WO2023185634A1 - Heterocyclic compound as plasma kallikrein inhibitor - Google Patents
Heterocyclic compound as plasma kallikrein inhibitor Download PDFInfo
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- WO2023185634A1 WO2023185634A1 PCT/CN2023/083409 CN2023083409W WO2023185634A1 WO 2023185634 A1 WO2023185634 A1 WO 2023185634A1 CN 2023083409 W CN2023083409 W CN 2023083409W WO 2023185634 A1 WO2023185634 A1 WO 2023185634A1
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- compound
- ethyl acetate
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- synthesis
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- 229940126155 plasma kallikrein inhibitor Drugs 0.000 title description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 166
- 108090000113 Plasma Kallikrein Proteins 0.000 claims abstract description 31
- 102000003827 Plasma Kallikrein Human genes 0.000 claims abstract description 29
- 239000003814 drug Substances 0.000 claims abstract description 16
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 230000001404 mediated effect Effects 0.000 claims abstract description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 29
- 229910052801 chlorine Inorganic materials 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 23
- 229910052794 bromium Inorganic materials 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 229910052740 iodine Inorganic materials 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 229940079593 drug Drugs 0.000 abstract description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 180
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 78
- 238000006243 chemical reaction Methods 0.000 description 68
- 238000003786 synthesis reaction Methods 0.000 description 55
- 230000015572 biosynthetic process Effects 0.000 description 54
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 49
- 239000012074 organic phase Substances 0.000 description 47
- 239000000243 solution Substances 0.000 description 47
- 238000003756 stirring Methods 0.000 description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000012043 crude product Substances 0.000 description 39
- 230000002829 reductive effect Effects 0.000 description 39
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000012141 concentrate Substances 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 26
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- -1 methoxy, ethoxy, propoxy Chemical group 0.000 description 24
- 239000012065 filter cake Substances 0.000 description 22
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 239000000460 chlorine Substances 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000007788 liquid Substances 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 239000008346 aqueous phase Substances 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 description 13
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 239000012071 phase Substances 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 239000012224 working solution Substances 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- GLNDAGDHSLMOKX-UHFFFAOYSA-N coumarin 120 Chemical compound C1=C(N)C=CC2=C1OC(=O)C=C2C GLNDAGDHSLMOKX-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000002953 preparative HPLC Methods 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 239000011535 reaction buffer Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 101800004538 Bradykinin Proteins 0.000 description 3
- 206010012689 Diabetic retinopathy Diseases 0.000 description 3
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229940127379 Kallikrein Inhibitors Drugs 0.000 description 3
- 102100035792 Kininogen-1 Human genes 0.000 description 3
- 108090001109 Thermolysin Proteins 0.000 description 3
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 3
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- PUYCICVJCRLABY-UHFFFAOYSA-N heptane;oxolane Chemical compound C1CCOC1.CCCCCCC PUYCICVJCRLABY-UHFFFAOYSA-N 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
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- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
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- 208000001344 Macular Edema Diseases 0.000 description 1
- 206010025415 Macular oedema Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
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- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
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- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
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- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 1
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000005101 aryl methoxy carbonyl group Chemical group 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- KZIBQYUFIVUOHY-UHFFFAOYSA-N bis(2-methylpropyl)alumane toluene Chemical compound Cc1ccccc1.[H][Al](CC(C)C)CC(C)C KZIBQYUFIVUOHY-UHFFFAOYSA-N 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- MSMGXWFHBSCQFB-UHFFFAOYSA-N ethyl cyanoformate Chemical compound CCOC(=O)C#N MSMGXWFHBSCQFB-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 238000002795 fluorescence method Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
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- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229940044173 iodine-125 Drugs 0.000 description 1
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- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 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
- 210000005229 liver cell Anatomy 0.000 description 1
- 201000010230 macular retinal edema Diseases 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229940051841 polyoxyethylene ether Drugs 0.000 description 1
- 229920000056 polyoxyethylene ether Polymers 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XCAQIUOFDMREBA-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(=O)OC(C)(C)C XCAQIUOFDMREBA-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 230000006442 vascular tone Effects 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- 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
- C07D413/10—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 aromatic rings
-
- 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
Definitions
- the present application belongs to the field of medicine, and specifically relates to compounds of formula (I), their preparation methods, and their applications in the preparation of drugs for the treatment of plasma kallikrein-mediated related diseases.
- Plasma kallikrein also known as Fletcher factor
- FXIIa Plasma kallikrein
- BK bradykinin
- PKal is often highly expressed in diabetic patients, leading to vasodilation and vasodilation. Increased permeability (RVP), causing diabetic retinopathy (DR) and diabetic macular edema (DME).
- the main function of plasma kallikrein inhibitors is to reduce the activity level of plasma kallikrein in the body and reduce the activation effect of bradykinin on two receptors, thereby alleviating vascular permeability and inflammation, and achieving the treatment of diabetic retinopathy and diabetes.
- Important role of macular edema In the clinical stage, the plasma kallikrein inhibitor KVD001 (WO2013005045) developed by KalVista Pharmaceuticals and the bicyclic peptide plasma kallikrein inhibitor developed by Oxurion have both demonstrated significant therapeutic effects in patients who were ineffective in VEGF monoclonal antibody treatment, but the administration The route of administration is intravitreal injection, and patient compliance needs to be improved.
- the invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof,
- T 1 is CR 1 or N
- R 1 is H, F, Cl, Br or I
- R 2 is H, F, Cl, Br or I
- R 3 is a C 1-3 alkoxy group, and the C 1-3 alkoxy group is optionally substituted by 1, 2 or 3 R a ;
- R 4 is F, Cl, Br, I, OH or C 1-3 alkoxy
- R 5 and R 6 are independently H, F, Cl, Br, I, OH or NH 2 ;
- R 7 is H, F, Cl, Br or I
- R a is D, F, Cl or Br.
- the invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof,
- T 1 is CR 1 or N
- R 1 is H, F, Cl, Br or I
- R 2 is H, F, Cl, Br or I
- R 3 is a C 1-3 alkoxy group, and the C 1-3 alkoxy group is optionally substituted by 1, 2 or 3 R a ;
- R 4 is F, Cl, Br, I, OH or C 1-3 alkoxy
- R 5 and R 6 are independently H, F, Cl, Br, I, OH or NH 2 ;
- R 7 is H, F, Cl, Br or I
- R a is D, F, Cl or Br.
- R 1 is F or Cl, and other variables are as defined in the present invention.
- R 2 is F or Cl, and other variables are as defined in the present invention.
- R 3 is -OCH 3 or -OCD 3 , and other variables are as defined in the present invention.
- R 4 is F, Cl, Br, I, OH or -OCH 3 , and other variables are as defined in the present invention.
- R 5 is H, and other variables are as defined in the present invention.
- R 6 is H or F, and other variables are as defined in the present invention.
- R 7 is F or H, and other variables are as defined in the present invention.
- R 7 is F, and other variables are as defined in the present invention.
- the present invention also provides compounds of the following formula or pharmaceutically acceptable salts thereof:
- the present invention provides the use of the above compounds or pharmaceutically acceptable salts thereof in the preparation of medicines for treating related diseases mediated by plasma kallikrein.
- the compounds of the present invention have significant plasma kallikrein inhibitory activity and good oral exposure.
- the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salts refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases.
- base addition salts can be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent.
- acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
- Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
- the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
- the compounds provided by the invention also exist in prodrug forms.
- Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to transform into the compounds of the present invention.
- prodrugs can be converted to compounds of the invention by chemical or biochemical methods in the in vivo environment.
- treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
- the effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
- Treatment encompasses any treatment of a subject's disease that the subject (a) inhibits the symptoms of the disease, i.e., prevents their progression; or (b) alleviates the symptoms of the disease, i.e., causes regression of the disease or symptoms.
- Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms.
- solvated and unsolvated forms are equivalent to each other and are included within the scope of the present invention.
- the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
- compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
- deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
- substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable of.
- oxygen it means that two hydrogen atoms are replaced.
- Oxygen substitution does not occur on aromatic groups.
- optionally substituted means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievability.
- any variable e.g., R
- its definition in each instance is independent.
- said group may optionally be substituted by up to two R's, with independent options for R in each case.
- substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
- C 1-3 alkoxy means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through an oxygen atom.
- the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups, etc.
- Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
- halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
- C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also include any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; similarly, n yuan to n The +m member indicates that the number of atoms in the ring is n to n+m.
- a 3-12 membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, and a 9-membered ring.
- 3-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, etc.
- leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction, such as a nucleophilic substitution reaction.
- representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonate Ester, etc.; acyloxy group, such as acetoxy group, trifluoroacetoxy group, etc.
- protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
- amino protecting group refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group.
- Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and so on.
- acyl such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as
- hydroxyl protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
- Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl (such as acetyl, Ac); arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert. Butyldimethylsilyl (TBS) etc.
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
- the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
- single crystal X-ray diffraction uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal.
- the light source is CuK ⁇ radiation.
- the scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
- the solvent used in the present invention is commercially available.
- the following abbreviations are used in the present invention: aq represents water; THF represents tetrahydrofuran.
- Tetrahydrofuran (6200 mL), 3-2 (1.23 kg, 5.64 mol), 3-3 (650.08 g, 5.75 mol) were added to the previously dried reaction. Then add potassium carbonate (1.56kg, 11.27mol). Stir the system at 62°C for 3 hours, cool the system to about 55°C, then filter while hot, rinse the filter cake with 3.1L x 2 of ethyl acetate at 40°C, collect the filtrate, and concentrate to dryness to obtain the crude product.
- N,N-dimethylformamide 3mL
- 5-2 0.2g, 479.20 ⁇ mol
- diisopropylethyl to the pre-dried reaction bottle.
- Amine (495mg, 3.83mmol)
- 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (273mg, 718.80umo)
- nitrogen replacement 3 times then 2-1 (110.50 mg, 527.12 ⁇ mol) was added, and the system was stirred at 20°C for 2 hours.
- PKal reaction buffer 25mM Tris-HCl (trishydroxymethylaminomethane-HCl), pH 8.0, 100mM NaCl, pH 8.5, 0.01% Brij35 (laureth polyoxyethylene ether), and 1% DMSO (final concentration ).
- PKal R&D Systems Cat#2497-SE
- Enzyme activation (1) dilute rhPKal to 200 ⁇ g/mL activation buffer (100mM Tris, 10mM CaCl 2 , 150mM NaCl, pH 7.5 (TCN)); (2) dilute thermolysin (Thermolysin) to 20 ⁇ g /mL activation buffer; (3) Mix rhPKal (200 ⁇ g/mL) and thermolysin (20 ⁇ g/mL) in equal volumes; (4) Incubate at 37°C for 30 minutes; (5) Then use 50 ⁇ M EDTA (ethylenediamine Tetraacetic acid) terminates the reaction.
- EDTA ethylenediamine Tetraacetic acid
- Matrix (Enzo Cat#P-139): 10 ⁇ M Z-FR-AMC (AMC: 7-amino-4-methylcoumarin).
- Reaction process (1) Prepare the specified enzyme and substrate in the newly prepared activation buffer; (2) Inject the enzyme solution into the reaction well; (3) Use acoustic technology (Echo 550, LabCyte Inc. Sunnyvale, CA ) Inject the DMSO solution of the test product into the reaction mixture and control it within the nanoliter range; (4) After pre-incubation for 10 minutes, inject the matrix solution into the reaction well to start the reaction; (5) The activity of the enzyme can be measured by fluorescence Indicated by an increase in the fluorescence signal of the labeled peptide matrix, monitor every 5 minutes for 120 minutes at room temperature; (6) Data analysis: measure the slope of the straight line * (fluorescence signal/time), the slope can be calculated by excel, and the curve can be fitted through Prism software .
- Table 1 The test results of the inhibitory effect of compounds on plasma kallikrein (PKal) are shown in Table 1 below.
- the compound of the present invention has a significant inhibitory effect on plasma kallikrein (PKal).
- PKal substrate Pro-Phe-Arg-AMC (AMC: 7-amino-4-methylcoumarin) (purchased from GenScript, C882QHC150-1);
- reaction buffer 50mM Tris-HCl pH7.5, 250mM NaCl
- substrate Pro-Phe-Arg-AMC working solution to a concentration of 250 ⁇ M
- Compound addition plate The starting concentration of the positive reference compound and the test compound is 30 ⁇ M, diluted 3 times, and diluted to 10 concentration points. Deliver 0.05 ⁇ L of compound in 100% DMSO into a 384-well plate via acoustic liquid delivery technology (Echo550; nanoliter range);
- Reading value After the incubation, use a PHERAstar FSX microplate reader (BMG) to read the fluorescence signal (ex380/em460). The activity of the enzyme is indicated by the fluorescence signal intensity of the fluorescently labeled substrate. Use GraphPad Prism software to perform curve fitting and obtain IC50 values.
- the compound of the present invention has a significant inhibitory effect on plasma kallikrein (PKal) in human plasma.
- mice Male SD rats were used as test animals, and the LC-MS/MS method was used to determine the drug concentration in the plasma of rats at different times after intravenous and gavage administration of test compounds. Study the pharmacokinetic behavior of compounds in rats and evaluate their pharmacokinetic characteristics.
- Test drug test compound.
- the LC-MS/MS method was used to determine the content of the test compound in the plasma of rats after intravenous and intragastric administration.
- the linear range of the method is 2.00 ⁇ 6000nmol/L; plasma samples are analyzed after being treated with acetonitrile to precipitate proteins.
- the pharmacokinetic test results of the compounds are shown in Table 3 below.
Abstract
The present application relates to the field of medicine, and particularly discloses a compound of formula (I), a preparation method therefor, and use of said compound in the preparation of a drug for treating plasma kallikrein-mediated related diseases.
Description
本发明主张如下优先权申请The present invention claims the following priority application
申请号：CN202210334521.5，申请日：2022年3月30日；Application number: CN202210334521.5, application date: March 30, 2022;
申请号：CN202210431376.2，申请日：2022年4月22日。Application number: CN202210431376.2, application date: April 22, 2022.
本申请属于医药领域，具体而言涉及式(I)化合物、其制备方法、以及它们在制备治疗血浆激肽释放酶介导的相关疾病的药物中的应用。The present application belongs to the field of medicine, and specifically relates to compounds of formula (I), their preparation methods, and their applications in the preparation of drugs for the treatment of plasma kallikrein-mediated related diseases.
血浆激肽释放酶(plasma kallikrein，PKal)又称Fletcher因子，特异地在肝细胞表达，是一种高分子量糖蛋白，是FXIIa作用于激肽释放酶原生成的，可介导激肽原裂解产生缓激肽(BK)，激活其B1受体和B2受体，调节血管紧张性、炎症反应以及内源性血液凝固和纤维蛋白溶解过程，糖尿病患者体内PKal往往高表达，导致血管舒张及血管通透性(RVP)增加，从而引起糖尿病视网膜病变(DR)和糖尿病黄斑水肿(DME)。血浆激肽释放酶抑制剂的主要作用是降低体内血浆激肽释放酶活性水平，降低缓激肽对两种受体的激活作用，从而缓解血管通透性及炎症，达到治疗糖尿病视网膜病变和糖尿病黄斑水肿的重要作用。临床阶段KalVista Pharmaceuticals公司开发的血浆激肽释放酶抑制剂KVD001(WO2013005045)和Oxurion公司开发的双环多肽血浆激肽释放酶抑制对VEGF单抗治疗无效的患者都展示了显著的治疗效果，但给药途径都为玻璃体腔注射给药，患者依从性有待改善。Plasma kallikrein (PKal), also known as Fletcher factor, is specifically expressed in liver cells. It is a high molecular weight glycoprotein that is produced by FXIIa acting on kallikreinogen and can mediate the cleavage of kininogen. Produces bradykinin (BK), activates its B1 receptors and B2 receptors, regulates vascular tone, inflammatory response, and endogenous blood coagulation and fibrinolysis processes. PKal is often highly expressed in diabetic patients, leading to vasodilation and vasodilation. Increased permeability (RVP), causing diabetic retinopathy (DR) and diabetic macular edema (DME). The main function of plasma kallikrein inhibitors is to reduce the activity level of plasma kallikrein in the body and reduce the activation effect of bradykinin on two receptors, thereby alleviating vascular permeability and inflammation, and achieving the treatment of diabetic retinopathy and diabetes. Important role of macular edema. In the clinical stage, the plasma kallikrein inhibitor KVD001 (WO2013005045) developed by KalVista Pharmaceuticals and the bicyclic peptide plasma kallikrein inhibitor developed by Oxurion have both demonstrated significant therapeutic effects in patients who were ineffective in VEGF monoclonal antibody treatment, but the administration The route of administration is intravitreal injection, and patient compliance needs to be improved.
鉴于血浆激肽释放酶抑制剂的重要作用，以及目前给药方式患者依从性问题，开发适用作口服治疗药物的血浆激肽释放酶抑制剂显得尤为重要。In view of the important role of plasma kallikrein inhibitors and the problem of patient compliance with current administration methods, it is particularly important to develop plasma kallikrein inhibitors suitable for oral therapeutic drugs.
发明内容Contents of the invention
本发明提供了式(I)化合物或其药学上可接受的盐，
The invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof,
The invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof,
其中，in,
T1为CR1或N；T 1 is CR 1 or N;
R1为H、F、Cl、Br或I；
R 1 is H, F, Cl, Br or I;
R2为H、F、Cl、Br或I；R 2 is H, F, Cl, Br or I;
R3为C1-3烷氧基，所述C1-3烷氧基任选地被1、2或3个Ra取代；R 3 is a C 1-3 alkoxy group, and the C 1-3 alkoxy group is optionally substituted by 1, 2 or 3 R a ;
R4为F、Cl、Br、I、OH或C1-3烷氧基；R 4 is F, Cl, Br, I, OH or C 1-3 alkoxy;
R5和R6分别独立地为H、F、Cl、Br、I、OH或NH2；R 5 and R 6 are independently H, F, Cl, Br, I, OH or NH 2 ;
R7为H、F、Cl、Br或I；R 7 is H, F, Cl, Br or I;
Ra为D、F、Cl或Br。R a is D, F, Cl or Br.
本发明提供了式(I)化合物或其药学上可接受的盐，
The invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof,
The invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof,
其中，in,
T1为CR1或N；T 1 is CR 1 or N;
R1为H、F、Cl、Br或I；R 1 is H, F, Cl, Br or I;
R2为H、F、Cl、Br或I；R 2 is H, F, Cl, Br or I;
R3为C1-3烷氧基，所述C1-3烷氧基任选地被1、2或3个Ra取代；R 3 is a C 1-3 alkoxy group, and the C 1-3 alkoxy group is optionally substituted by 1, 2 or 3 R a ;
R4为F、Cl、Br、I、OH或C1-3烷氧基；R 4 is F, Cl, Br, I, OH or C 1-3 alkoxy;
R5和R6分别独立地为H、F、Cl、Br、I、OH或NH2；R 5 and R 6 are independently H, F, Cl, Br, I, OH or NH 2 ;
R7为H、F、Cl、Br或I；R 7 is H, F, Cl, Br or I;
Ra为D、F、Cl或Br。R a is D, F, Cl or Br.
本发明的一些方案中，上述R1为F或Cl，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 1 is F or Cl, and other variables are as defined in the present invention.
本发明的一些方案中，上述R2为F或Cl，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 2 is F or Cl, and other variables are as defined in the present invention.
本发明的一些方案中，上述R3为-OCH3或-OCD3，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 3 is -OCH 3 or -OCD 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R4为F、Cl、Br、I、OH或-OCH3，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 4 is F, Cl, Br, I, OH or -OCH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R5为H，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 5 is H, and other variables are as defined in the present invention.
本发明的一些方案中，上述R6为H或F，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 6 is H or F, and other variables are as defined in the present invention.
本发明的一些方案中，上述R7为F或H，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 7 is F or H, and other variables are as defined in the present invention.
本发明的一些方案中，上述R7为F，其他变量如本发明所定义。In some solutions of the present invention, the above-mentioned R 7 is F, and other variables are as defined in the present invention.
本发明还有一些方案是由上述变量任意组合而来。
There are also some solutions of the present invention that are derived from any combination of the above variables.
本发明还提供了下式化合物或其药学上可接受的盐：
The present invention also provides compounds of the following formula or pharmaceutically acceptable salts thereof:
The present invention also provides compounds of the following formula or pharmaceutically acceptable salts thereof:
本发明提供了上述化合物或其药学上可接受的盐在制备治疗血浆激肽释放酶介导的相关疾病的药物中的应用。
The present invention provides the use of the above compounds or pharmaceutically acceptable salts thereof in the preparation of medicines for treating related diseases mediated by plasma kallikrein.
技术效果Technical effect
本发明化合物具有显著的血浆激肽释放酶抑制活性，同时具有较好的口服暴露量。The compounds of the present invention have significant plasma kallikrein inhibitory activity and good oral exposure.
定义和说明Definition and Description
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in its ordinary meaning. Where a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，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接触的方式获得碱加成盐。当本发明的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接触的方式获得酸加成盐。本发明的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。本发明的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。The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts. The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。In addition to salt forms, the compounds provided by the invention also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to transform into the compounds of the present invention. In addition, prodrugs can be converted to compounds of the invention by chemical or biochemical methods in the in vivo environment.
如本文所用，术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对主体疾病的任何治疗，包括：主体(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。As used herein, the term "treatment" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. "Treatment" as used herein encompasses any treatment of a subject's disease that the subject (a) inhibits the symptoms of the disease, i.e., prevents their progression; or (b) alleviates the symptoms of the disease, i.e., causes regression of the disease or symptoms.
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms. In general, solvated and unsolvated forms are equivalent to each other and are included within the scope of the present invention.
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). For another example, deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事
件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the subsequently described event or condition may, but need not, occur, and that the description includes what is stated therein circumstances in which an event or condition occurs and circumstances in which said event or condition does not occur.
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable of. When the substituent is oxygen (i.e. =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievability.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each instance is independent. Thus, for example, if a group is substituted by 0-2 R, then said group may optionally be substituted by up to two R's, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
当一个连接基团的数量为0时，比如-(CRR)0-，表示该连接基团为单键。When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
除非另有规定，术语“C1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷氧基包括C1-2、C2-3、C3和C2烷氧基等。C1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。Unless otherwise specified, the term "C 1-3 alkoxy" means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups, etc. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
除非另有规定，Cn-n+m或Cn-Cn+m包括n至n+m个碳的任何一种具体情况，例如C1-12包括C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、和C12，也包括n至n+m中的任何一个范围，例如C1-12包括C1-3、C1-6、C1-9、C3-6、C3-9、C3-12、C6-9、C6-12、和C9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。Unless otherwise specified, C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also include any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; similarly, n yuan to n The +m member indicates that the number of atoms in the ring is n to n+m. For example, a 3-12 membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, and a 9-membered ring. , 10-membered ring, 11-membered ring, and 12-membered ring, also including any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, etc.
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲核取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction, such as a nucleophilic substitution reaction. For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonate Ester, etc.; acyloxy group, such as acetoxy group, trifluoroacetoxy group, etc.
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基，Ac)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)
等等。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and so on. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl (such as acetyl, Ac); arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert. Butyldimethylsilyl (TBS) etc.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal. The light source is CuKα radiation. The scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；THF代表四氢呋喃。The solvent used in the present invention is commercially available. The following abbreviations are used in the present invention: aq represents water; THF represents tetrahydrofuran.
化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称。Compounds are named according to conventional naming principles in the field or use For software naming, commercially available compounds adopt supplier catalog names.
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本申请，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。本申请所使用的所有溶剂是市售的，无需进一步纯化即可使用。本申请用于合成的初始化合物原料通过市售获得，也可以通过现有技术的方法制备。The present invention is described in detail below through examples, which do not mean any adverse limitations to the present invention. The present application has been described in detail, and its specific embodiments have also been disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. will be obvious. All solvents used in this application were commercially available and used without further purification. The starting compound raw materials used for synthesis in this application are commercially available and can also be prepared by methods in the prior art.
实施例1
Example 1
Example 1
合成路线：
synthetic route:
synthetic route:
1)化合物1-2的合成1) Synthesis of compound 1-2
在三口瓶中加入化合物1-1(92g，665.88mmol)，盐酸(12M，277.45mL)和无水甲苯(920mL)，25℃下搅拌4小时。加入饱和碳酸氢钠溶液调pH至7，加入乙酸乙酯(300mL*3)萃取，收集合并有机相加入饱和食盐水(500mL)洗，分离有机相加入无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物1-2。LCMS(ESI)m/z:139[M-17]+。Compound 1-1 (92g, 665.88mmol), hydrochloric acid (12M, 277.45mL) and anhydrous toluene (920mL) were added to the three-necked flask, and stirred at 25°C for 4 hours. Add saturated sodium bicarbonate solution to adjust the pH to 7, add ethyl acetate (300mL*3) for extraction, collect the combined organic phase and add saturated brine (500mL) to wash, separate the organic phase and add anhydrous sodium sulfate to dry, filter, and depressurize the filtrate Concentration gave compound 1-2. LCMS(ESI)m/z:139[M-17] + .
2)化合物1-3的合成2) Synthesis of compounds 1-3
向预先干燥的单口瓶中加入5-氟-2-羟基吡啶(14.7g，130.26mmol)，化合物1-2(17.0g，108.55mmol)，
N,N-二甲基甲酰胺(160mL)，碳酸钾(15.0g，108.55mmol)，65℃搅拌18小时。待体系自然回温至40℃后，将体系过滤，滤饼用乙酸乙酯(100mL*3)淋洗，收集滤液加入饱和食盐水(200mL)，乙酸乙酯(300mL*3)萃取，收集有机相加入无水硫酸钠干燥过滤，滤液减压浓缩至干得到粗品。粗品中加入乙酸乙酯(40mL)，25℃，搅拌10分钟，过滤，滤饼乙酸乙酯(10mL*3)淋洗，收集滤饼，真空干燥得到化合物1-3。LCMS(ESI)m/z:234[M+1]+。Add 5-fluoro-2-hydroxypyridine (14.7g, 130.26mmol) and compound 1-2 (17.0g, 108.55mmol) to the pre-dried one-neck bottle. N,N-dimethylformamide (160 mL), potassium carbonate (15.0 g, 108.55 mmol), stir at 65°C for 18 hours. After the system naturally warms back to 40°C, filter the system, rinse the filter cake with ethyl acetate (100mL*3), collect the filtrate, add saturated brine (200mL), extract with ethyl acetate (300mL*3), and collect the organic matter. Anhydrous sodium sulfate was added to the phase, dried and filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain crude product. Add ethyl acetate (40 mL) to the crude product, stir at 25°C for 10 minutes, filter, rinse the filter cake with ethyl acetate (10 mL*3), collect the filter cake, and dry under vacuum to obtain compound 1-3. LCMS(ESI)m/z:234[M+1] + .
3)化合物1-4的合成3) Synthesis of compounds 1-4
向预先干燥的反应瓶中加入二氯甲烷(25mL)，化合物1-3(2.2g，8.49mmol)，三乙胺(1.3g，12.73mmol)，降温至0℃，滴加甲基磺酰氯(1.4g，11.88mmol)。滴加完毕，升温至20℃搅拌16小时。反应液用二氯甲烷(20mL)稀释，加入水(50mL)，搅拌10分钟，除去水相，有机相用无水硫酸钠干燥，过滤，减压浓缩，得到化合物1-4。1HNMR(400MHz,CDCl3)δppm 7.36-7.43(m,2H),7.31(d,J＝8.2Hz,2H),7.24-7.29(m,1H),7.16(t,J＝3.6Hz,1H),6.61(dd,J＝5.4,10.0Hz,1H),5.10(s,2H),4.58(s,2H)；LCMS(ESI)m/z:252[M+1]+。Add dichloromethane (25mL), compound 1-3 (2.2g, 8.49mmol), and triethylamine (1.3g, 12.73mmol) to the pre-dried reaction bottle, cool to 0°C, and add methylsulfonyl chloride ( 1.4g, 11.88mmol). After the dropwise addition is completed, the temperature is raised to 20°C and stirred for 16 hours. The reaction solution was diluted with dichloromethane (20 mL), water (50 mL) was added, stirred for 10 minutes, the aqueous phase was removed, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-4. 1 HNMR (400MHz, CDCl 3 ) δppm 7.36-7.43 (m, 2H), 7.31 (d, J = 8.2Hz, 2H), 7.24-7.29 (m, 1H), 7.16 (t, J = 3.6Hz, 1H) ,6.61(dd,J=5.4,10.0Hz,1H),5.10(s,2H),4.58(s,2H); LCMS(ESI)m/z:252[M+1] + .
4)化合物1-5b的合成4) Synthesis of compound 1-5b
向预先干燥的反应瓶中加入1-5a(150g,1.07mol)，丙酮(1500mL)，碳酸铯(697.49g,2.14mol))，(三甲基硅)乙氧基甲基氯(356.9g,2.14mol)。体系15℃搅拌16小时。将体系直接过滤，滤液减压浓缩得到粗品，粗品经柱层析纯化得到化合物1-5b。LCMS(ESI)m/z:271[M+1]+。Add 1-5a (150g, 1.07mol), acetone (1500mL), cesium carbonate (697.49g, 2.14mol)), (trimethylsilyl) ethoxymethyl chloride (356.9g, 2.14mol). The system was stirred at 15°C for 16 hours. The system was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain compound 1-5b. LCMS(ESI)m/z:271[M+1] + .
5)化合物1-5c的合成5) Synthesis of compound 1-5c
向预先干燥的三口瓶中加入THF(250mL)，1-5b(25g,92.46mmol)，-60℃滴加二异丙基氨基锂的四氢呋喃正庚烷混合溶液(2M,69.34mL)，滴加完毕搅拌0.5小时，然后-60℃加入氧杂环丁酮(9.99g，138.68mmol)，-60℃搅拌2小时。向反应液中加入200mL饱和食盐水和100mL乙酸乙酯，分液，有机相无水硫酸钠干燥，过滤，减压浓缩溶剂至干得到粗品，粗品经柱层析纯化得到化合物1-5c。LCMS(ESI)m/z:343[M+1]+。Add THF (250mL) and 1-5b (25g, 92.46mmol) to the pre-dried three-necked flask, and add dropwise a mixed solution of lithium diisopropylamide in tetrahydrofuran-n-heptane (2M, 69.34mL) at -60°C. After completion of stirring for 0.5 hours, oxetanone (9.99g, 138.68mmol) was added at -60°C and stirred at -60°C for 2 hours. Add 200 mL saturated brine and 100 mL ethyl acetate to the reaction solution, separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the solvent to dryness under reduced pressure to obtain a crude product, which is purified by column chromatography to obtain compound 1-5c. LCMS(ESI)m/z:343[M+1] + .
6)化合物1-5d的合成6) Synthesis of compound 1-5d
在预先干燥的单口瓶中加入1-5c(14.6g,42.63mmol)和二氯甲烷(150mL)，加入二乙胺基三氟化硫(10.31g,63.95mmol)，15℃搅拌2小时。将反应液缓慢倒入200mL饱和碳酸氢钠水溶液中淬灭，然后加入100mL二氯甲烷萃取分液，有机相无水硫酸钠干燥过滤减压浓缩溶剂至干得到粗品化合物1-5d。LCMS(ESI)m/z:345[M+1]+。Add 1-5c (14.6g, 42.63mmol) and dichloromethane (150mL) to a pre-dried one-neck bottle, add diethylamine sulfur trifluoride (10.31g, 63.95mmol), and stir at 15°C for 2 hours. The reaction solution was slowly poured into 200 mL of saturated sodium bicarbonate aqueous solution to quench, and then 100 mL of dichloromethane was added for extraction and separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to dryness to obtain crude compound 1-5d. LCMS(ESI)m/z:345[M+1] + .
7)化合物1-5的合成7) Synthesis of compounds 1-5
在预先干燥的单口瓶中加入1-5d(12.3g,35.71mmol)和四氢呋喃(120mL)，然后加入四丁基氟化铵溶液(1M,89.27mL)，体系75℃搅拌16小时。向反应液中加入500mL乙酸乙酯，分别用200mL饱和食盐水200mL 1M稀盐酸洗涤，分液，有机相无水硫酸钠干燥，过滤，减压浓缩至干得到粗品化合物1-5。
Add 1-5d (12.3g, 35.71mmol) and tetrahydrofuran (120mL) to a pre-dried one-neck bottle, then add tetrabutylammonium fluoride solution (1M, 89.27mL), and stir the system at 75°C for 16 hours. Add 500 mL of ethyl acetate to the reaction solution, wash with 200 mL of saturated brine and 200 mL of 1 M dilute hydrochloric acid, separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure to obtain crude compound 1-5.
LCMS(ESI)m/z:215[M+1]+。LCMS(ESI)m/z:215[M+1] + .
8)化合物1-6的合成8) Synthesis of compounds 1-6
在预先干燥的单口瓶中加入1-5(11.1g,23.32mmol,45％纯度),N,N-二甲基甲酰胺(90mL)，然后加入碳酸钾(6.45g,46.64mmol,)和1-4(7.04g,27.98mmol)，体系65℃搅拌10小时。向反应液中加入300ml乙酸乙酯和300mL饱和食盐水，分液后有机相无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品柱层析纯化后得到化合物1-6。LCMS(ESI)m/z:430[M+1]+。Add 1-5 (11.1g, 23.32mmol, 45% purity), N,N-dimethylformamide (90mL) to a pre-dried single-neck bottle, then add potassium carbonate (6.45g, 46.64mmol,) and 1 -4 (7.04g, 27.98mmol), the system was stirred at 65°C for 10 hours. Add 300 ml of ethyl acetate and 300 ml of saturated saline to the reaction solution. After liquid separation, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain compound 1-6. LCMS(ESI)m/z:430[M+1] + .
9)化合物1-7的合成9) Synthesis of compounds 1-7
在预先干燥的单口瓶中加入1-6(2.3g,5.36mmol)，乙醇(21mL)，四氢呋喃(21mL)，水(7mL)，然后加入氢氧化钠(642.73mg,16.07mmol)，65℃搅拌1小时。向反应液中加入50mL乙酸乙酯和50mL饱和食盐水，分液，水相加入50mL乙酸乙酯后用1M的稀盐酸调pH至2～3，分液，有机相用50mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩溶剂至干得到化合物1-7。LCMS(ESI)m/z:402[M+1]+。Add 1-6 (2.3g, 5.36mmol), ethanol (21mL), tetrahydrofuran (21mL), water (7mL) to the pre-dried single-neck bottle, then add sodium hydroxide (642.73mg, 16.07mmol), and stir at 65°C 1 hour. Add 50 mL of ethyl acetate and 50 mL of saturated saline to the reaction solution, and separate the layers. Add 50 mL of ethyl acetate to the aqueous phase and adjust the pH to 2~3 with 1M dilute hydrochloric acid. Separate the layers. Wash the organic phase with 50 mL of saturated saline. Dry over anhydrous sodium sulfate, filter, and concentrate the solvent to dryness under reduced pressure to obtain compound 1-7. LCMS(ESI)m/z:402[M+1] + .
10)化合物1-8b的合成10) Synthesis of compound 1-8b
在氮气保护下向预先干燥的三口瓶中加入化合物1-8a(25.0g，190.06mmol)的四氢呋喃(200mL)溶液，降温至-78℃滴加二异丙基胺锂2M四氢呋喃正庚烷混合溶液(2M，104.53mL)，搅拌2小时后滴加原料硼酸三甲酯(39.5g，380.13mmol，42.93mL)，自然升至室温25℃继续搅拌22小时。向体系中加入饱和氯化铵水溶液(200mL)将体系淬灭，加入乙酸乙酯(200mL)搅拌30分钟，分离收集有机相，减压浓缩得粗品1-8b。Add a solution of compound 1-8a (25.0g, 190.06mmol) in tetrahydrofuran (200mL) to a pre-dried three-necked flask under nitrogen protection, cool the temperature to -78°C and add dropwise a 2M tetrahydrofuran-n-heptane mixed solution of lithium diisopropylamine. (2M, 104.53mL), after stirring for 2 hours, the raw material trimethyl borate (39.5g, 380.13mmol, 42.93mL) was added dropwise, and the mixture was naturally raised to room temperature 25°C and continued to stir for 22 hours. Add saturated aqueous ammonium chloride solution (200 mL) to the system to quench the system, add ethyl acetate (200 mL) and stir for 30 minutes, separate and collect the organic phase, and concentrate under reduced pressure to obtain crude product 1-8b.
11)化合物1-8c的合成11) Synthesis of compound 1-8c
0-5℃下，向化合物1-8b(33.3g，189.90mmol)的乙醇溶液(330mL)中滴加双氧水(59.0g，520.36mmol，50mL，30％纯度)，得到的混合物自然升至室温25℃搅拌4.5小时。补加双氧水(118.0g，1.04mol，100mL，30％纯度)继续搅拌18小时。向饱和亚硫酸钠水溶液(500mL)中缓慢加入反应体系，搅拌1小时，至淀粉碘化钾试纸不变色，乙酸乙酯(300mL*3)萃取，收集合并有机相，加入无水硫酸钠干燥过滤，滤液减压浓缩，得到化合物1-8c。LCMS(ESI)m/z:148[M+1]+。At 0-5°C, hydrogen peroxide (59.0g, 520.36mmol, 50mL, 30% purity) was added dropwise to the ethanol solution (330mL) of compound 1-8b (33.3g, 189.90mmol), and the resulting mixture naturally rose to room temperature 25 °C and stirred for 4.5 hours. Add additional hydrogen peroxide (118.0g, 1.04mol, 100mL, 30% purity) and continue stirring for 18 hours. Slowly add the reaction system to the saturated sodium sulfite aqueous solution (500mL), stir for 1 hour, until the starch potassium iodide test paper does not change color, extract with ethyl acetate (300mL*3), collect and combine the organic phases, add anhydrous sodium sulfate, dry and filter, and reduce the pressure of the filtrate Concentration gave compound 1-8c. LCMS(ESI)m/z:148[M+1] + .
12)化合物1-8d的合成12) Synthesis of compound 1-8d
向预先干燥的单口瓶中加入化合物1-8c(7.9g，53.41mmol)，N,N-二甲基甲酰胺(80mL)，碳酸钾(14.8g，106.82mmol)，碘甲烷(11.4g，80.12mmol，4.99mL)，25℃搅拌18小时。向体系中加入乙酸乙酯(30mL)搅拌10分钟后，通过布氏漏斗将体系过滤，滤饼通过乙酸乙酯(15mL*3)淋洗，收集滤液加入饱和食盐水(40mL*3)洗涤，分离出有机相加入无水硫酸钠干燥过滤，滤液减压浓缩，粗品通过柱层析(梯度洗脱：乙酸乙酯/石油醚，乙酸乙酯％：0～30％，流速30mL/min)纯化得到化合物1-8d。LCMS(ESI)m/z:162[M+1]+。Add compound 1-8c (7.9g, 53.41mmol), N,N-dimethylformamide (80mL), potassium carbonate (14.8g, 106.82mmol), methyl iodide (11.4g, 80.12 mmol, 4.99mL), stirred at 25°C for 18 hours. Add ethyl acetate (30mL) to the system and stir for 10 minutes. The system is filtered through a Buchner funnel. The filter cake is washed with ethyl acetate (15mL*3). The filtrate is collected and washed with saturated brine (40mL*3). Separate the organic phase, add anhydrous sodium sulfate, dry and filter, the filtrate is concentrated under reduced pressure, and the crude product is purified by column chromatography (gradient elution: ethyl acetate/petroleum ether, ethyl acetate%: 0~30%, flow rate 30mL/min) Compound 1-8d was obtained. LCMS(ESI)m/z:162[M+1] + .
13)化合物1-8e的合成
13) Synthesis of compound 1-8e
向预先干燥的单口瓶中加入化合物1-8d(2.9g，17.95mmol)，N,N-二甲基甲酰胺(30mL)，氰化锌(2.1g，17.95mmol，1.14mL)，1,1-双(二苯基膦基)二茂铁(995mg，1.79mmol)，三(二亚苄基丙酮)二钯(822mg，897.49μmol)，氮气置换三次120℃搅拌16小时。将体系过滤，滤饼用乙酸乙酯(30mL*5)淋洗，滤液中加入饱和食盐水搅拌20分钟，使用分液漏斗分离，有机相加入无水硫酸钠干燥过滤，滤液减压浓缩，粗品通过柱层析(梯度洗脱：乙酸乙酯/石油醚，乙酸乙酯％：0～50％，流速30mL/min)纯化得到化合物1-8e。LCMS(ESI)m/z:153[M+1]+。Add compound 1-8d (2.9g, 17.95mmol), N,N-dimethylformamide (30mL), zinc cyanide (2.1g, 17.95mmol, 1.14mL), 1,1 to the pre-dried single-neck bottle. -Bis(diphenylphosphino)ferrocene (995 mg, 1.79 mmol), tris(dibenzylideneacetone)dipalladium (822 mg, 897.49 μmol), replaced with nitrogen three times and stirred at 120°C for 16 hours. Filter the system, rinse the filter cake with ethyl acetate (30mL*5), add saturated salt water to the filtrate and stir for 20 minutes, separate using a separatory funnel, add anhydrous sodium sulfate to the organic phase, dry and filter, the filtrate is concentrated under reduced pressure, and the crude product Compound 1-8e was purified by column chromatography (gradient elution: ethyl acetate/petroleum ether, ethyl acetate %: 0 to 50%, flow rate 30 mL/min). LCMS(ESI)m/z:153[M+1] + .
14)化合物1-8的合成14) Synthesis of compounds 1-8
向预先干燥的单口瓶中加入化合物1-8e(1.8g,11.83mmol)，无水乙醇(10mL)，无水四氢呋喃(10mL)，盐酸(1.20g，11.83mmol，1.17mL，36％纯度)，钯/碳(500mg，10％纯度)，通入氢气(15psi)，25℃搅拌4小时。体系通过硅藻土过滤，滤饼用甲醇(20mL*4)淋洗至无产物残留，滤液减压浓缩得到化合物1-8。1HNMR(400MHz,DMSO-d6)δppm 8.36(d,J＝5.6Hz,1H),7.34(t,J＝6.2Hz,1H),4.20-4.15(m,2H),3.96(s,3H)；LCMS(ESI)m/z:156[M+1]+。Add compound 1-8e (1.8g, 11.83mmol), anhydrous ethanol (10mL), anhydrous tetrahydrofuran (10mL), hydrochloric acid (1.20g, 11.83mmol, 1.17mL, 36% purity) to the pre-dried one-neck bottle, Palladium/carbon (500 mg, 10% purity), add hydrogen (15 psi), and stir at 25°C for 4 hours. The system was filtered through diatomaceous earth, the filter cake was rinsed with methanol (20 mL*4) until no product remained, and the filtrate was concentrated under reduced pressure to obtain compound 1-8. 1 HNMR (400MHz, DMSO-d 6 ) δppm 8.36 (d, J＝5.6Hz, 1H), 7.34 (t, J＝6.2Hz, 1H), 4.20-4.15 (m, 2H), 3.96 (s, 3H) ;LCMS(ESI)m/z:156[M+1] + .
15)化合物1的合成15) Synthesis of compound 1
在预先干燥的单口瓶中加入1-7(200mg,498.30μmol)和N,N-二甲基甲酰胺(2mL)，然后加入1-8(115.2mg,597.96μmol)，二异丙基乙基胺(289.8mg,2.24mmol)，2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(284.2mg,747.45μmol)，20℃搅拌1小时。体系过滤，滤液经制备高效液相色谱(色谱柱:Waters Xbridge Prep OBD C18 150*40mm*10μm；流动相:[H2O(0.04％NH3H2O+10mM NH4HCO3)-ACN]；ACN％:20％-50％,8min)纯化得到化合物1。1HNMR(400MHz,DMSO-d6)δppm 8.55(s,1H),8.37(s,1H)，8.21(s,1H),8.02-8.04(m,1H),7.56-7.58(m,1H),7.16-7.33(m,5H),6.42-6.46(m,1H),5.35(s,2H),4.81-5.02(m,6H),4.47-4.48(m,2H),3.90(s,3H)；LCMS(ESI)m/z:540[M+1]+。Add 1-7 (200 mg, 498.30 μmol) and N, N-dimethylformamide (2 mL) to a pre-dried single-neck bottle, then add 1-8 (115.2 mg, 597.96 μmol), diisopropylethyl Amine (289.8mg, 2.24mmol), 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (284.2mg, 747.45μmol), stir at 20°C 1 hour. The system was filtered, and the filtrate was subjected to preparative high-performance liquid chromatography (chromatographic column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [H 2 O (0.04% NH 3 H 2 O + 10mM NH 4 HCO 3 )-ACN] ; ACN%: 20%-50%, 8min) to obtain compound 1 after purification. 1 HNMR (400MHz, DMSO-d 6 ) δppm 8.55 (s, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 8.02-8.04 (m, 1H), 7.56-7.58 (m, 1H), 7.16-7.33(m,5H),6.42-6.46(m,1H),5.35(s,2H),4.81-5.02(m,6H),4.47-4.48(m,2H),3.90(s,3H); LCMS(ESI)m/z:540[M+1] + .
实施例2
Example 2
Example 2
合成路线：
synthetic route:
synthetic route:
1)化合物2-1b的合成1) Synthesis of compound 2-1b
向预先干燥的反应瓶加入2-1a(23.0g，159.59mmol)，四氢呋喃(460mL)氮气保护下反应降温至-78℃后，加入二异丙基胺锂的四氢呋喃正庚烷混合溶液(2M，119.69mL)反应2小时后，向反应液中加入氰基甲酸乙酯(39.5g，398.98mmol，39.14mL)的四氢呋喃(230mL)溶液，继续反应0.5小时，将反应液缓慢升至15℃，向反应液中加入饱和氯化铵水溶液(700mL)，乙酸乙酯(700mL*2)萃取，合并有机相，加入饱和食盐水(300mL)洗涤，收集有机相加入无水硫酸钠干燥过滤，滤液减压浓缩至干，粗品通过柱层析纯化得到化合物2-1b。LCMS(ESI)m/z:217[M+1]+。2-1a (23.0g, 159.59mmol) was added to the pre-dried reaction flask, and tetrahydrofuran (460mL) was cooled to -78°C under nitrogen protection. After the reaction was cooled to -78°C, a mixed solution of lithium diisopropylamine in tetrahydrofuran-n-heptane (2M, 119.69mL) after reacting for 2 hours, add a solution of ethyl cyanoformate (39.5g, 398.98mmol, 39.14mL) in tetrahydrofuran (230mL) to the reaction solution, continue the reaction for 0.5 hours, slowly raise the reaction solution to 15°C, and add Add saturated ammonium chloride aqueous solution (700mL) to the reaction solution, extract with ethyl acetate (700mL*2), combine the organic phases, add saturated brine (300mL) to wash, collect the organic phases, add anhydrous sodium sulfate, dry and filter, and reduce the pressure of the filtrate Concentrate to dryness, and the crude product is purified by column chromatography to obtain compound 2-1b. LCMS(ESI)m/z:217[M+1] + .
