CN118084881A - Protac小分子及其药物组合物和应用 - Google Patents
Protac小分子及其药物组合物和应用 Download PDFInfo
- Publication number
- CN118084881A CN118084881A CN202410213718.2A CN202410213718A CN118084881A CN 118084881 A CN118084881 A CN 118084881A CN 202410213718 A CN202410213718 A CN 202410213718A CN 118084881 A CN118084881 A CN 118084881A
- Authority
- CN
- China
- Prior art keywords
- acid
- synthesis
- reaction
- yield
- esi
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229940124823 proteolysis targeting chimeric molecule Drugs 0.000 title claims abstract description 24
- 238000011865 proteolysis targeting chimera technique Methods 0.000 title claims abstract description 23
- 108010026668 snake venom protein C activator Proteins 0.000 title claims abstract description 23
- 150000003384 small molecules Chemical class 0.000 title claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- 102100038970 Histone-lysine N-methyltransferase EZH2 Human genes 0.000 claims abstract description 29
- 101000882127 Homo sapiens Histone-lysine N-methyltransferase EZH2 Proteins 0.000 claims abstract description 29
- 239000000203 mixture Substances 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 208000005678 Rhabdomyoma Diseases 0.000 claims abstract description 4
- 230000003211 malignant effect Effects 0.000 claims abstract description 4
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 4
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 3
- 229960004106 citric acid Drugs 0.000 claims description 3
- 235000015165 citric acid Nutrition 0.000 claims description 3
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- 229960002598 fumaric acid Drugs 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims description 3
- 235000014655 lactic acid Nutrition 0.000 claims description 3
- 229960000448 lactic acid Drugs 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 239000011976 maleic acid Substances 0.000 claims description 3
- 229940098895 maleic acid Drugs 0.000 claims description 3
- 229960002510 mandelic acid Drugs 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 229960001367 tartaric acid Drugs 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- KSEBMYQBYZTDHS-HWKANZROSA-M (E)-Ferulic acid Natural products COC1=CC(\C=C\C([O-])=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-M 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 208000017604 Hodgkin disease Diseases 0.000 claims description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 claims description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 2
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 230000000593 degrading effect Effects 0.000 claims description 2
- KSEBMYQBYZTDHS-HWKANZROSA-N ferulic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-N 0.000 claims description 2
- 229940114124 ferulic acid Drugs 0.000 claims description 2
- 235000001785 ferulic acid Nutrition 0.000 claims description 2
- KSEBMYQBYZTDHS-UHFFFAOYSA-N ferulic acid Natural products COC1=CC(C=CC(O)=O)=CC=C1O KSEBMYQBYZTDHS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 229940099690 malic acid Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 229940107700 pyruvic acid Drugs 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 9
- 210000004881 tumor cell Anatomy 0.000 abstract description 5
- 206010025323 Lymphomas Diseases 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 238000001727 in vivo Methods 0.000 abstract description 4
- 239000003446 ligand Substances 0.000 abstract description 4
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 abstract description 2
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 abstract description 2
- 230000004663 cell proliferation Effects 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 description 174
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 173
- 238000003786 synthesis reaction Methods 0.000 description 173
- 238000006243 chemical reaction Methods 0.000 description 123
- 238000005160 1H NMR spectroscopy Methods 0.000 description 98
- 238000004896 high resolution mass spectrometry Methods 0.000 description 98
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 88
- 239000007787 solid Substances 0.000 description 84
- 239000007858 starting material Substances 0.000 description 76
- 239000012043 crude product Substances 0.000 description 49
- 239000011734 sodium Substances 0.000 description 37
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 34
- 238000003756 stirring Methods 0.000 description 30
- 238000001308 synthesis method Methods 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 28
- 239000000047 product Substances 0.000 description 28
- 238000004809 thin layer chromatography Methods 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 27
- 239000012074 organic phase Substances 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- -1 small molecule compound Chemical class 0.000 description 15
- 239000012265 solid product Substances 0.000 description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 238000004090 dissolution Methods 0.000 description 11
- 238000000034 method Methods 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 108010022429 Polycomb-Group Proteins Proteins 0.000 description 7
- 102000012425 Polycomb-Group Proteins Human genes 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 108010033040 Histones Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 229920001213 Polysorbate 20 Polymers 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 238000012136 culture method Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- NSQSAUGJQHDYNO-UHFFFAOYSA-N n-[(4,6-dimethyl-2-oxo-1h-pyridin-3-yl)methyl]-3-[ethyl(oxan-4-yl)amino]-2-methyl-5-[4-(morpholin-4-ylmethyl)phenyl]benzamide Chemical compound C=1C(C=2C=CC(CN3CCOCC3)=CC=2)=CC(C(=O)NCC=2C(NC(C)=CC=2C)=O)=C(C)C=1N(CC)C1CCOCC1 NSQSAUGJQHDYNO-UHFFFAOYSA-N 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 3
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000017854 proteolysis Effects 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- OMKHWTRUYNAGFG-IEBDPFPHSA-N 3-deazaneplanocin a Chemical compound C1=NC=2C(N)=NC=CC=2N1[C@@H]1C=C(CO)[C@@H](O)[C@H]1O OMKHWTRUYNAGFG-IEBDPFPHSA-N 0.000 description 2
- AZEKNJGFCSHZID-UHFFFAOYSA-N 4-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]cyclohexane-1-carboxylic acid Chemical compound CC(C)(C)OC(=O)NCC1CCC(C(O)=O)CC1 AZEKNJGFCSHZID-UHFFFAOYSA-N 0.000 description 2
- UZOVYGYOLBIAJR-UHFFFAOYSA-N 4-isocyanato-4'-methyldiphenylmethane Chemical compound C1=CC(C)=CC=C1CC1=CC=C(N=C=O)C=C1 UZOVYGYOLBIAJR-UHFFFAOYSA-N 0.000 description 2
- 102000005234 Adenosylhomocysteinase Human genes 0.000 description 2
- 108020002202 Adenosylhomocysteinase Proteins 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 101000866766 Homo sapiens Polycomb protein EED Proteins 0.000 description 2
- 101000584499 Homo sapiens Polycomb protein SUZ12 Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 102000002273 Polycomb Repressive Complex 1 Human genes 0.000 description 2
- 108010000598 Polycomb Repressive Complex 1 Proteins 0.000 description 2
- 102100031338 Polycomb protein EED Human genes 0.000 description 2
- 102100030702 Polycomb protein SUZ12 Human genes 0.000 description 2
- 108010071000 Retinoblastoma-Binding Protein 7 Proteins 0.000 description 2
- 102000007503 Retinoblastoma-Binding Protein 7 Human genes 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000001973 epigenetic effect Effects 0.000 description 2
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 238000007747 plating Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000000779 smoke Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229950004774 tazemetostat Drugs 0.000 description 2
- MOLUHRBHXXGWDP-UHFFFAOYSA-N tert-butyl n-(azetidin-3-ylmethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCC1CNC1 MOLUHRBHXXGWDP-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 239000012224 working solution Substances 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- ZLOXMSNKPDWMEF-ZIFCJYIRSA-N (2s,4r)-1-[(2s)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-n-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide Chemical compound N1=CSC(C=2C=CC(CNC(=O)[C@H]3N(C[C@H](O)C3)C(=O)[C@@H](N)C(C)(C)C)=CC=2)=C1C ZLOXMSNKPDWMEF-ZIFCJYIRSA-N 0.000 description 1
- VXWBQOJISHAKKM-UHFFFAOYSA-N (4-formylphenyl)boronic acid Chemical compound OB(O)C1=CC=C(C=O)C=C1 VXWBQOJISHAKKM-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PXGZQGDTEZPERC-UHFFFAOYSA-N 1,4-cyclohexanedicarboxylic acid Chemical compound OC(=O)C1CCC(C(O)=O)CC1 PXGZQGDTEZPERC-UHFFFAOYSA-N 0.000 description 1
- JWOHBPPVVDQMKB-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-4-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC(C(O)=O)CC1 JWOHBPPVVDQMKB-UHFFFAOYSA-N 0.000 description 1
- UHUHBFMZVCOEOV-UHFFFAOYSA-N 1h-imidazo[4,5-c]pyridin-4-amine Chemical compound NC1=NC=CC2=C1N=CN2 UHUHBFMZVCOEOV-UHFFFAOYSA-N 0.000 description 1
- CRAUTELYXAAAPW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione Chemical compound O=C1C=2C(F)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O CRAUTELYXAAAPW-UHFFFAOYSA-N 0.000 description 1
- XMPJICVFSDYOEG-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindole-1,3-dione Chemical compound O=C1C=2C(O)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O XMPJICVFSDYOEG-UHFFFAOYSA-N 0.000 description 1
- AGHXYRKTAZEQQW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindole-1,3-dione Chemical compound O=C1C=2C=C(F)C(F)=CC=2C(=O)N1C1CCC(=O)NC1=O AGHXYRKTAZEQQW-UHFFFAOYSA-N 0.000 description 1
- LXPQNTNSSNXGIN-UHFFFAOYSA-N 2-[4-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]acetic acid Chemical compound CC(C)(C)OC(=O)NCC1=CC=C(CC(O)=O)C=C1 LXPQNTNSSNXGIN-UHFFFAOYSA-N 0.000 description 1
- KHMBXNKCMNGLKG-UHFFFAOYSA-N 4-(hydroxymethyl)cyclohexan-1-one Chemical compound OCC1CCC(=O)CC1 KHMBXNKCMNGLKG-UHFFFAOYSA-N 0.000 description 1
- VQMIUUBKKPIDBN-UHFFFAOYSA-N 4-(hydroxymethyl)cyclohexane-1-carboxylic acid Chemical compound OCC1CCC(C(O)=O)CC1 VQMIUUBKKPIDBN-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 201000005231 Epithelioid sarcoma Diseases 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 102000006947 Histones Human genes 0.000 description 1
- 229940124036 Hydrolase inhibitor Drugs 0.000 description 1
- 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 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 241001024304 Mino Species 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000235648 Pichia Species 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- YIMQCDZDWXUDCA-UHFFFAOYSA-N [4-(hydroxymethyl)cyclohexyl]methanol Chemical compound OCC1CCC(CO)CC1 YIMQCDZDWXUDCA-UHFFFAOYSA-N 0.000 description 1
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 239000003911 antiadherent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- DUEPRVBVGDRKAG-UHFFFAOYSA-N carbofuran Chemical compound CNC(=O)OC1=CC=CC2=C1OC(C)(C)C2 DUEPRVBVGDRKAG-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000008380 degradant Substances 0.000 description 1
- 238000013400 design of experiment Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 238000012226 gene silencing method Methods 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000004093 hydrolase inhibitor Substances 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000007422 luminescence assay Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000025036 lymphosarcoma Diseases 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- NTNUDYROPUKXNA-UHFFFAOYSA-N methyl 2-(triphenyl-$l^{5}-phosphanylidene)acetate Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OC)C1=CC=CC=C1 NTNUDYROPUKXNA-UHFFFAOYSA-N 0.000 description 1
- KQEVIFKPZOGBMZ-UHFFFAOYSA-N methyl 3-bromopropanoate Chemical compound COC(=O)CCBr KQEVIFKPZOGBMZ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002018 overexpression 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
- 239000006072 paste Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 229940074439 potassium sodium tartrate Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000006994 rRNA 2'-O-methylation Effects 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012146 running buffer Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- AWRPXOMRXIZAIW-UHFFFAOYSA-N tert-butyl 1-(aminomethyl)pyrrolidine-3-carboxylate Chemical compound CC(C)(C)OC(=O)C1CCN(CN)C1 AWRPXOMRXIZAIW-UHFFFAOYSA-N 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- VMKIXWAFFVLJCK-UHFFFAOYSA-N tert-butyl 3-oxoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(=O)C1 VMKIXWAFFVLJCK-UHFFFAOYSA-N 0.000 description 1
- PWQLFIKTGRINFF-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)CC1 PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- KHPQHXGYYXYTDN-UHFFFAOYSA-N tert-butyl n-(piperidin-3-ylmethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCC1CCCNC1 KHPQHXGYYXYTDN-UHFFFAOYSA-N 0.000 description 1
- DQQJBEAXSOOCPG-UHFFFAOYSA-N tert-butyl n-pyrrolidin-3-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNC1 DQQJBEAXSOOCPG-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种PROTAC小分子及其药物组合物和应用。该类化合物的结构为P‑L‑E，其中P表示EZH2蛋白的配体，E表示E3连接酶的配体，L表示连接E和Z的链。还包含其立体异构体、几何异构体、药学上可接受的盐或它们的混合物，其可有效降解肿瘤细胞中的EZH2蛋白，并且具有显著的抗肿瘤细胞增殖作用，IC50值达到纳摩尔浓度水平，甚至低于5nM；口服生物利用度高，体内暴露量大。疗效确切，可广泛应用于与EZH2蛋白相关的疾病，特别是各类淋巴瘤和恶性横纹肌瘤。
Description
技术领域
本发明涉及一种基于PROTAC策略的小分子化合物及其药物组合物和应用，尤其涉及一种可制备为治疗或预防EZH2相关性疾病药物的PROTAC小分子化合物及其药物组合物和应用。
背景技术
多梳家族(Polycomb group，PcG)是一类重要的调节组蛋白修饰的酶类，包含PRC1(polycomb repressive complex 1)和PRC2(polycomb repressive complex 2)两个复合物。作为PcG家族的重要成员之一，EZH2是PRC2复合物的酶活性核心亚基，该复合物还包括SUZ12、EED和RbAp46/48(也称为RBBP7/4)，从果蝇到哺乳动物都高度保守。EZH2通过SUZ12、EED、RbAp46/48三个亚基形成PRC2复合物发挥转录路调控作用，它能催化组蛋白H3第27位(H3K27)赖氨酸的单甲基化(H3K27me1)、二甲基化(H3K27me2)、三甲基化(H3K27me3)。H3K27me3与基因表达抑制有关，是组织和干细胞发育过程中的关键表观遗传学事件，具有调控下游基因的表达，维持细胞正常的功能。但是过度的H3K27三甲基化将导致肿瘤抑制基因沉默，从而促进多种人类癌症的发生。研究发现，EZH2还具有非组蛋白修饰的新功能，它参与rRNA 2'-O-甲基化修饰，调控蛋白质翻译。
EZH2活性的异常增高与多种癌症的发生有关。在乳腺癌、前列腺癌、子宫内膜癌、黑色素瘤、膀胱癌、胶质母细胞瘤、肝癌、肺癌、T细胞淋巴瘤、卵巢癌等多种肿瘤组织中过表达，在非霍奇金淋巴瘤、多发性骨髓瘤等恶性肿瘤中突变，同时还发现EZH2表达增高与肿瘤的进展以及预后相关。因此，EZH2是基于表观遗传治疗肿瘤的一个非常有前景的靶点。
蛋白降解靶向嵌合体技术(Proteolysis Targeting Chimera，PROTAC)利用细胞固有的泛素-蛋白酶体系统(ubiquitinproteasome system，UPS)调控靶向蛋白质降解，已成为一种具潜力的疾病治疗手段。与传统小分子相比，PROTAC分子具有选择性高、抗突变、且理论上可以催化量使用，在克服耐药和靶向非成药靶点方面均具有很大的潜力。
根据EZH2在多种肿瘤的发生和发展过程中表达异常的特点，通过抑制肿瘤细胞内EZH2酶活性的方式，理论上就可以作为遏制肿瘤细胞增殖、侵袭和转移的治疗方法。目前EZH2小分子抑制剂主要有通过抑制SAH水解酶而间接抑制EZH2的EZH2抑制剂、与SAM竞争结合SET活性位点的EZH2抑制剂以及基于蛋白降解技术的EZH2抑制剂三种。其中，SAH水解酶抑制剂3-去氮腺嘌呤A(3-deazaneplanocinA，DZNep)并非EZH2的特异性抑制剂，缺乏选择性，有较大的毒性，制约了其进一步的研发。与SAM竞争结合SET活性位点的EZH2抑制剂中，EPZ-6438(Tazemetostat，他折司他)已经于2020年1月23日上市，这是全球首个上市的EZH2抑制剂，用于16岁及以上患者治疗转移或局部晚期上皮样肉瘤和复发或难治性成人滤泡性淋巴瘤。
传统小分子药物使用后均会产生耐药性，将导致药效急剧下降，而基于蛋白降解技术的EZH2抑制剂陆续发展起来，代表性化合物如下：
以上PROTAC分子的相关生物活性、成药性等信息并没有过多披露。因此，寻求更多结构类型的具有更佳成药性的PROTAC分子迫在眉睫。
发明内容
发明目的：本发明的第一目的是提供一种基于PROTAC策略的小分子化合物，第二目的是提供一种含有所述化合物的药物组合物，第三目的是提供一种所述化合物及其药物组合物的药物应用。
技术方案：本发明所述的PROTAC小分子具有式I的结构，还包含其立体异构体、几何异构体、药学上可接受的盐或它们的混合物：
P-L-E
I
P表示EZH2蛋白的配体，E表示E3连接酶的配体，L表示连接E和Z的链。
其中：
P选自X1、X2选自CH或N；
E选自X3选自CH2或C(O)，M1、M2选自NH、O、H或不存在且不相同，M3选自卤素；
L选自 m、n、k选自0～5的整数，p、q选自1或2，Y1、Y2选自N、C或CH且Y1、Y2与所连接的碳形成饱和或不饱和环系，Z选自CH2或C(O)。
优选，所述结构中P选自以下任一的基团：
优选，所述结构中E选自以下任一的基团：
优选，所述结构中L选自以下任一的基团：
进一步优选，所述结构中L选自以下任一的基团：
优选，本发明所述的PROTAC小分子选自以下任一的化合物：
优选，本发明所述的药学上可接受的盐为所述化合物与选自以下任一的酸形成的盐：
盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸或阿魏酸。
将以上方法制得的式I化合物与相应的酸成盐，即得所述化合物的药学上可接受的盐。
“药学上可接受的盐”是指化合物的盐，由具有特定取代基的化合物与相对无毒的酸或碱制备。当化合物中含有相对酸性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的游离体形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的游离体形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸(形成碳酸盐或碳酸氢盐)、磷酸(形成磷酸盐、磷酸一氢盐、磷酸二氢盐、硫酸(形成硫酸盐或硫酸氢盐)、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；有机酸盐还包括氨基酸(如精氨酸等)、葡糖醛酸等有机酸的盐。当某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的游离体形式。化合物的游离体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
“药学上可接受的盐”可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
优选，所述的立体异构体为P、E、L中的手性C、N引入的异构体；所述的几何异构体为L中双键引入的顺反异构体。
优选，所述的同位素化合物为所述化合物中的氢被氘取代的化合物。
本发明所述的药物组合物包含本发明所述的所述PROTAC小分子以及药学上可接受的载体。
优选，所述的药物组合药的制剂形式选自片剂、胶囊剂、散剂、丸剂、颗粒剂、注射剂、口服液、糖浆剂、吸入剂、软膏剂、贴剂或栓剂。
“药学上可接受的载体”可为药物生产领域中广泛采用的辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望的速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
本发明所述的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如，常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
本发明所述的药物组合物可以任何形式给药，包括注射(静脉内)、粘膜、口服(固体和液体制剂)、吸入、眼部、直肠、局部或胃肠外(输注、注射、植入、皮下、静脉内、动脉内、肌内)给药。本发明的药物组合物还可以是控释或缓释剂型(例如脂质体或微球)。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干粉制剂、注射用悬浮液和注射用乳剂。所述的药物组合物的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂；气雾剂，如鼻腔喷雾剂或吸入剂；适于胃肠外给药的液体剂型；栓剂以及锭剂。
本发明所述的PROTAC小分子或其药物组合物应用在制备降解EZH2或抑制EZH2的药物中。
优选，所述药物为抗肿瘤药物。
进一步优选，所述肿瘤选自霍奇金淋巴瘤、非霍奇金淋巴瘤、弥漫大B细胞淋巴瘤、乳腺癌、前列腺癌或恶性横纹肌瘤。
有益效果：与现有技术相比，本发明具有如下显著优点：
该类化合物可有效降解肿瘤细胞中的EZH2蛋白，并且具有显著的抗肿瘤细胞增殖作用，IC50值达到纳摩尔浓度水平，甚至低于5nM；口服生物利用度高，体内暴露量大。疗效确切，可广泛应用于与EZH2蛋白相关的疾病，特别是各类淋巴瘤和恶性横纹肌瘤。
附图说明
图1为本发明的小分子在部分细胞系上对EZH2蛋白的降解作用；
图2为化合物ZJ-21的药代动力学参数图。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
化合物的结构是通过核磁共振(NMR()或质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)；MS的测定用Agilent 6120B(ESI)；HPLC的测定使用Agilent 1260DAD高效液相色谱仪(Zorbax SB-C18100×4.6mm，3.5μM)；薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm；柱层析一般使用烟台黄海硅胶200-400目硅胶为载体；
下述实施例中的己知起始原料、试剂等，可以采用或按照本领域已知的方法来合成，或可购买于毕得医药、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司；
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
实施例1：L的合成
1、L1的合成
L1-1的合成：于反应瓶中加入3-Boc-氨甲基氮杂环丁烷(3.0g，16.1mmol)，乙腈(50mL)。搅拌下加热至40℃全溶解后，再加入碳酸钾(4.4g，31.8mmol)和3-溴丙酸甲酯(3.7g，22.2mmol)。然后控制反应液温度40℃下反应，TLC监测反应进程。约2小时反应完成后，将反应液减压浓缩除去乙腈，加入DCM(50mL)和水(20mL)，充分搅拌后分层。有机相减压浓缩得粗品，粗品分离纯化得到无色油状产物(3.6g)，产率：82.0％。1HNMR(400MHz,CDCl3)δ4.86(s,1H),3.68(s,3H),3.32(t,J＝7.4Hz,2H),3.27(t,J＝5.8Hz,2H),2.91(t,J＝6.5Hz,2H),2.70(t,J＝7.2Hz,2H),2.58(dt,J＝12.9,6.5Hz,1H),2.34(t,J＝7.2Hz,2H),1.44(s,9H)ppm.HR-MS(m/z)(ESI):[M+H]+:273.1811.
L1的合成：于反应瓶中加入L1-1(1.0g，3.67mmol)，加入THF(3mL)。室温搅拌溶解后，加入一水合氢氧化锂(0.31g，7.34mmol)和水(2mL)。室温下搅拌反应，TLC监测反应进程。反应完成后，减压浓缩除去溶剂，再加入EA(10mL)，H2O(10mL)，萃取杂质。然后水层用1N盐酸调PH至8左右，悬浊液减压浓缩至干。向浓缩后的残留物中加入甲醇(10mL)，室温搅拌1小时，过滤，缩至干后，再加入甲醇(10mL)，室温搅拌1小时，过滤。滤液减压浓缩得到油状产物(0.63g)，产率：66.4％。
2、L2的合成
L2-1的合成：于反应瓶中加入3-Boc-氨甲基环丁基甲醇(1.4g，6.6mmol)，DCM(5mL)。搅拌溶解后，降温0～5℃，滴加DMP(5.6g，13.2mmol)的DCM(56mL)的溶液。滴加完毕后，室温下搅拌反应，TLC监测反应进程。反应完成后，用五水合硫代硫酸钠(2.5g)、碳酸氢钠(1.67g)、H2O(50mL)的混合水溶液淬灭反应。加入DCM(40mL)萃取产物，有机相用饱和氯化钠溶液洗后，无水硫酸钠干燥，垫层析硅胶过滤后，减压浓缩得到粗品(1.38g)。粗品直接用于下一步反应。
L2-2的合成：于反应瓶中加入L2-1(390mg，1.8mmol)，DCM(2mL)。搅拌溶解后，加入甲氧羰基亚甲基三苯基磷(636mg，2.0mmol)。室温下搅拌反应，TLC监测反应进程。反应完成后，将反应液减压浓缩得到粗品。粗品柱层析(10％EA/heptane)分离纯化，得到白色固体产物(400mg)，产率：81.2％。1HNMR(400MHz,CDCl3)δ7.15-6.93(m,1H),5.82-5.68(m,1H),4.51(s,1H),3.76-3.70(m,3H),3.30-3.20(m,2H),3.17-3.02(m,1H),2.50-2.32(m,1H),2.31-2.20(m,2H),2.10-1.90(m,1H),1.70-1.58(m,1H),1.44(s,9H).HR-MS(m/z)(ESI):[M+Na]+:292.1521。
L2的合成：于反应瓶中加入L2-2(400mg，1.48mmol)，加入THF(3mL)。搅拌溶解后加入一水合氢氧化锂(250mg，5.94mmol)和水(0.5mL)的溶液。室温下搅拌反应，TLC监测反应进程。反应完成后，将反应液减压浓缩干，加入H2O(10mL)，用EA(10mL)，萃取杂质。水相调pH至4～5，用EA(20mL)萃取产物。有机相减压浓缩得到产物(320mg)，产率：84.4％。1HNMR(400MHz,CDCl3)δ7.24-7.00(m,1H),5.84-5.68(m,1H),4.52(s,1H),3.29-3.05(m,2H),2.50-2.35(m,1H),2.34-2.17(m,2H),2.12-1.93(m,1H),1.74-1.58(m,1H),1.44(s,9H).HR-MS(m/z)(ESI):[M+Na]+:278.1364.
3、L3的合成
L3-1的合成：以3-Boc-氨甲基环丁基甲醇为起始原料，参考L2-1的合成方法。淡黄色油状物，产率：100％。粗品直接用于下一步反应。
L3-2的合成：以L3-1为起始原料，参考L2-2的合成方法。类白色固体，产率：95.7％。1HNMR(400MHz,CDCl3)δ6.93(dd,J＝15.6,7.9Hz,1H),5.79(d,J＝15.6Hz,1H),4.56(s,1H),3.72(s,3H),3.09(t,J＝5.9Hz,2H),2.65(dd,J＝16.9,8.6Hz,1H),2.21-2.09(m,1H),2.04-1.96(m,1H),1.90-1.76(m,2H),1.56-1.31(m,12H),1.07(dd,J＝22.5,10.2Hz,1H)ppm.HR-MS(m/z)(ESI):[M+Na]+:306.1676.
L3的合成：以L3-2为起始原料，参考L2的合成方法。类白色固体，产率：89.3％。1HNMR(400MHz,CDCl3)δ7.02(dd,J＝15.5,7.8Hz,1H),5.80(d,J＝15.5Hz,1H),4.60(s,1H),3.10(s,2H),2.68(dd,J＝16.7,8.4Hz,1H),2.15(dd,J＝15.8,7.8Hz,1H),2.06-1.96(m,1H),1.91-1.77(m,2H),1.52-1.36(m,11H),1.09(dd,J＝21.4,10.4Hz,1H)ppm.HR-MS(m/z)(ESI):[M+Na]+:292.1521.
4、L4的合成
L4-1的合成：以4-Boc-氨甲基环己酮为起始原料，参考L2-2的合成方法。类白色固体，产率：99.8％。1H NMR(400MHz,CDCl3)δ5.63(s,1H),4.60(s,1H),3.94-3.75(m,1H),3.68(s,3H),3.06-2.94(m,2H),2.31(d,J＝13.5Hz,1H),2.18(td,J＝12.8,3.7Hz,1H),2.05-1.81(m,3H),1.72(s,1H),1.44(s,9H),1.12(ddt,J＝24.4,20.1,8.5Hz,2H)ppm.HR-MS(m/z)(ESI):[M+Na]+:306.1677.
L4的合成：以L4-1起始原料，参考L2的合成方法。白色固体粗品，产率：95.8％。粗品直接用于下一步反应。
5、L5的合成
L5-1的合成：于反应瓶中加入4-Boc-氨甲基环己烷甲酸甲酯(1.57g，5.79mmol)，THF(7mL)。搅拌溶解澄清后，平均分三批一共加入硼氢化钠(0.63g，16.65mmol，)。加完后缓慢滴加甲醇(0.5mL)，然后室温下反应，TLC监测反应进程。反应完成后，将反应液倒入氯化铵水溶液中，搅拌至无气泡产生。加入DCM(60mL)分两次萃取产物。合并有机相，减压浓缩得到粗品。粗品分离纯化得到油状目标产物(1.41g)，产率：100％。1HNMR(400MHz,CDCl3)δ4.97(s,1H),4.63(s,1H),3.46(t,J＝5.9Hz,2H),2.99(t,J＝6.3Hz,2H),1.90-1.77(m,4H),1.77(s,1H),1.52(t,J＝5.6Hz,1H),1.45(s,9H),0.96(dd,J＝11.1,9.3Hz,4H)ppm.HR-MS(m/z)(ESI):[M+Na]+:266.1727.
L5-2的合成：
以L5-1为起始原料，参考L2-1的合成方法。淡黄色油状物，产率：93.0％。粗品直接用于下一步反应。
L5-3的合成：
以L5-2为起始原料，参考L2-2的合成方法。淡黄色油状物，产率：62.5％。1H NMR(400MHz,CDCl3)δ6.92(dd,J＝15.8,6.9Hz,1H),5.80(dd,J＝15.8,1.3Hz,1H),4.60(s,1H),3.74(s,3H),3.00(t,J＝6.2Hz,2H),2.11(ddd,J＝15.4,9.0,3.6Hz,1H),1.84(d,J＝10.8Hz,4H),1.62(s,1H),1.46(s,9H),1.19(dt,J＝21.9,7.3Hz,2H),1.07-0.95(m,2H)ppm.HR-MS(m/z)(ESI):[M+Na]+:320.1832.
L5的合成：以L5-3为起始原料，参考L2的合成方法。类白色固体，产率：70.5％。1HNMR(400MHz,CDCl3)δ6.93(dd,J＝15.8,6.8Hz,1H),5.71(dd,J＝15.8,1.2Hz,1H),4.52(s,1H),2.92(t,J＝6.2Hz,2H),2.10-1.99(m,1H),1.76(dd,J＝6.2,3.4Hz,4H),1.37(s,10H),1.16-1.04(m,2H),0.99-0.87(m,2H)ppm.HR-MS(m/z)(ESI):[M+Na]+:306.1676.
6、L6的合成
L6-1的合成：于反应瓶中加入THF(3mL)，70％RedAl(3.2g，11.0mmol)，氮气置换后，降温至0～5℃，滴加L1-1(1.0g，3.67mmol)的THF(5mL)溶液。滴加完后，保温搅拌反应，TLC监测反应进程。反应完成后，将反应液倒入酒石酸钾钠的水溶液中，DCM(30mL)分三次萃取产物。有机相用饱和氯化钠容易洗涤一次，无水硫酸钠干燥，减压浓缩后得到粗品。粗品分离纯化得到物色油状物(0.87g)，产率：97.0％。1HNMR(400MHz,CDCl3)δ4.60(s,1H),3.67(dd,J＝6.5,4.1Hz,2H),3.32(t,J＝7.3Hz,2H),3.20(t,J＝6.3Hz,2H),2.88(t,J＝6.8Hz,2H),2.71-2.58(m,2H),2.57-2.47(m,1H),1.49(dt,J＝11.0,5.5Hz,2H),1.37(s,9H)ppm.HR-MS(m/z)(ESI):[M+H]+:245.1861.
L6的合成：于反应瓶中加入L6-1(100mg，0.41mmol)和DCM(2mL)，甲磺酸酐(106mg，0.62mmol)，三乙胺(79mg，0.62mmol)。室温搅拌反应，TLC监测反应进程。反应完成后，向反应液中加入H2O(5mL)，DCM(10mL)，搅拌均匀后分层。水相再用10mLDCM萃取一次，有机相合并，用饱和氯化钠(10mL)洗一次，无水硫酸钠干燥，低温减压浓缩得到油状目标产物(114mg)，产率：86.0％。产品不稳定，直接用于下一步反应。
7、L7的合成
L7-1的合成：以L4-1为起始原料，参考L6-1的合成方法。无色油状物，产率：73.2％。1HNMR(400MHz,CDCl3)δ5.39(t,J＝7.0Hz,1H),4.58(s,1H),4.14(d,J＝7.0Hz,2H),2.99(t,J＝6.0Hz,2H),2.64(d,J＝14.0Hz,1H),2.25(d,J＝13.0Hz,1H),2.06(t,J＝12.5Hz,1H),1.92-1.73(m,3H),1.72-1.58(m,2H),1.44(s,9H),1.10-0.92(m,2H)ppm.HR-MS(m/z)(ESI):[M+Na]+:278.1732.
L7的合成：于反应瓶中加入L7-1(200mg，0.783mmol)，DCM(2mL)，三乙胺(159mg，1.567mmol)，甲基磺酰氯(117mg，1.02mmol)。室温搅拌反应，TLC监测反应进程。反应完成后，向反应液中加入水(5mL)，用DCM(30mL)分两次萃取产物，合并有机相，减压浓缩得到粗品。粗品使用柱层析分离纯化得到白色固体产物(120mg)，产率：46.1％。1H NMR(400MHz,CDCl3)δ5.35(t,J＝8.0Hz,1H),4.51(s,1H),4.02(d,J＝8.0Hz,2H),2.93(t,J＝6.3Hz,2H),2.59(d,J＝14.6Hz,1H),2.19(d,J＝13.7Hz,1H),2.07-1.94(m,1H),1.90-1.68(m,3H),1.58(s,1H),1.37(s,9H),1.05-0.88(m,2H)ppm.HR-MS(m/z)(APCI):[M+H]+:274.1570.
8、L8的合成
L8-1的合成：以4-羟甲基环己酮为起始原料，参照L6的合成方法。白色固体，产率：90.0％。粗品直接用于下一步反应。
L8-2的合成：以L8-1为起始原料，参照L2-2的合成方法。白色固体，产率：43.2％。1HNMR(400MHz,DMSO)δ5.68(s,1H),4.06(d,J＝6.3Hz,2H),3.67(d,J＝12.7Hz,1H),3.60(s,3H),3.17(s,3H),2.34(d,J＝12.9Hz,1H),2.20(td,J＝12.8,3.7Hz,1H),2.08-1.82(m,4H),1.25-1.04(m,2H)ppm.HR-MS(m/z)(ESI):[M+H]+:263.0953.
L8的合成：以L8-2为起始原料，参照L2的合成方法。白色固体，产率：76.0％。1HNMR(400MHz,DMSO)δ11.98(s,1H),5.59(s,1H),4.07(dd,J＝16.4,6.4Hz,2H),3.68(d,J＝13.5Hz,1H),3.17(s,3H),2.29(d,J＝13.2Hz,1H),2.17(td,J＝12.7,3.5Hz,1H),2.03-1.80(m,4H),1.26-1.03(m,2H).HR-MS(m/z)(ESI):[M+Na]+:271.0614.
9、L9的合成
L9的合成：于反应瓶中加入MDK-7526(750mg，1.74mmol)，1,4-环己烷二甲酸(330mg，1.92mmol)，三乙胺(879mg，8.70mmol)，DCM(3mL)。搅拌溶解澄清后，加入HATU(795mg，2.09mmol)，室温搅拌反应，TLC监测反应进程。反应完成后，向反应液中加入水(50mL)，DCM(50mL)。搅拌均匀后分层，有机层依次用1N HCl(25mL)/饱和氯化钠(10mL)洗涤，有机层减压浓缩得到粗品。粗品柱层析(2～5％MeOH/DCM)分离纯化，得到类白色固体产物(357mg)，产率：35.0％。1HNMR(400MHz,MeOD)δ8.87(s,1H),7.46(d,J＝8.3Hz,2H),7.41(d,J＝8.3Hz,2H),4.64-4.60(m,1H),4.58-4.47(m,3H),4.35(d,J＝15.5Hz,1H),3.89(d,J＝11.1Hz,1H),3.79(dd,J＝11.0,3.8Hz,1H),2.59-2.54(m,1H),2.47(s,3H),2.44-2.38(m,1H),2.24-2.19(m,1H),2.15-2.03(m,3H),1.72-1.55(m,6H),1.01(d,J＝12.5Hz,9H)ppm.HR-MS(m/z)(ESI):calcd for C30H40N4O6S[M+H]+:585.2747,found:585.2747.
10、L10的合成
L10-1的合成：于反应瓶中加入4-羟甲基-1-环己羧酸(1.07g，6.76mmol)，TEMPO(50mg，0.32mmol)，DCM(5mL)。搅拌溶解后，加入DAIB(2.24g，6.95mmol)，然后加热升温至45℃下反应，TLC监测反应进程。反应完成后，向反应液中加入饱和碳酸钠溶液(10mL)和DCM(10mL)，搅拌均匀后分层。水相用0.5N HCl调pH至3左右，加入DCM(10mL)萃取产物。有机相减压浓缩得到油状物产物粗品(1.0g，95.2％)，粗品不纯化直接用于下一步反应。
L10的合成：于反应瓶中加入L10-1(1.0g，6.40mmol)，MeOH(15mL)。搅拌溶解后，加入来那度胺(1.41g，5.44mmol)，氰基硼氢化钠(1.97g，31.37mmol)。50℃下搅拌反应，TLC监测反应进程。反应完成后，将反应液减压浓缩除去溶剂，再加入水(20mL)和DCM(20mL)，搅拌析出固体。过滤，滤饼干燥后得到类白色固体产品(1.02g),产率：47.0％。1HNMR(400MHz,DMSO)δ11.02(s,1H),7.26(t,J＝7.7Hz,1H),6.90(d,J＝7.3Hz,1H),6.71(d,J＝8.1Hz,1H),5.61(t,J＝5.5Hz,1H),5.11(dd,J＝13.2,5.1Hz,1H),4.17(dd,J＝44.9,17.2Hz,2H),3.63-3.31(m,1H),3.04-2.86(m,3H),2.65-2.56(m,1H),2.35-2.24(m,1H),2.24-2.13(m,1H),2.07-2.00(m,1H),1.93-1.83(m,2H),1.67(s,1H),1.68-1.47(m,2H),1.47-1.15(m,4H)ppm.HR-MS(m/z)(ESI):[M+H]+:400.1872.
11、L11的合成
L11-1的合成：以1,4-环己烷二甲醇为起始原料，参考L6的合成方法。白色固体产率：85.0％。1HNMR(400MHz,DMSO)δ4.03(d,J＝6.3Hz,4H),3.17(d,J＝4.9Hz,6H),1.77(t,J＝9.3Hz,4H),1.64(s,2H),1.12-0.92(m,4H).HR-MS(m/z)(ESI):[M+Na]+:323.0599.
L11-2的合成：氮气保护下于反应瓶中加入氢化钠(1.5g，60％in oil，37.26mmol)，THF(30mL)，N-Boc-4-羟基哌啶(5.0g，24.84mmol)的DMF(150ml)溶液。室温下搅拌30分钟后，再加入L11-1(14.9g，49.69mmol)。70℃搅拌下反应，TLC监测反应进程。反应完成后，将反应液降温至40℃左右，然后倾倒入水(200mL)中，析出固体，过滤，用水淋洗后得到白色粗品L10-2(10.0g)。粗品不纯化直接用于下一步反应。
L11的合成：反应瓶中加入L11-2粗品(10.0g)，DCM(50mL)。搅拌溶解后，加入TFA(20g)。室温反应结束后，减压浓缩掉大部分TFA，用碳酸钠溶液调PH至8～9，用DCM(60mL)分三次萃取水相，合并有机相减压浓缩得到粗品。粗品纯化后得到类白色固体产物(3.0g)，产率：39.5％。1HNMR(400MHz,CDCl3)δ9.31(s,1H),4.04(d,J＝6.4Hz,2H),3.60(s,1H),3.24(t,J＝8.8Hz,4H),3.10(dd,J＝8.4,4.2Hz,2H),3.01(s,3H),2.01-1.93(m,3H),1.90-1.82(m,4H),1.74(s,3H),1.12-0.93(m,4H)ppm.HR-MS(m/z)(ESI):[M+H]+:306.1745.
实施例2：IM-1～IM-24中间体的合成
IM-1的合成：于反应瓶中加入5-溴-N-[(1,2-二氢-4,6-二甲基-2-氧代-3-吡啶)甲基]-3-[乙基(四氢-2H-吡喃-4-基)氨基]-2-甲基-苯甲酰胺(1.50g，3.15mmol)，4-甲酰基苯硼酸频哪醇酯(1.10g，4.72mmol)，碳酸钠(1.0g，9.45mmol)，再加入1,4-二氧六环(20.0mL)和水(4.5mL)。搅拌均匀后，反应体系氮气置换三次，加入四三苯基磷钯(364mg，0.315mmol，0.1eq)，然后加热至80℃下反应。通过TLC监测反应进程，约4～5小时后反应完成。反应液冷却降温至室温，将反应液倒入DCM(100mL)和水(20mL)的混合溶液里，搅拌均匀后分层。水层再用DCM(20mL)萃取一次。合并有机相，减压浓缩至干得到粗品。分离纯化得到类白色固体产物(1.5g)，收率95.0％。1H NMR(400MHz,CDCl3)δ11.47(s,1H),10.05(s,1H),8.25(t,J＝4.9Hz,1H),7.98(d,J＝8.3Hz,2H),7.89(d,J＝8.3Hz,2H),7.52(d,J＝1.6Hz,1H),7.34(d,J＝1.6Hz,1H),5.86(s,1H),4.30(d,J＝4.9Hz,2H),3.93(s,1H),3.84(d,J＝9.9Hz,2H),3.26(t,J＝10.9Hz,2H),3.08(ddd,J＝21.7,14.1,8.8Hz,3H),2.27(s,3H),2.21(d,J＝8.9Hz,3H),2.11(s,3H),1.67(d,J＝11.0Hz,2H),1.62-1.45(m,2H),1.16(s,1H),1.07(s,8H),0.84(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:502.2701.
IM-2的合成：于反应瓶中加入IM-1(500mg，1.0mmol)，1-Boc-哌嗪(557mg，2.991mmol)，醋酸(120mg，1.994mmol)，DCM(5mL)。搅拌溶解澄清后，再加入三乙酰氧基硼氢化钠(0.58g，3.99mmol)，然后室温下搅拌反应。TLC监测反应进程。反应完成后，向反应液中加入饱和碳酸氢钠水溶液(5mL)和DCM(10mL)。搅拌均匀后分层，有机相减压浓缩得粗品。粗品分离纯化得到类白色固体产物(570mg)，收率：85.0％。1HNMR(400MHz,CDCl3)δ11.46(s,1H),8.18(t,J＝4.9Hz,1H),7.58(d,J＝8.1Hz,2H),7.38(dd,J＝12.2,4.7Hz,3H),7.22(d,J＝1.5Hz,1H),5.86(s,1H),4.29(d,J＝4.9Hz,2H),3.83(d,J＝10.3Hz,2H),3.50(s,2H),3.44-3.19(m,6H),3.15-2.93(m,3H),2.38-2.28(m,4H),2.25(s，3H),2.25(s，3H),2.11(s,3H),1.66(d,J＝11.0Hz,2H),1.52(dd,J＝11.9,3.7Hz,2H),1.39(s,9H),0.83(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+672.4118.
IM-3的合成：于反应瓶中加入IM-2(0.54g，0.74mmol)，DCM(7.0mL)。搅拌溶解后，加入TFA(2.04g，17.8mmol)，然后室温下搅拌反应。TLC监测反应进程，反应完成后，减压浓缩掉大部分溶剂，然后加入碳酸钠水溶液调pH至8～9，再用DCM(60mL)分两次萃取产物，合并有机相，减压浓缩得粗产品。分离纯化得到类白色固体产物(0.45g)，产率：98.0％。1HNMR(400MHz,CDCl3)δ7.45(s,1H),7.43(s,1H),7.32(s,2H),7.31(s,1H),7.28(s,1H),7.14(d,J＝4.5Hz,1H),5.91(s,1H),4.55(d,J＝5.7Hz,2H),3.94(d,J＝11.2Hz,2H),3.49(s,2H),3.32(t,J＝9.9Hz,2H),3.10(q,J＝6.9Hz,2H),3.04-2.97(m,1H),2.91(t,J＝4.6Hz,4H),2.45(s,4H),2.40(s,3H),2.34(s,3H),2.15(s,3H),2.08-1.84(m,2H),1.68(d,J＝20.3Hz,4H),0.89(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:572.3593.
IM-4的合成：于反应瓶中加入化合物IM-3(200mg，0.35mmol)，二氯甲烷(1.5mL)。搅拌溶解澄清后，加入氯乙酰氯(79mg，0.69mmol)。然后室温下搅拌反应，TLC监测反应进程，2～3小时反应完成。加入二氯甲烷(20mL)稀释反应液，然后搅拌下缓慢加入5％碳酸钠溶液(10mL)，充分搅拌后分层，有机相减压浓缩得到粗品。粗品分离纯化得到类白色固体产物(184mg)，收率81.2％。1HNMR(400MHz,CDCl3)δ11.66(s,1H),7.47(s,1H),7.45(s,1H),7.34(s,1H),7.32(s,2H),7.28(s,1H),7.10(s,1H),5.94(s,1H),4.55(d,J＝5.8Hz,2H),4.06(s,2H),3.95(d,J＝11.3Hz,2H),3.65(s,2H),3.56(s,2H),3.54(s,2H),3.32(t,J＝9.9Hz,2H),3.10(d,J＝7.0Hz,2H),3.00(dd,J＝9.8,4.7Hz,1H),2.51(d,J＝19.6Hz,4H),2.42(s,3H),2.34(s,3H),2.17(s,3H),1.76-1.67(m,4H),0.89(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:648.3310.
IM-5-1的合成：反应瓶中加入IM-4(140mg，0.22mmol)，加入3-Boc-氨基吡咯烷(80.0mg，0.43mmol)，碳酸钾(59.7mg，0.43mmol)，碘化钾(18mg，0.11mmol)，乙腈(2mL)及DMSO(2mL)，室温下搅拌反应，TLC监测反应进程，3～4小时反应完成。加入水(10mL)稀释，用DCM(60mL)分三次萃取产物，合并有机相，减压浓缩得到粗品。粗品分离纯化得到类白色固体产物(170.2mg)，收率：98.8％。1HNMR(400MHz,CDCl3)δ11.31(s,1H),7.46(s,1H),7.44(s,1H),7.34(s,1H),7.32(s,2H),7.28(s,1H),7.12(s,1H),5.90(s,1H),5.00(d,J＝8.1Hz,1H),4.55(d,J＝5.8Hz,2H),4.17(s,1H),3.95(d,J＝11.2Hz,2H),3.61(s,2H),3.53(s,4H),3.39-3.23(m,4H),3.10(d,J＝7.0Hz,2H),3.00(dd,J＝9.9,4.6Hz,1H),2.89(s,1H),2.74(dd,J＝9.4,6.5Hz,1H),2.64(s,1H),2.43(d,J＝2.4Hz,4H),2.40(s,3H),2.34(s,3H),2.24(d,J＝19.0Hz,1H),2.15(s,3H),1.77-1.61(m,6H),1.44(s,9H),0.89(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:798.4914.
IM-5-2的合成：以IM-4和3-Boc-氨甲基吡咯烷为起始原料，参考IM-5-1的合成方法。白色固体，产率96.3％。1H NMR(400MHz,CDCl3)δ11.61(s,1H),7.46(s,1H),7.44(s,1H),7.34(s,1H),7.32(s,2H),7.28(s,1H),7.14(t,J＝5.8Hz,1H),5.91(s,1H),4.88(s,1H),4.55(d,J＝5.8Hz,2H),3.94(d,J＝11.2Hz,2H),3.59(d,J＝4.5Hz,4H),3.53(s,2H),3.30(q,J＝13.0Hz,4H),3.10(dd,J＝13.8,6.8Hz,4H),3.04-2.98(m,1H),2.74(d,J＝4.2Hz,1H),2.66(t,J＝8.4Hz,1H),2.57-2.51(m,1H),2.45(dd,J＝14.0,8.1Hz,4H),2.40(s,3H),2.34(s,3H),2.14(s,3H),2.06-1.75(m,5H),1.66-1.56(m，1H)，1.56-1.45(m，2H)，1.42(s,9H),0.89(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:812.5067.
IM-5-3的合成：以IM-4和1-Boc-哌嗪为起始原料，参考IM-5-1的合成方法。白色固体，产率94.6％。1H NMR(400MHz,CDCl3)δ10.61(s,1H),7.40(s,1H),7.38(s,1H),7.29(d,J＝7.9Hz,3H),7.25(s,1H),7.21(d,J＝1.6Hz,1H),7.05(t,J＝5.8Hz,1H),5.84(s,1H),4.48(d,J＝5.9Hz,2H),3.88(d,J＝11.2Hz,2H),3.59(s,4H),3.52(s,2H),3.37(s,4H),3.28-3.22(m,2H),3.11(d,J＝7.4Hz,2H),3.06-3.00(m,2H),2.94(dd,J＝10.0,4.7Hz,1H),2.39(s,8H),2.34(s,3H),2.27(s,3H),2.10(s,3H),1.64(s,4H),1.39(s,9H),0.82(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:798.4908.
IM-5-4的合成：以IM-4和4-N-叔丁氧羰基氨基哌啶为起始原料，参考IM-5-1的合成方法。白色固体，产率90.2％。1H NMR(400MHz,CDCl3)δ11.33(s,1H),7.46(s,1H),7.44(s,1H),7.34(s,1H),7.32(s,2H),7.28(s,1H),7.12(s,1H),5.91(s,1H),4.55(d,J＝5.8Hz,2H),4.50(s,1H),3.94(d,J＝11.2Hz,2H),3.59(s,4H),3.52(s,2H),3.49-3.41(m,1H),3.32(dd,J＝12.2,10.0Hz,2H),3.16(s,2H),3.10(q,J＝7.0Hz,2H),3.04-2.98(m,1H),2.81(d,J＝10.7Hz,2H),2.41(d,J＝9.1Hz,7H),2.34(s,3H),2.21(d,J＝10.7Hz,2H),2.15(s,3H),1.91(d,J＝10.5Hz,2H),1.76-1.60(m,6H),1.44(s,9H),0.89(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:812.5070.
IM-5-5的合成：以IM-4和3-Boc-氨甲基哌啶为起始原料，参考IM-5-1的合成方法。白色固体，产率91.4％。1H NMR(400MHz,CDCl3)δ11.61(s,1H),7.46(s,1H),7.44(s,1H),7.34(s,1H),7.32(s,2H),7.28(d,J＝1.4Hz,1H),7.13(s,1H),5.90(s,1H),4.68(s,1H),4.55(d,J＝5.8Hz,2H),3.95(d,J＝11.3Hz,2H),3.61(s,4H),3.53(s,2H),3.31(d,J＝10.7Hz,2H),3.19-3.06(m,4H),3.06-2.87(m,3H),2.71(t,J＝12.7Hz,2H),2.55-2.36(m,7H),2.34(s,3H),2.14(s,4H),1.90(d,J＝9.5Hz,1H),1.76(d,J＝47.7Hz,7H),1.53(d,J＝10.8Hz,1H),1.44(s,9H),1.01(d,J＝9.5Hz,1H),0.89(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:826.5223.
IM-5-6的合成：以IM-4和3-Boc-氨甲基氮杂环丁烷为起始原料，参考IM-5-1的合成方法。白色固体，产率48.9％。1H NMR(400MHz,CDCl3)δ11.21(s,1H),7.47(d,J＝8.1Hz,2H),7.35(d,J＝6.8Hz,3H),7.29(d,J＝1.6Hz,1H),7.15(t,J＝5.7Hz,1H),5.93(s,1H),4.96(s,1H),4.57(d,J＝5.9Hz,2H),3.97(d,J＝11.2Hz,2H),3.70-3.43(m,8H),3.43-3.24(m,6H),3.24-3.07(m,4H),3.06-2.99(m,1H),2.69(s,1H),2.45(d,J＝18.1Hz,7H),2.36(s,3H),2.18(s,3H),1.69(dt,J＝11.7,6.0Hz,4H),1.45(s,9H),0.91(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:798.4910.
IM-6-1的合成：于反应瓶中加入IM-5-1(172mg，0.21mmol)，DCM(1mL)，搅拌溶解后，加入TFA(590mg，5.2mmol)。室温下搅拌反应，TLC监测反应进程，2～3小时反应完成。减压浓缩掉DCM和大部分TFA，用碳酸钠水溶液调pH至8～9，再用DCM(60mL)分两次萃取产物，合并有机相，减压浓缩得到粗品。粗品分离纯化得到类白色固体产物(111.2mg)，收率：73.9％。1HNMR(400MHz,CDCl3)δ7.46(s,1H),7.44(s,1H),7.34(s,1H),7.32(s,2H),7.27(s,1H),7.10(t,J＝5.8Hz,1H),5.91(s,1H),4.55(d,J＝5.9Hz,2H),3.95(d,J＝11.5Hz,2H),3.60(s,2H),3.55(s,4H),3.33(d,J＝15.6Hz,4H),3.10(q,J＝6.9Hz,2H),3.01(s,1H),2.84(d,J＝5.6Hz,1H),2.75(dd,J＝9.4,6.1Hz,1H),2.50(d,J＝8.7Hz,2H),2.42(d,J＝7.9Hz,7H),2.34(s,3H),2.26-2.10(m,4H),1.96-1.75(m,3H),1.75-1.65(m,4H),1.61-1.54(m,2H),0.90(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:698.4387.
IM-6-2的合成：以IM-5-2为起始原料，参考IM-6-1的合成方法。白色固体，产率72.7％。1HNMR(400MHz,CDCl3)δ7.48(s,1H),7.46(s,1H),7.34(d,J＝3.7Hz,3H),7.29(s,1H),7.17(d,J＝5.3Hz,1H),5.93(s,1H),4.56(d,J＝5.2Hz,2H),3.96(d,J＝11.2Hz,2H),3.60(s,2H),3.55(s,4H),3.38-3.25(m,4H),3.11(d,J＝6.8Hz,2H),3.03(s,1H),2.78(d,J＝6.2Hz,2H),2.74-2.62(m,3H),2.57-2.48(m,3H),2.42(s,7H),2.36(s,3H),2.32-2.28(m,1H),2.18(s,3H),2.00(d,J＝8.4Hz,2H),1.72(s,4H),1.56(d,J＝6.5Hz,1H),0.91(t,J＝6.8Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:712.4548.
IM-6-3的合成：以IM-5-3为起始原料，参考IM-6-1的合成方法。白色固体，产率66.8％。1HNMR(400MHz,CDCl3)δ7.39(t,J＝7.7Hz,2H),7.26(d,J＝2.0Hz,2H),7.23(s,1H),7.22-7.20(m,1H),7.06(t,J＝5.8Hz,1H),5.85(d,J＝5.2Hz,1H),4.47(d,J＝5.7Hz,2H),3.88(d,J＝11.3Hz,2H),3.49(dd,J＝15.7,10.3Hz,6H),3.29-3.21(m,2H),3.10(s,2H),3.03(q,J＝6.9Hz,2H),3.01-2.77(m,5H),2.50(s,4H),2.42(s,2H),2.36(s,4H),2.33(s,3H),2.28(s,3H),2.14(s,3H),1.64(s,4H),0.83(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:698.4384.
IM-6-4的合成：以IM-5-4为起始原料，参考IM-6-1的合成方法。白色固体，产率70.9％。1HNMR(400MHz,CDCl3)δ12.25(s,1H),7.37(d,J＝7.4Hz,2H),7.25(d,J＝7.2Hz,3H),7.19(s,1H),7.16(s,1H),5.82(s,1H),4.45(s,2H),3.85(d,J＝9.6Hz,2H),3.47(s,6H),3.30(s,1H),3.23(d,J＝10.1Hz,4H),2.96(d,J＝29.2Hz,5H),2.54-2.16(m,12H),2.08(s,5H),1.93(s,3H),1.61(s,5H),0.80(t,J＝6.6Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:712.4547.
IM-6-5的合成：以IM-5-5为起始原料，参考IM-6-1的合成方法。类白色固体，产率99.0％。
IM-6-6的合成：以IM-5-6为起始原料，参考IM-6-1的合成方法。白色固体，产率86.7％。1HNMR(400MHz,CDCl3)δ7.38(d,J＝8.1Hz,2H),7.31-7.22(m,3H),7.20(s,1H),7.05(t,J＝5.8Hz,1H),5.84(s,1H),4.48(d,J＝5.7Hz,2H),3.87(d,J＝11.3Hz,2H),3.48(d,J＝13.3Hz,4H),3.39(s,4H),3.31-3.17(m,4H),3.13-2.98(m,4H),2.95(dd,J＝9.9,5.5Hz,1H),2.88(t,J＝7.9Hz,2H),2.51(dd,J＝13.0,6.6Hz,1H),2.35(d,J＝11.2Hz,7H),2.27(s,3H),2.08(d,J＝9.6Hz,6H),1.68-1.56(m,4H),0.82(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:698.4385.
IM-7-1的合成：于反应瓶中加入EDC·HCl(0.21g，1.1mmol)，HOBt(0.17g，1.1mmol)，L1(0.28g，1.1mmol)，DCM(2mL)。搅拌溶清后，加入TEA(0.15g，1.47mmolq)和IM-3(0.42mg，0.73mmol)。室温下搅拌反应，TLC监测反应进程。反应完成后，向反应液中加入H2O(10mL)和DCM(10mL)，搅拌均匀后分层，有机相减压浓缩得到粗品。粗品分离纯化得到IM-7-1(0.35g)，产率：58.7％。1HNMR(400MHz,CDCl3)δ11.38(s,1H),7.39(s,1H),7.37(s,1H),7.25(s,2H),7.23(s,1H),7.20(s,1H),7.07(s,1H),5.84(s,1H),5.19(s,1H),4.48(d,J＝5.8Hz,2H),3.86(t,J＝10.9Hz,4H),3.52(s,4H),3.40(s,2H),3.25(t,J＝9.1Hz,4H),3.15(s,2H),3.03(dd,J＝13.9,6.9Hz,2H),2.99-2.80(m,3H),2.63(d,J＝7.2Hz,3H),2.39(s,2H),2.34(s,5H),2.27(s,3H),2.09(d,J＝16.7Hz,3H),1.71-1.53(m,4H),1.34(s,9H),0.82(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:812.5069.
IM-7-2的合成：以IM-3与L2为起始原料，参考IM-6-1的合成方法。白色固体，产率：91.2％。1HNMR(400MHz,CDCl3)δ11.53(s,1H),7.46(s,1H),7.44(s,1H),7.33(s,1H),7.32(d,J＝2.2Hz,2H),7.28(d,J＝1.5Hz,1H),7.12(t,J＝5.7Hz,1H),7.04-6.82(m,1H),6.13(t,J＝14.7Hz,1H),5.90(s,1H),4.56(d,J＝5.9Hz,3H),3.95(d,J＝11.2Hz,2H),3.68(s,2H),3.53(s,4H),3.32(td,J＝11.2,2.7Hz,2H),3.08(t,J＝14.0Hz,4H),3.04-2.86(m,2H),2.45(s,4H),2.40(s,3H),2.34(s,3H),2.31-2.19(m,2H),2.14(s,3H),2.06-1.92(m,1H),1.70-1.56(m,6H),1.44(s,9H),0.89(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:809.4961.
IM-7-3的合成：以IM-3与L3为起始原料，参考IM-6-1的合成方法。类白色固体，产率：87.2％。1H NMR(400MHz,CDCl3)δ11.51(s,1H),7.46(s,1H),7.44(s,1H),7.34(s,1H),7.32(s,2H),7.28(d,J＝1.5Hz,1H),7.12(t,J＝5.8Hz,1H),6.83(dd,J＝15.0,7.9Hz,1H),6.18(d,J＝14.6Hz,1H),5.90(s,1H),4.57(dd,J＝17.1,5.9Hz,3H),3.94(d,J＝11.3Hz,2H),3.68(s,2H),3.54(s,4H),3.31(td,J＝11.3,2.9Hz,2H),3.18-3.03(m,4H),3.03-2.97(m,1H),2.63(dd,J＝17.2,8.3Hz,1H),2.45(s,4H),2.40(s,3H),2.33(s,3H),2.14(s,3H),1.98(dd,J＝12.6,6.5Hz,1H),1.82(ddd,J＝18.6,11.1,5.4Hz,2H),1.67(dd,J＝17.9,11.1Hz,6H),1.43(s,9H),1.37(dd,J＝7.9,4.0Hz,1H),1.07(dd,J＝22.5,10.2Hz,1H),0.89(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:823.5119.
IM-7-4的合成：用IM-3与Boc-氨甲环酸,参考IM-6-1的合成方法。白色固体,产率：99.7％。1HNMR(400MHz,CDCl3)δ11.38(s,1H),7.46(s,1H),7.44(s,1H),7.34(s,1H),7.32(s,2H),7.28(s,1H),7.11(t,J＝5.8Hz,1H),5.91(s,1H),4.55(d,J＝5.8Hz,3H),3.95(d,J＝11.4Hz,2H),3.62(s,2H),3.53(s,2H),3.49(s,2H),3.32(t,J＝10.1Hz,2H),3.10(d,J＝7.0Hz,2H),2.99(d,J＝5.5Hz,3H),2.58-2.35(m,8H),2.34(s,3H),2.15(s,3H),1.83(d,J＝12.7Hz,2H),1.77-1.65(m,7H),1.55(d,J＝13.6Hz,2H),1.44(s,9H),0.97(d,J＝12.7Hz,2H),0.89(t,J＝6.8Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:811.5114.
IM-7-5的合成：以IM-3与L4为起始原料，参考IM-6-1的合成方法。白色固体，产率：94.5％。1H NMR(400MHz,CDCl3)δ11.49(s,1H),7.46(s,1H),7.44(s,1H),7.34(s,1H),7.32(s,2H),7.28(s,1H),7.12(t,J＝5.7Hz,1H),5.90(s,1H),5.68(s,1H),4.62(s,1H),4.55(d,J＝5.8Hz,2H),3.94(d,J＝11.2Hz,2H),3.65(s,2H),3.52(d,J＝8.1Hz,4H),3.31(dd,J＝16.6,5.9Hz,2H),3.09(q,J＝6.9Hz,2H),3.05-2.93(m,3H),2.84(d,J＝13.8Hz,1H),2.41(d,J＝9.6Hz,7H),2.33(s,3H),2.28(d,J＝13.5Hz,1H),2.14(s,4H),1.88(d,J＝11.2Hz,3H),1.69(d,J＝8.9Hz,5H),1.43(s,9H),1.17-1.03(m,2H),0.89(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:823.5117.
IM-7-6的合成：以IM-3与L5为起始原料，参考IM-6-1的合成方法。类白色固体，产率：80.5％。1H NMR(400MHz,CDCl3)δ11.32(s,1H),7.46(s,1H),7.44(s,1H),7.34(s,1H),7.32(s,2H),7.28(d,J＝1.6Hz,1H),7.12(t,J＝5.8Hz,1H),6.80(dd,J＝15.2,7.0Hz,1H),6.17(d,J＝15.2Hz,1H),5.90(s,1H),4.56(t,J＝7.4Hz,3H),3.95(d,J＝11.4Hz,2H),3.68(s,2H),3.54(s,4H),3.32(td,J＝11.2,2.8Hz,2H),3.10(q,J＝6.9Hz,2H),3.05-2.86(m,3H),2.46(s,4H),2.40(s,3H),2.34(s,3H),2.14(s,3H),2.08(d,J＝7.8Hz,1H),1.81(d,J＝10.3Hz,4H),1.70(d,J＝5.8Hz,5H),1.44(s,9H),1.23-1.10(m,2H),1.06-0.92(m,2H),0.89(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:859.5098.
IM-7-7的合成：以IM-3与N-叔丁氧羰基-(4-氨基甲基苯基)乙酸为起始原料，参考IM-6-1的合成方法。白色固体，产率：41.1％。1HNMR(400MHz,CDCl3)δ11.05(s,1H),7.45(s,1H),7.43(s,1H),7.31(s,2H),7.29(s,1H),7.26-7.25(m,1H),7.20(dd,J＝17.7,8.1Hz,4H),7.05(t,J＝5.3Hz,1H),5.94(s,1H),4.85(s,1H),4.54(d,J＝5.9Hz,2H),4.29(d,J＝4.8Hz,2H),3.95(d,J＝11.3Hz,2H),3.70(s,2H),3.65(s,2H),3.49(s,2H),3.43(s,2H),3.32(s,2H),3.09(q,J＝6.9Hz,2H),3.04-2.97(m,1H),2.41(s,5H),2.33(s,3H),2.29(s,2H),2.18(s,3H),1.75-1.65(m,4H),1.46(s,9H),0.89(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:819.4806.
IM-7-8的合成：于反应瓶中加入IM-3(98mg，0.17mmol)L6(110mg，0.34mmol)，THF(1.5mL)。搅拌溶解澄清后，加入三乙胺(45mg，0.34mmol)，升温至50℃下反应，TLC监测反应进程。反应完成后，减压浓缩反应液得到粗品。粗品柱层析分离纯化，得到类白色固体产物(140mg)，产率：81.2％。1H NMR(400MHz,CDCl3)δ11.42(s,1H),7.44(s,4H),7.25(s,2H),7.17(s,1H),5.85(s,1H),4.46(d,J＝5.3Hz,2H),4.24-3.75(s,7H),3.35-3.17(m,6H),3.15-2.70(m,12H),2.48-2.03(m,13H),1.97(s,2H),1.64(d,J＝11.1Hz,4H),1.30(s,9H),0.82(t,J＝6.8Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:798.5277.
IM-7-9的合成：用IM-3与L7为起始原料，参考IM-7-8的合成方法。类白色产物，产率：72.6％。1H NMR(400MHz,CDCl3)δ11.35(s,1H),7.45(d,J＝7.9Hz,2H),7.32(d,J＝7.4Hz,3H),7.27(s,1H),7.12(s,1H),5.92(s,1H),5.42(t,J＝6.4Hz,1H),4.62(s,1H),4.55(d,J＝5.6Hz,2H),3.94(d,J＝11.4Hz,2H),3.61(s,2H),3.41(s,2H),3.32(t,J＝10.0Hz,2H),3.10(dd,J＝13.8,6.9Hz,2H),2.98(dd,J＝13.7,7.8Hz,5H),2.86(s,4H),2.58(d,J＝13.0Hz,2H),2.41(s,3H),2.34(s,3H),2.31(s,1H),2.17(s,3H),2.15-1.98(m,2H),1.91-1.78(m,3H),1.75-1.60(m,5H),1.43(s,9H),1.08-0.93(m,2H),0.88(d,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:809.5328.
IM-8-1的合成：于反应瓶中加入IM-7-1(0.30g，0.37mmol)，DCM(4.0mL)。搅拌溶解后，滴加三氟乙酸(1.01g，8.87mmol)。室温下搅拌反应，TLC监测反应进程。反应完成后，减压蒸馏掉大部分TFA，加入碳酸钠水溶液调PH为8～9，用DCM(60mL)分两次萃取产物，合并有机相减压浓缩，得到类白色固体产物(252mg)，产率：96.1％。
IM-8-2的合成：以IM-7-2为起始原料，参考IM-8-1的合成方法。白色固体，产率：95.1％。1HNMR(400MHz,CDCl3)δ7.46(s,1H),7.44(s,1H),7.33(s,2H),7.31(s,1H),7.26(s,1H),7.08(t,J＝5.7Hz,1H),7.02-6.78(m,1H),6.14(t,J＝16.4Hz,1H),5.91(s,1H),4.55(d,J＝5.7Hz,2H),3.95(d,J＝11.4Hz,2H),3.66(s,2H),3.55(s,4H),3.32(t,J＝9.7Hz,2H),3.10(dd,J＝13.7,6.7Hz,2H),3.05-2.90(m,3H),2.83(d,J＝6.6Hz,2H),2.57-2.24(m,14H),2.17(s,3H),2.09-2.02(m,1H),1.82-1.60(m,6H),0.90(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:709.4435.
IM-8-3的合成：以IM-7-3为起始原料，参考IM-8-1的合成方法。类白色固体，产率：95.1％。1H NMR(400MHz,MeOD)δ7.54(s,2H),7.45(d,J＝1.6Hz,1H),7.41(d,J＝8.2Hz,2H),7.32(d,J＝1.6Hz,1H),6.73(dd,J＝15.0,8.3Hz,1H),6.42(d,J＝15.0Hz,1H),6.12(s,1H),4.49(s,2H),3.92(d,J＝11.2Hz,2H),3.65(s,4H),3.59(s,2H),3.40-3.35(m,2H),3.15(dd,J＝14.2,7.2Hz,2H),3.11-3.05(m,1H),2.93(d,J＝8.9Hz,2H),2.78(dd,J＝17.3,8.4Hz,1H),2.54-2.43(m,4H),2.39(s,3H),2.32(s,3H),2.24(s,3H),2.13-2.06(m,1H),1.96-1.90(m,2H),1.75(d,J＝12.4Hz,2H),1.70-1.42(m,5H),1.18-1.11(m,1H),0.90(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:723.4594.
IM-8-4的合成：以IM-7-4为起始原料，参考IM-8-1的合成方法。类白色固体，产率98.0％。1HNMR(400MHz,CDCl3)δ7.46(s,1H),7.44(s,1H),7.32(t,J＝5.4Hz,3H),7.27(s,1H),7.09(t,J＝5.7Hz,1H),5.91(s,1H),4.55(d,J＝5.7Hz,2H),3.95(d,J＝11.3Hz,2H),3.60(s,2H),3.54(s,2H),3.47(s,2H),3.32(t,J＝9.9Hz,2H),3.10(dd,J＝13.8,6.8Hz,2H),3.00(dd,J＝9.7,4.6Hz,1H),2.82(d,J＝7.0Hz,1H),2.64(d,J＝6.6Hz,1H),2.57(s,1H),2.41(d,J＝10.8Hz,9H),2.34(s,3H),2.16(d,J＝1.5Hz,3H),1.88(d,J＝11.7Hz,1H),1.72(dd,J＝29.6,16.7Hz,8H),1.58-1.49(m,3H),0.94(dt,J＝13.9,8.8Hz,5H)ppm.HR-MS(m/z)(ESI):[M+H]+:711.4591.
IM-8-5的合成：以IM-7-5为起始原料，参考IM-8-1的合成方法。白色固体，产率：95.0％。1HNMR(400MHz,MeOD)δ7.55(d,J＝8.2Hz,2H),7.45(d,J＝1.6Hz,1H),7.40(d,J＝8.2Hz,2H),7.31(d,J＝1.6Hz,1H),6.11(s,1H),5.84(s,1H),4.49(s,2H),3.92(d,J＝11.3Hz,2H),3.64(s,2H),3.60-3.50(m,4H),3.39-3.34(m,2H),3.15(dd,J＝14.2,7.1Hz,2H),3.12-3.04(m,1H),2.81(d,J＝6.9Hz,3H),2.47(dd,J＝8.8,4.3Hz,4H),2.42-2.34(m,4H),2.32(s,3H),2.24(s,3H),2.20(dd,J＝12.4,4.9Hz,1H),2.01-1.83(m,4H),1.75(d,J＝12.1Hz,2H),1.69-1.59(m,2H),1.22-1.11(m,2H),0.90(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:723.4604.
IM-8-6的合成：以IM-7-6为起始原料，参考IM-8-1的合成方法。类白色固体，产率：60.3％。1H NMR(400MHz,CDCl3)δ7.46(s,1H),7.44(s,1H),7.34(s,1H),7.32(s,2H),7.28(s,1H),7.12(t,J＝5.8Hz,1H),6.81(dd,J＝15.2,6.9Hz,1H),6.17(d,J＝15.2Hz,1H),5.91(s,1H),4.55(d,J＝5.8Hz,2H),3.95(d,J＝11.1Hz,2H),3.68(s,2H),3.53(s,4H),3.32(t,J＝9.8Hz,2H),3.10(q,J＝6.9Hz,2H),3.04-2.95(m,1H),2.55(d,J＝6.4Hz,2H),2.51-2.42(m,4H),2.40(s,3H),2.34(s,3H),2.15(s,3H),2.11-2.02(m,1H),1.84(d,J＝9.8Hz,4H),1.71(s,8H),1.23-1.12(m,2H),1.04-0.92(m,2H),,0.89(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:759.4574.
IM-8-7的合成：以IM-7-7为起始原料，参考IM-8-1的合成方法。白色固体，产率：64.6％。1HNMR(400MHz,CDCl3)δ7.43(d,J＝8.1Hz,2H),7.30(d,J＝2.4Hz,2H),7.28(s,1H),7.27(s,2H),7.25(s,1H),7.19(d,J＝8.0Hz,2H),7.11(t,J＝5.8Hz,1H),5.90(s,1H),4.55(d,J＝5.9Hz,2H),3.94(d,J＝11.3Hz,2H),3.85(s,2H),3.70(s,2H),3.64(s,2H),3.49(s,2H),3.46-3.39(m,2H),3.31(td,J＝11.3,3.0Hz,2H),3.09(q,J＝7.0Hz,2H),3.04-2.97(m,1H),2.46-2.37(m,5H),2.34(s,3H),2.28(d,J＝4.5Hz,2H),2.15(s,3H),1.85-1.58(m,7H),0.89(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:741.4108.
IM-8-8的合成：以IM-7-8为起始原料，参考IM-8-1的合成方法。类白色固体粗品，产率：57.5％。
IM-8-9的合成：以IM-7-9为起始原料，参考IM-8-1的合成方法。类白色固体，产率：74.3％。1HNMR(400MHz,CDCl3)δ7.44(s,1H),7.42(s,1H),7.34(s,1H),7.32(d,J＝4.7Hz,2H),7.26(s,1H),7.09(t,J＝5.8Hz,1H),5.90(s,1H),5.23(t,J＝7.2Hz,1H),4.55(d,J＝5.8Hz,2H),3.94(d,J＝11.5Hz,2H),3.53(dd,J＝27.3,13.0Hz,2H),3.32(t,J＝9.9Hz,2H),3.09(q,J＝7.0Hz,2H),2.99(d,J＝7.6Hz,3H),2.64(d,J＝13.0Hz,2H),2.95-2.43(m,7H),2.40(s,3H),2.34(s,3H),2.24(d,J＝14.4Hz,2H),2.15(s,3H),2.04(t,J＝13.5Hz,2H),1.83(s,3H),1.80-1.60(m,8H),1.09-0.92(m,2H),0.89(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:709.4808.
IM-9的合成：以IM-3和1-Boc-4-哌啶甲酸为起始原料，参考IM-7-1的合成方法。类白色固体，产率：95.8％。1HNMR(400MHz,CDCl3)δ11.21(s,1H),7.46(s,1H),7.44(s,1H),7.34(s,1H),7.32(s,2H),7.28(d,J＝1.5Hz,1H),7.11(t,J＝5.8Hz,1H),5.91(s,1H),4.55(d,J＝5.9Hz,2H),4.14(s,2H),3.95(d,J＝11.3Hz,2H),3.63(d,J＝10.5Hz,2H),3.52(d,J＝9.2Hz,4H),3.32(td,J＝11.3,2.9Hz,2H),3.10(q,J＝6.9Hz,2H),3.00(dt,J＝9.6,5.1Hz,1H),2.75(s,2H),2.61(s,1H),2.44(d,J＝14.4Hz,4H),2.41(s,3H),2.34(s,3H),2.15(s,3H),1.73-1.62(m,8H),1.45(s,9H),0.89(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:805.4633.
IM-10的合成：以IM-9为起始原料，参考IM-6-1的合成方法。类白色固体，产率：97.0％。1HNMR(400MHz,CDCl3)δ11.94(s,1H),9.48(s,1H),7.46(d,J＝8.0Hz,2H),7.41-7.29(m,3H),7.25(s,1H),7.19(s,1H),5.94(s,1H),4.53(d,J＝4.6Hz,2H),3.94(d,J＝11.1Hz,2H),3.74-3.40(m,8H),3.31(t,J＝9.9Hz,2H),3.10(d,J＝6.2Hz,4H),3.03-2.97(m,1H),2.92(s,1H),2.48(s,4H),2.40(s,3H),2.35(s,3H),2.22(s,3H),2.05(d,J＝8.4Hz,4H),1.88(d,J＝11.5Hz,4H),0.89(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:705.4104.
IM-11-1的合成：以IM-10和1-Boc-3-氮杂环丁酮为起始原料，参考IM-2的合成方法。类白色固体，产率：69.2％。1H NMR(400MHz,CDCl3)δ11.46(s,1H),7.45(d,J＝8.1Hz,2H),7.33(d,J＝7.9Hz,3H),7.28(d,J＝1.5Hz,1H),7.13(t,J＝5.8Hz,1H),5.90(s,1H),4.55(d,J＝5.8Hz,2H),4.14(dd,J＝10.0,6.7Hz,1H),3.92(dd,J＝18.6,9.9Hz,4H),3.87-3.73(m,3H),3.63(s,2H),3.55(s,2H),3.51(s,2H),3.32(td,J＝11.2,2.7Hz,2H),3.17-2.96(m,4H),2.85(s,2H),2.46(s,5H),2.40(s,3H),2.34(s,3H),2.14(s,3H),1.94-1.81(m,4H),1.71-1.62(m,4H),1.43(d,J＝3.1Hz,9H),0.89(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:860.5052.
IM-11-2的合成：以IM-10和1-Boc-4-哌啶酮为起始原料，参考IM-11-1的合成方法。白色固体，产率：37.6％。1HNMR(400MHz,CDCl3)δ11.32(s,1H),7.46(d,J＝8.1Hz,2H),7.38-7.29(m,3H),7.27(s,1H),7.09(t,J＝5.9Hz,1H),5.93(s,1H),4.55(d,J＝5.8Hz,2H),4.21(s,2H),3.95(d,J＝11.2Hz,2H),3.60(s,2H),3.54(s,2H),3.48(s,2H),3.40-3.18(m,4H),3.10(dd,J＝13.8,6.8Hz,2H),3.06-2.93(m,2H),2.70(s,4H),2.54-2.36(m,8H),2.34(s,3H),2.18(s,3H),1.92(s,2H),2.02-1.76(m,4H),1.75-1.65(m,4H),1.64-1.52(m,2H),1.45(s,9H),0.89(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:888.5364.
IM-12-1的合成：以IM-11-1为起始原料，参考IM-10的合成方法。类白色固体，产率：63.2％。1H NMR(400MHz,CDCl3)δ11.83(s,1H),7.45(d,J＝8.0Hz,2H),7.38-7.29(m,3H),7.27(s,1H),7.09(t,J＝5.5Hz,1H),5.92(s,1H),4.55(d,J＝5.4Hz,3H),4.17-3.78(m,7H),3.60(s,2H),3.53(s,2H),3.47(s,3H),3.32(t,J＝10.2Hz,2H),3.10(dd,J＝13.7,6.7Hz,2H),3.05-2.97(m,1H),2.77(d,J＝9.9Hz,2H),2.55-2.36(m,8H),2.34(s,3H),2.18(s,3H),1.92(t,J＝11.9Hz,2H),1.78(d,J＝11.2Hz,2H),1.68(d,J＝15.4Hz,5H),0.89(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:760.4526.
IM-12-2的合成：以IM-11-2为起始原料，参考IM-12-1的合成方法。白色固体，产率：88.5％。1H NMR(400MHz,MeOD)δ7.55(d,J＝8.1Hz,2H),7.45(d,J＝1.4Hz,1H),7.40(d,J＝8.1Hz,2H),7.31(d,J＝1.5Hz,1H),6.11(s,1H),4.49(s,2H),3.92(d,J＝10.9Hz,2H),3.65-3.54(m,6H),3.40-3.33(m,2H),3.20-3.05(m,5H),2.99(d,J＝11.6Hz,2H),2.70-2.62(m,1H),2.57(t,J＝12.5Hz,2H),2.46(d,J＝17.2Hz,5H),2.39(s,3H),2.35-2.26(m,5H),2.24(s,3H),1.86(d,J＝12.4Hz,2H),1.80-1.58(m,8H),1.45(dd,J＝12.1,3.6Hz,2H),0.89(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:766.5020.
IM-13的合成：以IM-3和L8为起始原料，参考IM-7-1的合成方法。白色固体，产率：89.8％。1HNMR(400MHz,CDCl3)δ10.92(s,1H),7.46(s,1H),7.44(s,1H),7.35(s,1H),7.32(d,J＝1.7Hz,2H),7.28(d,J＝1.6Hz,1H),7.10(t,J＝5.8Hz,1H),5.90(s,1H),5.73(s,1H),4.55(d,J＝5.9Hz,2H),4.05(d,J＝6.1Hz,2H),3.95(d,J＝11.3Hz,2H),3.66(s,2H),3.54(s,4H),3.32(td,J＝11.3,2.9Hz,2H),3.10(q,J＝6.9Hz,2H),3.0(s,3H),2.93(d,J＝14.9Hz,1H),2.42(d,J＝14.0Hz,7H),2.32(d,J＝10.8Hz,4H),2.22-2.10(m,4H),1.94(t,J＝11.9Hz,4H),1.76-1.64(m,4H),1.31-1.10(m,3H),0.89(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:824.4034.
IM-14的合成：以IM-1和L11为起始原料，参考IM-2的合成方法。白色固体，产率：52.9％。1H NMR(400MHz,CDCl3)δ11.55(s,1H),7.48(s,1H),7.46(s,1H),7.41-7.33(m,3H),7.30(d,J＝1.4Hz,1H),7.17(t,J＝5.8Hz,1H),5.92(s,1H),4.57(d,J＝5.8Hz,2H),4.05(d,J＝6.5Hz,2H),3.97(d,J＝11.1Hz,2H),3.57(s,2H),3.34(dd,J＝10.9,8.7Hz,3H),3.26(d,J＝6.4Hz,2H),3.11(dd,J＝13.9,6.9Hz,2H),3.03(d,J＝8.5Hz,4H),2.78(s,2H),2.42(s,3H),2.36(s,3H),2.27(d,J＝8.3Hz,2H),2.14(s,3H),2.00-1.82(m,7H),1.71-1.49(m,7H),1.10-0.95(m,4H),0.91(dd,J＝8.5,5.4Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:791.4418.
IM-15的合成：于反应瓶中加入IM-14(200mg，0.25mmol)，邻苯二甲酰亚铵钾盐(94mg，0.5mmol)，碳酸钾(235mg，0.25mmol)，DMF(2mL)。溶解均匀后，搅拌加热至110℃下反应。TLC监测反应进程。反应完成后，反应液冷却至50℃左右，加入水(40mL)和DCM(40mL)。搅拌均匀后分层，有机相减压浓缩得到粗品。粗品分离纯化得到白色固体产物(90mg)，产率：42.0％。1H NMR(400MHz,CDCl3)δ11.47(s,1H),7.85(dd,J＝5.4,3.0Hz,2H),7.72(dd,J＝5.4,3.0Hz,2H),7.56(s,2H),7.49(d,J＝7.7Hz,2H),7.31(d,J＝1.4Hz,1H),7.26-7.24(m,1H),7.22-7.15(m,1H),5.92(s,1H),4.55(d,J＝5.9Hz,2H),3.95(d,J＝11.2Hz,4H),3.54(d,J＝6.9Hz,3H),3.32(td,J＝11.3,2.7Hz,2H),3.19(d,J＝6.3Hz,2H),3.09(dd,J＝13.8,6.8Hz,2H),3.03-2.98(m,1H),2.91(s,2H),2.55-2.25(m,8H),2.15(s,3H),1.94-1.60(m,13H),1.51(s,1H),1.06(dd,J＝23.2,12.8Hz,2H),0.95(d,J＝12.2Hz,2H),0.88(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:964.4679.
IM-16的合成：于反应瓶中加入IM-15(85mg，0.1mmol)，98％水合肼(0.5g，10mmol)，甲醇(2mL)。搅拌溶清后，升温至65℃下反应，TLC监测反应进程。反应完成后，减压浓缩除去反应溶剂得到的粗品。粗品分离纯化得到白色固体产物(45mg)，产率：62.0％。1HNMR(400MHz,CDCl3)δ7.44(dd,J＝15.6,7.8Hz,4H),7.26(s,1H),7.21(s,1H),7.16-7.07(m,1H),5.86(s,1H),4.46(d,J＝4.7Hz,2H),3.87(d,J＝11.1Hz,4H),3.35(s,1H),3.25(t,J＝9.9Hz,2H),3.09-2.98(m,4H),2.97-2.91(m,1H),2.80(s,2H),2.70(d,J＝5.9Hz,4H),2.32(s,3H),2.28(s,3H),2.12(s,3H),2.08-1.89(m,3H),1.88-1.40(m,13H),1.36(s,1H),0.91-0.76(m,7H)ppm.HR-MS(m/z)(ESI):[M+H]+:712.4805.
IM-17的合成：以6-溴-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-1-异丙基-1为起始原料，参考IM-1的合成方法。类白色固体，产率：95.0％。1H NMR(400MHz,CDCl3)δ12.15(s,1H),10.05(s,1H),8.58(s,1H),8.08(dd,J＝7.8,3.1Hz,2H),7.98-7.86(m,2H),7.84-7.75(m,2H),7.70(s,1H),5.93(s,1H),4.89-4.78(m,1H),4.66(d,J＝5.7Hz,2H),2.44(d,J＝9.0Hz,3H),2.12(s,3H),1.74-1.62(m,6H)ppm.HR-MS(m/z)(ESI):[M+H]+:443.2083.
IM-18的合成：以IM-17和1-Boc-哌嗪为起始原料，参考IM-2的合成方法。类白色固体，产率：76.4％。1HNMR(400MHz,CDCl3)δ11.72(s,1H),8.53(s,1H),8.00(s,1H),7.92(t,J＝5.8Hz,1H),7.66(d,J＝1.1Hz,1H),7.58(d,J＝8.1Hz,2H),7.37(d,J＝8.1Hz,2H),5.91(s,1H),4.85-4.73(m,1H),4.62(d,J＝5.9Hz,2H),3.55(s,2H),3.45(d,J＝4.5Hz,4H),2.43(d,J＝6.8Hz,7H),2.11(s,3H),1.66(s,3H),1.64(s,3H),1.45(s,9H)ppm.HR-MS(m/z)(ESI):[M+H]+:613.3508.
IM-19的合成：以IM-18为起始原料，参考IM-3的合成方法。类白色固体，产率：23.6％。1HNMR(400MHz,CDCl3)δ8.55(d,J＝0.7Hz,1H),8.00(d,J＝1.0Hz,1H),7.95(t,J＝5.8Hz,1H),7.65(d,J＝1.2Hz,1H),7.57(d,J＝8.2Hz,2H),7.32(d,J＝8.2Hz,2H),5.93(s,1H),4.81(dt,J＝13.4,6.7Hz,1H),4.62(d,J＝5.8Hz,2H),3.47(s,2H),2.93(t,J＝4.8Hz,4H),2.56-2.32(m,9H),2.14(s,3H),1.66(d,J＝6.7Hz,6H)ppm.HR-MS(m/z)(ESI):[M+H]+:513.2977.
IM-20的合成：以IM-19与Boc-氨甲环酸为起始原料，参考IM-7-1的合成方法。白色固体，产率：98.6％。1HNMR(400MHz,CDCl3)δ11.55(s,1H),8.53(s,1H),8.01(s,1H),7.90(s,1H),7.68(s,1H),7.59(d,J＝8.0Hz,2H),7.36(d,J＝8.0Hz,2H),5.93(s,1H),4.81(dt,J＝13.4,6.7Hz,1H),4.62(d,J＝5.8Hz,2H),4.58(s,1H),3.63(s,2H),3.54(s,2H),3.50(s,2H),2.97(d,J＝5.9Hz,2H),2.42(d,J＝10.9Hz,8H),2.14(s,3H),1.87-1.76(m,5H),1.66(d,J＝6.7Hz,6H),1.61-1.52(m,2H),1.44(s,9H),0.97(d,J＝12.4Hz,2H)ppm.HR-MS(m/z)(ESI):[M+Na]+:744.4319.
IM-21的合成：以IM-20为起始原料，参考IM-6-1的合成方法。白色固体，产率：71.0％。1HNMR(400MHz,CDCl3)δ8.54(s,1H),8.01(s,1H),7.89(s,1H),7.67(d,J＝1.1Hz,1H),7.59(d,J＝8.1Hz,2H),7.36(d,J＝8.1Hz,2H),5.91(s,1H),4.85-4.76(m,1H),4.62(d,J＝5.8Hz,2H),3.63(s,2H),3.54(s,2H),3.50(s,2H),2.55(d,J＝6.3Hz,2H),2.50-2.33(m,8H),2.13(s,3H),1.87(d,J＝13.1Hz,2H),1.78(d,J＝11.7Hz,3H),1.66(d,J＝6.7Hz,6H),1.62-1.51(m,3H),1.44-1.28(m,2H),0.94(ddd,J＝25.3,13.1,3.3Hz,2H)ppm.HR-MS(m/z)(ESI):[M+H]+:652.3979.
IM-22的合成：以IM-17与L10为起始原料，参考IM-14的合成方法。类白色固体，产率：39.4％。1H NMR(400MHz,CDCl3)δ11.62(s,1H),8.53(s,1H),7.97(s,2H),7.77-7.48(m,5H),5.97(s,1H),4.80(dt,J＝13.2,6.5Hz,1H),4.61(d,J＝4.9Hz,2H),4.00(d,J＝6.4Hz,4H),3.53(s,1H),3.19(d,J＝6.2Hz,2H),3.14-2.76(m,7H),2.41(s,3H),2.34-2.12(m,5H),1.90(d,J＝11.4Hz,2H),1.80(t,J＝9.8Hz,4H),1.65(d,J＝6.7Hz,6H),1.49(s,1H),1.14-0.76(m,5H)ppm.HR-MS(m/z)(ESI):[M+H]+:732.3792.
IM-23的合成：以IM-22为起始原料，参考IM-15的合成方法。类白色固体，产率：73.4％。1HNMR(400MHz,CDCl3)δ11.87(s,1H),8.53(s,1H),7.98(s,2H),7.84(dd,J＝5.4,3.1Hz,2H),7.71(dd,J＝5.4,3.0Hz,2H),7.69-7.60(m,3H),7.56(s,2H),5.94(s,1H),4.80(dd,J＝13.3,6.6Hz,1H),4.61(d,J＝5.3Hz,2H),3.86(s,2H),3.53(d,J＝6.9Hz,2H),3.45(s,1H),3.19(d,J＝6.2Hz,2H),2.88(s,4H),2.41(s,3H),2.25-2.05(m,5H),1.76(t,J＝13.2Hz,6H),1.64(d,J＝6.7Hz,6H),1.50(s,1H),1.39-1.28(m,1H),1.05(dd,J＝24.8,12.4Hz,2H),0.91(dd,J＝23.6,10.7Hz,2H)ppm.HR-MS(m/z)(ESI):[M+H]+:783.4236.
IM-24的合成：以IM-23为起始原料，参考IM-16的合成方法。类白色固体，产率：81.7％。1HNMR(400MHz,MeOD)δ8.61(s,1H),8.01(s,1H),7.86(t,J＝5.1Hz,3H),7.68(d,J＝8.2Hz,2H),6.13(s,1H),4.92-4.89(m,1H),4.56(s,2H),4.38(s,2H),3.63(s,1H),3.35(s,2H),3.28(s,2H),2.75(d,J＝7.0Hz,2H),2.42(s,3H),2.25(s,3H),2.20-1.92(m,4H),1.83(d,J＝4.1Hz,5H),1.67(d,J＝6.7Hz,6H),1.65-1.42(m,3H),1.08-0.96(m,4H)ppm.HR-MS(m/z)(ESI):[M+H]+:653.4176.
实施例3：ZJ-01～ZJ-31的合成
ZJ-01～ZJ-31的合成路线
/>
/>
/>
ZJ-01的合成：于反应瓶中加入IM-6-1(56mg，0.086mmol)，加入2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮(28.5mg，0.103mmol)，DIPEA(55.6mg，0.43mmol)，DMSO(1mL)。于118℃下搅拌反应，TLC监测反应进程，约1～1.5小时反应结束。加水(20mL)，用DCM(60mL)分三次萃取产物，合并有机相并减压浓缩得到粗品。粗品分离纯化得到亮黄色固体产物(38.1mg)，产率：49.7％。1H NMR(400MHz,MeOD)δ7.58-7.53(m,1H),7.48(d,J＝8.1Hz,1H),7.44(d,J＝8.1Hz,2H),7.34(dd,J＝8.1,3.5Hz,2H),7.28(dd,J＝6.7,1.4Hz,1H),7.08(d,J＝7.1Hz,1H),7.02(dd,J＝8.5,6.0Hz,1H),6.10(s,1H),5.05-4.98(m,1H),4.49(s,2H),4.20(s,1H),3.91(d,J＝10.9Hz,2H),3.67(s,2H),3.64-3.45(m,4H),3.39(s,2H),3.35(s,2H),3.13(dt,J＝10.9,5.3Hz,3H),2.91(dt,J＝20.2,6.8Hz,1H),2.84-2.58(m,5H),2.50(s,2H),2.39(t,J＝5.2Hz,7H),2.32(s,3H),2.23(s,3H),2.09-2.00(m,1H),1.82-1.57(m,5H),0.89(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:954.4874.
ZJ-02的合成：以IM-6-2为起始原料，参考ZJ-01的合成方法。黄色固体，产率39.2％。1HNMR(400MHz,CDCl3)δ10.88(s,1H),10.38(d,J＝44.4Hz,1H),7.48(dd,J＝15.6,7.8Hz,3H),7.32(d,J＝5.9Hz,3H),7.26-7.24(m,1H),7.16(d,J＝3.2Hz,1H),7.10(dd,J＝7.0,2.1Hz,1H),6.88(dd,J＝8.5,3.8Hz,1H),6.53-6.36(m,1H),5.92(s,1H),4.99-4.83(m,1H),4.67-4.46(m,2H),3.95(d,J＝11.1Hz,2H),3.87-3.47(m,6H),3.47-3.16(m,6H),3.10(dd,J＝13.6,6.9Hz,2H),3.02(s,1H),2.96-2.72(m,3H),2.72-2.60(m,3H),2.52(d,J＝21.6Hz,4H),2.42(s,3H),2.36(s,3H),2.18(d,J＝1.4Hz,3H),2.07(d,J＝4.9Hz,2H),1.73(s,4H),1.68-1.53(m,3H),0.91(t,J＝6.8Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:968.5034.
ZJ-03的合成：以IM-6-3为起始原料，参考ZJ-01的合成方法。黄色固体，产率：63.1％。1HNMR(400MHz,CDCl3)δ10.46(s,1H),9.07(s,1H),7.57(d,J＝7.7Hz,1H),7.47(d,J＝7.9Hz,2H),7.40(d,J＝7.1Hz,1H),7.33(d,J＝8.1Hz,3H),7.27(s,1H),7.16(d,J＝8.4Hz,1H),7.08(s,1H),5.91(s,1H),4.94(dd,J＝11.9,5.2Hz,1H),4.64-4.48(m,2H),3.95(d,J＝11.4Hz,2H),3.61(s,6H),3.50-3.28(m,6H),3.26(s,2H),3.15-3.06(m,2H),3.05-2.98(m,1H),2.93-2.78(m,2H),2.78-2.64(m,5H),2.48(s,4H),2.42(s,3H),2.35(s,3H),2.17(s,3H),2.13-2.07(m,1H),1.71(s,4H),0.90(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:954.4867.
ZJ-04的合成：以IM-6-4为起始原料，参考ZJ-01的合成方法。黄色固体，产率：31.5％。1HNMR(600MHz,DMSO)δ11.48(s,1H),11.12(s,1H),8.21(t,J＝4.9Hz,1H),7.74-7.54(m,3H),7.39(d,J＝8.7Hz,3H),7.23(d,J＝1.3Hz,1H),7.18(d,J＝8.7Hz,1H),7.06(d,J＝7.0Hz,1H),6.25(d,J＝8.0Hz,1H),5.86(s,1H),5.06(dd,J＝12.8,5.5Hz,1H),4.29(d,J＝4.9Hz,2H),3.83(d,J＝10.3Hz,2H),3.74-3.46(m,6H),3.45(s,2H),3.24(t,J＝11.1Hz,2H),3.16(s,1H),3.08(dd,J＝13.4,6.5Hz,2H),3.01(dd,J＝12.7,9.1Hz,1H),2.88(ddd,J＝17.1,14.0,5.4Hz,1H),2.74(d,J＝6.1Hz,2H),2.64-2.52(m,2H),2.43(s,2H),2.31(s,2H),2.23(d,J＝22.5Hz,7H),2.11(s,3H),2.08-1.97(m,2H),1.92(d,J＝9.7Hz,2H),1.66(d,J＝11.0Hz,2H),1.57-1.45(m,4H),0.83(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:968.5025.
ZJ-05的合成：以IM-6-5为起始原料，参考ZJ-01的合成方法。黄色固体，产率：32.0％。1H NMR(400MHz,CDCl3)δ10.88(s,2H),7.49(dd,J＝12.4,5.1Hz,3H),7.34(d,J＝8.8Hz,3H),7.24(s,1H),7.15(d,J＝6.3Hz,1H),7.12-7.04(m,1H),6.86(dd,J＝8.5,5.1Hz,1H),6.26(d,J＝36.0Hz,1H),5.94(s,1H),4.89(dd,J＝12.2,5.7Hz,1H),4.63-4.45(m,2H),3.95(d,J＝11.1Hz,2H),3.52(dd,J＝69.7,23.0Hz,6H),3.33(t,J＝10.8Hz,2H),3.28-2.92(m,7H),2.92-2.61(m,5H),2.43(s,7H),2.36(d,J＝3.8Hz,3H),2.20(d,J＝3.1Hz,3H),2.09(s,2H),1.99-1.86(m,5H),1.70-1.51(m,4H),1.10(d,J＝11.3Hz,1H),0.90(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:982.5184.HPLC purity:97.66％.
ZJ-06的合成：以IM-6-6为起始原料，参考ZJ-01的合成方法。黄色固体，产率：48.0％。1H NMR(400MHz,CDCl3)δ10.78(s,1H),9.87(s,1H),7.38(d,J＝7.9Hz,3H),7.25(s,3H),7.19(s,1H),7.10(s,1H),7.02(d,J＝6.4Hz,1H),6.83(d,J＝8.1Hz,1H),6.55(s,1H),5.84(s,1H),4.82(d,J＝5.5Hz,1H),4.47(d,J＝5.6Hz,2H),3.87(d,J＝11.3Hz,2H),3.66-3.30(m,12H),3.25(t,J＝10.1Hz,2H),3.02(d,J＝6.8Hz,2H),2.94(s,1H),2.87-2.71(m,2H),2.71-2.48(m,3H),4.48-2.30(m,7H),2.28(s,3H),2.10(d,J＝5.3Hz,3H),2.00(s,1H),1.64(s,5H),0.82(t,J＝6.7Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:954.4874.
ZJ-07的合成：以IM-8-1为起始原料，参考ZJ-01的合成方法。黄色固体，产率：43.0％。1H NMR(400MHz,CDCl3)δ10.72(s,1H),10.19(s,1H),7.56-7.44(m,3H),7.40-7.29(m,3H),7.25(s,1H),7.11(dd,J＝10.4,6.5Hz,2H),6.89(d,J＝8.6Hz,1H),6.77(s,1H),5.93(s,1H),4.88(dd,J＝12.2,5.3Hz,1H),4.54(d,J＝6.0Hz,2H),3.95(d,J＝11.3Hz,2H),3.65(s,2H),3.53(s,2H),3.49-3.45(m,3H),3.41(dd,J＝12.9,5.9Hz,2H),3.33(t,J＝10.6Hz,2H),3.16(s,2H),3.10(dd,J＝14.1,7.2Hz,2H),3.05-2.98(m,1H),2.90-2.62(m,6H),2.56-2.24(m,12H),2.19(s,3H),2.09(dd,J＝13.1,6.9Hz,2H),1.71(s,4H),0.90(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:968.5028.
ZJ-08的合成：以IM-8-2为起始原料，参考ZJ-01的合成方法。黄色固体，产率：13.3％。1H NMR(400MHz,CDCl3)δ11.20(s,1H),9.59(s,1H),7.54-7.42(m,3H),7.33(d,J＝7.9Hz,3H),7.25(s,1H),7.09(d,J＝7.1Hz,1H),7.08-6.96(m,1H),6.95-6.79(m,2H),6.20(d,J＝20.9Hz,1H),6.13(d,J＝15.1Hz,1H),5.93(s,1H),4.89(dd,J＝12.1,5.3Hz,1H),4.55(qd,J＝14.1,6.0Hz,2H),3.95(d,J＝11.3Hz,2H),3.71(s,2H),3.56(s,4H),3.33(t,J＝11.0Hz,2H),3.24(t,J＝6.1Hz,2H),3.10(q,J＝6.9Hz,2H),3.06-2.93(m,2H),2.92-2.68(m,3H),2.64-2.55(m,1H),2.51(s,2H),2.46-2.48(m,5H),2.38-2.35(m,1H),2.34(s,3H),2.17(s,3H),2.14-2.03(m,2H),1.75-1.64(m,6H),0.90(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:965.4922.
ZJ-09的合成：以IM-8-3为起始原料，参考ZJ-01的合成方法。黄色固体，产率：33.5％。1H NMR(400MHz,CDCl3)δ10.45(s,1H),9.86(d,J＝85.5Hz,1H),7.48(dd,J＝16.0,8.1Hz,3H),7.41-7.29(m,3H),7.24(s,1H),7.09(dd,J＝7.0,3.3Hz,1H),7.02(d,J＝14.6Hz,1H),6.88(dd,J＝8.3,3.9Hz,1H),6.86-6.77(m,1H),6.27(d,J＝17.7Hz,1H),6.18(d,J＝15.2Hz,1H),5.93(s,1H),4.88(dd,J＝12.2,6.0Hz,1H),4.62-4.48(m,2H),3.95(d,J＝11.4Hz,2H),3.74(s,2H),3.54(d,J＝13.8Hz,4H),3.33(t,J＝10.3Hz,3H),3.10(dd,J＝13.8,6.8Hz,3H),3.03-2.90(m,1H),2.90-2.65(m,4H),2.53(s,2H),2.43(s,3H),2.39-2.26(m,5H),2.20(s,3H),2.15-2.06(m,2H),1.97-1.87(m,2H),1.68(d,J＝17.9Hz,4H),1.51-1.41(m,2H),1.18(dd,J＝22.2,10.1Hz,2H),0.90(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):calcd for C56H66N8O8[M+H]+:979.5082,found:979.5079.
ZJ-10的合成：以IM-8-4为起始原料，参考ZJ-01的合成方法。黄色固体，产率：50.0％。1H NMR(400MHz,CDCl3)δ11.15(s,1H),9.59(s,1H),7.53-7.42(m,3H),7.33(d,J＝5.8Hz,3H),7.25(s,1H),7.08(d,J＝7.1Hz,1H),7.02(t,J＝5.9Hz,1H),6.88(d,J＝8.6Hz,1H),5.94(s,1H),4.90(dd,J＝12.2,5.2Hz,1H),4.55(dt,J＝14.1,8.1Hz,2H),3.95(d,J＝11.3Hz,2H),3.65(s,2H),3.57(s,2H),3.49(s,2H),3.33(t,J＝9.7Hz,2H),3.18(s,2H),3.10(d,J＝7.0Hz,2H),3.06-2.98(m,1H),2.92-2.70(m,3H),2.47(s,2H),2.43(s,3H),2.39(s,2H),2.34(s,3H),2.18(s,3H),2.14-2.08(m,1H),1.84(dd,J＝36.2,12.0Hz,8H),1.67-1.52(m,4H),1.13(d,J＝12.5Hz,2H),0.90(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:967.5075.
ZJ-11的合成：以IM-8-5为起始原料，参考ZJ-01的合成方法。黄色固体，产率：59.3％。1H NMR(400MHz,CDCl3)δ10.86(s,1H),9.00(d,J＝65.8Hz,1H),7.55-7.42(m,3H),7.41-7.29(m,3H),7.27(s,1H),7.09(d,J＝7.1Hz,2H),6.87(d,J＝8.6Hz,1H),6.34(s,1H),5.92(s,1H),5.71(s,1H),4.94-4.86(m,1H),4.55(d,J＝5.1Hz,2H),3.95(d,J＝11.4Hz,2H),3.68(s,2H),3.54(d,J＝14.6Hz,4H),3.32(t,J＝9.7Hz,2H),3.16(s,2H),3.10(dd,J＝14.0,6.9Hz,2H),3.04-2.97(m,1H),2.88(d,J＝13.9Hz,2H),2.78-2.73(m,1H),2.49(s,2H),2.42(s,5H),2.36-2.25(m,4H),2.24-2.08(m,5H),2.01-1.89(m,3H),1.84(s,1H),1.64(d,J＝8.3Hz,5H),1.17(d,J＝13.2Hz,2H),0.89(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:979.5076.
ZJ-12的合成：以IM-8-6为起始原料，参考ZJ-01的合成方法。黄色固体，产率：38.0％。1H NMR(400MHz,CDCl3)δ10.62(s,1H),8.89(s,1H),7.51-7.44(m,3H),7.33(d,J＝9.3Hz,3H),7.26(s,1H),7.08(d,J＝7.1Hz,1H),7.04(s,1H),6.87(d,J＝8.5Hz,1H),6.78(dd,J＝15.2,6.8Hz,1H),6.16(d,J＝15.5Hz,1H),5.91(s,1H),4.90(dd,J＝12.1,5.4Hz,1H),4.59-4.51(m,2H),3.95(d,J＝11.1Hz,2H),3.70(s,2H),3.57(s,4H),3.33(t,J＝9.6Hz,2H),3.17-3.06(m,4H),3.01(dd,J＝10.0,4.6Hz,1H),2.89-2.70(m,3H),2.45(d,J＝29.5Hz,7H),2.33(s,3H),2.17(s,3H),2.12(d,J＝5.3Hz,2H),1.95-1.83(m,4H),1.71(s,5H),1.22-1.06(m,4H),0.90(s,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:1015.5054.
ZJ-13的合成：以IM-8-7为起始原料，参考ZJ-01的合成方法。黄色固体，产率：18.0％。1H NMR(400MHz,CDCl3)δ11.09(s,1H),10.18(s,1H),7.51-7.39(m,3H),7.29(d,J＝6.0Hz,5H),7.22(d,J＝7.8Hz,3H),7.13(dd,J＝12.8,6.3Hz,2H),6.87(d,J＝8.5Hz,1H),6.61(t,J＝5.6Hz,1H),5.92(s,1H),4.90(dd,J＝12.2,5.1Hz,1H),4.58(dd,J＝14.0,6.2Hz,1H),4.50(d,J＝5.8Hz,1H),4.46(d,J＝5.5Hz,2H),3.94(d,J＝11.1Hz,2H),3.80-3.58(m,4H),3.46(s,2H),3.43-3.25(m,4H),3.09(q,J＝6.9Hz,2H),3.04-2.96(m,1H),2.88-2.63(m,3H),2.46(s,2H),2.42(s,3H),2.34(s,3H),2.18(s,3H),2.16-2.02(m,3H),1.75-1.66(m,4H),0.89(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:997.4589.
ZJ-14的合成：以IM-8-8为起始原料，参考ZJ-01的合成方法。黄色固体，产率：24.0％。1H NMR(400MHz,CDCl3)δ10.96(s,1H),10.51(s,1H),7.52(t,J＝7.6Hz,1H),7.43(d,J＝8.0Hz,2H),7.39-7.28(m,3H),7.15(dd,J＝19.0,11.6Hz,2H),7.00(s,1H),6.84(d,J＝8.6Hz,1H),6.21(s,1H),5.93(s,1H),4.89(d,J＝12.2Hz,1H),4.64(dd,J＝13.9,6.3Hz,1H),4.46(dd,J＝14.2,5.2Hz,1H),4.08(d,J＝32.0Hz,2H),3.95(d,J＝11.3Hz,2H),3.73-3.65(m,2H),3.58-3.27(m,7H),3.26-3.00(m,7H),2.99-2.56(m,9H),2.42(s,3H),2.34(s,4H),2.19(s,3H),2.11(d,J＝6.5Hz,1H),2.02(s,1H),1.96-1.70(m,6H),0.90(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:954.5238.
ZJ-15的合成：以IM-8-9为起始原料，参考ZJ-01的合成方法。黄色固体，产率：51.8％。1H NMR(400MHz,CDCl3)δ11.27(s,1H),9.35(d,J＝73.0Hz,1H),7.47(dd,J＝14.5,7.5Hz,3H),7.42-7.29(m,3H),7.26(s,1H),7.12(d,J＝5.7Hz,1H),7.08(d,J＝7.1Hz,1H),6.87(d,J＝8.6Hz,1H),6.33(t,J＝5.3Hz,1H),5.92(s,1H),5.37(s,1H),4.93-4.85(m,1H),4.66-4.45(m,2H),3.95(d,J＝11.2Hz,2H),3.59(dd,J＝32.0,12.9Hz,2H),3.32(t,J＝9.8Hz,2H),3.26-3.13(m,3H),3.09(dd,J＝13.6,6.6Hz,2H),3.03-2.98(m,1H),2.95-2.54(m,11H),2.41(s,3H),2.34(s,3H),2.31(s,1H),2.16(s,3H),2.10(t,J＝11.5Hz,3H),1.93(t,J＝13.3Hz,2H),1.81(t,J＝11.0Hz,2H),1.78-1.53(m,5H),1.14(dd,J＝18.0,6.3Hz,1H),1.03(dd,J＝25.7,13.6Hz,1H),0.89(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:987.5107.
ZJ-16的合成：以IM-12-1为起始原料，参考ZJ-01的合成方法。黄色固体，产率：75.8％。1H NMR(400MHz,CDCl3)δ11.14(s,1H),8.91(s,1H),7.45(dd,J＝11.9,6.3Hz,3H),7.31(d,J＝7.3Hz,3H),7.27(s,1H),7.16(d,J＝6.9Hz,1H),7.07(t,J＝5.9Hz,1H),6.60(d,J＝8.4Hz,1H),5.92(s,1H),4.90(dd,J＝12.2,5.3Hz,1H),4.62-4.49(m,2H),4.35(d,J＝6.2Hz,2H),4.07(s,2H),3.95(d,J＝11.3Hz,2H),3.81-3.52(m,5H),3.49(s,2H),3.32(t,J＝9.8Hz,2H),3.27-3.20(m,1H),3.10(q,J＝6.8Hz,2H),3.05-2.98(m,1H),2.92(d,J＝10.5Hz,2H),2.89-2.57(m,4H),2.46(d,J＝11.6Hz,5H),2.41(s,3H),2.34(s,3H),2.16(s,3H),2.12-2.06(m,1H),1.99-1.91(m,2H),1.89-1.81(m,2H),1.71-1.66(m,4H),0.90(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:1016.5010.
ZJ-17的合成：以IM-12-2为起始原料，参考ZJ-01的合成方法。黄色固体，产率：58.5％。1HNMR(400MHz,CDCl3)δ11.11(s,1H),8.88(s,1H),7.58(t,J＝7.7Hz,1H),7.46(d,J＝8.0Hz,2H),7.40(d,J＝7.1Hz,1H),7.32(d,J＝8.0Hz,3H),7.27(d,J＝1.5Hz,1H),7.14(d,J＝8.4Hz,1H),7.10(t,J＝5.5Hz,1H),5.92(s,1H),4.95(dd,J＝12.2,5.4Hz,1H),4.55(d,J＝5.8Hz,2H),3.94(d,J＝11.3Hz,2H),3.81(d,J＝11.5Hz,2H),3.61(s,2H),3.57(s,2H),3.48(s,2H),3.32(t,J＝9.7Hz,4H),3.10(dd,J＝13.8,6.8Hz,2H),3.07-2.95(m,2H),2.95-2.63(m,7H),2.44(s,5H),2.41(s,3H),2.34(s,3H),2.25-2.15(m,4H),2.14-2.05(m,2H),1.94(s,6H),1.74-1.65(m,4H),0.89(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:1044.5324.
ZJ-18的合成：于反应瓶中加入ZJ-08(22mg，0.023mmol)，甲醇(3mL)。搅拌溶解澄清后，氮气置换三次。加入Pd/C(22mg)，抽真空氢气置换二次后，室温下搅拌反应，LC-MS监测反应进程。反应完成后，过滤除去钯碳，滤液减压浓缩得到粗品。粗品用柱层析(2～6％MeOH/DCM)分离纯化，得到黄色固体产物14mg，产率：63.6％。1H NMR(600MHz,CDCl3)δ11.64(s,1H),9.78(d,J＝83.4Hz,1H),7.47(dd,J＝12.3,7.9Hz,3H),7.34(d,J＝7.2Hz,2H),7.32(s,1H),7.26(s,1H),7.14(s,1H),7.08(d,J＝7.0Hz,1H),6.85(d,J＝8.5Hz,1H),6.19(t,J＝5.1Hz,1H),5.93(s,1H),4.90(dd,J＝11.8,4.9Hz,1H),4.55(ddd,J＝30.5,14.1,5.9Hz,2H),3.95(d,J＝11.2Hz,2H),3.58(s,2H),3.48(s,2H),3.32(t,J＝10.4Hz,2H),3.21(t,J＝5.8Hz,2H),3.09(dd,J＝13.6,6.7Hz,2H),3.04-2.98(m,1H),2.85(d,J＝15.5Hz,1H),2.79-2.69(m,2H),2.55-2.44(m,4H),2.42(s,3H),2.38-2.29(m,4H),2.26-2.20(m,4H),2.16(s,3H),2..12-2.09(m,1H),2.06-1.96(m,1H),1.1.95-1.86(m,1H),1.84-1.77(m,1H),1.73-1.61(m,6H),1.45-1.36(m,2H),0.89(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:967.5075.
ZJ-19的合成：以ZJ-09为起始原料，参考ZJ-18的合成方法。亮黄色固体，产率：52.1％。1HNMR(400MHz,CDCl3)δ10.86(s,1H),10.01(d,J＝38.2Hz,1H),7.55-7.43(m,3H),7.33(d,J＝10.2Hz,3H),7.25(s,1H),7.08(d,J＝6.8Hz,2H),6.87(d,J＝8.5Hz,1H),6.26(d,J＝17.8Hz,1H),5.93(s,1H),4.89(dd,J＝11.4,4.1Hz,1H),4.62-4.48(m,2H),3.95(d,J＝10.9Hz,2H),3.66(s,2H),3.55(s,2H),3.45(s,2H),3.37-3.26(m,3H),3.10(dd,J＝13.5,6.6Hz,3H),3.05-2.97(m,1H),2.89-2.69(m,3H),2.49(s,2H),2.42(s,3H),2.38(s,2H),2.36-2.20(m,6H),2.18(s,3H),2.09(d,J＝6.7Hz,2H),1.97-1.77(m,4H),1.64(s,6H),1.43-1.29(m,2H),0.90(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:981.5232.
ZJ-20的合成：以ZJ-11为起始原料，参考ZJ-18的合成方法。黄色固体，产率：56.6％。1HNMR(600MHz,CDCl3)δ11.77(s,1H),9.33(d,J＝83.2Hz,1H),7.47(dd,J＝14.4,7.6Hz,3H),7.34(d,J＝6.5Hz,2H),7.32(s,1H),7.27(s,1H),7.16(dt,J＝12.0,5.9Hz,1H),7.07(d,J＝7.1Hz,1H),6.87(dd,J＝8.6,3.5Hz,1H),6.31(dt,J＝16.8,5.7Hz,1H),5.92(s,1H),4.93-4.88(m,1H),4.60-4.51(m,2H),3.95(d,J＝11.3Hz,2H),3.72-3.47(m,6H),3.32(t,J＝11.1Hz,2H),3.21(t,J＝6.3Hz,1H),3.14-3.07(m,3H),3.04-2.99(m,1H),2.89-2.83(m,1H),2.80-2.69(m,2H),2.47(s,4H),2.41(s,3H),2.34(d,J＝2.4Hz,3H),2.32(d,J＝7.2Hz,1H),2.21(d,J＝6.7Hz,1H),2.15(s,3H),2.12-2.10(m,1H),1.88-1.81(m,3H),1.73-1.66(m,4H),1.64-1.55(m,3H),1.48-1.38(m,2H),1.08(dd,J＝23.2,12.0Hz,1H),1.00(dd,J＝23.7,10.8Hz,1H),0.89(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:981.5235.
ZJ-21的合成：以ZJ-12为起始原料，参考ZJ-18的合成方法。黄色固体，产率：48.9％。1HNMR(400MHz,CDCl3)δ11.21(s,1H),9.23(s,1H),7.53-7.43(m,3H),7.33(d,J＝8.7Hz,3H),7.26(s,1H),7.08(t,J＝6.3Hz,2H),6.87(d,J＝8.6Hz,1H),6.33(t,J＝5.7Hz,1H),5.92(s,1H),4.90(dd,J＝12.1,5.3Hz,1H),4.62-4.48(m,2H),3.95(d,J＝11.4Hz,2H),3.64(s,2H),3.55(s,2H),3.46(s,2H),3.32(t,J＝9.7Hz,2H),3.11(t,J＝6.9Hz,4H),3.05-2.96(m,1H),2.90-2.69(m,3H),2.44(d,J＝18.7Hz,7H),2.32(d,J＝13.3Hz,5H),2.17(s,3H),2.14-2.08(m,1H),1.82(t,J＝14.3Hz,4H),1.76-1.61(m,6H),1.55-1.50(m,2H),1.08-0.92(m,4H),0.89(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:1017.5214.
ZJ-22的合成：以ZJ-15为起始原料，参考ZJ-18的合成方法。黄色固体，产率：50.2％。1HNMR(400MHz,CDCl3)δ11.16(s,1H),8.85(d,J＝194.7Hz,1H),7.57-7.42(m,3H),7.32(d,J＝8.4Hz,3H),7.27(s,1H),7.18-7.10(m,1H),7.07(d,J＝7.1Hz,1H),6.92-6.83(m,1H),6.30(dt,J＝17.1,5.7Hz,1H),5.92(s,1H),4.93-4.86(m,1H),4.55(d,J＝5.6Hz,2H),3.95(d,J＝11.3Hz,2H),3.60(s,2H),3.32(t,J＝10.6Hz,2H),3.19(t,J＝6.0Hz,1H),3.09(dd,J＝14.0,6.8Hz,3H),3.04-2.98(m,1H),2.95-2.53(m,12H),2.41(s,3H),2.34(s,3H),2.24-2.07(m,5H),2.06-1.96(m,1H),1.88-1.76(m,3H),1.74-1.66(m,4H),1.62-1.56(m,4H),1.47-1.40(m,2H),1.00(dd,J＝21.1,11.5Hz,2H),0.89(t,J＝6.8Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:989.5265.
ZJ-23的合成：于反应瓶中依次加入IM-13(85mg，0.106mmol)，2-(2,6-二氧代-哌啶-3-基)-4-羟基-异吲哚-1,3-二酮(58mg，0.21mmol)，碳酸氢钾(21mg，0.21mmol)，KI(5mg)，DMF(1.5mL)。然后加热至140℃下反应，TLC监测反应进程。反应完成后降温至80℃，将反应液倒入到水(15mL)中，加入EA(30mL)分两次萃取产物。合并有机相，减压浓缩得到粗品。粗品分离纯化得到黄色固体产物(25mg)，产率：24.0％。1H NMR(400MHz,CDCl3)δ11.16(s,1H),9.33(d,J＝67.1Hz,1H),7.66(t,J＝7.9Hz,1H),7.52-7.41(m,3H),7.39-7.29(m,3H),7.26(s,1H),7.19(d,J＝8.5Hz,2H),5.92(s,1H),5.72(s,1H),4.92(dd,J＝12.1,5.4Hz,1H),4.54(d,J＝5.3Hz,2H),4.05-3.91(m,4H),3.79-3.64(m,2H),3.56(s,4H),3.32(t,J＝9.8Hz,2H),3.09(q,J＝6.9Hz,2H),3.04-2.97(m,1H),2.89-2.80(m,2H),2.78-2.71(m,1H),2.60-2.37(m,7H),2.37-2.28(m,4H),2.22(d,J＝13.2Hz,1H),2.17(s,3H),2.12-1.94(m,5H),1.76-1.67(m,4H),1.45-1.28(m,3H),0.89(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:1002.4742.
ZJ-24的合成：以ZJ-23为起始原料，参考ZJ-18的合成方法。类白色固体，产率：19.2％。1HNMR(600MHz,CDCl3)δ11.63(s,1H),9.44(d,J＝281.7Hz,1H),7.66(t,J＝7.8Hz,1H),7.46(d,J＝7.6Hz,2H),7.43(t,J＝7.7Hz,1H),7.41-7.27(m,4H),7.26-7.24(m,1H),7.19(d,J＝8.4Hz,1H),5.93(s,1H),4.98-4.87(m,1H),4.53(d,J＝4.7Hz,2H),4.06(d,J＝4.7Hz,1H),3.94(t,J＝8.2Hz,3H),3.80-3.44(m,6H),3.32(t,J＝11.2Hz,2H),3.09(d,J＝6.8Hz,2H),3.01(t,J＝10.2Hz,1H),2.87-2.67(m,3H),2.46(s,4H),2.40(s,3H),2.34(d,J＝5.6Hz,3H),2.23(d,J＝6.5Hz,2H),2.17(d,J＝4.3Hz,3H),2.11-2.05(m,1H),2.03-1.91(m,2H),1.90-1.77(m,2H),1.73-1.67(m,4H),1.64-1.56(m,3H),1.18(dd,J＝24.8,12.4Hz,1H),1.05(dd,J＝23.7,11.2Hz,1H),0.98-0.82(m,4H)ppm.HR-MS(m/z)(ESI):[M+Na]+:1004.4899.
ZJ-25的合成：于反应瓶中加入L9(257mg，0.4mmol)，IM-3(220mg，0.38mmol)，三乙胺(240mg，2.37mmol)，DCM(0.5mL)。搅拌溶解澄清后，加入HATU(161mg，0.42mmol)。室温搅拌反应，TLC监测反应进程。反应完成后，减压浓缩得到粗品。粗品柱层析(2～5％MeOH/DCM)分离纯化，得到淡黄色固体产物(173mg)，产率：39.5％。1HNMR(400MHz,CDCl3)δ11.27(s,1H),8.68(s,1H),7.55(t,J＝5.7Hz,1H),7.44(d,J＝8.1Hz,2H),7.37-7.27(m,7H),7.25(s,1H),7.07(t,J＝5.6Hz,1H),6.30(d,J＝8.8Hz,1H),5.90(s,1H),4.75(t,J＝8.1Hz,1H),4.62-4.46(m,5H),4.32(dd,J＝14.9,5.2Hz,1H),4.07(d,J＝11.3Hz,1H),3.94(d,J＝11.1Hz,3H),3.66-3.40(m,7H),3.32(td,J＝11.4,2.7Hz,2H),3.09(q,J＝6.9Hz,2H),3.04-2.97(m,1H),2.58-2.50(m,4H),2.48-2.36(m,8H),2.34(s,3H),2.20-2.13(m,4H),2.10-2.05(m,1H),1.99-1.81(m,4H),1.75-1.66(m,4H),1.62-1.46(m,4H),0.94(s,9H),0.89(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:1160.5984.
ZJ-26的合成：以IM-3和L10为起始原料，参考IM-7-1的合成方法，淡黄色固体，产率：78.0％。1H NMR(400MHz,CDCl3)δ11.45(s,1H),9.32(s,1H),7.47(d,J＝8.0Hz,2H),7.37-7.29(m,4H),7.28(s,1H),7.21(d,J＝7.4Hz,1H),7.13(s,1H),6.76(d,J＝8.0Hz,1H),5.92(s,1H),5.22(dd,J＝13.0,5.1Hz,1H),4.55(d,J＝5.8Hz,2H),4.28(d,J＝15.5Hz,1H),4.11(d,J＝15.5Hz,1H),3.94(d,J＝11.1Hz,2H),3.72(s,1H),3.59(s,2H),3.49(s,2H),3.32(t,J＝10.8Hz,2H),3.22(d,J＝5.9Hz,2H),3.09(dd,J＝13.6,6.6Hz,2H),3.05-2.97(m,1H),2.87-2.73(m,2H),2.62(s,1H),2.53-2.38(m,7H),2.33(s,3H),2.30-2.23(m,1H),2.16(s,4H),1.88(s,2H),1.82-1.64(m,9H),1.62-1.49(m,4H),0.89(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:975.5109.
ZJ-27的合成：于反应瓶中加入IM-8-4(50mg，0.07mmol)，2-(2,6-二氧代-哌啶-3-基)-5,6-二氟-异吲哚-1,3-二酮(42mg，0.14mmol)，DIEA(46mg，0.35mmol)，DMSO(0.5mL)。搅拌溶解后，115℃下搅拌反应，TLC监测反应进程。反应完成后降温至80℃，将反应液倒入到水(10mL)中，加入DCM(10mL)分两次萃取产物。合并有机相，减压浓缩得到粗品。粗品直接柱层析(2～5％MeOH/DCM)分离纯化，得到淡黄色固体产物(35mg)，产率：50.5％。1H NMR(400MHz,CDCl3)δ11.15(s,1H),9.67(s,1H),7.46(d,J＝8.0Hz,2H),7.39(d,J＝9.9Hz,1H),7.37-7.28(m,3H),7.26(s,1H),7.08(d,J＝7.1Hz,1H),7.05-6.97(m,1H),5.94(s,1H),4.90(dd,J＝12.3,5.2Hz,1H),4.76(dd,J＝10.2,5.6Hz,1H),4.60(dd,J＝14.0,6.3Hz,1H),4.50(dd,J＝14.0,5.6Hz,1H),3.95(dJ＝11.3Hz,2H),3.66(s,2H),3.56(s,2H),3.49(s,2H),3.32(t,J＝9.7Hz,2H),3.19(dd,J＝12.2,6.2Hz,2H),3.09(dd,J＝13.7,6.7Hz,2H),3.04-2.97(m,1H),2.91-2.70(m,3H),2.53-2.37(m,7H),2.31(s,3H),2.19(s,3H),2.14-2.08(m,1H),1.89(d,J＝12.1Hz,2H),1.81(d,J＝12.4Hz,2H),1.72-1.53(m,8H),1.12-1.11(m,2H),0.90(t,J＝6.9Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:1007.4801.
ZJ-28的合成：以IM-14为起始物料，参考ZJ-23的合成方法。白色固体产物，产率：12.0％。1H NMR(400MHz,CDCl3)δ11.18(s,1H),9.80(s,1H),7.70-7.65(m,1H),7.60(s,1H),7.54(d,J＝7.2Hz,2H),7.45(d,J＝7.2Hz,1H),7.33(s,1H),7.26-7.24(m,2H),7.21(d,J＝8.5Hz,1H),7.14(s,1H),5.93(s,1H),4.96(dd,J＝12.1,5.3Hz,1H),4.60(dd,J＝14.1,6.1Hz,1H),4.50(dd,J＝14.1,5.6Hz,1H),4.11-3.87(m,6H),3.55(s,1H),3.33(t,J＝10.8Hz,2H),3.27-3.21(m,2H),3.09(dd,J＝13.9,6.9Hz,2H),3.04-2.99(m,1H),2.96-2.71(m,5H),2.42(s,3H),2.41-2.22(m,5H),2.17(s,3H),2.11(dd,J＝9.5,4.2Hz,1H),1.98(s,2H),1.93-1.78(m,6H),1.76-1.62(m,5H),1.56(s,1H),1.19-1.00(m,4H),0.89(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+Na]+:991.4946.
ZJ-29的合成：以IM-16为起始原料，参考ZJ-01的合成方法。黄色固体，产率：51.4％。1H NMR(400MHz,CDCl3)δ11.34(s,1H),9.57(s,1H),7.60(s,2H),7.55-7.43(m,3H),7.32(s,1H),7.26(s,1H),7.15(s,1H),7.09(d,J＝7.0Hz,1H),6.88(d,J＝8.6Hz,1H),6.32(t,J＝5.6Hz,1H),5.92(s,1H),4.93(t,J＝6.1Hz,1H),4.55(qd,J＝14.2,6.0Hz,2H),4.15-3.87(m,4H),3.56(s,1H),3.33(t,J＝10.3Hz,2H),3.22(dd,J＝6.0,1.9Hz,2H),3.15-3.07(m,4H),3.03-2.98(m,1H),2.96-2.69(m,5H),2.51-2.25(m,8H),2.16(s,3H),2.13(dd,J＝8.0,5.3Hz,1H),1.89(d,J＝11.0Hz,4H),1.82(d,J＝11.0Hz,3H),1.74-1.65(m,4H),1.55(s,3H),1.11-0.93(m,4H),0.88(t,J＝7.0Hz,3H)ppm.HR-MS(m/z)(ESI):[M+H]+:968.5281.
ZJ-30的合成：以IM-21为起始原料，参考ZJ-01的缩合合成方法。黄色固体，产率：50.7％。1H NMR(400MHz,MeOD)δ8.61(s,1H),7.96(s,1H),7.84(d,J＝1.0Hz,1H),7.76(d,J＝8.1Hz,2H),7.55-7.49(m,3H),7.02(dd,J＝7.8,5.6Hz,2H),6.15(s,1H),5.05(dd,J＝12.6,5.5Hz,1H),4.86-4.79(m,1H),4.57(s,2H),3.92(s,2H),3.71(s,4H),3.21-3.16(m,2H),2.90-2.60(m,8H),2.42(s,3H),2.24(s,3H),2.13-2.06(m,1H),1.90(d,J＝10.8Hz,2H),1.79(d,J＝11.6Hz,2H),1.65(d,J＝6.7Hz,7H),1.48(dd,J＝23.4,11.9Hz,2H),1.14(dd,J＝23.9,11.2Hz,2H)ppm.HR-MS(m/z)(ESI):[M+Na]+:930.4279.
ZJ-31的合成：以IM-24为起始原料，参考ZJ-01的合成方法。黄色固体，产率：35.5％。1H NMR(400MHz,CDCl3)δ11.57(s,1H),9.07(s,1H),8.55(s,1H),8.01(s,1H),7.91(s,1H),7.67(s,1H),7.62(d,J＝7.9Hz,2H),7.50-7.38(m,3H),7.07(d,J＝7.0Hz,1H),6.86(d,J＝8.6Hz,1H),6.32(t,J＝5.6Hz,1H),5.92(s,1H),4.92(dd,J＝12.0,5.3Hz,1H),4.80(dt,J＝13.3,6.7Hz,1H),4.66-4.57(m,2H),3.67(s,2H),3.35(s,1H),3.22(d,J＝6.3Hz,2H),3.10(t,J＝6.1Hz,2H),2.90-2.70(m,5H),2.42(s,4H),2.33-2.19(m,1H),2.17-2.09(m,4H),1.99(dd,J＝13.1,6.7Hz,2H),1.85(t,J＝12.0Hz,5H),1.71(s,1H),1.65(d,J＝6.7Hz,6H),1.54(s,2H),1.08-0.90(m,4H)ppm.HR-MS(m/z)(ESI):[M+H]+:909.4661.
实施例4：化合物在LY7细胞系中对EZH2蛋白水平的影响
1、实验材料
(1)细胞系及培养方法
| 细胞系 | 肿瘤类型 | 供应商 | 货号 | 生长特点 | 培养方法 |
| OCI-LY7 | Lymphoma | DSMZ | ACC-688 | 悬浮生长 | IMDM+10％FBS |
(2)抗体信息
2、实验方法
(1)细胞全蛋白抽提
收集细胞：将处理后的细胞于培养基中刮下，充分混悬后300g离心5分钟收集，PBS洗一遍后，弃去PBS。
裂解细胞：每一样品加入150μl的2×Loading Buffer，充分震荡混匀，95℃变性15分钟，混匀后于-20℃保存或直接用于Western Blot检测。
(2)Western Blot检测
上样：样品解冻，SDS-PAGE胶中，每孔上样10-20μL。
电泳：1X MES电泳缓冲液中，80伏，30分钟，然后120伏，90分钟。
转膜：利用iBlot2转膜套装及转膜仪转膜，P3程序运行7分钟。
转膜结束后，按所需检测蛋白的分子量大小裁剪膜，5-10mL 1X TBS洗膜，2次，5分钟每次，室温，摇动。
封闭：膜置于封闭液((TBS)封闭液)中封闭，室温，摇动1小时。
5-10mL 1X TBST洗膜，3次，5分钟每次，室温摇动。
孵育一抗：加入5-10mL合适稀释度的一抗(用含0.1％的tween-20的(TBS)封闭液稀释，比例～1:1000)，4℃过夜，缓慢摇动。
5-10mL 1X TBST洗膜，3次，10分钟每次，室温摇动。
孵育二抗：加入5-10mL合适稀释度的二抗(用含0.1％的tween-20的(TBS)封闭液稀释，稀释比例～1:20000)，室温，缓慢摇动1小时。
5-10mL 1X TBST洗膜，3次，10分钟每次，室温摇动。
1X TBS洗膜2次，去除膜上残留的Tween-20。
用Odyssey Clx及其软件Image Studio检测荧光信号值。
3、实验结果
由图1A和B可见，本例中化合物ZJ-02、08、09、11、18、19在100nM和300nM下可以明显诱导细胞中EZH2的降解。
实施例5：化合物ZJ-01～31在肿瘤细胞系中的抗细胞增殖作用
1、实验材料
| 细胞系 | 肿瘤类型 | 供应商 | 货号 | 生长特点 | 培养方法 |
| OCI-LY7 | Lymphoma | DSMZ | ACC-688 | 悬浮生长 | IMDM+10％FBS |
| Mino | Leukemia | ATCC | CRL-3000 | 悬浮生长 | RPMI1640+20％FBS |
2、实验方法
(1)细胞培养，将细胞放在37℃，5％CO2的培养箱中进行培养。定期传代，取处于对数生长期的细胞用于铺板。
(2)细胞铺板，用台盼兰进行细胞染色并计数活细胞，将细胞浓度调整至合适浓度。在培养板中每孔加入90μL细胞悬液，在空白对照空中加入不含细胞的培养液。将培养板在合适培养条件的培养箱中培养过夜。
(3)制备400X化合物存储板：将化合物用DMSO从最高浓度梯度稀释至最低浓度。
(4)10X化合物工作液的配制及化合物处理细胞，在V形底的96孔板中加入78μL细胞培养液，从400X化合物存储板中吸取2μL化合物加入96孔板的细胞培养液中。在溶媒对照和空白对照中加入2μL DMSO。加入化合物或DMSO后用排枪吹打混匀。取10μL的10X化合物工作液按表1所示加入到细胞培养板中。在溶媒对照和空白对照中加入10μLDMSO-细胞培养液混合液。DMSO终浓度为0.25％。将96孔细胞板放回培养箱中培养3天。
(5)按照Promega CellTiter-Glo发光法细胞活性检测试剂盒(Promega-G7573)的说明书来进行。
(6)用下列公式来计算检测化合物的抑制率(Inhibition rate，IR)：IR(％)＝(1–(RLU化合物–RLU空白对照)/(RLU溶媒对照–RLU空白对照)*100％。在Excel中计算不同浓度化合物的抑制率，然后用GraphPad Prism软件作抑制曲线图和计算相关参数，包括曲线底值，曲线顶值及IC50。
3、实验结果
表1.化合物对大B弥漫淋巴瘤细胞系的抑制IC50值
在EZH2野生型的DLBCL细胞系mino细胞和LY7细胞中，化合物ZJ05、07-10、12、14-15、18-22、29与对照化合物Tazemetostat相比，对细胞有更明显的细胞抑制作用，说明降解剂可以用于传统抑制剂无效的细胞系。
实施例6：单次静脉注射或灌胃口服给予ICR小鼠不同化合物的体内药代动力学研究
单次静脉注射或灌胃口服给予ICR小鼠不同化合物后，于不同时间点采集血样，LC-MS/MS测定给予受试物后小鼠血浆中受试物的浓度并计算相关参数。
1、实验动物
种属：ICR小鼠，SPF级；
来源：动物转移自实验机构动物储备库(999M-018)。
2、实验设计
注：*口服给药组动物给药前禁食过夜(10-14小时)，给药4小时后给食。
3、采血时间点
IV：0.083h，0.25h，0.5h，1h，2h，4h，8h，24h；
PO：0.25h，0.5h，1h，2h，4h，6h，8h，24h。
经颌下静脉或其他合适静脉采血，每个样品采集约0.03mL，肝素钠抗凝，采集后放置冰上。
4、血浆样品处理
血液样本采集后置于冰上，并于1小时之内离心分离血浆(离心条件：6800g，6分钟，2-8℃)。血浆样本在分析前存放时则放于-80℃冰箱内。
5、结果分析
通过不同时间点的血药浓度数据，运用PhoenixWinNonlin7.0计算药代动力学参数(含AUC0-t、AUC0-∞、MRT0-∞、Cmax、Tmax、T1/2等参数及其平均值和标准差)。
表2.不同化合物的药代动力学参数
在该实验中，选取实验5中所得优势化合物，进行小鼠的体内药代动力学评价，并与专利CN111303133公开的化合物10进行对比。由表2和图2可见，本发明设计的化合物在小鼠体内的暴露量显著提高，生物利用度也提高到5％左右。
Claims (10)
1.一种PROTAC小分子，其特征在于，具有式I的结构，还包含其立体异构体、几何异构体、药学上可接受的盐或它们的混合物：
P-L-E
I
其中：
P选自X1、X2选自CH或N；
E选自X3选自CH2或C(O)，M1、M2选自NH、O、H或不存在且不相同，M3选自卤素；
L选自 m、n、k选自0～5的整数，p、q选自1或2，Y1、Y2选自N、C或CH且Y1、Y2与所连接的碳形成饱和或不饱和环系，Z选自CH2或C(O)。
2.根据权利要求1所述的PROTAC小分子，其特征在于，所述结构中P选自以下任一的基团：
3.根据权利要求1所述的PROTAC小分子，其特征在于，所述结构中E选自以下任一的基团：
4.根据权利要求1所述的PROTAC小分子，其特征在于，所述结构中L选自以下任一的基团：
5.根据权利要求1所述的PROTAC小分子，其特征在于，选自以下任一的化合物：
6.根据权利要求1所述的PROTAC小分子，其特征在于，所述药学上可接受的盐为所述化合物与选自以下任一的酸形成的盐：
盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸或阿魏酸。
7.一种药物组合物，其特征在于，包含权利要求1所述PROTAC小分子以及药学上可接受的载体。
8.一种权利要求1所述的PROTAC小分子或权利要求7所述的药物组合物在制备降解EZH2或抑制EZH2的药物中的应用。
9.根据权利要求8所述的应用，其特征在于，所述药物为抗肿瘤药物。
10.根据权利要求9所述的应用，其特征在于，所述肿瘤选自霍奇金淋巴瘤、非霍奇金淋巴瘤、弥漫大B细胞淋巴瘤、乳腺癌、前列腺癌或恶性横纹肌瘤。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410213718.2A CN118084881A (zh) | 2024-02-27 | 2024-02-27 | Protac小分子及其药物组合物和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410213718.2A CN118084881A (zh) | 2024-02-27 | 2024-02-27 | Protac小分子及其药物组合物和应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118084881A true CN118084881A (zh) | 2024-05-28 |
Family
ID=91143429
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202410213718.2A Pending CN118084881A (zh) | 2024-02-27 | 2024-02-27 | Protac小分子及其药物组合物和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN118084881A (zh) |
-
2024
- 2024-02-27 CN CN202410213718.2A patent/CN118084881A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20220281815A1 (en) | Cyclopropyl-amide compounds as dual lsd1/hdac inhibitors | |
| EP3761980B1 (en) | Amino acid compounds and methods of use | |
| EP3686196B1 (en) | Polycyclic compound acting as ido inhibitor and/or ido-hdac dual inhibitor | |
| CN112566916B (zh) | 作为pad4抑制剂的经取代的噻吩并吡咯 | |
| JP2018536702A (ja) | Ｔｌｒ７アゴニストとしての７−（チアゾール−５−イル）ピロロピリミジン化合物 | |
| CN112689638B (zh) | 作为lsd1抑制剂的环丙胺类化合物及其应用 | |
| CN114616232A (zh) | 氮杂环庚烷并嘧啶类衍生物及其医药用途 | |
| AU2016284383B2 (en) | Crystal of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1- yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4- hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2Hpyrazino[ 2,1-c][1,2,4]triazine-1-(6H)-carboxamide | |
| CN112300153B (zh) | 一种杂环化合物、药物组合物和用途 | |
| UA125516C2 (uk) | Заміщені діазагетеробіциклічні сполуки та їх застосування | |
| CN112851663B (zh) | 一种并杂环化合物及其用途 | |
| WO2015048567A1 (en) | Spirocyclic ebi2 modulators | |
| CN113024544A (zh) | 一种含氰基并杂环化合物及其用途 | |
| CZ20021906A3 (cs) | Antipikornavirální sloučeniny a kompozice, jejich farmaceutické použití a materiály pro jejich syntézu | |
| CA3217317A1 (en) | Compounds | |
| AU2020410900B2 (en) | Compound used as RET kinase inhibitor and application thereof | |
| EP4079748A1 (en) | Modulators of sortilin activity | |
| CN113387932B (zh) | 一种诱导brd4蛋白降解的双功能化合物 | |
| WO2007039578A1 (en) | Imidazolyl-substituted azabenzophenone compounds | |
| US20240174635A1 (en) | Tlr 9 inhibitors | |
| KR20230031990A (ko) | 인플루엔자의 치료를 위한 오르토믹소바이러스 복제의 억제제로서의 10-(디(페닐)메틸)-4-히드록시-8,9,9a,10-테트라히드로-7h-피롤로[1',2':4,5]피라지노[1,2-b]피리다진-3,5-디온 유도체 및 관련 화합물 | |
| CN114292270B (zh) | 一种btk抑制剂及其制备方法与应用 | |
| CN118084881A (zh) | Protac小分子及其药物组合物和应用 | |
| CN115340502B (zh) | Bcl-xl抑制剂及其制备方法和用途 | |
| CN110092799B (zh) | 一种环状化合物、其制备方法和应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination |