CN116730940A - 杂环取代联苯类化合物及其医药用途 - Google Patents
杂环取代联苯类化合物及其医药用途 Download PDFInfo
- Publication number
- CN116730940A CN116730940A CN202310696498.9A CN202310696498A CN116730940A CN 116730940 A CN116730940 A CN 116730940A CN 202310696498 A CN202310696498 A CN 202310696498A CN 116730940 A CN116730940 A CN 116730940A
- Authority
- CN
- China
- Prior art keywords
- methyl
- oxadiazol
- synthesis
- dmso
- nmr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 biphenyl compound Chemical class 0.000 title claims abstract description 121
- 235000010290 biphenyl Nutrition 0.000 title claims abstract description 13
- 125000000623 heterocyclic group Chemical group 0.000 title claims abstract description 11
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 239000004305 biphenyl Substances 0.000 title claims abstract description 10
- 102100040678 Programmed cell death protein 1 Human genes 0.000 claims abstract description 25
- 108010074708 B7-H1 Antigen Proteins 0.000 claims abstract description 24
- 102000008096 B7-H1 Antigen Human genes 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 230000001394 metastastic effect Effects 0.000 claims description 8
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000012453 solvate Substances 0.000 claims description 6
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 4
- 206010005003 Bladder cancer Diseases 0.000 claims description 4
- 208000037845 Cutaneous squamous cell carcinoma Diseases 0.000 claims description 4
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 4
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 4
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 201000004101 esophageal cancer Diseases 0.000 claims description 4
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 4
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 3
- 201000010106 skin squamous cell carcinoma Diseases 0.000 claims description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 3
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 2
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 claims description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 2
- 208000017604 Hodgkin disease 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
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 2
- 208000033755 Neutrophilic Chronic Leukemia Diseases 0.000 claims description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 2
- 201000010903 chronic neutrophilic leukemia Diseases 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 201000011066 hemangioma Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000001404 mediated effect Effects 0.000 claims description 2
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 2
- 230000037361 pathway Effects 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 101710089372 Programmed cell death protein 1 Proteins 0.000 abstract description 24
- 230000005764 inhibitory process Effects 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- 230000019491 signal transduction Effects 0.000 abstract description 5
- 239000003112 inhibitor Substances 0.000 abstract description 4
- 150000003384 small molecules Chemical class 0.000 abstract description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052794 bromium Chemical group 0.000 abstract description 2
- 230000002503 metabolic effect Effects 0.000 abstract description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 102
- 230000015572 biosynthetic process Effects 0.000 description 88
- 238000003786 synthesis reaction Methods 0.000 description 88
- 239000007787 solid Substances 0.000 description 75
- 238000006243 chemical reaction Methods 0.000 description 73
- 238000000034 method Methods 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- 239000000243 solution Substances 0.000 description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- 239000012074 organic phase Substances 0.000 description 22
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
- 239000007788 liquid Substances 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 238000004440 column chromatography Methods 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 16
- 229960001153 serine Drugs 0.000 description 16
- 239000004576 sand Substances 0.000 description 15
- 206010028980 Neoplasm Diseases 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 230000003993 interaction Effects 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 7
- JHHZLHWJQPUNKB-SCSAIBSYSA-N (3r)-pyrrolidin-3-ol Chemical compound O[C@@H]1CCNC1 JHHZLHWJQPUNKB-SCSAIBSYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- IUNJCFABHJZSKB-UHFFFAOYSA-N 2,4-dihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C(O)=C1 IUNJCFABHJZSKB-UHFFFAOYSA-N 0.000 description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- 108010092262 T-Cell Antigen Receptors Proteins 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000009169 immunotherapy Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 229960002685 biotin Drugs 0.000 description 3
- 239000011616 biotin Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 3
- OZSJLLVVZFTDEY-HJXLNUONSA-N methyl (2s,3r)-2-amino-3-hydroxybutanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)[C@@H](C)O OZSJLLVVZFTDEY-HJXLNUONSA-N 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical group OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- NWPNXBQSRGKSJB-UHFFFAOYSA-N 2-methylbenzonitrile Chemical compound CC1=CC=CC=C1C#N NWPNXBQSRGKSJB-UHFFFAOYSA-N 0.000 description 2
- FNHPUOJKUXFUKN-UHFFFAOYSA-N 3-(bromomethyl)pyridine;hydron;bromide Chemical compound Br.BrCC1=CC=CN=C1 FNHPUOJKUXFUKN-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- JEDPSOYOYVELLZ-UHFFFAOYSA-N COc1nc(OCc2cccc(c2C)-c2ccccc2)ccc1CNCCNC(C)=O Chemical compound COc1nc(OCc2cccc(c2C)-c2ccccc2)ccc1CNCCNC(C)=O JEDPSOYOYVELLZ-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 2
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 2
- 102000008070 Interferon-gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 102000004388 Interleukin-4 Human genes 0.000 description 2
- 108090000978 Interleukin-4 Proteins 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 2
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 150000004074 biphenyls Chemical class 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 229960003130 interferon gamma Drugs 0.000 description 2
- 229940028885 interleukin-4 Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 229940125645 monoclonal antibody drug Drugs 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 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 description 1
- 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
- XYDXDWXAAQXHLK-UHFFFAOYSA-N (3-bromo-2-methylphenyl)methanol Chemical compound CC1=C(Br)C=CC=C1CO XYDXDWXAAQXHLK-UHFFFAOYSA-N 0.000 description 1
- RBLQMXTZTSXCJV-UHFFFAOYSA-N 1-bromo-3-(chloromethyl)-2-methylbenzene Chemical compound CC1=C(Br)C=CC=C1CCl RBLQMXTZTSXCJV-UHFFFAOYSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- STVDCFOBQWMSHN-UHFFFAOYSA-N 2,1,3-benzoxadiazole-5-carbaldehyde Chemical compound C1=C(C=O)C=CC2=NON=C21 STVDCFOBQWMSHN-UHFFFAOYSA-N 0.000 description 1
- HQLILHPGWSURBT-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxy]acetic acid Chemical compound CC(C)(C)OCC(O)=O HQLILHPGWSURBT-UHFFFAOYSA-N 0.000 description 1
- KDGFTIJXTPBJBP-UHFFFAOYSA-N 2-bromo-1-(bromomethyl)-3-iodobenzene Chemical compound BrCC1=CC=CC(I)=C1Br KDGFTIJXTPBJBP-UHFFFAOYSA-N 0.000 description 1
- VJNUZLYTGSGDHR-UHFFFAOYSA-N 2-bromo-3-methylaniline Chemical compound CC1=CC=CC(N)=C1Br VJNUZLYTGSGDHR-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- CVKOOKPNCVYHNY-UHFFFAOYSA-N 3-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=CC(C#N)=C1 CVKOOKPNCVYHNY-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- HAAKSCUEVFJSTN-UHFFFAOYSA-N 3-bromo-2-methylbenzohydrazide Chemical compound CC1=C(Br)C=CC=C1C(=O)NN HAAKSCUEVFJSTN-UHFFFAOYSA-N 0.000 description 1
- BJGKVCKGUBYULR-UHFFFAOYSA-N 3-bromo-2-methylbenzoic acid Chemical compound CC1=C(Br)C=CC=C1C(O)=O BJGKVCKGUBYULR-UHFFFAOYSA-N 0.000 description 1
- VJMRAGHVKBZNAF-UHFFFAOYSA-N 3-bromo-2-methylbenzonitrile Chemical compound CC1=C(Br)C=CC=C1C#N VJMRAGHVKBZNAF-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- AVRWBBOTOYJPNS-UHFFFAOYSA-N 4-[(3-bromo-2-methylphenyl)methoxy]-2-hydroxybenzaldehyde Chemical compound BrC=1C(=C(COC2=CC(=C(C=O)C=C2)O)C=CC=1)C AVRWBBOTOYJPNS-UHFFFAOYSA-N 0.000 description 1
- AMHMRTCZQPWJBD-UHFFFAOYSA-N 4-azido-3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC(C=O)=CC=C1N=[N+]=[N-] AMHMRTCZQPWJBD-UHFFFAOYSA-N 0.000 description 1
- ILKWFRCNNILIJW-UHFFFAOYSA-N 4-fluoro-3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC(C=O)=CC=C1F ILKWFRCNNILIJW-UHFFFAOYSA-N 0.000 description 1
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 1
- BUJFLTNYWUEROF-UHFFFAOYSA-N 5-(bromomethyl)-2,1,3-benzoxadiazole Chemical compound C1=C(CBr)C=CC2=NON=C21 BUJFLTNYWUEROF-UHFFFAOYSA-N 0.000 description 1
- IPOSHVWRFQTHGK-UHFFFAOYSA-N 5-chloro-2,4-dihydroxybenzaldehyde Chemical compound OC1=CC(O)=C(C=O)C=C1Cl IPOSHVWRFQTHGK-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-Serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 description 1
- 229930195711 D-Serine Natural products 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N L-Serine Natural products OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- 125000002842 L-seryl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])O[H] 0.000 description 1
- 102000006833 Multifunctional Enzymes Human genes 0.000 description 1
- 108010047290 Multifunctional Enzymes Proteins 0.000 description 1
- IDPDCMUAENNHDH-UHFFFAOYSA-N O=CC1=CC(Cl)=C(C=C1O)OCC1=CC=CC(=C1Br)I Chemical compound O=CC1=CC(Cl)=C(C=C1O)OCC1=CC=CC(=C1Br)I IDPDCMUAENNHDH-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 description 1
- 101710116241 Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- ISZDEZLLBGJTTF-UHFFFAOYSA-N ethyl 3-bromo-2-methylbenzoate Chemical compound CCOC(=O)C1=CC=CC(Br)=C1C ISZDEZLLBGJTTF-UHFFFAOYSA-N 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 210000003071 memory t lymphocyte Anatomy 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- NDBQJIBNNUJNHA-AENDTGMFSA-N methyl (2r)-2-amino-3-hydroxypropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@H](N)CO NDBQJIBNNUJNHA-AENDTGMFSA-N 0.000 description 1
- NDBQJIBNNUJNHA-DFWYDOINSA-N methyl (2s)-2-amino-3-hydroxypropanoate;hydrochloride Chemical group Cl.COC(=O)[C@@H](N)CO NDBQJIBNNUJNHA-DFWYDOINSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000001483 mobilizing effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- MJFMYCFSWLEPMM-UHFFFAOYSA-N oxadiazol-5-ylmethanol Chemical compound OCC1=CN=NO1 MJFMYCFSWLEPMM-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- XBXHCBLBYQEYTI-UHFFFAOYSA-N piperidin-4-ylmethanol Chemical group OCC1CCNCC1 XBXHCBLBYQEYTI-UHFFFAOYSA-N 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 238000002165 resonance energy transfer Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
本发明公开了一类杂环取代联苯类化合物及其医药用途。本发明的化合物通过在杂环上引入亲水性基团（引硝基或者溴原子），在保持与PD‑L1蛋白高结合率的同时提高了代谢稳定性，使PD‑1/PD‑L1抑制活性得到提高。本发明的化合物可以阻断PD‑1/PD‑L1信号通路，并作为免疫检查点PD‑1/PD‑L1小分子抑制剂。
Description
技术领域
本发明属于药物技术领域，具体涉及一类杂环取代联苯类化合物及其医药用途。
背景技术
近年来肿瘤免疫疗法成为癌症治疗领域中的一大热点，并已逐步发展成为继手术切除、化学药物治疗、放射治疗和靶向治疗后的第五种肿瘤治疗模式。肿瘤免疫疗法通过刺激调动机体的免疫系统，干扰肿瘤微环境，提高机体对肿瘤的免疫力，从而特异性控制和杀伤肿瘤细胞。免疫检查点抑制剂是最成熟的免疫疗法，其中，针对免疫检查点PD-1/PD-L1信号通路的抑制剂是目前研究和应用最广泛的肿瘤免疫治疗药物。
程序性死亡蛋白1(Programmed cell death protein 1，PD-1)是一种经诱导表达的蛋白，即T细胞只有在被激活之后，PD-1才会被诱导表达。活化的T细胞会释放的干扰素γ(IFN-γ)、白细胞介素-4(IL-4)等细胞因子，这些细胞因子会上调PD-L1、PD-L2的表达，PD-L1或PD-L2通过与PD-1结合抑制T细胞抗原受体(TCR)信号通路，配体的结合会导致PD-1胞质域信号转导基序ITIM和ITSM的酪氨酸磷酸化并招募酪氨酸磷酸酶SHP-2，从而降低TCR信号分子的磷酸化，减弱TCR下游的信号刺激，并降低T细胞活化和细胞因子产生(Immunity.2016,44(5):955-972)。PD-1/PD-L1检查点抑制剂通过阻断PD-1与PD-L1的相互作用，解除其相互作用对T细胞受体信号传导的抑制作用，并促进分化为效应T细胞和记忆T细胞，增强特异性抗肿瘤T细胞反应，导致肿瘤的抑制和消除(N Engl J Med.2015,372(4):320-330)。
自2014年以来，国内外已有多款针对PD-1/PD-L1信号通路的单克隆抗体药物上市，PD-1/PD-L1单克隆抗体药物在多种肿瘤的临床治疗中纷纷取得了突破性进展，尤其是黑色素瘤、前列腺癌和非小细胞肺癌等实体肿瘤，可显著延长患者的生存期，部分患者得到完全缓解。虽然靶向PD-1/PD-L1信号通路的单克隆抗体不断取得突破性成果，但也存在对实体瘤响应率低、稳定性较差无法口服、免疫相关不良反应和开发成本高等问题，而小分子具有可口服给药、开发成本较低和更好的组织分布等优势，受到了研究者的青睐，成为了新药开发的热点。
发明内容
本发明的目的在于提供一类对PD-1/PD-L1相互作用有抑制活性的新型杂环取代联苯类化合物，该化合物可作为免疫检查点抑制剂应用于肿瘤免疫治疗。
本发明提供的杂环取代联苯类化合物或其药学上可接受的盐、水合物或溶剂合物，为如下任一种：
本发明“药学上可接受的盐”包括上述所示的杂环取代联苯类化合物与下列酸形成的酸加成盐：盐酸、氢溴酸、硫酸、硝酸、磷酸、甲酸、乙酸、三氟乙酸、乳酸、草酸、己二酸、戊二酸、丙二酸、马来酸、琥珀酸、富马酸、酒石酸、柠檬酸、棕榈酸、苯甲酸、甲磺酸、对甲苯磺酸、水杨酸、苯基乙酸、杏仁酸以及类似的已知可以接受的酸成盐。
本发明的另一目的是上述杂环取代联苯类化合物或其药学上可接受的盐、水合物或溶剂合物在制备用于治疗与PD-1/PD-L1免疫检查点通路介导的疾病的药物中的用途，所述的疾病主要为癌症，包括但不限于：黑色素瘤、非小细胞肺癌、头颈部肿瘤、转移性头颈癌、膀胱癌、转移性膀胱癌、霍奇金病、骨髓瘤、急性淋巴细胞白血病、急性粒细胞白血病、极性早幼粒细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病、慢性嗜中性粒细胞白血病、食管癌、转移性食管癌、皮肤鳞状细胞癌(CSCC)、转移性/局部晚期皮肤鳞状细胞癌、急性髓性白血病、血管瘤、结肠肿瘤、弥漫性大B细胞淋巴瘤。
本发明的目的之三是提供一种药物组合物，包含治疗有效量的上述杂环取代联苯类化合物或其药学上可接受的盐、水合物或溶剂合物，以及药学上可接受的载体。
本发明的化合物通过在联苯结构上引入亲水性基团(引硝基或者溴原子)，在保持与PD-L1蛋白高结合率的同时提高了代谢稳定性，使PD-1/PD-L1抑制活性得到提高。本发明的化合物可以阻断PD-1/PD-L1信号通路，并作为免疫检查点PD-1/PD-L1小分子抑制剂。
具体实施方式
下面将结合实施例对本发明的优选实施方式进行详细说明。需要理解的是以下实施例的给出仅是为了起到说明的目的，并不是用于对本发明的范围进行限制。本领域的技术人员在不背离本发明的宗旨和精神的情况下，可以对本发明进行各种修改和替换。
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。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1
(2S)-2-((2-((3-氰基苄基)氧基)-4-((3'-(5-(羟甲基)-1,2,4-噁二唑-3-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-硝基苄基)氨基)-3-羟基丁酸(I-1)
步骤1：(3-溴-2-甲基苯基)甲醇(I-1B)的合成
将3-溴-2-甲基苯甲酸(I-1A)(10.00g,46.50mmol)溶于无水四氢呋喃(50mL)中，置换氮气，在冰浴条件下，缓慢加入1mol/L的BH3·THF(5.92g,69.75mmol)，待反应稳定后，撤去冰浴，室温条件下继续反应12h。经TLC检测反应完全，在冰浴条件下，缓慢加入甲醇(3mL)直至无气泡产生。将淬灭后的反应液滴加入1mol/L的稀盐酸(100mL)，搅拌充分后，将反应液减压浓缩，加少量水稀释，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩，得白色固体9.35g，收率为100.00％。1H NMR(300MHz,DMSO-d6)δ7.48(d,J＝8.0Hz,1H),7.38(d,J＝7.4Hz,1H),7.11(t,J＝7.8Hz,1H),5.24(s,1H),4.52(s,2H),2.30(s,3H).
步骤2：1-溴-3-(氯甲基)-2-甲基苯(I-1C)的合成
冰浴下，将10mL POCl3滴入I-1B(9.50g，46.50mmol)的35mL N-甲基吡咯烷酮溶液(NMP)，常温搅拌两小时后反应完全，加少量水淬灭多余的POCl3，使用1M碳酸钠溶液调节溶液PH至6-7，乙酸乙酯萃取，无水硫酸钠干燥，柱层析纯化，石油醚直接冲出得透明液体10.256g，产率99％。1H NMR(300MHz,DMSO-d6)δ7.61(d,J＝8.0Hz,1H),7.43(d,J＝7.5Hz,1H),7.14(t,J＝7.8Hz,1H),4.85(s,2H),2.43(s,3H).
步骤3：4-((3-溴-2-甲基苄基)氧基)-2-羟基苯甲醛(I-1D)的合成
将2,4-二羟基苯甲醛(6.44g,46.60mmol)和碳酸氢钠(7.12g,84.74mmol)溶于乙腈(80mL)中，缓慢加入I-1C(9.30g,42.37mmol)的N,N-二甲基甲酰胺(DMF)(10mL)溶液，升温至70℃加热反应8h。经TLC检测反应完全，加少量水稀释，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩制砂，柱层析纯化(石油醚/二氯甲烷＝12/1)，得白色固体7.52g，收率55.26％。1H NMR(300MHz,DMSO-d6)δ10.97(s,1H),10.02(s,1H),7.63(t,J＝8.0Hz,2H),7.44(d,J＝7.4Hz,1H),7.17(t,J＝7.8Hz,1H),6.67(dd,J＝8.7,2.1Hz,1H),6.59(d,J＝2.1Hz,1H),5.22(s,2H),2.37(s,3H).
步骤4：4-((3-溴-2-甲基苄基)氧基)-2-羟基-5-硝基苯甲醛(I-1E)的合成
将I-1D(1.73g,5.39mmol)溶于乙酸(18mL)，在冰浴条件下缓慢加入浓硝酸(18mL)，待反应稳定后，撤去冰浴，室温搅拌反应6h。经TLC检测反应完全，在冰浴条件下，加入适量水，搅拌一段时间后，有大量淡黄色固体析出，抽滤，水洗2遍，滤饼干燥后得到淡黄色固体1.68g，收率为85.18％。1H NMR(300MHz,DMSO-d6)δ10.12(s,1H),8.34(s,1H),7.64(d,J＝7.9Hz,1H),7.54(d,J＝7.7Hz,1H),7.21(t,J＝8.0Hz,1H),6.88(s,1H),5.40(s,2H),2.40(s,3H).
步骤5：3-((5-((3-溴-2-甲基苄基)氧基)-2-甲酰基-4-硝基苯氧基)甲基)苯甲腈(I-1F)的合成
将I-1E(1.68g,4.59mmol)和碳酸钾(1.27g,9.18mmol)溶于DMF(20mL)中，加入3-氰基溴苄(0.99g,5.05mmol)，室温搅拌反应12h。经TLC检测反应完全，加入适量水，搅拌一段时间后，有大量淡黄色固体析出，抽滤，水洗2遍，滤饼干燥后得到未经纯化的淡黄色固体2.30g，直接用于下一步反应。1H NMR(300MHz,DMSO-d6)δ10.25(s,1H),8.33(s,1H),8.08(s,1H),7.94–7.84(m,2H),7.66(t,J＝8.2Hz,2H),7.54(d,J＝7.4Hz,1H),7.29(s,1H),7.20(t,J＝7.8Hz,1H),5.52(d,J＝13.7Hz,4H),2.41(s,3H).
步骤6：3-((2-甲酰基-5-((2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苄基)氧基)-4-硝基苯氧基)甲基)苯甲腈(I-1G)的合成
将I-1F(3.78g,7.85mmol)、联硼酸频那醇酯(3.99g,15.71mmol)、醋酸钾(3.85g,39.27mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(Pd(dppf)Cl2)(0.34g,464.66μmol)溶于1,4-二氧六环(40mL)，置换氮气，油浴加热至100℃反应6h。经TLC检测反应完全，待反应液冷却至室温后，硅藻土抽滤，滤液加水稀释，用乙酸乙酯萃取至水相无荧光，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩制砂，柱层析纯化(石油醚/乙酸乙酯＝2/1)，得黄色固体3.67g，收率88.44％。1H NMR(300MHz,DMSO-d6)δ10.25(s,1H),8.32(s,1H),8.07(s,1H),7.93–7.84(m,2H),7.66(t,J＝7.0Hz,2H),7.58(d,J＝7.7Hz,1H),7.29(s,1H),7.22(t,J＝7.4Hz,1H),5.55(s,2H),5.44(s,2H),2.41(s,3H),1.32(s,12H).
步骤7：(Z)-3-溴-N'-羟基-2-甲基苯甲酰胺(I-1I)的合成
将3-溴-2-甲基苯甲腈(I-1H)(6.00g,30.60mmol)溶于乙醇(60mL)中，依次加入碳酸钾(21.15g,153.02mmol)和盐酸羟胺(8.51g,122.42mmol)的水溶液(12mL)，搅拌充分后，升温至80℃加热8h。经TLC监测反应完全后，将反应液减压浓缩，加水稀释，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤3次后，加入无水硫酸干燥，过滤，滤液经减压蒸馏，得白色固体6.48g，收率为92.37％。1H NMR(300MHz,DMSO-d6)δ9.39(s,1H),7.62(d,J＝7.0Hz,1H),7.26(d,J＝6.7Hz,1H),7.15(t,J＝7.7Hz,1H),5.85(s,2H),2.37(s,3H).
步骤8：(Z)-3-溴-N'-(2-(叔丁氧基)乙酰氧基)-2-甲基苯甲酰胺(I-1J)的合成
将2-(叔丁氧基)乙酸(3.74g,28.29mmol)和HATU(12.91g,33.94mmol)溶于DMF(30mL)中，依次加入N,N-二异丙基乙胺(9.85mL,56.57mmol)和I-1I(6.48g,28.29mmol)，室温条件下反应4h。TLC监测反应完全，加水稀释，用乙酸乙酯萃取直至水相无荧光，收集有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩制砂，柱层析纯化(石油醚/乙酸乙酯＝6/1～3/1)，得白色固体8.58g，收率88.37％。1H NMR(300MHz,DMSO-d6)δ7.71(d,J＝7.1Hz,1H),7.34–7.31(m,1H),7.21(t,J＝6.1Hz,1H),6.92(s,2H),4.15(d,J＝9.1Hz,2H),2.38(s,3H),1.17(s,9H).
步骤9：3-(3-溴-2-甲基苯基)-5-(叔丁氧基甲基)-1,2,4-噁二唑(I-1K)的合成
将I-1J(8.42g,24.53mmol)溶于乙腈(50mL)中，加入乙酸(8.5mL)，加热至70℃回流反应8h。TLC监测反应完全后，加入少量水稀释，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩制砂，柱层析纯化(石油醚/乙酸乙酯＝10/1)，得黄色油状液体5.12g，收率64.18％。1H NMR(300MHz,DMSO-d6)δ7.84(d,J＝8.1Hz,1H),7.81(d,J＝7.8Hz,1H),7.32(dd,J＝9.7,5.9Hz,1H),4.81(s,2H),2.58(s,3H),1.24(s,9H).
步骤10：(3-(3-溴-2-甲基苯基)-1,2,4-噁二唑-5-基)甲醇(I-1L)的合成
将I-1K(5.12g,15.74mmol)溶于二氯甲烷(50mL)，缓慢滴加三氟乙酸(16.7mL)，室温搅拌反应4h。经TLC监测反应完全后，减压浓缩除去二氯甲烷，用饱和碳酸氢钠溶液调pH至7，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤多次后，无水硫酸钠干燥，过滤，滤液经减压蒸馏，得淡黄色固体3.67g，收率86.63％。1H NMR(300MHz,DMSO-d6)δ7.83(t,J＝8.3Hz,2H),7.32(dd,J＝9.9,5.9Hz,1H),6.11(t,J＝6.4Hz,1H),4.82(d,J＝6.4Hz,2H),2.58(s,3H).
步骤11：3-((2-甲酰基-5-((3'-(5-(羟甲基)-1,2,4-噁二唑-3-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-硝基苯氧基)甲基)苯甲腈(I-1M)的合成
将I-1L(0.20g,743.22μmol)、I-1G(0.47g,889.53μmol)、Pd(dppf)Cl2(0.043g,58.77μmol)溶于乙二醇二甲醚(DME)(15mL)中，加入1mol/L的碳酸氢钠(0.20g,2.37mmol)水溶液，置换氮气，油浴加热至90℃反应12h。经TLC检测反应完全，待反应液冷却至室温后，硅藻土抽滤，滤液加水稀释，用乙酸乙酯萃取至水相无荧光，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩制砂，柱层析纯化(石油醚/乙酸乙酯＝1/1)，得黄色固体0.23g，收率53.31％。1H NMR(300MHz,DMSO-d6)δ10.25(s,1H),8.33(s,1H),8.09(s,1H),7.90(dd,J＝13.2,7.8Hz,3H),7.67(t,J＝7.8Hz,1H),7.58(d,J＝7.3Hz,1H),7.47(t,J＝7.7Hz,1H),7.34(dd,J＝11.9,6.1Hz,3H),7.19(d,J＝6.8Hz,1H),6.09(s,1H),5.54(d,J＝8.9Hz,4H),4.82(s,2H),2.18(s,3H),2.06(s,3H).