2)化合物2-1c的合成2) Synthesis of compound 2-1c
向预先干燥的三口瓶中加入硼氢化锂(9.3g，427.42mmol)，无水四氢呋喃(220mL)，氮气保护，降温至0℃加入2-1b(22 0g，101.77mmol)和无水四氢呋喃(20mL)的混合溶液，自然回温至25℃后移至油浴40℃搅拌17小时。将合并体系缓慢倒入装有饱和氯化铵(1L)的溶液中淬灭，缓慢搅拌至无气泡产生。加入乙酸乙酯(200mL*3)萃取分液，收集有机相加入饱和食盐水(100mL)洗，有机相用无水硫酸钠干燥过滤，滤液减压浓缩至干得到化合物2-1c。LCMS(ESI)m/z:157[M-17]+。Add lithium borohydride (9.3g, 427.42mmol) and anhydrous tetrahydrofuran (220mL) to the pre-dried three-necked flask under nitrogen protection. Cool to 0°C and add 2-1b (220g, 101.77mmol) and anhydrous tetrahydrofuran (20mL). ), the mixed solution was naturally warmed to 25°C, then moved to an oil bath at 40°C and stirred for 17 hours. Slowly pour the combined system into a solution containing saturated ammonium chloride (1L) to quench, and stir slowly until no bubbles are generated. Add ethyl acetate (200 mL*3) for extraction and separation. Collect the organic phase and add saturated brine (100 mL) to wash. The organic phase is dried and filtered over anhydrous sodium sulfate. The filtrate is concentrated under reduced pressure to dryness to obtain compound 2-1c. LCMS(ESI)m/z:157[M-17] + .
3)化合物2-1d的合成3) Synthesis of compound 2-1d
向预先干燥的单口瓶中加入2-1c(14.0g，80.39mmol)，N,N-二甲基甲酰胺(140mL)，二氯亚砜(44.0g，369.81mmol，26.83mL)，25℃搅拌0.5小时，后体系升温至40℃，冰浴降温至25℃继续搅拌0.5小时。向体系中加入乙酸乙酯(100mL)，饱和氯化钠水溶液(100mL*3)洗，收集有机相加入无水硫酸钠干燥过滤，滤液减压浓缩至干，得到化合物2-1d。Add 2-1c (14.0g, 80.39mmol), N,N-dimethylformamide (140mL), and dichlorosulfoxide (44.0g, 369.81mmol, 26.83mL) to the pre-dried single-neck bottle, and stir at 25°C. After 0.5 hours, the system was heated to 40°C, and the ice bath was cooled to 25°C to continue stirring for 0.5 hours. Add ethyl acetate (100 mL) to the system and wash with saturated aqueous sodium chloride solution (100 mL*3). Collect the organic phase and add anhydrous sodium sulfate to dry it and filter. The filtrate is concentrated to dryness under reduced pressure to obtain compound 2-1d.
4)化合物2-1的合成
4) Synthesis of compound 2-1
向预先干燥的单口瓶中加入2-1d(15.4g，79.96mmol)，氨气/甲醇(14M，150mL)，25℃搅拌24小时。将体系旋干，加入无水二氯甲烷(100mL)，25℃搅拌0.5小时，过滤，滤饼用二氯甲烷(10mL*3)淋洗，收集滤出固体减压浓缩至干，得到目标化合物2-1。1HNMR(400MHz,DMSO-d6)δppm 7.28(dt,J＝5.4,9.4Hz,1H),7.14(dt,J＝1.8,9.2Hz,1H),4.03(s,2H),3.85(s,3H)；LCMS(ESI)m/z:174[M+1]+。Add 2-1d (15.4g, 79.96mmol) and ammonia/methanol (14M, 150mL) to the pre-dried one-neck bottle, and stir at 25°C for 24 hours. Spin the system to dryness, add anhydrous dichloromethane (100mL), stir at 25°C for 0.5 hours, filter, rinse the filter cake with dichloromethane (10mL*3), collect the filtered solid and concentrate to dryness under reduced pressure to obtain the target compound 2-1. 1 HNMR (400MHz, DMSO-d 6 ) δppm 7.28 (dt, J＝5.4, 9.4Hz, 1H), 7.14 (dt, J＝1.8, 9.2Hz, 1H), 4.03 (s, 2H), 3.85 (s, 3H); LCMS (ESI) m/z: 174[M+1] + .
5)化合物2的合成5) Synthesis of compound 2
在预先干燥的单口瓶中加入1-7(1g,2.49mmol)和N,N-二甲基甲酰胺(1mL)，四氢呋喃(5mL)，二异丙基乙基胺(1.45g,11.21mmol,1.95mL)，2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(1.42g,3.74mmol)，搅拌15分钟后加入化合物2-1(522.27mg,3.02mmol)，20℃搅拌45分钟。体系过滤，滤液经制备高效液相色谱(column:Waters Xbridge Prep OBD C18 150*40mm*10μm；流动相:[H2O(0.05％NH3H2O+10mM NH4HCO3)-ACN]；ACN:20％-60％,8min)纯化得到化合物2。1HNMR(400MHz,DMSO-d6)δppm 8.44-8.45(m,1H),8.42(s,1H),8.02-8.04(m,1H),7.56-7.58(m,1H),7.01-7.33(m,6H),6.4-6.46(m,1H),5.33(s,2H),4.84-5.04(m,6H),4.38-4.39(m,2H),3.81(s,3H)；LCMS(ESI)m/z:557[M+1]+。Add 1-7 (1g, 2.49mmol), N,N-dimethylformamide (1mL), tetrahydrofuran (5mL), and diisopropylethylamine (1.45g, 11.21mmol) to a pre-dried single-neck bottle. 1.95mL), 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (1.42g, 3.74mmol), stir for 15 minutes and then add compound 2- 1 (522.27 mg, 3.02 mmol), stir at 20°C for 45 minutes. The system was filtered , and the filtrate was subjected to preparative high-performance liquid chromatography ( column : Waters ACN: 20%-60%, 8 min) and purified to obtain compound 2. 1 HNMR(400MHz,DMSO-d6)δppm 8.44-8.45(m,1H),8.42(s,1H),8.02-8.04(m,1H),7.56-7.58(m,1H),7.01-7.33(m, 6H),6.4-6.46(m,1H),5.33(s,2H),4.84-5.04(m,6H),4.38-4.39(m,2H),3.81(s,3H); LCMS(ESI)m/ z:557[M+1] + .
实施例3
Example 3
Example 3
合成路线：
synthetic route:
synthetic route:
1)化合物3-2的合成1) Synthesis of compound 3-2
反应瓶清洗干净吹干，使用双排针加入二异丁基氢化铝的甲苯溶液(1M,15L)。氮气保护下控温15-30℃，滴加3-1(1.5kg,6.07mol)的四氢呋喃溶液(1.5L)。滴加完毕后体系15℃搅拌0.5小时。控温0-25℃，把反应液加入到搅拌的2M盐酸18L中淬灭。加入乙酸乙酯15L萃取，有机相用饱和食盐水5L洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物3-2。1HNMR(400MHz,CDCl3)δppm 7.36-7.39(m,1H),7.09-7.12(m,2H),4.70(s,2H),4.52(s,2H),1.83(s,1H)。Clean and blow dry the reaction bottle, and add diisobutylaluminum hydride toluene solution (1M, 15L) using a double-row needle. Control the temperature at 15-30°C under nitrogen protection, and add dropwise the tetrahydrofuran solution (1.5L) of 3-1 (1.5kg, 6.07mol). After the dropwise addition was completed, the system was stirred at 15°C for 0.5 hours. Control the temperature between 0-25°C and add the reaction solution to 18L of stirred 2M hydrochloric acid to quench. Add 15 L of ethyl acetate for extraction, wash the organic phase with 5 L of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 3-2. 1 HNMR (400MHz, CDCl 3 ) δppm 7.36-7.39 (m, 1H), 7.09-7.12 (m, 2H), 4.70 (s, 2H), 4.52 (s, 2H), 1.83 (s, 1H).
2)化合物3-4的合成2) Synthesis of compound 3-4
向预先干燥的反应中加入四氢呋喃(6200mL)，3-2(1.23kg,5.64mol)，3-3(650.08g,5.75mol)。然后加入碳酸钾(1.56kg,11.27mol)。体系62℃搅拌3小时，体系降温至约55℃，然后趁热过滤，用40℃的乙酸乙酯3.1L x 2淋洗滤饼，收集滤液，浓缩至干得到粗品。粗品加入乙酸乙酯6.2L溶解粗品，搅拌下缓慢滴加正庚烷3.7L，有大量固体析出，过滤，滤饼减压浓缩得到化合物3-4。LCMS(ESI)m/z:252[M+1]+。Tetrahydrofuran (6200 mL), 3-2 (1.23 kg, 5.64 mol), 3-3 (650.08 g, 5.75 mol) were added to the previously dried reaction. Then add potassium carbonate (1.56kg, 11.27mol). Stir the system at 62°C for 3 hours, cool the system to about 55°C, then filter while hot, rinse the filter cake with 3.1L x 2 of ethyl acetate at 40°C, collect the filtrate, and concentrate to dryness to obtain the crude product. Add 6.2L of ethyl acetate to the crude product to dissolve the crude product, slowly add 3.7L of n-heptane dropwise with stirring, a large amount of solid precipitates, filter, and the filter cake is concentrated under reduced pressure to obtain compound 3-4. LCMS(ESI)m/z:252[M+1] + .
3)化合物3-5的合成3) Synthesis of compound 3-5
预先洗净的反应瓶中加入3-4(1180g,4.70mol)，二氯甲烷(5900mL)，N,N-二甲基甲酰胺(102.99g，1.41mol)。搭好尾气吸收装置和干燥管。控温15-30℃滴加氯化亚砜(1.69kg,14.18mol)。滴加完毕，体系15℃搅拌12小时。有大量白色固体析出，体系过滤，滤饼用正庚烷(1770mL x 2，1.5V)淋洗。滤饼分批加入到饱和碳酸氢钠水溶液4L和乙酸乙酯4L的混合溶剂中搅拌10分钟，pH＝9。分液，有机相用饱和食盐水500mL洗涤，无水硫酸钠干燥，过滤，减压浓缩滤液得到化合物3-5。LCMS(ESI)m/z:
270[M+1]+。Add 3-4 (1180g, 4.70mol), dichloromethane (5900mL), and N,N-dimethylformamide (102.99g, 1.41mol) to the previously cleaned reaction bottle. Set up the exhaust gas absorption device and drying pipe. Add thionyl chloride (1.69kg, 14.18mol) dropwise while controlling the temperature to 15-30°C. After the dropwise addition was completed, the system was stirred at 15°C for 12 hours. A large amount of white solid precipitated, the system was filtered, and the filter cake was rinsed with n-heptane (1770mL x 2, 1.5V). The filter cake was added in batches to a mixed solvent of 4L of saturated sodium bicarbonate aqueous solution and 4L of ethyl acetate and stirred for 10 minutes, pH=9. The liquids were separated, and the organic phase was washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3-5. LCMS(ESI)m/z: 270[M+1] + .
4)化合物3-6的合成4) Synthesis of compounds 3-6
在预先干燥的反应瓶中加入3-5(113mg,420.18μmol)和N,N-二甲基甲酰胺(mL)，然后加入碳酸钾(116mg,840.36μmol)和1-5(90mg,420.18μmol)，氮气抽排三次，油浴65℃搅拌6小时。向反应液中加入水10mL，饱和食盐水20mL和乙酸乙酯20mL，分液，有机相无水硫酸钠干燥过滤，减压浓缩溶剂至干得到粗品。粗品柱层析纯化得到化合物3-6。LCMS(ESI)m/z:448[M+1]+。Add 3-5 (113mg, 420.18μmol) and N,N-dimethylformamide (mL) to the pre-dried reaction bottle, then add potassium carbonate (116mg, 840.36μmol) and 1-5 (90mg, 420.18μmol ), exhaust nitrogen three times, and stir in an oil bath at 65°C for 6 hours. Add 10 mL of water, 20 mL of saturated brine and 20 mL of ethyl acetate to the reaction solution, separate the layers, dry and filter the organic phase over anhydrous sodium sulfate, and concentrate the solvent under reduced pressure to dryness to obtain a crude product. The crude product was purified by column chromatography to obtain compound 3-6. LCMS(ESI)m/z:448[M+1] + .
5)化合物3-7的合成5) Synthesis of compounds 3-7
在预先干燥的单口瓶中加入3-6(260mg,581.13μmol)，乙醇(2.65mL)，四氢呋喃(2.65mL)，水(0.9mL)，然后加入氢氧化钠(69mg,1.74mmol)，65℃搅拌3小时。向反应液中一边搅拌一边缓慢加入0.5M的柠檬酸水溶液到约pH＝2，有大量白色固体析出，过滤，滤饼用5mL水洗涤后滤饼减压浓缩至干得到化合物3-7。LCMS(ESI)m/z:420[M+1]+。Add 3-6 (260 mg, 581.13 μmol), ethanol (2.65 mL), tetrahydrofuran (2.65 mL), water (0.9 mL) to the pre-dried single-neck bottle, then add sodium hydroxide (69 mg, 1.74 mmol), 65°C Stir for 3 hours. Slowly add 0.5 M citric acid aqueous solution to the reaction solution while stirring until the pH is about 2. A large amount of white solid precipitates. Filter. The filter cake is washed with 5 mL of water and concentrated under reduced pressure to dryness to obtain compound 3-7. LCMS(ESI)m/z:420[M+1] + .
6)化合物3的合成6) Synthesis of compound 3
在预先干燥的单口瓶中加入3-7(120mg,286.15μmol)和四氢呋喃(2mL)，然后加入羰基二咪唑(61.71mg,380.59μmol)和二异丙基乙基胺(129.44mg,1.00mmol,174.45uL)，50℃搅拌0.5小时。加入2-1(99.10mg,572.31μmol)，50℃搅拌2小时。向反应液中加入10mL饱和食盐水和10mL乙酸乙酯，分液，有机相无水硫酸钠干燥过滤减压浓缩溶剂至干，粗品后送制备分离(column:Waters Xbridge Prep OBD C18150*40mm*10μm；流动相:[H2O(10mM NH4HCO3)-ACN]；ACN:25％-55％,8min)得到化合物3。1HNMR(400MHz,CDCl3)δppm 7.85(s,1H),7.47-7.49(m,1H),7.29-7.30(m,2H),6.55-7.03(m,6H),5.24(s,2H),4.96-5.18(m,6H),4.62-4.64(m,2H),3.86(s,3H)；LCMS(ESI)m/z:575[M+1]+。Add 3-7 (120mg, 286.15μmol) and tetrahydrofuran (2mL) to a pre-dried single-neck bottle, then add carbonyldiimidazole (61.71mg, 380.59μmol) and diisopropylethylamine (129.44mg, 1.00mmol). 174.45uL), stir at 50°C for 0.5 hours. Add 2-1 (99.10 mg, 572.31 μmol) and stir at 50°C for 2 hours. Add 10 mL saturated brine and 10 mL ethyl acetate to the reaction solution, separate the liquids, dry the organic phase over anhydrous sodium sulfate, filter and concentrate the solvent under reduced pressure to dryness, and send the crude product to preparation and separation (column: Waters Xbridge Prep OBD C18150*40mm*10μm ; Mobile phase: [H 2 O (10mM NH 4 HCO 3 )-ACN]; ACN: 25%-55%, 8min) to obtain compound 3. 1 HNMR (400MHz, CDCl 3 ) δppm 7.85 (s, 1H), 7.47-7.49 (m, 1H), 7.29-7.30 (m, 2H), 6.55-7.03 (m, 6H), 5.24 (s, 2H), 4.96-5.18(m,6H),4.62-4.64(m,2H),3.86(s,3H); LCMS(ESI)m/z:575[M+1] + .
实施例4
Example 4
Example 4
合成路线：
synthetic route:
synthetic route:
1)化合物4-1的合成1) Synthesis of compound 4-1
在反应瓶中加入1-5c(3.1g,9.05mmol)，二氯甲烷(30mL)，三乙胺(4.58g,45.26mmol)，4-二甲氨基吡啶(110mg,905.21μmol)，降温至0℃加入乙酸酐(1.85g,18.10mmol)，0℃反应2小时，反应液直接旋干得到粗产品。粗品经柱层析纯化得到化合物4-1。LCMS(ESI)m/z:385[M+1]+。Add 1-5c (3.1g, 9.05mmol), dichloromethane (30mL), triethylamine (4.58g, 45.26mmol), 4-dimethylaminopyridine (110mg, 905.21μmol) into the reaction bottle, and cool to 0 Acetic anhydride (1.85g, 18.10mmol) was added at 0°C, and the reaction was carried out at 0°C for 2 hours. The reaction solution was directly spun to dryness to obtain a crude product. The crude product was purified by column chromatography to obtain compound 4-1. LCMS(ESI)m/z:385[M+1] + .
2)化合物4-2的合成2) Synthesis of compound 4-2
0℃下，向预先干燥的反应瓶中加入二氯甲烷(10mL)，4-1(0.9g,2.34mmol)，然后加入三氟乙酸(6.93g,60.78mmol)。0℃搅拌0.5小时。向体系中缓慢加入饱和碳酸氢钠水溶液调节pH＝8～9，然后加入二氯甲烷5mL，分液，有机相无水硫酸钠干燥，过滤，浓缩得到粗品，柱层析纯化后得到化合物4-2。LCMS(ESI)m/z:255[M+1]+。At 0°C, add dichloromethane (10 mL), 4-1 (0.9 g, 2.34 mmol) to the pre-dried reaction bottle, and then add trifluoroacetic acid (6.93 g, 60.78 mmol). Stir at 0°C for 0.5 hours. Slowly add saturated sodium bicarbonate aqueous solution to the system to adjust pH=8~9, then add 5 mL of methylene chloride, separate the liquids, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. After purification by column chromatography, compound 4- is obtained. 2. LCMS(ESI)m/z:255[M+1] + .
3)化合物4-3的合成3) Synthesis of compound 4-3
向预先干燥的反应瓶中加入N,N-二甲基甲酰胺(5mL)，4-2(0.35g,1.38mmol)，然后加入碳酸钾(380mg,2.75mmol)，1-4(346.48mg,1.38mmol)。体系65℃搅拌3小时。向体系中加入水10mL，乙酸乙酯10mL，分液，水相用乙酸乙酯10mL*3萃取，合并有机相，有机相无水硫酸钠干燥，过滤，浓缩得到粗品化合物4-3。LCMS(ESI)m/z:470[M+1]+。Add N,N-dimethylformamide (5mL), 4-2 (0.35g, 1.38mmol) to the pre-dried reaction bottle, then add potassium carbonate (380mg, 2.75mmol), 1-4 (346.48mg, 1.38mmol). The system was stirred at 65°C for 3 hours. Add 10 mL of water and 10 mL of ethyl acetate to the system, separate the layers, extract the aqueous phase with 10 mL*3 of ethyl acetate, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate to obtain crude compound 4-3. LCMS(ESI)m/z:470[M+1] + .
4)化合物4-4的合成4) Synthesis of compound 4-4
向预先干燥的反应瓶中加入甲醇(5mL)，4-3(0.5g,1.07mmol)，然后加入2M氢氧化钠2.66mL。体系70℃搅拌3小时。向体系中加入1M柠檬酸水溶液调节pH＝3～4，然后浓缩除去甲醇，无固体析出。加入10mL乙酸乙酯，分液，有机相无水硫酸钠干燥，过滤，浓缩得到粗品，粗品制备薄层色谱纯化得到化合物4-4。LCMS(ESI)m/z:400[M+1]+。Methanol (5 mL), 4-3 (0.5 g, 1.07 mmol) was added to the pre-dried reaction flask, and then 2.66 mL of 2M sodium hydroxide was added. The system was stirred at 70°C for 3 hours. Add 1M citric acid aqueous solution to the system to adjust the pH to 3-4, then concentrate to remove methanol, and no solid will precipitate. Add 10 mL of ethyl acetate and separate the layers. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product is purified by preparative thin layer chromatography to obtain compound 4-4. LCMS(ESI)m/z:400[M+1] + .
5)化合物4的合成5) Synthesis of compound 4
0℃，向预先干燥的反应瓶中加入N,N-二甲基甲酰胺(1mL)，4-4(75mg,187.79μmol)，二异丙基乙基胺(97mg,751.18μmol)，然后加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(105mg,277.94
μmol)，氮气置换3次，加入2-1(47.24mg,225.35μmol)。20℃搅拌2小时。制备高效液相色谱(column:Phenomenex Gemini-NX C18 75*30mm*3μm；mobile phase:[H2O(10mM NH4HCO3)-ACN]；ACN％:25％-55％,8min)纯化得到化合物4。1HNMR(400MHz,DMSO-d6)δppm 8.71-8.73(m,1H),8.32(s,1H),8.03-8.05(m,1H),7.56-7.59(m,1H),7.02-7.14(m,5H),6.41-6.45(m,1H),5.30(s,2H),5.01(s,2H),4.82-4.84(m,2H),4.42-4.57(m,4H),3.81(s,3H)；LCMS(ESI)m/z:555[M+1]+。0°C, add N,N-dimethylformamide (1mL), 4-4 (75mg, 187.79μmol), diisopropylethylamine (97mg, 751.18μmol) to the pre-dried reaction bottle, and then add 2-(7-Azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (105mg, 277.94 μmol), replaced with nitrogen three times, and added 2-1 (47.24 mg, 225.35 μmol). Stir at 20°C for 2 hours. Purified by preparative high performance liquid chromatography (column: Phenomenex Gemini-NX C18 75*30mm*3μm; mobile phase: [H 2 O (10mM NH 4 HCO 3 )-ACN]; ACN%: 25%-55%, 8min) Compound 4. 1 HNMR (400MHz, DMSO-d 6 ) δppm 8.71-8.73(m,1H),8.32(s,1H),8.03-8.05(m,1H),7.56-7.59(m,1H),7.02-7.14(m ,5H),6.41-6.45(m,1H),5.30(s,2H),5.01(s,2H),4.82-4.84(m,2H),4.42-4.57(m,4H),3.81(s,3H ); LCMS(ESI)m/z:555[M+1] + .
实施例5
Example 5
Example 5
合成路线：
synthetic route:
synthetic route:
1)化合物5-1的合成1) Synthesis of compound 5-1
向预先干燥的反应瓶中加入N,N-二甲基甲酰胺(6mL)，4-2(0.5g,1.97mmol)，然后加入碳酸钾(543.62mg,3.93mmol)，3-5(583mg,2.16mmol)。体系65℃搅拌3小时。向体系中加入水10mL，乙酸乙酯10mL，分液，有机相无水硫酸钠干燥，过滤，浓缩至干得到化合物5-1。LCMS(ESI)m/z:488[M+1]+。Add N,N-dimethylformamide (6mL), 4-2 (0.5g, 1.97mmol) to the pre-dried reaction bottle, then add potassium carbonate (543.62mg, 3.93mmol), 3-5 (583mg, 2.16mmol). The system was stirred at 65°C for 3 hours. Add 10 mL of water and 10 mL of ethyl acetate to the system, separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate to dryness to obtain compound 5-1. LCMS(ESI)m/z:488[M+1] + .
2)化合物5-2的合成2) Synthesis of compound 5-2
向预先干燥的反应瓶中加入甲醇(10mL)，5-1(1.2g,2.46mmol,1eq)，然后加入2.5M氢氧化钠2mL。体系65℃搅拌3小时。体系降温至20℃，浓缩除去甲醇，向体系中加入水10mL，乙酸乙酯10mL，分液，收集水相，浓缩至干得到粗品，粗品制备薄层色谱纯化得到化合物5-2。LCMS(ESI)m/z:418[M+1]+
Add methanol (10 mL), 5-1 (1.2 g, 2.46 mmol, 1 eq) to the pre-dried reaction bottle, and then add 2 mL of 2.5 M sodium hydroxide. The system was stirred at 65°C for 3 hours. The system was cooled to 20°C, concentrated to remove methanol, 10 mL of water and 10 mL of ethyl acetate were added to the system, the liquids were separated, the aqueous phase was collected, concentrated to dryness to obtain a crude product, and the crude product was purified by thin layer chromatography to obtain compound 5-2. LCMS(ESI)m/z:418[M+1] +
3)化合物5的合成3) Synthesis of compound 5
0℃下，向预先干燥的反应瓶中加入N,N-二甲基甲酰胺(3mL)，5-2(0.2g,479.20μmol)，二异丙基乙基
胺(495mg,3.83mmol)，然后加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(273mg,718.80umo)，氮气置换3次，然后加入2-1(110.50mg,527.12μmol)，体系20℃搅拌2小时。体系过滤，滤液高效液相色谱(column:Phenomenex Gemini-NX C18 75*30mm*3μm；流动相:[H2O(0.05％NH3H2O+10mM NH4HCO3)-ACN]；ACN％:15％-45％,8min)纯化得到化合物5。1HNMR(400MHz,CD3OD)δppm 8.16(s,1H),7.73-7.74(m,1H),7.54-7.55(m,1H),7.29-7.31(m,1H),6.90-7.10(m,4H),6.52-6.56(m,1H),5.33(s,2H),5.16(s,2H),5.00-5.01(m,2H),4.70-4.72(m,2H),4.55(s,2H),3.85(s,3H)；LCMS(ESI)m/z:573[M+1]+。At 0°C, add N,N-dimethylformamide (3mL), 5-2 (0.2g, 479.20μmol), and diisopropylethyl to the pre-dried reaction bottle. Amine (495mg, 3.83mmol), then add 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (273mg, 718.80umo), nitrogen replacement 3 times, then 2-1 (110.50 mg, 527.12 μmol) was added, and the system was stirred at 20°C for 2 hours. The system was filtered, and the filtrate was subjected to high performance liquid chromatography (column: Phenomenex Gemini-NX C18 75*30mm*3μm; mobile phase: [H 2 O (0.05% NH 3 H 2 O + 10mM NH 4 HCO 3 )-ACN]; ACN% :15%-45%, 8min) and purified to obtain compound 5. 1 HNMR (400MHz, CD 3 OD) δppm 8.16 (s, 1H), 7.73-7.74 (m, 1H), 7.54-7.55 (m, 1H), 7.29-7.31 (m, 1H), 6.90-7.10 (m, 4H),6.52-6.56(m,1H),5.33(s,2H),5.16(s,2H),5.00-5.01(m,2H),4.70-4.72(m,2H),4.55(s,2H) ,3.85(s,3H); LCMS(ESI)m/z:573[M+1] + .
实施例6
Example 6
Example 6
合成路线：
synthetic route:
synthetic route:
1)化合物6-1的合成1) Synthesis of compound 6-1
向预先干燥的反应瓶中加入1-5a(50g,356.79mmol)，乙腈(500mL)，然后加入对甲氧基苄氯(6.99g,363.90mmol)，碳酸钾(59.17g,428.14mmol)，体系90℃反应16小时。反应液直接过滤，滤饼用100mL
乙腈洗涤，滤液减压浓缩得到化合物6-1。1HNMR(400MHz,DMSO-d6)δppm 8.39s,1H),7.84(s,1H),7.24-7.26(m,2H),6.89-6.91(m,2H),5.27(s,2H),4.16-4.22(m,2H),3.72(s,3H),1.22-1.26(m,3H)。Add 1-5a (50g, 356.79mmol) and acetonitrile (500mL) to the pre-dried reaction flask, then add p-methoxybenzyl chloride (6.99g, 363.90mmol), potassium carbonate (59.17g, 428.14mmol), and the system React at 90°C for 16 hours. The reaction solution is filtered directly, and 100mL of filter cake is used. Washed with acetonitrile, the filtrate was concentrated under reduced pressure to obtain compound 6-1. 1 HNMR(400MHz, DMSO-d 6 )δppm 8.39s,1H),7.84(s,1H),7.24-7.26(m,2H),6.89-6.91(m,2H),5.27(s,2H),4.16 -4.22(m,2H),3.72(s,3H),1.22-1.26(m,3H).
2)化合物6-2的合成2) Synthesis of compound 6-2
在预先干燥的三口瓶中加入6-1(49g,188.25mmol)和四氢呋喃(500mL)，降温至-60℃后加入二异丙基氨基锂(2M,141.19mL)，-60℃搅拌0.5小时后加入氧杂环丁酮(20.35g,282.38mmol)，-60℃反应1.5小时。向反应液中倒入饱和氯化铵水溶液200mL，搅拌至室温后再加入饱和食盐水200mL和乙酸乙酯200mL。分液，有机相减压浓缩溶剂至干得到粗品，粗品用乙酸乙酯打浆得到化合物6-2。1HNMR(400MHz,DMSO-d6)δppm 7.85(s,1H),7.14-7.16(m,2H),6.87-6.89(m,2H),5.00(s,2H),4.92-4.94(m,2H),4.67-4.69(m,2H),4.16-4.21(m,2H),3.72(s,3H),1.24-1.27(m,3H)。Add 6-1 (49g, 188.25mmol) and tetrahydrofuran (500mL) to a pre-dried three-necked flask, cool to -60°C, add lithium diisopropylamide (2M, 141.19mL), and stir at -60°C for 0.5 hours. Add oxetanone (20.35g, 282.38mmol) and react at -60°C for 1.5 hours. Pour 200 mL of saturated aqueous ammonium chloride solution into the reaction solution, stir to room temperature, and then add 200 mL of saturated brine and 200 mL of ethyl acetate. The liquids were separated, and the organic phase was concentrated under reduced pressure to dryness to obtain a crude product. The crude product was slurried with ethyl acetate to obtain compound 6-2. 1HNMR (400MHz, DMSO-d 6 ) δppm 7.85 (s, 1H), 7.14-7.16 (m, 2H) ),6.87-6.89(m,2H),5.00(s,2H),4.92-4.94(m,2H),4.67-4.69(m,2H),4.16-4.21(m,2H),3.72(s,3H ),1.24-1.27(m,3H).
3)化合物6-3的合成3) Synthesis of compound 6-3
向预先干燥的反应瓶中加入四氢呋喃(23mL)，6-2(1.5g,4.51mmol)，然后加入氢化钠(361mg,9.03mmol,60％纯度)，碘甲烷(1.28g,9.03mmol)。体系20℃搅拌5小时。向体系中加入乙酸乙酯20mL，水20mL，分液，有机相用饱和食盐水20mL洗涤，无水硫酸钠干燥，过滤，浓缩至干得到粗品化合物6-3。LCMS(ESI)m/z:347[M+1]+。Add tetrahydrofuran (23 mL) and 6-2 (1.5 g, 4.51 mmol) to the pre-dried reaction flask, then add sodium hydride (361 mg, 9.03 mmol, 60% purity) and methyl iodide (1.28 g, 9.03 mmol). The system was stirred at 20°C for 5 hours. Add 20 mL of ethyl acetate and 20 mL of water to the system, separate the layers, wash the organic phase with 20 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness to obtain crude compound 6-3. LCMS(ESI)m/z:347[M+1] + .
4)化合物6-4的合成4) Synthesis of compound 6-4
向预先干燥的反应瓶中加入乙腈(2mL)，6-3(1g,2.89mmol)，然后加入溶于水(7mL)的硝酸铈铵(3.17g,5.77mmol)。20℃搅拌1小时。向体系中加入乙酸乙酯20mL，水10mL，分液，水相用乙酸乙酯15mL萃取，合并有机相，有机相用饱和食盐水20mL洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品，粗品柱层析纯化得到化合物6-4。LCMS(ESI)m/z:227[M+1]+。Acetonitrile (2 mL), 6-3 (1 g, 2.89 mmol) was added to the pre-dried reaction flask, and then ceric ammonium nitrate (3.17 g, 5.77 mmol) dissolved in water (7 mL) was added. Stir at 20°C for 1 hour. Add 20 mL of ethyl acetate and 10 mL of water to the system, separate the liquids, extract the aqueous phase with 15 mL of ethyl acetate, combine the organic phases, wash the organic phase with 20 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. Purification by column chromatography gave compound 6-4. LCMS(ESI)m/z:227[M+1] + .
5)化合物6-5的合成5) Synthesis of compound 6-5
向预先干燥的反应瓶中加入6-4(377mg,1.67mmol)，N,N二甲基甲酰胺(6mL)，碳酸钾(461.28mg,3.34mmol)，然后加入1-4(0.42g,1.67mmol)。体系65℃搅拌12小时。向体系中加入乙酸乙酯20mL，水20mL，分液，水相用乙酸乙酯20mL萃取，合并有机相，有机相用饱和食盐水20mL洗涤，无水硫酸钠干燥，过滤，浓缩至干得到粗品化合物6-5。LCMS(ESI)m/z:442[M+1]+。Add 6-4 (377mg, 1.67mmol), N,N dimethylformamide (6mL), potassium carbonate (461.28mg, 3.34mmol) to the pre-dried reaction bottle, then add 1-4 (0.42g, 1.67 mmol). The system was stirred at 65°C for 12 hours. Add 20 mL of ethyl acetate and 20 mL of water to the system, separate the liquids, extract the aqueous phase with 20 mL of ethyl acetate, combine the organic phases, wash the organic phase with 20 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness to obtain the crude product Compound 6-5. LCMS(ESI)m/z:442[M+1] + .
6)化合物6-6的合成6) Synthesis of compound 6-6
向预先干燥的反应瓶中加入乙醇(8mL)，6-5(0.8g,1.81mmol)，四氢呋喃(8mL)，然后加入2.5M氢氧化钠1.45mL。体系65℃搅拌3小时。体系降温至20℃，然后加入1M柠檬酸水溶液调节pH＝3～4，减压浓缩除去乙醇，然后加入乙酸乙酯10mL，分液，水相用乙酸乙酯10mL萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得到粗品，粗品柱层析纯化得到化合物6-6。LCMS(ESI)m/z:414[M+1]+
Add ethanol (8 mL), 6-5 (0.8 g, 1.81 mmol), and tetrahydrofuran (8 mL) to the pre-dried reaction bottle, and then add 1.45 mL of 2.5 M sodium hydroxide. The system was stirred at 65°C for 3 hours. Cool the system to 20°C, then add 1M citric acid aqueous solution to adjust pH = 3 to 4, concentrate under reduced pressure to remove ethanol, then add 10 mL of ethyl acetate, separate the liquids, extract the aqueous phase with 10 mL of ethyl acetate, combine the organic phases, and anhydrous Dry over sodium sulfate, filter, and concentrate to obtain a crude product, which is purified by column chromatography to obtain compound 6-6. LCMS(ESI)m/z:414[M+1] +
7)化合物6-的合成
7) Synthesis of compound 6-
向预先干燥的反应瓶中加入N,N二甲基甲酰胺(2mL)，6-6(0.2g,483.80μmol)，降温至0℃，加入二异丙基乙基胺(500.22mg,3.87mmol),2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(275.93mg,725.69μmol)，氮气置换3次，然后加入2-1(119mg,532.17μmol)，加料完毕，氮气置换3次，自然升温至20℃搅拌2小时。体系过滤，滤液制备高效液相色谱(column:Kromasil C18(250*50mm*10μm)；流动相:[H2O(10mM NH4HCO3)-ACN]；ACN％:15％-55％,10min)纯化得到化合物6。1HNMR(400MHz,DMSO-d6)δppm 8.27(s,1H),8.18-8.20(m,1H),8.01-8.02(m,1H),7.54-7.56(m,1H),7.01-7.29(m,6H),6.41-6.45(m,1H),5.32(s,2H),5.00(s,2H),4.83-4.85(m,2H),4.63-4.65(m,2H),4.39-4.40(m,2H),3.81(s,3H),2.93(s,3H)；LCMS(ESI)m/z:569[M+1]+。Add N,N dimethylformamide (2mL), 6-6 (0.2g, 483.80μmol) to the pre-dried reaction bottle, cool to 0°C, add diisopropylethylamine (500.22mg, 3.87mmol) ), 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (275.93mg, 725.69μmol), replace with nitrogen 3 times, then add 2-1 (119 mg, 532.17 μmol), after the addition was completed, nitrogen was replaced three times, and the temperature was naturally raised to 20°C and stirred for 2 hours. The system was filtered, and the filtrate was prepared for high-performance liquid chromatography (column: Kromasil C18 (250*50mm*10μm); mobile phase: [H 2 O (10mM NH 4 HCO 3 )-ACN]; ACN%: 15%-55%, 10min ) was purified to obtain compound 6. 1 HNMR(400MHz, DMSO-d 6 )δppm 8.27(s,1H),8.18-8.20(m,1H),8.01-8.02(m,1H),7.54-7.56(m,1H),7.01-7.29(m ,6H),6.41-6.45(m,1H),5.32(s,2H),5.00(s,2H),4.83-4.85(m,2H),4.63-4.65(m,2H),4.39-4.40(m ,2H),3.81(s,3H),2.93(s,3H); LCMS(ESI)m/z:569[M+1] + .
实施例7
Example 7
Example 7
合成路线：
synthetic route:
synthetic route:
1)化合物7-1的合成1) Synthesis of compound 7-1
向预先干燥的反应瓶中加入6-4(587mg,2.60mmol)，N,N二甲基甲酰胺(7mL)，碳酸钾(717mg,5.19mmol)，然后加入3-5(0.7g,2.60mmol)。体系65℃搅拌12小时。向体系中加入乙酸乙酯20mL，水20mL，分液，水相用乙酸乙酯20mL萃取，合并有机相，有机相用饱和食盐水20mL洗涤，无水硫酸钠干燥，过滤，浓缩至干得到化合物7-1。LCMS(ESI)m/z:460[M+1]+。Add 6-4 (587mg, 2.60mmol), N,N dimethylformamide (7mL), potassium carbonate (717mg, 5.19mmol) to the pre-dried reaction flask, then add 3-5 (0.7g, 2.60mmol) ). The system was stirred at 65°C for 12 hours. Add 20 mL of ethyl acetate and 20 mL of water to the system, separate the liquids, extract the aqueous phase with 20 mL of ethyl acetate, combine the organic phases, wash the organic phase with 20 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness to obtain the compound. 7-1. LCMS(ESI)m/z:460[M+1] + .
2)化合物7-2的合成
2) Synthesis of compound 7-2
向预先干燥的反应瓶中加入乙醇(10mL)，四氢呋喃(10mL)，7-1(1.7g,3.70mmol)，然后加入2.5M氢氧化钠3.40mL。体系65℃搅拌3小时。体系降温至20℃，减压浓缩除去乙醇，加入10mL水，水相用1M盐酸水溶液调节pH＝3～4，搅拌10min,有固体析出，过滤，收集滤饼，用10mL乙腈打浆，过滤，滤饼减压浓缩至干得到化合物7-2。LCMS(ESI)m/z:432[M+1]+。Add ethanol (10 mL), tetrahydrofuran (10 mL), 7-1 (1.7 g, 3.70 mmol) to the pre-dried reaction bottle, and then add 3.40 mL of 2.5 M sodium hydroxide. The system was stirred at 65°C for 3 hours. Cool the system to 20°C, concentrate under reduced pressure to remove ethanol, add 10 mL of water, adjust the water phase to pH=3~4 with 1M hydrochloric acid aqueous solution, stir for 10 minutes, if solid precipitates, filter, collect the filter cake, beat with 10 mL of acetonitrile, filter, filter The cake was concentrated to dryness under reduced pressure to obtain compound 7-2. LCMS(ESI)m/z:432[M+1] + .
3)化合物7的合成3) Synthesis of compound 7
向预先干燥的反应瓶中加入7-2(0.1g,231.81μmol)，2-1(48mg,278.17μmol),N,N二甲基甲酰胺(1mL)，二异丙基乙基胺(239mg,1.85mmol)，0℃加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(132mg,347.71μmol)。体系25℃搅拌1小时，体系过滤，滤液制备高效液相色谱column:Waters Xbridge BEH C18 100*30mm*10μm；流动相:[H2O(10mM NH4HCO3)-ACN]；ACN％:20％-45％,8min纯化得到化合物7。1HNMR(400MHz,DMSO-d6)δppm 8.29(s,1H),8.19-8.21(m,1H),7.94-7.95(m,1H),7.59-7.61(m,1H),7.02-7.14(m,5H),6.41-6.45(m,1H),5.35(s,2H),5.05(s,2H),4.83-4.85(m,2H),4.63-4.65(m,2H),4.40-4.41(m,2H),3.81(s,3H),2.94(s,3H)；LCMS(ESI)m/z:587[M+1]+。Add 7-2 (0.1g, 231.81μmol), 2-1 (48mg, 278.17μmol), N,N dimethylformamide (1mL), and diisopropylethylamine (239mg) to the pre-dried reaction bottle. ,1.85mmol), add 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (132mg, 347.71μmol) at 0°C. The system was stirred at 25°C for 1 hour, the system was filtered, and the filtrate was prepared for HPLC column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [H 2 O (10mM NH 4 HCO 3 )-ACN]; ACN%: 20 %-45%, purified in 8 minutes to obtain compound 7. 1 HNMR(400MHz, DMSO-d 6 )δppm 8.29(s,1H),8.19-8.21(m,1H),7.94-7.95(m,1H),7.59-7.61(m,1H),7.02-7.14(m ,5H),6.41-6.45(m,1H),5.35(s,2H),5.05(s,2H),4.83-4.85(m,2H),4.63-4.65(m,2H),4.40-4.41(m ,2H),3.81(s,3H),2.94(s,3H); LCMS(ESI)m/z:587[M+1] + .
实施例8
Example 8
Example 8
合成路线：
synthetic route:
synthetic route:
1)化合物8-2的合成1) Synthesis of compound 8-2
向预先干燥的反应瓶中加入N,N二甲基甲酰胺(50mL)，8-1(5g,38.43mmol)，氘代碘甲烷(8.36g,57.65mmol)，碳酸钾(10.62g,76.87mmol)。65℃搅拌3小时。降温至-65℃，缓慢滴加二异丙基氨基锂的四氢
呋喃和正己烷的混合溶液(2M,23.08mL)，搅拌1小时。向体系加入饱和氯化铵水溶液50mL，乙酸乙酯50mL，静置分液，水相用乙酸乙酯50mL萃取，合并有机相用饱和食盐水100mL洗涤，有机相无水硫酸钠干燥，减压浓缩得到粗品，粗品柱层析纯化得到化合物8-2。LCMS(ESI)m/z:176[M+1]+。Add N,N dimethylformamide (50mL), 8-1 (5g, 38.43mmol), deuterated methyl iodide (8.36g, 57.65mmol), and potassium carbonate (10.62g, 76.87mmol) to the pre-dried reaction bottle. ). Stir at 65°C for 3 hours. Cool the temperature to -65°C and slowly add tetrahydrogen lithium diisopropylamide dropwise. A mixed solution of furan and n-hexane (2M, 23.08mL) was stirred for 1 hour. Add 50 mL of saturated ammonium chloride aqueous solution and 50 mL of ethyl acetate to the system, let stand for liquid separation, extract the aqueous phase with 50 mL of ethyl acetate, wash the combined organic phase with 100 mL of saturated brine, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. A crude product was obtained, and the crude product was purified by column chromatography to obtain compound 8-2. LCMS(ESI)m/z:176[M+1] + .
2)化合物8-3的合成2) Synthesis of compound 8-3
向预先干燥的反应瓶中加入8-2(2.6g,14.84mmol)，甲醇(35mL)，-5℃分批加入硼氢化钠(561mg,14.84mmol)，体系自然升温至25℃搅拌1小时，向体系中加入饱和氯化铵溶液20mL，25℃搅拌0.5小时，减压浓缩除去甲醇，加入乙酸乙酯40mL，水20mL，分液，水相用乙酸乙酯20mL萃取，合并有机相，无水硫酸钠干燥，减压浓缩得到化合物8-3。1HNMR(400MHz,DMSO-d6)δppm 7.11-7.14(m,1H),6.97-7.09(m,1H),5.20-5.22(m,1H),4.47-4.48(m,2H)。Add 8-2 (2.6g, 14.84mmol) and methanol (35mL) to the pre-dried reaction bottle. Add sodium borohydride (561mg, 14.84mmol) in batches at -5°C. The system will naturally warm to 25°C and stir for 1 hour. Add 20 mL of saturated ammonium chloride solution to the system, stir at 25°C for 0.5 hours, concentrate under reduced pressure to remove methanol, add 40 mL of ethyl acetate and 20 mL of water, separate the liquids, extract the aqueous phase with 20 mL of ethyl acetate, combine the organic phases, and anhydrous Dry over sodium sulfate and concentrate under reduced pressure to obtain compound 8-3. 1HNMR (400MHz, DMSO-d6) δppm 7.11-7.14(m,1H),6.97-7.09(m,1H),5.20-5.22(m,1H),4.47 -4.48(m,2H).
3)化合物8-4的合成3) Synthesis of compound 8-4
向预先干燥的反应瓶中加入二氯甲烷(40mL)，8-3(3.9g,22.01mmol)，N,N二甲基甲酰胺(884.98mg,12.11mmol)，降温至0℃，缓慢滴加氯化亚砜(7.86g,66.04mmol)。体系25℃搅拌2小时。将体系倒入50g冰水中，分液，有机相用饱和食盐水50mL洗涤，无水硫酸钠干燥，过滤，减压浓缩至干得到化合物8-4。1HNMR(400MHz,DMSO-d6)δppm 7.20-7.26(m,1H),7.11-7.13(m,1H),4.76(s,2H)。Add dichloromethane (40mL), 8-3 (3.9g, 22.01mmol), N,N dimethylformamide (884.98mg, 12.11mmol) to the pre-dried reaction bottle, cool to 0°C, and slowly add dropwise Thionyl chloride (7.86g, 66.04mmol). The system was stirred at 25°C for 2 hours. Pour the system into 50 g of ice water, separate the layers, wash the organic phase with 50 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure to obtain compound 8-4. 1 HNMR (400MHz, DMSO-d6) δppm 7.20-7.26 (m, 1H), 7.11-7.13 (m, 1H), 4.76 (s, 2H).
4)化合物8-5的合成4) Synthesis of compound 8-5
向预先干燥的反应瓶中加入N,N二甲基甲酰胺(37mL)，双(叔丁氧羰基)胺(4.10g,18.86mmol)，8-4(3.69g,18.86mmol)，然后加入碳酸钾(6.52g,47.16mmol)。体系65℃搅拌16小时。体系降温至室温，然后加入水100mL，乙酸乙酯100mL，分液，有机相用饱和食盐水100mL洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物8-5。1HNMR(400MHz,DMSO-d6)δppm 6.96-7.12(m,2H),4.79(s,2H),1.38-1.39(m,18H)。Add N,N dimethylformamide (37mL), bis(tert-butoxycarbonyl)amine (4.10g, 18.86mmol), 8-4 (3.69g, 18.86mmol) to the pre-dried reaction bottle, and then add carbonic acid Potassium (6.52g, 47.16mmol). The system was stirred at 65°C for 16 hours. The system was cooled to room temperature, and then 100 mL of water and 100 mL of ethyl acetate were added to separate the layers. The organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 8-5. 1 HNMR (400MHz, DMSO-d6) δppm 6.96-7.12 (m, 2H), 4.79 (s, 2H), 1.38-1.39 (m, 18H).
5)化合物8-6的合成5) Synthesis of compound 8-6
向预先干燥的反应瓶中加入8-5(7.7g,20.46mmol)，盐酸/乙酸乙酯(4M,70mL)，体系20℃搅拌2小时。体系过滤，滤饼用乙酸乙酯30mL淋洗，减压浓缩至干得到化合物8-6。1HNMR(400MHz,DMSO-d6)δppm8.59(s,2H),7.23-7.28(m,1H),7.11-7.15(m,2H),4.03(s,2H)。Add 8-5 (7.7g, 20.46mmol) and hydrochloric acid/ethyl acetate (4M, 70mL) to the pre-dried reaction flask, and stir the system at 20°C for 2 hours. The system was filtered, the filter cake was rinsed with 30 mL of ethyl acetate, and concentrated to dryness under reduced pressure to obtain compound 8-6. 1 HNMR (400MHz, DMSO-d6) δppm8.59 (s, 2H), 7.23-7.28 (m, 1H), 7.11-7.15 (m, 2H), 4.03 (s, 2H).
6)化合物8的合成6) Synthesis of compound 8
向预先干燥的反应瓶中加入7-2(40mg,85.31μmol),N,N二甲基甲酰胺(1mL)，体系浑浊，然后加入二异丙基乙基胺(88mg,682.45μmol)，2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(48mg,127.96μmol)，8-6(20mg,93.84μmol)。20℃搅拌2小时。体系过滤，滤液制备高效液相色谱column:Waters Xbridge BEH C18 100*30mm*10μm；流动相:[H2O(10mM NH4HCO3)-ACN]；ACN％:25％-50％,8min纯化得到化合物8。1HNMR(400MHz,DMSO-d6)δppm 8.29(s,1H),8.20-8.21(m,1H),7.94-7.95(m,1H),7.58-7.60(m,1H),
7.01-7.12(m,5H),6.41-6.45(m,1H),5.35(s,2H),5.04(s,2H),4.83-4.85(m,2H),4.63-4.65(m,2H),4.39-4.41(m,2H),2.93(s,3H)；LCMS(ESI)m/z:590[M+1]+。Add 7-2 (40 mg, 85.31 μmol), N, N dimethylformamide (1 mL) to the pre-dried reaction bottle. The system becomes turbid, then add diisopropylethylamine (88 mg, 682.45 μmol), 2 -(7-Azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (48 mg, 127.96 μmol), 8-6 (20 mg, 93.84 μmol). Stir at 20°C for 2 hours. The system was filtered, and the filtrate was prepared for high performance liquid chromatography. Column: Waters Compound 8 was obtained. 1 HNMR (400MHz, DMSO-d 6 ) δppm 8.29 (s, 1H), 8.20-8.21 (m, 1H), 7.94-7.95 (m, 1H), 7.58-7.60 (m, 1H), 7.01-7.12(m,5H),6.41-6.45(m,1H),5.35(s,2H),5.04(s,2H),4.83-4.85(m,2H),4.63-4.65(m,2H), 4.39-4.41(m,2H),2.93(s,3H); LCMS(ESI)m/z:590[M+1] + .
实施例9
Example 9
Example 9
合成路线：
synthetic route:
synthetic route:
向预先干燥的反应瓶中加入7-2(0.1g,231.81μmol)，N,N二甲基甲酰胺(1mL)，然后加入二异丙基乙基胺(239mg,1.85mmol)，2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(13mg,347.71μmol)，1-8(53mg,278.17μmol)。体系20℃搅拌2小时。体系过滤，滤液制备高效液相色谱column:Phenomenex Gemini-NX C18 75*30mm*3μm；流动相:[H2O(10mM NH4HCO3)-ACN]；ACN％:35％-65％,8min纯化得到化合物9。1HNMR(400MHz,DMSO-d6)δppm 8.36-8.38(m,2H),8.22-8.24(m,1H),7.95-7.97(m,1H),7.60-7.61(m,1H),7.03-7.19(m,4H),6.42-6.46(m,1H),5.37(s,2H),5.05(s,2H),4.84-4.86(m,2H),4.68-4.70(m,2H),4.49-4.50(m,2H),3.91(s,3H),2.97(s,3H)；LCMS(ESI)m/z:570[M+1]+。Add 7-2 (0.1g, 231.81μmol), N,N dimethylformamide (1mL) to the pre-dried reaction bottle, then add diisopropylethylamine (239mg, 1.85mmol), 2-( 7-Azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (13 mg, 347.71 μmol), 1-8 (53 mg, 278.17 μmol). The system was stirred at 20°C for 2 hours. The system was filtered, and the filtrate was prepared for HPLC column: Phenomenex Gemini-NX C18 75*30mm*3μm; mobile phase: [H 2 O (10mM NH 4 HCO 3 )-ACN]; ACN%: 35%-65%, 8min Purification gave compound 9. 1 HNMR(400MHz,DMSO-d6)δppm 8.36-8.38(m,2H),8.22-8.24(m,1H),7.95-7.97(m,1H),7.60-7.61(m,1H),7.03-7.19( m,4H),6.42-6.46(m,1H),5.37(s,2H),5.05(s,2H),4.84-4.86(m,2H),4.68-4.70(m,2H),4.49-4.50( m,2H),3.91(s,3H),2.97(s,3H); LCMS(ESI)m/z:570[M+1] + .
实施例10
Example 10
Example 10
合成路线：
synthetic route:
synthetic route:
在预先干燥的烧瓶中加入3-7(0.22g,524.62μmol)和N,N二甲基甲酰胺(2.2mL)和二异丙基乙基胺(271mg,2.10mmol)，然后加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(299mg,786.93μmol)，搅拌10分钟后，向其中加入1-8(121mg,629.54μmol)，反应液在25℃搅拌1小时。向反应液中加入1M氢氧化钠溶液10mL和乙酸乙酯10mL，分液，水相用乙酸乙酯10mLX3萃取，合并有机相减压浓缩得到产物粗品。粗品经制备高效液相色谱(column:Phenomenex C18 80*40mm*3μm；流动相:[H2O(NH4HCO3)-ACN]；ACN％:15％-45％,8min)纯化得到产物化合物10。1HNMR(400MHz,CDCl3)δppm8.23-8.24(m,1H),7.91(s,1H),7.27-7.49(m,3H),7.00-7.05(m,2H),6.87-6.97(m,1H),6.54-6.58(m,1H),5.10-5.27(m,8H),4.70-4.71(m,2H),3.95(s,3H)；LCMS(ESI)m/z:558[M+1]+。Add 3-7 (0.22g, 524.62μmol), N,N dimethylformamide (2.2mL) and diisopropylethylamine (271mg, 2.10mmol) into the pre-dried flask, then add 2-( 7-Azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (299mg, 786.93μmol), after stirring for 10 minutes, add 1-8 (121mg, 629.54μmol) ), the reaction solution was stirred at 25°C for 1 hour. Add 10 mL of 1M sodium hydroxide solution and 10 mL of ethyl acetate to the reaction solution, separate the layers, extract the aqueous phase with 10 mL x 3 of ethyl acetate, combine the organic phases and concentrate under reduced pressure to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (column: Phenomenex C18 80*40mm*3μm; mobile phase: [H 2 O (NH 4 HCO 3 )-ACN]; ACN%: 15%-45%, 8min) to obtain the product compound 10. 1 HNMR (400MHz, CDCl 3 ) δppm8.23-8.24(m,1H),7.91(s,1H),7.27-7.49(m,3H),7.00-7.05(m,2H),6.87-6.97(m, 1H),6.54-6.58(m,1H),5.10-5.27(m,8H),4.70-4.71(m,2H),3.95(s,3H); LCMS(ESI)m/z:558[M+1 ] + .
实施例11
Example 11
Example 11
合成路线：
synthetic route:
synthetic route:
1)化合物11-2的合成1) Synthesis of compound 11-2
在预先干燥三口瓶中加入11-1(100g，723.78mmol)，盐酸(12M，150.79mL)和无水甲苯(1000mL)，40℃下搅拌2.5小时。待体系自然降温至20℃，将体系静置，分液，分离有机相加入饱和碳酸氢钠溶液调pH至8，分液，分离有机相加入无视硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品中加入石油醚(230mL)，搅拌1小时，过滤，收集滤饼，干燥得到目标化合物11-2。LCMS(ESI)m/z:139[M-17]+；1HNMR
(400MHz,CDCl3)δppm 7.30-7.41(m,4H),4.65(s,2H),4.59(s,2H),2.37(s,1H)。Add 11-1 (100g, 723.78mmol), hydrochloric acid (12M, 150.79mL) and anhydrous toluene (1000mL) to a pre-dried three-necked flask, and stir at 40°C for 2.5 hours. After the system naturally cools down to 20°C, let the system stand still, separate the liquids, separate the organic phase, add saturated sodium bicarbonate solution to adjust the pH to 8, separate the organic phases, add disregarded sodium sulfate to dry, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. . Petroleum ether (230 mL) was added to the crude product, stirred for 1 hour, filtered, and the filter cake was collected and dried to obtain target compound 11-2. LCMS(ESI)m/z:139[M-17] + ; 1 HNMR (400MHz, CDCl 3 ) δppm 7.30-7.41 (m, 4H), 4.65 (s, 2H), 4.59 (s, 2H), 2.37 (s, 1H).
2)化合物11-3的合成2) Synthesis of compound 11-3
在预先干燥反应瓶中加入11-2(98.4g，628.32mmol)，丙酮(1000mL)，2-羟基吡啶(71.70g，753.98mmol)，碳酸钾(217.09g，1.57mmol)，60℃下搅拌21小时。待体系自然降温至40℃，趁热过滤，滤饼用二氯甲烷(500mL)淋洗，滤饼减压浓缩得到粗品。粗品中加入乙酸乙酯(330mL)，搅拌5分钟，过滤，滤饼用乙酸乙酯(100mL)淋洗，收集滤饼，干燥得到目标产物11-3。LCMS(ESI)m/z:216[M+1]+。Add 11-2 (98.4g, 628.32mmol), acetone (1000mL), 2-hydroxypyridine (71.70g, 753.98mmol), potassium carbonate (217.09g, 1.57mmol) to the pre-dried reaction bottle, and stir at 60°C for 21 Hour. Allow the system to naturally cool to 40°C, filter while hot, rinse the filter cake with dichloromethane (500 mL), and concentrate the filter cake under reduced pressure to obtain a crude product. Add ethyl acetate (330 mL) to the crude product, stir for 5 minutes, filter, and rinse the filter cake with ethyl acetate (100 mL). Collect the filter cake and dry it to obtain the target product 11-3. LCMS(ESI)m/z:216[M+1] + .
3)化合物11-4的合成3) Synthesis of compound 11-4
在预先干燥反应瓶中加入二氯甲烷(940mL)，11-3(93.7g，435.31mmol)，N,N-二甲基甲酰胺(33.49mL)，0℃滴加氯化亚砜(129.47g，1.09mol)，滴加完毕，升温至20℃搅拌2小时。反应液直接过滤，用石油醚(100mL)淋洗滤饼，收集滤饼，干燥得到目标产物11-4。LCMS(ESI)m/z:234[M+1]+。1HNMR(400MHz,DMSO-d6)δppm 7.84(dd,J＝6.78,1.76Hz,1H),7.45(ddd,J＝8.97,6.78,1.95Hz,1H),7.25-7.41(m,4H),6.46(d,J＝9.16Hz,1H),6.28(t,J＝6.40Hz,1H),5.11(s,2H),4.72(s,2H)。Add dichloromethane (940mL), 11-3 (93.7g, 435.31mmol), N,N-dimethylformamide (33.49mL) to the pre-dried reaction bottle, and add sulfoxide chloride (129.47g) dropwise at 0°C. , 1.09 mol), after the dropwise addition is completed, the temperature is raised to 20°C and stirred for 2 hours. The reaction solution was directly filtered, and the filter cake was rinsed with petroleum ether (100 mL). The filter cake was collected and dried to obtain the target product 11-4. LCMS(ESI)m/z:234[M+1] + . 1 HNMR (400MHz, DMSO-d 6 ) δppm 7.84 (dd, J＝6.78, 1.76Hz, 1H), 7.45 (ddd, J＝8.97, 6.78, 1.95Hz, 1H), 7.25-7.41 (m, 4H), 6.46(d,J＝9.16Hz,1H), 6.28(t,J＝6.40Hz,1H), 5.11(s,2H), 4.72(s,2H).
4)化合物11-5的合成4) Synthesis of compound 11-5
在预先干燥的烧瓶中加入1-5(0.2g,933.74μmol)和11-4(218mg,933.74μmol)，碳酸钾(258mg,1.87mmol)，N,N-二甲基甲酰胺(1.4mL)，反应液在70℃搅拌16小时。向反应液中加入水10mL,乙酸乙酯10mL，分液，有机相用水10mL萃取，合并有机相，减压浓缩至干得到粗品11-5。LCMS(ESI)m/z:412[M+1]+。Add 1-5 (0.2g, 933.74μmol) and 11-4 (218mg, 933.74μmol), potassium carbonate (258mg, 1.87mmol), N,N-dimethylformamide (1.4mL) to the pre-dried flask. , the reaction solution was stirred at 70°C for 16 hours. Add 10 mL of water and 10 mL of ethyl acetate to the reaction solution, separate the layers, extract the organic phase with 10 mL of water, combine the organic phases, and concentrate to dryness under reduced pressure to obtain crude product 11-5. LCMS(ESI)m/z:412[M+1] + .
5)化合物11-6的合成5) Synthesis of compound 11-6
在预先干燥的烧瓶中加入11-5(0.28g,680.56μmol)和2M氢氧化钠溶液0.7mL，甲醇(3mL)，反应液在60℃搅拌2小时。体系减压浓缩除去甲醇，向其中加入水10mL，用1M盐酸调节pH至1，加入乙酸乙酯10mL，分液，水相用乙酸乙酯10mL萃取，合并有机相减压浓缩得到粗品11-6。LCMS(ESI)m/z:384[M+1]+。Add 11-5 (0.28g, 680.56 μmol), 0.7 mL of 2M sodium hydroxide solution, and methanol (3 mL) to the pre-dried flask, and stir the reaction solution at 60°C for 2 hours. The system was concentrated under reduced pressure to remove methanol, 10 mL of water was added, 1M hydrochloric acid was used to adjust the pH to 1, 10 mL of ethyl acetate was added, and the liquids were separated. The aqueous phase was extracted with 10 mL of ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to obtain crude product 11-6. . LCMS(ESI)m/z:384[M+1] + .
6)化合物11的合成6) Synthesis of compound 11
在预先干燥的烧瓶中加入11-6(0.26g,678.19μmol)和N,N-二甲基甲酰胺(2.6mL)和二异丙基乙基胺(350mg,2.71mmol)，2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(386mg,1.02mmol)，搅拌10分钟后，向其中加入1-8(156mg,813.83μmol)，反应液在25℃搅拌1小时。向反应液中加入1M氢氧化钠溶液10mL和乙酸乙酯10mL，分液，水相用乙酸乙酯10mL萃取，合并有机相减压浓缩得到粗品，粗品通过高效液相色谱(column:Phenomenex C18 80*40mm*3μm；流动相:[water(NH4HCO3)-ACN]；ACN:15％-45％,8min)纯化得到化合物11。1HNMR(400MHz,CDCl3)δppm 8.22-8.24(m,1H),7.87(s,1H),7.24-7.45(m,6H),6.85-6.88(m,1H),6.60-6.62(m,1H),6.15-6.19(m,1H),5.12-5.27(m,8H),4.69-4.70(m,2H),3.95(s,3H)；LCMS(ESI)m/z:522[M+1]+。Add 11-6 (0.26g, 678.19μmol), N,N-dimethylformamide (2.6mL) and diisopropylethylamine (350mg, 2.71mmol) to the pre-dried flask, 2-(7 -Azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (386mg, 1.02mmol), after stirring for 10 minutes, add 1-8 (156mg, 813.83μmol) , the reaction solution was stirred at 25°C for 1 hour. Add 10 mL of 1M sodium hydroxide solution and 10 mL of ethyl acetate to the reaction solution, separate the layers, extract the aqueous phase with 10 mL of ethyl acetate, combine the organic phases and concentrate under reduced pressure to obtain a crude product, which is passed through high performance liquid chromatography (column: Phenomenex C18 80 *40mm*3μm; mobile phase: [water(NH4HCO3)-ACN]; ACN: 15%-45%, 8min) to obtain compound 11. 1 HNMR (400MHz, CDCl 3 ) δppm 8.22-8.24(m,1H),7.87(s,1H),7.24-7.45(m,6H),6.85-6.88(m,1H),6.60-6.62(m,1H ),6.15-6.19(m,1H),5.12-5.27(m,8H),4.69-4.70(m,2H),3.95(s,3H); LCMS(ESI)m/z:522[M+1] + .
生物测试数据
Biological test data
实验例1：测试化合物对血浆激肽释放酶(PKal)的抑制作用Experimental Example 1: Inhibitory effect of test compounds on plasma kallikrein (PKal)
1.PKal反应缓冲液：25mM Tris-HCl(三羟甲基氨基甲烷-HCl),pH 8.0,100mM NaCl,pH 8.5,0.01％Brij35(月桂醇聚氧乙烯醚),and 1％DMSO(最终浓度)。1.PKal reaction buffer: 25mM Tris-HCl (trishydroxymethylaminomethane-HCl), pH 8.0, 100mM NaCl, pH 8.5, 0.01% Brij35 (laureth polyoxyethylene ether), and 1% DMSO (final concentration ).
2.酶：PKal(R&D Systems Cat#2497-SE)，在小鼠骨髓瘤细胞株中表达的重组人源血浆激肽释放酶，由NS0-衍生的Gly20-Ala638，C-端带有60-His附属物，MW＝70kDa。酶的活化：(1)将rhPKal稀释为200μg/mL的激活缓冲液(100mM Tris,10mM CaCl2,150mM NaCl,pH 7.5(TCN))；(2)将嗜热菌蛋白酶(Thermolysin)稀释为20μg/mL的激活缓冲液；(3)将rhPKal(200μg/mL)和嗜热菌蛋白酶(20μg/mL)等体积混合；(4)37℃孵育30min；(5)再用50μM EDTA(乙二胺四乙酸)终止反应。2. Enzyme: PKal (R&D Systems Cat#2497-SE), a recombinant human plasma kallikrein expressed in mouse myeloma cell lines, derived from NS0-derived Gly20-Ala638, with a 60- on the C-terminal His appendage, MW=70kDa. Enzyme activation: (1) dilute rhPKal to 200 μg/mL activation buffer (100mM Tris, 10mM CaCl 2 , 150mM NaCl, pH 7.5 (TCN)); (2) dilute thermolysin (Thermolysin) to 20 μg /mL activation buffer; (3) Mix rhPKal (200 μg/mL) and thermolysin (20 μg/mL) in equal volumes; (4) Incubate at 37°C for 30 minutes; (5) Then use 50 μM EDTA (ethylenediamine Tetraacetic acid) terminates the reaction.
3.基质(Enzo Cat#P-139)：10μM Z-FR-AMC(AMC:7-氨基-4-甲基香豆素)。3. Matrix (Enzo Cat#P-139): 10μM Z-FR-AMC (AMC: 7-amino-4-methylcoumarin).
4.检测：EnVision(PE)，Ex/Em 355/460nm。4. Detection: EnVision(PE), Ex/Em 355/460nm.
5.反应过程：(1)准备指定的酶和基质在新配制的激活缓冲液中；(2)将酶溶液注入反应孔中；(3)采用声学技术(Echo 550,LabCyte Inc.Sunnyvale,CA)将供试品的DMSO溶液注入反应混合液中，并控制在纳升范围内；(4)预培养10min后，将基质溶液注入到反应孔中开始反应；(5)酶的活性可通过荧光标记肽基质的荧光信号增加来指示，每5min监测一次，室温下持续120min；(6)数据分析：测量直线的斜率*(荧光信号/时间)，斜率可由excel计算出来，通过Prism软件拟合曲线。化合物对血浆激肽释放酶(PKal)的抑制作用测试结果如下表1所示。5. Reaction process: (1) Prepare the specified enzyme and substrate in the newly prepared activation buffer; (2) Inject the enzyme solution into the reaction well; (3) Use acoustic technology (Echo 550, LabCyte Inc. Sunnyvale, CA ) Inject the DMSO solution of the test product into the reaction mixture and control it within the nanoliter range; (4) After pre-incubation for 10 minutes, inject the matrix solution into the reaction well to start the reaction; (5) The activity of the enzyme can be measured by fluorescence Indicated by an increase in the fluorescence signal of the labeled peptide matrix, monitor every 5 minutes for 120 minutes at room temperature; (6) Data analysis: measure the slope of the straight line * (fluorescence signal/time), the slope can be calculated by excel, and the curve can be fitted through Prism software . The test results of the inhibitory effect of compounds on plasma kallikrein (PKal) are shown in Table 1 below.
表1化合物对血浆激肽释放酶的抑制作用测试结果
Table 1 Test results of the inhibitory effect of compounds on plasma kallikrein
Table 1 Test results of the inhibitory effect of compounds on plasma kallikrein
实验结论：本发明化合物对血浆激肽释放酶(PKal)的抑制作用显著。
Experimental conclusion: The compound of the present invention has a significant inhibitory effect on plasma kallikrein (PKal).
实验例2：利用荧光方法测试人新鲜血浆中化合物对血浆激肽释放酶(PKal)的抑制作用Experimental Example 2: Using fluorescence method to test the inhibitory effect of compounds in human fresh plasma on plasma kallikrein (PKal)
1.准备试剂和材料：1. Prepare reagents and materials:
(1)PKal底物：Pro-Phe-Arg-AMC(AMC:7-氨基-4-甲基香豆素)(购自金斯瑞，C882QHC150-1)；(1) PKal substrate: Pro-Phe-Arg-AMC (AMC: 7-amino-4-methylcoumarin) (purchased from GenScript, C882QHC150-1);
(2)人新鲜血浆：来自上海合佑生生物科技有限公司。(2) Human fresh plasma: from Shanghai Heyousheng Biotechnology Co., Ltd.
2.实验过程：2. Experimental process:
(1)人血浆工作液配制：首先配制反应缓冲液(50mM Tris-HCl pH7.5，250mM NaCl)，利用反应缓冲液对人新鲜血浆进行5倍稀释，完成人新鲜血浆工作液配制；(1) Preparation of human plasma working solution: First prepare the reaction buffer (50mM Tris-HCl pH7.5, 250mM NaCl), use the reaction buffer to dilute human fresh plasma 5 times, and complete the preparation of human fresh plasma working solution;
(2)底物工作液配制：利用反应缓冲液(50mM Tris-HCl pH7.5，250mM NaCl)制备底物(Pro-Phe-Arg-AMC)工作液，使浓度为250μM；(2) Preparation of substrate working solution: Use reaction buffer (50mM Tris-HCl pH7.5, 250mM NaCl) to prepare substrate (Pro-Phe-Arg-AMC) working solution to a concentration of 250μM;
(3)化合物加板：阳性参照化合物和供试化合物起始浓度为30μM,3倍稀释，稀释10个浓度点。通过声学液体输送技术(Echo550；纳升范围)将100％DMSO中的化合物0.05μL输送到384孔板中；(3) Compound addition plate: The starting concentration of the positive reference compound and the test compound is 30 μM, diluted 3 times, and diluted to 10 concentration points. Deliver 0.05 μL of compound in 100% DMSO into a 384-well plate via acoustic liquid delivery technology (Echo550; nanoliter range);
(4)反应：转移5μL人新鲜血浆工作液到384反应板中，1000转离心1分钟，于25℃孵育15分钟；转移5μL底物工作液到384反应板中，1000转离心1分钟，25℃孵育60分钟；(4) Reaction: Transfer 5 μL human fresh plasma working solution to the 384 reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 15 minutes; transfer 5 μL of the substrate working solution into the 384 reaction plate, centrifuge at 1000 rpm for 1 minute, 25 Incubate at ℃ for 60 minutes;
(5)读值：孵育结束后，用PHERAstar FSX酶标仪(BMG)读取荧光信号(ex380/em460)，酶的活性通过荧光标记底物的荧光信号强度来指示。使用GraphPad Prism软件进行曲线拟合，获得IC50值。(5) Reading value: After the incubation, use a PHERAstar FSX microplate reader (BMG) to read the fluorescence signal (ex380/em460). The activity of the enzyme is indicated by the fluorescence signal intensity of the fluorescently labeled substrate. Use GraphPad Prism software to perform curve fitting and obtain IC50 values.
3.化合物对人新鲜血浆中血浆激肽释放酶(PKal)的抑制作用测试结果如下表2所示。3. The test results of the inhibitory effect of the compound on plasma kallikrein (PKal) in human fresh plasma are shown in Table 2 below.
表2化合物对血浆激肽释放酶的抑制作用测试结果
Table 2 Test results of the inhibitory effect of compounds on plasma kallikrein
Table 2 Test results of the inhibitory effect of compounds on plasma kallikrein
实验结论：本发明化合物对人血浆中血浆激肽释放酶(PKal)的抑制作用显著。Experimental conclusion: The compound of the present invention has a significant inhibitory effect on plasma kallikrein (PKal) in human plasma.
实验例3：本发明化合物的药代动力学测试Experimental Example 3: Pharmacokinetic test of the compound of the present invention
1.摘要1.Abstract
以雄性SD大鼠为受试动物，应用LC-MS/MS法测定大鼠静脉和灌胃给予受试化合物后不同时刻血浆中的药物浓度。研究化合物在大鼠体内的药代动力学行为，评价其药动学特征。Male SD rats were used as test animals, and the LC-MS/MS method was used to determine the drug concentration in the plasma of rats at different times after intravenous and gavage administration of test compounds. Study the pharmacokinetic behavior of compounds in rats and evaluate their pharmacokinetic characteristics.
2.实验方案2. Experimental plan
2.1试验药品：受试化合物。2.1 Test drug: test compound.
2.2试验动物：健康成年雄性SD大鼠28只，分成14组，每组2只。动物购买自北京维通利华实验动物技术有限公司2.2 Experimental animals: 28 healthy adult male SD rats were divided into 14 groups, 2 rats in each group. Animals were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.
2.3药物配制2.3 Drug Preparation
称取适量样品，按照体积比例10:10:80依次加入适量DMSO、聚氧乙烯蓖麻油和无菌注射用水，搅拌超声后达到3mg/mL的澄清状态用于灌胃给药。
Weigh an appropriate amount of sample, add an appropriate amount of DMSO, polyoxyethylene castor oil and sterile water for injection in sequence according to the volume ratio of 10:10:80, stir and ultrasonic to reach a clear state of 3mg/mL for intragastric administration.
2.4给药：雄性SD大鼠28只，分成14组，禁食一夜后，灌胃给药，给药体积为10mL/kg,剂量为30mg/kg。2.4 Administration: 28 male SD rats were divided into 14 groups. After fasting overnight, they were administered intragastrically. The administration volume was 10 mL/kg and the dose was 30 mg/kg.
3.实验操作及结果3. Experimental operations and results
雄性SD大鼠静脉给予化合物后，分别在0.0833，0.25，0.5，1，2，4，8及24小时采血40μL，置于含有2μL EDTA-K2的试管中。灌胃给药组给予化合物后，分别在0.25，0.5，1，2，4，6，10及24小时采血40μL，置于含有2μL EDTA-K2的试管中。试管在4000rpm离心15分钟分离血浆，并于-60℃保存。给药2小时后动物可进食。After intravenous administration of the compound to male SD rats, 40 μL of blood was collected at 0.0833, 0.25, 0.5, 1, 2, 4, 8 and 24 hours respectively, and placed in test tubes containing 2 μL EDTA-K 2 . After the compound was administered to the intragastric administration group, 40 μL of blood was collected at 0.25, 0.5, 1, 2, 4, 6, 10 and 24 hours respectively, and placed in test tubes containing 2 μL EDTA-K 2 . The tubes were centrifuged at 4000 rpm for 15 minutes to separate the plasma and stored at -60°C. Animals can eat 2 hours after administration.
用LC-MS/MS法测定大鼠静脉和灌胃给药后，血浆中待测化合物的含量。方法的线性范围为2.00～6000nmol/L；血浆样品经乙腈沉淀蛋白处理后进行分析。化合物的药代动力学测试结果如下表3所示。The LC-MS/MS method was used to determine the content of the test compound in the plasma of rats after intravenous and intragastric administration. The linear range of the method is 2.00~6000nmol/L; plasma samples are analyzed after being treated with acetonitrile to precipitate proteins. The pharmacokinetic test results of the compounds are shown in Table 3 below.
表3化合物的药代动力学测试结果
Table 3 Pharmacokinetic test results of compounds
Table 3 Pharmacokinetic test results of compounds
实验结论：本发明化合物有较好的口服暴露量。
Experimental conclusion: The compound of the present invention has better oral exposure.
Claims (10)
- 式(I)化合物或其药学上可接受的盐，
A compound of formula (I) or a pharmaceutically acceptable salt thereof,
其中，in,T1为CR1或N；T 1 is CR 1 or N;R1为H、F、Cl、Br或I；R 1 is H, F, Cl, Br or I;R2为H、F、Cl、Br或I；R 2 is H, F, Cl, Br or I;R3为C1-3烷氧基，所述C1-3烷氧基任选地被1、2或3个Ra取代；R 3 is a C 1-3 alkoxy group, and the C 1-3 alkoxy group is optionally substituted by 1, 2 or 3 R a ;R4为F、Cl、Br、I、OH或C1-3烷氧基；R 4 is F, Cl, Br, I, OH or C 1-3 alkoxy;R5和R6分别独立地为H、F、Cl、Br、I、OH或NH2；R 5 and R 6 are independently H, F, Cl, Br, I, OH or NH 2 ;R7为H、F、Cl、Br或I；R 7 is H, F, Cl, Br or I;Ra为D、F、Cl或Br。R a is D, F, Cl or Br. - 根据权利要求1所述化合物或其药学上可接受的盐，其中，R1为F或Cl。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is F or Cl.
- 根据权利要求1所述化合物或其药学上可接受的盐，其中，R2为F或Cl。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is F or Cl.
- 根据权利要求1所述化合物或其药学上可接受的盐，其中，R3为-OCH3或-OCD3。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is -OCH 3 or -OCD 3 .
- 根据权利要求1所述化合物或其药学上可接受的盐，其中，R4为F、Cl、Br、I、OH或-OCH3。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is F, Cl, Br, I, OH or -OCH 3 .
- 根据权利要求1所述化合物或其药学上可接受的盐，其中，R5为H。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 is H.
- 根据权利要求1所述化合物或其药学上可接受的盐，其中，R6为H或F。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 is H or F.
- 根据权利要求1所述化合物或其药学上可接受的盐，其中，R7为H或F。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 is H or F.
- 下式化合物或其药学上可接受的盐：
Compounds of the following formula or pharmaceutically acceptable salts thereof:
- 根据权利要求1-9任意一项所述化合物或其药学上可接受的盐在制备治疗血浆激肽释放酶介导的相关疾病的药物中的应用。 Use of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating related diseases mediated by plasma kallikrein.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105143201A (en) * | 2013-01-08 | 2015-12-09 | 卡尔维斯塔制药有限公司 | Benzylamine derivatives |
| CN105452240A (en) * | 2013-05-23 | 2016-03-30 | 卡尔维斯塔制药有限公司 | Heterocyclic derivates |
| CN107108576A (en) * | 2014-11-27 | 2017-08-29 | 卡尔维斯塔制药有限公司 | It is used as N ((miscellaneous) aryl methyl) heteroaryl carboxamides compound of inhibitors of plasma kallikrein |
| TW201925188A (en) * | 2017-11-29 | 2019-07-01 | 英商卡爾維斯塔製藥有限公司 | Enzyme inhibitors |
| WO2021175290A1 (en) * | 2020-03-04 | 2021-09-10 | 南京明德新药研发有限公司 | Heterocyclic compound |
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- 2023-03-23 WO PCT/CN2023/083409 patent/WO2023185634A1/en unknown
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105143201A (en) * | 2013-01-08 | 2015-12-09 | 卡尔维斯塔制药有限公司 | Benzylamine derivatives |
| CN105452240A (en) * | 2013-05-23 | 2016-03-30 | 卡尔维斯塔制药有限公司 | Heterocyclic derivates |
| CN107108576A (en) * | 2014-11-27 | 2017-08-29 | 卡尔维斯塔制药有限公司 | It is used as N ((miscellaneous) aryl methyl) heteroaryl carboxamides compound of inhibitors of plasma kallikrein |
| TW201925188A (en) * | 2017-11-29 | 2019-07-01 | 英商卡爾維斯塔製藥有限公司 | Enzyme inhibitors |
| WO2021175290A1 (en) * | 2020-03-04 | 2021-09-10 | 南京明德新药研发有限公司 | Heterocyclic compound |
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