Wherein：
X is O, S or NH；
R is hydrogen, alkyl or aryl.
In some embodiments of the present invention, compound is Formulas I-a-1 S- enantiomters；
Wherein：
X is O, S or NH；
R is hydrogen, alkyl or aryl.
In some embodiments of the present invention, Formulas I-a compounds have following structure：
Wherein：
Y is O, S or NH.
In some embodiments of the present invention, compound is Formulas I-a-2 S- enantiomters；
Wherein：
Y is O, S or NH.
The new boric acid compound that the present invention is provided, its structure also as shown in Formula II,
Wherein：
X is O, S or NH；
R1、R2、R3、R4And R5Stand alone as hydrogen, alkyl, cycloalkyl, alkoxy, haloalkyl, halogen or nitro.
In some embodiments of the present invention, Formula II compound has Formula II-a structures：
Wherein：
X is O, S or NH；
R1、R2、R3、R4And R5Stand alone as hydrogen, alkyl, cycloalkyl, alkoxy, haloalkyl, halogen or nitro.
In some embodiments of the present invention, compound is Formula II-a S- enantiomters；
Wherein：
X is O, S or NH；
R1、R2、R3、R4And R5Stand alone as hydrogen, alkyl, cycloalkyl, alkoxy, haloalkyl, halogen or nitro.
In some embodiments of the present invention, Formula II-a compounds have Formula II-a-1 structures：
Wherein：
R1、R2、R3、R4And R5Stand alone as hydrogen, alkyl, cycloalkyl, alkoxy, haloalkyl, halogen or nitro.
In some embodiments of the present invention, compound is Formula II-a-1 S- enantiomters；
Wherein：
R1、R2、R3、R4And R5Stand alone as hydrogen, alkyl, cycloalkyl, alkoxy, haloalkyl, halogen or nitro.
In some embodiments of the present invention, Formula II-a-1 compounds have Formula II-a-1-1, II-a-1-2, II-a-1-3, II-a-1-4 or
II-a-1-5 structures：
Wherein：
R1、R2、R3、R4And R5For hydrogen, alkyl, cycloalkyl, alkoxy, haloalkyl, halogen or nitro.
In some embodiments of the present invention, compound is Formula II-a-1-1, II-a-1-2, II-a-1-3, II-a-1-4 or II-a-1-5
S- enantiomters；
Wherein：
R1、R2、R3、R4And R5For hydrogen, alkyl, cycloalkyl, alkoxy, haloalkyl, halogen or nitro.
In some embodiments of the present invention, compound has Formula II-a-1-3, II-a-1-4 or II-a-1-5 structures；
Wherein：
R3、R4And R5For hydrogen, alkyl, cycloalkyl, alkoxy, haloalkyl, halogen or nitro.
In some embodiments of the present invention, compound is Formula II-a-1-3, II-a-1-4 or II-a-1-5 S- enantiomters；
Wherein：
R3、R4And R5For hydrogen, alkyl, cycloalkyl, alkoxy, haloalkyl, halogen or nitro.
In some embodiments of the present invention, compound has Formula II-a-1-3 structures；
Wherein：
R3For hydrogen, alkyl, cycloalkyl, alkoxy, haloalkyl, halogen or nitro.
In some embodiments of the present invention, compound is Formula II-a-1-3 S- enantiomters；
Wherein：
R3For hydrogen, alkyl, cycloalkyl, alkoxy, haloalkyl, halogen or nitro.
In the present invention,
Term " hydrocarbon " (no matter it is used alone or as a part for another group) refers to only include carbon atom (at most 14 carbon
Atom) and hydrogen atom any structure；
Term " alkyl " is used for the saturated hydrocarbyl for representing straight or branched；
Term " aryl " is used to represent aromatic carbocyclyl groups, including monocyclic or polycyclic aromatic hydrocarbon；
Term " cycloalkyl " is used to represent non-aromatic carbocyclyl, includes the alkyl of cyclisation, cycloalkyl can include two rings or multi-loop system；
Term " alkoxy " is used to represent-O- alkyl groups；
Term " haloalkyl " is used to represent the alkyl that wherein one or more (including all) hydrogen atoms are substituted by halogen atom；
Term " halogen " is used to represent fluorine, chlorine, bromine and iodine；
Dotted line and thick line are used for the chemical constitution for representing one or more Stereocenters, indicate the absolute stereo at chemical constitution neutral body center
Chemical constitution.
In the present invention, the key described in structure schema not represents preferably stereochemical structure；Containing in one or more solids
The chemical constitution of the heart includes all possible stereoisomer form and its mixture.
In the present invention, term " inhibitor ", which is used for expression, can block or reduce enzyme, enzyme system, acceptor or other pharmacology
The compound of target activity.
In the present invention, term " treatment " is used to represent to include reverse, mitigates or prevent the pathological state of clinical disease and correlation,
To improve or stablize the situation of patient.
The invention provides the preparation method of described compound：
The compound of the present invention can be prepared by a variety of synthetic methods, and a part of raw material for preparing the compounds of this invention can
So that from commercial reagents company, another part can then use concise conversion method well known in the art to prepare.
In the present invention, lead to the following synthetic route formula I of fruit compound, wherein, the substituent of compound of formula I has above
Described meaning.The exemplary only explanation present invention of the synthetic method, and not it is limited to the invention.
The synthesis of Formulas I-a compounds：
Formula III -1 obtains formula III -2, formula III -2 and B (OCH under n-BuLi effects3)3Reaction obtains formula III -3, formula III -3 and III-4-a
Formula III -5-a, formula III -5-a are obtained through ester exchange reaction to react with metal reagent i-BuMgBr, then through anhydrous ZnCl2It is catalyzed
To formula III -6-a, formula III -6-a and LiN (SiMe3)2Reaction obtains formula III -7-a, formula III -7-a and is deprotected under HCl effects
To formula III -8-a, formula III -8-a formula IV -2-a, the group that formula IV -2-a removings are connected with B are obtained with formula IV -1 through condensation reaction
Obtain Formulas I-a.
Formulas I-a S- enantiomter compound synthesis：
Formula III -1 obtains formula III -2, formula III -2 and B (OCH under n-BuLi effects3)3Reaction obtains formula III -3, formula III -3 and III-4-b
Formula III -5-b, formula III -5-b are obtained through ester exchange reaction to react with metal reagent i-BuMgBr, then through anhydrous ZnCl2It is catalyzed
To formula III -6-b, formula III -6-b and LiN (SiMe3)2Reaction obtains formula III -7-b, formula III -7-b and is deprotected under HCl effects
To formula III -8-b, formula III -8-b formula IV -2-b, the group that formula IV -2-b removings are connected with B are obtained with formula IV -1 through condensation reaction
Obtain Formulas I-a S- enantiomters.
The compound of the Formula II prepared in the present invention by a variety of synthetic methods, wherein, one for preparing the compound
Raw material is divided to derive from commercial reagents company, another part can then use concise conversion method well known in the art to prepare.
Formula II compounds press following synthetic routes, wherein, the substituent of Formula II compound has previously described meaning.
The exemplary only explanation present invention of the synthetic method, and not it is limited to the invention.
Synthesis type II-a compounds：
Formula III -1 obtains formula III -2, formula III -2 and B (OCH under n-BuLi effects3)3Reaction obtains formula III -3, formula III -3 and III-4-a
Formula III -5-a, formula III -5-a are obtained through ester exchange reaction to react with metal reagent i-BuMgBr, then through anhydrous ZnCl2It is catalyzed
To formula III -6-a, formula III -6-a and LiN (SiMe3)2Reaction obtains formula III -7-a, formula III -7-a and is deprotected under HCl effects
Formula V -2-a is obtained through condensation reaction with Formula V -1 to formula III -8-a, formula III -8-a, the group that Formula V -2-a removings are connected with B is obtained
To Formula II-a.
Synthesis type II-a S- enantiomter compounds：
Formula III -1 obtains formula III -2, formula III -2 and B (OCH under n-BuLi effects3)3Reaction obtains formula III -3, formula III -3 and III-4-b
Formula III -5-b, formula III -5-b are obtained through ester exchange reaction to react with metal reagent i-BuMgBr, then through anhydrous ZnCl2It is catalyzed
To formula III -6-b, formula III -6-b and LiN (SiMe3)2Reaction obtains formula III -7-b, formula III -7-b and is deprotected under HCl effects
Formula V -2-b is obtained through condensation reaction with Formula V -1 to formula III -8-b, formula III -8-b, the group that Formula V -2-b removings are connected with B is obtained
To Formula II-a S- enantiomters.
More specifically,
The invention provides the method for preparing compound of formula I, wherein the substituent of the compound has previously described meaning；It is wrapped
Include：
1, synthesis type I-a compounds：
1) compound of the structure of formula III -1 reacts the organolithium intermediate obtained shown in formula III -2 under the conditions of -110 DEG C with n-BuLi；
2) compound of the structure of formula III -2 under the conditions of -110 DEG C with B (OCH3)3Reaction obtains the trimethyl borate structure shown in III-3；
3) compound of the structure of formula III -3 carries out ester exchange reaction with the chiral pinane diol shown in formula III -4-a and obtained at ambient temperature
To the boric acid ester structure shown in III-5-a；
4) compound of formula III -5-a structures is first reacted under the conditions of -78 DEG C with metal reagent i-BuMgBr, afterwards again at ambient temperature
Through anhydrous ZnCl2Catalysis obtains the boric acid ester structure shown in III-6-a；
5.) compound of formula III -6-a structures under the conditions of -78 DEG C with LiN (SiMe3)2Reaction obtains double (front threes shown in formula III -7-a
Base silicon) protection aminoboronic acid ester structure；
6) compound of formula III -7-a structures obtains formula III -8-a under the conditions of -78 DEG C with HCl effect removing double (trimethyl silicanes) protection
Shown unshielded aminoboronic acid ester hydrochloride structure；
7) compound of the compound of formula III -8-a structures and the structure of formula IV -1 is in condensing agent 1- (3- dimethylamino-propyls) -3- ethyl carbon
Diimmonium salt hydrochlorate (being abbreviated as EDCHCl) and 1- hydroxy benzo triazoles (being abbreviated as HOBt) react under conditions of existing to be obtained
Boric acid ester structure shown in formula IV -2-a；
8) compound of formula IV -2-a structures is obtained shown in Formulas I-a with 2- methyl-propyls boric acid generation ester exchange reaction at ambient temperature
Target boronic acid compounds；
2, synthesis type I-a S- enantiomter compounds：
1) compound of the structure of formula III -1 reacts the organolithium intermediate obtained shown in formula III -2 under the conditions of -110 DEG C with n-BuLi；
2) compound of the structure of formula III -2 under the conditions of -110 DEG C with B (OCH3)3Reaction obtains the trimethyl borate structure shown in III-3；
3) compound of the structure of formula III -3 carries out ester exchange reaction with the chiral pinane diol shown in formula III -4-b and obtained at ambient temperature
Boric acid ester structure shown in III-5-b；
4) compound of formula III -5-b structures is first reacted under the conditions of -78 DEG C with metal reagent i-BuMgBr, rear again in room temperature condition
It is lower through anhydrous ZnCl2Catalysis obtains the boric acid ester structure shown in III-6-b；
5) compound of formula III -6-b structures under the conditions of -78 DEG C with LiN (SiMe3)2Reaction obtains double (front threes shown in formula III -7-b
Base silicon) protection aminoboronic acid ester structure；
6) compound of formula III -7-b structures obtains formula III -8-b under the conditions of -78 DEG C with HCl effect removing double (trimethyl silicanes) protection
Shown unshielded aminoboronic acid ester hydrochloride structure；
7) compound of the compound of formula III -8-b structures and the structure of formula IV -1 is in condensing agent 1- (3- dimethylamino-propyls) -3- ethyls carbon two
Reaction obtains formula under conditions of inferior amine salt hydrochlorate (being abbreviated as EDCHCl) and 1- hydroxy benzo triazoles (being abbreviated as HOBt) are present
Boric acid ester structure shown in IV-2-b；
8) S- that ester exchange reaction obtains Formulas I-a occurs with 2- methyl-propyls boric acid at ambient temperature for the compound of formula IV -2-b structures
Enantiomter target boronic acid compounds.
And,
The invention provides the method for formula II compounds, wherein the substituent of the compound has previously described meaning；
It includes：
Synthesis type II-a compounds：
1) compound of the structure of formula III -1 reacts the organolithium intermediate obtained shown in formula III -2 under the conditions of -110 DEG C with n-BuLi；
2) compound of the structure of formula III -2 under the conditions of -110 DEG C with B (OCH3)3Reaction obtains the trimethyl borate structure shown in III-3；
3) compound of the structure of formula III -3 carries out ester exchange reaction with the chiral pinane diol shown in formula III -4-a and obtained at ambient temperature
To the boric acid ester structure shown in III-5-a；
4) compound of formula III -5-a structures is first reacted under the conditions of -78 DEG C with metal reagent i-BuMgBr, rear again in room temperature condition
It is lower through anhydrous ZnCl2Catalysis obtains the boric acid ester structure shown in III-6-a；
5) compound of formula III -6-a structures under the conditions of -78 DEG C with LiN (SiMe3)2Reaction obtains double (trimethyls shown in formula III -7-a
Silicon) protection aminoboronic acid ester structure；
6) compound of formula III -7-a structures obtains formula III -8-a institutes under the conditions of -78 DEG C with HCl effect removing double (trimethyl silicanes) protection
The unshielded aminoboronic acid ester hydrochloride structure shown；
7) compound of the compound of formula III -8-a structures and the structure of Formula V -1 is in condensing agent 1- (3- dimethylamino-propyls) -3- ethyls carbon two
Reaction obtains formula under conditions of inferior amine salt hydrochlorate (being abbreviated as EDCHCl) and 1- hydroxy benzo triazoles (being abbreviated as HOBt) are present
Boric acid ester structure shown in V-2-a；
8) compound of Formula V -2-a structures is obtained shown in Formula II-a with 2- methyl-propyls boric acid generation ester exchange reaction at ambient temperature
Target boronic acid compounds；
And, synthesis type II-a S- enantiomter compounds：
1) compound of the structure of formula III -1 reacts the organolithium intermediate obtained shown in formula III -2 under the conditions of -110 DEG C with n-BuLi；
2) compound of the structure of formula III -2 under the conditions of -110 DEG C with B (OCH3)3Reaction obtains the trimethyl borate structure shown in III-3；
3) compound of the structure of formula III -3 carries out ester exchange reaction with the chiral pinane diol shown in formula III -4-b and obtained at ambient temperature
Boric acid ester structure shown in III-5-b；
4) compound of formula III -5-b structures is first reacted under the conditions of -78 DEG C with metal reagent i-BuMgBr, rear again in room temperature condition
It is lower through anhydrous ZnCl2Catalysis obtains the boric acid ester structure shown in III-6-b；
5) compound of formula III -6-b structures under the conditions of -78 DEG C with LiN (SiMe3)2Reaction obtains double (front threes shown in formula III -7-b
Base silicon) protection aminoboronic acid ester structure；
6) compound of formula III -7-b structures obtains formula III -8-b under the conditions of -78 DEG C with HCl effect removing double (trimethyl silicanes) protection
Shown unshielded aminoboronic acid ester hydrochloride structure；
7) compound of the compound of formula III -8-b structures and the structure of Formula V -1 is in condensing agent 1- (3- dimethylamino-propyls) -3- ethyls carbon two
Reaction obtains formula under conditions of inferior amine salt hydrochlorate (being abbreviated as EDCHCl) and 1- hydroxy benzo triazoles (being abbreviated as HOBt) are present
Boric acid ester structure shown in V-2-b；
8) compound of Formula V -2-b structures obtains Formula II-a's with 2- methyl-propyls boric acid generation ester exchange reaction at ambient temperature
S- enantiomter target boronic acid compounds.
The present invention shows that obtained Formulas I and II compounds has good proteasome inhibition activity, portion through pharmaceutical research
Differentiation compound shows good proteasome inhibition activity under nanomolar range, can further prepare proteasome inhibitor use
In treatment and proteasome relevant disease.
Embodiment
The present invention is further illustrated with reference to embodiments, but these embodiments are not limit the scope of the invention.
In the experiment of the present invention, commercial reagents company can be derived from for preparing a part of raw material of the compounds of this invention, it is another
Part can then use concise conversion method well known in the art to prepare；Compound structure is joined by nuclear magnetic resonance (NMR) and liquid matter
Determined with (LCMS)；.NMR, which is determined, uses Varian 400MHz NMRs, and measure reagent is CDCl3、CD3OD
And DMSO-d6, TMS is inside designated as, chemical shift (δ) is in units of ppm；LCMS is determined using Agilent Technologies
6120 LC-MS instrument；Column chromatography uses pressure preparative chromatograph in YAMAZEN AI-580S to carry out product purification.
Embodiment 1：The preparation of dichloromethylene lithium (compound III-2)
LiCHCl2
(III-2)
Under nitrogen protective condition, anhydrous methylene chloride (4.6mL, 72mmol), temperature drop are added into 200mL anhydrous tetrahydro furans
To -110 DEG C, it is added dropwise after 1.6M n-BuLi hexane solution (38mL, 60mmol), completion of dropping, continues at -110 DEG C dropwise
At a temperature of stir 1 hour；Reaction solution is not purified to be directly used in the next step.
Embodiment 2：The preparation of dichloromethylene trimethyl borate (compound III-3)
Under nitrogen protective condition, temperature continues to control at -110 DEG C, is added in the compound III-2 solution prepared to embodiment 1
Trimethylborate (8mL, 72mmol), continues to stir at a temperature of -110 DEG C 1 hour, then adds 5N HCl solution 12mL,
Reaction is slowly warmed to room temperature, and reaction solution is transferred in separatory funnel, separates organic phase, and aqueous phase extracts (3 × 10mL) using ether,
Merge organic phase, add anhydrous sodium sulfate drying, dry and filtered after finishing, using Rotary Evaporators except solvent obtains white solid
8.7g, yield 92%.Reaction product is not purified to be directly used in the next step.
Embodiment 3：The preparation of (+)-australene alkane glycol (compound III-4-a)
Under nitrogen protective condition, Me is added into the 100mL tert-butyl alcohols3NO·2H2O (11g, the 102mmol) aqueous solution, stirring
Under sequentially add (+)-australene (15mL, 97mmol), pyridine (7mL) and osmium tetroxide (51mg, 0.2mmol), then heat up
To flowing back, TLC detections display reaction is complete after 24 hours, and room temperature is down in reaction, adds NaHSO3(1.2g, 12mmol)
Stirring 1 hour, reaction solution is transferred in separatory funnel, separates organic phase, and aqueous phase is merged using ether extraction (3 × 20mL)
Organic phase, adds anhydrous sodium sulfate drying, dries and is filtered after finishing, solvent, column chromatography for separation (stone are removed using Rotary Evaporators
Oily ether：Ethyl acetate=30：1) white solid 15g, yield 91% are obtained.
Embodiment 4：The preparation of dichloromethylene boric acid-(+)-australene alkane diol ester (compound III-5-a)
The compound III-3 (10g, 63mmol) of embodiment 2 and the compound of embodiment 3 are added into 150mL anhydrous tetrahydro furans
III-4-a (7.2g, 42mmol), is stirred at room temperature, and TLC detections display reaction is complete after 18 hours, using Rotary Evaporators except molten
Agent, column chromatography for separation (petroleum ether：Ethyl acetate=10：1) colourless oil liquid 10g, yield 91% are obtained.1H NMR(CDCl3,
400MHz) δ 5.39 (s, 1H), 4.46 (d, 1H, J=8.8Hz), 2.33 (m, 2H), 2.12 (t, 1H, J=5.2Hz), 1.94 (m, 2H),
1.46 (s, 3H), 1.30 (s, 3H), 1.21 (d, 1H, J=11.2Hz), 0.84 (s, 3H).
Embodiment 5：The preparation of 2- methyl -4- chloro- butyl boron dihydroxide-(+)-australene alkane diol ester (compound III-6-a)
Under nitrogen protective condition, the compound III-5 (10g, 38mmol) of embodiment 4, temperature drop are added into 100mL absolute ethers
To -78 DEG C, it is added dropwise dropwise after 2M selenium alkynide diethyl ether solution (17mL, 33mmol), completion of dropping, adds drying
ZnCl2Powder, reaction is slowly warmed to room temperature, and TLC detections display reaction is complete after 20 hours, is filtered to remove solid, profit
Solvent, column chromatography for separation (petroleum ether are removed with Rotary Evaporators：Ethyl acetate=200：1) colourless oil liquid 7.6g, yield are obtained
81%.1H NMR(CDCl3, 400MHz) δ 4.36 (d, 1H, J=9.1Hz), 3.52 (m, 1H), 2.35 (m, 1H), 2.24 (m,
1H), 2.08 (t, 1H, J=5.4Hz), 1.92 (m, 2H), 1.87 (d, 1H, J=1.6Hz), 1.79 (m, 1H), 1.62 (m, 1H), 1.41
(s, 3H), 1.29 (s, 3H), 1.18 (d, 1H, J=11.0Hz), 0.92 (d, 3H, J=6.6Hz), 0.90 (d, 3H, J=6.6Hz), 0.84 (s,
3H)。
Embodiment 6：The preparation of 2- methyl -4- Amino-butyls boric acid-(+)-australene alkane glycol ester hydrochloride (compound III-8-a)
Under nitrogen protective condition, the compound III-6-a (4.5g, 16mmol) of embodiment 5 is added into 100mL anhydrous tetrahydro furans,
Temperature is down to -78 DEG C, and 1M LiN (SiMe are added dropwise dropwise3)2After tetrahydrofuran solution (24mL, 24mmol), completion of dropping,
Reaction is slowly warmed to room temperature, and TLC detections display reaction is complete after 24 hours, removes solvent using Rotary Evaporators, adds 50mL
N-hexane dissolution, is filtered to remove solid, and filtrate temperature is down to -78 DEG C, adds 2M HCl diethyl ether solutions (24mL, 48mmol),
Reaction is slowly warmed to room temperature, and a large amount of white solids occurs, is filtered and is washed with ether, obtains white solid 3.2g, yield 66%.1H NMR(DMSO-d6,400MHz)δ7.84(s,3H),7.41(s,1H),7.29(s,1H),7.16(s,1H),4.44(m,
1H), 2.74 (m, 1H), 2.32 (m, 1H), 2.18 (m, 1H), 1.99 (t, 1H, J=5.5Hz), 1.88 (m, 1H), 1.73 (m, 2H),
1.47 (m, 2H), 1.35 (s, 3H), 1.24 (s, 3H), 1.11 (d, 1H, J=10.8Hz), 0.86 (d, 6H, J=6.5Hz), 0.81 (s,
3H)。
Embodiment 7：The preparation of (-)-australene alkane glycol (compound III-4-b)
Under nitrogen protective condition, Me3NO2H is added into the 100mL tert-butyl alcohols2O (11g, the 102mmol) aqueous solution, stirring
Under sequentially add (-)-australene (15mL, 97mmol), pyridine (7mL) and osmium tetroxide (51mg, 0.2mmol), then heat up
To flowing back, TLC detections display reaction is complete after 20 hours, and room temperature is down in reaction, adds NaHSO3(1.2g, 12mmol)
Stirring 1 hour, reaction solution is transferred in separatory funnel, separates organic phase, and aqueous phase is merged using ether extraction (3 × 20mL)
Organic phase, adds anhydrous sodium sulfate drying, dries and is filtered after finishing, solvent, column chromatography for separation (stone are removed using Rotary Evaporators
Oily ether：Ethyl acetate=30：1) white solid 14g, yield 85% are obtained.
Embodiment 8：The preparation of dichloromethylene boric acid-(-)-australene alkane diol ester (compound III-5-b)
The compound III-3 (10g, 63mmol) of embodiment 2 and the compound of embodiment 7 are added into 150mL anhydrous tetrahydro furans
III-4-b (7.2g, 42mmol), is stirred at room temperature, and TLC detections display reaction is complete after 23 hours, is removed using Rotary Evaporators
Solvent, column chromatography for separation (petroleum ether：Ethyl acetate=10：1) colourless oil liquid 9g, yield 81% are obtained.1H NMR(CDCl3,
400MHz) δ 5.39 (s, 1H), 4.46 (d, 1H, J=8.7Hz), 2.33 (m, 2H), 2.12 (t, 1H, J=5.4Hz), 1.94 (m, 2H),
1.46 (s, 3H), 1.30 (s, 3H), 1.20 (d, 1H, J=11.2Hz), 0.84 (s, 3H).
Embodiment 9：The preparation of 2- methyl -4- chloro- butyl boron dihydroxide-(-)-australene alkane diol ester (compound III-6-b)
Under nitrogen protective condition, the compound III-5-b (10g, 38mmol) of embodiment 8, temperature are added into 100mL absolute ethers
- 78 DEG C are down to, is added dropwise dropwise after 2M selenium alkynide diethyl ether solution (17mL, 33mmol), completion of dropping, is added dry
Dry ZnCl2Powder, reaction is slowly warmed to room temperature, and TLC detections display reaction is complete after 22 hours, is filtered to remove solid,
Solvent, column chromatography for separation (petroleum ether are removed using Rotary Evaporators：Ethyl acetate=200：1) colourless oil liquid 5.8g, production are obtained
Rate 62%.1H NMR(CDCl3, 400MHz) and δ 4.36 (d, 1H, J=8.8Hz), 3.52 (m, 1H), 2.35 (m, 1H), 2.24
(m, 1H), 2.08 (t, 1H, J=5.4Hz), 1.91 (s, 2H), 1.87 (s, 1H), 1.79 (m, 1H), 1.61 (m, 1H), 1.41 (s, 3H),
1.29 (s, 3H), 1.18 (d, 1H, J=11.1Hz), 0.92 (d, 3H, J=6.6Hz), 0.90 (d, 3H, J=6.6Hz), 0.84 (s, 3H).
Embodiment 10：The preparation of 2- methyl -4- Amino-butyls boric acid-(-)-australene alkane glycol ester hydrochloride (compound III-8-b)
Under nitrogen protective condition, the compound III-6-b (4.5g, 16mmol) of embodiment 9 is added into 100mL anhydrous tetrahydro furans,
Temperature is down to -78 DEG C, and 1M LiN (SiMe are added dropwise dropwise3)2After tetrahydrofuran solution (24mL, 24mmol), completion of dropping,
Reaction is slowly warmed to room temperature, and TLC detections display reaction is complete after 18 hours, removes solvent using Rotary Evaporators, adds 50mL
N-hexane dissolution, is filtered to remove solid, and filtrate temperature is down to -78 DEG C, adds 2M HCl diethyl ether solutions (24mL, 48mmol),
Reaction is slowly warmed to room temperature, and a large amount of white solids occurs, is filtered and is washed with ether, obtains white solid 4.1g, yield 85%.1H NMR(DMSO-d6,400MHz)δ7.85(s,3H),7.42(s,1H),7.29(s,1H),7.16(s,1H),4.45(d,
1H, J=8.3Hz), 2.76 (m, 1H), 2.32 (m, 1H), 2.20 (m, 1H), 2.00 (t, 1H, J=5.3Hz), 1.88 (s, 1H), 1.73
(m, 2H), 1.48 (t, 2H, J=7.3Hz), 1.36 (s, 3H), 1.25 (s, 3H), 1.11 (dd, 1H, J=5.5Hz, J=10.6Hz), 0.86
(d, 6H, J=4.8Hz), 0.82 (s, 3H).
Embodiment 11：(R)-(1- (furans -2- the formamidos) -3- methyl butyls) preparation of boric acid (compound I-1)
Under nitrogen protective condition, furans -2- formic acid (12mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides, is stirred at room temperature,
HOBt (18mg, 0.13mmol) is added, continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes, so
The compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol) is added afterwards, after 10 hours
TLC detection display reactions are complete, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3It is molten
Liquid and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes Rotary Evaporators
Except solvent, products therefrom is added directly into 5mL methanol, is stirred at room temperature, and adds 2- methyl-propyls boric acid (22mg, 0.22mmol)
With 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC detections display is anti-after 3 hours
Should be complete, reaction solution is stood to being layered, lower floor is washed with n-hexane, adds anhydrous sodium sulfate drying, dry and filtered after finishing,
Solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=50：1) colorless solid 11mg, yield 44% are obtained.1H NMR(CD3OD, 400MHz) δ 7.85 (s, 1H), 7.39 (s, 1H), 6.70 (s, 1H), 2.83 (t, 1H, J=7.3Hz),
1.74 (m, 1H), 1.42 (t, 2H, J=7.3Hz), 0.94 (d, 6H, J=6.6Hz) .MS (ESI) m/z 224.0 [M-H]-,252.0
[M+2CH2-H]-.。
Embodiment 12：(R)-(3- methyl isophthalic acids-(thiophene-2-carboxamide derivatives base) butyl) preparation of boric acid (compound I-2)
Under nitrogen protective condition, thiophene -2-carboxylic acid (14mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides, is stirred at room temperature,
HOBt (18mg, 0.13mmol) is added, continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes, so
The compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol) is added afterwards, after 13 hours
TLC detection display reactions are complete, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3It is molten
Liquid and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes Rotary Evaporators
Except solvent, products therefrom is added directly into 5mL methanol, is stirred at room temperature, and adds 2- methyl-propyls boric acid (22mg, 0.22mmol)
With 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC detections display is anti-after 5 hours
Should be complete, reaction solution is stood to being layered, lower floor is washed with n-hexane, adds anhydrous sodium sulfate drying, dry and filtered after finishing,
Solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=50：1) colorless solid 15mg, yield 57% are obtained.1H NMR(CD3OD, 400MHz) δ 8.01 (d, 1H, J=3.8Hz), 7.92 (d, 1H, J=4.9Hz), 7.25 (t, 1H,
), J=4.4Hz (d, 6H, the J=5.6Hz) .MS of 2.84 (t, 1H, J=7.6Hz), 1.76 (m, 1H), 1.43 (t, 2H, J=7.3Hz), 0.95
(ESI)m/z 240.0[M-H]-,268.0[M+2CH2-H]-.。
Embodiment 13：(R)-(3- methyl isophthalic acids-(1H- pyrroles -2- formamidos) butyl) preparation of boric acid (compound I-3)
Under nitrogen protective condition, pyrroles -2- formic acid (12mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides, is stirred at room temperature,
HOBt (18mg, 0.13mmol) is added, continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes, so
The compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol) is added afterwards, after 11 hours
TLC detection display reactions are complete, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3It is molten
Liquid and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes Rotary Evaporators
Except solvent, products therefrom is added directly into 5mL methanol, is stirred at room temperature, and adds 2- methyl-propyls boric acid (22mg, 0.22mmol)
With 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC detections display is anti-after 5 hours
Should be complete, reaction solution is stood to being layered, lower floor is washed with n-hexane, adds anhydrous sodium sulfate drying, dry and filtered after finishing,
Solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=30：1) colorless solid 8mg, yield 32% are obtained.1H NMR(CD3OD, 400MHz) δ 7.11 (m, 2H), 6.29 (m, 1H), 2.76 (t, 1H, J=7.6Hz), 1.75 (m, 1H),
1.40 (t, 2H, J=7.3Hz), 0.95 (d, 6H, J=6.6Hz) .MS (ESI) m/z 223.1 [M-H]-,237.1[M+CH2-H]-,
251.0[M+2CH2-H]-.。
Embodiment 14：(R)-(1- (furans -3- the formamidos) -3- methyl butyls) preparation of boric acid (compound I-4)
Under nitrogen protective condition, furans -3- formic acid (12mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides, is stirred at room temperature,
HOBt (18mg, 0.13mmol) is added, continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes, so
The compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol) is added afterwards, after 8 hours
TLC detection display reactions are complete, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3It is molten
Liquid and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes Rotary Evaporators
Except solvent, products therefrom is added directly into 5mL methanol, is stirred at room temperature, and adds 2- methyl-propyls boric acid (22mg, 0.22mmol)
With 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC detections display is anti-after 5 hours
Should be complete, reaction solution is stood to being layered, lower floor is washed with n-hexane, adds anhydrous sodium sulfate drying, dry and filtered after finishing,
Solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=70：1) colorless solid 14mg, yield 57% are obtained.1H NMR(CD3OD, 400MHz) δ 8.35 (s, 1H), 7.70 (s, 1H), 6.95 (s, 1H), 2.78 (t, 1H, J=7.5Hz),
1.74 (m, 1H), 1.40 (t, 2H, J=7.3Hz), 0.96 (d, 6H, J=6.6Hz) .MS (ESI) m/z 224.0 [M-H]-,237.9
[M+CH2-H]-,252.0[M+2CH2-H]-.。
Embodiment 15：(R)-(3- methyl isophthalic acids-(thiophene -3- formamidos) butyl) preparation of boric acid (compound I-5)
Under nitrogen protective condition, thiophene -3- formic acid (14mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides, is stirred at room temperature,
HOBt (18mg, 0.13mmol) is added, continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes, so
The compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol) is added afterwards, after 10 hours
TLC detection display reactions are complete, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3It is molten
Liquid and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes Rotary Evaporators
Except solvent, products therefrom is added directly into 5mL methanol, is stirred at room temperature, and adds 2- methyl-propyls boric acid (22mg, 0.22mmol)
With 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC detections display is anti-after 4 hours
Should be complete, reaction solution is stood to being layered, lower floor is washed with n-hexane, adds anhydrous sodium sulfate drying, dry and filtered after finishing,
Solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=50：1) colorless solid 12mg, yield 45% are obtained.1H NMR(CD3OD, 400MHz) δ 8.43 (d, 1H, J=2.5Hz), 7.63 (m, 2H), 2.82 (t, 1H, J=7.6Hz), 1.77
(m, 1H), 1.42 (t, 2H, J=7.3Hz), 0.96 (d, 6H, J=6.5Hz) .MS (ESI) m/z 240.0 [M-H]-,253.9[M+
CH2-H]-,268.0[M+2CH2-H]-.。
Embodiment 16：(R)-(3- methyl isophthalic acids-(the 1H- pyrrole-3-carboxamides base) butyl) preparation of boric acid (compound I-6)
Under nitrogen protective condition, pyrroles -3- formic acid (12mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides, is stirred at room temperature,
HOBt (18mg, 0.13mmol) is added, continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes, so
The compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol) is added afterwards, after 11 hours
TLC detection display reactions are complete, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3It is molten
Liquid and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes Rotary Evaporators
Except solvent, products therefrom is added directly into 5mL methanol, is stirred at room temperature, and adds 2- methyl-propyls boric acid (22mg, 0.22mmol)
With 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC detections display is anti-after 5 hours
Should be complete, reaction solution is stood to being layered, lower floor is washed with n-hexane, adds anhydrous sodium sulfate drying, dry and filtered after finishing,
Solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=30：1) colorless solid 18mg, yield 73% are obtained.1H NMR(CD3OD, 400MHz) δ 7.58 (s, 1H), 6.84 (s, 1H), 6.69 (s, 1H), 2.73 (t, 1H, J=7.4Hz),
1.76 (m, 1H), 1.38 (t, 2H, J=7.1Hz), 0.95 (d, 6H, J=6.5Hz) .MS (ESI) m/z 223.0 [M-H]-,237.0
[M+CH2-H]-,251.0[M+2CH2-H]-.。
Embodiment 17：(S)-(1- (furans -2- the formamidos) -3- methyl butyls) preparation of boric acid (compound I-1 S- enantiomters)
Under nitrogen protective condition, furans -2- formic acid (12mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides, is stirred at room temperature,
HOBt (18mg, 0.13mmol) is added, continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes, so
The compound III-8-b (50mg, 0.17mmol) of embodiment 10 and DIPEA (0.04mL, 0.22mmol) is added afterwards, after 9 hours
TLC detection display reactions are complete, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3It is molten
Liquid and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes Rotary Evaporators
Except solvent, products therefrom is added directly into 5mL methanol, is stirred at room temperature, and adds 2- methyl-propyls boric acid (22mg, 0.22mmol)
With 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC detections display is anti-after 5 hours
Should be complete, reaction solution is stood to being layered, lower floor is washed with n-hexane, adds anhydrous sodium sulfate drying, dry and filtered after finishing,
Solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=50：1) colorless solid 13mg, yield 53% are obtained.1H NMR(CD3OD, 400MHz) δ 7.85 (s, 1H), 7.38 (d, 1H, J=3.0Hz), 6.70 (s, 1H), 2.83 (t, 1H,
), J=7.5Hz [the M- of 1.74 (m, 1H), 1.42 (t, 2H, J=7.4Hz), 0.95 (d, 6H, J=6.5Hz) .MS (ESI) m/z 224.1
H]-,252.0[M+2CH2-H]-.。
Embodiment 18：(S)-(3- methyl isophthalic acids-(thiophene-2-carboxamide derivatives base) butyl) preparation of boric acid (compound I-2 S- enantiomters)
Under nitrogen protective condition, thiophene -2-carboxylic acid (14mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides, is stirred at room temperature,
HOBt (18mg, 0.13mmol) is added, continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes, so
The compound III-8-b (50mg, 0.17mmol) of embodiment 10 and DIPEA (0.04mL, 0.22mmol), 11 hours are added afterwards
TLC detections display reaction is complete afterwards, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3
Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes rotary evaporation
Instrument removes solvent, and products therefrom is added directly into 5mL methanol, is stirred at room temperature, addition 2- methyl-propyls boric acid (22mg,
0.22mmol) with 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC is examined after 4 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=50：1) colorless solid 6mg, production are obtained
Rate 23%.1H NMR(CD3OD,400MHz)δ8.00(s,1H),7.92(m,1H),7.25(s,1H),2.84(t,1H,
), J=7.0Hz [the M- of 1.75 (m, 1H), 1.42 (t, 2H, J=6.6Hz), 0.95 (d, 6H, J=6.3Hz) .MS (ESI) m/z 240.0
H]-,253.9[M+CH2-H]-,268.0[M+2CH2-H]-.。
Embodiment 19：(S)-(3- methyl isophthalic acids-(1H- pyrroles -2- formamidos) butyl) system of boric acid (compound I-3 S- enantiomters)
It is standby
Under nitrogen protective condition, pyrroles -2- formic acid (12mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides, is stirred at room temperature,
HOBt (18mg, 0.13mmol) is added, continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes, so
The compound III-8-b (50mg, 0.17mmol) of embodiment 10 and DIPEA (0.04mL, 0.22mmol), 13 hours are added afterwards
TLC detections display reaction is complete afterwards, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3
Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes rotary evaporation
Instrument removes solvent, and products therefrom is added directly into 5mL methanol, is stirred at room temperature, addition 2- methyl-propyls boric acid (22mg,
0.22mmol) with 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC is examined after 7 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=30：1) colorless solid 11mg is obtained,
Yield 45%.1H NMR(CD3OD, 400MHz) δ 7.11 (m, 2H), 6.29 (s, 1H), 2.76 (t, 1H, J=7.5Hz), 1.74
(m, 1H), 1.40 (t, 2H, J=4.6Hz), 0.95 (d, 6H, J=6.5Hz) .MS (ESI) m/z 223.0 [M-H]-,237.1[M+
CH2-H]-,251.0[M+2CH2-H]-.。
Embodiment 20：(S)-(1- (furans -3- the formamidos) -3- methyl butyls) preparation of boric acid (compound I-4 S- enantiomters)
Under nitrogen protective condition, furans -3- formic acid (12mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides, is stirred at room temperature,
HOBt (18mg, 0.13mmol) is added, continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes, so
The compound III-8-b (50mg, 0.17mmol) of embodiment 10 and DIPEA (0.04mL, 0.22mmol), 13 hours are added afterwards
TLC detections display reaction is complete afterwards, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3
Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes rotary evaporation
Instrument removes solvent, and products therefrom is added directly into 5mL methanol, is stirred at room temperature, addition 2- methyl-propyls boric acid (22mg,
0.22mmol) with 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC is examined after 5 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=70：1) colorless solid 10mg is obtained,
Yield 40%.1H NMR(CD3OD,400MHz)δ8.35(s,1H),7.70(s,1H),6.95(s,1H),2.78(t,1H,
), J=7.5Hz [the M- of 1.74 (m, 1H), 1.40 (t, 2H, J=7.2Hz), 0.95 (d, 6H, J=6.5Hz) .MS (ESI) m/z 224.0
H]-,238.1[M+CH2-H]-,252.0[M+2CH2-H]-.。
Embodiment 21：(S)-(3- methyl isophthalic acids-(thiophene -3- formamidos) butyl) preparation of boric acid (compound I-5 S- enantiomters)
Under nitrogen protective condition, thiophene -3- formic acid (14mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides, is stirred at room temperature,
HOBt (18mg, 0.13mmol) is added, continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes, so
The compound III-8-b (50mg, 0.17mmol) of embodiment 10 and DIPEA (0.04mL, 0.22mmol), 11 hours are added afterwards
TLC detections display reaction is complete afterwards, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3
Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes rotary evaporation
Instrument removes solvent, and products therefrom is added directly into 5mL methanol, is stirred at room temperature, addition 2- methyl-propyls boric acid (22mg,
0.22mmol) with 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC is examined after 5 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=50：1) colorless solid 15mg is obtained,
Yield 57%.1H NMR(CD3OD, 400MHz) δ 8.42 (s, 1H), 7.63 (m, 2H), 2.81 (t, 1H, J=7.5Hz), 1.76
(m, 1H), 1.42 (t, 2H, J=7.4Hz), 0.96 (d, 6H, J=6.5Hz) .MS (ESI) m/z 240.0 [M-H]-,254.1[M+
CH2-H]-,268.0[M+2CH2-H]-.。
Embodiment 22：(R)-(3- methyl isophthalic acids-(the 1H- pyrrole-3-carboxamides base) butyl) system of boric acid (compound I-6 S- enantiomters)
It is standby
Under nitrogen protective condition, pyrroles -3- formic acid (12mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides, is stirred at room temperature,
HOBt (18mg, 0.13mmol) is added, continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes, so
The compound III-8-b (50mg, 0.17mmol) of embodiment 10 and DIPEA (0.04mL, 0.22mmol), 13 hours are added afterwards
TLC detections display reaction is complete afterwards, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3
Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes rotary evaporation
Instrument removes solvent, and products therefrom is added directly into 5mL methanol, is stirred at room temperature, addition 2- methyl-propyls boric acid (22mg,
0.22mmol) with 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC is examined after 6 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=30：1) colorless solid 11mg is obtained,
Yield 45%.1H NMR(CD3OD,400MHz)δ7.57(s,1H),6.84(s,1H),6.68(s,1H),2.72(t,1H,
), J=7.5Hz [the M- of 1.75 (m, 1H), 1.58 (t, 2H, J=7.2Hz), 0.95 (d, 6H, J=5.7Hz) .MS (ESI) m/z 223.0
H]-,237.1[M+CH2-H]-,251.0[M+2CH2-H]-.。
Embodiment 23：(R)-(3- methyl isophthalic acids-(5- methylfuran -2- formamidos) butyl) preparation of boric acid (compound I-7)
Under nitrogen protective condition, 5- methylfuran -2- formic acid (14mg, 0.11mmol), room are added into 5mL anhydrous methylene chlorides
Temperature stirring, adds HOBt (18mg, 0.13mmol), continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes,
Then the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol), 12 hours are added
TLC detections display reaction is complete afterwards, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3
Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes rotary evaporation
Instrument removes solvent, and products therefrom is added directly into 5mL methanol, is stirred at room temperature, addition 2- methyl-propyls boric acid (22mg,
0.22mmol) with 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC is examined after 6 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=50：1) colorless solid 10mg is obtained,
Yield 38%.1H NMR(CD3OD, 400MHz) δ 7.30 (d, 1H, J=3.3Hz), 6.34 (d, 1H, J=2.5Hz), 2.78 (t,
1H, J=7.5Hz), 2.42 (s, 3H), 1.74 (m, 1H), 1.40 (t, 2H, J=7.3Hz), 0.94 (d, 6H, J=6.4Hz) .MS (ESI)
m/z 238.1[M-H]-,266.2[M+2CH2-H]-.。
Embodiment 24：(R)-(3- methyl isophthalic acids-(5- benzofurane -2- formamidos) butyl) preparation of boric acid (compound I-8)
Under nitrogen protective condition, 5- benzofurane -2- formic acid (21mg, 0.11mmol), room are added into 5mL anhydrous methylene chlorides
Temperature stirring, adds HOBt (18mg, 0.13mmol), continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes,
Then the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol), 15 hours are added
TLC detections display reaction is complete afterwards, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3
Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes rotary evaporation
Instrument removes solvent, and products therefrom is added directly into 5mL methanol, is stirred at room temperature, addition 2- methyl-propyls boric acid (22mg,
0.22mmol) with 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC is examined after 5 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=70：1) faint yellow solid 17mg is obtained,
Yield 51%.1H NMR(CD3OD, 400MHz) δ 7.90 (d, 2H, J=7.2Hz), 7.43 (m, 4H), 7.04 (d, 1H,
), J=3.7Hz (d, 6H, the J=4.6Hz) .MS of 2.86 (t, 1H, J=7.5Hz), 1.79 (m, 1H), 1.46 (t, 2H, J=7.2Hz), 0.97
(ESI)m/z 300.1[M-H]-,314.2[M+CH2-H]-,328.1[M+2CH2-H]-.。
Embodiment 25：(R)-(3- methyl isophthalic acids-(5- methylthiophene -2- formamidos) butyl) preparation of boric acid (compound I-9)
Under nitrogen protective condition, 5- methylthiophene -2- formic acid (16mg, 0.11mmol), room are added into 5mL anhydrous methylene chlorides
Temperature stirring, adds HOBt (18mg, 0.13mmol), continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes,
Then the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol), 12 hours are added
TLC detections display reaction is complete afterwards, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3
Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes rotary evaporation
Instrument removes solvent, and products therefrom is added directly into 5mL methanol, is stirred at room temperature, addition 2- methyl-propyls boric acid (22mg,
0.22mmol) with 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC is examined after 3 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=50：1) colorless solid 11mg is obtained,
Yield 39%.1H NMR(CD3OD, 400MHz) δ 7.81 (d, 1H, J=3.7Hz), 6.95 (d, 1H, J=2.9Hz), 2.80 (t,
1H, J=7.4Hz), 2.57 (s, 3H), 1.75 (m, 1H), 1.40 (t, 2H, J=7.2Hz), 0.95 (d, 6H, J=6.5Hz) .MS (ESI)
m/z 254.1[M-H]-,268.1[M+CH2-H]-,282.1[M+2CH2-H]-.。
Embodiment 26：(R)-(3- methyl isophthalic acids-(5- tolylthiophene -2- formamidos) butyl) preparation of boric acid (compound I-10)
Under nitrogen protective condition, 5- tolylthiophene -2- formic acid (22mg, 0.11mmol), room are added into 5mL anhydrous methylene chlorides
Temperature stirring, adds HOBt (18mg, 0.13mmol), continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes,
Then the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol), 12 hours are added
TLC detections display reaction is complete afterwards, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3
Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes rotary evaporation
Instrument removes solvent, and products therefrom is added directly into 5mL methanol, is stirred at room temperature, addition 2- methyl-propyls boric acid (22mg,
0.22mmol) with 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC is examined after 5 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=50：1) faint yellow solid 9mg is obtained,
Yield 26%.1H NMR(CD3OD, 400MHz) δ 7.98 (d, 1H, J=4.0Hz), 7.73 (d, 2H, J=7.0Hz), 7.54 (d,
1H, J=4.0Hz), 7.43 (m, 3H), 2.86 (t, 1H, J=7.5Hz), 1.77 (m, 1H), 1.44 (t, 2H, J=7.2Hz), 0.97 (d,
6H, J=6.4Hz) .MS (ESI) m/z 316.2 [M-H]-,330.1[M+CH2-H]-,344.0[M+2CH2-H]-.。
Embodiment 27：(R)-(3- methyl isophthalic acids-(the 5- methyl isophthalic acid H- pyrroles -2- formamidos) butyl) preparation of boric acid (compound I-11)
Under nitrogen protective condition, 5- methylpyrrole -2- formic acid (14mg, 0.11mmol), room are added into 5mL anhydrous methylene chlorides
Temperature stirring, adds HOBt (18mg, 0.13mmol), continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes,
Then the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol), 15 hours are added
TLC detections display reaction is complete afterwards, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3
Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes rotary evaporation
Instrument removes solvent, and products therefrom is added directly into 5mL methanol, is stirred at room temperature, addition 2- methyl-propyls boric acid (22mg,
0.22mmol) with 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC is examined after 5 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=50：1) colorless solid 16mg is obtained,
Yield 61%.1H NMR(CD3OD, 400MHz) δ 6.79 (d, 1H, J=3.4Hz), 5.78 (d, 1H, J=3.5Hz), 2.51 (t,
1H, J=7.3Hz), 2.07 (s, 3H), 1.51 (m, 1H), 1.16 (t, 2H, J=7.1Hz), 0.73 (d, 6H, J=6.3Hz) .MS (ESI)
m/z 237.1[M-H]-,251.1[M+CH2-H]-,265.1[M+2CH2-H]-.。
Embodiment 28：The preparation of 5- bromine pyrroles's -2- Ethyl formates
Pyrroles -2- Ethyl formates (1g, 7.2mmol) are added into 20mL tetrahydrofurans and 10mL methanol mixed solvents, temperature is down to
0 DEG C, NBS (0.6g, 3.6mmol) is added, continues 0 DEG C of stirring, TLC detections display reaction is complete after 2 hours, utilizes rotation
Turn evaporimeter except solvent, column chromatography for separation (petroleum ether：Ethyl acetate=100：1) product 170mg, yield 22% are obtained.1H NMR
(CDCl3, 400MHz) δ 9.23 (s, 1H), 6.82 (m, 1H), 6.21 (m, 1H), 4.32 (q, 2H, J=7.1Hz), 1.35 (t, 3H,
J=7.1Hz) .MS (ESI) m/z 220.1 [M+H]+.
The preparation of 5- phenylpyrrole -2- Ethyl formates
5- bromine pyrroles -2- Ethyl formates (170mg, 0.8mmol) are added into 5mL toluene and 1mL water mixed solvents, are stirred at room temperature,
Add Na2CO3(170mg, 1.6mmol), then sequentially adds Pd (PPh3)4(92mg, 0.08mmol) and phenylboric acid
(146mg, 1.2mmol), is warming up to backflow, and TLC detections display reaction is complete after 2 hours, adds water dilution, will react
Liquid is transferred in separatory funnel, separates organic phase, and aqueous phase profit is extracted with ethyl acetate (3 × 5mL), merges organic phase, adds nothing
Aqueous sodium persulfate is dried, and is dried and is filtered after finishing, solvent, column chromatography for separation (petroleum ether are removed using Rotary Evaporators：Ethyl acetate
=80：1) product 130mg, yield 75% are obtained.1H NMR(CDCl3,400MHz)δ9.31(s,1H),7.57(d,2H,
J=7.2Hz), 7.42 (t, 2H, J=7.4Hz), 7.32 (d, 1H, J=7.3Hz), 6.97 (s, 1H), 6.55 (s, 1H), 4.36 (q, 2H,
), J=7.1Hz 1.39 (t, 3H, J=7.1Hz) .MS (ESI) m/z 216.1 [M+H]+,238.1[M+Na]+.
The preparation of 5- phenylpyrrole -2- formic acid
Added into 1mL tetrahydrofurans, 0.5mL methanol and 0.5mL water mixed solvents 5- phenylpyrrole -2- Ethyl formates (20mg,
0.09mmol), it is stirred at room temperature, adds LiOH (4mg, 0.18mmol), TLC detections display reaction after 2 hours is stirred at room temperature
Completely, solvent is removed using Rotary Evaporators, frozen water is added into reaction residual, then add 1M HCl solution acidifying,
It is filtrated to get product 10mg, yield 59%.1H NMR(CDCl3,400MHz)δ9.37(s,1H),7.59(d,2H,
), J=7.5Hz 7.43 (t, 2H, J=7.4Hz), 7.33 (t, 1H, J=7.2Hz), 7.11 (s, 1H), 6.59 (s, 1H) .MS (ESI) m/z
186.1[M-H]-.
(R)-(3- methyl isophthalic acids-(5- phenyl -1H- pyrroles -2- formamidos) butyl) preparation of boric acid (compound I-12)
Under nitrogen protective condition, 5- phenylpyrrole -2- formic acid (21mg, 0.11mmol), room are added into 5mL anhydrous methylene chlorides
Temperature stirring, adds HOBt (18mg, 0.13mmol), continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes,
Then the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol), 16 hours are added
TLC detections display reaction is complete afterwards, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3
Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes rotary evaporation
Instrument removes solvent, and products therefrom is added directly into 5mL methanol, is stirred at room temperature, addition 2- methyl-propyls boric acid (22mg,
0.22mmol) with 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC is examined after 6 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=30：1) yellow solid 13mg is obtained,
Yield 39%.1H NMR(CD3OD, 400MHz) δ 7.64 (d, 2H, J=7.2Hz), 7.36 (t, 2H, J=7.7Hz), 7.23 (m,
1H), 6.83 (d, 1H, J=3.8Hz), 6.51 (d, 1H, J=3.8Hz), 3.36 (t, 1H, J=7.4Hz), 1.66 (m, 1H), 1.49 (t,
2H, J=7.1Hz), 0.95 (d, 6H, J=6.6Hz) .MS (ESI) m/z 299.2 [M-H]-,313.1[M+CH2-H]-,327.0
[M+2CH2-H]-.。
Embodiment 29：(R)-(1- (benzofuran-2-carboxamides the base) -3- methyl butyls) preparation of boric acid (compound II-1)
Under nitrogen protective condition, coumarilic acid (18mg, 0.11mmol), room temperature are added into 5mL anhydrous methylene chlorides
Stirring, adds HOBt (18mg, 0.13mmol), continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes,
Then the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol), 8 hours are added
TLC detections display reaction is complete afterwards, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3
Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes rotary evaporation
Instrument removes solvent, and products therefrom is added directly into 5mL methanol, is stirred at room temperature, addition 2- methyl-propyls boric acid (22mg,
0.22mmol) with 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC is examined after 5 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=60：1) faint yellow solid 15mg is obtained,
Yield 50%.1H NMR(CD3OD, 400MHz) δ 7.75 (m, 2H), 7.62 (d, 1H, J=8.4Hz), 7.52 (t, 1H,
), J=7.7Hz 7.35 (t, 1H, J=7.5Hz), 2.94 (t, 1H, J=7.6Hz) 1.77 (m, 1H), 1.48 (t, 2H, J=7.3Hz), 0.96
(d, 6H, J=6.6Hz) .MS (ESI) m/z 274.2 [M-H]-,302.1[M+2CH2-H]-.。
Embodiment 30：(R)-(1- (benzothiophene -2- the formamidos) -3- methyl butyls) preparation of boric acid (compound II-2)
Under nitrogen protective condition, benzothiophene -2- formic acid (20mg, 0.11mmol), room temperature are added into 5mL anhydrous methylene chlorides
Stirring, adds HOBt (18mg, 0.13mmol), continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes,
Then the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol), 10 hours are added
TLC detections display reaction is complete afterwards, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3
Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes rotary evaporation
Instrument removes solvent, and products therefrom is added directly into 5mL methanol, is stirred at room temperature, addition 2- methyl-propyls boric acid (22mg,
0.22mmol) with 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC is examined after 4 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=50：1) faint yellow solid 17mg is obtained,
Yield 53%.1H NMR(CD3OD,400MHz)δ8.25(s,1H),7.96(m,2H),7.50(m,2H),2.91(t,1H,
), J=7.6Hz [the M- of 1.78 (m, 1H), 1.47 (t, 2H, J=7.3Hz), 0.97 (d, 6H, J=6.6Hz) .MS (ESI) m/z 290.1
H]-,304.1[M+CH2-H]-,318.1[M+2CH2-H]-.。
Embodiment 31：(R)-(1- (1H- indole 2-carboxamides the base) -3- methyl butyls) preparation of boric acid (compound II-3)
Under nitrogen protective condition, indole-2-carboxylic acid (18mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides, is stirred at room temperature,
HOBt (18mg, 0.13mmol) is added, continues to add EDCHCl (25mg, 0.13mmol) after stirring 10 minutes, so
The compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol) is added afterwards, after 15 hours
TLC detection display reactions are complete, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution, 5%NaHCO3It is molten
Liquid and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing, utilizes Rotary Evaporators
Except solvent, products therefrom is added directly into 5mL methanol, is stirred at room temperature, and adds 2- methyl-propyls boric acid (22mg, 0.22mmol)
With 5mL n-hexanes, 1M HCl solution (0.33mL, 0.33mmol) is then added, TLC detections display is anti-after 6 hours
Should be complete, reaction solution is stood to being layered, lower floor is washed with n-hexane, adds anhydrous sodium sulfate drying, dry and filtered after finishing,
Solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=40：1) faint yellow solid 12mg, yield 40% are obtained.1H NMR(CD3OD, 400MHz) δ 7.65 (d, 1H, J=8.1Hz), 7.47 (d, 1H, J=8.4Hz), 7.42 (s, 1H), 7.30 (t,
1H, J=7.2Hz), 7.11 (t, 1H, J=7.2Hz), 2.86 (t, 1H, J=6.7Hz), 1.79 (m, 1H), 1.45 (t, 2H, J=7.1Hz),
0.98 (d, 6H, J=6.6Hz) .MS (ESI) m/z 273.2 [M-H]-,287.3[M+CH2-H]-,301.2[M+2CH2-
H]-.。
Embodiment 32：(R)-(3- methyl isophthalic acids-(3- methyl benzofuran -2- formamidos) butyl) preparation of boric acid (compound II-4)
Under nitrogen protective condition, 3- methyl benzofuran -2- formic acid (19mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides,
Be stirred at room temperature, add HOBt (18mg, 0.13mmol), continue stir 10 minutes after add EDCHCl (25mg,
0.13mmol), the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol) is then added,
TLC detections display reaction is complete after 12 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution,
5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing,
Solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl-propyl boron
Sour (22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), 5 is small
When after TLC detection display reactions it is complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate and do
It is dry, dry and filtered after finishing, solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=60：1) obtain white
Solid 16mg, yield 50%.1H NMR(CD3OD, 400MHz) δ 7.73 (d, 1H, J=7.9Hz), 7.53 (m, 2H),
7.36 (m, 1H), 2.84 (t, 1H, J=7.6Hz), 2.62 (s, 3H), 1.79 (m, 1H), 1.46 (t, 2H, J=7.3Hz), 0.97 (d, 6H,
J=6.6Hz) .MS (ESI) m/z 288.2 [M-H]-,302.3[M+CH2-H]-,316.3[M+2CH2-H]-.。
Embodiment 33：(R)-(3- methyl isophthalic acids-(4- methyl benzofuran -2- formamidos) butyl) preparation of boric acid (compound II-5)
Under nitrogen protective condition, 4- methyl benzofuran -2- formic acid (19mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides,
Be stirred at room temperature, add HOBt (18mg, 0.13mmol), continue stir 10 minutes after add EDCHCl (25mg,
0.13mmol), the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol) is then added,
TLC detections display reaction is complete after 11 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution,
5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing,
Solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl-propyl boron
Sour (22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), 3 is small
When after TLC detection display reactions it is complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate and do
It is dry, dry and filtered after finishing, solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=60：1) obtain white
Solid 11mg, yield 35%.1H NMR(CD3OD,400MHz)δ7.82(s,1H),7.41(m,2H),7.15(d,1H,
J=6.4Hz), 2.93 (t, 1H, J=7.5Hz), 2.56 (s, 3H), 1.78 (m, 1H), 1.47 (t, 2H, J=7.3Hz), 0.97 (d, 6H,
J=5.0Hz) .MS (ESI) m/z 288.0 [M-H]-,315.9[M+2CH2-H]-.。
Embodiment 34：The preparation of 5- methyl benzofuran -2- formic acid
5- cresotinic acids aldehyde (1g, 7.3mmol), potassium carbonate (2g, 15mmol), tetrabuthyl-phosphonium bromide are sequentially added into 100mL toluene
Ammonium (0.2g, 0.7mmol) and KI (0.6g, 3.7mmol), are warming up to 80 DEG C of stirrings, then add bromomalonic acid diethyl
Ester (2.6g, 11mmol), is warming up to addition 3mL potassium hydroxide solutions in backflow, 24 hours backward reaction solutions, continues to stir
24 hours, room temperature is cooled to, solvent is removed using Rotary Evaporators, 1g potassium hydroxide and 100mL is sequentially added into residue
Ethanol, is warming up to 80 DEG C of stirrings, and TLC detections display reaction is complete after 1 hour, and solvent is removed using Rotary Evaporators, to surplus
50mL water is added in excess, it is 3 to be adjusted to pH value using 2M HCl solution, yellow solid occurs, filters and be washed with water
Wash, obtain faint yellow solid 0.8g, yield 62%.1H NMR(CDCl3,400MHz)δ7.57(s,1H),7.47(s,2H),
7.29(m,1H),2.45(s,3H).MS(ESI)m/z 177.1[M+H]+,199.1[M+Na]+.
(R)-(3- methyl isophthalic acids-(5- methyl benzofuran -2- formamidos) butyl) preparation of boric acid (compound II-6)
Under nitrogen protective condition, 5- methyl benzofuran -2- formic acid (19mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides,
Be stirred at room temperature, add HOBt (18mg, 0.13mmol), continue stir 10 minutes after add EDCHCl (25mg,
0.13mmol), the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol) is then added,
TLC detections display reaction is complete after 10 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution,
5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing,
Solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl-propyl boron
Sour (22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), 4 is small
When after TLC detection display reactions it is complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate and do
It is dry, dry and filtered after finishing, solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=60：1) obtain white
Solid 14mg, yield 44%.1H NMR(CD3OD,400MHz)δ7.65(s,1H),7.55(s,1H),7.46(m,2H),
(d, 6H, the J=6.2Hz) of 2.91 (t, 1H, J=7.2Hz), 2.44 (s, 3H), 1.75 (m, 1H), 1.45 (t, 2H, J=7.6Hz), 0.95
MS(ESI)m/z 288.1[M-H]-,302.1[M+CH2-H]-,316.1[M+2CH2-H]-.。
Embodiment 35：The preparation of 6- methyl benzofuran -2- formic acid
4-Methyl Salicylaldehyde (1g, 7.3mmol), potassium carbonate (2g, 15mmol), tetrabuthyl-phosphonium bromide are sequentially added into 100mL toluene
Ammonium (0.2g, 0.7mmol) and KI (0.6g, 3.7mmol), are warming up to 80 DEG C of stirrings, then add bromomalonic acid diethyl
Ester (2.6g, 11mmol), is warming up to addition 3mL potassium hydroxide solutions in backflow, 20 hours backward reaction solutions, continues to stir
24 hours, room temperature is cooled to, solvent is removed using Rotary Evaporators, 1g potassium hydroxide and 100mL is sequentially added into residue
Ethanol, is warming up to 80 DEG C of stirrings, and TLC detections display reaction is complete after 3 hours, and solvent is removed using Rotary Evaporators, to surplus
50mL water is added in excess, it is 3 to be adjusted to pH value using 2M HCl solution, yellow solid occurs, filters and be washed with water
Wash, obtain faint yellow solid 0.6g, yield 47%.1H NMR(CD3OD, 400MHz) δ 7.39 (d, 1H, J=8.0Hz), 7.29
(s, 1H), 7.20 (s, 1H), 6.96 (d, 1H, J=8.0Hz), 2.29 (s, 3H) .MS (ESI) m/z 177.1 [M+H]+,199.0
[M+Na]+.
(R)-(3- methyl isophthalic acids-(6- methyl benzofuran -2- formamidos) butyl) preparation of boric acid (compound II-7)
Under nitrogen protective condition, 6- methyl benzofuran -2- formic acid (19mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides,
Be stirred at room temperature, add HOBt (18mg, 0.13mmol), continue stir 10 minutes after add EDCHCl (25mg,
0.13mmol), the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol) is then added,
TLC detections display reaction is complete after 11 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution,
5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing,
Solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl-propyl boron
Sour (22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), 5 is small
When after TLC detection display reactions it is complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate and do
It is dry, dry and filtered after finishing, solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=60：1) obtain white
Solid 14mg, yield 44%.1H NMR(CD3OD,400MHz)δ7.41(m,2H),7.19(s,1H),6.96(d,1H,
J=8.0Hz), 2.65 (t, 1H, J=7.4Hz), 2.24 (s, 3H), 1.51 (m, 1H), 1.20 (t, 2H, J=7.3Hz), 0.71 (d, 6H,
J=5.4Hz) .MS (ESI) m/z 288.0 [M-H]-,301.9[M+CH2-H]-,316.0[M+2CH2-H]-.。
Embodiment 36：The preparation of 7- methyl benzofuran -2- formic acid
3- cresotinic acids aldehyde (1g, 7.3mmol), potassium carbonate (2g, 15mmol), tetrabuthyl-phosphonium bromide are sequentially added into 100mL toluene
Ammonium (0.2g, 0.7mmol) and KI (0.6g, 3.7mmol), are warming up to 80 DEG C of stirrings, then add bromomalonic acid diethyl
Ester (2.6g, 11mmol), is warming up to addition 3mL potassium hydroxide solutions in backflow, 26 hours backward reaction solutions, continues to stir
24 hours, room temperature is cooled to, solvent is removed using Rotary Evaporators, 1g potassium hydroxide and 100mL is sequentially added into residue
Ethanol, is warming up to 80 DEG C of stirrings, and TLC detections display reaction is complete after 3 hours, and solvent is removed using Rotary Evaporators, to surplus
50mL water is added in excess, it is 3 to be adjusted to pH value using 2M HCl solution, yellow solid occurs, filters and be washed with water
Wash, obtain faint yellow solid 0.4g, yield 31%.1H NMR(CD3OD, 400MHz) δ 7.27 (d, 2H, J=10.6Hz),
6.96(m,2H),2.27(s,3H).MS(ESI)m/z 177.1[M+H]+,199.0[M+Na]+.
(R)-(3- methyl isophthalic acids-(7- methyl benzofuran -2- formamidos) butyl) preparation of boric acid (compound II-8)
Under nitrogen protective condition, 7- methyl benzofuran -2- formic acid (19mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides,
Be stirred at room temperature, add HOBt (18mg, 0.13mmol), continue stir 10 minutes after add EDCHCl (25mg,
0.13mmol), the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol) is then added,
TLC detections display reaction is complete after 10 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution,
5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing,
Solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl-propyl boron
Sour (22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), 5 is small
When after TLC detection display reactions it is complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate and do
It is dry, dry and filtered after finishing, solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=60：1) obtain white
Solid 17mg, yield 53%.1H NMR(CD3OD, 400MHz) δ 7.46 (s, 1H), 7.31 (d, 1H, J=7.5Hz), 7.06
(d, 1H, J=7.1Hz), 6.99 (d, 1H, J=7.6Hz), 2.66 (t, 1H, J=6.7Hz), 2.31 (s, 3H), 1.52 (m, 1H), 1.22 (t,
2H, J=7.2Hz), 0.70 (d, 6H, J=4.4Hz) .MS (ESI) m/z 288.0 [M-H]-,302.0[M+CH2-H]-,315.9
[M+2CH2-H]-.。
Embodiment 37：(R)-(1- (5- ethyl benzofuran -2- the formamidos) -3- methyl butyls) preparation of boric acid (compound II-9)
Under nitrogen protective condition, 5- ethyl benzofuran -2- formic acid (21mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides,
Be stirred at room temperature, add HOBt (18mg, 0.13mmol), continue stir 10 minutes after add EDCHCl (25mg,
0.13mmol), the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol) is then added,
TLC detections display reaction is complete after 13 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution,
5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing,
Solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl-propyl boron
Sour (22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), 6 is small
When after TLC detection display reactions it is complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate and do
It is dry, dry and filtered after finishing, solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=50：1) obtain white
Solid 13mg, yield 39%.1H NMR(CD3OD,400MHz)δ7.69(s,1H),7.59(s,1H),7.54(d,1H,
), J=8.5Hz 7.39 (d, 1H, J=7.6Hz), 2.92 (t, 1H, J=7.6Hz), 2.76 (q, 2H, J=7.5Hz), 1.77 (m, 1H), 1.47
(t, 2H, J=7.2Hz), 1.28 (t, 3H, J=7.6Hz), 0.97 (d, 6H, J=5.0Hz) .MS (ESI) m/z 302.0 [M-H]-,
315.9[M+CH2-H]-,330.0[M+2CH2-H]-.。
Embodiment 38：The preparation of 5- tert-butyl-benzofuran -2- formic acid
5- tert-butyl groups salicylide (1.3g, 7.3mmol), potassium carbonate (2g, 15mmol), bromination four are sequentially added into 100mL toluene
Butyl ammonium (0.2g, 0.7mmol) and KI (0.6g, 3.7mmol), are warming up to 80 DEG C of stirrings, then add bromomalonic acid
Diethylester (2.6g, 11mmol), is warming up to addition 3mL potassium hydroxide solutions in backflow, 20 hours backward reaction solutions, continues
Stirring 24 hours, be cooled to room temperature, using Rotary Evaporators remove solvent, sequentially added into residue 1g potassium hydroxide and
100mL ethanol, is warming up to 80 DEG C of stirrings, and TLC detections display reaction is complete after 1 hour, and solvent is removed using Rotary Evaporators,
50mL water is added into residue, it is 3 to be adjusted to pH value using 2M HCl solution, yellow solid occurs, and filtering is used in combination
Water washing, obtains faint yellow solid 0.7g, yield 44%.1H NMR(CD3OD,400MHz)δ7.49(s,1H),7.29(m,
3H),1.13(s,9H).MS(ESI)m/z 219.1[M+H]+,241.0[M+Na]+.
(R)-(1- (5- tert-butyl-benzofuran -2- the formamidos) -3- methyl butyls) preparation of boric acid (compound II-10)
Under nitrogen protective condition, added into 5mL anhydrous methylene chlorides 5- tert-butyl-benzofuran -2- formic acid (24mg,
0.11mmol), it is stirred at room temperature, adds HOBt (18mg, 0.13mmol), continues to add EDCHCl after stirring 10 minutes
(25mg, 0.13mmol), then add the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL,
0.22mmol), TLC detections display reaction is complete after 11 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% lemon
Acid solution, 5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, and drying is finished
After filter, remove solvent using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- first
Base propyl boric acid (22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol),
TLC detections display reaction is complete after 5 hours, stands reaction solution to being layered, lower floor is washed with n-hexane, adds anhydrous slufuric acid
Sodium is dried, and is dried and is filtered after finishing, solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=70：1)
Obtain yellow solid 13mg, yield 36%.1H NMR(CD3OD,400MHz)δ7.53(s,1H),7.47(s,1H),7.39(d,
1H, J=8.9Hz), 7.30 (d, 1H, J=8.5Hz), 2.66 (t, 1H, J=7.3Hz), 1.51 (m, 1H), 1.21 (t, 2H, J=7.2Hz),
1.13 (s, 9H), 0.71 (d, 6H, J=5.3Hz) .MS (ESI) m/z 330.0 [M-H]-,343.9[M+CH2-H]-,358.0[M
+2CH2-H]-.。
Embodiment 39：(R)-(1- (5- Methoxvbenzofuran -2- the formamidos) -3- methyl butyls) preparation of boric acid (compound II-11)
Under nitrogen protective condition, added into 5mL anhydrous methylene chlorides 5- Methoxvbenzofuran -2- formic acid (21mg,
0.11mmol), it is stirred at room temperature, adds HOBt (18mg, 0.13mmol), continues to add EDCHCl after stirring 10 minutes
(25mg, 0.13mmol), then add the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL,
0.22mmol), TLC detections display reaction is complete after 10 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% lemon
Acid solution, 5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, and drying is finished
After filter, remove solvent using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- first
Base propyl boric acid (22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol),
TLC detections display reaction is complete after 3 hours, stands reaction solution to being layered, lower floor is washed with n-hexane, adds anhydrous slufuric acid
Sodium is dried, and is dried and is filtered after finishing, solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=40：1)
Obtain yellow solid 9mg, yield 27%.1H NMR(CD3OD, 400MHz) δ 7.43 (s, 1H), 7.27 (d, 1H, J=8.6Hz),
7.00 (s, 1H), 6.88 (d, 1H, J=8.9Hz), 3.60 (s, 3H), 2.67 (t, 1H, J=7.1Hz), 1.52 (m, 1H), 1.22 (t, 2H,
), J=6.1Hz 0.72 (d, 6H, J=4.6Hz) .MS (ESI) m/z 304.1 [M-H]-,318.2[M+CH2-H]-,332.1[M+
2CH2-H]-.。
Embodiment 40：The preparation of 5- Fluorobenzofur -2- formic acid
5- fluorine salicylide (1g, 7.3mmol), potassium carbonate (2g, 15mmol), Tetrabutylammonium bromide are sequentially added into 100mL toluene
(0.2g, 0.7mmol) and KI (0.6g, 3.7mmol), is warming up to 80 DEG C of stirrings, then adds bromo diethyl malonate
(2.6g, 11mmol), is warming up to addition 3mL potassium hydroxide solutions in backflow, 21 hours backward reaction solutions, continues to stir 24
Hour, room temperature is cooled to, solvent is removed using Rotary Evaporators, 1g potassium hydroxide and 100mL second is sequentially added into residue
Alcohol, is warming up to 80 DEG C of stirrings, and TLC detections display reaction is complete after 1 hour, solvent is removed using Rotary Evaporators, to residue
50mL water is added in thing, it is 3 to be adjusted to pH value using 2M HCl solution, yellow solid occurs, filters and be washed with water,
Obtain faint yellow solid 1.2g, yield 91%.1H NMR(DMSO-d6,400MHz)δ7.74(m,1H),7.58(m,2H),
7.34(m,1H).MS(ESI)m/z 181.1[M+H]+,203.1[M+Na]+.
(R)-(1- (5- Fluorobenzofur -2- the formamidos) -3- methyl butyls) preparation of boric acid (compound II-12)
Under nitrogen protective condition, 5- Fluorobenzofur -2- formic acid (20mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides,
Be stirred at room temperature, add HOBt (18mg, 0.13mmol), continue stir 10 minutes after add EDCHCl (25mg,
0.13mmol), the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol) is then added,
TLC detections display reaction is complete after 10 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution,
5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing,
Solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl-propyl boron
Sour (22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), 5 is small
When after TLC detection display reactions it is complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate and do
It is dry, dry and filtered after finishing, solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=50：1) yellow is obtained
Solid 17mg, yield 53%.1H NMR(CD3OD, 400MHz) δ 7.66 (m, 2H), 7.49 (d, 1H, J=8.0Hz), 7.30
(t, 1H, J=8.8Hz), 2.98 (t, 1H, J=7.2Hz), 1.76 (m, 1H), 1.48 (t, 2H, J=7.1Hz), 0.96 (d, 6H, J=6.5Hz)
MS(ESI)m/z 292.1[M-H]-,306.1[M+CH2-H]-,320.1[M+2CH2-H]-.。
Embodiment 41：(R)-(1- (5- chlorobenzofur -2- the formamidos) -3- methyl butyls) preparation of boric acid (compound II-13)
Under nitrogen protective condition, 5- chlorobenzofur -2- formic acid (22mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides,
Be stirred at room temperature, add HOBt (18mg, 0.13mmol), continue stir 10 minutes after add EDCHCl (25mg,
0.13mmol), the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol) is then added,
TLC detections display reaction is complete after 10 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution,
5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing,
Solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl-propyl boron
Sour (22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), 5 is small
When after TLC detection display reactions it is complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate and do
It is dry, dry and filtered after finishing, solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=50：1) yellow is obtained
Solid 19mg, yield 56%.1H NMR(CD3OD, 400MHz) δ 7.63 (m, 3H), 7.44 (d, 1H, J=8.4Hz),
2.97 (t, 1H, J=7.1Hz), 1.75 (m, 1H), 1.49 (t, 2H, J=7.4Hz), 0.95 (d, 6H, J=5.3Hz) .MS (ESI) m/z
308.1[M-H]-,322.1[M+CH2-H]-,336.0[M+2CH2-H]-.。
Embodiment 42：(R)-(3- methyl isophthalic acids-(5- nitrobenzofuran -2- formamidos) butyl) preparation of boric acid (compound II-14)
Under nitrogen protective condition, 5- nitrobenzofuran -2- formic acid (23mg, 0.11mmol) is added into 5mL anhydrous methylene chlorides,
Be stirred at room temperature, add HOBt (18mg, 0.13mmol), continue stir 10 minutes after add EDCHCl (25mg,
0.13mmol), the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL, 0.22mmol) is then added,
TLC detections display reaction is complete after 15 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid solution,
5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing,
Solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl-propyl boron
Sour (22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), 5 is small
When after TLC detection display reactions it is complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate and do
It is dry, dry and filtered after finishing, solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=60：1) yellow is obtained
Solid 17mg, yield 48%.1H NMR(CD3OD, 400MHz) δ 8.52 (s, 1H), 8.17 (d, 1H, J=8.5Hz), 7.60
(m, 2H), 2.84 (t, 1H, J=7.4Hz), 1.51 (m, 1H), 1.27 (t, 2H, J=7.2Hz), 0.73 (d, 6H, J=2.9Hz) .MS
(ESI)m/z 319.0[M-H]-,333.1[M+CH2-H]-,347.1[M+2CH2-H]-.。
Embodiment 43：(R)-(3- methyl isophthalic acids-(5- trifluoromethylbenzofur -2- formamidos) butyl) preparation of boric acid (compound II-15)
Under nitrogen protective condition, added into 5mL anhydrous methylene chlorides 5- trifluoromethylbenzofur -2- formic acid (25mg,
0.11mmol), it is stirred at room temperature, adds HOBt (18mg, 0.13mmol), continues to add EDCHCl after stirring 10 minutes
(25mg, 0.13mmol), then add the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL,
0.22mmol), TLC detections display reaction is complete after 17 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% lemon
Acid solution, 5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, and drying is finished
After filter, remove solvent using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- first
Base propyl boric acid (22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol),
TLC detections display reaction is complete after 5 hours, stands reaction solution to being layered, lower floor is washed with n-hexane, adds anhydrous slufuric acid
Sodium is dried, and is dried and is filtered after finishing, solvent, column chromatography for separation (dichloromethane are removed using Rotary Evaporators：Methanol=50：1)
Obtain yellow solid 14mg, yield 37%.1H NMR(CD3OD,400MHz)δ8.18(s,1H),7.82(s,3H),3.03(t,
1H, J=7.3Hz), 1.76 (m, 1H), 1.50 (t, 2H, J=6.6Hz), [M of 0.97 (d, 6H, J=3.9Hz) .MS (ESI) m/z 341.9
-H]-,369.9[M+2CH2-H]-.。
Embodiment 44：The determination test of the compounds of this invention proteasome inhibition activity
Use and tested purchased from Chemicon (Chemicon, USA) 20S proteasome kits in the present embodiment.Should
The general principle of method of testing is that 20S proteasomes hydrolyze fluorogenic substrate
Suc-LLVY-AMC (Suc-Leu-Leu-Val-Tyr-AMC, Suc are succinyl group, and AMC is 7- acid amides -4- methylcoumarins),
The AMC with fluorescence is discharged, by changing the concentration of compound to be tested, SpectraMax M5 ELIASAs are utilized
(380nm/460nm) measures the fluorescent value that AMC is discharged under various concentrations, so as to judge that compound is rotten to 20S proteasomes
The inhibition level in chymotrypsin-like activity site (CT-L), compound is calculated to 20S proteasomes using GraphPad Prism softwares
The IC that chymotrypsinlike activity site suppresses50Value；Table 1 shows that part of compounds is lived to 20S proteasome chymotrypsins sample
Property site suppress IC50Value.
Inhibitory action of the test-compound of table 1. to mankind's 20S proteasome chymotrypsinlike activities site
·IC50It is worth for the average value of independent experiment at least twice,
NA represents inactive under 10000nM concentration.
Claims (20)
1. boric acid compound, it is characterised in that described compound is substituted five-membered heterocyclic boronic acids class and replaced benzo five-membered
Heterocyclic boronic acids class compound, it has Formulas I structure or Formula II structure,
In Formulas I：
X is C, O, S or NH；Y is CR, O, S or NH, and wherein R is hydrogen, alkyl or aryl；
In Formula II：
X is O, S or NH；
R1、R2、R3、R4And R5Stand alone as hydrogen, alkyl, cycloalkyl, alkoxy, haloalkyl, halogen or nitro.
2. compound according to claim 1, it is characterised in that described compound is the compound of Formulas I structure,
3. compound according to claim 2, it is characterised in that described compound is S- enantiomters.
4. compound according to claim 2, it is characterised in that wherein X is O, S or NH, and Y is CR, wherein
R is hydrogen, alkyl or aryl.
5. compound according to claim 4, it is characterised in that it is S- enantiomters.
6. compound according to claim 2, wherein X are C, Y is O, S or NH.
7. compound according to claim 6, it is S- enantiomters.
8. compound according to claim 1, it is characterised in that described compound is the compound of Formula II structure,
Wherein：
X is O, S or NH；
R1、R2、R3、R4And R5Stand alone as hydrogen, alkyl, cycloalkyl, alkoxy, haloalkyl, halogen or nitro.
9. compound according to claim 8, it has following structure,
10. compound according to claim 9, it is S- enantiomters.
11. compound according to claim 9, wherein X are O；
R1、R2、R3、R4And R5Stand alone as hydrogen, alkyl, cycloalkyl, alkoxy, haloalkyl, halogen or nitro.
12. compound according to claim 11, it is S- enantiomters.
13. compound according to claim 11, wherein X are O；
R1、R2、R3、R4And R5Can only at most there is a presence；
R1、R2、R3、R4And R5Stand alone as hydrogen, alkyl, cycloalkyl, alkoxy, haloalkyl, halogen or nitro.
14. compound according to claim 13, it is S- enantiomters.
15. compound according to claim 13, wherein X are O；
R1、R2For hydrogen, R3、R4And R5Can only at most there is a presence；
R3、R4And R5Stand alone as hydrogen, alkyl, cycloalkyl, alkoxy, haloalkyl, halogen or nitro.
16. compound according to claim 15, it is S- enantiomters.
17. compound according to claim 15, wherein X are O；
R1、R2、R4And R5For hydrogen；
R3For hydrogen, alkyl, cycloalkyl, alkoxy, haloalkyl, halogen or nitro.
18. compound according to claim 17, it is S- enantiomters.
19. purposes of any described compound in proteasome inhibitor is prepared in claim 1-18.
20. the purposes as described in claim 19, wherein described proteasome inhibitor is to be used to treat disease related to proteasome
The medicine of disease.
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