步骤12：(2S)-2-((2-((3-氰基苄基)氧基)-4-((3'-(5-(羟甲基)-1,2,4-噁二唑-3-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-硝基苄基)氨基)-3-羟基丁酸(I-1)的合成
将L-苏氨酸甲酯盐酸盐(0.046g,271.22μmol)和醋酸钠(0.022g,268.18μmol)溶于甲醇(6mL)和DMF(3mL)的混合溶液中，室温搅拌30分钟后，向反应液中加入I-1M(0.090g,136.43μmol)和醋酸(16μL,279.76μmol)，活化30分钟后，加入氰基硼氢化钠(0.026g,413.74μmol)，在室温条件下继续反应24h。经TLC检测反应完全，加少量水稀释，用乙酸乙酯萃取，合并有机相，用饱和氯化铵溶液洗涤两次，再用饱和食盐水洗涤多次，无水硫酸钠干燥，浓缩制砂，柱层析纯化(二氯甲烷/甲醇＝40/1)，得黄色固体(目标化合物Ⅰ-1的甲酯中间体)0.060g，收率56.61％。将该中间体(0.060g,77.24μmol)和一水合氢氧化锂(0.013g,309.80μmol)溶于甲醇(4mL)和水(1mL)的混合溶剂中，室温搅拌反应12h。经TLC检测反应完全，将反应液减压浓缩，加少量水稀释，用1mol/L的稀盐酸调pH至5，析出黄色固体，抽滤，水洗两遍，滤饼干燥后得黄色固体0.020g，收率49.77％。1H NMR(300MHz,DMSO-d6)δ8.14(s,1H),8.03(s,1H),7.88(dd,J＝14.8,7.1Hz,3H),7.64(t,J＝7.8Hz,1H),7.56(d,J＝7.3Hz,1H),7.46(t,J＝7.7Hz,1H),7.33(t,J＝7.0Hz,2H),7.17(d,J＝9.6Hz,2H),5.41(d,J＝4.8Hz,4H),4.83(s,2H),3.94–3.79(m,3H),2.98(d,J＝4.6Hz,1H),2.18(s,3H),2.04(s,3H),1.13(d,J＝6.1Hz,3H)；HRMS(ESI)m/z:calculated for C37H35N5O9[M+H]+:694.2435,found:694.2505.
实施例2
(2S)-2-((2-((3-氰基苄基)氧基)-4-((3'-(5-(((R)-3-羟基吡咯烷-1-基)甲基)-1,2,4-噁二唑-3-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-硝基苄基)氨基)-3-羟基丁酸(I-2)
步骤1：3-(3-溴-2-甲基苯基)-5-(氯甲基)-1,2,4-噁二唑(I-2A)的合成
参照实施例1中步骤2所述的方法，将I-1C替换成I-1L，制得黄色油状液体2.83g，产率88.28％。1H NMR(300MHz,CDCl3)δ7.82(dd,J＝7.8,0.8Hz,1H),7.72(d,J＝8.0Hz,1H),7.17(t,J＝7.9Hz,1H),4.77(s,2H),2.68(s,3H).
步骤2：(R)-1-(((3-(3-溴-2-甲基苯基)-1,2,4-噁二唑-5-基)甲基)吡咯烷-3-醇(I-2B)的合成
将I-2A(0.20g,695.55μmol)，碳酸钾(0.19g,1.39mmol)和碘化钾(0.012g,69.56μmol)溶于DMF(4mL)中，加入(R)-3-吡咯烷醇(0.061g,695.55μmol)，升温至40℃加热反应2h。经TLC检测反应完全，加少量水稀释，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩制砂，柱层析纯化(石油醚/乙酸乙酯＝1/1)，得黄色油状液体0.13g，收率56.54％。1H NMR(300MHz,CDCl3)δ7.81(d,J＝7.8Hz,1H),7.71(d,J＝8.0Hz,1H),7.16(t,J＝7.9Hz,1H),4.41(ddd,J＝6.5,4.5,2.1Hz,1H),4.12(s,2H),3.12(dd,J＝15.1,8.2Hz,1H),2.98–2.87(m,2H),2.75–2.68(m,1H),2.67(s,3H),2.22(ddt,J＝13.4,8.6,6.6Hz,1H),1.87(dd,J＝13.1,6.5Hz,1H).
步骤3：(R)-3-((2-甲酰基-5-((3'-(5-((3-羟基吡咯烷-1-基)甲基)-1,2,4-噁二唑-3-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-硝基苯氧基)甲基苯甲腈(I-2C)的合成
参照实施例1中步骤11所述的方法，将I-1L替换成I-2B，制得淡黄色固体0.14g，产率36.40％。1H NMR(300MHz,DMSO-d6)δ10.25(s,1H),8.32(s,1H),8.10(s,1H),7.89(dd,J＝16.1,8.8Hz,3H),7.66(t,J＝7.8Hz,1H),7.58(d,J＝6.9Hz,1H),7.46(t,J＝7.7Hz,1H),7.36(d,J＝17.3Hz,3H),7.18(d,J＝6.8Hz,1H),5.57(d,J＝12.2Hz,4H),4.81(s,1H),4.21(s,1H),4.05(s,2H),2.92–2.83(m,1H),2.80–2.72(m,1H),2.66–2.57(m,2H),2.18(s,3H),2.05(s,3H),1.95(d,J＝23.2Hz,1H),1.59(s,1H).
步骤4：(2S)-2-((2-((3-氰基苄基)氧基)-4-((3'-(5-(((R)-3-羟基吡咯烷-1-基)甲基)-1,2,4-噁二唑-3-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-硝基苄基)氨基)-3-羟基丁酸(I-2)的合成
参照实施例1中步骤12所述的方法，将I-1M替换为I-2C,制得黄色固体0.020g，产率33.95％。1H NMR(300MHz,DMSO-d6)δ8.14(s,1H),8.03(s,1H),7.94–7.82(m,3H),7.64(t,J＝7.7Hz,1H),7.56(d,J＝7.3Hz,1H),7.46(t,J＝7.6Hz,1H),7.32(t,J＝7.2Hz,2H),7.24–7.09(m,2H),5.41(d,J＝4.6Hz,4H),4.23(s,1H),4.06(s,2H),3.97–3.80(m,3H),3.03(d,J＝4.6Hz,1H),2.89(dd,J＝9.4,6.2Hz,1H),2.79(dd,J＝15.4,7.8Hz,1H),2.63(dd,J＝13.9,7.9Hz,1H),2.56–2.51(m,1H),2.18(s,3H),2.04(s,3H),1.95(d,J＝14.9Hz,1H),1.58(dd,J＝8.2,4.4Hz,1H),1.14(d,J＝6.1Hz,3H)；HRMS(ESI)m/z:calculated forC41H42N6O9[M+H]+:763.3013,found:763.3089.
实施例3
(R)-3-((2-(((1,3-二羟基-2-(羟基甲基)丙-2-基)氨基)甲基)-5-((3'-(5-((3-羟基吡咯烷-1-基)甲基)-1,2,4-噁二唑-3-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-硝基苯氧基)甲基)苯甲腈(I-3)的合成
将I-2C(0.10g,151.58μmol)溶于甲醇(8mL)和DMF(4mL)的混合溶液中，加入三羟甲基氨基甲烷(0.028g,231.15μmol)和醋酸(9μL,157.36μmol)，活化30分钟后，加入氰基硼氢化钠(0.029g,461.18μmol)，在室温条件下继续反应24h。经TLC检测反应完全，加少量水稀释，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤多次，无水硫酸钠干燥，浓缩制砂，柱层析纯化(二氯甲烷/甲醇＝25/1)，得黄色固体0.043g，收率37.09％。1H NMR(300MHz,DMSO-d6)δ8.09(s,1H),8.00(s,1H),7.87(t,J＝9.4Hz,3H),7.64(t,J＝7.8Hz,1H),7.54(d,J＝7.3Hz,1H),7.46(t,J＝7.7Hz,1H),7.32(dd,J＝6.8,4.9Hz,2H),7.16(d,J＝5.5Hz,2H),5.40(d,J＝13.1Hz,4H),4.80(d,J＝4.1Hz,1H),4.28(d,J＝34.8Hz,4H),4.05(s,2H),3.79(s,2H),3.40(s,6H),2.88(dd,J＝9.5,6.1Hz,1H),2.78(dd,J＝15.3,7.6Hz,1H),2.61(dd,J＝13.8,8.2Hz,1H),2.52(d,J＝3.2Hz,1H),2.18(s,3H),2.04(s,3H),1.96(dd,J＝18.2,10.7Hz,1H),1.64–1.52(m,1H)；HRMS(ESI)m/z:calculated for C41H44N6O9[M+H]+:765.3170,found:765.3241.
实施例4
(2-((3-氰基苄基)氧基)-4-((3'-(5-(((R)-3-羟基吡咯烷-1-基)甲基)-1,2,4-噁二唑-3-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-硝基苄基)-L-丝氨酸(I-4)的合成
参照实施例3所述的方法，将三羟甲基氨基甲烷替换成L-丝氨酸，制得黄色固体0.028g，产率24.67％。1H NMR(300MHz,DMSO-d6)δ8.14(s,1H),8.04(s,1H),7.89(dd,J＝18.6,9.4Hz,3H),7.64(t,J＝7.7Hz,1H),7.55(d,J＝7.2Hz,1H),7.46(t,J＝7.5Hz,1H),7.31(d,J＝7.3Hz,2H),7.26–7.10(m,2H),5.42(d,J＝7.5Hz,4H),4.22(s,1H),4.05(s,2H),3.94(s,2H),3.64(s,3H),3.16(s,1H),2.92–2.83(m,1H),2.77(dd,J＝15.2,7.9Hz,1H),2.61(dd,J＝14.0,8.2Hz,1H),2.52(s,1H),2.18(s,3H),2.04(s,3H),1.98(d,J＝7.3Hz,1H),1.58(s,1H)；HRMS(ESI)m/z:calculated for C40H40N6O9[M+H]+:749.2857,found:749.2929.
实施例5
(2-((3-氰基苄基)氧基)-4-((3'-(5-(((R)-3-羟基吡咯烷-1-基)甲基)-1,2,4-噁二唑-3-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-硝基苄基)-D-丝氨酸(I-5)的合成
参照实施例3所述的方法，将三羟甲基氨基甲烷替换成D-丝氨酸,制得淡黄色固体0.055g，产率40.38％。1H NMR(300MHz,DMSO-d6)δ8.13(s,1H),8.03(s,1H),7.89(dd,J＝16.8,8.5Hz,3H),7.64(t,J＝7.8Hz,1H),7.55(d,J＝7.2Hz,1H),7.46(t,J＝7.6Hz,1H),7.31(d,J＝7.0Hz,2H),7.16(d,J＝10.4Hz,2H),5.41(d,J＝6.3Hz,4H),4.83(s,1H),4.22(s,1H),4.05(s,2H),3.95–3.83(m,2H),3.63(s,3H),3.14(s,1H),2.93–2.84(m,1H),2.78(dd,J＝15.1,7.5Hz,1H),2.61(dd,J＝13.8,8.0Hz,1H),2.52(s,1H),2.18(s,3H),2.04(s,3H),1.97(s,1H),1.58(s,1H)；HRMS(ESI)m/z:calculated for C40H40N6O9[M+H]+:749.2857,found:749.2930.
实施例6
(2S)-2-((2-((3-氰基苄基)氧基)-4-((2,2'-二甲基-3'-(3-(吗啉甲基)-1,2,4-噁二唑-5-基)-[1,1'-联苯]-3-基)甲氧基)-5-硝基苄基)氨基)-3-羟基丁酸(I-6)
步骤1：4-((3-(3-溴-2-甲基苯基)-1,2,4-噁二唑-5-基)甲基)吗啉(I-6A)的合成
参照实施例2中步骤2所述的方法，将(R)-3-吡咯烷醇替换为吗啉，得黄色油状液体0.23g，产率96.07％。1H NMR(300MHz,DMSO-d6)δ7.83(t,J＝6.8Hz,2H),7.32(dd,J＝9.9,5.9Hz,1H),3.99(s,2H),3.66–3.54(m,4H),2.58(s,3H),2.55(d,J＝4.6Hz,4H).
步骤2：3-((5-((2,2'-二甲基-3'-(3-(吗啉甲基)-1,2,4-噁二唑-5-基)-[1,1'-联苯]-3-基)甲氧基)-2-甲酰基-4-硝基苯氧基)甲基)苯甲腈(I-6B)的合成
参照实施例1中步骤11所述的方法，将I-1L替换成I-6A，得黄色固体0.20g，产率49.98％。1H NMR(300MHz,DMSO-d6)δ10.25(s,1H),8.33(s,1H),8.10(s,1H),7.90(dd,J＝13.8,7.3Hz,3H),7.67(t,J＝7.8Hz,1H),7.58(d,J＝7.2Hz,1H),7.47(t,J＝7.7Hz,1H),7.38–7.30(m,3H),7.18(d,J＝7.1Hz,1H),5.54(d,J＝9.1Hz,4H),4.00(s,2H),3.66–3.53(m,4H),2.60–2.54(m,4H),2.18(s,3H),2.05(s,3H).
步骤3：(2S)-2-((2-((3-氰基苄基)氧基)-4-((2,2'-二甲基-3'-(3-(吗啉甲基)-1,2,4-噁二唑-5-基)-[1,1'-联苯]-3-基)甲氧基)-5-硝基苄基)氨基)-3-羟基丁酸(I-6)的合成
参照实施例1中步骤12所述的方法，将I-1M替换为I-6B，制得黄色固体0.020g，收产率40.74％。1H NMR(300MHz,DMSO-d6)δ8.13(s,1H),8.02(s,1H),7.89(d,J＝7.4Hz,3H),7.65(s,1H),7.56(d,J＝6.5Hz,1H),7.45(d,J＝6.9Hz,1H),7.33(s,2H),7.17(s,2H),5.41(s,4H),4.00(s,2H),3.85(dd,J＝31.6,14.5Hz,3H),3.60(s,4H),2.98(s,1H),2.54(d,J＝15.6Hz,4H),2.18(s,3H),2.04(s,3H),1.13(d,J＝5.2Hz,3H)；HRMS(ESI)m/z:calculatedfor C41H42N6O9[M+H]+:763.3013,found:763.3087.
实施例7
(2S)-2-((2-((3-氰基苄基)氧基)-4-((3'-(3-((4-羟基哌啶-1-基)甲基)-1,2,4-噁二唑-5-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-硝基苄基)氨基)-3-羟基丁酸(I-7)
步骤1：1-((3-(3-溴-2-甲基苯基)-1,2,4-噁二唑-5-基)甲基)哌啶-4-醇(I-7A)的合成
参照实施例2中步骤2所述的方法，将(R)-3-吡咯烷醇替换为4-羟基哌啶，得黄色油状液体0.20g，收率80.41％。1H NMR(300MHz,DMSO-d6)δ7.83(t,J＝7.0Hz,2H),7.32(t,J＝7.9Hz,1H),4.59(d,J＝4.1Hz,1H),3.95(s,2H),3.50–3.39(m,1H),2.83–2.73(m,2H),2.58(s,3H),2.28(t,J＝9.4Hz,2H),1.72(d,J＝9.5Hz,2H),1.41(td,J＝12.6,3.4Hz,2H).
步骤2：3-((2-甲酰基-5-((3'-(3-((4-羟基哌啶-1-基)甲基)-1,2,4-噁二唑-5-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-硝基苯氧基甲基)苯甲腈(I-7B)的合成
参照实施例1中步骤11所述的方法，将I-1L替换成I-7A，得黄色固体0.20g，收率52.28％。1H NMR(300MHz,DMSO-d6)δ10.25(s,1H),8.33(s,1H),8.09(s,1H),7.90(dd,J＝14.2,7.5Hz,3H),7.67(t,J＝7.7Hz,1H),7.58(d,J＝7.5Hz,1H),7.46(t,J＝7.7Hz,1H),7.34(t,J＝9.0Hz,3H),7.18(d,J＝7.3Hz,1H),5.54(d,J＝8.8Hz,4H),4.58(d,J＝4.0Hz,1H),3.96(s,2H),3.46(d,J＝4.1Hz,1H),2.85–2.74(m,2H),2.29(t,J＝9.7Hz,2H),2.18(s,3H),2.05(s,3H),1.73(d,J＝9.7Hz,2H),1.42(dd,J＝18.6,9.2Hz,2H).
步骤3：(2S)-2-((2-((3-氰基苄基)氧基)-4-((3'-(3-((4-羟基哌啶-1-基)甲基)-1,2,4-噁二唑-5-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-硝基苄基)氨基)-3-羟基丁酸(I-7)的合成
参照实施例1中步骤12所述的方法，将I-1M替换为I-7B，制得黄色固体0.026g，收率32.28％。1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝13.1Hz,1H),8.03(s,1H),7.97–7.83(m,3H),7.65(t,J＝7.6Hz,1H),7.55(d,J＝7.1Hz,1H),7.46(t,J＝7.5Hz,1H),7.31(d,J＝7.2Hz,2H),7.25–7.12(m,2H),5.41(s,4H),4.00(s,2H),3.88(dd,J＝46.7,13.3Hz,3H),3.47(s,1H),3.19(s,1H),2.81(s,2H),2.35(d,J＝9.5Hz,2H),2.18(s,3H),2.04(s,3H),1.72(s,2H),1.44(d,J＝9.4Hz,2H),1.16(d,J＝5.7Hz,3H)；HRMS(ESI)m/z:calculatedfor C42H44N6O9[M+H]+:777.3170,found:777.3250.
实施例8
(2S)-2-((2-((3-氰基苄基)氧基)-4-((3'-(3-((4-(羟甲基)哌啶-1-基)甲基)-1,2,4-噁二唑-5-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-硝基苄基)氨基)-3-羟基丁酸(I-8)
步骤1：(1-((3-(3-溴-2-甲基苯基)-1,2,4-噁二唑-5-基)甲基)哌啶-4-基)甲醇(I-8A)的合成
参照实施例2中步骤2所述的方法，将(R)-3-吡咯烷醇替换为4-羟甲基哌啶，得无色油状液体0.22g，收率85.57％。1H NMR(300MHz,DMSO-d6)δ7.86–7.79(m,2H),7.32(t,J＝7.9Hz,1H),4.44(t,J＝5.2Hz,1H),3.95(s,2H),3.23(t,J＝5.6Hz,2H),2.90(d,J＝11.1Hz,2H),2.58(s,3H),2.14(t,J＝10.4Hz,2H),1.64(d,J＝12.0Hz,2H),1.32–1.24(m,1H),1.20–1.07(m,2H).
步骤2：3-((2-甲酰基-5-((3'-((4-(羟甲基)哌啶-1-基)甲基)-1,2,4-噁二唑-5-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-硝基苯氧基)甲基苯甲腈(I-8B)的合成
参照实施例1中步骤11所述的方法，将I-1L替换为I-8A，得黄色固体0.32g，收率69.02％。1H NMR(300MHz,DMSO-d6)δ10.25(s,1H),8.33(s,1H),8.09(s,1H),7.90(dd,J＝13.8,7.4Hz,3H),7.67(t,J＝7.3Hz,1H),7.58(d,J＝6.7Hz,1H),7.47(t,J＝7.7Hz,1H),7.34(s,3H),7.18(d,J＝7.2Hz,1H),5.55(d,J＝8.4Hz,4H),4.43(s,1H),3.96(s,2H),3.23(s,2H),2.91(d,J＝11.0Hz,2H),2.18(s,3H),2.12(s,2H),2.05(s,3H),1.65(d,J＝12.3Hz,2H),1.29(s,1H),1.17(s,2H).
步骤3：(2S)-2-((2-((3-氰基苄基)氧基)-4-((3'-(3-((4-(羟甲基)哌啶-1-基)甲基)-1,2,4-噁二唑-5-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-硝基苄基)氨基)-3-羟基丁酸(I-8)的合成
参照实施例1中步骤12所述的方法，将I-1M替换为I-8B，制得黄色固体0.062g，收率63.10％。1H NMR(300MHz,DMSO-d6)δ8.16(s,1H),8.03(s,1H),7.90(d,J＝7.1Hz,3H),7.65(s,1H),7.56(d,J＝5.8Hz,1H),7.46(s,1H),7.32(s,2H),7.19(s,2H),5.42(s,4H),3.98(s,2H),3.92(d,J＝6.4Hz,3H),3.23(d,J＝5.0Hz,2H),3.09(s,1H),2.92(d,J＝9.0Hz,2H),2.18(s,3H),2.17–2.10(m,2H),2.04(s,3H),1.65(d,J＝10.9Hz,2H),1.29(s,1H),1.27–1.18(m,2H),1.15(d,J＝5.4Hz,3H)；HRMS(ESI)m/z:calculated for C43H46N6O9[M+H]+:791.3326,found:791.3404.
实施例9
(2S)-2-((2-((3-氰基苄基)氧基)-4-((3'-(5-(羟甲基)-1,3,4-噁二唑-2-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-硝基苄基)氨基)-3-羟基丁酸(I-9)
步骤1：3-溴-2-甲基苯甲酰肼(I-9B)的合成
将2-甲基-3-溴苯甲酸乙酯(I-9A)(5.00g,21.83mmol)溶于甲醇(30mL)中，缓慢滴加入水合肼(8mL)，升温至80℃反应8h。TLC检测反应完全，待反应液冷却后，将反应液浓缩，加少量水稀释，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩，得白色固体4.98g，收率为99.60％。1H NMR(300MHz,DMSO-d6)δ9.51(s,1H),7.66(dd,J＝7.8,1.1Hz,1H),7.25(dd,J＝7.5,1.1Hz,1H),7.17(t,J＝7.7Hz,1H),4.48(s,2H),2.33(s,3H).
步骤2：3-溴-N'-(2-叔丁氧基)乙酰基)-2-甲基苯甲酰肼(I-9C)的合成
参照实施例1中步骤8所述的方法，将I-1I替换为I-9B,制得黄色油状液体0.91g，收率60.74％。1H NMR(300MHz,DMSO-d6)δ10.10(s,1H),9.66(s,1H),7.71(d,J＝7.7Hz,1H),7.33(d,J＝7.2Hz,1H),7.22(t,J＝7.7Hz,1H),3.93(s,2H),2.42(s,3H),1.21(s,9H).
步骤3：2-(3-溴-2-甲基苯基)-5-(叔丁氧基甲基)-1,3,4-噁二唑(I-9D)的合成
将I-9C(0.91g,2.65mmol)溶于乙腈(10mL)中，依次加入DIPEA(1.39mL,7.95mmol)，对甲苯磺酰氯(1.01g,5.30mmol)，在室温条件下反应12h。TLC检测反应完全，将反应液浓缩，加少量水稀释，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩，残留物经硅胶柱层析纯化(石油醚/乙酸乙酯＝40/1)，得淡黄色油状液体0.73g，收率84.66％。1H NMR(300MHz,DMSO-d6)δ7.89(d,J＝7.5Hz,1H),7.84(d,J＝7.8Hz,1H),7.37(t,J＝7.9Hz,1H),4.72(s,2H),2.68(s,3H),1.24(s,9H).
步骤4：(5-(3-溴-2-甲基苯基)-1,3,4-噁二唑-2-基)甲醇(I-9E)的合成
参照实施例1中步骤10所述的方法，将I-1L替换为I-9D，得淡白色固体0.55g，收率91.05％。1H NMR(300MHz,DMSO-d6)δ7.88(d,J＝8.0Hz,1H),7.85(d,J＝7.9Hz,1H),7.36(t,J＝7.9Hz,1H),5.98(t,J＝6.3Hz,1H),4.73(d,J＝6.2Hz,2H),2.68(s,3H).
步骤5：3-((2-甲酰基-5-((3'-(5-(羟甲基)-1,3,4-噁二唑-2-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-硝基苯氧基)甲基)苯甲腈(I-9F)的合成
参照实施例1中步骤11所述的方法，将I-1L替换为I-9E，得黄色固体0.12g，收率45.56％。1H NMR(300MHz,DMSO-d6)δ10.25(s,1H),8.33(s,1H),8.10(s,1H),7.91(s,3H),7.68(d,J＝7.5Hz,1H),7.59(d,J＝7.2Hz,1H),7.51(s,1H),7.37(d,J＝8.1Hz,3H),7.20(s,1H),5.55(d,J＝7.3Hz,4H),4.74(s,2H),2.27(s,3H),2.05(s,3H).
步骤6：(2S)-2-((2-((3-氰基苄基)氧基)-4-((3'-(5-(羟甲基)-1,3,4-噁二唑-2-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-硝基苄基)氨基)-3-羟基丁酸(I-9)的合成
参照实施例1中步骤12所述的方法，将I-1M替换为I-9F，制得淡黄色固体0.030g，收率51.01％。1H NMR(300MHz,DMSO-d6)δ8.12(s,1H),8.02(s,1H),7.88(dd,J＝12.2,7.8Hz,3H),7.64(t,J＝7.7Hz,1H),7.60–7.52(m,1H),7.49(d,J＝7.7Hz,1H),7.34(dd,J＝11.7,7.1Hz,2H),7.22–7.12(m,2H),5.41(d,J＝3.6Hz,4H),4.74(s,2H),3.89–3.80(m,3H),2.96(d,J＝4.6Hz,1H),2.26(s,3H),2.04(s,3H),1.13(d,J＝6.2Hz,3H)；HRMS(ESI)m/z:calculated forC37H35N5O9[M+H]+:694.2435,found:694.2509.
实施例10
(2S)-2-((2-((3-氰基苄基)氧基)-4-((3'-(5-(((R)-3-羟基吡咯烷-1-基)甲基)-1,3,4-噁二唑-2-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-硝基苄基)氨基)-3-羟基丁酸(I-10)
步骤1：3-溴-N'-(2-氯乙酰基)-2-甲基苯甲酰肼(I-10A)的合成
将I-9B(5.47g,23.88mmol)溶于二氯甲烷(50mL)中，加入DIPEA(8.32mL,47.76mmol)，在冰浴条件下，缓慢滴加氯乙酰氯(2.28mL,28.65mmol)，待反应稳定后，撤去冰浴，在室温条件下继续反应2h。TLC检测反应完全，将反应液浓缩，加少量水稀释，用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩，残留物经硅胶柱层析纯化(二氯甲烷/甲醇＝50/1)，得白色固体3.80g，收率52.08％。1H NMR(300MHz,DMSO-d6)δ10.39(d,J＝15.2Hz,2H),7.72(d,J＝7.9Hz,1H),7.35(d,J＝7.4Hz,1H),7.23(t,J＝7.7Hz,1H),4.20(s,2H),2.41(s,3H).
步骤2：2-(3-溴-2-甲基苯基)-5-(氯甲基)-1,3,4-噁二唑(I-10B)的合成
参照实施例9中步骤3所述的方法，将I-9C替换为I-10A，制得白色固体1.09g，收率79.74％。1H NMR(300MHz,DMSO-d6)δ7.91(d,J＝8.0Hz,1H),7.86(d,J＝7.8Hz,1H),7.37(t,J＝7.9Hz,1H),5.16(s,2H),2.68(s,3H).
步骤3：(R)-1-((5-(3-溴-2-甲基苯基)-1,3,4-噁二唑-2-基)甲基)吡咯烷-3-醇(I-10C)的合成
参照实施例2中步骤2所述的方法，将I-2A替换为I-10B，制得黄色油状液体0.56g，收率95.22％。1H NMR(300MHz,DMSO-d6)δ7.86(dd,J＝10.6,8.0Hz,2H),7.36(t,J＝7.9Hz,1H),4.76(d,J＝3.4Hz,1H),4.20(s,1H),3.96(s,2H),2.85(dd,J＝9.5,6.1Hz,1H),2.78–2.71(m,1H),2.69(s,3H),2.63–2.53(m,1H),2.46–2.23(m,1H),1.99(dq,J＝14.6,7.3Hz,1H),1.56(dt,J＝12.8,8.0Hz,1H).
步骤4：(R)-3-((2-甲酰基-5-((3'-(5-((3-羟基吡咯烷-1-基)甲基)-1,3,4-噁二唑-2-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-硝基苯氧基甲基)苯甲腈(I-10D)的合成
参照实施例1中步骤11所述的方法，将I-1L替换为I-10C，得黄色固体0.30g，收率76.90％。1H NMR(300MHz,DMSO-d6)δ10.24(s,1H),8.32(s,1H),8.09(s,1H),7.89(dd,J＝15.9,7.8Hz,3H),7.66(t,J＝7.7Hz,1H),7.59(d,J＝7.4Hz,1H),7.49(t,J＝7.7Hz,1H),7.35(d,J＝7.2Hz,3H),7.17(d,J＝7.4Hz,1H),5.54(d,J＝7.6Hz,4H),4.78(d,J＝3.7Hz,1H),4.21(s,1H),3.97(s,2H),2.86(dd,J＝9.4,6.2Hz,1H),2.76(dd,J＝15.3,7.7Hz,1H),2.69–2.55(m,2H),2.27(s,3H),2.05(s,3H),1.97(dd,J＝13.8,6.7Hz,1H),1.57(dd,J＝8.2,4.7Hz,1H).
步骤5：(2S)-2-((2-((3-氰基苄基)氧基)-4-((3'-(5-(((R)-3-羟基吡咯烷-1-基)甲基)-1,3,4-噁二唑-2-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-硝基苄基)氨基)-3-羟基丁酸(I-10)的合成
参照实施例1中步骤12所述的方法，将I-1M替换为I-10D，得黄色固体0.085g，收率86.56％。1H NMR(300MHz,DMSO-d6)δ8.14(s,1H),8.03(s,1H),7.96–7.77(m,3H),7.71–7.61(m,1H),7.57(d,J＝7.1Hz,1H),7.54–7.44(m,1H),7.34(s,2H),7.16(d,J＝10.0Hz,2H),5.41(s,4H),4.21(s,1H),3.97(s,2H),3.93–3.78(m,3H),3.01(s,1H),2.87(d,J＝8.7Hz,1H),2.75(d,J＝7.4Hz,1H),2.59(d,J＝5.4Hz,1H),2.26(s,3H),2.04(s,3H),2.01–1.90(m,1H),1.57(s,1H),1.14(d,J＝5.2Hz,3H)；HRMS(ESI)m/z:calculated for C41H42N6O9[M+H]+:763.3013,found:763.3083.
实施例11
(2S)-2-((2-((3-氰基苄基)氧基)-4-((2,2'-二甲基-3'-(5-(吗啉甲基)-1,3,4-噁二唑-2-基)-[1,1'-联苯]-3-基)甲氧基)-5-硝基苄基)氨基)-3-羟基丁酸(I-11)
步骤1：4-((5-(3-溴-2-甲基苯基)-1,3,4-噁二唑-2-基)甲基)吗啉(I-11A)的合成
参照实施例10中步骤3所述的方法，将(R)-3-吡咯烷醇替换为吗啉，得白色固体3.80g，收率52.08％。1H NMR(300MHz,DMSO-d6)δ7.96–7.78(m,2H),7.36(t,J＝7.9Hz,1H),3.91(s,2H),3.59(s,4H),2.68(s,3H),2.51(s,4H).
步骤2：3-((5-((2,2'-二甲基--3'-(5-(吗啉甲基)-1,3,4-噁二唑-2-基)-[1,1'-联苯]-3-基)甲氧基)-2-甲酰基-4-硝基苯氧基)甲基)苯甲腈(I-11B)的合成
参照实施例1中步骤11所述的方法，将I-1L替换为I-11A，制得黄色固体0.14g，收率43.33％。1H NMR(300MHz,DMSO-d6)δ10.25(s,1H),8.33(s,1H),8.10(s,1H),7.90(dd,J＝13.3,6.8Hz,3H),7.67(t,J＝7.7Hz,1H),7.59(d,J＝7.6Hz,1H),7.50(d,J＝7.6Hz,1H),7.35(t,J＝7.7Hz,3H),7.18(d,J＝7.5Hz,1H),5.55(d,J＝7.9Hz,4H),3.91(s,2H),3.61–3.57(m,4H),2.53(s,4H),2.27(s,3H),2.05(s,3H).
步骤3：(2S)-2-((2-((3-氰基苄基)氧基)-4-((2,2'-二甲基-3'-(5-(吗啉甲基)-1,3,4-噁二唑-2-基)-[1,1'-联苯]-3-基)甲氧基)-5-硝基苄基)氨基)-3-羟基丁酸(I-11)的合成
参照实施例1中步骤12所述的方法，将I-1M替换为I-11B，得黄色固体0.015g，收率30.55％。1H NMR(300MHz,DMSO-d6)δ8.14(s,1H),8.03(s,1H),7.94–7.83(m,3H),7.64(t,J＝7.7Hz,1H),7.57(d,J＝7.4Hz,1H),7.50(t,J＝7.7Hz,1H),7.34(dd,J＝12.8,7.3Hz,2H),7.23–7.13(m,2H),5.41(d,J＝3.8Hz,4H),3.96(d,J＝10.6Hz,1H),3.91(s,2H),3.82(d,J＝14.4Hz,2H),3.59(s,4H),2.99(d,J＝4.7Hz,1H),2.53(s,4H),2.26(s,3H),2.04(s,3H),1.14(d,J＝6.1Hz,3H)；HRMS(ESI)m/z:calculated for C41H42N6O9[M+H]+:763.3013,found:763.3012.
实施例12
(S)-1-(3-氯-4-((3'-(5-(羟甲基)-1,3,4-噁二唑-2-基)-2,2'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苄基)哌啶-2-羧酸(I-12)
步骤1：1-((5-(3-溴-2-甲基苯基)-1,3,4-噁二唑-2-基)甲基)哌啶-4-醇(I-12A)的合成
参照实施例10中步骤3所述的方法，将(R)-3-吡咯烷醇替换为4-羟基哌啶，得黄色油状液体0.48g，收率77.72％。1H NMR(300MHz,DMSO-d6)δ7.88(d,J＝8.1Hz,1H),7.84(d,J＝7.9Hz,1H),7.36(t,J＝7.9Hz,1H),4.58(d,J＝4.1Hz,1H),3.87(s,2H),3.44(dt,J＝13.1,4.5Hz,1H),2.80–2.72(m,2H),2.68(s,3H),2.29–2.18(m,2H),1.77–1.64(m,2H),1.46–1.33(m,2H).
步骤2：3-((2-甲酰基-5-((3'-(5-((4-羟基哌啶-1-基)甲基)-1,3,4-噁二唑-2-基)-2,2'-二甲基-[1，1'-联苯]-3-基)甲氧基)-4-硝基苯氧基甲基)苯甲腈(I-12B)的合成
参照实施例1中步骤11所述的方法，将I-1L替换为I-12A，将碳酸氢钠替换为碳酸铯，将DME替换为二氧六环：水(7:1)，制得棕黄色固体0.17g，收率43.92％。1H NMR(300MHz,DMSO-d6)δ10.25(s,1H),8.33(s,1H),8.09(s,1H),7.90(dd,J＝13.9,7.4Hz,3H),7.67(t,J＝7.8Hz,1H),7.59(d,J＝7.4Hz,1H),7.50(t,J＝7.7Hz,1H),7.35(dd,J＝9.1,5.6Hz,3H),7.18(d,J＝7.1Hz,1H),5.54(d,J＝8.2Hz,4H),4.60(d,J＝4.1Hz,1H),3.88(s,2H),3.51–3.42(m,1H),2.77(d,J＝10.9Hz,2H),2.27(s,3H),2.19(d,J＝11.6Hz,2H),2.05(s,3H),1.71(d,J＝
10.0Hz,2H),1.46–1.37(m,2H).
步骤3：(2S)-2-((2-((3-氰基苄基)氧基)-4-((3'-(5-((4-羟基哌啶-1-基)甲基)-1,3,4-噁二唑-2-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-硝基苄基)氨基)-3-羟基丁酸(I-12)的合成
参照实施例1中步骤12所述的方法，将I-1M替换为I-12B，得黄色固体0.015g，收率30.54％。1H NMR(300MHz,DMSO-d6)δ8.04(s,1H),7.99(s,1H),7.87(dd,J＝10.2,8.5Hz,3H),7.65(t,J＝7.7Hz,1H),7.57(d,J＝7.5Hz,1H),7.50(t,J＝7.6Hz,1H),7.39–7.28(m,2H),7.15(d,J＝5.9Hz,2H),5.41(s,4H),3.88(s,2H),3.86–3.74(m,2H),3.61(d,J＝14.6Hz,1H),3.49–3.40(m,1H),3.10(d,J＝4.6Hz,1H),2.83–2.70(m,2H),2.33–2.18(m,5H),2.04(s,3H),1.72(d,J＝9.6Hz,2H),1.48–1.34(m,2H),1.11(d,J＝6.3Hz,3H)；HRMS(ESI)m/z:calculated for C42H44N6O9[M+H]+:777.3170,found:777.3233.
实施例13
(4-((2-溴-3'-(3-(羟甲基)-1,2,4-噁二唑-5-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基苄基)-L-丝氨酸(II-1)
步骤1：2-溴-1-碘-3-甲苯(II-1B)的合成
将2-溴-3-甲基苯胺(II-1A)(5.00g,26.87mmol)溶于适量水中，在冰浴条件下，缓慢滴加盐酸(7.14ml,231.12mmol)，搅拌5分钟后，分四批加入亚硝酸钠(2.23g,32.25mmol)的水溶液，冰浴下反应30分钟。分四批加入碘化钾(8.92g,53.73mmol)的水溶液，撤去冰浴，在室温条件下反应4h。经TLC检测反应完全后，加入饱和硫代硫酸钠溶液，用乙酸乙酯萃取两遍，合并有机相，饱和食盐水洗涤三次，无水硫酸钠干燥，浓缩制砂，柱层析纯化(石油醚/乙酸乙酯＝50/1)，得淡黄色液体7.07g，收率为88.60％。1H NMR(300MHz,DMSO-d6)δ7.77(d,J＝7.4Hz,1H),7.35(d,J＝7.2Hz,1H),7.04(t,J＝7.4Hz,1H),2.45(s,3H).
步骤2：2-溴-1-(溴甲基)-3-碘苯(II-1C)的合成
将II-1B(6.94g,23.37mmol)溶于四氯化碳(80mL)中，加入N-溴代丁二酰亚胺(8.32g,46.74mmol)，搅拌充分后，升温至80℃，趁热分批加入过氧化苯甲酰(1.13g,4.67mmol)，在80℃下继续反应8h，经TLC监测反应完全。将反应液冷却至室温后，加水淬灭，用二氯甲烷萃取直至水相无荧光，合并有机相，饱和食盐水洗涤多遍，加入无水硫酸钠干燥，过滤，滤液经减压浓缩，残留物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝20/1)，得无色透明油状液体6.80g，收率为77.41％。1H NMR(300MHz,DMSO-d6)δ7.92(dd,J＝7.9,1.5Hz,1H),7.62(dd,J＝7.6,1.5Hz,1H),7.15(t,J＝7.7Hz,1H),4.83(s,2H).
步骤3：5-氯-2,4-二羟基苯甲醛(II-1E)的合成
将2,4-二羟基苯甲醛(II-1D)(5.00g,36.20mmol)和N-氯代丁二酰亚胺(5.32g,39.82mmol)溶于乙酸(50mL)中，搅拌充分后，升温至80℃反应8h。TLC检测反应完全后，用1mol/L的稀盐酸调节pH至中性，用乙酸乙酯萃取，收集有机相，用饱和食盐水洗涤数次，无水硫酸钠干燥30分钟后，浓缩制砂，柱层析纯化(石油醚/乙酸乙酯＝40/1)，收集得白色固体3.25g，收率为52.03％。1H NMR(300MHz,DMSO-d6)δ11.39(s,1H),10.87(s,1H),9.97(s,1H),7.59(s,1H),6.58(s,1H).
步骤4：4-((2-溴-3-碘苄基)氧基)-5-氯-2-羟基苯甲醛(II-1F)的合成
将II-1E(1.10g,6.39mmol)溶于乙腈(20mL)中，加入碳酸氢钠(0.89g,10.64mmol)，室温搅拌40分钟后，加入II-1C(2.00g,5.32mmol)，升温至70℃反应2h，经TLC检测反应完全。待反应液冷却后，加入适量水析出白色固体，搅拌10分钟后抽滤，用水洗涤滤饼，干燥后得未经纯化的白色固体粗品2.04g，直接用于下一步反应。1H NMR(300MHz,DMSO-d6)δ9.94(s,1H),7.99(d,J＝7.6Hz,1H),7.81(s,1H),7.69(d,J＝7.3Hz,1H),7.63(d,J＝7.6Hz,1H),7.22(q,J＝7.9Hz,1H),5.30(d,J＝6.7Hz,2H).
步骤5：(3-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-1,2,4-噁二唑-5-基)甲醇(II-1G)的合成
参照实施例1中步骤6所述的方法，将I-1L替换成I-1F，制得黄色油状液体0.24g，产率85.11％。1H NMR(300MHz,DMSO-d6)δ7.88(d,J＝8.1Hz,1H),7.80(d,J＝7.0Hz,1H),7.37(t,J＝7.5Hz,1H),6.07(t,J＝6.3Hz,1H),4.81(d,J＝6.4Hz,2H),2.66(s,3H),1.35(s,12H).
步骤6：4-((2-溴-3'-(3-(羟甲基)-1,2,4-噁二唑-5-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(II-1H)的合成
将II-1F(0.20g,427.82μmol)、II-1G(0.15g,474.44μmol)、Pd(dppf)Cl2(0.031g,42.37μmol)和碳酸钾(0.12g,868.28μmol)溶于1,4-二氧六环(7mL)和水(1mL)的混合溶液中，置换氮气，油浴加热至90℃反应8h。经TLC检测反应完全，待反应液冷却至室温后，硅藻土抽滤，滤液加水稀释，用乙酸乙酯萃取至水相无荧光，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩制砂，柱层析纯化(石油醚/乙酸乙酯＝1/1)，得黄色固体0.20g，收率88.24％。1H NMR(300MHz,DMSO-d6)δ11.23(s,1H),10.06(d,J＝4.3Hz,1H),7.93–7.87(m,1H),7.69(d,J＝10.0Hz,2H),7.58(t,J＝7.6Hz,1H),7.48(t,J＝7.7Hz,1H),7.40(s,2H),6.84(s,1H),6.10(s,1H),5.43–5.24(m,2H),4.83(s,2H),2.21(s,3H).
步骤7：4-((2-溴-3'-(5-(羟甲基)-1,2,4-噁二唑-3-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苯甲醛(II-1I)的合成
将II-1H(0.22g,415.27μmol)和碳酸铯(0.41g,1.26mmol)溶于DMF(3mL)中，加入3-(溴甲基)吡啶氢溴酸盐(0.16g,632.57μmol)，室温搅拌反应12h。经TLC检测反应完全，加入适量水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩制砂，柱层析纯化(石油醚/乙酸乙酯＝1/1)，得黄色固体0.12g，收率46.54％。1H NMR(300MHz,DMSO-d6)δ10.19(s,1H),8.75(d,J＝1.4Hz,1H),8.58(dd,J＝4.7,1.4Hz,1H),7.97(d,J＝7.9Hz,1H),7.90(dd,J＝7.7,1.0Hz,1H),7.73(d,J＝3.9Hz,2H),7.58(t,J＝7.6Hz,1H),7.52–
7.42(m,2H),7.38(dd,J＝12.2,4.6Hz,2H),7.28(s,1H),6.11(t,J＝6.4Hz,1H),5.45(d,J＝14.1Hz,4H),4.83(d,J＝6.4Hz,2H),2.22(s,3H).
步骤8：(4-((2-溴-3'-(3-(羟甲基)-1,2,4-噁二唑-5-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基苄基)-L-丝氨酸(Ⅱ-1)的合成
参照实施例1中步骤12所述的方法，将I-1M替换为II-1I，将L-苏氨酸甲酯盐酸盐替换为L-丝氨酸甲酯盐酸盐，得棕黄色固体0.065g，收率60.26％。1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.54(d,J＝4.0Hz,1H),7.97(d,J＝7.7Hz,1H),7.89(d,J＝7.5Hz,1H),7.68(d,J＝7.3Hz,1H),7.55(t,J＝7.6Hz,1H),7.47(t,J＝7.6Hz,2H),7.41(dd,J＝7.5,4.7Hz,1H),7.34(d,J＝7.4Hz,2H),7.09(s,1H),5.32(s,2H),5.25(s,2H),4.83(s,2H),3.84(s,2H),3.57(d,J＝5.3Hz,3H),3.01(d,J＝5.0Hz,1H),2.21(s,3H)；HRMS(ESI)m/z:calculated for C33H30BrClN4O9[M+H]+:709.0986,found:709.1062.
实施例14
(4-((2溴-2'-甲基-3'-(3-(吗啉甲基)-1,2,4-噁二唑-5-基)-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基苄基)-L-丝氨酸(Ⅱ-2)
步骤1：4-((3-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-1,2,4-噁二唑-5-基)甲基)吗啉(Ⅱ-2A)的合成
参照实施例13中步骤5所述的方法，将I-6A替换成I-1L，制得淡黄色油状液体0.45g，收率99.41％。1H NMR(300MHz,DMSO-d6)δ7.89(d,J＝8.1Hz,1H),7.80(d,J＝7.0Hz,1H),7.36(t,J＝7.5Hz,1H),3.99(s,2H),3.61(d,J＝4.2Hz,4H),2.66(s,3H),2.56(s,4H),1.32(s,12H).
步骤2：4-((2-溴-2'-甲基-3'-(3-(吗啉甲基)-1,2,4-噁二唑-5-基)-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(Ⅱ-2B)的合成
参照实施例13中步骤6所述的方法，将II-1G替换为Ⅱ-2A，得棕黄色固体0.18g，收率28.10％。1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),10.05(d,J＝8.0Hz,1H),7.95–7.90(m,1H),7.72(s,1H),7.70–7.67(m,1H),7.58(t,J＝7.6Hz,1H),7.48(t,J＝7.7Hz,1H),7.39–7.32(m,2H),6.82(s,1H),5.36(s,2H),4.01(s,2H),3.63–3.59(m,4H),2.60–2.55(m,4H),2.23(s,3H).
步骤3：4-((2-溴-2'-甲基-3'-(3-(吗啉甲基)-1,2,4-噁二唑-5-基)-[1,1'-联苯]-3-基)甲氧基)-5-氯-2(吡啶-3-基甲氧基)苯甲醛(II-2C)的合成
参照实施例13中步骤7所述的方法，将II-1H替换为Ⅱ-2B，得淡黄色固体0.15g，收率65.10％。1H NMR(300MHz,DMSO-d6)δ10.19(s,1H),8.75(s,1H),8.58(s,1H),7.95(dd,J＝14.6,7.4Hz,2H),7.72(s,2H),7.58(s,1H),7.47(d,J＝6.5Hz,2H),7.37(s,2H),7.28(s,1H),5.45(d,J＝14.1Hz,4H),4.00(s,2H),3.60(s,4H),2.56(s,4H),2.22(s,3H).
步骤4：(4-((2溴-2'-甲基-3'-(3-(吗啉甲基)-1,2,4-噁二唑-5-基)-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基苄基)-L-丝氨酸(II-2)的合成
参照实施例13中步骤8所述的方法，将II-1I替换为II-2C，得白色固体0.020g，收率15.66％。1H NMR(300MHz,DMSO-d6)δ8.73(s,1H),8.55(d,J＝3.7Hz,1H),7.95(dd,J＝17.6,7.7Hz,2H),7.69(d,J＝7.1Hz,1H),7.60–7.50(m,2H),7.50–7.40(m,2H),7.35(d,J＝7.4Hz,2H),7.12(s,1H),5.31(d,J＝19.1Hz,4H),4.00(s,2H),3.94(s,2H),3.72–3.64(m,2H),3.61(d,J＝4.0Hz,4H),3.15(s,1H),2.57(s,4H),2.22(s,3H)；HRMS(ESI)m/z:calculated for C37H37BrClN5O7[M+H]+:778.1565,found:778.1640.
实施例15
(4-((2-溴-3'-(3-((4-羟基哌啶-1-基)甲基)-1,2,4-噁二唑-5-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基苄基)-L-丝氨酸(II-3)的合成
步骤1：1-((3-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-1,2,4-噁二唑-5-基)甲基)哌啶-4-醇(Ⅱ-3A)的合成
参照实施例13中步骤5所述的方法，将I-6A替换成I-7A，制得黄色油状液体0.59g，收率86.74％。1H NMR(300MHz,DMSO-d6)δ7.89(d,J＝8.1Hz,1H),7.80(d,J＝6.8Hz,1H),7.36(t,J＝7.6Hz,1H),4.59(d,J＝4.0Hz,1H),3.94(s,2H),3.45(d,J＝3.8Hz,1H),2.84–2.73(m,2H),2.65(s,3H),2.28(t,J＝9.6Hz,2H),1.72(d,J＝9.4Hz,2H),1.46–1.37(m,2H),1.32(s,12H).
步骤2：4-((2-溴-3'-(3-((4-羟基哌啶-1-基)甲基)-1,2,4-噁二唑-5-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(Ⅱ-3B)的合成
参照实施例13中步骤6所述的方法，将II-1G替换为Ⅱ-3A，得黄色固体0.056g，收率42.71％。1H NMR(300MHz,DMSO-d6)δ11.20(s,1H),10.06(s,1H),7.92(d,J＝7.3Hz,1H),7.69(d,J＝11.3Hz,2H),7.63–7.54(m,1H),7.48(s,1H),7.37(d,J＝7.5Hz,2H),6.83(s,1H),5.35(s,2H),4.60(s,1H),3.96(s,2H),3.43(s,1H),2.77(s,2H),2.28(s,2H),2.22(s,3H),1.71(s,2H),1.42(d,J＝9.2Hz,2H).
步骤3：4-((2-溴-3'-(3-((4-羟基哌啶-1-基)甲基)-1,2,4-噁二唑-5-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2(吡啶-3-基甲氧基)苯甲醛(II-3C)的合成
参照实施例13中步骤7所述的方法，将II-1H替换为Ⅱ-3B，得黄色固体0.11g，收率47.88％。1H NMR(300MHz,DMSO-d6)δ10.19(s,1H),8.74(s,1H),8.58(d,J＝3.8Hz,1H),7.95(dd,J＝15.2,7.7Hz,2H),7.72(s,2H),7.58(t,J＝7.7Hz,1H),7.51–7.43(m,2H),7.37(t,J＝7.2Hz,2H),7.28(s,1H),5.43(s,J＝14.9Hz,4H),4.59(d,J＝3.5Hz,1H),3.96(s,2H),3.45(s,1H),2.77(t,J＝11.7Hz,2H),2.30(dd,J＝20.1,11.2Hz,2H),2.22(s,3H),1.71(s,2H),1.42(d,J＝9.3Hz,2H).
步骤4：(4-((2-溴-3'-(3-((4-羟基哌啶-1-基)甲基)-1,2,4-噁二唑-5-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基苄基)-L-丝氨酸(II-3)的合成
参照实施例13中步骤8所述的方法，将II-1I替换为II-3C，得黄色固体0.020g，收率24.23％。1H NMR(300MHz,DMSO-d6)δ8.73(s,1H),8.56(s,1H),7.95(dd,J＝20.1,7.4Hz,2H),7.68(s,1H),7.53(s,2H),7.46(d,J＝8.8Hz,2H),7.36(s,2H),7.13(s,1H),5.31(d,J＝18.0Hz,4H),3.96(s,2H),3.67(d,J＝16.5Hz,3H),3.44(s,2H),3.18(s,1H),2.77(s,2H),2.28(s,2H),2.22(s,3H),1.70(s,2H),1.41(d,J＝8.7Hz,2H)；MS(ESI)m/z:calculated for C38H39BrClN5O7[M+H]+:792.2,found:792.2.
实施例16
(4-((2-溴-3'-(3-((4-(羟甲基)哌啶-1-基)甲基)-1,2,4-噁二唑-5-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基苄基)-L-丝氨酸(II-4)
步骤1：(1-((3-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-1,2,4-噁二唑-5-基)甲基)哌啶-4-基)甲醇(II-4A)的合成
参照实施例13中步骤5所述的方法，将I-6A替换成I-8A，得黄色油状液体0.35g，收率77.54％。1H NMR(300MHz,DMSO-d6)δ7.88(d,J＝7.2Hz,1H),7.80(d,J＝7.1Hz,1H),7.37(t,J＝7.6Hz,1H),4.44(s,1H),3.94(s,2H),3.23(s,2H),2.90(d,J＝10.2Hz,2H),2.65(s,3H),2.15(t,J＝10.8Hz,2H),1.64(d,J＝11.8Hz,2H),1.32(s,12H),1.23(s,1H),1.11(d,J＝28.1Hz,2H).
步骤2：4-((2-溴3'-(3-((4-(羟甲基)哌啶-1-基)甲基)-1,2,4-噁二唑-5-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(II-4B)的合成
参照实施例13中步骤6所述的方法，将II-1G替换为Ⅱ-4A，得黄色固体0.23g，收率42.88％。1H NMR(300MHz,DMSO-d6)δ11.17(s,1H),10.06(s,1H),7.92(d,J＝7.0Hz,1H),7.69(d,J＝11.8Hz,2H),7.58(s,1H),7.48(s,1H),7.37(d,J＝7.5Hz,2H),6.82(s,1H),5.35(s,2H),4.44(s,1H),3.96(s,2H),3.23(s,2H),2.91(d,J＝9.2Hz,2H),2.22(s,3H),2.15(t,J＝9.2Hz,2H),1.64(d,J＝11.6Hz,2H),1.29(s,1H),1.15(d,J＝12.1Hz,2H).
步骤3：4-((2-溴-3'-(3-((4-(羟甲基)哌啶-1-基)甲基)-1,2,4-噁二唑-5-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2(吡啶-3-基甲氧基)苯甲醛(II-4C)的合成
参照实施例13中步骤7所述的方法，将II-1H替换为II-4B，得黄色固体0.11g，收率53.44％。1H NMR(300MHz,DMSO-d6)δ10.19(s,1H),8.75(s,1H),8.58(s,1H),7.95(dd,J＝15.2,8.0Hz,2H),7.73(s,2H),7.58(t,J＝7.6Hz,1H),7.47(dd,J＝14.4,7.5Hz,2H),7.37(t,J＝7.4Hz,2H),7.28(s,1H),5.46(d,J＝14.3Hz,4H),4.43(t,J＝5.1Hz,1H),3.96(s,2H),3.23(t,J＝5.5Hz,2H),2.91(d,J＝11.1Hz,2H),2.22(s,3H),2.15(t,J＝11.2Hz,2H),1.64(d,J＝12.5Hz,2H),1.31(d,J＝11.9Hz,1H),1.15(d,J＝10.0Hz,2H).
步骤4：(4-((2-溴-3'-(3-((4-(羟甲基)哌啶-1-基)甲基)-1,2,4-噁二唑-5-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基苄基)-L-丝氨酸(II-4)的合成
参照实施例13中步骤8所述的方法，将II-1I替换为II-4C，得黄色固体0.028g，收率25.90％。1H NMR(300MHz,DMSO-d6)δ8.73(s,1H),8.55(s,1H),7.98(d,J＝7.6Hz,1H),7.92(d,J＝7.6Hz,1H),7.69(d,J＝7.3Hz,1H),7.54(dd,J＝15.4,7.2Hz,2H),7.44(dd,J＝14.3,7.9Hz,2H),7.35(d,J＝7.3Hz,2H),7.13(s,1H),5.31(d,J＝18.5Hz,4H),3.96(s,2H),3.72–3.60(m,4H),3.23(d,J＝5.9Hz,2H),3.16(s,1H),2.91(d,J＝10.5Hz,2H),2.22(s,3H),2.13(d,J＝10.6Hz,2H),1.64(d,J＝11.6Hz,2H),1.31(d,J＝11.5Hz,1H),1.15(d,J＝9.8Hz,2H)；MS(ESI)m/z:calculated for C39H41BrClN5O7[M+H]+:806.2,found:806.6.
实施例17
(4-((2-溴-3'-(5-(羟甲基)-1,3,4-噁二唑-2-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基苄基)-L-丝氨酸(II-5)
步骤1：(5-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-1,3,4-噁二唑-2-基)甲醇(II-5A)的合成
参照实施例13中步骤5所述的方法，将I-6A替换成I-9E，得无色油状液体0.10g，收率56.74％。1H NMR(300MHz,DMSO-d6)δ7.95–7.88(m,1H),7.88–7.81(m,1H),7.41(t,J＝7.7Hz,1H),5.95(dd,J＝7.1,5.4Hz,1H),4.72(d,J＝6.3Hz,2H),2.75(s,2H),1.36(s,12H).
步骤2：4-((2-溴-3'-(5-(羟甲基)-1,3,4-噁二唑-2-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(II-5B)的合成
参照实施例13中步骤6所述的方法，将II-1G替换为Ⅱ-5A，得黄色固体0.20g，收率35.30％。1H NMR(300MHz,DMSO-d6)δ11.18(s,1H),10.06(s,1H),7.92(d,J＝7.8Hz,1H),7.70(d,J＝10.0Hz,2H),7.59(t,J＝7.6Hz,1H),7.53(t,J＝7.8Hz,1H),7.38(d,J＝7.9Hz,2H),6.82(s,1H),5.98(t,J＝6.2Hz,1H),5.36(s,2H),4.74(d,J＝6.2Hz,2H),2.29(d,J＝10.1Hz,3H).
步骤3：4-((2-溴-3'-(5-(羟甲基)-1,3,4-噁二唑-2-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2(吡啶-3-基甲氧基)苯甲醛(II-5C)的合成
参照实施例13中步骤7所述的方法，将II-1H替换为II-5B，得黄色固体0.12g，收率56.88％。1H NMR(300MHz,DMSO-d6)δ10.19(s,1H),8.75(s,1H),8.58(d,J＝3.6Hz,1H),7.95(dd,J＝15.8,7.3Hz,2H),7.74(d,J＝6.6Hz,2H),7.59(t,J＝7.6Hz,1H),7.56–7.43(m,2H),7.43–7.37(m,2H),7.29(s,1H),5.98(t,J＝6.3Hz,1H),5.46(d,J＝14.1Hz,4H),4.74(d,J＝6.3Hz,2H),2.30(s,3H).
步骤4：(4-((2-溴-3'-(5-(羟甲基)-1,3,4-噁二唑-2-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基苄基)-L-丝氨酸(II-5)的合成
参照实施例13中步骤8所述的方法，将II-1I替换为II-5C，得白色固体0.023g，收率42.64％。1H NMR(300MHz,DMSO-d6)δ8.73(s,1H),8.55(d,J＝3.7Hz,1H),7.98(d,J＝7.8Hz,1H),7.92(d,J＝7.4Hz,1H),7.70(d,J＝7.1Hz,1H),7.61–7.48(m,3H),7.40(dt,J＝16.3,6.5Hz,3H),7.13(s,1H),5.31(d,J＝18.3Hz,4H),4.74(s,2H),3.97(s,2H),3.66(ddd,J＝17.1,10.9,6.4Hz,3H),3.18(t,J＝5.1Hz,1H),2.30(s,3H)；HRMS(ESI)m/z:calculated for C33H30BrClN4O9[M+H]+:709.0986,found:709.1059.
实施例18
(4-((2-溴-3'-(5-(((R)-3-羟基吡咯烷-1-基)甲基)-1,3,4-噁二唑-2-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基苄基)-L-丝氨酸(II-6)
步骤1：(R)-1-((5-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-1,3,4-噁二唑-2-基)甲基)吡咯烷-3-醇(II-6A)的合成
参照实施例13中步骤5所述的方法，将I-6A替换成I-10C，得棕黄色油状液体0.060g，收率52.67％。1H NMR(300MHz,DMSO-d6)δ7.90(d,J＝7.0Hz,1H),7.83(d,J＝7.1Hz,1H),7.40(t,J＝7.6Hz,1H),4.77(d,J＝4.4Hz,1H),4.20(d,J＝3.0Hz,1H),3.95(s,2H),2.85(dd,J＝9.5,6.1Hz,1H),2.74(s,3H),2.70(d,J＝4.5Hz,1H),2.63–2.55(m,1H),2.44(t,J＝8.4Hz,1H),2.01–1.89(m,1H),1.56(dd,J＝8.5,5.0Hz,1H),1.33(s,12H).
步骤2：(R)-4-((2-溴-3'-(5-((3-羟基吡咯烷-1-基)甲基)-1,3,4-噁二唑-2-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(II-6B)的合成
参照实施例13中步骤6所述的方法，将II-1G替换为Ⅱ-6A，得黄色固体0.15g，收率32.08％。1H NMR(300MHz,DMSO-d6)δ11.18(s,1H),10.06(s,1H),7.92(d,J＝8.0Hz,1H),7.70(d,J＝10.8Hz,2H),7.59(t,J＝7.5Hz,1H),7.51(d,J＝7.7Hz,1H),7.43–7.34(m,2H),6.82(s,1H),5.36(s,2H),4.76(d,J＝4.3Hz,1H),4.21(s,1H),3.98(s,2H),2.86(dd,J＝9.5,6.1Hz,1H),2.74(t,J＝7.4Hz,1H),2.63–2.56(m,1H),2.46(s,1H),2.30(s,3H),2.02(dd,J＝13.3,5.7Hz,1H),1.57(d,J＝3.2Hz,1H).
步骤3：(R)-4-((2-溴-3'-(5-((3-羟基吡咯烷-1-基)甲基)-1,3,4-噁二唑-2-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2(吡啶-3-基甲氧基)苯甲醛(II-6C)的合成
参照实施例13中步骤7所述的方法，将II-1H替换为II-6B，得黄色固体0.10g，收率66.77％。1H NMR(300MHz,DMSO-d6)δ10.19(s,1H),8.74(s,1H),8.57(d,J＝3.7Hz,1H),7.95(dd,J＝15.1,7.8Hz,2H),7.73(d,J＝6.3Hz,2H),7.62–7.56(m,1H),7.52–7.45(m,2H),7.42–7.36(m,2H),7.28(s,1H),5.46(d,J＝14.3Hz,4H),4.77(d,J＝4.2Hz,1H),4.22(s,1H),3.98(s,2H),2.86(dd,J＝9.5,6.0Hz,1H),2.76(dd,J＝15.3,7.7Hz,1H),2.65–2.55(m,1H),2.30(s,3H),2.21(d,J＝25.0Hz,1H),2.07–1.95(m,1H),1.57(s,1H).
步骤4：(4-((2-溴-3'-(5-(((R)-3-羟基吡咯烷-1-基)甲基)-1,3,4-噁二唑-2-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基苄基)-L-丝氨酸(II-6)的合成
参照实施例13中步骤8所述的方法，将II-1I替换为II-6C，得白色固体0.057g，收率78.41％。1H NMR(300MHz,DMSO-d6)δ8.73(s,1H),8.55(d,J＝3.7Hz,1H),7.94(dd,J＝15.1,7.9Hz,2H),7.70(d,J＝7.2Hz,1H),7.54(dd,J＝19.1,9.8Hz,3H),7.46–7.31(m,3H),7.14(s,1H),5.31(d,J＝20.2Hz,4H),4.22(s,1H),4.02(s,2H),3.73(dd,J＝16.6,6.6Hz,3H),3.36(s,1H),2.88(dd,J＝9.1,6.0Hz,1H),2.78(dd,J＝15.2,7.6Hz,1H),2.63(dd,J＝13.6,7.9Hz,1H),2.52(s,1H),2.30(s,3H),2.00(dd,J＝12.8,6.9Hz,1H),1.59(s,1H)；HRMS(ESI)m/z:calculated for C37H37BrClN5O7[M+H]+:778.1565,found:778.1636.
实施例19
(4-((2-溴-2'-甲基-3'-(5-(吗啉甲基)-1,3,4-噁二唑-2-基)-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基苄基)-L-丝氨酸(II-7)的合成
步骤1：4-((5-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-1,3,4-噁二唑-2-基)甲基)吗啉(II-7A)的合成
参照实施例13中步骤5所述的方法，将I-6A替换成I-11A，得无色油状液体1.03g，收率80.02％。1H NMR(300MHz,DMSO-d6)δ7.90(d,J＝7.7Hz,1H),7.83(d,J＝7.4Hz,1H),7.40(t,J＝7.5Hz,1H),3.90(s,2H),3.59(s,4H),2.73(s,3H),2.51(s,4H),1.32(s,12H).
步骤2：4-((2-溴-2'-甲基-3'-(5-(吗啉甲基)-1,3,4-噁二唑-2-基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(II-7B)的合成
参照实施例13中步骤6所述的方法，将II-1G替换为Ⅱ-7A，得黄色固体0.12g，收率29.27％。1H NMR(300MHz,DMSO-d6)δ11.16(s,1H),10.05(d,J＝8.0Hz,1H),7.95–7.90(m,1H),7.72(s,1H),7.70–7.67(m,1H),7.58(t,J＝7.6Hz,1H),7.48(t,J＝7.7Hz,1H),7.39–7.32(m,2H),6.82(s,1H),5.36(s,2H),4.01(s,2H),3.63–3.59(m,4H),2.60–2.55(m,4H),2.23(s,3H).
步骤3：4-((2-溴-2'-甲基-3'-(5-(吗啉甲基)-1,3,4-噁二唑-2-基)-[1,1'-联苯]-3-基)甲氧基)-5-氯-2(吡啶-3-基甲氧基)苯甲醛(II-7C)的合成
参照实施例13中步骤7所述的方法，将II-1H替换为II-7B，得黄色固体0.088g，收率36.37％。1H NMR(300MHz,DMSO-d6)δ10.19(s,1H),8.74(s,1H),8.57(d,J＝3.3Hz,1H),7.95(dd,J＝15.3,7.3Hz,2H),7.73(d,J＝6.5Hz,2H),7.56(dt,J＝18.8,7.7Hz,2H),7.46(dd,J＝7.4,4.8Hz,1H),7.39(t,J＝6.4Hz,2H),7.28(s,1H),5.45(d,J＝14.2Hz,4H),3.91(s,2H),3.62–3.56(m,4H),2.56–2.51(m,4H),2.30(s,3H).
步骤4：(4-((2-溴-2'-甲基-3'-(5-(吗啉甲基)-1,3,4-噁二唑-2-基)-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基苄基)-L-丝氨酸(II-7)的合成
参照实施例13中步骤8所述的方法，将II-1I替换为II-7C，得棕黄色固体0.20g，收率96.95％。1H NMR(300MHz,DMSO-d6)δ8.72(s,1H),8.53(d,J＝4.0Hz,1H),7.99(d,J＝7.7Hz,1H),7.90(d,J＝7.6Hz,1H),7.68(d,J＝7.2Hz,1H),7.51(dd,J＝12.6,8.2Hz,3H),7.38(td,J＝12.2,7.5Hz,3H),7.13(s,1H),5.33(s,2H),5.25(s,2H),3.99(s,2H),3.90(s,2H),3.69(s,1H),3.63(s,1H),3.57(s,4H),3.17(s,1H),2.49(s,3H),2.28(s,3H)；HRMS(ESI)m/z:calculated for C37H37BrClN5O7[M+H]+:778.1565,found:778.1637.
实施例20
(2-(苯并[c][1,2,5]噁二唑-5-基甲氧基)-4-((2-溴-3'-(5-(羟甲基)-1,3,4-噁二唑-2-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯苯基)-D-丝氨酸(II-8)
步骤1：4-氟-3-硝基苯甲醛(II-8B)的合成
将对氟苯甲醛(II-8A)(6.00g,48.34mmol)溶于硫酸(24mL)，在冰浴条件下缓慢加入浓硝酸(3mL)，待反应稳定后，撤去冰浴，室温搅拌反应2h。经TLC检测反应完全，在冰浴条件下，加入适量水，搅拌一段时间后，有大量白色固体析出，抽滤，水洗2遍，滤饼干燥后得到白色固体5.40g，收率为66.05％。1H NMR(300MHz,DMSO-d6)δ10.07(s,1H),8.68(dd,J＝7.4,2.0Hz,1H),8.33(ddd,J＝8.6,4.4,2.1Hz,1H),7.83(dd,J＝11.1,8.6Hz,1H).
步骤2：4-叠氮-3-硝基苯甲醛(II-8C)的合成
将II-8B(3.00g,17.74mmol)溶于DMSO(20mL)，分批缓慢加入叠氮化钠(1.50g,23.06mmol)，室温搅拌反应2h。经TLC检测反应完全，用饱和碳酸氢钠溶液调pH至9，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤多次，无水硫酸钠干燥，得到未经纯化的黄色固体3.40g，直接用于下一步反应。
步骤3：苯并[c][1,2,5]噁二唑-5-甲醛(II-8D)的合成
将II-8C(3.40g,17.70mmol)溶于甲苯(30mL)，升温至110℃反应6h。经TLC检测反应完全，将反应液浓缩，得暗黄色固体2.74g(中间体II-8D的中间体)。将该中间体溶于乙醇(30mL)，加入三苯基膦(3.39g,12.92mmol)，升温至70℃反应2h，TLC检测反应完全。待反应液冷却至室温，浓缩制砂，柱层析纯化(石油醚/乙酸乙酯＝30/1)，得到黄色固体2.01g，收率为76.68％。
步骤4：苯并[c][1,2,5]噁二唑-5-基甲醇(II-8E)的合成
将II-8D(3.09g,20.84mmol)溶于甲醇(15mL)和四氢呋喃(3mL)的混合溶液中，在冰浴条件下，缓慢加入硼氢化钠(0.89g,23.00mmol)，在室温条件下继续反应1h。经TLC检测反应完全，加少量水稀释，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤多次，无水硫酸钠干燥，浓缩制砂，柱层析纯化(石油醚/乙酸乙酯＝20/1)，得白色固体1.96g，收率62.64％。1H NMR(300MHz,DMSO-d6)δ8.00(d,J＝9.3Hz,1H),7.83(s,1H),7.51(dd,J＝9.3,1.0Hz,1H),5.62(t,J＝5.3Hz,1H),4.62(d,J＝3.7Hz,2H).
步骤5：5-(溴甲基)苯并[c][1,2,5]噁二唑(II-8F)的合成
将II-8E(0.80g,5.33mmol)和三苯基膦(2.80g,10.66mmol)溶于无水四氢呋喃(10mL)，在冰浴条件下，缓慢加入四溴化碳(3.53g,10.66mmol)，在室温条件下继续反应4h。经TLC检测反应完全，加少量水稀释，硅藻土抽滤，滤液加水稀释，用乙酸乙酯萃取至水相无荧光，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩制砂，柱层析纯化(石油醚/乙酸乙酯＝10/1)，得黄色固体0.75g，收率66.07％。1H NMR(300MHz,DMSO-d6)δ8.15(s,1H),8.09(d,J＝9.4Hz,1H),7.63(dd,J＝9.3,1.2Hz,1H),4.83(s,2H).
步骤6：2-(苯并[c][1,2,5]噁二唑-5-基甲氧基)-4-((2-溴-3'-(5-(羟甲基)-1,3,4-噁二唑-2-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基]-5-氯苯甲醛(II-8G)的合成
参照实施例13中步骤7所述的方法，将II-1H替换为II-6B，将3-(溴甲基)吡啶氢溴酸盐替换为II-8F，得黄色固体0.12g，收率56.88％。1H NMR(300MHz,DMSO-d6)δ10.19(s,1H),8.75(s,1H),8.58(d,J＝3.6Hz,1H),7.95(dd,J＝15.8,7.3Hz,2H),7.74(d,J＝6.6Hz,2H),7.59(t,J＝7.6Hz,1H),7.56–7.43(m,2H),7.43–7.37(m,2H),7.29(s,1H),5.98(t,J＝6.3Hz,1H),5.46(d,J＝14.1Hz,4H),4.74(d,J＝6.3Hz,2H),2.30(s,3H).
步骤7：(2-(苯并[c][1,2,5]噁二唑-5-基甲氧基)-4-((2-溴-3'-(5-(羟甲基)-1,3,4-噁二唑-2-基)-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯苯基)-D-丝氨酸(II-8)的合成
参照实施例1中步骤12所述的方法，将I-1M替换为II-8G，将L-苏氨酸甲酯盐酸盐替换为D-丝氨酸甲酯盐酸盐，得淡黄色固体0.070g，收率89.13％。1H NMR(300MHz,DMSO-d6)δ8.17(s,1H),8.08(d,J＝9.4Hz,1H),7.92(d,J＝7.8Hz,1H),7.78–7.63(m,2H),7.60–7.45(m,3H),7.42–7.29(m,2H),7.12(s,1H),5.36(d,J＝21.7Hz,4H),4.74(s,2H),4.02(s,2H),3.79–3.57(m,3H),3.20(s,1H),2.29(s,3H)；HRMS(ESI)m/z:calculated forC34H29BrClN5O8[M+H]+:750.0888,found:750.0959.
实施例21
(2-(苯并[c][1,2,5]噁二唑-5-基甲氧基)-4-((2-溴-2'-甲基-3'-(5-(吗啉甲基)-1,3,4-噁二唑-2-基)-[1,1'-联苯]-3-基)甲氧基)-5-氯苯基)-D-丝氨酸(II-9)
步骤1：2-(苯并[c][1,2,5]噁二唑-5-基甲氧基)-4-((2-溴-2'-甲基-3'-(5-(吗啉甲基)-1,3,4-噁二唑-2-基)-[1,1'-联苯]-3-基)甲氧基)-5-氯苯甲醛(II-9A)的合成
参照实施例20中步骤6所述的方法，将II-6B替换为II-7B，得淡黄色固体0.16g，收率87.39％。1H NMR(400MHz,DMSO-d6)δ10.31(d,J＝11.7Hz,1H),8.22(s,1H),8.12(d,J＝9.3Hz,1H),7.92(dd,J＝7.8,1.2Hz,1H),7.77(s,1H),7.71(d,J＝8.3Hz,2H),7.55(t,J＝7.6Hz,1H),7.49(t,J＝7.6Hz,1H),7.36(dd,J＝9.7,3.9Hz,2H),7.26(s,1H),5.58–5.50(m,2H),5.50–5.42(m,2H),4.00(s,2H),3.64–3.57(m,4H),2.61–2.52(m,4H),2.22(d,J＝5.3Hz,3H).
步骤2：(2-(苯并[c][1,2,5]噁二唑-5-基甲氧基)-4-((2-溴-2'-甲基-3'-(5-(吗啉甲基)-1,3,4-噁二唑-2-基)-[1,1'-联苯]-3-基)甲氧基)-5-氯苯基)-D-丝氨酸(II-9)的合成
参照实施例20中步骤7所述的方法，将II-8G替换为II-9A，得淡黄色固体0.048g，收率80.03％。1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),8.09(d,J＝9.3Hz,1H),7.93(d,J＝7.8Hz,1H),7.71(dd,J＝14.9,8.5Hz,2H),7.54(dd,J＝15.0,7.4Hz,3H),7.35(dt,J＝17.5,8.7Hz,2H),7.13(s,1H),5.41(s,2H),5.33(s,2H),4.06(s,2H),3.92(s,2H),3.77–3.71(m,1H),3.69–3.64(m,1H),3.59(d,J＝4.5Hz,4H),3.30–3.25(m,1H),2.56–2.51(m,4H),2.29(s,3H)；HRMS(ESI)m/z:calculated for C38H36BrClN6O8[M+H]+:819.1467,found:819.1541.
实施例22
本发明化合物对PD-1/PD-L1相互作用的抑制活性
1.实验目的：利用时间分辨荧光共振能量转移(time-resolved fuorescenceresonance energy transfer,TR-FRET)技术，检测化合物抑制PD-1和PD-L1相互作用的活性。
2.实验材料：PD-1-Eu、PD-L1-Biotin和Dye labeled acceptor购自BPSBioscience公司；阳性药BMS-202购自Selleckchem公司；384well microplate购自PerkinElmer公司。
3.实验仪器：Eppendorf 5430离心机；Perkin Elmer EnVision多功能酶标检测仪。
4.实验方法：
(1)配制1×modified TR-FRET assay buffer。
(2)化合物浓度梯度的配制：设立阴性对照组、阳性对照组和给药组，每组3个复孔。化合物以1000nM起始，3倍稀释，8～10个浓度点。在384孔板中用DMSO稀释成100倍终浓度的溶液，然后用Echo550转移200nL到384反应板中备用。阴性对照孔和阳性对照孔中分别加200nL的100％ DMSO。
(3)用1×modified TR-FRET assay buffer配制4倍终浓度的PD-L1-Biotin溶液。
(4)在化合物孔和阳性对照孔分别加5μL的4倍终浓度的PD-L1-Biotin溶液；在阴性对照孔中加5μL的1×modified TR-FRET assay buffer。
(5)1000rpm离心30秒，振荡混匀后室温孵育15分钟。
(6)用1×modified TR-FRET assay buffer配制4倍终浓度的PD-1-Eu和2倍终浓度的Dye labeled acceptor混合溶液。
(7)加入15μL PD-1-Eu和Dye labeled acceptor混合溶液(其中含5μL的4倍终浓度的PD-1-Eu和10μL 2倍终浓度的Dye labeled acceptor)。
(8)1000rpm离心30秒，振荡混匀后室温孵育90分钟。
(9)将384孔板1000rpm离心30秒，振荡混匀后用EnVision读取665nm和620nm的荧光强度，并计算TR-FRET ratio(665nm emission/620nm emission)。
(10)数据分析：Inhibitor％(Inh％)＝*100％
其中：Ratio_sample：样品孔的比值；Ratio_min：阴性对照孔比值均值，代表没有PD-1/PD-L1相互作用孔的读数；Ratio_max：阳性对照孔比值均值，代表没有化合物抑制孔的读数。
(11)拟合量效曲线：以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC50值。
5.实验结果：化合物对PD-1/PD-L1相互作用的抑制活性如下表所示。
| 化合物 | IC50(nM) | 化合物 | IC50(nM) |
| I-1 | 6.77 | I-12 | 5.24 |
| I-2 | 8.27 | II-1 | 9.26 |
| I-3 | 6.51 | II-2 | 10.21 |
| I-4 | 8.36 | II-3 | 8.06 |
| I-5 | 5.77 | II-4 | 7.57 |
| I-6 | 11.16 | II-5 | 10.01 |
| I-7 | 6.13 | II-6 | 8.56 |
| I-8 | 5.47 | II-7 | 10.60 |
| I-9 | 6.67 | II-8 | 10.35 |
| I-10 | 6.52 | II-9 | 8.58 |
| I-11 | 5.78 | BMS-202 | 18.7 |
以上结果表明，本发明化合物能显著抑制PD-1/PD-L1的相互作用。
Claims (4)
1.杂环取代联苯类化合物或其药学上可接受的盐、水合物或溶剂合物，所述化合物为如下任一种：
2.权利要求1所述的杂环取代联苯类化合物或其药学上可接受的盐、水合物或溶剂合物在制备用于治疗与PD-1/PD-L1免疫检查点通路介导的疾病的药物中的用途。
3.根据权利要求2所述的用途，其特征在于，所述疾病包括：黑色素瘤、非小细胞肺癌、头颈部肿瘤、转移性头颈癌、膀胱癌、转移性膀胱癌、霍奇金病、骨髓瘤、急性淋巴细胞白血病、急性粒细胞白血病、极性早幼粒细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病、慢性嗜中性粒细胞白血病、食管癌、转移性食管癌、皮肤鳞状细胞癌、转移性/局部晚期皮肤鳞状细胞癌、急性髓性白血病、血管瘤、结肠肿瘤、弥漫性大B细胞淋巴瘤。
4.一种药物组合物，其特征在于，包含治疗有效量的权利要求1所述的杂环取代联苯类化合物或其药学上可接受的盐、水合物或溶剂合物，以及药学上可接受的载体。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310696498.9A CN116730940B (zh) | 2023-06-13 | 2023-06-13 | 杂环取代联苯类化合物及其医药用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310696498.9A CN116730940B (zh) | 2023-06-13 | 2023-06-13 | 杂环取代联苯类化合物及其医药用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116730940A true CN116730940A (zh) | 2023-09-12 |
| CN116730940B CN116730940B (zh) | 2024-08-30 |
Family
ID=87905682
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310696498.9A Active CN116730940B (zh) | 2023-06-13 | 2023-06-13 | 杂环取代联苯类化合物及其医药用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116730940B (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180305315A1 (en) * | 2017-04-20 | 2018-10-25 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
| CN113307779A (zh) * | 2021-05-25 | 2021-08-27 | 中国药科大学 | 杂环取代联苯类化合物、制备方法及用途 |
| CN114761085A (zh) * | 2019-10-04 | 2022-07-15 | 百时美施贵宝公司 | 可用作免疫调节剂的化合物 |
-
2023
- 2023-06-13 CN CN202310696498.9A patent/CN116730940B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180305315A1 (en) * | 2017-04-20 | 2018-10-25 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
| CN114761085A (zh) * | 2019-10-04 | 2022-07-15 | 百时美施贵宝公司 | 可用作免疫调节剂的化合物 |
| CN113307779A (zh) * | 2021-05-25 | 2021-08-27 | 中国药科大学 | 杂环取代联苯类化合物、制备方法及用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116730940B (zh) | 2024-08-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2957233T3 (es) | Inhibidores de quinasa tipo receptor de activina | |
| JP4954086B2 (ja) | １ｈ−ピロロ［２，３−ｂ］ピリジン | |
| US9255089B2 (en) | Benzimidazolone derivatives as bromodomain inhibitors | |
| JP6466335B2 (ja) | ＲＯＲ−γ−Ｔのメチレン連結キノリニルモジュレーター | |
| KR20210089195A (ko) | 비페닐계 화합물, 이의 중간체, 제조 방법, 약학 조성물 및 용도 | |
| CN113307779B (zh) | 杂环取代联苯类化合物、制备方法及用途 | |
| WO2002088112A1 (fr) | Compose heterocyclique et agent antitumoral contenant ce dernier en tant qu'ingredient actif | |
| KR102654710B1 (ko) | 신규 벤즈이미다졸 화합물 및 그의 의약 용도 | |
| TW202104166A (zh) | Notch訊息傳遞路徑抑制劑及其在癌症治療之用途 | |
| CN111566102B (zh) | 作为激活素受体样激酶抑制剂的取代的吡咯并吡啶 | |
| JP2021523168A (ja) | がん幹細胞を標的化するがん治療 | |
| JP2022528042A (ja) | アミド類化合物の調製方法及びその医薬分野の使用 | |
| CN109748911B (zh) | 一种含三氮唑的ido抑制剂、其制备方法及其医药用途 | |
| AU2014366436B2 (en) | Fluorophenyl pyrazol compounds | |
| CN113773305B (zh) | 一种氨基嘧啶衍生物及其作为egfr酪氨酸激酶抑制剂的应用 | |
| CN116730940B (zh) | 杂环取代联苯类化合物及其医药用途 | |
| WO2023134753A1 (zh) | 微管蛋白-src双靶点抑制剂 | |
| WO2023134751A1 (zh) | 微管蛋白-Src双靶点抑制剂和用途 | |
| CN107573336B (zh) | 苯并杂环-甲酰胺-吡啶酮衍生物及其制备方法和用途 | |
| CN107540624B (zh) | 热休克蛋白抑制剂及其制备方法和应用 | |
| CN111138417B (zh) | 一种三氮唑修饰的5-氟-2,4-嘧啶二胺类化合物及其应用 | |
| CN108774224B (zh) | 吡唑并[3,4-b]吡啶类化合物及其制备方法和应用 | |
| WO2019115709A1 (en) | Mitochondrial inhibitors for the treatment of proliferation disorders | |
| AU2022305807B2 (en) | Pyrimidine compounds for use as map4k1 inhibitors | |
| CN112979562B (zh) | 一种苯并芳杂环化合物及其应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |