WO2024109707A1 - 稠环吡啶酮衍生物及其制备方法和用途 - Google Patents
稠环吡啶酮衍生物及其制备方法和用途 Download PDFInfo
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- WO2024109707A1 WO2024109707A1 PCT/CN2023/132727 CN2023132727W WO2024109707A1 WO 2024109707 A1 WO2024109707 A1 WO 2024109707A1 CN 2023132727 W CN2023132727 W CN 2023132727W WO 2024109707 A1 WO2024109707 A1 WO 2024109707A1
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title abstract description 3
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 92
- 125000001424 substituent group Chemical group 0.000 claims description 83
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- 229910052717 sulfur Inorganic materials 0.000 claims description 50
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 33
- 125000001188 haloalkyl group Chemical group 0.000 claims description 28
- 229910052760 oxygen Inorganic materials 0.000 claims description 28
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 27
- 239000000126 substance Substances 0.000 claims description 25
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- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 17
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 17
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- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 12
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- 101000900567 Pisum sativum Disease resistance response protein Pi49 Proteins 0.000 claims description 5
- 101000621511 Potato virus M (strain German) RNA silencing suppressor Proteins 0.000 claims description 5
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- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 5
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- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 5
- CXWGKAYMVASWDQ-UHFFFAOYSA-N 1,2-dithiane Chemical group C1CCSSC1 CXWGKAYMVASWDQ-UHFFFAOYSA-N 0.000 claims description 4
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical group C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 claims description 4
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- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical group C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 claims description 4
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical group C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 claims description 4
- 125000003566 oxetanyl group Chemical group 0.000 claims description 4
- HZIVRQOIUMAXID-UHFFFAOYSA-N oxocane Chemical group C1CCCOCCC1 HZIVRQOIUMAXID-UHFFFAOYSA-N 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical group C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 claims description 4
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 4
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical group C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 claims description 4
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 3
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- 125000002393 azetidinyl group Chemical group 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000000532 dioxanyl group Chemical group 0.000 claims description 3
- 125000003551 oxepanyl group Chemical group 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 125000002053 thietanyl group Chemical group 0.000 claims description 3
- 125000001730 thiiranyl group Chemical group 0.000 claims description 3
- 241000713297 Influenza C virus Species 0.000 claims description 2
- 241000401051 Influenza D virus Species 0.000 claims description 2
- 241000725681 Swine influenza virus Species 0.000 claims description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 2
- AMIGYDGSJCJWSD-UHFFFAOYSA-N thiocane Chemical group C1CCCSCCC1 AMIGYDGSJCJWSD-UHFFFAOYSA-N 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims 2
- 125000004414 alkyl thio group Chemical group 0.000 claims 1
- 125000000466 oxiranyl group Chemical group 0.000 claims 1
- 229960005486 vaccine Drugs 0.000 claims 1
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- 231100000053 low toxicity Toxicity 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 632
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 573
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- 238000006243 chemical reaction Methods 0.000 description 263
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- OEKGSPIIBSAZMG-UHFFFAOYSA-N pyrrolo[2,1-c][1,2,4]triazine Chemical compound N1=NC=CN2C=CC=C21 OEKGSPIIBSAZMG-UHFFFAOYSA-N 0.000 description 140
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- 239000002994 raw material Substances 0.000 description 99
- 239000007787 solid Substances 0.000 description 98
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 79
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 78
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 47
- 238000010791 quenching Methods 0.000 description 45
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 41
- 238000004440 column chromatography Methods 0.000 description 39
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 39
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 30
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- LRFZIPCTFBPFLX-SSDOTTSWSA-N (2s)-3,3-dimethyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)C(C)(C)C LRFZIPCTFBPFLX-SSDOTTSWSA-N 0.000 description 26
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- 238000000034 method Methods 0.000 description 25
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- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 20
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- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 10
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- MHZYNARBCAZWSZ-UHFFFAOYSA-N ethyl 1-amino-4-oxo-3-phenylmethoxypyridine-2-carboxylate Chemical compound CCOC(=O)C1=C(OCC2=CC=CC=C2)C(=O)C=CN1N MHZYNARBCAZWSZ-UHFFFAOYSA-N 0.000 description 9
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
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- 125000006413 ring segment Chemical group 0.000 description 6
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- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 6
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- PUSKHXMZPOMNTQ-UHFFFAOYSA-N ethyl 2,1,3-benzoselenadiazole-5-carboxylate Chemical compound CCOC(=O)C1=CC=C2N=[Se]=NC2=C1 PUSKHXMZPOMNTQ-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- ZCGNOVWYSGBHAU-UHFFFAOYSA-N favipiravir Chemical compound NC(=O)C1=NC(F)=CNC1=O ZCGNOVWYSGBHAU-UHFFFAOYSA-N 0.000 description 1
- 229950008454 favipiravir Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229950004244 laninamivir Drugs 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- LGFZMXDFNYFURS-UHFFFAOYSA-N methyl 2-(4-methylpiperazin-1-yl)acetate Chemical compound COC(=O)CN1CCN(C)CC1 LGFZMXDFNYFURS-UHFFFAOYSA-N 0.000 description 1
- OBMOHPOERFYDIR-UHFFFAOYSA-N methyl 2-[1-(nitromethyl)cyclobutyl]acetate Chemical compound [N+](=O)([O-])CC1(CCC1)CC(=O)OC OBMOHPOERFYDIR-UHFFFAOYSA-N 0.000 description 1
- UFQQDNMQADCHGH-UHFFFAOYSA-N methyl 2-bromobutanoate Chemical compound CCC(Br)C(=O)OC UFQQDNMQADCHGH-UHFFFAOYSA-N 0.000 description 1
- SGXHANSUXZAOSN-UHFFFAOYSA-N methyl 2-cyclobutylacetate Chemical compound COC(=O)CC1CCC1 SGXHANSUXZAOSN-UHFFFAOYSA-N 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- CDRSBPYJKRZQAY-UHFFFAOYSA-N methyl morpholine-4-carboxylate Chemical compound COC(=O)N1CCOCC1 CDRSBPYJKRZQAY-UHFFFAOYSA-N 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940113083 morpholine Drugs 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960003752 oseltamivir Drugs 0.000 description 1
- NENPYTRHICXVCS-YNEHKIRRSA-N oseltamivir acid Chemical compound CCC(CC)O[C@@H]1C=C(C(O)=O)C[C@H](N)[C@H]1NC(C)=O NENPYTRHICXVCS-YNEHKIRRSA-N 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- UHHKSVZZTYJVEG-UHFFFAOYSA-N oxepane Chemical compound C1CCCOCC1 UHHKSVZZTYJVEG-UHFFFAOYSA-N 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- XRQDFNLINLXZLB-CKIKVBCHSA-N peramivir Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N XRQDFNLINLXZLB-CKIKVBCHSA-N 0.000 description 1
- 229960001084 peramivir Drugs 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 229960000888 rimantadine Drugs 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000002911 sialidase inhibitor Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 150000003527 tetrahydropyrans Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JWCVYQRPINPYQJ-UHFFFAOYSA-N thiepane Chemical compound C1CCCSCC1 JWCVYQRPINPYQJ-UHFFFAOYSA-N 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 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
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 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
- 229960000281 trometamol Drugs 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229960004854 viral vaccine Drugs 0.000 description 1
- 230000005727 virus proliferation Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 1
- 229960001028 zanamivir Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
Definitions
- the invention relates to the field of pharmaceutical chemistry, and in particular to a fused-ring pyridone derivative and a preparation method and medical use thereof.
- the RNA polymerase of influenza virus contains a cap-dependent endonuclease domain, which cleaves host mRNA to produce capped RNA fragments that serve as primers for the synthesis of viral mRNA.
- the translation of viral mRNA by host ribosomes requires the 5' cap end of the mRNA, which can be achieved in cells infected with influenza virus by a cap-snatching mechanism, in which the cap-dependent endonuclease cuts off the 5' cap end from the host mRNA and then uses it as a transcription primer (10 to 13 nucleotides).
- These capped RNA primers are used to synthesize mRNA encoding viral proteins.
- cap-dependent endonucleases Inhibition of the activity of cap-dependent endonucleases can lead to inhibition of viral proliferation, and therefore, cap-dependent endonucleases are considered to be important biological targets for effective anti-influenza drugs.
- Different heterocyclic compounds have been used as cap-dependent endonuclease inhibitors.
- baloxavir disoproxil is the first cap-dependent endonuclease inhibitor to be marketed, and was approved by the US FDA in 2020 for the treatment of patients infected with influenza virus.
- the median EC 50 of baloxavir against A/H1N1 virus reached 17.96nM [Omoto S, Speranzini V, Hashimoto T, et al.
- baloxavir disoproxil is a substrate of Pgp, which is easily excreted and has low bioavailability, and clinically, patients with influenza virus resistant to baloxavir disoproxil have appeared.
- Chinese patent CN201680081836.6 discloses a class of cap endonuclease inhibitors, among which reference example 583/584 (racemate) has a CEN_IC 50 as high as 43.4 nM.
- Ring A is selected from C 3 -C 8 carbocyclic ring or 3 to 8 membered heterocyclic ring, which is optionally substituted by one or more groups selected from the following: halogen, oxo, C 1 -C 20 alkyl, C 1 -C 20 haloalkyl, C 1 -C 20 alkoxy, C 1 -C 20 alkylcarbonyl, C 1 -C 20 alkoxycarbonyl, C 1 -C 20 alkylcarbonyloxy, C 1 -C 20 alkoxycarbonyloxy, benzyloxycarbonyl, benzyloxycarbonyloxy;
- R1 is selected from:
- X 1 is selected from CH 2 , O, S, NH, S ⁇ O, S( ⁇ O) 2 ;
- X2 is selected from CH, N;
- R 3 , R 3 ', and R 4 are each independently selected from hydrogen, halogen, C 1 -C 20 alkyl, C 1 -C 20 haloalkyl, and C 1 -C 20 alkoxy; or R 3 , R 3 ' and the carbon atom to which they are commonly attached together form a C 3 -C 8 carbocyclic ring;
- Ring B is phenyl or 6-membered heteroaryl, which is optionally substituted by one or more groups selected from the group consisting of halogen, C 1 -C 20 alkyl, C 1 -C 20 haloalkyl, C 1 -C 20 alkoxy;
- Ring C is C 6 -C 10 aryl or 6- to 10-membered heteroaryl, which is optionally substituted by one or more groups selected from the group consisting of halogen, C 1 -C 20 alkyl, C 1 -C 20 haloalkyl, C 1 -C 20 alkoxy;
- R2 is selected from:
- L is a linear or branched C 1 -C 20 alkylene or C 1 -C 20 alkenylene group which is optionally substituted by any one of the substituents in group B,
- K is a hydrogen atom, or a C 1 -C 20 alkyl group optionally substituted by any one of the substituents in Group A,
- PR0 is a C1 - C20 alkyl group or a C1 - C20 alkenyl group optionally substituted by any one of the substituent groups A,
- PR1 is a carbocyclic group, a heterocyclic group, a C1 - C20 alkylamino group, or a C1 - C20 alkylthio group optionally substituted by any one of Substituent Group A,
- PR2 is a C 1 -C 20 alkyl group, a carbocyclic group, a heterocyclic group, or a tri(C 1 -C 20 alkyl)silyl group optionally substituted by any one of Substituent Group A,
- PR3 are each independently a hydrogen atom, a C1 - C20 alkyl group or a hydroxyl group, or two PR3 groups on adjacent carbon atoms optionally form an alkenylene group or an alkylene group together,
- PR4 is each independently a C1 - C20 alkyl group, a C3 - C8 carbocyclic group, a heterocyclic group, a C1 - C20 alkylamino group, or a tri( C1 - C20 alkyl)silyl group optionally substituted by any one of Substituent Group A,
- PR5 are each independently hydroxyl or benzyloxy
- PR6 is a C 3 -C 8 carbocyclic or heterocyclic group optionally substituted by any one of the substituent groups A,
- PR7 is each independently a C1 - C20 alkyl group optionally substituted by any one of Substituent Group A,
- PR8 is a C1 - C20 alkoxy group optionally substituted by any one of Substituent Group A,
- PR9 is a C1 - C20 alkoxy group, a C1 - C20 alkylamino group, a C3 - C8 carbocyclic group, a heterocyclic group, a C3 - C8 carbocyclic amino group, or a heterocyclic amino group optionally substituted by any one of Substituent Group A, and
- PR8 and PR9 optionally form together with the adjacent phosphorus atom a heterocyclic ring optionally substituted by any one of the substituents in group A,
- PR10 is a C1 - C20 alkyl group, a C3 - C8 carbocyclic group, or a heterocyclic group optionally substituted by any one of the substituent groups A,
- PR11 is a C1 - C20 alkyl group, a C1 - C20 alkenyl group, a C1 - C20 alkynyl group, a carbocyclic group, or a heterocyclic group optionally substituted by any one of Substituent Group A,
- PR12 is each independently a hydrogen atom, or a C1 - C20 alkyl group optionally substituted by any one of the substituents in Group A,
- PR13 is a C1 - C20 alkylsulfonyl group optionally substituted by any one of Substituent Group A,
- p is an integer from 2 to 3
- q is an integer from 1 to 2
- r is an integer from 2 to 4,
- t is an integer from 2 to 4,
- Substituent Group A includes: oxo, C 1 -C 20 alkyl, C 1 -C 20 alkenyl, C 1 -C 20 haloalkyl , C 1 -C 20 hydroxyalkyl, amino, C 1 -C 20 alkylamino, C 3 -C 8 carbocyclyl, heterocyclyl, carbocyclylalkyl, C 3 -C 8 spiro, C 1 -C 20 alkylcarbonyl, halogen, hydroxy, carboxyl, C 1 -C 20 alkylcarbonylamino, C 1 -C 20 alkylcarbonylaminoC 1 -C 20 alkyl, C 1 -C 20 alkylcarbonyloxy, C 1 -C 20 alkoxycarbonyl, C 1 -C 20 alkoxycarbonylC 1 -C 20 alkyl , C 1 -C 20 alkoxycarbonyloxy, C 1 -C 20 alkylaminocarbonyloxy
- Substituent group B includes: C 3 -C 8 spiro ring, halogen.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound represented by formula (I) or its stereoisomers, tautomers, solvates, prodrugs, isotope labels, pharmaceutically acceptable salts, and pharmaceutically acceptable carriers.
- the present invention provides a compound represented by formula (I) or its stereoisomers, tautomers, solvates, prodrugs, isotope-labeled substances, pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same for use in the preparation of drugs for preventing and/or treating diseases caused by viruses having cap-dependent endonucleases.
- the compounds of the present invention not only have significantly better anti-influenza virus activity, but also have significantly reduced cytotoxicity, higher bioavailability, and better therapeutic effects on influenza viruses resistant to existing drugs.
- FIG1 shows the single crystal structure of the compound of Example 20.
- FIG2 shows the unit cell packing diagram of the compound of Example 20.
- alkyl refers to a monovalent group of a straight or branched saturated hydrocarbon chain having 1 to 20 carbon atoms, more typically 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 6 carbon atoms.
- This term is exemplified by groups such as methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, 1-non
- alkylene refers to a divalent group of a straight or branched saturated hydrocarbon chain having 1 to 20 carbon atoms (more typically 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 6 carbon atoms).
- the term is exemplified by groups such as methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like.
- alkenyl refers to a linear or branched unsaturated hydrocarbon chain monovalent group having 2 to 20 carbon atoms (more typically 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 6 carbon atoms) and having carbon-carbon double bonds (e.g., 1, 2 or 3 carbon-carbon double bonds).
- alkenylene refers to a divalent group of a straight or branched unsaturated hydrocarbon chain having 1 to 20 carbon atoms (more typically 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 6 carbon atoms) and having carbon-carbon double bonds (e.g., 1, 2 or 3 carbon-carbon double bonds).
- the term is exemplified by groups such as vinylene, propenylene, butenylene, pentenylene, hexenylene, etc.
- alkynyl refers to a straight or branched chain alkyl radical having 2 to 20 carbon atoms (more typically 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 6 carbon atoms) and having carbon-carbon triple bonds (e.g., 1, 2 or 3 carbon-carbon triple bonds).
- This term is exemplified by groups such as ethynyl (ie, -C ⁇ CH), propargyl (ie, -CH 2 C ⁇ CH), propynyl (ie, -C ⁇ CCH 3 ), and the like.
- aryl refers to an aromatic carbocyclic group of 6 to 14 carbon atoms (more typically 6 to 10 carbon atoms, or 6 carbon atoms) having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl) or multiple condensed (fused) rings (e.g., naphthyl, fluorenyl, and anthracenyl).
- the term is exemplified by groups such as phenyl, fluorenyl, naphthyl, anthracenyl, 1,2,3,4-tetrahydronaphthalene (if the point of attachment is through the aryl group), and the like.
- halogen refers to fluorine, chlorine, bromine and iodine.
- alkoxy refers to an "alkyl-O-" group, wherein alkyl is as defined herein. This term is exemplified by groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
- haloalkyl refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen, wherein alkyl is as defined herein.
- the term is exemplified by the groups trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, 1,1,-difluoroethyl, etc.
- Carbocycle refers to a monoradical saturated or partially unsaturated group of 3 to 8-membered monocycles or multiple thick (fused) rings or bridged rings or spirocycles having 3 to 14 carbon atoms as ring atoms.
- Carbocycle or carbocyclic radical can be saturated or partially unsaturated, and can be fused with another saturated, partially unsaturated or aromatic ring, provided that the ring atom connected to the target molecule is not aromatic carbon.
- Examples of carbocycle or carbocyclic radical include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene etc.
- heteroaryl refers to an aromatic ring group containing a monocyclic or multiple condensed (fused) ring (e.g., containing 2 or 3 rings) of 5 to 14 ring atoms in the ring, wherein in addition to carbon atoms, the ring atoms also contain at least one heteroatom selected from oxygen, nitrogen and/or sulfur. If the ring is aromatic, the sulfur and nitrogen atoms can also exist in oxidized form.
- Multiple condensed (fused) ring heteroaryl is a monocyclic heteroaryl as defined above fused with one or more rings selected from the following to form a multiple condensed ring system: heteroaryl (to form, for example, naphthyridinyl, such as 1,8-naphthyridinyl), heterocyclic (for example, 1,2,3,4-tetrahydronaphthyridinyl, such as 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocyclic (to form, for example, 5,6,7,8-tetrahydroquinolinyl) and aryl (to form, for example, indazolyl).
- heteroaryl to form, for example, naphthyridinyl, such as 1,8-naphthyridinyl
- heterocyclic for example, 1,2,3,4-tetrahydronaphthyridinyl, such as 1,2,3,4-te
- Such multiple fused ring systems can be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portions of the fused rings.
- the rings of the multiple fused ring systems can be interconnected by fusion, spirocyclic, and bridging bonds. It should be understood that the individual rings of the multiple fused ring systems can be connected to each other in any order. It should also be understood that the attachment point of the multiple fused ring system can be at any position of the multiple fused ring system, including heteroaryl, heterocyclic, aryl, or carbocyclic portions of the multiple fused system.
- heteroaryl group can be on any suitable atom of the heteroaryl group, including carbon atoms and heteroatoms (e.g., nitrogen).
- exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thiophenyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolyl, benzofuranyl, benzimidazolyl, thiaindenyl, pyrrolo[2,3-b]
- heterocycle refers to a monoradical saturated or partially unsaturated group having a 3- to 8-membered monocyclic ring or multiple condensed (fused) rings or bridged rings having 3 to 14 ring atoms in the ring, wherein in addition to carbon atoms, the ring atoms also contain at least one heteroatom selected from oxygen, nitrogen and/or sulfur.
- heterocyclyl groups include, but are not limited to, aziridine, azetidine, tetrahydropyrrole, piperidine, azepane, aziroxane, oxetane, tetrahydrofuran, tetrahydropyran, oxepane, oxocane, thiirane, thietane, tetrahydrothiophene, tetrahydrothiopyran, thiepane, thiocane, tetrahydroimidazole, tetrahydropyrazole, tetrahydrooxazole, tetrahydroisoxazole, tetrahydrothiazole, tetrahydroisothiazole, piperazine, morpholine, dioxane, thioxane, dithiane, dihydropyridyl, 4,5,6,7-tetrahydro-1H-benzo
- the term "therapeutically effective amount” refers to an amount sufficient to affect treatment as defined below when administered to a mammal in need of such treatment.
- the therapeutically effective amount will vary with the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the mode of administration, etc., and can be readily determined by one of ordinary skill in the art.
- stereoisomer refers to a compound having the same chemical composition and connectivity, but whose atoms have different orientations in space that cannot be interchanged by single bond rotation.
- Stepoisomer includes “diastereomers” and “enantiomers”.
- Diastereomers refers to stereoisomers with two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral characteristics and reactivity. Diastereomeric mixtures can be separated under high-resolution analytical procedures (such as crystallization, electrophoresis and chromatography).
- Enantiomers refers to two stereoisomers that are non-overlapping mirror images of each other.
- tautomer refers to the coexistence of two (or more) compounds that differ only in the position and electron distribution of one (or more) mobile atoms, such as keto-enol tautomers.
- pharmaceutically acceptable salt refers to a salt that retains the biological effectiveness and properties of a given compound and is not biologically or otherwise undesirable.
- Pharmaceutically acceptable salts may be acid addition salts and/or base addition salts.
- Acid addition salts may be prepared from inorganic acids and organic acids.
- Salts derived from inorganic acids include hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, carbonates, bisulfates, hydrogen phosphates, dihydrogen phosphates, bicarbonates, and the like; salts derived from organic acids include formate, acetate, propionate, glycolate, pyruvate, oxalate, malate, malonate, succinate, maleate, fumarate, tartrate, citrate, benzoate, cinnamate, mandelate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, salicylate, lactate, nicotinate, lauryl sulfate, naphthalenesulfonate, camphorsulfonate, gluconate, glucuronate, oleate, palmitate, stearate, distearate, succinate ...succinate, succinate, succ
- Base addition salts can be formed with inorganic bases or organic bases.
- Salts derived from inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, lithium, barium, aluminum salts, etc.
- salts derived from organic bases include salts formed with various primary amines, secondary amines, and tertiary amines, such as ethylamine, diethylamine, n-propylamine, isopropylamine, diethanolamine, meglumine, lysine, piperazine, piperidine, morpholine, tromethamine, choline, and the like.
- the term "pharmaceutically acceptable” means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal to be treated therewith.
- solvate refers to an association or complex of one or more solvent molecules with a compound of the invention.
- solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
- hydrate refers to a complex in which the solvent molecule is water.
- prodrug refers to those compounds that readily undergo chemical changes under physiological conditions to provide compounds of the present invention.
- prodrugs can be converted into compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when a prodrug is placed in a transdermal patch reservoir together with a suitable enzyme or chemical reagent, the prodrug can be slowly converted into a compound of the present invention.
- any general formula or structure given herein, including any general formula disclosed herein, including general formula I, is also intended to represent unlabeled forms and isotope-labeled forms of compounds. These forms of compounds may also be referred to as "isotope-labeled substances" or “isotope-enriched analogs". Isotope-labeled compounds have structures as described herein, except that one or more atoms are replaced by atoms with selected atomic mass or mass number.
- isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as, but not limited to, 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I.
- isotopically labeled compounds of the invention for example those into which radioactive isotopes such as3H , 13C and14C are incorporated, are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced with deuterium.
- the compound of the present invention is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof, wherein ring A is selected from
- X 3 , X 4 , X 5 are each independently CR 5 R 5 ', S, O, SO, SO 2 or NR 6 , wherein R 5 , R 5 ' and R 6 are each independently selected from H, halogen, C 1 -C 20 alkyl, C 1 -C 20 haloalkyl, C 1 -C 20 alkoxy, C 1 -C 20 alkylcarbonyl, C 1 -C 20 alkoxycarbonyl, C 1 -C 20 alkylcarbonyloxy, C 1 -C 20 alkoxycarbonyloxy, benzyloxycarbonyl, benzyloxycarbonyloxy;
- n is an integer selected from 0, 1, 2, 3, and 4.
- the compound of the present invention is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope label, or pharmaceutically acceptable salt thereof, wherein ring A is selected from a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, an aziridine ring, an azetidine ring, a tetrahydropyrrole ring, a piperidine ring, an aziridine ring, an azirocidine ring, an oxetane ring, a tetrahydropyrrole ring, a piperidine ring, an aziridine ring, an azirocidine ring, an oxetane ring, a tetrahydropyrrole ring, a
- the compound of the present invention is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof, wherein ring A is selected from It is optionally substituted with one or more groups selected from the group consisting of halogen, C 1 -C 20 alkyl, C 1 -C 20 haloalkyl, C 1 -C 20 alkoxy, C 1 -C 20 alkylcarbonyl, C 1 -C 20 alkoxycarbonyl, C 1 -C 20 alkylcarbonyloxy, C 1 -C 20 alkoxycarbonyloxy, benzyloxycarbonyl, benzyloxycarbonyloxy.
- formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof, wherein ring A is selected from It is optionally substituted with one or more groups selected
- the compound of the present invention is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof, wherein R 1 is selected from:
- R7 is halogen, C1 - C20 alkyl, C1 - C20 haloalkyl, C1- C20 alkoxy, m is an integer selected from 0, 1 , 2, 3 , 4, and X1, X2 , R3, R3 ', and R4 are as defined herein.
- the compound of the present invention is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof, wherein R 1 is selected from:
- the compound of the present invention is a compound represented by formula (II),
- the compound of the present invention is a compound represented by formula (III),
- the compound of the present invention is a compound represented by formula (IV),
- the compound of the present invention is a compound represented by formula (II'), (III') or (IV'),
- n, X 3 , X 4 , X 5 and R 2 are as defined herein.
- the compound of the present invention is a compound represented by formula (V),
- the compound of the present invention is a compound represented by formula (VI) or formula (VI'),
- the compound of the present invention is a compound represented by formula (VII), (VII') or (VII"),
- X 8 is selected from CH 2 , O, S, NH, S ⁇ O, S( ⁇ O) 2 , and X 1 , R 2 , R 7 and m are as defined herein.
- the compound of the present invention is a compound represented by formula (VIII),
- the compound of the present invention is a compound represented by formula (IX) or formula (IX'),
- the compound of the present invention is a compound represented by formula (X), (X') or (X"),
- X 8 is selected from CH 2 , O, S, NH, S ⁇ O, S( ⁇ O) 2 , and X 2 , R 2 , R 7 and m are as defined herein.
- the compound of the present invention is a compound represented by formula (XI),
- the compound of the present invention is a compound represented by formula (XII) or formula (XII'),
- the compound of the present invention is a compound represented by formula (XIII), (XIII') or (XIII"),
- X 8 is selected from CH 2 , O, S, NH, S ⁇ O, S( ⁇ O) 2 , and R 2 , R 7 and m are as defined herein.
- the compound of the present invention is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope label, or pharmaceutically acceptable salt thereof, wherein R 2 is selected from:
- L is a linear or branched C 1 -C 20 alkylene group which is optionally substituted by any one of the substituents in group B,
- K is a hydrogen atom, or a C 1 -C 20 alkyl group optionally substituted by any one of the substituents in Group A,
- PR0 is a C1 - C20 alkyl group optionally substituted by any one of the substituent groups A,
- PR1 is a C 3 -C 8 carbocyclic or heterocyclic group optionally substituted by any one of the substituent groups A,
- PR2 is an alkyl group, a C 3 -C 8 carbocyclic group, or a heterocyclic group optionally substituted by any one of the substituent groups A,
- PR3 are each independently a hydrogen atom, a C1 - C20 alkyl group or a hydroxyl group, or
- Two PR3 groups on adjacent carbon atoms may optionally form a C 1 -C 20 alkenylene group or a C 1 -C 20 alkylene group together.
- PR4 is a C 1 -C 20 alkyl group, a C 3 -C 8 carbocyclic group, or a heterocyclic group optionally substituted by any one of the substituent groups A,
- PR6 is a C 3 -C 8 carbocyclic or heterocyclic group optionally substituted by any one of the substituent groups A,
- PR8 is a C1 - C20 alkoxy group optionally substituted by any one of Substituent Group A,
- PR9 is a C 1 -C 20 alkoxy group, a C 1 -C 20 alkylamino group, a C 3 -C 8 carbocyclic group, a heterocyclic group, a C 3 -C 8 carbocyclic amino group, or a heterocyclic amino group optionally substituted by any one of Substituent Group A, or
- PR8 and PR9 optionally form together with the adjacent phosphorus atom a heterocyclic ring optionally substituted by any one of the substituents in group A,
- PR10 is a C1 - C20 alkyl group or a C3 - C8 carbocyclic group optionally substituted by any one of Substituent Group A,
- PR11 is a C1 - C20 alkyl group, a C1 - C20 alkenyl group, a C1 - C20 alkynyl group, a C3 - C8 carbocyclic group, or a heterocyclic group optionally substituted by any one of Substituent Group A,
- PR12 is each independently a hydrogen atom, or a C1 - C20 alkyl group optionally substituted by any one of the substituents in Group A,
- PR13 is a C1 - C20 alkylsulfonyl group optionally substituted by any one of Substituent Group A,
- p is an integer from 2 to 3
- q is an integer from 1 to 2
- r is an integer from 2 to 4,
- t is an integer from 2 to 4,
- Substituent Group A includes: oxo, C 1 -C 20 alkyl, C 1 -C 20 alkenyl, C 1 -C 20 haloalkyl , C 1 -C 20 hydroxyalkyl, amino, C 1 -C 20 alkylamino, C 3 -C 8 carbocyclyl, heterocyclyl, carbocyclylalkyl, C 3 -C 8 spiro, C 1 -C 20 alkylcarbonyl, halogen, hydroxyl , carboxyl, C 1 -C 20 alkylcarbonylamino , C 1 -C 20 alkylcarbonylaminoC 1 -C 20 alkyl, C 1 -C 20 alkylcarbonyloxy, C 1 -C 20 alkoxycarbonyl, C 1 -C 20 alkoxycarbonylC 1 -C 20 alkyl, C 1 -C 20 alkoxycarbonyloxy, C 1 -C 20 alkylaminocarbony
- Substituent group B includes: C 3 -C 8 spiro ring, halogen.
- the compound of the present invention is a compound represented by formula (XIV):
- Ring A is selected from C 3 -C 8 carbocyclic ring or 3 to 8 membered heterocyclic ring, which is optionally substituted by one or more groups selected from the following: halogen, oxo, C 1 -C 20 alkyl, C 1 -C 20 haloalkyl, C 1 -C 20 alkoxy, C 1 -C 20 alkylcarbonyl, C 1 -C 20 alkoxycarbonyl, C 1 -C 20 alkylcarbonyloxy, C 1 -C 20 alkoxycarbonyloxy, benzyloxycarbonyl, benzyloxycarbonyloxy;
- R1 is selected from:
- X 1 is selected from CH 2 , O, S, NH, S ⁇ O, S( ⁇ O) 2 ;
- X2 is selected from CH, N;
- R 3 , R 3 ′, and R 4 are each independently selected from hydrogen, halogen, C 1 -C 20 alkyl, C 1 -C 20 haloalkyl, and C 1 -C 20 alkoxy; or R 3 , R 3 ′ and the carbon atom to which they are commonly attached together form a C 3 -C 8 carbocyclic ring;
- Ring B is phenyl or 6-membered heteroaryl, which is optionally substituted by one or more groups selected from the group consisting of halogen, C 1 -C 20 alkyl, C 1 -C 20 haloalkyl, C 1 -C 20 alkoxy;
- Ring C is C 6 -C 10 aryl or 6- to 10-membered heteroaryl, which is optionally substituted by one or more groups selected from the group consisting of halogen, C 1 -C 20 alkyl, C 1 -C 20 haloalkyl, C 1 -C 20 alkoxy;
- R2 is selected from:
- L is a linear or branched C 1 -C 20 alkylene or C 1 -C 20 alkene group which is optionally substituted by any one of the substituents in group B. base,
- K is a hydrogen atom, or a C 1 -C 20 alkyl group optionally substituted by any one of the substituents in Group A,
- PR0 is a C1 - C20 alkyl group or a C1 - C20 alkenyl group optionally substituted by any one of the substituent groups A,
- PR1 is a carbocyclic group, a heterocyclic group, a C1 - C20 alkylamino group, or a C1 - C20 alkylthio group optionally substituted by any one of Substituent Group A,
- PR2 is a C 1 -C 20 alkyl group, a carbocyclic group, a heterocyclic group, or a tri(C 1 -C 20 alkyl)silyl group optionally substituted by any one of Substituent Group A,
- PR3 are each independently a hydrogen atom, a C1 - C20 alkyl group or a hydroxyl group, or two PR3 groups on adjacent carbon atoms optionally form an alkenylene group or an alkylene group together,
- PR4 is each independently a C1 - C20 alkyl group, a C3 - C8 carbocyclic group, a heterocyclic group, a C1 - C20 alkylamino group, or a tri( C1 - C20 alkyl)silyl group optionally substituted by any one of Substituent Group A,
- PR5 are each independently hydroxyl or benzyloxy
- PR6 is a C 3 -C 8 carbocyclic or heterocyclic group optionally substituted by any one of the substituent groups A,
- PR7 is each independently a C1 - C20 alkyl group optionally substituted by any one of Substituent Group A,
- PR8 is a C1 - C20 alkoxy group optionally substituted by any one of Substituent Group A,
- PR9 is a C1 - C20 alkoxy group, a C1 - C20 alkylamino group, a C3 - C8 carbocyclic group, a heterocyclic group, a C3 - C8 carbocyclic amino group, or a heterocyclic amino group optionally substituted by any one of Substituent Group A, and
- PR8 and PR9 optionally form together with the adjacent phosphorus atom a heterocyclic ring optionally substituted by any one of the substituents in group A,
- PR10 is a C1 - C20 alkyl group, a C3 - C8 carbocyclic group, or a heterocyclic group optionally substituted by any one of the substituent groups A,
- PR11 is a C1 - C20 alkyl group, a C1 - C20 alkenyl group, a C1 - C20 alkynyl group, a carbocyclic group, or a heterocyclic group optionally substituted by any one of Substituent Group A,
- PR12 is each independently a hydrogen atom, or a C1 - C20 alkyl group optionally substituted by any one of the substituents in Group A,
- PR13 is a C1 - C20 alkylsulfonyl group optionally substituted by any one of Substituent Group A,
- p is an integer from 2 to 3
- q is an integer from 1 to 2
- r is an integer from 2 to 4,
- t is an integer from 2 to 4,
- Substituent Group A includes: oxo, C 1 -C 20 alkyl, C 1 -C 20 alkenyl, C 1 -C 20 haloalkyl , C 1 -C 20 hydroxyalkyl, amino, C 1 -C 20 alkylamino, C 3 -C 8 carbocyclyl, heterocyclyl, carbocyclylalkyl, C 3 -C 8 spiro, C 1 -C 20 alkylcarbonyl, halogen, hydroxy, carboxyl, C 1 -C 20 alkylcarbonylamino, C 1 -C 20 alkylcarbonylaminoC 1 -C 20 alkyl, C 1 -C 20 alkylcarbonyloxy , C 1 -C 20 alkoxycarbonyl, C 1 -C 20 alkoxycarbonylC 1 -C 20 alkyl, C 1 -C 20 alkoxycarbonyloxy, C 1 -C 20 alkylaminocarbonyloxy
- Substituent group B includes: C 3 -C 8 spiro ring, halogen.
- the compound of the present invention is a compound represented by formula (XIV) or a tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof, wherein ring A is selected from
- X 3 , X 4 , X 5 are each independently CR 5 R 5 ', S, O, SO, SO 2 or NR 6 , wherein R 5 , R 5 ' and R 6 are each independently selected from H, halogen, C 1 -C 20 alkyl, C 1 -C 20 haloalkyl, C 1 -C 20 alkoxy, C 1 -C 20 alkylcarbonyl, C 1 -C 20 alkoxycarbonyl, C 1 -C 20 alkylcarbonyloxy, C 1 -C 20 alkoxycarbonyloxy, benzyloxycarbonyl, benzyloxycarbonyloxy;
- n is an integer selected from 0, 1, 2, 3, and 4.
- the compound of the present invention is a compound represented by formula (XIV) or a tautomer, solvate, prodrug, isotope label, or pharmaceutically acceptable salt thereof, wherein ring A is selected from a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, an aziridine ring, an azetidine ring, a tetrahydropyrrole ring, a piperidine ring, an aziridine ring, an aziridine ring, an aziridine ring, an oxetane ring, a tetrahydrofuran ring
- the present invention comprises a pyranyl ring, a tetrahydropyranyl ring, an oxepane ring, an oxocane ring
- the compound of the present invention is a compound represented by formula (XIV) or a tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof, wherein ring A is selected from It is optionally substituted with one or more groups selected from the group consisting of halogen, C 1 -C 20 alkyl, C 1 -C 20 haloalkyl, C 1 -C 20 alkoxy, C 1 -C 20 alkylcarbonyl, C 1 -C 20 alkoxycarbonyl, C 1 -C 20 alkylcarbonyloxy, C 1 -C 20 alkoxycarbonyloxy, benzyloxycarbonyl, benzyloxycarbonyloxy.
- formula (XIV) or a tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof, wherein ring A is selected from It is optionally substituted with one or more groups selected from the group consisting of hal
- the compound of the present invention is a compound represented by formula (XIV) or a tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof, wherein R 1 is selected from:
- R7 is halogen, C1 - C20 alkyl, C1 - C20 haloalkyl, C1- C20 alkoxy, m is an integer selected from 0, 1 , 2, 3 , 4, and X1, X2 , R3, R3 ', and R4 are as defined herein.
- the compound of the present invention is a compound represented by formula (XIV) or a tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof, wherein R 1 is selected from:
- the compound of the present invention is a compound represented by formula (XV),
- the compound of the present invention is a compound represented by formula (XVI),
- the compound of the present invention is a compound represented by formula (XVII),
- the compound of the present invention is a compound represented by formula (XV'), (XVI') or (XVII'),
- n, X 3 , X 4 , X 5 and R 2 are as defined herein.
- the compound of the present invention is a compound represented by formula (XVIII),
- the compound of the present invention is a compound represented by formula (XIX) or formula (XIX'),
- the compound of the present invention is a compound represented by formula (XX), (XX') or (XX"),
- X 8 is selected from CH 2 , O, S, NH, S ⁇ O, S( ⁇ O) 2 , and X 1 , R 2 , R 7 and m are as defined herein.
- the compound of the present invention is a compound represented by formula (XXI),
- the compound of the present invention is a compound represented by formula (XXII) or formula (XXII'),
- the compound of the present invention is a compound represented by formula (XXIII), (XXIII') or (XXIII"),
- X 8 is selected from CH 2 , O, S, NH, S ⁇ O, S( ⁇ O) 2 , and X 2 , R 2 , R 7 and m are as defined herein.
- the compound of the present invention is a compound represented by formula (XXIV),
- X 6 is selected from CH 2 , O, S, NH, S ⁇ O, S( ⁇ O) 2 , and R 2 , R 7 and m are as defined herein.
- the compound of the present invention is a compound represented by formula (XXV) or formula (XXV'),
- the compound of the present invention is a compound represented by formula (XXVI), (XXVI') or (XXVI"),
- X 8 is selected from CH 2 , O, S, NH, S ⁇ O, S( ⁇ O) 2 , and R 2 , R 7 and m are as defined herein.
- the compound of the present invention is a compound represented by formula (XIV) or a tautomer, solvate, prodrug, isotope label, or pharmaceutically acceptable salt thereof, wherein R 2 is selected from:
- L is a linear or branched C 1 -C 20 alkylene group which is optionally substituted by any one of the substituents in group B,
- K is a hydrogen atom, or a C 1 -C 20 alkyl group optionally substituted by any one of the substituents in Group A,
- PR0 is a C1 - C20 alkyl group optionally substituted by any one of the substituent groups A,
- PR1 is a C 3 -C 8 carbocyclic or heterocyclic group optionally substituted by any one of the substituent groups A,
- PR2 is an alkyl group, a C 3 -C 8 carbocyclic group, or a heterocyclic group optionally substituted by any one of the substituent groups A,
- PR3 are each independently a hydrogen atom, a C1 - C20 alkyl group or a hydroxyl group, or
- Two PR3 groups on adjacent carbon atoms may optionally form a C 1 -C 20 alkenylene group or a C 1 -C 20 alkylene group together.
- PR4 is a C 1 -C 20 alkyl group, a C 3 -C 8 carbocyclic group, or a heterocyclic group optionally substituted by any one of the substituent groups A,
- PR6 is a C 3 -C 8 carbocyclic or heterocyclic group optionally substituted by any one of the substituent groups A,
- PR8 is a C1 - C20 alkoxy group optionally substituted by any one of Substituent Group A,
- PR9 is a C 1 -C 20 alkoxy group, a C 1 -C 20 alkylamino group, a C 3 -C 8 carbocyclic group, a heterocyclic group, a C 3 -C 8 carbocyclic amino group, or a heterocyclic amino group optionally substituted by any one of Substituent Group A, or
- PR8 and PR9 optionally form together with the adjacent phosphorus atom a heterocyclic ring optionally substituted by any one of the substituents in group A,
- PR10 is a C1 - C20 alkyl group or a C3 - C8 carbocyclic group optionally substituted by any one of Substituent Group A,
- PR11 is a C1 - C20 alkyl group, a C1 - C20 alkenyl group, a C1 - C20 alkynyl group, a C3 - C8 carbocyclic group, or a heterocyclic group optionally substituted by any one of Substituent Group A,
- PR12 is each independently a hydrogen atom, or a C1 - C20 alkyl group optionally substituted by any one of the substituents in Group A,
- PR13 is a C1 - C20 alkylsulfonyl group optionally substituted by any one of Substituent Group A,
- p is an integer from 2 to 3
- q is an integer from 1 to 2
- r is an integer from 2 to 4,
- t is an integer from 2 to 4,
- Substituent Group A includes: oxo, C 1 -C 20 alkyl, C 1 -C 20 alkenyl, C 1 -C 20 haloalkyl , C 1 -C 20 hydroxyalkyl, amino, C 1 -C 20 alkylamino, C 3 -C 8 carbocyclyl, heterocyclyl, carbocyclylalkyl, C 3 -C 8 spiro, C 1 -C 20 alkylcarbonyl, halogen, hydroxy, carboxyl, C 1 -C 20 alkylcarbonylamino, C 1 -C 20 alkylcarbonylaminoC 1 -C 20 alkyl, C 1 -C 20 alkylcarbonyloxy, C 1 -C 20 alkoxycarbonyl, C 1 -C 20 alkoxycarbonylC 1 -C 20 alkyl , C 1 -C 20 alkoxycarbonyloxy, C 1 -C 20 alkylaminocarbonyloxy
- Substituent group B includes: C 3 -C 8 spiro ring, halogen.
- compounds of the invention include but are not limited to the following compounds:
- the pharmaceutical composition provided by the present invention comprises the compound of the present invention or its stereoisomer, tautomer, solvate, prodrug, isotope label, pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier.
- Pharmaceutically acceptable carriers are known to those skilled in the art, including diluents, lubricants, disintegrants, adhesives, buffers, preservatives, stabilizers, wetting agents, glidants, emulsifiers, colorants, flavoring agents, sweeteners, etc.
- the pharmaceutical composition of the present invention can be made in solid form (including but not limited to tablets, capsules, pills, granules, powders, powders, suppositories) or liquid form (including but not limited to solutions, suspensions, emulsions, tinctures, syrups).
- the pharmaceutically acceptable carrier generally includes one or more of the following: a) diluents, such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose, etc.; b) lubricants, such as silicon dioxide, talc, stearic acid, polyethylene glycol, etc.; c) binders, such as magnesium aluminosilicate, gelatinized starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, etc.; d) disintegrants, such as starch, alginic acid, agar, corn starch; e) stabilizers, such as antioxidants such as ascorbic acid; f) glidants, such as silicon dioxide; g) flavoring agents, such as mint, methyl salicylate; sweeteners, such as sucrose, saccharin.
- diluents such as lactose, glucose, sucrose
- the pharmaceutically acceptable carrier generally includes one or more of the following: a) diluents, such as water for injection, physiological saline, Ringer's solution, polyethylene glycol, glycerol, propylene glycol, etc.; b) antioxidants, such as ascorbic acid or sodium bisulfite; c) buffers, such as acetates, phosphates, etc.
- diluents such as water for injection, physiological saline, Ringer's solution, polyethylene glycol, glycerol, propylene glycol, etc.
- antioxidants such as ascorbic acid or sodium bisulfite
- buffers such as acetates, phosphates, etc.
- the effective dosage of the compounds of the invention depends at least on the nature, extent, delivery method and dosage form of the condition being treated. And will be ultimately determined by the clinician. It can be expected that about 0.0001 to about 100 mg per kilogram of body weight per day; usually about 0.01 to about 10 mg per kilogram of body weight per day; more typically, about 0.01 to about 5 mg per kilogram of body weight per day; most typically about 0.05 to about 0.5 mg per kilogram of body weight per day.
- a candidate daily dose for an adult of about 70 kg body weight will be in the range of 1 mg to 1000 mg, preferably in the range of 5 mg to 500 mg, and can be administered in the form of a single dose or multiple doses.
- the compounds of the present invention have inhibitory activity against viral RNA polymerases, especially cap-dependent endonucleases, and can be used to prevent and/or treat diseases caused by viruses having cap-dependent endonucleases, including influenza virus infections, such as influenza A virus infection, influenza B virus infection, influenza C virus infection, influenza D virus infection, avian influenza virus infection, swine influenza virus infection, etc.
- influenza virus infections such as influenza A virus infection, influenza B virus infection, influenza C virus infection, influenza D virus infection, avian influenza virus infection, swine influenza virus infection, etc.
- the compounds and/or pharmaceutical compositions of the present invention can be used to prevent, alleviate, relieve and/or cure symptoms and/or diseases caused by various influenza viruses, such as cold symptoms such as fever, chills, headache, myalgia, respiratory inflammation symptoms such as sore throat, runny nose, nasal congestion, cough, gastrointestinal symptoms such as abdominal pain, vomiting, diarrhea, etc.
- influenza viruses such as cold symptoms such as fever, chills, headache, myalgia, respiratory inflammation symptoms such as sore throat, runny nose, nasal congestion, cough, gastrointestinal symptoms such as abdominal pain, vomiting, diarrhea, etc.
- the compounds of the present invention can be co-administered with one or more other agents simultaneously or sequentially.
- the compounds of the present invention and other agents can be administered separately by the same or different routes of administration, or can be administered simultaneously as a combined agent in a pharmaceutical composition.
- agents suitable for use in the present invention can be various antiviral agents that have inhibitory activity against influenza viruses, including but not limited to neuraminidase inhibitors (e.g., oseltamivir, peramivir, zanamivir, laninamivir), M2 protein inhibitors (e.g., amantadine, rimantadine), RNA polymerase inhibitors (e.g., favipiravir, ribavirin), PB1/PB2 inhibitors (e.g., VX-787), and antiviral vaccines, etc.
- neuraminidase inhibitors e.g., oseltamivir, peramivir, zanamivir, laninamivir
- M2 protein inhibitors e.g., amantadine, rimantadine
- RNA polymerase inhibitors e.g., favipiravir, ribavirin
- PB1/PB2 inhibitors e.g., VX
- Step 1 Intermediate 1 is reacted with intermediate 2 in the presence of a catalyst, such as a Lewis acid including but not limited to tin tetrachloride, in a suitable organic solvent such as acetonitrile, tetrahydrofuran, etc. to obtain intermediate 3; wherein PG represents an amino protecting group, especially an amino protecting group that is easily removed under alkaline conditions, including but not limited to allyloxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl, etc.
- a catalyst such as a Lewis acid including but not limited to tin tetrachloride
- a suitable organic solvent such as acetonitrile, tetrahydrofuran, etc.
- Step 2 In the presence of a catalyst, particularly a metal catalyst such as a palladium catalyst, intermediate 3 undergoes a ring-closing reaction under alkaline conditions to obtain intermediate 4, wherein the palladium catalyst includes tetrakistriphenylphosphine palladium and the like;
- a catalyst particularly a metal catalyst such as a palladium catalyst
- Step 3 The intermediate 4 undergoes a substitution reaction with R 1 X under alkaline conditions (such as carbonates, bicarbonates, etc. of alkali metals, alkaline earth metals, etc.) to obtain the intermediate 5; wherein R 1 is as defined herein, and X represents a halogen such as chlorine, bromine, or iodine;
- alkaline conditions such as carbonates, bicarbonates, etc. of alkali metals, alkaline earth metals, etc.
- Step 4 After chiral resolution, the intermediate 5 is reacted in the presence of LiCl to remove the benzyl protecting group to obtain a compound of formula (I) ( R2 is H);
- Step 5 Substitution reaction of the compound of formula (I) (R 2 is H) with R 2 X under basic conditions (such as inorganic base or organic base) in a suitable organic solvent to obtain a compound of formula (XIV), wherein R 2 is a group other than H as defined herein.
- Step 1 the raw material reacts with ethyl acetate under alkaline conditions (such as lithium diisopropylamide, butyl lithium, sodium hydrogen hydride, sodium tert-butoxide, etc.) to obtain intermediate 1-a;
- alkaline conditions such as lithium diisopropylamide, butyl lithium, sodium hydrogen hydride, sodium tert-butoxide, etc.
- Step 2 Intermediate 1-a reacts with TMSCN in the presence of TMSOTf to generate intermediate 1-b;
- Step 3 The intermediate 1-b is hydrogenated in the presence of a catalyst such as palladium on carbon to obtain the intermediate 1-c;
- Step 4 Intermediate 1-c undergoes a ring-closure reaction under alkaline conditions to obtain intermediate 1-d;
- Step 5 the intermediate 1-d is reacted with a protecting group reagent (such as allyl chloroformate, benzyl chloroformate, fluorenylmethyl chloroformate) to generate the intermediate 1-e;
- a protecting group reagent such as allyl chloroformate, benzyl chloroformate, fluorenylmethyl chloroformate
- Step 6 intermediate 1-e undergoes a reduction reaction in the presence of a reducing agent to obtain intermediate 1-f;
- the reducing agent includes diisobutylaluminum hydride, etc.;
- Step 7 Intermediate 1-f reacts with methanol under acidic conditions to form ether to obtain intermediate 1.
- Step 4 3-((3-(Benzyloxy)-2-(ethoxycarbonyl)-4-oxo-1,4-dihydropyridin-1-yl)amino)-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester (Intermediate 4)
- Step 5 9'-(Benzyloxy)-3a',4'-dihydro-1'H,3'H-spiro[cyclohexane-1,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'-dione (Intermediate 5)
- Step 6 9'-(Benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of cyclohexane-1,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'-dione (Intermediate 6)
- Step 7 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of cyclohexane-1,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'-dione (Example 1)
- Ether (10 mL) and chloroform (1 mL) were added to the crude product and slurried for 2 h. Filter, wash the filter cake with ether (5 mL) and dry it in vacuo to obtain 194 mg of a yellow solid with a yield of 70%.
- Step 6 9'-(Benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of 2,3,3a',4',5,6-hexahydro-1'H,3'H-azaspiro[pyran-4,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'-dione (Intermediate 7)
- intermediate 6 (0.80 g, 2.1 mmol), 11-chloro-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine (1.50 g, 5.3 mmol), acetonitrile (100 mL) and cesium carbonate (2.73 g, 8.4 mmol), nitrogen protection, room temperature overnight reaction.
- Step 7 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of 9'-hydroxy-2,3,3a',4',5,6-hexahydro-1'H,3'H-azaspiro[pyran-4,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'-dione
- Example 3 3-oxo-8-oxa-2-azaspiro[4.5]decane-8-carboxylic acid benzyl ester was used to replace 3-oxo-8-oxa-2-azaspiro[4.5]decane, and after the above intermediate compound, 140 mg of Example 3 compound was finally obtained as a brown solid with a yield of 81.8%.
- Step 10 9'-(Benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of 3,3a',4,4',5,6-hexahydro-1'H,3'H-spiro[pyran-2,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'-dione (11)
- Step 11 9'-(Benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of 3',4',5,6-tetrahydro-1'H,2H,3'H,4H-spiro[pyran-3,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'-dione (12)
- Step 12 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of 3'-(11-yl)-9'-hydroxy-3a',4',5,6-tetrahydro-1'H,2H,3'H,4H-spiro[pyran-3,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'-dione (Example 5)
- intermediate 3 (18 g, 77.25 mmol), ethanol (200 mL), water (20 mL), ammonium chloride (20.66 g, 386.27 mmol) and iron powder (21.63 g, 386.27 mmol) were added in sequence, and the mixture was reacted at 80°C for 2 h under nitrogen protection.
- Step 10 9-(Benzyloxy)-4-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of 2',3a,3',4,5',6'-hexahydro-1H,3H-spiro[pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine-2,4'-(1',1'-dioxothiopyran)]-8,10-dione (11)
- intermediate 10 800 mg, 1.86 mmol
- 11-chloro-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine 1.6 g, 4.66 mmol
- acetonitrile 35 mL
- cesium carbonate 2.42 g, 7.46 mmol
- intermediate 11 (420 mg, 0.62 mmol), DMAc (10 mL) and LiCl (262 mg, 6.2 mmol) were added in sequence, and the mixture was reacted at 80°C for 5 h under N2 protection.
- Step 12 9-(Benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of 2-(4-(2-(2-(4-(2-(2-nitro-1-yl)-3-methyl-2,3,3a',4',5,6-hexahydro-1'H,3'H-spiro[pyran-4,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'-dione(14)
- Step 13 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of 2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-nitro-1-yl)-9'-hydroxy-3-methyl-2',3,3a',4,5,6-hexahydro-1'H,3'H-spiro[pyran-4,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'-dione (Example 7)
- intermediate 14 (210 mg, 0.33 mmol), DMAc (3 mL) and lithium chloride (139 mg, 3.27 mmol) were added in sequence, nitrogen was protected, and the reaction was carried out at 80°C for 4.5 h.
- Step 5 tert-butyl-9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine -11-yl)-8',10'-dioxo- Synthesis of 3a',4',8',10'-tetrahydro-1'H,3'H-spiro[piperidin-4,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]-triazine]-1-carboxylate (6)
- Step 6 9'-(Benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of 1,11-yl)-3a',4'-dihydro-1'H,3'H-spiro[piperidin-4,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]-triazine]-8',10'-dione (7)
- Step 7 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of 1,11-yl)-9'-hydroxy-1'H,3'H-spiro[piperidin-4,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]-triazine]-8',10'-dione (Example 8)
- Step 1 Referring to the method of Example 2, 1-amino-3-(hexyloxy)-4-oxo-1,4-dihydropyridine-2-carboxylic acid ethyl ester was used instead of 1-amino-3-(benzyloxy)-4-oxo-1,4-dihydropyridine-2-carboxylic acid ethyl ester to prepare 9'-(hexyloxy)-2,3,3a',4',5,6-hexahydro-1'H,3'H-spiro[pyran-4,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'-dione (SM2).
- SM2 9'-(hexyloxy)-2,3,3a',4',5,6-hexahydro-1'H,3'H-spiro[pyran-4,2'-pyrido[2,1-f]pyrrolo[2,
- Step 6 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of 1,11-yl)-9'-(hexyloxy)-3a',4'-dihydro-1'H,3'H-spiro[octane-3,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine-8',10'-dione methanesulfonate (8)
- Step 7 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of 1,11-yl)-9'-hydroxy-3a',4'-dihydro-1'H,3'H-spiro[octane-3,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine-8',10'-dione (Example 11)
- Step 9 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thia Synthesis of 8',10'-dioxo-3a',4',8',10'-tetrahydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-9'-hexanoic acid ester (10)
- intermediate 9 500 mg, 1.45 mmol
- (S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazine -11-ol 574 mg, 2.17 mmol
- propylphosphonic anhydride 50 wt% ethyl acetate solution, 2.76 g, 4.34 mmol
- methanesulfonic acid 278 mg, 2.89 mmol
- Step 10 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of cyclobutane-1,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'-dione (Example 12)
- Preparation conditions Method A: Instrument: MG ⁇ Preparative SFC (SFC-14). Chromatographic column: ChiralPak AD, 250 ⁇ 30mm ID, 10 ⁇ m. Mobile phase: A represents CO 2 , B represents isopropanol (0.1% NH 3 H 2 O). Gradient: B 45%. Flow rate: 80mL/min. Column pressure: 100bar. Column temperature: 38°C. Detector wavelength: 220nm. Sample preparation method: Dissolve the sample in a mixed solvent (methanol/dichloromethane, 38ml). Injection method: Inject once every 9min, 2mL each time. Post-treatment method: Concentrate under reduced pressure to obtain the desired isomer.
- Method B Instrument: MG ⁇ Preparative SFC (SFC-14). Chromatographic column: ChiralPak IG, 250 ⁇ 30mm ID, 10 ⁇ m. Mobile phase: A represents CO 2 , B represents methanol. Gradient: B 50%. Flow rate: 80mL/min. Column pressure: 100 bar. Column temperature: 38°C. Detector wavelength: 220 nm. Sample preparation method: Dissolve the sample in a mixed solvent (methanol/dichloromethane, 40 ml). Injection method: Inject once every 8.3 min, 4 mL each time. Post-treatment method: Concentrate under reduced pressure to obtain the desired isomer.
- Example 13 250 mg, 0.40 mmol, N,N-dimethylacetamide (4 mL) and lithium chloride (169 mg, 4.0 mmol) were added to a thumb bottle in sequence, and the mixture was reacted at 80°C for 5 h under nitrogen protection.
- 1 H NMR 600 MHz, DMSO-d 6 ) ⁇ (ppm): 7.52-7.48 (m, 2H, ArH), 7.40-7.30 (m, 2H, ArH), 7.10-7.01 (m, 2H, ArH), 6.97-6.80 (m, 2H, ArH), 5.76-5.68 (m, 1.5H, CH, CH 2 ), 5.65-5.56 (m, 2.5H, CH, CH 2 ), 4.21-4.14 (m, 1H, CH 2 ), 3.90-3.88 (m, 1H, CH 2 ), 3.58-3.48 (m, 4H, CH 2 ), 2.00-1.95 (m, 1H, CH 2 ), 1.53-1.40 (m, 2H, CH 2 ),1.37-1.30(m,2H,CH 2 ),1.26-1.20(
- FIG1 and FIG2 respectively show the single crystal structure diagram and single crystal stacking diagram of the compound of Example 20.
- SFC separation conditions Analytical conditions: Method A: Instrument: Waters UPC2 analytical SFC (SFC-H). Chromatographic column: ChiralCel OJ, 150 ⁇ 4.6mm ID, 3 ⁇ m. Mobile phase: A represents CO 2 , B represents isopropanol (0.05% DEA). Gradient: B 40%. Flow rate: 2.5mL/min. Column pressure: 100bar. Column temperature: 35 ⁇ . Detector wavelength: 220nm. Method B: Instrument: Waters UPC2 analytical SFC (SFC-H). Chromatographic column: ChiralPak AS, 150 ⁇ 4.6mm ID, 3 ⁇ m. Mobile phase: A represents CO 2 , B represents isopropanol (0.05% DEA). Gradient: B 40%. Flow rate: 2.5mL/min. Column pressure: 100bar. Column temperature: 35 ⁇ . Detector wavelength: 220nm.
- Preparation conditions Method A: Instrument: MG ⁇ Preparative SFC (SFC-14). Chromatographic column: ChiralCel OJ, 250 ⁇ 30 mm ID, 10 ⁇ m. Mobile phase: A represents CO 2 , B represents isopropanol (0.1% NH 3 H 2 O). Gradient: B 30%. Flow rate: 70 mL/min. Column pressure: 100bar. Column temperature: 38 ⁇ . Detector wavelength: 220nm. Sample preparation method: Dissolve the sample in a mixed solvent (methanol/dichloromethane, 60ml). Injection method: Inject once every 23min, 2mL each time. Post-treatment method: Concentrate under reduced pressure to obtain the desired isomer.
- Method B Instrument: MG ⁇ Preparative SFC (SFC-14). Chromatographic column: ChiralPak AS, 250 ⁇ 30mm ID, 10 ⁇ m. Mobile phase: A represents CO 2 , B represents methanol. Gradient: B 10%. Flow rate: 60mL/min. Column pressure: 100bar. Column temperature: 38 ⁇ . Detector wavelength: 220nm. Sample preparation method: Dissolve the sample in a mixed solvent (methanol/dichloromethane, 15ml). Injection method: Inject once every 20min, 4mL each time. Post-treatment method: Concentrate under reduced pressure to obtain the desired isomer.
- Example 25 Referring to the preparation method of Example 25, using Example 22 as the raw material, 135 mg of brown-red solid was obtained with a yield of 100%.
- Example 23 Referring to the preparation method of Example 25, using Example 23 as the raw material, 106 mg of brown-red solid was obtained with a yield of 79%.
- reaction solution is filtered through diatomaceous earth, the filtrate is concentrated, and the residue is dissolved in ethyl acetate (20 mL), washed with saturated sodium thiosulfate aqueous solution (50 mL) and saturated brine (50 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 600 mg of yellow oily intermediate 3 crude product, which is directly used for the next step.
- Step 3 (((S)-4'-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of 2,3,3a',4',5,6,8',10'-octahydro-1'H,3'H-spiro[pyran-4,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-9'-yl)oxy)methyl(tert-butyloxycarbonyl)-L-valine ester (Example 29)
- Step 1 (((R)-4'-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of 2-(1-yl)-9'-chloromethyloxy-2,3,3a',4',5,6-hexahydro-1'H,3'H-azaspiro[pyran-4,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'-dione (2)
- Example 20 500 mg, 0.93 mmol), DCM (10 mL), tetrabutylammonium hydrogen sulfate (32 mg, 0.09 mmol), water (10 mL) and sodium bicarbonate (313 mg, 3.72 mmol) were added to a 50 mL single-necked bottle in sequence and stirred at room temperature. After 20 minutes, chloromethyl chlorosulfonate (307 mg, 1.86 mmol) was added dropwise and stirred at room temperature overnight under nitrogen atmosphere.
- intermediate 2 120 mg, 0.21 mmol
- DMF 2 mL
- potassium carbonate 58 mg, 0.42 mmol
- morpholin-4-yl acetic acid 53 mg, 0.32 mmol
- Step 2 (((S)-4'-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of 2,3,3a',4',5,6,8',10'-octahydro-1'H,3'H-spiro[pyran-4,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-9'-yl)oxy)methyl methyl carbamate
- Example 20 The compound of Example 20 (200 mg, 0.37 mmol), acetonitrile (4 mL), potassium carbonate (103 mg, 0.74 mmol), intermediate 2 (55 mg, 0.44 mmol), and potassium iodide (62 mg, 0.37 mmol) were added to a 25 mL single-mouth bottle in sequence, and the mixture was reacted at 80°C for 6 h under nitrogen protection.
- Step 1 (((S)-4'-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of 2,3,3a',4',5,6-hexahydro-1'H,3'H-azaspiro[pyran-4,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'-dione
- Example 34 intermediate 2 500 mg, 0.85 mmol
- N, N-dimethylformamide 5 mL
- sodium azide 83 mg, 1.28 mmol
- water 2 mL
- Step 2 (((S)-4'-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of 2,3,3a',4',5,6-hexahydro-1'H,3'H-azaspiro[pyran-4,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'-dione
- Step 3 (((S)-4'-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of methyl 2-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-nitro-1-yl)-8',10'-dioxo-2,3,3a',4',5,6,8',10'-octahydro-1'H,3'H-spiro[pyran-4,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-9'-yl)oxy)methylcarbamate
- Example 34 Example 34 Intermediate 2 (500 mg, 0.85 mmol), DMF (10 mL), potassium carbonate (236 mg, 1.71 mmol) and N-Boc-L-tert-leucine (295 mg, 1.28 mmol) were added to the bottle in sequence and stirred at room temperature for 3 h under a nitrogen atmosphere.
- Step 4 (((S)-4'-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of (S)-2-((S)-2,6-diaminohexanoyl)amino-3,3-dimethylbutyrate (Example 39)
- Step 8 9'-(Benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolidine Synthesis of ethyl 8',10'-dioxo-3a',4',8',10'-tetrahydro-1'H,3'H-spiro[piperidin-4,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]-triazine]-1-carboxylate (9)
- Step 9 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thia -11-yl)-9'-hydroxy-8',10'-dioxo-3a',4',8',10'-tetrahydro Synthesis of ethyl 1'H,3'H-spiro[piperidine-4,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-1-carboxylate (Example 40)
- the positive control compound baloxavir disoproxil was provided by Shanghai WuXi AppTec Pharmaceutical Development Co., Ltd.
- the compound was prepared into a mother solution with 100% DMSO, tested at 8 concentration points, 3-fold gradient dilution, and double replicates.
- Canine kidney cells MDCK were purchased from ATCC, item number CCL-34. The cells were cultured in EMEM (Sigma) culture medium supplemented with 10% fetal bovine serum (Hyclone or ExCell Bio), 1% double antibody (Hyclone), 1% L-glutamine (Gibco) and 1% non-essential amino acids (Gibco).
- OptiPRO SFM (Gibco) culture medium supplemented with 1% double antibody, 1% L-glutamine and 1% non-essential amino acids was used as the experimental culture medium.
- the experimental culture medium supplemented with pancreatin (Invitrogen) was the virus infection culture medium.
- the influenza virus A/WSN/33 (H1N1) strain was purchased from Virapur, item number F1003A.
- the cytotoxicity experiment was carried out under the same conditions as the antiviral experiment, but without virus infection.
- the antiviral activity and cytotoxicity of the compound were expressed by the inhibition rate (%) of the virus-induced cytopathic effect of the compound at different concentrations and the viability (%) of MDCK cells, respectively.
- the calculation formula is as follows:
- Inhibition rate (%) (test well reading - virus control average) / (cell control average - virus control average) ⁇ 100
- GraphPad Prism software was used to perform nonlinear fitting analysis on the inhibition rate and cell viability of the compounds, and the half effective concentration (EC 50 ) and half cytotoxic concentration (CC 50 ) values of the compounds were calculated.
- Baloxavir dipeptide-resistant influenza virus A/PR/8/34 (H 1 N 1 ) strain was purchased from WuXi AppTec. Other experimental materials and methods were the same as above. From the results in Table 2, it can be seen that the inhibitory activity of the compound of Example 20 against the resistant strain is better than that of baloxavir dipeptide.
- MDCK cells source: ATCC
- high-glucose DMEM cell culture medium including 10% fetal bovine serum, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin, 200 ⁇ g/mL glutamine.
- the cells were placed in a 37 ⁇ incubator and cultured under 5% CO 2 saturated humidity conditions. The medium was changed every 1 to 2 days and observed under a fluorescent inverted microscope. After the cells grew into a monolayer, they were digested and passaged with 0.25% trypsin.
- Transwell chamber inoculation Inoculate cells at a fixed density of 13.0 ⁇ 10 5 cells/cm 2 in 0.4 mL on the villus surface (AP side) of the transwell, and add 1 mL of blank culture medium on the basal surface (BL side). Replace with fresh cell culture medium every two days after inoculation. Once, change the medium every day after one week, 300 ⁇ L on the A side and 1mL on the B side, and it will take about 12 days to form.
- Absorption (AP ⁇ BL) osmotic transport 0.3 mL of Hank's solution containing the test compound at a concentration of 20 ⁇ M was added to the AP side as the supply solution, and 1 mL of blank Hank's solution was added to the BL side as the receiving solution.
- Efflux (BL ⁇ AP) osmotic transport Take 1 mL of Hank’s solution with a concentration of 20 ⁇ M of the test compound and add it to the BL side as the supply solution, and at the same time add 0.3 mL of blank Hank’s solution to the A side as the receiving solution.
- the apparent permeability coefficient Papp (cm/sec) reflects the permeability of the drug in the cell;
- VR (mL) represents the volume of the solution in the receiving chamber;
- A represents the area of the membrane (A is 0.3 cm 2 at this time);
- C 0 ( ⁇ g ⁇ mL -1 ) represents the initial concentration of the drug in the test solution;
- dC/dt ( ⁇ g ⁇ mL -1 ⁇ sec -1 ) represents the drug concentration obtained in the receiving chamber per unit time.
- Papp(AP ⁇ BL) for transport from AP to BL and Papp(BL ⁇ AP) for transport from BL to AP were calculated respectively, and the ratio of Papp(BL ⁇ AP) to Papp(AP ⁇ BL) was used to represent the efflux capacity with the participation of transporters.
- the formula is as follows:
- Ratio B/A Papp(BL ⁇ AP)/Papp(AP ⁇ BL)
- Some compounds of the present invention were tested for permeability and drug transport properties in an in vitro Caco-2 (purchased from ATCC) monolayer cell model, and the results are shown in Table 3. Some compounds of the present invention have higher cell membrane permeability and lower efflux effect than baloxavir.
- Papp value 1 ⁇ 10 -6 ⁇ 2 ⁇ 10 -6 cm/s, low permeability; 2 ⁇ 10 -6 ⁇ 20 ⁇ 10 -6 cm/s, medium permeability; >20 ⁇ 10 -6 cm/s, high permeability.
- intravenous injection group was given a dose of 0.5 mg/kg
- oral gavage group was given a dose of 2 mg/kg.
- Both groups were blood drawn from the forelimb vein before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration.
- Each sample was collected for about 1.0 mL, anticoagulated with EDTA-K2, placed on wet ice after collection, and centrifuged within 1 hour to separate plasma (centrifugation conditions: 6000g, 3 minutes, 2-8°C). Plasma samples were stored in a -80°C refrigerator before analysis.
- Sample pretreatment Pipette 50.0 ⁇ L of plasma sample into a 96-well plate, add 500 ⁇ L of 50% methanol-acetonitrile solution containing internal standard (tolbutamide, 100 ng/mL). Vortex the sample for 5 minutes, centrifuge at 14000 rpm and 4°C for 5 minutes, pipette 80 ⁇ L into 80 ⁇ L of water, mix well, and perform LC-MS/MS analysis.
- internal standard tolbutamide, 100 ng/mL
- Chromatographic conditions Chromatographic column: Synergi 4 ⁇ m Fusion-RP 80A LC Column 50*2mm; Flow rate: 0.5ml/min; Injection volume: 2 ⁇ l; Column temperature: 40 ⁇ ; Mobile phase: Phase A: 0.1% formic acid aqueous solution, Phase B: acetonitrile; Gradient elution: 0 ⁇ 1.9min, 5% Phase A; 1.91 ⁇ 2.5min, 80% Phase A.
- Mass spectrometry conditions Ionization mode: electrospray ionization, positive ion mode (ESI+); mass spectrometry scanning mode: multiple reaction monitoring (MRM); the characteristic ion pairs of Example 20 and Example 30 are 538.20/247.20 and 626.20/247.10, respectively; tolbutamide is selected as the internal standard, and the characteristic ion pair is 271.10/155.00; the capillary voltage is 4.0 kV; the temperature of the desolvation is 400 ⁇ ;
- the results are shown in Tables 4 and 5.
- the compound of Example 30 has a certain absorption in dogs.
- the maximum blood concentration can be reached in 0.3 hours after oral administration.
- the oral half-life is 3.015 hours and the bioavailability is 5.87%.
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Abstract
本发明提供一种稠环吡啶酮衍生物及其制备方法和用途。具体地,本发明提供一种结构如式(I)所示的化合物,或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,以及包含其的药物组合物。本发明还提供了本发明的化合物和/或药物组合物在制备用于预防和/或治疗流感病毒感染疾病的药物中的用途。本发明的化合物和/或药物组合物表现出抗流感病毒活性好,毒性低,生物利用度高的有益效果。 (I)
Description
本发明涉及药物化学领域,具体地涉及一种稠环吡啶酮衍生物及其制备方法和医药用途。
流感病毒的RNA聚合酶含有帽依赖性核酸内切酶(cap-dependent endonuclease)结构域,其切割宿主mRNA而产生带帽的RNA片段,以作为引发病毒mRNA合成的引子。宿主核糖体对病毒mRNA的转译需要mRNA的5’帽端,这可在感染流感病毒的细胞中藉由抢帽(cap-snatching)机制来达成,该机制为帽依赖性核酸内切酶从宿主mRNA切下5’帽端,然后将其作为转录引物(10至13个核苷酸),这些带帽的RNA引子用于合成编码病毒蛋白的mRNA。
抑制帽依赖性核酸内切酶的活性可导致病毒增殖的抑制,因此,帽依赖性核酸内切酶被认为是有效抗流感药物的重要生物学靶标。已有不同的杂环化合物被用作帽依赖性核酸内切酶抑制剂。其中巴洛沙韦酯是第一个上市的帽依赖性核酸内切酶抑制剂,在2020年获得美国FDA批准上市用于流感病毒感染患者的治疗。巴洛沙韦对A/H1N1病毒的中位数EC50达到17.96nM[Omoto S,Speranzini V,Hashimoto T,et al.Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil.Sci Rep.2018Jun25;8(1):9633.]。但是,巴洛沙韦酯是Pgp的底物,容易被外排,生物利用度低,且临床上已经出现对巴洛沙韦酯耐药的流感病毒患者。另外,中国专利CN201680081836.6公开了一类帽核酸内切酶抑制剂,其中参考例583/584(外消旋体)的CEN_IC50高达43.4nM。
然而,这些药物化合物不仅体内生物利用度低,而且对正常细胞存在着不小的细胞毒性,导致临床上的安全用药受到限制。因此,迫切需要开发新的能够克服以上缺点的帽依赖性核酸内切酶抑制剂。
发明内容
为了克服现有技术的不足,一方面,本发明提供了一种具有下列式(I)的化合物,
或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、以及药学上可接受的盐,
其中
环A选自C3-C8碳环或者3至8元杂环,其任选地被一个或多个选自以下的基团取代:卤素、氧代基、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基、C1-C20烷基羰基、C1-C20烷氧基羰基、C1-C20烷基羰基氧基、C1-C20烷氧基羰基氧基、苄氧基羰基、苄氧基羰基氧基;
R1选自:
其中,X1选自CH2、O、S、NH、S=O、S(=O)2;
X2选自CH、N;
R3、R3’、R4各自独立地选自氢、卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基;或者R3、R3’与其共同连接的碳原子一起形成C3-C8碳环;
环B为苯基或者6元杂芳基,其任选地被一个或多个选自以下的基团取代:卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基;
环C为C6-C10芳基或者6至10元杂芳基,其任选地被一个或多个选自以下的基团取代:卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基;
R2选自:
a)H;
b)-C(=O)-PR0;
c)-C(=O)-PR1;
d)-C(=O)-L-PR1;
e)-C(=O)-L-O-PR1;
f)-C(=O)-L-O-L-O-PR1;
g)-C(=O)-L-O-C(=O)-PR1;
h)-C(=O)-O-PR2;
i)-C(=O)-N(-K)(PR2);
j)-C(=O)-O-L-O-PR2;
k)-C(=O)-O-L-N(-K)(PR2);
l)-C(PR3)2-O-PR4;
m)-C(PR3)2-O-L-O-PR4;
n)-C(PR3)2-O-C(=O)-PR4;
o)-C(PR3)2-O-C(=O)-O-PR4;
p)-C(PR3)2-O-C(=O)-N(-K)-PR4;
q)-C(PR3)2-O-C(=O)-O-L-O-PR4;
r)-C(PR3)2-O-C(=O)-O-L-N(PR4)2;
s)-C(PR3)2-O-C(=O)-N(-K)-L-O-PR4;
t)-C(PR3)2-O-C(=O)-N(-K)-L-N(PR4)2;
u)-C(PR3)2-O-C(=O)-O-L-O-L-O-PR4;
v)-C(PR3)2-O-C(=O)-O-L-N(-K)-C(=O)-PR4;
w)-C(PR3)2-O-P(=O)(-PR5)2;
x)-(C(PR3)2)p-PR6;
y)-C(=N+(PR7)2)(-N(PR7)2);
z)-(C(PR3)2)q-C(=O)-O-PR2;
aa)-(C(PR3)2)q-C(=O)-N(-K)-PR4;
bb)-(C(PR3)2)q-C(=O)-PR1;
cc)-C(PR3)2-N(-K)-C(=O)-O-PR2;
dd)-P(=O)(-PR8)(-PR9);
ee)-S(=O)2-PR10;
ff)-PR11;
gg)-(C(PR3)2)r-O-PR12;或
hh)-(C(PR3)2)t-N(-K)-PR13;
其中,L为直链或支链状的任选被取代基组B中任一项取代的C1-C20亚烷基或者C1-C20亚烯基,
K为氢原子、或任选被取代基组A中任一项取代的C1-C20烷基,
PR0为任选被取代基组A中任一项取代的C1-C20烷基或者C1-C20烯基,
PR1为任选被取代基组A中任一项取代的碳环基、杂环基、C1-C20烷基氨基、C1-C20烷基硫基,
PR2为任选被取代基组A中任一项取代的C1-C20烷基、碳环基、杂环基、或三(C1-C20烷基)甲硅烷基,
PR3各自独立地为氢原子、C1-C20烷基或羟基,或者相邻碳原子上的2个PR3任选地共同形成亚烯基或亚烷基,
PR4各自独立地为任选被取代基组A中任一项取代的C1-C20烷基、C3-C8碳环基、杂环基、C1-C20烷基氨基、或三(C1-C20烷基)甲硅烷基,
PR5各自独立地为羟基或苄氧基;
PR6为任选被取代基组A中任一项取代的C3-C8碳环基或杂环基,
PR7各自独立地为任选被取代基组A中任一项取代的C1-C20烷基,
PR8为任选被取代基组A中任一项取代的C1-C20烷氧基,
PR9为任选被取代基组A中任一项取代的C1-C20烷氧基、C1-C20烷基氨基、C3-C8碳环氧基、杂环氧基、C3-C8碳环氨基、或杂环氨基,以及
PR8及PR9任选与相邻的磷原子共同形成任选被取代基组A中任一项取代的杂环,
PR10为任选被取代基组A中任一项取代的C1-C20烷基、C3-C8碳环基、或杂环基,
PR11为任选被取代基组A中任一项取代的C1-C20烷基、C1-C20烯基、C1-C20炔基、碳环基、或杂环基,
PR12各自独立地为氢原子、或任选被取代基组A中任一项取代的C1-C20烷基,
PR13为任选被取代基组A中任一项取代的C1-C20烷基磺酰基,
p为2~3的整数,
q为1~2的整数,
r为2~4的整数,
t为2~4的整数,
取代基组A包括:氧代基、C1-C20烷基、C1-C20烯基、C1-C20卤代烷基、C1-C20羟基烷基、氨基、C1-C20烷基氨基、C3-C8碳环基、杂环基、碳环烷基、C3-C8螺环、C1-C20烷基羰基、卤素、羟基、羧基、C1-C20烷基羰基氨基、C1-C20烷基羰基氨基C1-C20烷基、C1-C20烷基羰氧基、C1-C20烷氧基羰基、C1-C20烷氧基羰基C1-C20烷基、C1-C20烷氧基羰氧基、C1-C20烷基氨基羰氧基、C1-C20烷基氨基C1-C20烷基、C1-C20烷氧基、氰基、硝基、叠氮基、C1-C20烷基磺酰基、三(C1-C20烷基)甲硅烷基、及磷酰基,
取代基组B包括:C3-C8螺环、卤素。
另一方面,本发明提供了一种药物组合物,其包含式(I)所示的化合物或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,以及药学上可接受的载体。
再一方面,本发明提供了式(I)所示的化合物或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,或者包含其的药物组合物在制备用于预防和/或治疗由具有帽依赖性核酸内切酶的病毒引起的疾病的药物中的用途。
有益效果:与现有技术相比,本发明的化合物,特别是具有光学活性的式(XIV)化合物不仅具有显著更佳的抗流感病毒活性,还具有显著降低的细胞毒性,更高的生物利用度,而且对于对现有药物耐药的流感病毒的治疗效果更佳。
图1示出了实施例20化合物的单晶结构图。
图2示出了实施例20化合物的晶胞堆积图。
定义
如在本说明书中所使用的,除非使用它们的上下文指示其它含义,否则下列词和短语通常旨在具有如下所阐述的含义。
如本文所使用的,术语“烷基”是指具有1至20个碳原子(更典型地具有1至10个碳原子,1至8个碳原子,或者1至6个碳原子)的直链或支链的饱和烃链的单价基团。该术语例示性地为基团如甲基、乙基、1-丙基(正丙基)、2-丙基(异丙基)、1-丁基(正丁基)、2-甲基-1-丙基(异丁基)、2-丁基(仲丁基)、2-甲基-2-丙基(叔丁基)、1-戊基(正戊基)、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、1-庚基、1-辛基、1-壬基、1-癸基等。
如本文所使用的的,术语“亚烷基”是指具有1至20个碳原子(更典型地具有1至10个碳原子,1至8个碳原子,或者1至6个碳原子)的直链或支链的饱和烃链的二价基团。该术语例示性地为基团如亚甲基、亚乙基、亚丙基、亚丁基、亚戊基、亚己基等。
如本文所使用的,术语“烯基”是指具有2至20个碳原子(更典型地具有2至10个碳原子,2至8个碳原子,或者2至6个碳原子)并具有碳-碳双键(例如1、2或3个碳-碳双键)的直链或支链的不饱和烃链单价基团。该术语例示性地为基团如乙烯基(即-CH=CH2)、丙烯-1-基(即-CH=CHCH3)、丙烯-3-基(或烯丙基,即-CH2CH=CH2)、丙烯-2-基(即-C(CH3)=CH2)、丁二烯基(包括1,2-丁二烯基和1,3-丁二烯基)等。
如本文所使用的的,术语“亚烯基”是指具有1至20个碳原子(更典型地具有1至10个碳原子,1至8个碳原子,或者1至6个碳原子)并具有碳-碳双键(例如1、2或3个碳-碳双键)的直链或支链的不饱和烃链的二价基团。该术语例示性地为基团如亚乙烯基、亚丙烯基、亚丁烯基、亚戊烯基、亚己烯基等。
如本文中使用的,术语“炔基”是指具有2至20个碳原子(更典型地具有2至10个碳原子,2至8个碳原子,或者2至6个碳原子)并具有碳-碳三键(例如1、2或3个碳-碳三键)的直链或支
链的不饱和烃链单价基团。该术语例示性地为基团如乙炔基(即-C≡CH)、炔丙基(即-CH2C≡CH)、丙炔基(即-C≡CCH3)等。
如本文所使用的,术语“芳基”是指具有单环(例如苯基)或多环(例如联苯基)或多个稠(稠合的)环(例如萘基、芴基和蒽基)的6至14个碳原子(更典型地具有6至10个碳原子,或者6个碳原子)的芳族碳环基团。该术语例示性地为基团如苯基、芴基、萘基、蒽基、1,2,3,4-四氢萘(如果连接点是通过芳基基团)等。
如本文所使用的,术语“卤素”是指氟、氯、溴和碘。
如本文所使用的,术语“烷氧基”是指“烷基-O-”基团,其中烷基如本文所定义。该术语例示性地为基团如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
如本文所使用的,术语“卤代烷基”是指其中一个或多个氢原子被卤素取代的烷基,其中烷基如本文所定义。该术语例示性地为基团三氟甲基、二氟甲基、一氟甲基、2,2,2-三氟乙基、1,1,-二氟乙基等。
如本文所使用的,术语“碳环”、“碳环基”是指具有3至14个碳原子作为环原子的3至8元单环或者多个稠(稠合的)环或桥环或螺环的单基饱和或部分不饱和基团。碳环或碳环基可以是饱和的或者部分不饱和的,并且可以与另一个饱和的、部分不饱和的或者芳族的环稠合,条件是与目标分子连接的环原子不是芳香碳。碳环或者碳环基的实例包括,但不限于环丙烷、环丁烷、环戊烷、环己烷、环丁烯、环戊烯、环己烯、环庚烯、环戊二烯等。
如本文所使用的,术语“杂芳环”、“杂芳基”是指在环中包含5至14个环原子的单环或多重稠(稠合的)环(例如,包含2个或3个环)的芳族环基团,其中除了碳原子以外,所述环原子还包含至少一个以上选自氧、氮和/或硫的杂原子。如果环是芳族的,则硫和氮原子也可以氧化形式存在。多重稠(稠合的)环杂芳基是由如上定义的单环杂芳基与选自以下的一个或多个环稠合以形成多重稠环系统:杂芳基(以形成例如萘啶基,诸如1,8-萘啶基),杂环(例如形成1,2,3,4-四氢萘啶基,如1,2,3,4-四氢-1,8-萘啶基),碳环(以形成例如5,6,7,8-四氢喹啉基)和芳基(以形成例如吲唑基)。这样的多重稠环系统可以任选地在稠环的碳环或杂环部分上被一个或多个(例如1、2、3或4)氧代基取代。当价数要求允许时,多重稠环系统的环可以通过稠合、螺环和桥连键相互连接。应当理解,多重稠环系统的各个环可以以任何顺序相对于彼此连接。还应理解,多重稠环系统的连接点可以在该多重稠环系统的任何位置,包括多重稠合系统的杂芳基、杂环、芳基或碳环部分。还应理解,杂芳基的连接点可以在杂芳基的任何合适的原子上,包括碳原子和杂原子(例如氮)。示例性杂芳基包括但不限于:吡啶基、吡咯基、吡嗪基、嘧啶基、哒嗪基、吡唑基、噻吩基、吲哚基、咪唑基、噁唑基、异噁唑基、噻唑基、呋喃基、噁二唑基、噻二唑基、喹啉基、异喹啉基、苯并噻唑基、苯并噁唑基、吲唑基、喹喔啉基、喹唑啉基、
5,6,7,8-四氢异喹啉基、苯并呋喃基、苯并咪唑基、硫杂茚基、吡咯并[2,3-b]吡啶基、喹唑啉基-4(3H)-酮、三唑基、4,5,6,7-四氢-1H-吲唑基和3b,4,4a,5-四氢-1H-环丙烷[3,4]环戊烷[1,2-c]吡唑基。
如本文所使用的,术语“杂环”、“杂环基”是指具有在环内具有3至14个环原子的3至8元单环或者多个稠(稠合的)环或桥环的单基饱和或部分不饱和基团,其中除了碳原子以外,所述环原子还包含至少一个以上选自氧、氮和/或硫的杂原子。杂环基基团的实例包括,但不限于氮杂环丙烷环、氮杂环丁烷环、四氢吡咯环、哌啶环、氮杂环庚烷环、氮杂环辛烷环、氧杂环丙烷环、氧杂环丁烷环、四氢呋喃环、四氢吡喃环、氧杂环庚烷环、氧杂环辛烷环、硫杂环丙烷环、硫杂环丁烷环、四氢噻吩环、四氢噻喃环、硫杂环庚烷环、硫杂环辛烷环、四氢咪唑环、四氢吡唑环、四氢噁唑环、四氢异噁唑环、四氢噻唑环、四氢异噻唑环、哌嗪环、吗啉环、二噁烷环、噻噁烷环、二噻烷环、二氢吡啶基、4,5,6,7-四氢-1H-苯并[d]咪唑、4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶等。
如本文所使用的,术语“治疗有效量”是指当给予需要这种治疗的哺乳动物时,如下所限定的足以影响治疗的量。治疗有效量将随着被治疗的对象和疾病状况、受试者的重量和年龄、疾病状况的严重性、给药方式等而变化,其可以由本领域的普通技术人员容易地确定。
如本文所使用的,术语“立体异构体”是指具有相同的化学组成和连接性,但是其原子在空间具有不同取向的化合物,该取向不能通过单键旋转互换。“立体异构体”包括了“非对映异构体”和“对映异构体”。“非对映异构体”是指具有两个或多个手性中心且其分子并非彼此镜像的立体异构体。非对映异构体具有不同的物理性质,如熔点、沸点、光谱特性和反应性。非对映异构体混合物可在高分辨率分析程序(诸如结晶、电泳和色谱法)下进行分离。“对映异构体”是指彼此为非重叠镜像化合物的两种立体异构体。
如本文所使用的,术语“互变异构体”指的是两种(或两种以上)化合物的共存,这些化合物之间的区别只在于一个(或一个以上)活动原子的位置和电子分布,例如酮-烯醇互变异构体。
如本文中使用的,术语“药学上可接受的盐”是指保留给定化合物的生物有效性和特性的盐,并且所述盐不是在生物学上或在其他方面不期望的。药学上可接受的盐可以是酸加成盐和/或碱加成盐。酸加成盐可以从无机酸和有机酸制得。从无机酸衍生的盐包括盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、碳酸盐、硫酸氢盐、磷酸氢盐、磷酸二氢盐、碳酸氢盐等;从有机酸衍生的盐包括甲酸盐、乙酸盐、丙酸盐、乙醇酸盐、丙酮酸盐、草酸盐、苹果酸盐、丙二酸盐、琥珀酸盐、马来酸盐、富马酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、肉桂酸盐、扁桃酸盐、甲磺酸盐、乙磺酸盐、对甲苯磺酸盐、水杨酸盐、乳酸盐、烟酸盐、月桂基硫酸盐、萘磺酸盐、樟脑磺酸盐、葡糖酸盐、葡萄糖醛酸盐、油酸盐、棕榈酸盐、硬脂酸盐、双
羟萘酸盐、三氟乙酸盐等。碱加成盐可以与无机碱或有机碱形成。从无机碱衍生的盐包括钠、钾、铵、钙、镁、铁、锌、铜、锂、钡、铝盐等;从有机碱衍生的盐包括与各种伯胺、仲胺、叔胺形成的盐,例如乙胺、二乙胺、正丙胺、异丙胺、二乙醇胺、葡甲胺、赖氨酸、哌嗪、哌啶、吗啉、氨丁三醇、胆碱等盐。
如本文所使用的,术语“药学上可接受的”表示该物质或组合物与包含制剂和/或用其处理的哺乳动物的其他成分必须化学和/或毒理学上兼容。
如本文所用,术语“溶剂化物”是指一种或多种溶剂分子与本发明化合物的缔合物或复合物。形成溶剂化物的溶剂的实例包括但不限于水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。术语“水合物”是指其中溶剂分子是水的复合物。
如文本所用,术语“前药”是指在生理条件下容易经历化学变化以提供本发明的化合物的那些化合物。另外,可以在离体环境中通过化学或生化方法将前药转化为本发明的化合物。例如,当将前药与合适的酶或化学试剂一起置于透皮贴剂储库中时,可以将前药缓慢转化为本发明的化合物。
本文中给出的任何通式或结构,包括通式I或本文公开的任何通式,还旨在表示化合物的未标记形式以及同位素标记形式。这些形式的化合物也可以称为“同位素标记物”或者“同位素富集类似物”。同位素标记的化合物具有本文所描绘的结构,不同之处在于一个或多个原子被具有选定原子质量或质量数的原子代替。可以掺入到本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟、氯和碘的同位素,例如但不限于2H(氘,D)、3H(氚)、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、36Cl、123I和125I。本发明的各种同位素标记的化合物,例如其中掺入了放射性同位素(例如3H、13C和14C)的那些。通过所属领域中熟知的手段,例如通过采用一个或多个氢已经被氘置换的起始材料来合成这类化合物。
化合物
在一个实施方案中,本发明的化合物为式(I)所示的化合物或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中环A选自
X3、X4、X5各自独立地为CR5R5’、S、O、SO、SO2或NR6,其中R5、R5’和R6各自独立地选自H、卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基、C1-C20烷基羰基、C1-C20烷氧基羰基、C1-C20烷基羰基氧基、C1-C20烷氧基羰基氧基、苄氧基羰基、苄氧基羰基氧基;
n为选自0、1、2、3、4的整数。
在一个实施方案中,本发明的化合物为式(I)所示的化合物或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中环A选自环丙烷环、环丁烷环、环戊烷环、环己烷环、环庚烷环、环辛烷环、氮杂环丙烷环、氮杂环丁烷环、四氢吡咯环、哌啶环、氮杂环庚烷环、氮杂环辛烷环、氧杂环丙烷环、氧杂环丁烷环、四氢呋喃环、四氢吡喃环、氧杂环庚烷环、氧杂环辛烷环、硫杂环丙烷环、硫杂环丁烷环、四氢噻吩环、四氢噻喃环、硫杂环庚烷环、硫杂环辛烷环、四氢咪唑环、四氢吡唑环、四氢噁唑环、四氢异噁唑环、四氢噻唑环、四氢异噻唑环、哌嗪环、吗啉环、二噁烷环、噻噁烷环、二噻烷环,其任选地被一个或多个选自以下的基团取代:卤素、氧代基、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基、C1-C20烷基羰基、C1-C20烷氧基羰基、C1-C20烷基羰基氧基、C1-C20烷氧基羰基氧基、苄氧基羰基、苄氧基羰基氧基。
在一个实施方案中,本发明的化合物为式(I)所示的化合物或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中环A选自
其任选地被一个或多个选自以下的基团取代:卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基、C1-C20烷基羰基、C1-C20烷氧基羰基、C1-C20烷基羰基氧基、C1-C20烷氧基羰基氧基、苄氧基羰基、苄氧基羰基氧基。
在一个实施方案中,本发明的化合物为式(I)所示的化合物或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中R1选自:
R7为卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基,m为选自0、1、2、3、4的整数,X1、X2、R3、R3’、R4如本文所定义。
在一个实施方案中,本发明的化合物为式(I)所示的化合物或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中R1选自:
在一个实施方案中,本发明化合物为式(II)所示的化合物,
或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中m、n、X1、X3、X4、X5、R2和R7如本文所定义。
在一个实施方案中,本发明化合物为式(III)所示的化合物,
或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中m、n、X2、X3、X4、X5、R2和R7如本文所定义。
在一个实施方案中,本发明化合物为式(IV)所示的化合物,
或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中m、n、X3、X4、X5、R2和R7如本文所定义。
在一个实施方案中,本发明的化合物为式(II’)、(III’)或(IV’)所示的化合物,
或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中n、X3、X4、X5和R2如本文所定义。
在一个实施方案中,本发明的化合物为式(V)所示的化合物,
或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中X6选自CH2、O、S、NH、S=O、S(=O)2,X1、R2、R7和m如本文所定义。
在一个实施方案中,本发明的化合物为式(VI)或式(VI’)所示的化合物,
或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中X7选自CH2、O、S、NH、S=O、S(=O)2,X1、R2、R7和m如本文所定义。
在一个实施方案中,本发明的化合物为式(VII)、(VII’)或(VII”)所示的化合物,
或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中X8选自CH2、O、S、NH、S=O、S(=O)2,X1、R2、R7和m如本文所定义。
在一个实施方案中,本发明的化合物为式(VIII)所示的化合物,
或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中X6选自CH2、O、S、NH、S=O、S(=O)2,X2、R2、R7和m如本文所定义。
在一个实施方案中,本发明的化合物为式(IX)或式(IX’)所示的化合物,
或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中X7选自CH2、O、S、NH、S=O、S(=O)2,X2、R2、R7和m如本文所定义。
在一个实施方案中,本发明的化合物为式(X)、(X’)或(X”)所示的化合物,
或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中X8选自CH2、O、S、NH、S=O、S(=O)2,X2、R2、R7和m如本文所定义。
在一个实施方案中,本发明的化合物为式(XI)所示的化合物,
或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中X6选自CH2、O、S、NH、S=O、S(=O)2,R2、R7和m如本文所定义。
在一个实施方案中,本发明的化合物为式(XII)或式(XII’)所示的化合物,
或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中X7选自CH2、O、S、NH、S=O、S(=O)2,R2、R7和m如本文所定义。
在一个实施方案中,本发明的化合物为式(XIII)、(XIII’)或(XIII”)所示的化合物,
或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中X8选自CH2、O、S、NH、S=O、S(=O)2,R2、R7和m如本文所定义。
在一个实施方案中,本发明的化合物为式(I)所示的化合物或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中R2选自:
a)H;
b)-C(=O)-PR0;
c)-C(=O)-PR1;
h)-C(=O)-O-PR2;
i)-C(=O)-N(-K)(PR2);
j)-C(=O)-O-L-O-PR2;
k)-C(=O)-O-L-N(-K)(PR2);
n)-C(PR3)2-O-C(=O)-PR4;
o)-C(PR3)2-O-C(=O)-O-PR4;
q)-C(PR3)2-O-C(=O)-O-L-O-PR4;
v)-C(PR3)2-O-C(=O)-O-L-N(-K)-C(=O)-PR4;
x)-(C(PR3)2)p-PR6;
z)-(C(PR3)2)q-C(=O)-O-PR2;
aa)-(C(PR3)2)q-C(=O)-N(-K)-PR4;
bb)-(C(PR3)2)q-C(=O)-PR1;
cc)-C(PR3)2-N(-K)-C(=O)-O-PR2;
dd)-P(=O)(-PR8)(-PR9);
ee)-S(=O)2-PR10;
ff)-PR11;
gg)-(C(PR3)2)r-O-PR12;及
hh)-(C(PR3)2)t-N(-K)-PR13;
其中,L为直链或支链状的任选被取代基组B中任一项取代的C1-C20亚烷基,
K为氢原子、或任选被取代基组A中任一项取代的C1-C20烷基,
PR0为任选被取代基组A中任一项取代的C1-C20烷基,
PR1为任选被取代基组A中任一项取代的C3-C8碳环基或杂环基,
PR2为任选被取代基组A中任一项取代的烷基、C3-C8碳环基、杂环基,
PR3各自独立地为氢原子、C1-C20烷基或羟基,或者
相邻的碳原子上的2个PR3任选共同形成C1-C20亚烯基或C1-C20亚烷基,
PR4为任选被取代基组A中任一项取代的C1-C20烷基、C3-C8碳环基、或杂环基,
PR6为任选被取代基组A中任一项取代的C3-C8碳环基或杂环基,
PR8为任选被取代基组A中任一项取代的C1-C20烷氧基,
PR9为任选被取代基组A中任一项取代的C1-C20烷氧基、C1-C20烷基氨基、C3-C8碳环氧基、杂环氧基、C3-C8碳环氨基、或杂环氨基,或者
PR8及PR9任选与相邻的磷原子共同形成任选被取代基组A中任一项取代的杂环,
PR10为任选被取代基组A中任一项取代的C1-C20烷基或C3-C8碳环基,
PR11为任选被取代基组A中任一项取代的C1-C20烷基、C1-C20烯基、C1-C20炔基、C3-C8碳环基、或杂环基,
PR12各自独立地为氢原子、或任选被取代基组A中任一项取代的C1-C20烷基,
PR13为任选被取代基组A中任一项取代的C1-C20烷基磺酰基,
p为2~3的整数,
q为1~2的整数,
r为2~4的整数,
t为2~4的整数,
取代基组A包括:氧代基、C1-C20烷基、C1-C20烯基、C1-C20卤代烷基、C1-C20羟基烷基、氨基、C1-C20烷基氨基、C3-C8碳环基、杂环基、碳环烷基、C3-C8螺环、C1-C20烷基羰基、卤素、羟基、羧基、C1-C20烷基羰基氨基、C1-C20烷基羰基氨基C1-C20烷基、C1-C20烷基羰氧基、
C1-C20烷氧基羰基、C1-C20烷氧基羰基C1-C20烷基、C1-C20烷氧基羰氧基、C1-C20烷基氨基羰氧基、C1-C20烷基氨基C1-C20烷基、C1-C20烷氧基、氰基、硝基、叠氮基、C1-C20烷基磺酰基、三(C1-C20烷基)甲硅烷基、及磷酰基,
取代基组B包括:C3-C8螺环、卤素。
在一个实施方案中,本发明的化合物为式(XIV)所示的化合物
或其互变异构体、溶剂化物、前药、同位素标记物、以及药学上可接受的盐,其中
环A选自C3-C8碳环或者3至8元杂环,其任选地被一个或多个选自以下的基团取代:卤素、氧代基、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基、C1-C20烷基羰基、C1-C20烷氧基羰基、C1-C20烷基羰基氧基、C1-C20烷氧基羰基氧基、苄氧基羰基、苄氧基羰基氧基;
R1选自:
其中,X1选自CH2、O、S、NH、S=O、S(=O)2;
X2选自CH、N;
R3、R3’、R4各自独立地选自氢、卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基;或者R3、R3’与其共同连接的碳原子一起形成C3-C8碳环;
环B为苯基或者6元杂芳基,其任选地被一个或多个选自以下的基团取代:卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基;
环C为C6-C10芳基或者6至10元杂芳基,其任选地被一个或多个选自以下的基团取代:卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基;
R2选自:
a)H;
b)-C(=O)-PR0;
c)-C(=O)-PR1;
d)-C(=O)-L-PR1;
e)-C(=O)-L-O-PR1;
f)-C(=O)-L-O-L-O-PR1;
g)-C(=O)-L-O-C(=O)-PR1;
h)-C(=O)-O-PR2;
i)-C(=O)-N(-K)(PR2);
j)-C(=O)-O-L-O-PR2;
k)-C(=O)-O-L-N(-K)(PR2);
l)-C(PR3)2-O-PR4;
m)-C(PR3)2-O-L-O-PR4;
n)-C(PR3)2-O-C(=O)-PR4;
o)-C(PR3)2-O-C(=O)-O-PR4;
p)-C(PR3)2-O-C(=O)-N(-K)-PR4;
q)-C(PR3)2-O-C(=O)-O-L-O-PR4;
r)-C(PR3)2-O-C(=O)-O-L-N(PR4)2;
s)-C(PR3)2-O-C(=O)-N(-K)-L-O-PR4;
t)-C(PR3)2-O-C(=O)-N(-K)-L-N(PR4)2;
u)-C(PR3)2-O-C(=O)-O-L-O-L-O-PR4;
v)-C(PR3)2-O-C(=O)-O-L-N(-K)-C(=O)-PR4;
w)-C(PR3)2-O-P(=O)(-PR5)2;
x)-(C(PR3)2)p-PR6;
y)-C(=N+(PR7)2)(-N(PR7)2);
z)-(C(PR3)2)q-C(=O)-O-PR2;
aa)-(C(PR3)2)q-C(=O)-N(-K)-PR4;
bb)-(C(PR3)2)q-C(=O)-PR1;
cc)-C(PR3)2-N(-K)-C(=O)-O-PR2;
dd)-P(=O)(-PR8)(-PR9);
ee)-S(=O)2-PR10;
ff)-PR11;
gg)-(C(PR3)2)r-O-PR12;或
hh)-(C(PR3)2)t-N(-K)-PR13;
其中,L为直链或支链状的任选被取代基组B中任一项取代的C1-C20亚烷基或者C1-C20亚烯
基,
K为氢原子、或任选被取代基组A中任一项取代的C1-C20烷基,
PR0为任选被取代基组A中任一项取代的C1-C20烷基或者C1-C20烯基,
PR1为任选被取代基组A中任一项取代的碳环基、杂环基、C1-C20烷基氨基、C1-C20烷基硫基,
PR2为任选被取代基组A中任一项取代的C1-C20烷基、碳环基、杂环基、或三(C1-C20烷基)甲硅烷基,
PR3各自独立地为氢原子、C1-C20烷基或羟基,或者相邻碳原子上的2个PR3任选地共同形成亚烯基或亚烷基,
PR4各自独立地为任选被取代基组A中任一项取代的C1-C20烷基、C3-C8碳环基、杂环基、C1-C20烷基氨基、或三(C1-C20烷基)甲硅烷基,
PR5各自独立地为羟基或苄氧基;
PR6为任选被取代基组A中任一项取代的C3-C8碳环基或杂环基,
PR7各自独立地为任选被取代基组A中任一项取代的C1-C20烷基,
PR8为任选被取代基组A中任一项取代的C1-C20烷氧基,
PR9为任选被取代基组A中任一项取代的C1-C20烷氧基、C1-C20烷基氨基、C3-C8碳环氧基、杂环氧基、C3-C8碳环氨基、或杂环氨基,以及
PR8及PR9任选与相邻的磷原子共同形成任选被取代基组A中任一项取代的杂环,
PR10为任选被取代基组A中任一项取代的C1-C20烷基、C3-C8碳环基、或杂环基,
PR11为任选被取代基组A中任一项取代的C1-C20烷基、C1-C20烯基、C1-C20炔基、碳环基、或杂环基,
PR12各自独立地为氢原子、或任选被取代基组A中任一项取代的C1-C20烷基,
PR13为任选被取代基组A中任一项取代的C1-C20烷基磺酰基,
p为2~3的整数,
q为1~2的整数,
r为2~4的整数,
t为2~4的整数,
取代基组A包括:氧代基、C1-C20烷基、C1-C20烯基、C1-C20卤代烷基、C1-C20羟基烷基、氨基、C1-C20烷基氨基、C3-C8碳环基、杂环基、碳环烷基、C3-C8螺环、C1-C20烷基羰基、卤素、羟基、羧基、C1-C20烷基羰基氨基、C1-C20烷基羰基氨基C1-C20烷基、C1-C20烷基羰氧基、C1-C20烷氧基羰基、C1-C20烷氧基羰基C1-C20烷基、C1-C20烷氧基羰氧基、C1-C20烷基氨基羰氧
基、C1-C20烷基氨基C1-C20烷基、C1-C20烷氧基、氰基、硝基、叠氮基、C1-C20烷基磺酰基、三(C1-C20烷基)甲硅烷基、及磷酰基,
取代基组B包括:C3-C8螺环、卤素。
在一个实施方案中,本发明的化合物为式(XIV)所示的化合物或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中环A选自
X3、X4、X5各自独立地为CR5R5’、S、O、SO、SO2或NR6,其中R5、R5’和R6各自独立地选自H、卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基、C1-C20烷基羰基、C1-C20烷氧基羰基、C1-C20烷基羰基氧基、C1-C20烷氧基羰基氧基、苄氧基羰基、苄氧基羰基氧基;
n为选自0、1、2、3、4的整数。
在一个实施方案中,本发明的化合物为式(XIV)所示的化合物或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中环A选自环丙烷环、环丁烷环、环戊烷环、环己烷环、环庚烷环、环辛烷环、氮杂环丙烷环、氮杂环丁烷环、四氢吡咯环、哌啶环、氮杂环庚烷环、氮杂环辛烷环、氧杂环丙烷环、氧杂环丁烷环、四氢呋喃环、四氢吡喃环、氧杂环庚烷环、氧杂环辛烷环、硫杂环丙烷环、硫杂环丁烷环、四氢噻吩环、四氢噻喃环、硫杂环庚烷环、硫杂环辛烷环、四氢咪唑环、四氢吡唑环、四氢噁唑环、四氢异噁唑环、四氢噻唑环、四氢异噻唑环、哌嗪环、吗啉环、二噁烷环、噻噁烷环、二噻烷环,其任选地被一个或多个选自以下的基团取代:卤素、氧代基、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基、C1-C20烷基羰基、C1-C20烷氧基羰基、C1-C20烷基羰基氧基、C1-C20烷氧基羰基氧基、苄氧基羰基、苄氧基羰基氧基。
在一个实施方案中,本发明的化合物为式(XIV)所示的化合物或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中环A选自
其任选地被一个或多个选自以下的基团取代:卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基、C1-C20烷基羰基、C1-C20烷氧基羰基、C1-C20烷基羰基氧基、C1-C20烷氧基羰基氧基、苄氧基羰基、苄氧基羰基氧基。
在一个实施方案中,本发明的化合物为式(XIV)所示的化合物或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中R1选自:
R7为卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基,m为选自0、1、2、3、4的整数,X1、X2、R3、R3’、R4如本文所定义。
在一个实施方案中,本发明的化合物为式(XIV)所示的化合物或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中R1选自:
在一个实施方案中,本发明化合物为式(XV)所示的化合物,
或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中m、n、X1、X3、X4、X5、R2和R7如本文所定义。
在一个实施方案中,本发明化合物为式(XVI)所示的化合物,
或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中m、n、X2、X3、X4、X5、R2和R7如本文所定义。
在一个实施方案中,本发明化合物为式(XVII)所示的化合物,
或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中m、n、X3、X4、X5、R2和R7如本文所定义。
在一个实施方案中,本发明的化合物为式(XV’)、(XVI’)或(XVII’)所示的化合物,
或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中n、X3、X4、X5和R2如本文所定义。
在一个实施方案中,本发明的化合物为式(XVIII)所示的化合物,
或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中X6选自CH2、O、S、NH、S=O、S(=O)2,X1、R2、R7和m如本文所定义。
在一个实施方案中,本发明的化合物为式(XIX)或式(XIX’)所示的化合物,
或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中X7选自CH2、O、S、NH、S=O、S(=O)2,X1、R2、R7和m如本文所定义。
在一个实施方案中,本发明的化合物为式(XX)、(XX’)或(XX”)所示的化合物,
或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中X8选自CH2、O、S、NH、S=O、S(=O)2,X1、R2、R7和m如本文所定义。
在一个实施方案中,本发明的化合物为式(XXI)所示的化合物,
或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中X6选自CH2、O、S、NH、S=O、S(=O)2,X2、R2、R7和m如本文所定义。
在一个实施方案中,本发明的化合物为式(XXII)或式(XXII’)所示的化合物,
或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中X7选自CH2、O、S、NH、S=O、S(=O)2,X2、R2、R7和m如本文所定义。
在一个实施方案中,本发明的化合物为式(XXIII)、(XXIII’)或(XXIII”)所示的化合物,
或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中X8选自CH2、O、S、NH、S=O、S(=O)2,X2、R2、R7和m如本文所定义。
在一个实施方案中,本发明的化合物为式(XXIV)所示的化合物,
或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中X6选自CH2、O、S、NH、S=O、S(=O)2,R2、R7和m如本文所定义。
在一个实施方案中,本发明的化合物为式(XXV)或式(XXV’)所示的化合物,
或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中X7选自CH2、O、S、NH、S=O、S(=O)2,R2、R7和m如本文所定义。
在一个实施方案中,本发明的化合物为式(XXVI)、(XXVI’)或(XXVI”)所示的化合物,
或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中X8选自CH2、O、S、NH、S=O、S(=O)2,R2、R7和m如本文所定义。
在一个实施方案中,本发明的化合物为式(XIV)所示的化合物或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,其中R2选自:
a)H;
b)-C(=O)-PR0;
c)-C(=O)-PR1;
h)-C(=O)-O-PR2;
i)-C(=O)-N(-K)(PR2);
j)-C(=O)-O-L-O-PR2;
k)-C(=O)-O-L-N(-K)(PR2);
n)-C(PR3)2-O-C(=O)-PR4;
o)-C(PR3)2-O-C(=O)-O-PR4;
q)-C(PR3)2-O-C(=O)-O-L-O-PR4;
v)-C(PR3)2-O-C(=O)-O-L-N(-K)-C(=O)-PR4;
x)-(C(PR3)2)p-PR6;
z)-(C(PR3)2)q-C(=O)-O-PR2;
aa)-(C(PR3)2)q-C(=O)-N(-K)-PR4;
bb)-(C(PR3)2)q-C(=O)-PR1;
cc)-C(PR3)2-N(-K)-C(=O)-O-PR2;
dd)-P(=O)(-PR8)(-PR9);
ee)-S(=O)2-PR10;
ff)-PR11;
gg)-(C(PR3)2)r-O-PR12;及
hh)-(C(PR3)2)t-N(-K)-PR13;
其中,L为直链或支链状的任选被取代基组B中任一项取代的C1-C20亚烷基,
K为氢原子、或任选被取代基组A中任一项取代的C1-C20烷基,
PR0为任选被取代基组A中任一项取代的C1-C20烷基,
PR1为任选被取代基组A中任一项取代的C3-C8碳环基或杂环基,
PR2为任选被取代基组A中任一项取代的烷基、C3-C8碳环基、杂环基,
PR3各自独立地为氢原子、C1-C20烷基或羟基,或者
相邻的碳原子上的2个PR3任选共同形成C1-C20亚烯基或C1-C20亚烷基,
PR4为任选被取代基组A中任一项取代的C1-C20烷基、C3-C8碳环基、或杂环基,
PR6为任选被取代基组A中任一项取代的C3-C8碳环基或杂环基,
PR8为任选被取代基组A中任一项取代的C1-C20烷氧基,
PR9为任选被取代基组A中任一项取代的C1-C20烷氧基、C1-C20烷基氨基、C3-C8碳环氧基、杂环氧基、C3-C8碳环氨基、或杂环氨基,或者
PR8及PR9任选与相邻的磷原子共同形成任选被取代基组A中任一项取代的杂环,
PR10为任选被取代基组A中任一项取代的C1-C20烷基或C3-C8碳环基,
PR11为任选被取代基组A中任一项取代的C1-C20烷基、C1-C20烯基、C1-C20炔基、C3-C8碳环基、或杂环基,
PR12各自独立地为氢原子、或任选被取代基组A中任一项取代的C1-C20烷基,
PR13为任选被取代基组A中任一项取代的C1-C20烷基磺酰基,
p为2~3的整数,
q为1~2的整数,
r为2~4的整数,
t为2~4的整数,
取代基组A包括:氧代基、C1-C20烷基、C1-C20烯基、C1-C20卤代烷基、C1-C20羟基烷基、氨基、C1-C20烷基氨基、C3-C8碳环基、杂环基、碳环烷基、C3-C8螺环、C1-C20烷基羰基、卤素、羟基、羧基、C1-C20烷基羰基氨基、C1-C20烷基羰基氨基C1-C20烷基、C1-C20烷基羰氧基、C1-C20烷氧基羰基、C1-C20烷氧基羰基C1-C20烷基、C1-C20烷氧基羰氧基、C1-C20烷基氨基羰氧基、C1-C20烷基氨基C1-C20烷基、C1-C20烷氧基、氰基、硝基、叠氮基、C1-C20烷基磺酰基、三(C1-C20烷基)甲硅烷基、及磷酰基,
取代基组B包括:C3-C8螺环、卤素。
在一个实施方案中,本发明的化合物包括但不限于下列化合物:
或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐。
药物组合物和给药
本发明提供的药物组合物包含本发明的化合物或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,和至少一种药学上可接受的载体。药学上可接受的载体是本领域技术人员已知的,包括稀释剂、润滑剂、崩解剂、粘合剂、缓冲剂、防腐剂、稳定剂、润湿剂、助流剂、乳化剂、着色剂、调味剂、甜味剂等。根据药物的给药途径的不同,例如口服给药、胃肠外给药和直肠给药等,本发明的药物组合物可以以固体形式(包括但不限于片剂、胶囊剂、丸剂、颗粒剂、散剂、粉剂、栓剂)或者液体形式(包括但不限于溶液剂、混悬剂、乳剂、酊剂、糖浆剂)制成。当本发明的药物组合物为固体形式时,药学上可接受的载体通常包括以下中的一种或多种:a)稀释剂,例如乳糖、葡萄糖、蔗糖、甘露糖醇、山梨糖醇、纤维素等;b)润滑剂,例如二氧化硅、滑石、硬脂酸、聚乙二醇等;c)粘合剂,例如硅铝酸镁、胶化淀粉、明胶、黄芪胶、甲基纤维素、羧甲基纤维素钠、微晶纤维素、聚乙烯吡咯烷酮等;d)崩解剂,例如淀粉、海藻酸、琼脂、玉米淀粉;e)稳定剂,例如抗氧化剂如抗坏血酸;f)助流剂,例如二氧化硅;g)调味剂,例如薄荷、水杨酸甲酯;甜味剂,例如蔗糖、糖精。当本发明的药物组合物为液体形式时,药学上可接受的载体通常包括以下中的一种或多种:a)稀释剂,例如注射用水、生理盐水、林格氏溶液、聚乙二醇、甘油、丙二醇等;b)抗氧化剂,例如抗坏血酸或亚硫酸氢钠;c)缓冲剂,例如乙酸盐、磷酸盐等。
本发明化合物的有效剂量至少取决于所治疗病症的性质、程度、递送方法和药物剂型,
并且将由临床医师最终确定。可以预期每天每千克体重约0.0001至约100mg;通常为每天每千克体重约0.01至约10mg;更典型地,每天每千克体重约0.01至约5mg;最典型的是每天每千克体重约0.05至约0.5mg。例如,约70kg体重的成年人的每日候选剂量将在1mg至1000mg的范围内,优选在5mg至500mg的范围内,并且可以采取单剂量或多剂量的形式给药。
适应症
本发明化合物对于病毒RNA聚合酶特别是帽依赖性核酸内切酶具有抑制活性,可用于预防和/或治疗由具有帽依赖性核酸内切酶的病毒引起的疾病,包括流感病毒感染疾病,例如甲型流感病毒感染、乙型流感病毒感染、丙型流感病毒感染、丁型流感病毒感染、禽流感病毒感染、猪流感病毒感染等。
本发明的化合物和/或药物组合物可用于预防、减轻、缓解和/或治愈由各种流感病毒引起的症状和/或疾病,例如伴有发热、发冷、头痛、肌痛等感冒症状,伴有咽痛、流鼻涕、鼻塞、咳嗽等呼吸道炎症症状,伴有腹痛、呕吐、腹泻等胃肠道症状等。
联合用药
本发明的化合物可以与另外一种或多种药剂同时或者顺次联合施用。本发明的化合物与另外的药剂可以通过相同或者不同的给药途径分开给药,或者作为联合试剂在一个药物组合物中同时给药。适用于本发明的另外的药剂可以是对流感病毒有抑制活性的各种抗病毒剂,包括但不限于神经氨酸酶抑制剂(例如奥司他韦、帕拉米韦、扎那米韦、拉尼米韦)、M2蛋白抑制剂(例如金刚烷胺、金刚乙胺)、RNA聚合酶抑制剂(例如法匹拉韦、利巴韦林)、PB1/PB2抑制剂(例如VX-787)、以及抗病毒疫苗等。
通用合成方法
本发明的化合物可以使用本文中公开的方法及其修改途径以及本领域中熟知的方法制备。根据本发明的化合物的典型实施方式可以使用以下的通用反应流程来合成。从本文中的描述显而易见的是,通过使用具有类似结构的其它材料代替反应原料可以获得相应不同的产物。反应原料典型地由商业来源获得或者使用公开的方法合成。
反应流程I
步骤1中间体1与中间2在催化剂,例如路易斯酸包括但不限于四氯化锡的存在下,在合适的有机溶剂例如乙腈、四氢呋喃等中反应得到中间体3;其中PG表示氨基保护基,特别是在碱性条件下容易脱除的氨基保护基,包括但不限于烯丙氧羰基、苄氧羰基、芴甲氧羰基等。
步骤2中间体3在催化剂,特别是金属催化剂例如钯催化剂的存在下,在碱性条件下发生关环反应得到中间体4,其中钯催化剂包括四三苯基膦钯等;
步骤3中间体4在碱性条件下(例如碱金属、碱土金属等的碳酸盐、碳酸氢盐等)与R1X发生取代反应得到中间体5;其中R1如本文所定义,X表示卤素氯、溴、碘;
步骤4中间体5经手性拆分后在LiCl存在下反应脱除苄基保护基得到式(I)化合物(R2为H);
步骤5将式(I)化合物(R2为H)与R2X在碱性条件下(例如无机碱或有机碱)在合适的有机溶剂中发生取代反应得到式(XIV)化合物,其中R2如本文所定义的H以外的基团。
反应流程II
步骤1原料与乙酸乙酯碱性条件(例如二异丙基胺基锂、丁基锂、钠氢、叔丁醇钠等)下发生加成反应得到中间体1-a;
步骤2中间体1-a与TMSCN在TMSOTf存在下反应生成中间体1-b;
步骤3中间体1-b在催化剂例如钯碳存在下发生氢化反应得到中间体1-c;
步骤4中间体1-c在碱性条件下发生关环反应得到中间体1-d;
步骤5中间体1-d与保护基试剂(例如氯甲酸烯丙基酯、氯甲酸苄基酯、氯甲酸芴甲基酯)反应生成中间体1-e;
步骤6中间体1-e在还原剂的存在下发生还原反应得到中间体1-f;所述还原剂包括二异丁基氢化铝等;
步骤7中间体1-f在酸性条件下与甲醇发生反应成醚,得到中间体1。
实施例1 4-(7’,8’-二氟-6’,11’-二氢二苯并[b,e]硫杂-11’-基)-9-羟基-3a,4-二氢-1H,3H-螺[环己烷-1,2-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8,10-二酮的制备
步骤1 3-氧代-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯(中间体1)的制备
向500mL三口瓶内依次加入2-氮杂螺[4.5]癸烷-3-酮(10.0g,65.3mmol)和无水四氢呋喃(200mL),在氮气保护下磁力搅拌。在-78℃下,向反应体系内滴加n-BuLi(2.5N正己烷溶液,26mL,65.3mmol)。滴毕,反应保温搅拌1.5h。再向反应体系内滴加氯甲酸烯丙酯(8.03g,65.3mmol)的无水四氢呋喃(50mL)溶液。滴毕,反应在-78℃下搅拌1h。TLC(V石油醚:V乙酸乙酯=10:1)监测原料反应完全。-78℃下向反应体系内加入饱和氯化铵水溶液(50mL)淬灭反应,析出大量白色固体,过滤,滤液分液,水相用乙酸乙酯(100mL×3)萃取。合并有机相,有机相用饱和食盐水(100mL×2)洗涤,无水硫酸钠干燥,过滤,浓缩,得到16.92g无色油状物,不经纯化直接进行下一步反应。
1H NMR(600MHz,DMSO-d6):δ(ppm):5.93-5.86(m,1H,烯氢),5.34(dq,J1=17.2Hz,J2=1.7Hz,1H,烯氢),5.19(dd,J1=10.6Hz,J2=1.6Hz,1H,烯氢),4.61(dt,J1=5.2Hz,J2=1.6Hz,2H,
OCH2),3.45(s,2H,NCH2),2.32(s,2H,OCCH2),1.43-1.29(m,10H,(CH2)5).
步骤2 3-羟基-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯(中间体2)
向500mL三口瓶内依次加入中间体1(16.92g,71.3mmol)和无水四氢呋喃(200mL),加毕,在氮气保护下磁力搅拌。在-78℃下,向反应体系内滴加DIBAL-H(1.0M正己烷溶液,71mL,71.3mmol)。滴毕,反应保温搅拌1h。TLC(V石油醚:V乙酸乙酯=4:1)监测原料反应完全。-78℃下向反应体系内加入丙酮(50mL)、酒石酸钾钠水溶液(由100g酒石酸钾钠溶于120mL水中制得),搅拌10min。分液,向水相滴加1M HCl水溶液调节pH至7后用乙酸乙酯(100mL×3)萃取。合并有机相,有机相用饱和食盐水(200mL)洗涤,无水硫酸钠干燥,过滤,浓缩,得到15.36g无色油状物,其不经纯化直接进行下一步反应。
1H NMR(600MHz,DMSO-d6):δ(ppm):5.95-5.82(m,1H,烯氢),5.37-5.19(m,2H,烯氢,CHOH),5.19-5.09(m,1H,烯氢),4.55-4.41(m,2H,OCH2),3.22-3.01(m,2H,NCH2),1.55-1.46(m,2H,CH2),1.43-1.18(m,10H,(CH2)5).
步骤3 3-甲氧基-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯(中间体3)
向250mL三口瓶内依次加入中间体2(15.36g,64.2mmol)、对甲苯磺酸一水合物(1.22g,6.42mmol)和甲醇(150mL),加毕,氮气保护,室温下反应2h。TLC(V石油醚:V乙酸乙酯=10:1)监测原料反应完全。向反应体系中加入饱和碳酸氢钠水溶液(50mL)淬灭反应,浓缩混合物,剩余溶液用乙酸乙酯(100mL×3)萃取,合并有机相,用饱和食盐水(200mL)洗涤,无水硫酸钠干燥,过滤,浓缩,浓缩物经快速制备色谱纯化(V石油醚:V乙酸乙酯=10:1),得到6.23g无色油状物,收率38%。
1H NMR(600MHz,DMSO-d6):δ(ppm):5.93-5.84(m,1H,烯氢),5.25(t,J=16.7Hz,1H,OCH),5.17-5.13(m,1H,烯氢),5.06-5.01(m,1H,烯氢),4.56-4.45(m,2H,OCH2),3.22-3.08(m,5H,NCH2,OCH3),1.83-1.66(m,2H,CH2),1.55-1.44(m,2H,CH2),1.43-1.22(m,8H,(CH2)4).
步骤4 3-((3-(苄氧基)-2-(乙氧羰基)-4-氧代-1,4-二氢吡啶-1-基)氨基)-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯(中间体4)
向100mL三口瓶内依次加入中间体3(2.53g,10.0mmol)、1-氨基-3-(苄氧基)-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(2.40g,8.3mmol)和乙腈(30mL),加毕,氮气保护,室温下搅拌待完全溶解后降温至-20℃,滴加四氯化锡(3.47g,13.3mmol),滴毕,保温反应1h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全。-20℃下向反应体系中滴加饱和碳酸氢钠水溶液(30mL)淬灭反应,加入二氯甲烷(50mL)在室温下搅拌10min后用硅藻土过滤混合物,滤饼用二氯甲烷(50mL)洗涤。将滤液分液,有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,浓缩,浓缩物经快速制备色谱纯化(V二氯甲烷:V甲醇=10:1),得到2.17g红棕色油状物,收率43%。
步骤5 9'-(苄氧基)-3a',4'-二氢-1'H,3'H-螺[环己烷-1,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮(中间体5)
向100mL三口瓶内依次加入中间体4(2.17g,4.26mmol)、无水四氢呋喃(30mL)、吗啉(3.71g,42.6mmol)和四三苯基膦钯(0.50g,0.43mmol)。加毕,氮气保护,室温下搅拌1h,有大量固体析出。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全。向反应体系中加入异丙醚(50mL),搅拌30min后过滤,滤饼用异丙醚(50mL)洗涤,滤饼经快速制备色谱纯化(V二氯甲烷:V甲醇=10:1),得到1.05g白色固体,收率65%。
1H NMR(600MHz,氯仿-d)δ(ppm):7.51-7.46(m,2H,ArH),7.36(d,J=7.6Hz,1H,ArH),7.30-7.26(m,2H,ArH),7.24-7.22(m,1H,ArH),6.28(d,J=7.7Hz,1H,ArH),5.85(d,J=13.1Hz,1H,NH),5.24(d,J=10.4Hz,1H,OCH2),5.18(d,J=10.5Hz,1H,OCH2),4.69-4.62(m,1H,NCH),3.35(d,J=11.9Hz,1H,NCH2),3.11(d,J=12.0Hz,1H,NCH2),2.08-2.01(m,1H,CH2),1.54-1.42(m,7H,CH2),1.40-1.29(m,4H,CH2)
步骤6 9'-(苄氧基)-4'-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-3a',4'-二氢-1'H,3'H-螺[环己烷-1,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮(中间体6)的合成
向100mL单口瓶中依次加入中间体5(0.83g,2.19mmol),11-氯-7,8-二氟-6,11-二氢二苯并[b,e]硫杂(1.24g,4.38mmol)、碳酸铯(2.14g,6.57mmol)和乙腈(20mL),加毕,氮气保护,50℃反应过夜。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全。向反应体系中加入水(30mL)淬灭反应,混合物用乙酸乙酯(50mL×3)萃取,合并有机相,有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,浓缩,浓缩物经快速制备色谱纯化(V二氯甲烷:V甲醇=10:1),得到502mg黄色固体,收率37%。
1H NMR(600MHz,DMSO-d6)δ(ppm):7.55(d,J=7.8Hz,0.5H,ArH),7.52-7.49(m,2H,ArH),7.78-7.44(m,0.5H,ArH),7.35-7.30(m,3H,ArH),7.30-7.23(m,2.5H,ArH),7.22-7.18(m,0.5H,ArH),7.17-7.15(m,1H,ArH),7.15-7.11(m,0.5H,ArH),7.07-7.03(m,0.5H,ArH),7.01-6.98(m,0.5H,ArH),6.85-6.81(m,1H,ArH),6.81-6.77(m,0.5H,ArH),5.74-5.69(m,1H,NCH),5.68-5.63(m,0.5H,OCH2),5.46-5.51(m,0.5H,OCH2),5.44(dd,J1=10.3Hz,J2=6.9Hz,0.5H,OCH2),5.35-5.32(m,0.5H,OCH2),5.15(d,J=2.2Hz,1H,SCH2),5.07-5.01(m,1H,NH),4.09(dd,J1=14.2Hz,J2=11.2Hz,1H,SCH2),3.66(d,J=11.8Hz,0.5H,NCH2),3.50(d,J=11.8Hz,0.5H,NCH2),3.37(d,J=11.7Hz,0.5H,NCH2),2.98(d,J=11.8Hz,0.5H,NCH2),1.86-1.77(m,1H,CH2),1.40-1.26(m,5H,CH2),1.25-1.16(m,5H,CH2),0.88-0.74(m,1H,CH2).
步骤7 4'-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-9'-羟基-3a',4'-二氢-1'H,3'H-螺[环己烷-1,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮(实施例1)的合成
向50mL单口瓶中依次加入中间体6(502mg,0.80mmol),氯化锂(339mg,8.00mmol)和无水DMA(10mL)。加毕,氮气保护,80℃反应过夜。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全。向反应体系中加入水(20mL)淬灭反应,混合物用乙酸乙酯(50mL×3)萃取,合并有机相,用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤、浓缩,浓缩物经快速制备色谱纯化(V二氯甲烷:V甲醇=15:1)得到粗品,向粗产物中加入乙醚(10mL)、氯仿(1mL)打浆2h。过滤,滤饼用乙醚(5mL)洗涤后真空干燥,得到194mg黄色固体,收率70%。
1H NMR(600MHz,DMSO-d6):δ(ppm):7.73(d,J=7.6Hz,1H,ArH),7.52(d,J=7.4Hz,2H,ArH),7.35(t,J=7.4Hz,2H,ArH),7.30(t,J=7.2Hz,1H,ArH),7.18(d,J=12.6Hz,1H,ArH),6.20(d,J=7.6Hz,1H,ArH),5.19(d,J=10.4Hz,1H,SCH2),5.02(d,J=10.4Hz,1H,SCH2),4.99-4.93(m,1H,NCH),3.43(d,J=11.8Hz,1H,NCH2),3.22(d,J=11.8Hz,1H,NCH2),2.23-2.16(m,1H,NCH),1.53-1.35(m,12H,CH2).HRMS(ESI):m/z[M+H]+C29H27F2N3O3S理论值:536.1819;实测值:536.1837.
实施例2 4'-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-9'-羟基-2,3,3a',4',5,6-六氢-1'H,3'H-氮杂螺环[吡喃-4,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮的制备
步骤1 3-氧代-8-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯(中间体2)的合成
向250mL单口瓶中依次加入1(9.00g,58mmol)和四氢呋喃(200mL),氮气保护,-78℃下滴加n-BuLi(23.2mL,58mmol,2.5N正己烷溶液),保温反应2h。再滴加Alloc-Cl(7.00g,58mmol)的四氢呋喃(40mL)溶液,加毕,保温反应2h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,低温下加入饱和氯化铵水溶液(200mL)淬灭反应,乙酸乙酯(200mL×3)萃取,合并有机相,有机相用饱和食盐水(300mL×2)洗涤,无水硫酸钠干燥,过滤,浓缩,得到12.75g黄色油状物,收率91.9%。
步骤2 3-羟基-8-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯(中间体3)的合成
向250mL单口瓶中依次加入2(12.75g,53.3mmol)和四氢呋喃(200mL),氮气保护,
降温至-78℃,滴加DIBAL-H(69.3mL,69.3mmol,1N正己烷溶液),保温反应2h。TLC(V石油醚:V乙酸乙酯=1:1)监测原料反应完全,低温下加入50wt%酒石酸钾钠溶液(200mL)淬灭反应,室温搅拌20min,呈胶状,加入1N稀盐酸(50mL),再用乙酸乙酯(200mL×3)萃取,合并有机相,有机相用饱和食盐水(300mL×2)洗涤,无水硫酸钠干燥,浓缩,并经柱层析(V石油醚:V乙酸乙酯=2:1)纯化得到7.80g黄色油状物,收率60.2%。
步骤3 3-甲氧基-8-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯(中间体4)的合成
向250mL单口瓶中依次加入3(7.80g,32.3mmol)、甲醇(50mL)和对甲苯磺酸一水合物(615mg,3.2mmol),氮气保护,室温反应过夜。TLC(V石油醚:V乙酸乙酯=2:1)监测原料反应完全,加入饱和碳酸氢钠水溶液(50mL),浓缩除去甲醇,用乙酸乙酯(70mL×3)萃取,合并有机相,有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤、浓缩,并经柱层析(V石油醚:V乙酸乙酯=3:1)纯化得到5.34g无色油状物,收率64.7%。
步骤4 3-((3-(苄氧基)-2-(乙氧基羰基)-4-氧代吡啶-1(4H)-基)氨基)-8-氧杂-2-氮杂螺环[4.5]癸烷-2-羧酸烯丙酯(中间体5)的合成
向250mL单口瓶中依次加入4(5.34g,20.9mmol)、1-氨基-3-(苄氧基)-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(5.13g,17.7mmol)和乙腈(100mL),氮气保护,降温至-25℃,滴加SnCl4(8.71g,33.4mmol),保温反应1.5h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,低温下加入饱和碳酸氢钠水溶液(200mL)淬灭反应,用二氯甲烷(100mL×3)萃取,合并有机相,有机相用饱和食盐水(150mL×2)洗涤,无水硫酸钠干燥,过滤,浓缩,并经柱层析(V二氯甲烷:V甲醇=20:1)纯化得到6.67g黄色油状物,收率62.3%。
步骤5 9'-(苄氧基)-2,3,3a',4',5,6-六氢-1'H,3'H-螺[吡喃-4,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮(中间体6)的合成
向250mL单口瓶中依次加入5(3.00g,5.9mmol)和吗啉(30mL),搅拌溶解,再加入Pd(PPh3)4(678mg,0.59mmol),氮气保护,室温反应1h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,加入异丙醚(250mL),打浆30min,过滤,滤饼经柱层析(V二氯甲烷:V甲醇=15:1)纯化得到1.90g黄色固体,收率85.0%。
1H NMR(600MHz,DMSO-d6)δ(ppm):7.74(d,J=7.8Hz,1H,ArH),7.54-7.51(m,2H,ArH),7.36-7.33(m,2H,ArH),7.31-7.28(m,1H,ArH),7.18(d,J=12.6Hz,1H,ArH),6.21(d,J=7.8Hz,1H,NH),5.19(d,J=10.2Hz,1H,CH),5.03-4.98(m,2H,CH2),3.67-3.49(m,6H,CH2),2.33-2.30(m,1H,CH2),1.59-1.57(m,2H,CH2),1.53-1.49(m,3H,CH2).
步骤6 9'-(苄氧基)-4'-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-2,3,3a',4',5,6-六氢-1'H,3'H-氮杂螺环[吡喃-4,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮(中间体7)的合成
向100mL单口瓶中依次加入中间体6(0.80g,2.1mmol)、11-氯-7,8-二氟-6,11-二氢二苯并[b,e]硫杂(1.50g,5.3mmol)、乙腈(100mL)和碳酸铯(2.73g,8.4mmol),氮气保护,室温反应过夜。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,加水(100mL)淬灭反应,用二氯甲烷(50mL×6)萃取,合并有机相,有机相用饱和食盐水(150mL×2)洗涤,无水硫酸钠干燥,过滤,浓缩,并经柱层析(V二氯甲烷:V甲醇=100:1)纯化得到510mg黄色固体,收率38.7%。
步骤7 4'-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-9'-羟基-2,3,3a',4',5,6-六氢-1'H,3'H-氮杂螺环[吡喃-4,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮的合成
向25mL单口瓶中依次加入中间体7(430mg,0.69mmol)、DMA(5mL)和LiCl(290mg,6.9mmol),氮气保护,80℃反应过夜。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,冷却至室温,滴加0.5N稀盐酸,调节pH至3,加水(25mL)稀释,用乙酸乙酯(25mL×3)萃取,合并有机相,有机相用食盐水(40mL×2)洗涤,无水硫酸钠干燥,过滤,浓缩,并经快速制备色谱(12g,V二氯甲烷:V甲醇=10:1)纯化得到120mg棕色固体,收率48.4%。
1H NMR(600MHz,DMSO-d6)δ(ppm):7.55-7.46(m,1H,ArH),7.46-7.08(m,5H,ArH),7.10-6.79(m,2H,ArH),5.74-5.59(m,2H,CH),5.58-5.44(m,1H,CH2),4.16-4.11(m,1H,CH2),3.90-3.81(m,1H,CH2),3.65-3.43(m,4H,CH2),2.19-1.95(m,1H,CH2),1.38-1.28(m,3H,CH2),1.26-1.19(m,3H,CH2).13C NMR(150MHz,DMSO-d6)δ(ppm):171.11,160.53,151.53,147.96,146.33,137.95,135.86,133.00,130.85,129.83,129.22,128.68,125.26,123.88,117.13,116.15,110.15,76.58,69.90,64.78,64.01,38.40,37.84,35.91,34.13,31.63,30.33,29.50,23.30,15.65.
HRMS(ESI):m/z[M+H]+C28H25F2N3O4S理论值:538.1612;实测值:538.1631.HPLC:99.94%.
实施例3 4'-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-9'-羟基-8',10'-二氧代-3a',4',8',10'-四氢-1'H,3'H-螺[哌啶-4,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-1-羧酸苄酯
参考实施例2的合成方法,用3-氧代-2,8-二氮杂螺[4.5]癸烷-8-羧酸苄酯替换3-氧代-8-氧杂-2-氮杂螺[4.5]癸烷,经过上述中间体化合物,最终制得实施例3化合物140mg,棕色固体,收率81.8%。
1H NMR(600MHz,CD3OD)δ(ppm):7.74-7.43(m,0.2H,ArH),7.42-7.19(m,9H,ArH),7.11-7.02(m,1.8H,ArH),6.94-6.87(m,1H,CH=CH),6.80-6.70(m,1H,CH=CH),5.85-5.71(m,1H,ArCH2),5.66-5.63(m,1H,ArCH2),5.54-5.42(m,1H,CH),5.30-5.20(m,0.8H,CHCH2),5.06-5.05(m,2.2H,CHCH2,SCH2),4.13-4.11(m,1H,NCH2),3.99-3.85(m,1H,NCH2),3.48-3.39(m,3H,NCH2CH2),3.22-3.16(m,1H,NCH2CH2),2.07-1.96(m,1H,CHCH2),1.48(br,3H,NCH2CH2,
CHCH2),1.21-1.01(m,2H,NCH2CH2).HRMS(ESI):m/z[M+H]+C36H32F2N4O5S理论值:671.2134;实测值:671.2131
实施例4 9'-羟基-4'-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-3,3a',4,4',5,6-六氢-1'H,3'H-螺[吡喃-2,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮的合成
步骤1 2-(2-羟基四氢-2H-吡喃-2-基)乙酸乙酯(2)的合成
向500mL三口瓶中依次加入无水乙酸乙酯(17.6g,200mmol)和四氢呋喃(200mL),氮气保护,降温至-78℃,滴加LDA(105mL,210mmol,2N正己烷溶液),保温反应1h。再滴加1(20g,200mmol),加毕,保温反应2h。TLC(V石油醚:V乙酸乙酯=50:1)监测原料反应完全,低温下加入乙醇(50mL)淬灭反应,再加入水(10mL),乙酸乙酯(200mL×3)萃取,合并有机相,有机相用饱和食盐水(300mL×2)洗涤,无水硫酸钠干燥,过滤,浓缩,并经柱层析纯化(V石油醚:V乙酸乙酯=5:1),得到23g淡黄色油状物,收率62%。
步骤2 2-(2-氰基四氢-2H-吡喃-2-基)乙酸乙酯(3)
向500mL三口瓶中依次加入化合物2(23g,122.34mmol)、乙腈(200mL),TMSCN(60.55g,611.7mmol)和TMSOTf(81.47g,367.02mmol),氮气保护,室温反应过夜。TLC(V石油醚:V乙酸乙酯=3:1)监测反应结束,加入饱和碳酸氢钠水溶液调节反应溶液pH至8,乙酸乙酯(200mL×3)萃取,合并有机相,有机相用饱和食盐水(300mL×2)洗涤,无水硫酸钠干燥,过滤,浓缩,并经柱层析纯化(V石油醚:V乙酸乙酯=10:1),得到11.5g无色透明油状物,收率47%。
1H NMR(400MHz,CDCl3)δ(ppm):4.22(q,J=7.2Hz,2H,COOCH2CH3),3.97-3.93(m,1H,CH2CH2),3.88-3.82(m,1H,CH2CH3),2.82-2.71(m,2H,COCH2),2.08-2.03(m,1H,OCH2CH2),1.86-1.81(m,2H,CH2CH2),1.70-1.64(m,1H,CH2CH2),1.62-1.56(m,2H,OCH2CH2),1.29(t,J=7.2Hz,3H,CH3).
步骤3 2-(2-(氨基甲基)四氢-2H-吡喃-2-基)乙酸乙酯(4)的合成
向1L单口瓶中依次加入化合物3(8g,40.16mmol)、甲醇(1L)、浓盐酸(2mL)和10%钯碳(800mg,10%wt),室温下进行氢化(15Psi)反应过夜,TLC(V石油醚:V乙酸乙酯=10:1)监测反应完全,将反应液过滤,浓缩,浓缩物经快速制备色谱纯化(V二氯甲烷:V甲醇=20:1),得到6.8g白色固体,收率83%。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.81(s,2H,NH2),4.05-4.01(m,2H,CH2CH3),3.64-3.56(m,2H,CH2CH2),3.05-2.97(m,2H,NH2CH2),2.77(d,J=9.6Hz,1H,COCH2),2.67(d,J=10.0Hz,1H,COCH2),1.60-1.53(m,3H,CH2),1.48-1.46(m,1H,CH2CH2),1.43-1.39(m,2H,CH2CH2),1.16(t,J=4.8Hz,3H,CH3).
步骤4 6-氧杂-2-氮杂螺[4.5]癸烷-3-酮(5)的合成
向500mL单口瓶中加入化合物4(8.8g,43.78mmol)、乙醇(200mL)和叔丁醇钠(4.2g,43.78mmol),氮气氛围下60℃反应1h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,将反应液浓缩至干,浓缩物经快速制备色谱纯化(V二氯甲烷:V甲醇=40:1),得到6.4g无色透明油状物,收率94%。
1H NMR(400MHz,CDCl3)δ(ppm):6.57(s,1H,NH),3.70-3.62(m,2H,CH2CH3),3.46(d,J=6.8Hz,1H,OCH2),3.30(d,J=6.8Hz,1H,OCH2),2.58(d,J=11.2Hz,1H,COCH2),2.33(d,J=11.2Hz,1H,COCH2),1.68-1.60(m,4H,CH2CH2),1.56-1.52(m,2H,CH2CH2).
步骤5 3-氧代-6-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯(6)的合成
向500mL三口瓶中加入化合物5(6.4g,41.29mmol)和四氢呋喃(100mL),氮气保护,
降温至-78℃,滴加n-BuLi(18mL,45.42mmol,2.5N正己烷溶液),保温反应1h。再滴加Alloc-Cl(5.47g,45.42mmol),加毕,保温反应1h。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全,低温下加入饱和氯化铵水溶液(200mL)淬灭,乙酸乙酯(150mL×3)萃取,合并有机相,有机相用饱和食盐水(200mL×2)洗涤,无水硫酸钠干燥,过滤,浓缩,经快速制备色谱纯化(V二氯甲烷:V甲醇=50:1),得到8.4g淡黄色油状物,收率85%。
步骤6 3-羟基-6-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯(7)的合成
向250mL三口瓶中加入化合物6(8.4g,35.11mmol)和四氢呋喃(120mL),氮气保护,降温至-78℃,滴加DIBAl-H(46mL,45.6mmol,1N正己烷溶液),保温反应1.5h。TLC(V二氯甲烷:V甲醇=20:1)监测反应完全,低温下加入饱和酒石酸钾钠溶液(30mL)淬灭反应,乙酸乙酯(300mL×3)萃取,合并有机相,有机相用饱和食盐水(300mL×3)洗涤,无水硫酸钠干燥,过滤,浓缩,得到6.5g棕色油状物,收率77%。
步骤7 3-甲氧基-6-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯(8)的合成
向250mL单口瓶中依次加入化合物7(6.28g,26.06mmol)、甲醇(100mL)和对甲苯磺酸一水合物(494mg,2.6mmol),氮气保护,室温反应1h。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全,加入饱和碳酸氢钠溶液(100mL),用乙酸乙酯(200mL×3)萃取,合并有机相,有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,浓缩,经快速制备色谱(V石油醚:V乙酸乙酯=10:1)纯化,得到3.31g无色透明油状物,收率46%。
步骤8 3-((3-(苄氧基)-2-(乙氧基羰基)-4-氧代吡啶-1(4H)-基)氨基)-6-氧杂-2-氮杂螺环[4.5]癸烷-2-羧酸烯丙酯(9)的合成
向100mL三口瓶中依次加入化合物8(2.6g,10.25mmol)、1-氨基-3-(苄氧基)-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(2.95g,10.25mmol)和乙腈(60mL),氮气保护,降温至-25℃,滴加SnCl4(4.26g,16.4mmol),保温反应3.5h。TLC(V二氯甲烷:V甲醇=20:1)监测反应结束,低温下加入饱和碳酸氢钠水溶液(40mL)淬灭反应,乙酸乙酯(200mL×3)萃取,合并有机相,有机相用饱和食盐水(150mL×2)洗涤,无水硫酸钠干燥,过滤,浓缩,经快速制备色谱(V二氯甲烷:V甲醇=20:1)纯化,得到1.84g黄色固体,收率34%。
步骤9 9'-(苄氧基)-3,3a',4,4',5,6-六氢-1'H,3'H-螺环[吡喃-2,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮(10)的合成
向50mL单口瓶中依次加入化合物9(1.84g,3.6mmol)和吗啉(10mL),搅拌溶解,再加入Pd(PPh3)4(415mg,0.36mmol),氮气保护,室温反应1h。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全,加入异丙醚(150mL),析出固体,过滤,滤饼经快速制备色谱(40g,V二氯甲烷:V甲醇=10:1)纯化,得到1.1g黄色固体,收率80%。
1H NMR(400MHz,CDCl3)δ(ppm):7.56-7.55(m,2H,ArH),7.46(d,J=4.8Hz,1H,ArH),7.34-7.32(m,2H,ArH),7.31-7.28(m,1H,ArH),6.35(d,J=5.2Hz,1H,ArH),6.06(d,J=8.8Hz,1H,NH),5.39(d,J=6.8Hz,1H,ArCH2),4.98(d,J=6.8Hz,1H,BnCH2),4.84-4.79(m,1H,NCH),3.63-3.55(m,3H,CH2),3.08(d,J=8.4Hz,1H,CH2CH2),2.26-2.23(m,1H,CH2)1.72-1.68(m,1H,CH2),1.65-1.52(m,5H,CH2),1.46-1.42(m,1H,CH2).
步骤10 9'-(苄氧基)-4'-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-3,3a',4,4',5,6-六氢-1'H,3'H-螺[吡喃-2,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮(11)的合成
向100mL单口瓶中依次加入化合物10(1.1g,2.89mmol)、11-氯-7,8-二氟-6,11-二氢二
苯并[b,e]硫杂(2.3g,7.21mmol)、乙腈(340mL)和碳酸铯(3.69g,11.56mmol),氮气保护,室温反应过夜。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,加水(40mL)淬灭反应,用乙酸乙酯(150mL×3)萃取,合并有机相,有机相用无水硫酸钠干燥,过滤,浓缩,经快速制备色谱纯化(40g,V二氯甲烷:V甲醇=30:1),得到350mg棕色固体,收率21%。
步骤11 9'-羟基-4'-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-3,3a',4,4',5,6-六氢-1'H,3'H-螺[吡喃-2,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮(实施例4)的合成
向25mL单口瓶中依次加入化合物11(330mg,0.53mmol)、DMA(5mL)和氯化锂(223mg,5.3mmol),氮气保护,80℃反应4h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,冷却至室温,加水(40mL)淬灭反应,二氯甲烷(30mL×3)萃取,合并有机相,有机相用无水硫酸钠干燥,过滤,浓缩,经快速制备色谱(12g,V二氯甲烷:V甲醇=10:1)纯化,得到170mg黄色固体,收率60%。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.48-7.44(m,1H,ArH),7.37-7.24(m,2H,ArH),7.18-7.12(m,1.5H,ArH),7.10(d,J=5.2Hz,0.5H,ArH),7.06-7.04(m,1H,ArH),6.99(d,J=4.8Hz,0.5H,ArH),6.94-6.92(m,0.5H,ArH),6.87-6.81(m,1H,ArH),5.71-5.67(m,0.6H,CH,SCH2),5.63-5.60(m,0.6H,CH,SCH2),5.55-5.52(m,0.8H,CH,SCH2),5.49-5.47(m,0.5H,CH),5.43-5.41(m,0.5H,CH),4.12-4.07(m,1H,CH2CH2),3.93(t,J=8.8Hz,0.6H,OCH2),3.57-3.52(m,2.8H,OCH2),2.30-2.26(m,0.6H,CH2CH2),1.47-1.26(m,5.5H,OCH2),1.24-1.12(m,2H,CH2CH2),1.02-0.99(m,1H,CH2CH2),0.97-0.91(m,0.5H,CH2CH2),0.83-0.79(m,0.5H,CH2CH2).
实施例5 4'-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-9'-羟基-3a',4',5,6-四氢-1'H,2H,3'H,4H-螺[吡喃-3,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮的合成
步骤1(E)-2-(二氢-2H-吡喃-3(4H)-亚甲基)乙酸甲酯(2)的合成
向1L单口瓶中依次加入化合物1(20g,200mmol)、2-(三苯基-λ5-亚膦亚基)乙酸甲酯(73.47g,220mmol)和甲苯(300mL),氮气保护,110℃反应过夜。TLC(V石油醚:V乙酸乙酯=5:1)监测原料反应完全,加入乙酸乙酯(300mL)稀释,用饱和食盐水洗涤(200mL×3),无水硫酸钠干燥,过滤,浓缩,并经柱层析(V石油醚:V乙酸乙酯=5:1)纯化,得到30g无色透明油状物,收率97%。
步骤2 2-(3-(硝基甲基)四氢-2H-吡喃-3-基)乙酸甲酯(3)的合成
向500mL单口瓶中依次加入化合物2(37g,237.18mmol)、四氢呋喃(300mL),硝基甲烷(28.95g,474.36mmol)和TBAF(1N四氢呋喃溶液,356mL,355.77mmol),氮气保护,70℃反应过夜。TLC(V石油醚:V乙酸乙酯=5:1)监测原料反应完全,加入乙酸乙酯(600mL)稀释,用1N盐酸洗涤(100mL×2),然后用饱和食盐水洗涤(200mL×3),无水硫酸钠干燥,过滤,浓缩,并经柱层析(V石油醚:V乙酸乙酯=10:1)纯化,得到37g无色透明油状物,收率73%。
1H NMR(400MHz,CDCl3)δ(ppm):4.83-4.78(m,2H,CH2CH2),3.79-3.74(m,2H,CH2CH2),3.69(s,3H,OCH3),3.60-3.56(m,1H,OCH2),3.49(d,J=7.6Hz,1H,CH2),2.60(d,J=8.4Hz,1H,CH2CH2),2.45(d,J=8.4Hz,1H,CH2CH2),1.81-1.73(m,2H,OCH2),1.65-1.60(m,2H,CH2CH2).
步骤3 7-氧杂-2-氮杂螺环[4.5]癸烷-3-酮(4)的合成
向1L单口瓶中依次加入化合物3(37g,170.50mmol)、乙醇(500mL)、水(50mL),氯化铵(45.60g,852.53mmol)和铁粉(47.74g,852.53mmol),氮气保护,80℃反应2h。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全,将反应液过滤,浓缩,并经柱层析(V二氯甲烷:V甲醇=40:1)纯化,得到25g无色透明油状物,收率95%。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.50(s,1H,NH),3.58-3.53(m,1H,CH2CH2),3.50-3.46(m,1H,CH2),3.37(d,J=7.2Hz,1H,CH2CH2),3.28(d,J=7.2Hz,1H,CH2CH2),3.07(d,J=6.8Hz,1H,CH2CH2),2.96(d,J=6.4Hz,1H,CH2),1.97(s,2H,CH2CH2),1.65-1.57(m,2H,CH2CH2),1.52-1.47(m,2H,CH2).
步骤4 3-氧代-7-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯(5)的合成
向500mL三口瓶中加入化合物4(25g,161.29mmol)和四氢呋喃(300mL),氮气保护,降温至-78℃,滴加n-BuLi(71mL,177.42mmol,2.5N正己烷溶液),保温反应2h。再滴加Alloc-Cl(21.38g,177.42mmol),加毕,保温反应1h。TLC(V二氯甲烷:V甲醇=30:1)监测原料反应完全,低温下加入饱和氯化铵水溶液(200mL)淬灭反应,乙酸乙酯(200mL×3)萃取,合并有机相,有机相用饱和食盐水(300mL×2)洗涤,无水硫酸钠干燥,过滤,浓缩,经柱层析(V二氯甲烷:V甲醇=50:1)纯化,得到25g黄色油状物,收率65%。
1H NMR(400MHz,DMSO-d6)δ(ppm):5.93-5.87(m,1H,CH=CH2),5.36-5.33(m,1H,CH=CH2),5.21-5.19(m,1H,CH=CH2),4.62-4.60(m,2H,OCH2),3.58(d,J=6.8Hz,1H,OCH2CH2),3.55-3.51(m,1H,CH2CH2),3.46-3.37(m,4H,CH2CH2),2.36-2.28(m,2H,CH2),1.64-1.60(m,1H,CH2),1.58-1.54(m,1H,CH2CH2),1.50-1.45(m,2H,CH2CH2).
步骤5 3-羟基-7-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯(6)的合成
向500mL单口瓶中加入化合物5(15g,62.69mmol)和四氢呋喃(150mL),氮气保护,降温至-78℃,滴加DIBAl-H(82mL,81.49mmol,1N正己烷溶液),保温反应4h。TLC(V二氯甲烷:V甲醇=30:1)监测原料反应完全,低温下加入饱和酒石酸钾钠溶液(100mL)淬灭反应,室温搅拌20min,乙酸乙酯(200mL×3)萃取,合并有机相,有机相用饱和食盐水(300mL×2)洗涤,无水硫酸钠干燥,过滤,浓缩,得到15.12g黄色油状物,其不经纯化直接用于下一步。
步骤6 3-甲氧基-7-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯(7)的合成
向1L单口瓶中加入化合物6(15.12g,62.7mmol)、甲醇(200mL)和对甲苯磺酸一水
合物(1.19g,6.27mmol),氮气保护,室温反应1h。TLC(V二氯甲烷:V甲醇=30:1)监测原料反应完全,加入饱和碳酸氢钠溶液(50mL),用乙酸乙酯(200mL×3)萃取,合并有机相,有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,浓缩,并经快速制备色谱(120g,V二氯甲烷:V甲醇=30:1)纯化,得到11g无色透明油状物,收率65%。
步骤7 3-((3-(苄氧基)-2-(乙氧基羰基)-4-氧代吡啶-1(4H)-基)氨基)-7-氧杂-2-氮杂螺环[4.5]癸烷-2-羧酸烯丙酯(8)的合成
向250mL三口瓶中加入化合物7(6.46g,25.32mmol)、1-氨基-3-(苄氧基)-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(7.3g,25.32mmol)和乙腈(150mL),氮气保护,降温至-25℃,滴加SnCl4(10.55g,40.51mmol),保温反应1.5h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,低温下加入饱和碳酸氢钠溶液(200mL)淬灭反应,用二氯甲烷(200mL×3)萃取,合并有机相,有机相用饱和食盐水(150mL×2)洗涤,无水硫酸钠干燥,过滤,浓缩,并经快速制备色谱(120g,V二氯甲烷:V甲醇=30:1)纯化,得到6.5g黄色固体,收率50%。
步骤8 9'-(苄氧基)-3a',4',5,6-四氢-1'H,2H,3'H,4H-螺[吡喃-3,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮(9)的合成
向250mL单口瓶中依次加入化合物8(6.5g,12.76mmol)和吗啉(100mL),搅拌溶解,再加入Pd(PPh3)4(1.47g,1.28mmol),氮气保护,室温反应1h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,加入异丙醚(600mL),析出固体,过滤,滤饼经快速制备色谱(80g,V二氯甲烷:V甲醇=30:1)纯化得到3.7g黄色固体,收率77%。
步骤9叔丁基9'-(苄氧基)-8',10'-二氧代-3',3a',5,6,8',10'-六氢-1'H,2H,4H,4'H-螺[吡喃-3,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-4'-羧酸盐(10)的合成
向250mL单口瓶中依次加入化合物9(3.7g,9.71mmol)和二氯甲烷(60mL),搅拌溶解,再加入三乙胺(1.96g,19.42mmol)、DMAP(120mg,0.97mmol)和(Boc)2O(4.23g,19.42mmol),氮气保护,室温反应过夜。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全,加入二氯甲烷(100mL)稀释,饱和食盐水洗涤(60mL×3),无水硫酸钠干燥,过滤,浓缩,并经快速制备色谱(80g,V二氯甲烷:V甲醇=30:1)纯化,得到化合物10(2.00g,收率42.8%)。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.85-7.83(m,1H,ArH),7.53-7.51(m,2H,ArH),7.36-7.33(m,2H,ArH),7.31-7.28(m,1H,ArH),6.27-6.24(m,1H,ArH),5.55(t,J=6.4Hz,1H,ArCH2),5.16(d,J=7.2Hz,1H,ArCH2),5.07(d,J=7.2Hz,1H,CH),3.67-3.60(m,1H,CH2),3.53-3.43(m,4H,CH2CH2),3.34-3.33(m,1H,CH2),2.89(dd,J1=8.4Hz,J2=6.0Hz,1H,OCH2),2.23(dd,J1=8.8Hz,J2=5.2Hz,1H,OCH2),1.71-1.56(m,4H,CH2CH2),1.36(s,9H,O(CH2)3).
步骤10 9'-(苄氧基)-3a',4',5,6-四氢-1'H,2H,3'H,4H-螺[吡喃-3,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮(11)的合成
向100mL闷罐中加入化合物10(2g,4.16mmol)和HCl/乙酸乙酯(3N,20mL),60℃反应2h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,反应液浓缩至干,加入水(10mL),饱和碳酸氢钠调节pH至7,二氯甲烷(60mL×5)萃取,合并有机相,有机相用无水硫酸钠干燥,过滤,浓缩,并经快速制备色谱(40g,V二氯甲烷:V甲醇=20:1)纯化,得到1.1g白色固体,收率70%。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.69(d,J=7.6Hz,1H,ArH),7.50-7.48(m,2H,ArH),7.33-7.23(m,3H,ArH),7.13(d,J=12.4Hz,1H,ArH),6.15(d,J=7.6Hz,1H,ArCH2),5.13(d,J=10.8Hz,1H,ArCH2),5.01-4.91(m,2H,CH,CH2),3.58-3.45(m,3H,NH,CH2),3.37-3.25(m,2H,CH2CH2),3.18(d,J=12.0Hz,1H,CH2CH2),2.20(dd,J1=12.8Hz,J2=6.4Hz,1H,OCH2),1.65-1.58(m,2H,CH2CH2),1.51-1.41(m,3H,CH2CH2).
步骤11 9'-(苄氧基)-4'-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-3a',4',5,6-四氢-1'H,2H,3'H,4H-螺[吡喃-3,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮(12)的合成
向100mL单口瓶中依次加入化合物11(600mg,1.57mmol)、11-氯-7,8-二氟-6,11-二氢二苯并[b,e]硫杂(1.3g,3.9mmol)、乙腈(15mL)和碳酸铯(2.05g,6.28mmol),氮气保护,室温反应过夜。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全,加水(100mL)淬灭反应,用二氯甲烷(50mL×6)萃取,合并有机相,食盐水(150mL×2)洗涤,无水硫酸钠干燥,过滤,浓缩,并经快速制备色谱(40g,V二氯甲烷:V甲醇=20:1)纯化,得到439mg黄色固体,收率45%。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.56-7.47(m,3H,ArH),7.36-7.22(m,6H,ArH),7.18-7.11(m,2H,ArH),7.08-6.99(m,1H,ArH),6.83-6.77(m,2H,ArH),5.74-5.64(m,1H,ArCH2),5.52-5.42(m,1H,ArCH2),5.42-5.35(m,1H,SCH2),5.19-5.13(m,2H,CH2CH2),5.10-5.01(m,1H,SCH2),4.08(dd,J1=14Hz,J2=5.2Hz,1H,CH2),3.78-3.42(m,3H,CH2),3.13-3.01(m,1H,CH2),1.93-1.86(m,1H,CH2),1.44-1.15(m,4H,CH2CH2),1.04-0.92(m,1H,CH2).
步骤12 4'-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-9'-羟基-3a',4',5,6-四氢-1'H,2H,3'H,4H-螺[吡喃-3,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮(实施例5)的合成
向25mL单口瓶中依次加入化合物12(230mg,0.37mmol)、DMAc(5mL)和氯化锂(156mg,3.7mmol),氮气保护,80℃反应5h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,冷却至室温,加乙酸乙酯(40mL)稀释,饱和食盐水(20mL×2)洗涤,无水硫酸钠干燥,过滤,浓缩,并经快速制备色谱(12g,V二氯甲烷:V甲醇=10:1)纯化,得到90mg棕红色固体,收率45%。
1H NMR(400MHz,CD3OD)δ(ppm):7.73-7.37(m,1H,ArH),7.29-6.97(m,3H,ArH),6.85-
6.41(m,2H),5.78-5.46(m,2H,ArH),5.42-5.10(m,1H,SCH2),4.28-4.00(m,2H,SCH2,CH),3.78-3.53(br,2H,CH2),3.50-3.32(m,2H,CH2),3.26-3.16(m,1H,CH2),2.11-1.93(m,1H,CH2),1.65-1.35(br,3.5H,CH2),1.33-1.07(m,4H,CH2CH2),0.90-0.81(m,0.5H,CH2).
HRMS(ESI):m/z[M+H]+C28H25F2N3O4S理论值:538.1612;实测值538.162.HPLC:97.174%.
实施例6 9-羟基-4-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-2’,3a,3’,4,5’,6’-六氢-1H,3H-螺[吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪-2,4’-(1’,1’-二氧代噻喃)]-8,10-二酮的合成
步骤1 2-(四氢-4H-噻喃-4-亚丙基)乙酸甲酯(2)的合成
向500mL单口瓶中依次加入化合物1(11.6g,100mmol)、甲氧甲酰基亚甲基三苯基膦(36.78g,110mmol)和甲苯(200mL),氮气保护,110℃反应过夜。TLC(V石油醚:V乙酸乙酯=10:1)监测反应完全,反应液浓缩干,经柱层析纯化(V石油醚:V乙酸乙酯=10:1),得到17g无色透明油状化合物2,收率98.9%。
步骤2 2-(4-(硝基甲基)四氢-2H-噻喃-4基)乙酸甲酯(3)的合成
向500mL单口瓶中依次加入化合物2(17g,98.8mmol)、四氢呋喃(120mL),硝基甲烷(12.05g,197.6mmol)和TBAF(1N四氢呋喃溶液,148mL,148.25mmol),氮气保护,70℃反应过夜。TLC(V石油醚:V乙酸乙酯=50:1)监测反应完全,加乙酸乙酯(400mL)稀释,1N盐酸洗涤(100mL×2),然后饱和食盐水洗涤(200mL×3),无水硫酸钠干燥,过滤,浓缩,经柱层析纯化(V石油醚:V乙酸乙酯=10:1),得到18g白色固体化合物3,收率74%。
1H NMR(400MHz,DMSO-d6)δ(ppm):4.71(s,2H,NO2CH2),3.57(s,3H,OCH3),2.61(t,J=6.0Hz,4H,CH2CH2),2.48-2.46(m,2H,CH2),1.85-1.71(m,4H,CH2CH2).
步骤3 8-硫杂-2-氮杂螺环[4.5]癸-3-酮(4)的合成
向1L单口瓶中依次加入中间体3(18g,77.25mmol)、乙醇(200mL)、水(20mL),氯化铵(20.66g,386.27mmol)和铁粉(21.63g,386.27mmol),氮气保护,80℃反应2h。TLC(V二氯甲烷:V甲醇=20:1)监测反应完全,反应液过滤,浓缩,柱层析纯化(V二氯甲烷:V甲醇=20:1),得到11.35g白色固体中间体4,收率86%。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.45(s,1H,NH),2.95(s,2H,NCH2),2.55-2.48(m,4H,CH2CH2),1.97(s,2H,COCH2),1.72-1.65(m,4H,CH2CH2).
步骤4 3-氧代-8-硫杂-2-氮杂螺环[4.5]癸烷-2-羧酸烯丙酯(5)的合成
向500mL三口瓶中加入中间体4(11.35g,161.29mmol)和四氢呋喃(150mL),氮气保护,降温至-78℃,滴加n-BuLi(29mL,72.90mmol,2.5N己烷溶液),保温反应1h。再滴加Alloc-Cl(8.77g,72.90mmol),加毕,保温反应1h。TLC(V二氯甲烷:V甲醇=30:1)监测原料反应完全,低温下加入饱和氯化铵溶液(200mL)淬灭反应,乙酸乙酯(100mL×3)萃取,合并有机相,饱和食盐水(300mL×2)洗涤,无水硫酸钠干燥,过滤,浓缩,柱层析纯化(V二氯甲烷:V甲醇=50:1),得到9.5g白色固体中间体5,收率56%。
步骤5 3-羟基-8-硫杂-2-氮杂螺环[4.5]癸烷-2-羧酸烯丙酯(6)的合成
向250mL三口瓶中加入中间体5(9.5g,37mmol)和四氢呋喃(100mL),氮气保护,降温至-78℃,滴加DIBAl-H(48mL,48mmol,1N己烷溶液),保温反应2h。TLC(V二氯
甲烷:V甲醇=30:1)监测反应不再变化后,低温下加入饱和氯化铵溶液(200mL)淬灭,乙酸乙酯(100mL×3)萃取,合并有机相,饱和食盐水(300mL×3)洗涤,无水硫酸钠干燥,过滤,浓缩得到10g无色透明油状中间体6,其不经纯化直接用于下一步。
步骤6 3-甲氧基-8-硫杂-2-氮杂螺环[4.5]癸烷-2-羧酸烯丙酯(7)的合成
向500mL单口瓶中依次加入中间体6(10g,38.86mmol)、甲醇(150mL)和对甲苯磺酸一水合物(0.71g,3.9mmol),氮气保护,室温反应1h。TLC(V二氯甲烷:V甲醇=30:1)监测原料反应完全,加入饱和酒石酸钾钠溶液(100mL),用乙酸乙酯(200mL×3)萃取,合并有机相,饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,浓缩,柱层析纯化(V二氯甲烷:V甲醇=40:1),得到3.39g无色透明油状物中间体7,两步收率32.2%。
步骤7 3-((3-(苄氧基)-2-(乙氧基羰基)-4-氧代吡啶-1(4H)-基)氨基)-8-硫杂-2-氮杂螺环[4.5]癸烷-2-羧酸烯丙酯(8)的合成
向100mL三口瓶中依次加入中间体7(3.39g,12.5mmol)、1-氨基-3-(苄氧基)-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(3.6g,12.5mmol)和乙腈(40mL),氮气保护,降温至-25℃,滴加SnCl4(5.2g,20mmol),保温反应2h。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全,低温下加入饱和碳酸氢钠溶液(200mL)淬灭反应,二氯甲烷(100mL×3)萃取,合并有机相,饱和食盐水(150mL×2)洗涤,无水硫酸钠干燥,过滤、浓缩,柱层析纯化(V二氯甲
烷:V甲醇=20:1),得到2.43g黄色固体中间体8,收率37%。
步骤8 9-(苄氧基)-2’,3a,3’,4,5’,6’-六氢-1H,3H-螺[吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪-2,4’-噻喃]-8,10-二酮(9)的合成
向100mL单口瓶中依次加入中间体8(2.43g,4.6mmol)和吗啉(30mL),搅拌溶解,再加入Pd(PPh3)4(532mg,0.46mmol),氮气保护,室温反应1h。TLC(V二氯甲烷:V甲醇=10:
1)监测原料反应完全,加入异丙醚(100mL),析出固体,过滤,滤饼40℃真空干燥1h,得到1.8g黄色固体中间体9,收率98%。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.74(d,J=5.2Hz,1H,ArH),7.53-7.52(m,2H,ArH),7.36-7.34(m,2H,ArH),7.31-7.28(m,1H,ArH),7.18(d,J=8.4Hz,1H,ArH),6.21(d,J=8.4Hz,1H,NH),5.20(d,J=6.8Hz,1H,ArCH2),5.03(d,J=6.8Hz,1H,ArCH2),5.00-4.96(m,1H,CH),3.49-3.47(m,1H,CH2CH2),3.23(d,J=8.0Hz,1H,CH2CH2),2.66-2.55(m,4H,CH2CH2),2.32(dd,J1=8.4Hz,J2=4.0Hz,1H,CH2),1.82-1.68(m,4H,CH2CH2),1.47-1.43(m,1H,CH2).
步骤9 9-(苄氧基)-2’,3a,3’,4,5’,6’-六氢-1H,3H-螺[吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪-2,4’-(1’,1’-二氧代噻喃)]-8,10-二酮(10)的合成
向100mL单口瓶中依次加入中间体9(1g,2.5mmol)、叔丁醇(10mL)和水(10mL),搅拌溶解,再加入过氧单磺酸钾(1.86g,3.02mmol),氮气保护,室温反应过夜。TLC(V二
氯甲烷:V甲醇=10:1)监测原料反应完全,加入水(10mL),二氯甲烷(40mL×5)萃取,合并有机相,饱和食盐水(150mL×2)洗涤,无水硫酸钠干燥,过滤、浓缩,快速制备色谱纯化(20g,V二氯甲烷:V甲醇=10:1),得到1g类白色固体中间体10,收率93%。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.76(d,J=4.8Hz,1H,ArH),7.53-7.52(m,2H,ArH),7.36-7.34(m,2H,ArH),7.31-7.29(m,1H,ArH),7.18(d,J=8.4Hz,1H,ArH),6.21(d,J=4.8Hz,1H,NH),5.20(d,J=7.2Hz,1H,ArCH2),5.03-4.98(m,3H,ArCH2,CH),3.63(d,J=8.0Hz,1H,CH2),3.35-3.33(m,1H,CH2),3.18-3.16(m,2H,CH2),3.11-3.09(m,2H,CH2CH2),2.48-2.47(m,1H,CH2CH2),2.09-1.93(m,4H,CH2CH2),1.59-1.56(m,1H,CH2).
HRMS(ESI):m/z[M+H]+C21H23N3O5S理论值:430.1436;实测值:430.1413.
步骤10 9-(苄氧基)-4-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-2’,3a,3’,4,5’,6’-六氢-1H,3H-螺[吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪-2,4’-(1’,1’-二氧代噻喃)]-8,10-二酮(11)的合成
向100mL单口瓶中依次加入中间体10(800mg,1.86mmol)、11-氯-7,8-二氟-6,11-二氢二苯并[b,e]硫杂(1.6g,4.66mmol)、乙腈(35mL)和碳酸铯(2.42g,7.46mmol),氮气保护,室温反应过夜。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,加水(40mL)淬灭反应,二氯甲烷(50mL×6)萃取,合并有机相,无水硫酸钠干燥,过滤,浓缩,快速制备色谱纯化(40g,V二氯甲烷:V甲醇=10:1),得到420mg黄色固体中间体11,收率34%。
步骤11 9-羟基-4-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-2’,3a,3’,4,5’,6’-六氢-1H,3H-螺[吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪-2,4’-(1’,1’-二氧代噻喃)]-8,10-二酮(实施例6)的合成
向50mL单口瓶中依次加入中间体11(420mg,0.62mmol)、DMAc(10mL)和LiCl(262mg,6.2mmol),N2保护,80℃反应5h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,冷却至室温,加水(40mL)淬灭反应,二氯甲烷(50mL×6)萃取,合并有机相,无水硫酸钠干燥,过滤,浓缩,快速制备色谱纯化(12g,V二氯甲烷:V甲醇=10:1),得到208mg黄色固体实施例6,收率70%。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.48-7.44(m,1H,ArH),7.36-7.22(m,2.5H,ArH),7.19-7.12(m,1.5H,ArH),7.07-7.04(m,1H,ArH),7.00-6.91(m,1H,ArH),6.86-6.78(m,1H,ArH),5.71-5.52(m,3H,NH,CH),4.21-4.09(m,1.5H,CH2),3.90(t,J=8.4Hz,0.5H,CH2),3.13-2.71(m,4.5H,CH2CH2,CH),1.94-1.81(m,3H,CH2CH2),1.61-1.41(m,1H,CH2),1.37-1.29(m,1H,CH2),1.26-1.18(m,1H,CH2),1.03-0.80(m,0.5H,CH2CH2).
实施例7
步骤1 3-甲基四氢-4H-吡喃-4-酮(2)的合成
向500mL单口瓶中依次加入LDA(198mL,2N四氢呋喃溶液,396mmol)和四氢呋喃(100mL),氮气保护,-78℃依次滴加化合物1(33.00g,330mmol)和HMPA(58mL,330mmol)。保温10min,再滴加碘甲烷(83mL,1.32mol),加毕,升温至0℃反应3h。TLC(V石油醚:V乙酸乙酯=10:1)监测原料反应完全,加入饱和氯化铵水溶液(200mL)淬灭反应,乙酸乙酯(100mL×3)萃取,合并有机相,饱和氯化钠溶液(200mL)洗涤,无水硫酸钠干燥,抽滤,浓缩,柱层析纯化(V石油醚:V乙酸乙酯=30:1),得到10.00g无色油状中间体2,收率26.6%。
步骤2(E)-2-(3-甲基四氢-4H-吡喃-4-亚甲基)乙酸甲酯(3)的合成
向250mL单口瓶中依次加入中间体2(15.00g,131mmol)、甲苯(100mL)和甲氧甲酰基亚甲基三苯基膦(48.33g,145mmol),氮气保护,110℃反应过夜。TLC(V石油醚:V乙酸
乙酯=10:1)监测原料反应完全,冷却至0℃,有固体析出,过滤收集滤液,浓缩,柱层析纯化(V石油醚:V乙酸乙酯=30:1),得到6.50g无色油状中间体3,收率29.6%。
1H NMR(600MHz,CDCl3)δ(ppm):5.68-5.63(m,1H,CH),3.85-3.89(m,2H,CH2CH2),3.69-3.68(m,3H,CH3),3.60-3.56(m,1H,CH2CH2),3.48-3.43(m,1H,CH2CH2),3.28-3.24(m,1H,CH2CH2),2.66-2.56(m,1H,CH2CH2),2.49-2.39(m,1H,CH2CH2),1.06-1.04(m,3H,CHCH3).
步骤3 2-(3-甲基-4-(硝基甲基)四氢-2H-吡喃-4-基)乙酸甲酯(4)的合成
向250mL单口瓶中依次加入中间体3(6.50g,38.2mml)、四氢呋喃(600mL)、
TBAF(57.3mL,57.3mmol,1N in THF)和硝基甲烷(4.1mL,76.3mmol),氮气保护,70℃反应过夜。TLC(V石油醚:V乙酸乙酯=10:1)监测原料反应完全,冷却至室温,加入乙酸乙酯(300mL)稀释反应液,2N稀盐酸(200mL×3)洗涤,饱和氯化钠溶液(200mL×3)洗涤,无水硫酸钠干燥,抽滤,浓缩,柱层析纯化(V石油醚:V乙酸乙酯=10:1),得到4.60g无色油状中间体4,收率52.1%。
1H NMR(400MHz,CDCl3)δ(ppm):4.92-4.89(m,1H,CH2CH2),4.77-4.74(m,1H,CH2CH2),3.81-3.74(m,1H,CH2CH2),3.72-3.70(m,4H,CH2CH2,CHCH3),3.69-3.66(m,1H,CH2CH2),3.41-3.36(m,1H,CH2CH2),2.75-3.72(m,1H,CH2CH2),2.42-2.38(m,1H,CH2CH2),1.97-1.89(m,1H,CH),1.76-1.73(m,2H,CH2CH2),0.92-0.90(m,3H,CH3).
步骤4 6-甲基-8-氧杂-2-氮杂螺环[4.5]癸-3-酮(5)的合成
向250mL单口瓶中依次加入中间体4(6.50g,38.2mmol)、乙醇(50mL)、水(5mL)、氯化铵(4.63g,86.5mmol)和铁粉(4.85g,86.5mmol),氮气保护,80℃反应2h。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全,冷却至室温,经硅藻土过滤,浓缩,柱层析纯化(V二氯甲烷:V甲醇=20:1),得到2.70g黄色油状中间体5,收率92.2%。
1H NMR(600MHz,CDCl3)δ(ppm):6.37(s,1H,NH),3.83-3.79(m,1H,CH2CH2),3.63-3.61(m,1H,CH2CH2),3.53-3.49(m,1H,CH2CH2),3.29-3.27(m,1H,CH2CH2),3.20-3.15(m,2H,CH2CH2),2.39-2.36(m,1H,CH2CH2),2.10-2.07(m,1H,CH2CH2),1.77-1.71(m,1H,CH),1.69-1.67(m,2H,CH2CH2),0.86-0.85(m,3H,CH3)
步骤5 6-甲基-3-氧代-8-氧杂-2-氮杂螺环[4.5]癸烷-2-羧酸烯丙酯(6)的合成
向500mL单口瓶中依次加入中间体5(11.00g,65mmol)和四氢呋喃(200mL),氮气保护,-78℃依次滴加n-BuLi(26mL,65mmol,2.5N四氢呋喃溶液),保温10min,再滴加Alloc-Cl(7.83g,65mmol)的四氢呋喃(10mL)溶液,加毕,保温反应1h。TLC(V二氯
甲烷:V甲醇=20:1)监测原料反应完全,加入饱和氯化铵溶液(200mL)淬灭反应,乙酸乙酯(100mL×3)萃取,合并有机相,饱和氯化钠溶液(200mL)洗涤,无水硫酸钠干燥,抽滤,浓缩,柱层析纯化(V石油醚:V乙酸乙酯=1:1),得到14.50g无色油状中间体6,收率88.1%。
1H NMR(600MHz,CDCl3)δ(ppm):6.08-5.98(m,1H,CHCH2),5.43-5.40(m,1H,CHCH2),5.30-5.27(m,1H,CHCH2),4.74-4.73(m,2H,CH2),3.84-3.80(m,1H,CH2CH2),3.78-3.63(m,3H,CH2CH2),3.54-3.50(m,1H,CCH2),3.21-3.18(m,1H,CCH2),2.62-2.59(m,1H,CH2CH2),2.35-2.32(m,1H,CH2CH2),1.78-1.75(m,1H,CH),1.70-1.62(m,2H,CH2CH2),0.87-0.86(m,3H,CH3).
步骤6 6-甲基-3-羟基-8-氧杂-2-氮杂螺环[4.5]癸烷-2-羧酸烯丙酯(7)的合成
向500mL单口瓶中依次加入中间体6(14.50g,57.2mmol)和四氢呋喃(200mL),氮气保护,-78℃下滴加DIBAl-H(86mL,86mmol,1N四氢呋喃溶液),加毕,保温反应3h。TLC(V二氯甲烷:V甲醇=50:1)监测原料反应完全,加入饱和酒石酸钾钠溶液(200mL)淬灭反应,乙酸乙酯(200mL×3)萃取,合并有机相,0.5N稀盐酸(200mL×3)洗涤,饱和氯化钠溶液(300mL)洗涤,无水硫酸钠干燥,抽滤,浓缩,得到9.00g无色油状中间体7,收率61.4%。
步骤7 6-甲基-3-甲氧基-8-氧杂-2-氮杂螺环[4.5]癸烷-2-羧酸烯丙酯(8)的合成
向250mL单口瓶中依次加入中间体7(9.00g,35.1mmol)、甲醇(50mL)和对甲苯磺酸一水合物(0.67g,3.5mmol),氮气保护,室温反应过夜。TLC(V二氯甲烷:V甲醇=50:1)监测原料反应完全,加入饱和碳酸氢钠溶液(100mL)淬灭反应,乙酸乙酯(150mL×3)萃取,合并有机相,无水硫酸钠干燥,抽滤,浓缩,柱层析纯化(V二氯甲烷:V甲醇=50:1),得到7.90g无色油状中间体8,收率83.2%。
步骤8 3-((3-(苄氧基)-2-(乙氧基羰基)-4-氧代吡啶-1(4H)-基)氨基)-6-甲基-8-氧杂-2-氮杂螺环
[4.5]癸烷-2-羧酸烯丙酯(10)的合成
向250mL三口瓶中依次加入中间体8(5.90g,21.9mml)、1-氨基-3-(苄氧基)-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(化合物9)(6.32g,21.9mmol)和乙腈(120mL),氮气保护,-25℃滴加四氯化锡(4.1mL,35.0mmol),加毕,保温反应2.5h。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全,加入饱和碳酸氢钠溶液,调节pH至7,二氯甲烷(100mL×3)萃取,合并有机相,饱和氯化钠溶液(200mL)洗涤,无水硫酸钠干燥,抽滤,浓缩,柱层析纯化(V二氯甲烷:V甲醇=50:1),得到4.7g黄色油状中间体10,收率40.8%。
步骤9 9’-(苄氧基)-3-甲基-2,3,3a’,4’,5,6-六氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8’,10’-二酮(11)的合成
向250mL单口瓶中依次加入中间体10(4.70g,8.9mmol)、吗啉(40mL)和四三苯基膦钯(1.03g,0.89mmol),氮气保护,室温反应2.5h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,加入异丙醚(400mL),有固体析出,抽滤,收集滤饼,柱层析纯化(V二氯甲烷:V甲醇=20:1),得到3.50g白色固体中间体11,收率99.4%。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.75-7.72(m,1H,ArH),7.53-7.52(m,2H,ArH),7.37-7.33(m,2H,ArH),7.32-7.27(m,1H,ArH),7.21-7.14(m,1H,ArH),6.21-6.20(m,1H,ArH),5.23-5.18(m,1H,CH),5.05-4.88(m,2H,ArCH2),3.67-3.57(m,2H,CH2),3.55-3.38(m,3H,CH2),3.27-3.25(m,1H,CH2),2.20-2.09(m,1H,CH2),1.70-1.58(m,2H,CH2),1.56-1.53(m,1H,CH2),1.46-1.37(m,1H,CH),0.92-0.81(m,3H,CH3).
步骤10 9’-(苄氧基)-3-甲基-8’,10’-二酮-2,3,3’,3a’,5,6,8’,10’-八氢-1’H,4’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-4’-羧酸叔丁酯(12)的合成
向250mL三口瓶中依次加入中间体11(3.50g,8.85mmol)、二氯甲烷(100mL)、二碳酸二叔丁酯(3.86g,17.7mmol)、三乙胺(1.79g,17.7mmol)和DMAP(108mg,0.89mmol),氮气保护,室温反应1.5h。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全,加入二氯甲烷(200mL)稀释,饱和氯化钠溶液(200mL×3)洗涤,无水硫酸钠干燥,抽滤,浓缩,柱层析纯化(V二氯甲烷:V甲醇=200:1),得到3.67g白色固体中间体12,收率83.7%。
1H NMR(600MHz,DMSO-d6)δ(ppm):7.84-7.83(m,1H,ArH),7.54-7.48(m,2H,ArH),7.35-7.33(m,2H,ArH),7.31-7.27(m,1H,ArH),6.26-6.24(m,1H,ArH),5.48(t,J=8.4Hz,1H,CH),5.22(d,J=10.8Hz,1H,ArCH2),5.07(d,J=10.8Hz,1H,ArCH2),3.71-3.54(m,3H,CH2),3.48-3.45(m,1H,CH2),3.30-3.21(m,2H,CH2),2.89-2.85(m,1H,CCH2),2.55-2.51(m,1H,CCH2),1.75-1.67(m,1H,CH),1.63-1.58(m,2H,CCH2),1.35(s,9H,C(CH3)3),0.78(d,J=7.2Hz,3H,CH3).
步骤11 9’-(苄氧基)-3-甲基-2,3,3a’,4’,5,6-六氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8’,10’-二酮(13)的合成
向闷罐中加入中间体12(670mg,1.33mmol)和HCl/乙酸乙酯(15mL,3N),密封,60℃反应2.5h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,冷却至室温,浓缩除去乙酸乙酯,加水(10mL),滴加饱和碳酸氢钠溶液,调节pH至7,二氯甲烷(30mL×3)萃取,合并有机相,无水硫酸钠干燥,抽滤,浓缩,柱层析纯化(V二氯甲烷:V甲醇=20:1),得到350mg白色固体中间体13,收率66.4%。
1H NMR(600MHz,DMSO-d6)δ(ppm):7.73(d,J=7.8Hz,1H,NH),7.56-7.50(m,2H,ArH),7.37-7.33(m,2H,ArH),7.31-7.27(m,1H,ArH),7.15(d,J=12.6Hz,1H,ArH),6.20(d,J=7.8Hz,1H,ArH),5.22(d,J=10.8Hz,1H,ArCH2),5.02(d,J=10.8Hz,1H,ArCH2),4.94-4.90(m,1H,CH),3.63-3.57(m,2H,CH2),3.50-3.43(m,3H,CH2),3.30-3.25(m,1H,CH2),2.49-2.45(m,1H,CH2),1.65-1.58(m,3H,CH2),1.45-1.42(m,1H,CH),0.82(d,J=7.2Hz,3H,CH3).
步骤12 9-(苄氧基)-4’-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-3-甲基-2,3,3a’,4’,5,6-六氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8’,10’-二酮(14)的合成
向50mL单口瓶中依次加入中间体13(350mg,0.89mmol)、乙腈(10mL)、11-氯-7,8-二氟-6,11-二氢二苯并[b,e]硫杂(751mg,2.66mmol)和碳酸铯(1.44g,4.43mmol),氮气保护,室温反应过夜。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全,加水(25mL)淬灭,二氯甲烷(25mL×4)萃取,合并有机相,饱和氯化钠溶液(50mL)洗涤,无水硫酸钠干燥,抽滤,浓缩,柱层析纯化(V二氯甲烷:V甲醇=200:1),得到220mg黄色固体中间体14,收率38.7%。
1H NMR(600MHz,DMSO-d6)δ(ppm):7.60(d,J=7.8Hz,1H,ArH),7.57-7.50(m,2.5H,ArH),7.43-7.34(m,3H,ArH),7.33-7.29(m,2H,ArH),7.25-7.22(m,1H,ArH),7.21-7.17(m,1H,ArH),7.11-7.07(m,0.5H,ArH),7.05-7.02(m,0.5H,ArH),6.89-6.83(m,1.5H,ArH),5.77-5.75(m,1H,CH),5.74-5.71(m,0.5H,CH),5.54-4.52(m,0.5H,CH),5.46-4.44(m,0.5H,CH2),5.39-5.33(m,1H,CH2),5.25-5.23(m,0.5H,CH2),5.20-5.16(m,1H,CH2),5.13-5.07(m,1H,CH2),4.18-4.14(m,1H,CH2),3.86-3.84(m,0.5H,CH2),3.68-3.66(m,0.5H,CH2),3.61-3.59(m,1H,CH2),3.55-3.49(m,0.5H,CH2),3.45-3.39(m,0.5H,CH2),3.34-3.33(m,0.5H,CH2),3.20-3.18(m,2H,CH2),3.13-3.03(m,0.5H,CH2),2.27-2.25(m,0.5H,CH2),2.16-2.13(m,0.5H,CH2),1.56-1.53(m,1H,CH2),1.50-1.48(m,1H,CH2),1.17-1.13(m,0.5H,CH),1.01-0.95(m,0.5H,CH),0.74(d,J=7.2Hz,1.5H,CH3),0.71(d,J=7.2Hz,1.5H,CH3).
步骤13 4’-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-9’-羟基-3-甲基-2’,3,3a’,4,5,6-六氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8’,10’-二酮(实施例7)的合成
向50mL单口瓶中依次加入中间体14(210mg,0.33mmol)、DMAc(3mL)和氯化锂(139mg,3.27mmol),氮气保护,80℃反应4.5h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,冷却至室温,加水(15mL)淬灭,二氯甲烷(25mL×4)萃取,合并有机相,饱和氯化钠溶液(50mL)洗涤,无水硫酸钠干燥,抽滤,浓缩,柱层析纯化(V二氯甲烷:V甲醇=10:1),得到119mg黄红色固体实施例7,收率65.9%。
1H NMR(600MHz,DMSO-d6)δ(ppm):7.67-7.49(m,1.5H,ArH),7.48-7.31(m,2H,ArH),7.29-7.06(m,3H,ArH),7.04-7.64(m,1.5H,ArH),5.85-5.3(m,3H,CH,CH2),5.46-5.32(m,1H,CH),4.25-4.13(m,1H,CH2),4.01-3.75(m,1H,CH2),3.57-3.50(m,1H,CH2),3.17-3.13(m,1H,CH2),2.25-2.11(m,1H,CH2),1.67-1.51(m,1H,CH2),1.42-1.31(m,1H,CH),1.29-1.17(m,3H,CH2),0.87-0.64(m,3H,CH3).
实施例8 4’-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-9’-羟基-1’H,3’H-螺[哌啶-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]-三嗪]-8’,10’-二酮的合成
步骤1 2-烯丙基-8-叔丁基-3-羟基-2,8-二氮杂螺[4.5]癸烷-2,8-二羧酸酯(2)的合成
向250mL三口瓶中依次加入化合物1(12.0g,35.5mmol)和无水四氢呋喃(75mL),氮气保护下,降温至-78℃。向上述反应体系中,缓慢滴加二异丁基氢化铝(1N四氢呋喃溶液,70.9mL,70.9mmol),保温反应1h。TLC(V石油醚:V乙酸乙酯=2:1)监测反应结束后,饱和酒石酸钾钠溶液(200L)淬灭,加入乙酸乙酯(200mL),室温搅拌15min。硅藻土铺垫下过滤,滤液以乙酸乙酯(100mL×2)萃取,收集有机相,饱和氯化钠溶液(100mL×2)洗涤。无水硫酸钠干燥,过滤,浓缩,得到12.10g无色油状物中间体2,其不经纯化直接投入下步使用。
步骤2 2-烯丙基-8-叔丁基-3-甲氧基-2,8-二氮杂螺[4.5]癸烷-2,8-二羧酸酯(3)的合成
向500mL单口瓶中依次加入中间体2(12.10g,35.5mmol)、甲醇(120mL)和对甲苯磺酸一水合物(675mg,3.55mmol),室温反应1h。TLC(V石油醚:V乙酸乙酯=2:1)监测反应
结束后,饱和碳酸氢钠溶液调节pH=7,浓缩。残留物以乙酸乙酯(20mL×3)萃取,收集有机相。无水硫酸钠干燥,过滤,浓缩,并经快速制备色谱纯化(80g,V石油醚:V乙酸乙酯=4:1)得到9.24g无色油状物中间体3,两步收率73.4%。
步骤3 2-烯丙基-8-叔丁基-3-((3-(苄氧基)-2-(乙氧基羰基)-4-氧代吡啶-1(4H)-基)氨基)-2,8-二氮杂螺[4.5]癸烷-2,8-二羧酸酯(4)的合成
向500mL单口瓶中依次加入中间体3(9.24g,26.1mmol)、1-氨基-3-(苄氧基)-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(7.52g,26.1mmol)和无水乙腈(370mL),氮气保护下,降温至-35℃。向上述反应体系中,缓慢滴加四氯化锡(8.16g,31.3mmol),保温反应1h。TLC(V二氯甲烷:V甲醇=10:1)监测反应结束后,反应液倒入饱和碳酸氢钠溶液(800mL)中。用乙酸乙酯(100mL×3)萃取,收集有机相,饱和氯化钠溶液(100mL×3)洗涤。无水硫酸钠干燥,过滤、浓缩并经快速制备色谱纯化(80g,V二氯甲烷:V甲醇=97:3)得到12.9g黄色固体中间体4,收率81.1%。
步骤4 9’-(苄氧基)-8’,10’-二氧代-3a’,4’,8’,10’-四氢-1’H,3’H-螺[哌啶-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-1-羧酸叔丁酯(5)的合成
向500mL单口瓶中依次加入中间体4(12.9g,21.1mmol)、四氢呋喃(150mL)、吗啉(18.4g,211mmol)和四三苯基膦钯(2.43mg,2.11mmol),氮气保护下,室温反应1h。TLC(V二氯甲烷:V甲醇=10:1)监测反应结束后,加入异丙醚(100mL),过滤,得到9.40g白色固体中间体5,收率90.6%。
步骤5叔丁基-9’-(苄氧基)-4’-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-8’,10’-二氧代-
3a’,4’,8’,10’-四氢-1’H,3’H-螺[哌啶-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]-三嗪]-1-羧酸酯(6)的合成
向50mL单口瓶中依次加入11-氯-7,8-二氟-6,11-二氢二苯并[b,e]硫杂(3.34g,6.96mmol)、乙腈(100mL)、碳酸铯(9.07g,27.8mmol)和中间体5(4.92g,17.4mmol),氮气保护下,室温反应过夜。TLC(V二氯甲烷:V甲醇=15:1)监测反应结束后,硅藻土铺垫下过滤,滤液浓缩并经快速制备色谱纯化(80g,V二氯甲烷:V甲醇=50:1)得到3.20g黄色固体中间体6,收率28.8%。
步骤6 9’-(苄氧基)-4’-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-3a’,4’-二氢-1’H,3’H-螺[哌啶-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]-三嗪]-8’,10’-二酮(7)的合成
向50mL两口瓶中依次加入中间体6(600mg,0.83mmol)和二氯甲烷(12mL),氮气保护下,降温至0℃。向上述反应液中加入三氟乙酸(0.6mL),保温30min后室温反应4h。TLC(V二氯甲烷:V甲醇=10:1)监测反应结束后,反应液倒入快速搅拌的饱和碳酸氢钠溶液(100mL)中。二氯甲烷(50mL×3)萃取,收集有机相,饱和氯化钠溶液(20mL×3)洗涤。无水硫酸钠干燥,过滤、浓缩并经快速制备色谱纯化(12g,V二氯甲烷:V甲醇=10:1)得到293mg黄色固体中间体7,收率56.4%。
1H NMR(600MHz,CDCl3)δ(ppm):7.61-7.58(m,2.27H,ArH),7.43(d,J=7.8Hz,0.72H,ArH),7.35-7.32(m,2.29H,ArH),7.30-7.27(m,1.07H,ArH),7.23-7.20(m,0.38H,ArH),7.17-7.09(m,1.19H,ArH),7.03-6.99(m,2.22H,ArH),6.84-6.81(m,1.04H,ArH),6.73-6.70(m,1.01H,ArH),6.64-6.62(m,0.55H,ArH),6.34-6.33(m,0.26H,ArH),5.88-5.84(m,0.9H,CH),5.48-5.44(m,1.12H,NH),5.42-5.29(m,2.08H,CH2),5.26-5.15(m,0.90H,CH2),4.98-4.88(m,0.74H,CH2),4.08-3.92(m,1.60H,CH2),3.72-3.63(m,0.40H,CH2),3.24-3.12(m,1.11H,CH2),2.93(br,0.9H,NH),2.88-2.81(m,1.80H,CH2),2.73-2.62(m,1.72H,CH2),1.87-1.75(m,1.40H,CH2),1.55-1.48
(m,1.31H,CH2),1.43-1.39(m,3.02H,CH2).
步骤7 4’-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-9’-羟基-1’H,3’H-螺[哌啶-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]-三嗪]-8’,10’-二酮(实施例8)的合成
向拇指瓶中依次加入中间体7(597mg,0.95mmol)、N,N-二甲基乙酰胺(1.5mL)和氯化锂(201mg,4.77mmol),氮气保护下,80℃反应3h。TLC(V二氯甲烷:V甲醇=10:1)监测反应结束后,反应液冷却至室温,加入水(5mL)搅拌,过滤,滤饼以二氯甲烷(15mL)打浆得到80mg白色固体,收率15.6%。
1H NMR(600MHz,DMSO-d6)δ(ppm):7.45-7.43(m,1.43H,ArH),7.34-7.30(m,1.41H,ArH),7.25-7.21(m,0.45H,ArH),7.06-7.03(m,1.35H,ArH),7.06-7.03(m,1.18H,ArH),6.99-6.98(m,0.75H,ArH),6.87-6.80(m,1.43H,ArH),5.68-5.60(m,1.64H,CH,CH2),5.55-5.50(m,2.89H,CH2),5.38(br,0.60H,CH2),4.11-4.07(m,1.43H,CH2),3.77-3.67(m,1.44H,CH2),2.98-2.96(m,0.41H,CH2),2.60-2.54(m,2.55H,NH,CH2),2.37-2.34(m,0.42H,CH2),1.90-1.84(m,0.90H,CH2),1.37-1.08(m,4.72H,CH2).
HRMS(ESI):m/z[M+H]+C28H26F2N4O3S理论值:537.1767;实测值:537.1768
实施例9 4’-(5H-二苯并[a,d][7]轮烯-5-基)-9’-羟基-2,3,3a’,4’,5,6-六氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8’,10’-二酮的合成
步骤1参考实施例2的方法,以1-氨基-3-(己氧基)-4-氧代-1,4-二氢吡啶-2-羧酸乙酯代替1-氨基-3-(苄氧基)-4-氧代-1,4-二氢吡啶-2-羧酸乙酯制备9'-(己氧基)-2,3,3a',4',5,6-六氢-1'H,3'H-螺[吡喃-4,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮(SM2)。
步骤2 4’-(5H-二苯并[a,d][7]轮烯-5-基)-9’-(己氧基)-2,3,3a’,4’,5,6-六氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8’,10’-二酮(3)的合成
向10mL单口瓶中依次加入化合物1(325mg,1.56mmol)、乙酸乙酯(6mL)和SM2(200mg,0.53mmol),室温搅拌下加入甲磺酸(77mg,0.81mmol)和T3P(50wt%乙酸乙酯溶液,1.11g,1.72mmol),在氮气氛围下,65℃下搅拌过夜。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,将反应液降到室温,加水(10mL)淬灭,二氯甲烷(20mL×3)萃取,饱和食盐水(10mL×3)洗涤,干燥,过滤,浓缩并经快速制备色谱纯化(12g,V二氯甲烷:V甲
醇=20:1),得到200mg淡红色固体中间体2,收率78.6%
1H NMR(600MHz,CD3OD)δ(ppm):7.65(d,J=7.6Hz,1H,ArH),7.53(d,J=7.6Hz,1H,ArH),7.36-7.31(m,3H,ArH),7.27-7.25(m,2H,ArH),7.24-7.21(m,2H,ArH),7.14(s,1H,ArH),6.89(d,J=2.1Hz,2H,ArH),5.71(d,J=13.2Hz,1H,CH),4.71-4.66(m,1H,CH),4.16-4.12(m,1H,CH),3.87-3.83(m,1H,CH2),3.63-3.59(m,1H,CH2),3.54-3.49(m,2H,CH2),3.25(t,J=11.4Hz,1H,CH2),3.09(d,J=12.4Hz,1H,CH2),2.54(d,J=12.4Hz,1H),2.13(dd,J1=12.7Hz,J2=5.6Hz,1H,CH2),1.72-1.67(m,2H,CH2),1.51(dd,J1=12.6Hz,J2=9.6Hz,1H,CH2),1.44-1.38(m,2H,CH2),1.37-1.32(m,3H,CH2),1.29-1.23(m,5H,CH2),0.88(t,J=6.9Hz,3H,CH2).
步骤2 4’-(5H-二苯并[a,d][7]轮烯-5-基)-9’-羟基-2,3,3a’,4’,5,6-六氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8’,10’-二酮(实施例9)的合成
向10mL拇指瓶中依次加入中间体2(150mg,0.27mmol)、氯化锂(103mg,2.39mmol)和NMP(0.5mL),在氮气氛围下100℃搅拌16h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,反应液降至室温直接拌样,浓缩,并经快速制备色谱纯化(12g,V二氯甲烷:
V甲醇=20:1)得到粗品,粗品再用EA(10mL)室温打浆3h后,过滤,收集滤饼并经真空干燥箱42℃烘干过夜得到75mg粉红色固体实施例9,收率11.2%。
1H NMR(600MHz,DMSO-d6)δ(ppm):7.66-7.53(m,2H,ArH),7.45-7.27(m,7H,ArH),7.15-6.89(m,3H,ArH),5.68-5.60(m,1H,CH2),5.02-4.90(m,1H,CH2),3.69-3.41(m,6H,CH2OCH2,NCH2),2.33-2.22(m,1H,H of NCHCH2),1.69-1.48(m,5H,CH2CCH2,H of NCHCH2).
实施例10 4’-((3,4-二氟苯基)苯甲基)-9’-羟基-2,3,3a’,4’,5,6-六氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8’,10’-二酮的合成
步骤1(3,4-二氟苯基)苯甲醇(2)的合成
向250mL单口瓶中依次加入化合物1(5.00g,22.9mmol)和MeOH(40mL),冰浴下分批加入硼氢化钠(520mg,1.38mmol),在氮气氛围下室温搅拌2h。TLC(V乙酸乙酯:V石油醚=1:5)监测原料反应完全,加水(100mL)淬灭,乙酸乙酯(120mL×3)萃取,饱和氯化钠水溶液(50mL×3)洗涤,收集有机相,无水硫酸钠干燥,过滤、浓缩并经快速制备色谱纯化(80g,V乙酸乙酯:V石油醚=1:5),得到5.0g无色油状中间体2,收率99.2%。
1H NMR(600MHz,DMSO-d6)δ(ppm):7.41-7.33(m,4H,ArH),7.32-7.29(m,2H,ArH),7.23-7.19(m,2H,ArH),6.06(br,1H,OH),5.71(s,1H,CH).
步骤2 4’-((3,4-二氟苯基)苯甲基)-9’-(己氧基)-2,3,3a’,4’,5,6-六氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8’,10’-二酮(3)的合成
向10mL闷罐中依次加入中间体2(200mg,0.82mmol)、乙酸乙酯(0.5mL)、SM2(200mg,0.53mmol)、甲磺酸(77mg,0.81mmol)和T3P(50wt%乙酸乙酯溶液,1.11g,1.72mmol),在100℃条件下搅拌过夜。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,将反应液降到室温,加水(10mL)淬灭,二氯甲烷(20mL×3)萃取,饱和食盐水(10mL×3)洗涤,干燥,过滤,浓缩并经快速制备色谱纯化(12g,V二氯甲烷:V甲醇=20:1),得到190mg白色固体中间体3,收率37.2%
1H NMR(600MHz,CD3OD)δ(ppm):7.93-7.80(m,1.5H,ArH),7.70(d,J=7.7Hz,1H,ArH),7.51-7.39(m,2H,ArH),7.33-7.31(m,0.5H,ArH),7.25-7.20(m,0.5H,ArH),7.15-7.09(m,2H,ArH),7.09-6.89(m,2H,ArH),5.78(d,J=7.2Hz,0.5H,ArH),5.68-5.65(m,1H,CH),5.63(s,0.5H,CH2),5.56-5.51(m,1H,CH),3.94-3.90(m,0.5H,CH2),3.89-3.84(m,1.5H,CH2),3.78(d,J=11.6Hz,1H,CH2),3.62-3.51(m,3H,CH2),3.50-3.46(m,0.5H,CH2),3.44-3.41(m,1H,CH2),1.92-1.82(m,1H,CH2),1.64-1.57(m,2H,CH2),1.50-1.42(m,4H,CH2),1.38-1.33(m,2H,CH2),1.31-1.27(m,3H,CH2),1.23(s,2H,CH2),0.89(t,J=6.6Hz,3H,CH3).
步骤3 4’-((3,4-二氟苯基)苯甲基)-9’-羟基-2,3,3a’,4’,5,6-六氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8’,10’-二酮(实施例10)的合成
向10mL拇指瓶中依次加入中间体3(190mg,0.33mmol)、氯化锂(128mg,2.97mmol)和NMP(0.5mL),在氮气氛围下100℃搅拌16h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,反应液降至室温直接拌样,浓缩,并经快速制备色谱纯化(12g,V二氯甲烷:V甲醇=20:1),得到粗品,再用乙酸乙酯(10mL)室温打浆3h后,过滤,收集滤饼并经真空干燥箱42℃烘干过夜得到100mg粉红色固体实施例10,收率37.2%。
1H NMR(600MHz,DMSO-d6)δ(ppm):8.04-7.63(m,2.5H,ArH),7.60-7.23(m,2.5H,ArH),7.20-6.85(m,4H,ArH),5.79(s,1H,ArH),5.65-5.56(m,2H,CH2),3.76(d,J=11.8Hz,1H,CH2),3.62-3.49(m,5H,CH2),1.90-1.68(m,1H,CH2),1.48-1.31(m,5H,CH2).
实施例11 4’-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-9’-羟基-3a’,4’-二氢-1’H,3’H-螺[辛烷-3,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪-8’,10’-二酮的合成
步骤1 7-氧代-2-氧杂-6-氮杂螺环[3,4]辛烷-6-羧酸烯丙酯(2)的合成
向150mL三口瓶中依次加入化合物1(2.00g,15.7mmol)和无水四氢呋喃(35mL),氮气保护下,降温至-78℃。向上述反应体系中,缓慢滴加正丁基锂(2.5N己烷溶液,6.3mL,15.7mmol),20min滴毕,保温反应45min。再缓慢滴加氯甲酸烯丙酯(1.89g,15.7mmol)的无水四氢呋喃溶液(5mL),15min滴毕,保温反应1h。TLC(V石油醚:V乙酸乙酯=1:2)监测反应结束后,反应液转移至室温,饱和氯化铵水溶液(25mL)淬灭反应,乙酸乙酯(50mL×3)萃取,收集有机相,饱和氯化钠溶液(10mL×2)洗涤。无水硫酸钠干燥,过滤、浓缩并经快速制备色谱纯化(40g,V石油醚:V乙酸乙酯=1:1)得到1.38g无色油状物中间体2,收率41.5%。
1H NMR(600MHz,DMSO-d6)δ(ppm):5.93-5.87(m,1H,CH2=CH),5.37-5.34(m,1H,CH2=CH),5.21-5.19(m,1H,CH2=CH),4.62-4.60(m,2H,CH2=CHCH2),4.52-4.51(m,2H,OCH2),4.48-4.47(m,2H,OCH2),3.94(s,2H,NCH2),2.82(s,2H,COCH2).
步骤2 7-羟基-2-氧杂-6-氮杂螺环[3,4]辛烷-6-羧酸烯丙酯(3)的合成
向50mL单口瓶中依次加入中间体2(1.38g,6.53mmol)和无水四氢呋喃(15mL),氮气保护下,降温至-78℃。向上述反应体系中,缓慢滴加二异丁基氢化铝(1N己烷溶液,8.5mL,8.49mmol),保温反应2h。TLC(V二氯甲烷:V甲醇=20:1)监测反应结束后,饱和酒石酸钾钠溶液(30mL)淬灭反应,加入乙酸乙酯(25mL),室温搅拌15min。硅藻土铺垫下过滤,滤液以乙酸乙酯(20mL×2)萃取,收集有机相,饱和氯化钠溶液(5mL×2)洗涤。无水硫酸钠干燥,过滤、浓缩得到1.23g无色油状物中间体3,其不经纯化直接投入下步使用。
步骤3 7-甲氧基-2-氧杂-6-氮杂螺环[3,4]辛烷-6-羧酸烯丙酯(4)的合成
向50mL单口瓶中依次加入中间体3(1.23g,5.77mmol)、甲醇(5mL)和对甲苯磺酸一水合物(0.11g,0.58mmol),室温反应1h。TLC(V二氯甲烷:V甲醇=20:1)监测反应结束后,饱和碳酸氢钠溶液调节pH值至约7,浓缩。残留物以乙酸乙酯(25mL×3)萃取,收集有机相。无水硫酸钠干燥,过滤、浓缩并经快速制备色谱纯化(20g,V石油醚:V乙酸乙酯=1:1)得到1.18g无色油状物中间体4,两步收率92.9%。
步骤4 7-((2-(乙氧基羰基)-3-(己氧基)-4-氧代吡啶-1(4H)-基)氨基)-2-氧杂-6-氮杂螺环[3.4]辛烷-6-羧酸烯丙酯(5)的合成
向50mL单口瓶中依次加入中间体4(1.00g,4.40mmol)、1-氨基-3-(己氧基)-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(1.13g,4.00mmol)和无水乙腈(28mL),氮气保护下,降温至-30℃。向上述反应体系中,缓慢滴加四氯化锡(1.67g,6.40mmol),保温反应1.5h。TLC(V二氯甲烷:V甲醇=15:1)监测反应结束后,反应液倒入饱和碳酸氢钠溶液(50mL)中。用乙酸乙酯(20mL×3)萃取,收集有机相,饱和氯化钠溶液(10mL×3)洗涤。无水硫酸钠干燥,过滤、浓缩并经快速制备色谱纯化(20g,V二氯甲烷:V甲醇=50:1)得到1.88g白色固体中间体5,收率98.5%。
步骤5 9’-(己氧基)-3a’,4’-二氢-1’H,3’H-螺[氧杂环丁烷-3,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8’,10’-二酮(6)的合成
向50mL单口瓶中依次加入中间体5(1.80g,3.77mmol)、四氢呋喃(1.6mL)、吗啉(8mL)和四三苯基膦钯(348mg,3.02mmol),氮气保护下,室温反应1h。TLC(V二氯甲烷:V甲醇=10:1)监测反应结束后,加入异丙醚(30mL),过滤,得到1.17g白色固体中间体6,收率89.0%。
1H NMR(600MHz,CDCl3)δ(ppm):7.41(d,J=7.7Hz,1H,CH=CH),6.24(d,J=7.7Hz,1H,CH=CH),6.09(d,J=13.2Hz,1H,NH),4.82-4.78(m,1H,NHCH),4.76-4.74(m,1H,OCH2),4.71-4.70(m,1H,OCH2),4.60-4.59(m,1H,OCH2CH2),4.55-4.54(m,1H,OCH2CH2),4.28-4.24(m,1H,NCH2),3.92-3.88(m,1H,NCH2),3.75(d,J=12.5Hz,1H,CHCH2),3.50(d,J=12.5Hz,1H,CHCH2),2.74-2.71(m,1H,CH2),2.15-2.12(m,1H,CH2),1.73-1.68(m,2H,CH2),1.40-1.35(m,2H,CH2),1.32-1.28(m,4H,CH2),0.88(t,J=7.1Hz,3H,CH3).
步骤6 4’-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-9’-(己氧基)-3a’,4’-二氢-1’H,3’H-螺[辛烷-3,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪-8’,10’-二酮甲磺酸盐(8)的合成
向100mL单口瓶中依次加入中间体6(1.00g,2.88mmol)、乙酸乙酯(20mL)、7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-醇(989mg,3.74mmol)、丙基磷酸酐(50wt%乙酸乙酯溶液,2.75g,4.32mmol)和甲磺酸(554mg,5.76mmol),氮气保护下,60℃反应1.5h。TLC(V二氯甲烷:V甲醇=15:1)监测反应结束后,反应液冷却至室温。用水(10mL×3)洗涤,收集有机相。无水硫酸钠干燥,过滤,浓缩并经快速制备色谱纯化(80g,V二氯甲烷:V甲醇=20:1)得到529mg白色固体中间体8,收率19.0%.
1H NMR(600MHz,CDCl3)δ(ppm):7.43(d,J=7.7Hz,1H,ArH),7.39-7.29(m,1H,ArH),7.12-7.11(m,2H,ArH,CH=CH),7.10-7.04(m,2H,ArH),7.03-7.00(m,1H,ArH),6.19(d,J=7.8Hz,1H,CH=CH),6.11-6.09(m,1H,CH),5.00-4.95(m,1H,CH),4.34-4.30(m,1H,CH2),4.24-4.16(m,2H,CH2),3.94-3.89(m,1H,CH2),3.64-3.58(m,2H,CH2),3.34-3.31(m,1H,CH2),3.23-3.16(m,1H,CH2),3.00-2.96(m,3H,CH3SO3H),2.39-2.34(m,1H,CH2),1.84-1.79(m,1H,CH2),1.75-1.69(m,2H,CH2),1.37-1.34(m,2H,CH2),1.28-1.24(m,5H,CH2),0.87-0.84(m,3H,CH3).
步骤7 4’-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-9’-羟基-3a’,4’-二氢-1’H,3’H-螺[辛烷-3,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪-8’,10’-二酮(实施例11)的合成
向封管中依次加入中间体8(320mg,0.46mmol)、氯化锂(177mg,4.18mmol)和N-甲基吡咯烷酮(1mL),100℃反应20h。TLC(V二氯甲烷:V甲醇=10:1)监测反应结束后,反应液冷却至40℃,依次加入乙腈(0.5mL)和水(8.5mL),降温至30℃搅拌30min。过滤,滤饼以(V乙腈:V乙酸乙酯=1:1,3mL)混合溶剂打浆1h得到70mg白色固体实施例11,收率29.9%。
1H NMR(600MHz,DMSO-d6)δ(ppm):7.48(br,1H,ArH),7.29(br,2H,ArH),7.20(br,1H,ArH),7.10(br,2H,ArH),7.05-6.92(m,1H,ArH),5.71(br,1.5H,CH=CH,CH),4.95(br,1.5H,CH=CH,CH),4.46(br,1H,CH2),3.82(br,2H,CH2),3.53(br,5H,CH2),2.25(br,1H,CH2),1.77(br,1H,CH2).
实施例12
步骤1 2-环丁基乙酸甲酯(2)的合成
向500mL单口瓶中依次加入化合物1(5.00g,71.3mmol)和四氢呋喃(150mL),氮气保护,冰水浴下分批加入60%钠氢(3.71g,92.7mmol),保温1h后滴加磷酸乙酸三甲酯(18.2g,99.9mmol)的四氢呋喃(150mL)溶液,加毕,室温过夜。TLC(V石油醚:V乙酸乙酯=10:1)监测原料反应完全,加水(100mL)淬灭反应,正己烷(150mL×3)萃取,合并有机相,饱和氯化钠溶液(200mL)洗涤,无水硫酸钠干燥,抽滤,浓缩,得到9.00g黄色油状物中间体2,其不经纯化直接用于下一步。
步骤2 2-(1-(硝基甲基)环丁基)乙酸甲酯(3)的合成
向250mL单口瓶中依次加入中间体2(9.00g,71.3mml)、硝基甲烷(90mL)和DBU(10.90g,71.3mmol),氮气保护,室温反应2h。TLC(V石油醚:V乙酸乙酯=10:1)监测原料反应完全,直接浓缩,柱层析纯化(V石油醚:V乙酸乙酯=10:1),得到9.50g黄色油状中间体3,收率71.1%。
1H NMR(600MHz,CDCl3)δ(ppm):(s,2H,CH2NO2),3.69(s,3H,CH3),2.73(s,2H,CH2),2.19-2.06(m,2H,(CH2)3),2.06-1.96(m,4H,(CH2)3).
步骤3 6-氮杂螺环[3,4]辛烷-7-酮(4)的合成
向250mL高压瓶中依次加入中间体3(4.00g,21.4mmol)、甲醇(50mL)、甲醇钠(1.33g,30%wt in MeOH)和雷尼镍(400mg),氢气加压到60psi,60℃反应过夜。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全,冷却至室温,经硅藻土过滤,浓缩,柱层析纯化(V二氯甲烷:V甲醇=40:1),得到2.30g白色固体中间体4,收率86.0%。
1H NMR(600MHz,CDCl3)δ(ppm):6.06(s,1H,NH),3.37(d,J=0.9Hz,2H,CH2),2.38(s,2H,CH2),2.09-2.00(m,4H,(CH2)3),1.94-1.85(m,2H,(CH2)3).
步骤4 7-氧代-6-氮杂螺环[3,4]辛烷-6-羧酸烯丙酯(5)的合成
向100mL单口瓶中依次加入中间体4(1.00g,8.0mmol)和四氢呋喃(20mL),氮气保护,-78℃下滴加n-BuLi(3.2mL,8.0mmol,2.5N四氢呋喃溶液),保温1h,再滴加Alloc-Cl(0.84mL,8.0mmol),加毕,保温反应1h。TLC(V二氯甲烷:V甲醇=20:1)监测原料
反应完全,加入饱和氯化铵溶液(20mL)淬灭反应,乙酸乙酯(30mL×3)萃取,合并有机相,饱和氯化钠溶液(50mL)洗涤,无水硫酸钠干燥,抽滤,浓缩,柱层析纯化(V二氯甲烷:V甲醇=100:1),得到1.55g无色油状中间体6,收率92.7%。
步骤5 7-羟基-6-氮杂螺环[3,4]辛烷-6-羧酸烯丙酯(6)的合成
向100mL单口瓶中依次加入中间体5(1.55g,7.4mmol)和THF(30mL),氮气保护,-78℃下滴加DIBAl-H(9.6mL,9.66mmol,1N四氢呋喃溶液),加毕,保温反应2h。TLC(V二氯甲烷:V甲醇=50:1)监测原料反应完全,加入0.5N稀盐酸(30mL)淬灭反应,乙酸乙酯(30mL×3)萃取,合并有机相,无水硫酸钠干燥,抽滤,浓缩,得到1.50g无色油状中间体6,不经纯化直接用于下一步。
步骤6 7-甲氧基-6-氮杂螺环[3,4]辛烷-6-羧酸烯丙酯7)的合成
向100mL单口瓶中依次加入中间体6(1.50g,7.1mmol)、甲醇(20mL)和对甲苯磺酸一水合物(135mg,0.71mmol),氮气保护,室温反应1h。TLC(V石油醚:V乙酸乙酯=3:1)监测原料反应完全,加入饱和碳酸氢钠溶液(40mL)淬灭反应,乙酸乙酯(40mL×3)萃取,合并有机相,无水硫酸钠干燥,抽滤,浓缩,柱层析纯化(V石油醚:V乙酸乙酯=10:1),得到1.22g无色油状中间体7,收率76.3%。
步骤7 7-((2-(乙氧基羰基)-3-(乙酰氧基)-4-氧代吡啶-1(4H)-基)氨基)-6-氮杂螺环[3.4]辛烷-6-羧酸烯丙酯(8)的合成
向100mL三口瓶中依次加入中间体7(1.20g,5.3mml)、1-氨基-3-(己氧基)-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(1.50g,5.3mmol)和乙腈(30mL),氮气保护,-25℃滴加四氯化锡(1.0mL,8.5mmol),加毕,保温反应2h。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全,加入饱和碳酸氢钠溶液,调节pH至7,二氯甲烷(50mL×3)萃取,合并有机相,饱和氯化钠溶液(50mL)洗涤,无水硫酸钠干燥,抽滤,浓缩,柱层析纯化(V二氯甲烷:V甲醇=50:1),得到2.45g黄色油状中间体8,收率92.4%。
步骤8 8’,10’-二氧代-3a’,4’,8’,10’-四氢-1’H,3’H-螺[环丁烷-1,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-己酸基酯(9)的合成
向100mL单口瓶中依次加入中间体8(2.45g,5.15mmol)、吗啉(20mL)和四三苯基膦钯(300mg,0.26mmol),氮气保护,室温反应1h。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全,加入异丙醚(400mL),有固体析出,抽滤,收集滤饼,得到1.45g白色固体中间体9,收率80.6%。
步骤9 4’-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-8’,10’-二氧代-3a’,4’,8’,10’-四氢-1’H,3’H-螺[环丁烷-1,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-己酸基酯(10)的合成
向50mL单口瓶中依次加入中间体9(500mg,1.45mmol)、乙酸乙酯(20mL)、(S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-醇(574mg,2.17mmol),丙基磷酸酐(50wt%乙酸乙酯溶液,2.76g,4.34mmol)和甲磺酸(278mg,2.89mmol),氮气保护,75℃反应过夜。TLC(V二氯甲烷:V甲醇=15:1)监测原料反应完全,冷却,加乙酸乙酯(50mL)稀释,饱和氯化钠溶液(30mL)洗涤,无水硫酸钠干燥,抽滤,浓缩,柱层析纯化(V二氯甲烷:V甲醇=200:1),得到370mg黄色固体中间体10,收率42.3%。
1H NMR(600MHz,CDCl3)δ(ppm):7.48(d,J=7.8Hz,1H,ArH),7.06-7.00(m,3H,ArH),6.82-6.75(m,3H,ArH),5.84(d,J=7.8Hz,1H,ArH),5.61-5.58(m,1H,CH),5.30-5.26(m,1H,CH),5.08(s,1H,CH2),4.29-4.20(m,2H,CH2),4.10(d,J=13.2Hz,1H,CH2),3.98(d,J=12.0Hz,1H,CH2),3.42(d,J=12.0Hz,1H,CH2),2.03-1.99(m,2H,CH2),1.96-1.84(m,5H,CH2),1.83-1.80(m,1H,CH2),1.73-1.70(m,1H,CH2),1.59-1.55(m,1H,CH2),1.47-1.43(m,2H,CH2),1.38-1.34(m,4H,CH2),0.92-0.89(m,3H,CH3).
步骤10 4’-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-9’-羟基-3a’,4’-二氢-1’H,3’H-螺[环丁烷-1,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8’,10’-二酮(实施例12)的合成
向5mL拇指瓶中依次加入中间体10(280mg,0.47mmol)、N-甲基吡咯烷酮(0.6mL)和氯化锂(181mg,4.26mmol),氮气保护,100℃反应过夜。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,冷却至室温,加水(20mL)淬灭,有固体析出,过滤,收集滤饼,再用甲醇(10mL)打浆,干燥得到100mg白色固体,收率42.6%。
1H NMR(600MHz,DMSO-d6)δ(ppm):7.39-7.25(m,3H,ArH),7.08-6.97(m,2H,ArH),6.95-6.69(m,2H,ArH),5.82-5.70(m,1H,ArH),5.49-5.34(m,1H,CH),5.30-4.92(m,1.7H,CH,CH2),4.21-4.07(m,1H,CH2),3.86-3.74(m,0.8H,CH2),3.48-3.41(m,1.5H,CH2),2.08-1.92(m,2H,CH2),1.88-1.72(m,4H,CH2),1.65-1.54(m,1H,CH2),1.41-1.29(m,1H,CH2).
HRMS(ESI):m/z[M+Na]+C27H23F2N3O3S理论值:530.1326;实测值530.1345.
实施例13-16
SFC分离条件:
分析条件:方法A:仪器:Waters UPC2分析SFC(SFC-H),色谱柱:ChiralPak AD,150×4.6mm I.D.,3μm。流动相:A表示CO2,B表示异丙醇(0.05%DEA)。梯度:B 50%。流速:2.5mL/min。柱压:100bar。柱温:35℃。检测器波长:220nm。方法B:仪器:Waters UPC2分析SFC(SFC-H)。色谱柱:ChiralPak IG,150×4.6mm I.D.,3μm。流动相:A表示CO2,B表示异丙醇(0.05%DEA)。梯度:B 50%。流速:2.5mL/min。柱压:100bar。柱温:35℃。检测器波长:220nm。
制备条件:方法A:仪器:MG□制备SFC(SFC-14)。色谱柱:ChiralPak AD,250×30mm I.D.,10μm。流动相:A表示CO2,B表示异丙醇(0.1%NH3H2O)。梯度:B 45%。流速:80mL/min。柱压:100bar。柱温:38℃。检测器波长:220nm。样品制备方法:将样品溶于混合溶剂(甲醇/二氯甲烷,38ml)。进样方式:每9min进样一次,每次2mL。后处理方法:减压浓缩得所需异构体。方法B:仪器:MG□制备SFC(SFC-14)。色谱柱:ChiralPak IG,250×30mm I.D.,10μm。流动相:A表示CO2,B表示甲醇。梯度:B 50%。流速:80mL/min。柱压:100bar。柱温:38℃。检测器波长:220nm。样品制备方法:将样品溶于混合溶剂(甲醇/二氯甲烷,40ml)。进样方式:每8.3min进样一次,每次4mL。后处理方法:减压浓缩得所需异构体。
实施例2中间体7(1.50g)经SFC拆分得262mg淡黄色固体实施例13,收率17.5%,ee=100%;234mg淡黄色固体实施例14,收率15.6%,ee=100%;260mg淡黄色固体实施例15,收率17.3%,ee=99.98%;237mg淡黄色固体实施例16,收率15.8%,ee=99.94%。
实施例13:1H NMR(600MHz,DMSO-d6)δ(ppm):7.57-7.54(m,2H,ArH),7.39-7.35(m,2H,
ArH),7.33-7.28(m,3H,ArH),7.25-7.17(m,4H,ArH),6.86-6.83(m,1H,ArH),5.75(d,J=7.8Hz,1H,ArH),5.55-5.52(m,1H,CH),5.46-5.43(m,1H,CH),5.22(s,1H,CH2),5.19(s,2H,CH2),4.13(d,J=14.4Hz,1H,CH2),3.69(d,J=12.0Hz,1H,CH2),3.57-3.47(m,2H,CH2),3.35-3.33(m,2H,CH2),3.09(d,J=12.0Hz,1H,CH2),2.03-2.00(m,1H,CH2),1.46-1.39(m,1H,CH2),1.38-1.33(m,1H,CH2),1.04-1.01(m,1H,CH2),1.00-0.95(m,1H,CH2),0.93-0.91(m,1H,CH2).
HRMS(ESI):m/z[M+H]+C35H31F2N3O4S理论值:628.2082;实测值628.2086.
实施例14:1H NMR(600MHz,DMSO-d6)δ(ppm):7.61(d,J=7.8Hz,1H,ArH),7.56-7.53(m,2H,ArH),7.52-7.50(m,1H,ArH),7.39-7.31(m,4H,ArH),7.11-7.08(m,1H,ArH),7.04-7.03(m,1H,ArH),6.89-6.84(m,2H,ArH),5.77(d,J=7.8Hz,1H,ArH),5.72-5.69(m,1H,CH),5.54-5.51(m,1H,CH),5.40(s,1H,CH2),5.12-5.04(m,2H,CH2),4.15(d,J=13.8Hz,1H,CH2),3.85(d,J=12.0Hz,1H,CH2),3.56-3.51(m,2H,CH2),3.48(d,J=12.0Hz,1H,CH2),3.42-3.39(m,2H,CH2),1.99-1.96(m,1H,CH2),1.47-1.43(m,1H,CH2),1.39-1.35(m,1H,CH2),1.33-1.30(m,2H,CH2),1.24-1.20(m,1H,CH2).
HRMS(ESI):m/z[M+H]+C35H31F2N3O4S理论值:628.2082;实测值628.2084.
实施例15:1H NMR(600MHz,DMSO-d6)δ(ppm):7.57-7.54(m,2H,ArH),7.39-7.35(m,2H,ArH),7.34-7.28(m,3H,ArH),7.26-7.16(m,4H,ArH),6.86-6.73(m,1H,ArH),5.75(d,J=7.8Hz,1H,ArH),5.55-5.52(m,1H,CH),5.46-5.43(m,1H,CH),5.22(s,1H,CH2),5.19(s,2H,CH2),4.13(d,J=14.4Hz,1H,CH2),3.69(d,J=12.0Hz,1H,CH2),3.58-3.47(m,2H,CH2),3.35-3.33(m,2H,CH2),3.09(d,J=12.0Hz,1H,CH2),2.03-2.00(m,1H,CH2),1.44-1.39(m,1H,CH2),1.38-1.34(m,1H,CH2),1.04-1.02(m,1H,CH2),0.98-0.94(m,1H,CH2),0.93-0.60(m,1H,CH2).
HRMS(ESI):m/z[M+H]+C35H31F2N3O4S理论值:628.2082;实测值628.2079.
实施例16:1H NMR(600MHz,DMSO-d6)δ(ppm):7.61(d,J=7.8Hz,1H,ArH),7.58-7.54(m,2H,ArH),7.52-7.50(m,1H,ArH),7.39-7.30(m,4H,ArH),7.11-7.08(m,1H,ArH),7.05-7.02(m,1H,ArH),6.0-6.85(m,2H,ArH),5.77(d,J=7.8Hz,1H,ArH),5.72-5.69(m,1H,CH),5.54-5.51(m,1H,CH),5.40(s,1H,CH2),5.11-5.05(m,2H,CH2),4.15(d,J=13.8Hz,1H,CH2),3.85(d,J=12.0Hz,1H,CH2),3.56-3.54(m,2H,CH2),3.48(d,J=12.0Hz,1H,CH2),3.43-3.39(m,2H,CH2),1.99-1.96(m,1H,CH2),1.46-1.43(m,1H,CH2),1.39-1.35(m,1H,CH2),1.33-1.30(m,2H,CH2),1.24-1.21(m,1H,CH2).
HRMS(ESI):m/z[M+H]+C35H31F2N3O4S理论值:628.2082;实测值628.2084.
实施例17-20
向拇指瓶中依次加入实施例13(250mg,0.40mmol)、N,N-二甲基乙酰胺(4mL)和氯化锂(169mg,4.0mmol),氮气保护,80℃反应5h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,反应液冷却至室温,向反应液中加水(10mL)淬灭,过滤,滤饼经快速制备色谱纯化(12g,V二氯甲烷:V甲醇=20:1)得到145mg棕红色固体实施例17,收率67.7%,ee=98.882%。
1H NMR(600MHz,DMSO-d6)δ(ppm):7.63-7.36(m,2H,ArH),7.35-7.25(m,2H,ArH),7.24-7.09(m,3H,ArH),7.09-6.66(m,1H,ArH),5.80-5.46(m,3H,CH,CH2),5.40-5.20(m,1H,CH2),4.22-4.11(m,1H,CH2),3.82-3.80(m,1H,CH2),3.68-3.51(m,2H,CH2),3.24-2.99(m,2H,CH2),2.22-1.95(m,1H,CH2),1.58-1.33(m,2H,CH2),1.29-1.11(m,2H,CH2),1.03-0.89(m,2H,CH2).
实施例18
参考实施例17的制备方法,以实施例14为原料,制得实施例18化合物,127mg棕红色固体,收率64.5%,ee=99.314%;1H NMR(600MHz,DMSO-d6)δ(ppm):7.52-7.48(m,2H,ArH),7.44-7.31(m,2H,ArH),7.10-7.00(m,2H,ArH),6.98-6.85(m,2H,ArH),5.75-5.68(m,1.5H,CH,CH2),5.63-5.58(m,2.5H,CH,CH2),4.24-4.13(m,1H,CH2),3.92-3.88(m,1H,CH2),3.57-3.46(m,4H,CH2),2.07-1.93(m,1H,CH2),1.53-1.31(m,4H,CH2),1.25-1.21(m,2H,CH2).
实施例19
参考实施例17的制备方法,以实施例15为原料,制得实施例19化合物,130mg棕红色固体,收率60.7%,ee=100%;1H NMR(600MHz,DMSO-d6)δ(ppm):7.63-7.37(m,2H,ArH),7.37-7.13(m,5H,ArH),7.13-6.75(m,1H,ArH),5.80-5.52(m,3H,CH,CH2),5.50-5.40(m,1H,CH2),
4.18-4.11(m,1H,CH2),3.83-3.80(m,1H,CH2),3.65-3.52(m,3H,CH2),3.16-3.06(m,1H,CH2),2.13-1.90(m,1H,CH2),1.56-1.33(m,2H,CH2),1.27-1.16(m,1H,CH2),1.06-0.79(m,3H,CH2).
实施例20
参考实施例17的制备方法,以实施例16为原料,制得实施例20化合物,130mg棕红色固体,收率66.0%,ee=100%。1H NMR(600MHz,DMSO-d6)δ(ppm):7.52-7.48(m,2H,ArH),7.40-7.30(m,2H,ArH),7.10-7.01(m,2H,ArH),6.97-6.80(m,2H,ArH),5.76-5.68(m,1.5H,CH,CH2),5.65-5.56(m,2.5H,CH,CH2),4.21-4.14(m,1H,CH2),3.90-3.88(m,1H,CH2),3.58-3.48(m,4H,CH2),2.00-1.95(m,1H,CH2),1.53-1.40(m,2H,CH2),1.37-1.30(m,2H,CH2),1.26-1.20(m,2H,CH2)
称取实施例20化合物样品10mg,溶于1.0ml甲醇中,室温挥发溶剂得到无色块状晶体,即实施例20化合物单晶。实施例20化合物的单晶结构分析结果如下所示。
表1.晶体学数据
表2.原子坐标(x 104)与等价各向同性位移参数
图1和图2分别示出了实施例20化合物的单晶结构图和单晶堆积图。
实施例21-24
SFC分离条件:分析条件:方法A:仪器:Waters UPC2分析SFC(SFC-H)。色谱柱:ChiralCel OJ,150×4.6mm I.D.,3μm。流动相:A表示CO2,B表示异丙醇(0.05%DEA)。梯度:B 40%。流速:2.5mL/min。柱压:100bar。柱温:35□。检测器波长:220nm。方法B:仪器:Waters UPC2分析SFC(SFC-H)。色谱柱:ChiralPak AS,150×4.6mm I.D.,3μm。流动相:A表示CO2,B表示异丙醇(0.05%DEA)。梯度:B 40%。流速:2.5mL/min。柱压:100bar。柱温:35□。检测器波长:220nm。
制备条件:方法A:仪器:MG□制备SFC(SFC-14)。色谱柱:ChiralCel OJ,250×30mm I.D.,10μm。流动相:A表示CO2,B表示异丙醇(0.1%NH3H2O)。梯度:B 30%。流速:70
mL/min。柱压:100bar。柱温:38□。检测器波长:220nm。样品制备方法:将样品溶于混合溶剂(甲醇/二氯甲烷,60ml)。进样方式:每23min进样一次,每次2mL。后处理方法:减压浓缩得所需异构体。方法B:仪器:MG□制备SFC(SFC-14)。色谱柱:ChiralPak AS,250×30mm I.D.,10μm。流动相:A表示CO2,B表示甲醇。梯度:B 10%。流速:60mL/min。柱压:100bar。柱温:38□。检测器波长:220nm。样品制备方法:将样品溶于混合溶剂(甲醇/二氯甲烷,15ml)。进样方式:每20min进样一次,每次4mL。后处理方法:减压浓缩得所需异构体
实施例3中间体化合物(1.40g,1.84mmol)经SFC拆分得270mg淡黄色固体实施例21,收率19%,ee>99%;230mg淡黄色固体实施例22,收率16%,ee>99%;260mg淡黄色固体实施例23,收率19%,ee=98.8%;230mg淡黄色固体实施例24,收率16%,ee=98.8%;
实施例25-28
向拇指瓶中依次加入实施例21(100mg,0.13mmol)、N,N-二甲基乙酰胺(3mL)和氯化锂(28mg,0.66mmol),氮气保护下,80℃反应5h。TLC(V二氯甲烷:V甲醇=10:1)监测反应结束后,反应液冷却至室温,向反应液中加水(10mL)淬灭,过滤,滤饼经快速制备色谱纯化(12g,V二
氯甲烷:V甲醇=20:1)得到60mg棕红色固体实施例25,收率69%。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.81-7.51(m,1H,ArH),7.52-7.41(m,1H,ArH),7.41-7.35(m,1.5H,ArH),7.34-7.29(m,1H,ArH),7.28-7.22(m,1H,ArH),7.17-7.02(m,1.5H,ArH),7.00-6.87(m,0.5H,ArH),6.85-6.70(m,1H,ArH),5.84-5.66(m,1H,SCH2),5.65-5.55(m,1H,SCH2),5.54-5.40(m,1H,NCH),5.39-5.23(m,1H,NCH),5.07-4.93(m,2H,OCH2),4.26-4.03(m,1H,NCH2),3.93-3.69(m,1H,NCH2),3.64-3.48(m,1H,NCH2),3.47-3.34(m,2H,NCH2),3.23-3.06(m,1H,NCH2),2.19-1.94(m,1H,CH2),1.53-1.29(m,3H,CH3),1.17-0.78(m,2H,CH2).
实施例26
参考实施例25的制备方法,以实施例22为原料,得到135mg棕红色固体,收率100%。
1H NMR(600MHz,DMSO-d6)δ(ppm):7.85-7.48(m,1H,ArH),7.47-7.40(m,1H,ArH),7.39-7.35(m,1H,ArH),7.34-7.27(m,5H,ArH),7.26-7.19(m,1.5H,ArH),7.16-7.01(m,1H,ArH),7.00-6.88(m,1.5H,ArH),6.87-6.71(m,1H,ArH),5.92-5.63(m,1H,SCH2),5.63-5.51(m,1H,SCH2),5.51-5.34(m,1H,NCH),5.34-5.25(m,1H,NCH),5.05-4.92(m,1H,OCH2),4.24-4.02(m,1H,NCH2),3.94-3.65(m,1H,NCH2),3.64-3.39(m,3H,NCH2),3.18-3.12(m,1H,NCH2),2.15-1.83(m,1H,CH2),1.54-1.23(m,3H,CH2),1.21-0.84(m,2H,CH2).
实施例27
参考实施例25的制备方法,以实施例23为原料,得到106mg棕红色固体,收率79%。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.53-7.36(m,1H,ArH),7.36-7.32(m,2H,ArH),7.32-7.25(m,5H,ArH),7.25-7.20(m,2H,ArH),7.20-6.97(m,2H,ArH),6.96-6.44(m,1H,ArH),5.83-5.62(m,1H,SCH2),5.61-5.51(m,1H,SCH2),5.51-5.24(m,1H,NCH),5.24-5.06(m,1H,NCH),5.05-4.92(m,2H,OCH2),4.20-4.10(m,1H,NCH2),4.09-3.93(m,1H,NCH2),3.85-3.50(m,1H,NCH2),3.45-3.35(m,2H,NCH2),3.15-3.09(m,1H,NCH2),2.18-1.87(m,1H,CH2),1.58-1.23(m,3H,CH2),1.02-0.77(m,2H,CH2).
实施例28
参考实施例25的制备方法,以实施例24为原料,得到100mg棕红色固体,收率75%。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.60-7.36(m,1H,ArH),7.36-7.31(m,2H,ArH),7.31-7.26(m,5H,ArH),7.25-7.18(m,2H,ArH),7.18-6.89(m,2H,ArH),6.88-6.37(m,1H,ArH),5.84-5.62(m,1H,SCH2),5.61-5.52(m,1H,SCH2),5.51-5.25(m,1H,NCH),5.24-5.04(m,1H,NCH),5.05-4.92(m,2H,OCH2),4.25-3.96(m,1H,NCH2),3.91-3.52(m,1H,NCH2),3.46-3.36(m,1H,NCH2),3.22-2.87(m,3H,NCH2),2.30-1.76(m,1H,CH2),1.62-1.31(m,2H,CH2),1.13-0.73(m,3H,CH2)
实施例29(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-8’,10’-二氧代-2,3,3a’,4’,5,6,8’,10’-八氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-基)氧基)甲基(叔丁氧羰基)-L-缬氨酸酯的合成
步骤1氯甲基(叔丁氧羰基)-L-缬氨酸(2)的合成
向100mL单口瓶中依次加入化合物1(2.0g,9.21mmol)、碳酸氢钠(3.09g,36.84mmol)、四丁基硫酸氢铵(312mg,0.92mmol)、二氯甲烷(20mL)和水(20mL),加毕,室温搅拌10min后加入氯甲基氯磺酸酯(1.82g,11.05mmol),加毕,室温反应过夜。TLC(V石油醚:V乙酸乙酯=10:1)监测原料反应完全。分液,水相用二氯甲烷(50mL×3)萃取,合并有机相,用饱和食盐水洗涤(200mL)洗涤,无水硫酸钠干燥,过滤,浓缩,并经快速制备色谱纯化(20g,V石油醚:V乙酸乙酯=10:1)得到1.95g无色油状物中间体2,收率79.7%。
1H NMR(600MHz,CDCl3)δ(ppm):5.87(d,J=6.1Hz,1H,CH2Cl),5.62(d,J=6.1Hz,1H,CH2Cl),4.97(d,J=9.0Hz,1H,NH),4.27(dd,J1=9.0Hz,J2=4.9Hz,1H,NHCH),2.23-2.13(m,1H,CH(CH3)2),1.45(s,9H,C(CH3)3),1.00(d,J=6.8Hz,3H,CH3),0.92(d,J=6.9Hz,3H,CH3).
步骤2碘甲基(叔丁氧羰基)-L-缬氨酸(3)的合成
向Schlenk反应管中加入中间体2(500mg,1.88mmol)、碘化钠(1.41g,9.41mmol)和丙酮(5mL),加毕,60℃避光反应2h。TLC(V石油醚:V乙酸乙酯=10:1)监测原料反应完全。反应液经硅藻土过滤,滤液浓缩,残渣加入乙酸乙酯(20mL)溶解,依次用饱和硫代硫酸钠水溶液(50mL)和饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,浓缩,得到600mg黄色油状物中间体3粗品,直接进行下一步反应。
1H NMR(600MHz,DMSO-d6)δ(ppm):6.86(d,J=8.5Hz,1H,NH),4.63(d,J=6.2Hz,1H,CH2I),3.76-3.71(m,1H,CH2I),1.99-1.91(m,1H,CH(CH3)2),1.34(s,9H,C(CH3)3),0.85-0.79(m,6H,CH(CH3)2).
步骤3(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-8’,10’-二氧代-2,3,3a’,4’,5,6,8’,10’-八氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-基)氧基)甲基(叔丁氧羰基)-L-缬氨酸酯(实施例29)的合成
向拇指瓶中加入实施例20(140mg,0.26mmol)、中间体3(279mg,0.78mmol)、碳酸铯(254mg,0.78mmol)和乙腈(5mL),加毕,氮气保护80℃反应过夜。TLC(V二氯甲烷:V甲醇=10:1)监测原料大量剩余。反应液经硅藻土过滤,滤液浓缩并经快速制备色谱纯化(4g,V二氯甲烷:V甲醇=10:1)得到30mg黄色固体,收率15.0%。
1H NMR(600MHz,DMSO-d6)δ(ppm):7.57(d,J=7.8Hz,1H,ArH),7.43(dd,J1=8.9Hz,J2=4.6Hz,1H,ArH),7.34-7.27(m,1H,ArH),7.08-7.03(m,1H,ArH),7.02-6.97(m,2H,ArH),6.89-6.84(m,1H,ArH),6.84-6.79(m,1H,ArH),5.75(d,J=7.8Hz,1H,NH),5.71-5.66(m,2H,SCH2),5.66-5.61(m,1H,NHCH),5.52(dd,J1=10.3Hz,J2=6.8Hz,1H,NCH),5.31(s,1H,NCH),4.12(d,J=13.9Hz,1H,OCH2),3.97(dd,J1=8.8Hz,J2=5.4Hz,1H,OCH2),3.84(d,J=11.9Hz,1H,NCH2),3.55-3.49(m,2H,OCH2),3.40(d,J=11.9Hz,1H,NCH2),3.38-3.34(m,2H,OCH2),2.07-2.00(m,1H,CH2),1.99-1.94(m,1H,CH2),1.47-1.38(m,1H,CH2),1.37-1.33(m,1H,CH2),1.31(s,9H,C(CH3)3),1.30-1.25(m,2H,CH2),1.22-1.13(m,1H,CH(CH3)),0.82(d,J=6.9Hz,3H,CH(CH3)),0.76(d,J=6.9Hz,3H,CH(CH3)).
实施例30(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-8’,10’-二氧代-2,3,3a’,4’,5,6,8’,10’-八氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-基)氧基)甲基碳酸甲酯的合成
向25mL单口瓶中依次加入化合物实施例20(P4)(130mg,0.24mmol)、乙腈(4mL)、碳酸钾(67mg,0.48mmol)、氯甲基碳酸二甲酯(45mg,0.36mmol)和碘化钾(40
mg,0.24mmol),氮气保护,80℃反应6h。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全,冷却至室温,经硅藻土过滤,浓缩,柱层析纯化(V二氯甲烷:V甲醇=50:1),得到45mg白色固体实施例30,收率30.9%。
1H NMR(600MHz,DMSO-d6)δ(ppm):7.64(d,J=7.8Hz,1H,ArH),7.54-7.49(m,1H,ArH),7.36-7.31(m,1H,ArH),7.12-7.09(m,1H,ArH),7.06-7.01(m,1H,ArH),6.92-6.86(m,2H,ArH),5.82(d,J=7.8Hz,1H,ArH),5.73-5.67(m,2H,CH2),5.61-5.59(m,1H,CH),5.55(d,J=6.8Hz,1H,CH),5.37(s,1H,CH2),4.16(d,J=13.8Hz,1H,CH2),3.81(d,J=12.0Hz,1H,CH2),3.76(s,3H,CH3),3.57-3.51(m,2H,CH2),3.49(d,J=12.0Hz,1H,CH2),3.41(t,J=5.4Hz,2H,CH2),2.01-1.97(m,1H,CH2),1.49-1.38(m,2H,CH2),1.36-1.30(m,2H,CH2),1.25-1.21(m,1H,CH2).
HRMS(ESI):m/z[M+H]+C31H29F2N3O7S理论值:626.1773;实测值:626.1766.
实施例31(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-8’,10’-二氧代-2,3,3a’,4’,5,6,8’,10’-八氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-基)氧基)丁酸甲酯的合成
向50mL单口瓶中加入化合物实施例20(P4)((100mg,0.19mmol)、溴丁酸甲酯(51mg,0.28mmol)、碳酸铯(309mg,0.95mmol)、碘化钾(32mg,0.19mmol)和DMF(4mL),氮气保护,100℃反应过夜。TLC(V二氯甲烷:V甲醇=10:1)监测反应完全,反应液加入水(20mL)淬灭,乙酸乙酯(20mL×3)萃取,合并有机相,饱和食盐水(30mL×3)洗涤,无水硫酸钠干燥,过滤,浓缩,快速制备色谱(V二氯甲烷:V甲醇=20:1)纯化,得到80mg红棕色固体实施例31,收率67.2%。
1H NMR(600MHz,DMSO-d6)δ(ppm):7.61(d,J=7.8Hz,1H,ArH),7.53-7.51(m,1H,ArH),7.36-7.33(m,1H,ArH),7.11-7.08(m,1H,ArH),7.04-7.02(m,1H,ArH),6.89-6.86(m,2H,ArH),5.72-5.70(m,2H,ArH,CH2),5.61-5.58(m,1H,CH2),5.40(s,1H,CH),4.16(d,J=14.4Hz,1H,CH2),4.05(t,J=6.0Hz,2H,CH2),3.86(d,J=12.0Hz,1H,CH2),3.62(s,3H,CH3),3.54(t,J=5.4Hz,2H,CH2),3.50(d,J=12.0Hz,1H,CH2),3.41(t,J=5.4Hz,2H,CH2),2.58(t,J=7.2Hz,2H,
CH2),2.00-1.96(m,1H,CH2),1.95-1.87(m,2H,CH2),1.50-1.46(m,1H,CH2CH3),1.41-1.38(m,1H,CH2CH2),1.36-1.32(m,2H,CH2CH2),1.22-1.20(m,1H,CH2).
实施例32(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-8’,10’-二氧代-2,3,3a’,4’,5,6,8’,10’-八氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-基)氧基)丁酸的合成
向50mL单口瓶中加入化合物实施例31(80mg,0.13mmol)、氢氧化锂一水合物(11mg,0.25mmol)、甲醇(4mL)和水(0.8mL),氮气保护,室温反应过夜。TLC(V二氯甲烷:V甲醇=20:1)监测反应完全,反应液浓缩去除甲醇,水相用乙酸乙酯(2mL×3)洗涤,1N盐酸调节pH至5,析出固体,过滤,水洗(1mL×3),室温真空干燥3h,得到55mg类白色固体实施例32,收率70.3%。
1H NMR(600MHz,DMSO-d6)δ(ppm):11.99(s,1H,COOH),7.57(d,J=7.8Hz,1H,ArH),7.49-7.46(m,1H,ArH),7.32-7.27(m,1H,ArH),7.07-7.04(m,1H,ArH),6.99-6.98(m,1H,ArH),6.85-6.83(m,2H,ArH),5.68-5.66(m,2H,ArH,CH2),5.57-5.54(m,1H,CH2),5.36(s,1H,CH),4.12(d,J=13.8Hz,1H,CH2),4.01(t,J=6.6Hz,2H,CH2),3.83(d,J=12.0Hz,1H,CH2),3.51(d,J=4.8Hz,2H,CH2),3.46(d,J=12.0Hz,1H,CH2),3.36(t,J=4.8Hz,2H,CH2),2.44-2.42(m,2H,CH2),1.96-1.92(m,1H,CH2),1.90-1.80(m,2H,CH2),1.45-1.43(m,1H,CH2CH3),1.37-1.28(m,3H,CH2CH2),1.19-1.15(m,1H,CH2CH2).
实施例33(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-8’,10’-二氧代-2,3,3a’,4’,5,6,8’,10’-八氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-基)氧基)丁酸钠的合成
向25mL单口瓶中加入化合物实施例32(32mg,0.05mmol)和甲醇(1mL),再加入氢氧化钠(2mg,0.05mmol)的水(0.1mL)溶液,氮气保护,室温反应1h。反应液浓缩干,甲醇带蒸(1mL),室温真空干燥4h,得到33mg黄棕色固体实施例33,收率100%。
1H NMR(600MHz,DMSO-d6)δ(ppm):7.54(d,J=7.8Hz,1H,ArH),7.48-7.46(m,1H,ArH),7.31-7.27(m,1H,ArH),7.06-7.03(m,1H,ArH),6.99-6.97(m,1H,ArH),6.91-6.88(m,1H,ArH),6.86-6.84(m,1H,ArH),5.68-5.64(m,2H,ArH,CH2),5.56(dd,J1=10.2Hz,J2=7.2Hz,1H,CH2),5.35(s,1H,CH),4.12(d,J=14.4Hz,1H,CH2),3.95(t,J=6.6Hz,2H,CH2),3.84(d,J=12.0Hz,1H,CH2),3.50(d,J=6.0Hz,2H,CH2),3.45(d,J=12.0Hz,1H,CH2),3.36-3.35(m,2H,CH2),1.95-1.90(m,3H,CH2,CH2),1.85-1.76(m,2H,CH2),1.46-1.42(m,1H,CH2),1.37-1.32(m,1H,CH2CH3),1.30-1.27(m,2H,CH2CH2),1.19-1.14(m,1H,CH2CH2).
实施例34(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-8’,10’-二氧代-2,3,3a’,4’,5,6,8’,10’-八氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-基)氧基)甲基2-吗啉代乙酸酯的合成
步骤1(((R)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-9'-氯甲基氧基-2,3,3a',4',5,6-六氢-1'H,3'H-氮杂螺环[吡喃-4,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮(2)的合成
向50mL单口瓶中依次加入实施例20(500mg,0.93mmol)、DCM(10mL)、四丁基硫酸氢铵(32mg,0.09mmol)、水(10mL)和碳酸氢钠(313mg,3.72mmol),室温搅拌
20min后滴加氯甲基氯磺酸酯(307mg,1.86mmol)在氮气氛围下室温搅拌过夜。TLC(V二
氯甲烷:V甲醇=10:1)监测原料反应完全,加水(20mL)淬灭,二氯甲烷(30mL×3)萃取,饱和食盐水(10mL×3)洗涤,干燥,过滤,浓缩并经快速制备色谱纯化(24g,V二氯甲烷:V甲醇=20:1),得到240mg白色固体中间体2,收率44.1%。
HRMS(ESI):m/z[M+H]+C29H26ClF2N3O4S理论值:586.1374;实测值:586.1388.
步骤2(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-8’,10’-二氧代-2,3,3a’,4’,5,6,8’,10’-八氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-基)氧基)甲基2-吗啉代乙酸酯(实施例34)的合成
向10mL拇指瓶中依次加入中间体2(120mg,0.21mmol)、DMF(2mL)、碳酸钾(58mg,0.42mmol)和吗啉-4-基乙酸(53mg,0.32mmol),在氮气氛围下室温搅拌3h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,加水(10mL)淬灭,二氯甲烷(20mL×3)萃取,饱和食盐水(10mL×3)洗涤,干燥,过滤,浓缩并经快速制备色谱纯化(12g,V二氯甲烷:V甲醇=20:1),得到得到粗品,粗品再用低沸点石油醚(10mL)室温打浆3h后,过滤,收集滤饼并经真空干燥箱42℃烘干过夜得到75mg粉红色固体实施例34,收率51.4%。
HRMS(ESI):m/z[M+H]+C35H36F2N4O7S理论值:695.2346;实测值:695.2355
实施例35(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-8’,10’-二氧代-2,3,3a’,4’,5,6,8’,10’-八氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-基)氧基)甲基-2-(4-甲基哌嗪-1-基)乙酸酯的合成
向10mL拇指瓶中依次加入化合物2(120mg,0.21mmol)、DMF(2mL)、碳酸钾(58mg,0.42mmol)和4-甲基-1-哌嗪乙酸(60mg,0.32mmol),在氮气氛围下室温搅拌3h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,加水(10mL)淬灭,二氯甲烷(20mL×3)萃取,饱和食盐水(10mL×3)洗涤,干燥,过滤,浓缩并经快速制备色谱纯化(12g,V二氯甲
烷:V甲醇=20:1),得到得到粗品,粗品再用低沸点石油醚(10mL)室温打浆3h后,过滤,收集滤饼并经真空干燥箱42℃烘干过夜得到70mg粉红色固体实施例35,收率47.1%。
HRMS(ESI):m/z[M+H]+C36H39F2N5O6S理论值:708.2662;实测值:708.2654.
实施例36(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-8’,10’-二氧代-2,3,3a’,4’,5,6,8’,10’-八氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-基)氧基)甲基吗啉-4-羧酸酯的合成
向25mL单口瓶中加入实施例20(100mg,0.20mmol)、氯甲基吗啉-4-羧酸酯(42.0mg,0.24mmol)、碳酸钾(60mg,0.40mmol)、碘化钾(40.0mg,0.20mmol)和N,N-二甲基甲酰胺(4mL),加毕,氮气保护65℃反应过夜。TLC(V二氯甲烷:V甲醇=20:1)监测原料剩余50%。反应液冷却至室温,水(20mL)淬灭反应,反应体系用二氯甲烷(30mL×3)萃取,收集有机相。饱和氯化钠溶液(50mL×3)洗涤,经无水硫酸钠干燥,过滤,浓缩并经快速制备色谱纯化(4g,V二氯甲烷:V甲醇=10:1)得到44mg黄色固体实施例36,收率32.3%。
1H NMR(600MHz,CDCl3)δ(ppm):7.41(d,J=7.8Hz,1H,CH=CH),7.07-7.01(m,3H,ArH),
6.89-6.82(m,2H,ArH),6.78(d,J=7.7Hz,1H,ArH),5.97(d,J=6.3Hz,1H,CH=CH),5.87-5.80(m,2H,CH2),5.53(d,J=11.1Hz,1H,CH2),5.41-5.38(m,1H,CH),5.02(s,1H,CH),4.11-4.07(m,1H,CH2),4.03(d,J=11.9Hz,1H,CH2),3.74-3.70(m,4H,CH2CH2),3.70-3.66(m,1H,CH2),3.59-3.579(m,4H,CH2),3.56-3.52(m,2H,CH2),3.48-3.43(m,1H,CH2),3.26(d,J=11.9Hz,1H,CH2),1.93-1.88(m,1H,CH2),1.48-1.44(m,3H,CH2CH2),1.38-1.34(m,1H,CH2),1.32-1.30(m,1H,CH2).
HRMS(ESI):m/z[M+Na]+C34H34F2N4O7S理论值:703.2014;实测值:703.1985.
实施例37(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-8’,10’-二氧代-2,3,3a’,4’,5,6,8’,10’-八氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-基)氧基)甲基甲基氨基甲酸酯的合成
步骤1甲基氨基甲酸氯甲酯(2)的合成
向100mL三口瓶中依次加入化合物1(2.15g,16.7mmol)和二氯甲烷(20mL),氮气保护,-30℃下滴加甲胺溶液(3.14g,33.3mmol,33wt%乙醇溶液),加毕缓慢升至室温反应2h。TLC(V石油醚:V乙酸乙酯=3:1)监测原料反应完全,冷却至室温,加水(30mL)淬灭反应,二氯甲烷(20mL×3)萃取,合并有机相,饱和氯化钠溶液(30mL)洗涤,无水硫酸钠干燥,浓缩,得到1.60g黄色油状物2,未经纯化直接用于下一步。
步骤2(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-8’,10’-二氧代-2,3,3a’,4’,5,6,8’,10’-八氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-基)氧基)甲基甲基氨基甲酸酯的合成
向25mL单口瓶中依次加入实施例20化合物(200mg,0.37mmol)、乙腈(4mL)、碳酸钾(103mg,0.74mmol)、中间体2(55mg,0.44mmol)、碘化钾(62mg,0.37mmol),氮气保护,80℃反应6h。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全,冷却至室温,经
硅藻土过滤,浓缩,柱层析纯化(V二氯甲烷:V甲醇=50:1),得到50mg白色固体实施例37,收率21.5%。
HRMS(ESI):m/z[M+H]+C31H30F2N4O6S理论值:625.1932;实测值:625.1344.
实施例38(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-8’,10’-二氧代-2,3,3a’,4’,5,6,8’,10’-八氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-基)氧基)甲基氨基甲酸甲酯的合成
步骤1(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-9'-叠氮基甲氧基-2,3,3a',4',5,6-六氢-1'H,3'H-氮杂螺环[吡喃-4,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮的合成
向25mL单口瓶中依次加入实施例34中间体2(500mg,0.85mmol)和N,N-二甲基甲酰胺(5mL),缓慢滴加叠氮化钠(83mg,1.28mmol)的水溶液(2mL),氮气保护下,室温反应过夜。TLC(V二氯甲烷:V甲醇=10:1)监测反应结束后,饱和碳酸氢钠溶液(3ml)淬灭反应,用二氯甲烷(5mL×3)萃取,收集有机相。饱和氯化钠溶液(4mL×3)洗涤,无水硫酸钠干燥,过滤、浓缩并经快速制备色谱纯化(4g,V二氯甲烷:V甲醇=10:1)得到176mg白色固体,收率35.0%。
步骤2(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-9'-氨基甲氧基-2,3,3a',4',5,6-六氢-1'H,3'H-氮杂螺环[吡喃-4,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-8',10'-二酮的合成
向25mL单口瓶中依次加入化合物2(160mg,0.27mmol)、四氢呋喃(4mL)、水(0.4
mL)和三苯基膦(106mg,0.41mmol),氮气保护下,室温反应过夜。TLC(V二氯甲烷:V甲醇=10:1)监测反应结束后,用水(5ml)淬灭反应,二氯甲烷(5mL×3)萃取,收集有机相。饱和氯化钠溶液(4mL×3)洗涤,无水硫酸钠干燥,过滤、浓缩并经快速制备色谱纯化(4g,V二
氯甲烷:V甲醇=10:1)得到105mg白色固体,收率68.6%。
步骤3(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-8’,10’-二氧代-2,3,3a’,4’,5,6,8’,10’-八氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-基)氧基)甲基氨基甲酸甲酯的合成
向25mL单口瓶中依次加入化合物3(100mg,0.18mmol)、N,N-二甲基甲酰胺(1mL)、氯甲酸甲酯(20mg,0.21mmol)和N,N-二异丙基乙胺(35mg,0.27mmol),氮气保护下,室温反应2h。TLC(V二氯甲烷:V甲醇=10:1)监测反应结束后,用水(4ml)淬灭反应,二氯甲烷(5mL×3)萃取,收集有机相。饱和氯化钠溶液(5mL×3)洗涤,无水硫酸钠干燥,过滤、浓缩并经快速制备色谱纯化(4g,V二氯甲烷:V甲醇=10:1)得到80mg白色固体,收率71.4%。
HRMS(ESI):m/z[M+H]+C31H30F2N4O6S3理论值:625.1932;实测值:625.1922.
实施例39(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-8’,10’-二氧代-2,3,3a’,4’,5,6,8’,10’-八氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-基)氧基)甲基(S)-2-((S)-2,6-二氨基己酰基)氨基-3,3-二甲基丁酸酯的合成
步骤1(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-8’,10’-二氧代-2,3,3a’,4’,5,6,8’,10’-八氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-基)氧基)甲基(S)-2-叔丁氧羰基氨基-3,3-二甲基丁酸酯(2)的合成
实施例34中间体2瓶中依次加入实施例34中间体2(500mg,0.85mmol)、DMF(10mL)、碳酸钾(236mg,1.71mmol)和N-Boc-L-叔亮氨酸(295mg,1.28mmol),在氮气氛围下室温搅拌3h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,加水(20mL)淬灭,二氯甲烷(35mL×3)萃取,饱和食盐水(20mL×3)洗涤,干燥,过滤,浓缩并经快速制备色谱纯化(24g,V二氯甲烷:V甲醇=20:1),得到500mg白色固体,收率75.4%。
步骤2(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-8’,10’-二氧代-2,3,3a’,4’,5,6,8’,10’-八氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-基)氧基)甲基(S)-2-氨基-3,3-二甲基丁酸酯盐酸盐(3)的合成
向25mL单口瓶中依次加入化合物2(500mg,0.64mmol)、乙酸乙酯(5mL)和4N HCl/乙酸乙酯(5mL),氮气保护,室温反应2h。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全。直接浓缩,得到400mg白色固体3,不经纯化直接用于下一步。
步骤3(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-8’,10’-二氧代-2,3,3a’,4’,5,6,8’,10’-八氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-基)氧基)甲基(S)-2-((S)-2,6-二叔丁氧羰基氨基己酰基)氨基-3,3-二甲基丁酸酯(4)的合成
向25mL单口瓶中依次加入化合物3(400mg,0.56mmol)、DMF(8mL)、(S)-2,6-二叔丁氧羰基氨基己酸(291mg,0.84mmol)、HATU(425mg,1.12mmol)和DIPEA(434mg,3.36mmol),氮气保护,室温反应16h。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全。加水(20mL)淬灭,二氯甲烷(40mL×3)萃取,饱和食盐水(20mL×4)洗涤,干燥,过滤,浓缩并经快速制备色谱纯化(24g,V二氯甲烷:V甲醇=20:1),得到380mg白色固体4,两步收率58.8%。
步骤4(((S)-4’-((S)-7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11基)-8’,10’-二氧代-2,3,3a’,4’,5,6,8’,10’-八氢-1’H,3’H-螺[吡喃-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-9’-基)氧基)甲基(S)-2-((S)-2,6-二氨基己酰基)氨基-3,3-二甲基丁酸酯(实施例39)的合成
向25mL单口瓶中依次加入化合物4(380mg,0.38mmol)、乙酸乙酯(5mL)和4N HCl/乙酸乙酯(5mL),氮气保护,室温反应2h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全。加入饱和碳酸氢钠溶液调节pH至8,二氯甲烷(30mL×3)萃取,合并有机相,饱和氯化钠溶液(20mL×3),无水硫酸钠干燥,抽滤,浓缩并经快速制备色谱纯化(24g,V二氯甲烷:V甲醇=10:1),得到150mg白色固体实施例39化合物,两步收率48.8%。
HRMS(ESI):m/z[M+H]+C41H50F2N6O7S理论值:809.3503;实测值:809.3492
实施例40 4'-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-9'-羟基-8',10'-二氧代-3a',4',8',10'-
四氢-1'H,3'H-螺[哌啶-4,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-1-羧酸乙酯的合成
步骤1 2-烯丙基-8-叔丁基-3-氧代-2,8-二氮杂螺[4.5]癸烷-2,8-二羧酸酯(2)的合成
向500mL三口瓶中加入化合物1(15g,58.98mmol)和THF(200mL),氮气保护,降温至-78℃,滴加n-BuLi(41mL,64.88mmol,1.6N己烷溶液),保温反应1h。再滴加烯丙基氯Alloc-Cl(7.82g,64.88mmol),加毕,保温反应1h。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全,低温下加入饱和氯化铵溶液(200mL)淬灭,乙酸乙酯(100mL×3)萃取,合并有机相,饱和食盐水(300mL×2)洗涤,无水硫酸钠干燥,过滤,浓缩,柱层析纯化(V二氯甲烷:V甲醇=50:1),得到19.6g无色透明油状物化合物2,收率98.0%。
步骤2 2-烯丙基-3-氧代-2,8-二氮杂螺[4.5]癸烷-2-羧酸酯三氟乙酸盐(3)的合成
向50mL单口瓶中加入化合物2(2g,5.91mmol)、二氯甲烷(20mL)和三氟乙酸(4mL),氮气保护,室温反应2h。TLC(V石油醚:V乙酸乙酯=1:1)监测原料反应完全,反应液浓缩,甲苯带蒸一次(5mL),得到3.0g黄色油状物化合物3,直接用于下一步。
步骤3 2-烯丙基-8-乙基-3-氧代-2,8-二氮杂螺[4.5]癸烷-2,8-二羧酸酯(4)的合成
向100mL单口瓶中加入化合物3(2.5g,7.43mmol)、二氯甲烷(40mL)、甲醇(4mL)、碳酸钾(3.08g,22.29mmol)和氯甲酸乙酯(1.61g,14.87mmol),氮气保护,室温反应1h。TLC(V石油醚:V乙酸乙酯=1:1)监测原料反应完全,反应液加入水(100mL)淬灭,二氯甲烷(100mL×3)萃取,合并有机相,饱和食盐水(100mL×2)洗涤,无水硫酸钠干燥,过滤,浓缩,快速制备色谱纯化(V二氯甲烷:V甲醇=20:1),得到1.35g无色透明油状物4,收率61.3%。
1H NMR(600MHz,CDCl3)δ(ppm):6.00-5.93(m,1H,CH=CH2),5.44-5.40(m,1H,
CH=CH2),5.31-5.28(m,1H,CH=CH2),4.75-4.73(m,2H,CH2),4.15-4.12(m,2H,CH2CH3),3.63(s,2H,CH2),3.59-3.55(m,2H,CH2CH2),3.39-3.35(m,2H,CH2CH2)2.46(s,2H,CH2),1.63-1.59(m,4H,CH2CH2),1.27(t,J=7.2Hz,3H,CH2CH3)
步骤4 2-烯丙基-8-乙基-3-羟基-2,8-二氮杂螺[4.5]癸烷-2,8-二羧酸酯(5)的合成
向100mL单口瓶中加入化合物4(1.62g,5.47mmol)和THF(20mL),氮气保护,降温至-78℃,滴加DIBAl-H(11mL,10.94mmol,1N己烷溶液),保温反应1h。TLC(V石
油醚:V乙酸乙酯=1:1)监测反应完全,低温下加入饱和酒石酸钾钠(60mL)溶液淬灭,乙酸乙酯(100mL×3)萃取,合并有机相,无水硫酸钠干燥,过滤,浓缩得到2.2g白色泡状固体化合物5,不经纯化直接用于下一步。
步骤5 2-烯丙基-8-乙基-3-甲氧基-2,8-二氮杂螺[4.5]癸烷-2,8-二羧酸酯(6)的合成
向150mL单口瓶中依次加入化合物5(2.2g,5.47mmol)、甲醇(50mL)和对甲苯磺酸一水合物(105mg,0.55mmol),氮气保护,室温反应1h。TLC(V二氯甲烷:V甲醇=30:1)监测原料反应完全,加入饱和碳酸氢钠(100mL)溶液,乙酸乙酯(100mL×3)萃取,合并有机相,饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,浓缩,经快速制备色谱(40g,V石油醚:V乙酸乙酯=3:1)纯化,得到0.69g无色透明油状物6,2步收率40.5%。
步骤6 2-烯丙基-8-乙基-3-((3-(苄氧基)-2-(乙氧基羰基)-4-氧代吡啶-1(4H)-基)氨基)-2,8-二氮杂螺[4.5]癸烷-2,8-二羧酸酯(7)的合成
向100mL三口瓶中依次加入化合物6(690mg,2.21mmol)、1-氨基-3-(苄氧基)-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(637mg,2.21mmol)和乙腈(15mL),氮气保护,降温至-
25℃,滴加SnCl4(921mg,3.54mmol),保温反应2h。TLC(V二氯甲烷:V甲醇=20:1)监测原料反应完全,低温下加入饱和碳酸氢钠溶液(20mL)淬灭反应,二氯甲烷(100mL×3)萃取,合并有机相,饱和食盐水(150mL×2)洗涤,无水硫酸钠干燥,过滤、浓缩,柱层析纯化(V二氯甲烷:V甲醇=50:1),得到360mg黄色固体化合物7,收率28.6%。
步骤7 9’-(苄氧基)-8’,10’-二氧代-3a’,4’,8’,10’-四氢-1’H,3’H-螺[哌啶-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-1-羧酸乙酯(8)的合成
向50mL单口瓶中依次加入化合物7(360mg,0.63mmol)和吗啉(5mL),搅拌溶解,再加入Pd(PPh3)4(37mg,0.03mmol),氮气保护,室温反应1h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,加入异丙醚(100mL),析出固体,过滤,滤饼40℃真空干燥2h,得到322mg棕色固体化合物8,未经纯化直接用于下一步。
步骤8 9’-(苄氧基)-4’-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-8’,10’-二氧代-3a’,4’,8’,10’-四氢-1’H,3’H-螺[哌啶-4,2’-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]-三嗪]-1-羧酸乙酯(9)的合成
向50mL单口瓶中依次加入化合物8(322mg,0.63mmol)、11-氯-7,8-二氟-二氢二苯并[b,e]硫杂(635mg,1.58mmol)、乙腈(10mL)和碳酸铯(821g,2.52mmol),氮气保护,室温反应过夜。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,加水(20mL)淬灭反应,二氯甲烷(50mL×6)萃取,合并有机相,无水硫酸钠干燥,过滤,浓缩,快速制备色谱纯化(12g,V二氯甲烷:V甲醇=100:1),得到152mg黄色固体化合物9,两步收率35.2%。
步骤9 4'-(7,8-二氟-6,11-二氢二苯并[b,e]硫杂-11-基)-9'-羟基-8',10'-二氧代-3a',4',8',10'-四氢
-1'H,3'H-螺[哌啶-4,2'-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪]-1-羧酸乙酯(实施例40)的合成
向25mL单口瓶中依次加入化合物9(150mg,0.21mmol)、DMAc(2mL)和LiCl(90mg,2.1mmol),N2保护,80℃反应5h。TLC(V二氯甲烷:V甲醇=10:1)监测原料反应完全,冷却至室温,制砂,快速制备色谱纯化(12g,V二氯甲烷:V甲醇=10:1),得到75mg粗品,甲醇带蒸(2mL×2),石油醚(5mL)打浆过夜,过滤,40℃鼓风干燥4h,得到48mg黄色固体实施例40,收率36.6%。
1H NMR(600MHz,DMSO-d6)δ(ppm):7.47(br,1H,ArH),7.31(br,2H,ArH),7.21(br,1H,ArH),7.13(br,1H,ArH),7.03(br,1H,ArH),6.84-6.74(m,1H,ArH),5.69-5.62(m,1.4H,ArH,CH2),5.52(br,1.6H,CH2,CH),5.41-5.25(m,0.75H,CH),5.16-5.12(m,0.25H,CH),4.19(t,J=7.2Hz,1H,CH2),3.96(br,2H,CH2CH3),3.44-3.33(m,1H,CH2CH2),3.21-3.05(m,2H,CH2CH2),2.10-2.01(m,1H,CH2),1.41(br,2H,CH2CH2),1.29-1.23(m,1H,CH2CH2),1.22-1.18(m,1H,CH2CH2),,1.15-1.01(m,5H,CH2CH2),0.93-0.88(m,1H,CH2CH2),0.83-0.79(m,1H,CH2CH2).
HRMS(ESI):m/z[M+H]+C31H30F2N4O5S理论值:609.1983;实测值:609.1974
生物活性测试
一、化合物体外抗流感病毒A/WSN/33(H1N1)活性
1.实验材料及方法
阳性对照化合物巴洛沙韦酯由上海药明康德新药开发有限公司提供。化合物用100%DMSO配制成母液,测试8个浓度点,3倍梯度稀释,双复孔。犬肾细胞MDCK购自ATCC,货号CCL-34。细胞使用添加了10%胎牛血清(Hyclone或ExCell Bio),1%双抗(Hyclone),1%L-谷氨酰胺(Gibco)和1%非必需氨基酸(Gibco)的EMEM(Sigma)培养液培养。添加了1%双抗,1%L-谷氨酰胺和1%非必需氨基酸的OptiPRO SFM(Gibco)培养液为实验用培养液。添加了胰酶(Invitrogen)的实验用培养液为病毒感染培养液。流感病毒A/WSN/33(H1N1)株购自Virapur,货号F1003A。
2.实验步骤
MDCK细胞以每孔2,000个细胞的密度接种到384孔测试板中并于5%CO2、37℃培养箱中培养过夜。第二天,将化合物(8个浓度点、3倍梯度稀释,双复孔)和病毒(MOI=0.03)加入384孔细胞培养板。培养液中DMSO和胰酶的终浓度分别为0.5%和2.5μg/ml。细胞于5%CO2、37℃培养箱中培养5天直至无化合物的病毒对照孔内细胞病变达80-95%。使用Cell counting kit 8试剂盒(上海李记)检测细胞活力。细胞毒性实验与抗病毒实验条件相同,但无病毒感染。化合物的抗病毒活性和细胞毒性分别由不同浓度下的化合物对病毒引起的细胞病变效应的抑制率(%)和MDCK细胞的活率(%)表示。计算公式如下:
抑制率(%)=(测试孔读值-病毒对照平均值)/(细胞对照平均值-病毒对照平均值)×100
细胞活率(%)=(测试孔读值-培养液对照平均值)/(细胞对照平均值-培养液对照平均值)×100
使用GraphPad Prism软件对化合物的抑制率和细胞活率进行非线性拟合分析,计算化合物的半数有效浓度(EC50)和半数细胞毒性浓度(CC50)值。
模式:log(抑制剂)vs.响应-可变斜率
公式:Y=最小响应+(最大响应-最小响应)/(1+10^((LogIC50-X)*曲线坡度))
从表1结果可知,本发明化合物1-28均具有显著的抗流感病毒A/WSN/33(H1N1)活性,化合物的活性优于参考例583化合物,甚至优于阳性化合物巴洛沙韦。CC50代表化合物对细胞的毒性,从表1结果可知,本发明化合物的细胞毒性低,显著低于阳性化合物巴洛沙韦酯和参考例583化合物。
表1本发明化合物体外抗流感病毒A/WSN/33(H1N1)活性及细胞毒性评价
++++:EC50<10nM;+++:10nM<EC50<50nM;++:50nM<EC50<100nM;+:EC50>100nM
A:CC50<20μM;B:20μM<CC50<100μM;C:100μM<CC50<200μM;D:CC50>200μM
++++:EC50<10nM;+++:10nM<EC50<50nM;++:50nM<EC50<100nM;+:EC50>100nM
A:CC50<20μM;B:20μM<CC50<100μM;C:100μM<CC50<200μM;D:CC50>200μM
二、化合物对耐药株的影响
1.实验材料及方法
巴洛沙韦酯耐药流感病毒A/PR/8/34(H1N1)株购自药明康德。其他实验材料及方法同上。由表2结果可知,实施例20化合物对耐药株的抑制活性优于巴洛沙韦酯。
表2本发明部分化合物对巴洛沙韦酯耐药流感病毒A/PR/8/34(H1N1)株的抑制活性
三、化合物体外细胞模型跨膜转运评价
3.1细胞培养
MDCK细胞(来源ATCC),高糖DMEM细胞培养液(包括10%胎牛血清、100U/mL青霉素和100μg/mL链霉素,200μg/mL谷氨酰胺)。细胞置于37□培养箱中,5%CO2饱和湿度的条件下培养,每1~2天换一次液,在荧光倒置显微镜下观察,待细胞长满单层后,0.25%胰蛋白酶消化传代。
Transwell小室接种:将细胞按照固定密度13.0×105个/cm2 0.4mL接种至transwell绒毛面(AP侧),并在基底面(BL侧)加入空白培养液1mL,接种后每两天换上新鲜的细胞培养液
一次,一周以后每日换液,A侧300μL,B侧1mL,约12天成型。
3.2细胞模型跨膜转运实验
吸弃培养孔和插入式培养皿中的旧培养液,在AP侧和BL侧均加入预热至37□的Hank’S溶液,37□,5%CO2条件下温孵10min。
吸收(AP→BL)渗透转运:取浓度为20μM待测化合物的Hank’S溶液0.3mL加入AP侧作为供给液,同时在BL侧加入1mL空白Hank’S作为接收液。培养板置于37□,5%CO2孵箱中分别温孵30min、60min和90min后,取BL侧样本200μL进行测定(n=5),接着加入200μL空白Hank’S溶液补充静水压力。
外排(BL→AP)渗透转运:取浓度为20μM待测化合物的Hank’S溶液1mL加入BL侧作为供给液,同时在A侧加入0.3mL空白Hank’S作为接收液。
培养板置于37□,5%CO2孵箱中温孵30min、60min和90min后,分别取AP侧样本200μL进行测定(n=5),接着加入200μL空白Hank’S溶液补充静水压力。
3.3数据分析方法
表观透过系数Papp的计算公式如下:
表观透过系数Papp(cm/sec)反应了药物在细胞中的渗透能力;VR(mL)表示接收室的溶液体积;A表示膜的面积(此时A为0.3cm2);C0(μg·mL-1)表示供试液中药物的起始浓度;dC/dt(μg·mL-1·sec-1)表示接收室在单位时间获得的药物浓度。
分别计算AP侧向BL侧转运的Papp(AP→BL)和BL侧向AP侧转运的Papp(BL→AP),并以Papp(BL→AP)与Papp(AP→BL)的比率Ratio B/A表示有转运体参与的外排能力。公式如下:
Ratio B/A=Papp(BL→AP)/Papp(AP→BL)
3.4结果
本发明部分化合物检测了体外Caco-2(购自ATCC)单层细胞模型中渗透性及药物转运特性的研究,结果如表3所示。本发明部分化合物相对于巴洛沙韦酯具有更高的细胞膜透过性和更低的外排作用。
表3.本发明化合物体外细胞模型跨膜转运评价
Papp值:1×10-6~2×10-6cm/s,低渗透性;2×10-6~20×10-6cm/s,中等渗透;>20×10-6cm/s,高渗透性.
外排率>20提示外排作用比较强.
四、化合物的犬体内药代动力学参数研究
4.1实验方法
选取6只比格犬,均为雄性,按体重随机分成2组,即静脉注射组及口服灌胃组,每组3只。静脉注射组给药剂量为0.5mg/kg,口服灌胃组给药剂量为2mg/kg,两组均于给药前,给药后0.083、0.25、0.5、1、2、4、6、8、24h时间点经前肢静脉采血,每个样品采集约1.0mL,EDTA-K2抗凝,采集后放置湿冰上并于1小时之内离心分离血浆(离心条件:6000g,3分钟,2-8℃)。血浆样本在分析前存放时则放于-80℃冰箱内。
1.样本前处理:移取50.0μL血浆样品至96孔板中,加入500μL含内标(甲苯磺丁脲,100ng/mL)50%甲醇乙腈溶液。将样品涡旋5分钟后,在14000rpm、4℃条件下离心5分钟,移取80μL加入到80μL的水中,混合均匀,进行LC-MS/MS分析
2.色谱条件色谱柱:Synergi 4μm Fusion-RP 80A LC Column 50*2mm;流速:0.5ml/min;进样体积:2μl;柱温:40□;流动相:A相:0.1%甲酸水溶液,B相:乙腈;梯度洗脱:0~1.9min,5%A相;1.91~2.5min,80%A相。
3.质谱条件电离模式:电喷雾电离,正离子模式(ESI+);质谱扫描方式:多反应监测(MRM);实施例20及实施例30特征离子对分别为538.20/247.20,626.20/247.10;内标选择甲苯磺丁脲,特征离子对为271.10/155.00;毛细管电压为4.0kV;去溶剂的温度为400□;
4.2实验结果
结果如表4、表5所示,实施例30化合物在犬中具有一定的吸收,口服0.3h即可达到最大血药浓度,口服半衰期3.015h,生物利用度5.87%。
表4:单次静脉注射给予实施例20后比格犬血浆PK数据-
表5:单次灌胃给予实施例30化合物后的比格犬血浆PK数据
本文提及的参考文献均通过引用并入本文。应当理解,在不脱离本公开的精神和范围的情况下,可以对本发明的技术方案进行许多变化和修改。
Claims (14)
- 式(XIV)所示的化合物
或其互变异构体、溶剂化物、前药、同位素标记物、以及药学上可接受的盐,其中环A选自C3-C8碳环或者3至8元杂环,其任选地被一个或多个选自以下的基团取代:卤素、氧代基、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基、C1-C20烷基羰基、C1-C20烷氧基羰基、C1-C20烷基羰基氧基、C1-C20烷氧基羰基氧基、苄氧基羰基、苄氧基羰基氧基;R1选自:
其中,X1选自CH2、O、S、NH、S=O、S(=O)2;X2选自CH、N;R3、R3’、R4各自独立地选自氢、卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基;或者R3、R3’与其共同连接的碳原子一起形成C3-C8碳环;环B为苯基或者6元杂芳基,其任选地被一个或多个选自以下的基团取代:卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基;环C为C6-C10芳基或者6至10元杂芳基,其任选地被一个或多个选自以下的基团取代:卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基;R2选自:a)H;b)-C(=O)-PR0;c)-C(=O)-PR1;d)-C(=O)-L-PR1;e)-C(=O)-L-O-PR1;f)-C(=O)-L-O-L-O-PR1;g)-C(=O)-L-O-C(=O)-PR1;h)-C(=O)-O-PR2;i)-C(=O)-N(-K)(PR2);j)-C(=O)-O-L-O-PR2;k)-C(=O)-O-L-N(-K)(PR2);l)-C(PR3)2-O-PR4;m)-C(PR3)2-O-L-O-PR4;n)-C(PR3)2-O-C(=O)-PR4;o)-C(PR3)2-O-C(=O)-O-PR4;p)-C(PR3)2-O-C(=O)-N(-K)-PR4;q)-C(PR3)2-O-C(=O)-O-L-O-PR4;r)-C(PR3)2-O-C(=O)-O-L-N(PR4)2;s)-C(PR3)2-O-C(=O)-N(-K)-L-O-PR4;t)-C(PR3)2-O-C(=O)-N(-K)-L-N(PR4)2;u)-C(PR3)2-O-C(=O)-O-L-O-L-O-PR4;v)-C(PR3)2-O-C(=O)-O-L-N(-K)-C(=O)-PR4;w)-C(PR3)2-O-P(=O)(-PR5)2;x)-(C(PR3)2)p-PR6;y)-C(=N+(PR7)2)(-N(PR7)2);z)-(C(PR3)2)q-C(=O)-O-PR2;aa)-(C(PR3)2)q-C(=O)-N(-K)-PR4;bb)-(C(PR3)2)q-C(=O)-PR1;cc)-C(PR3)2-N(-K)-C(=O)-O-PR2;dd)-P(=O)(-PR8)(-PR9);ee)-S(=O)2-PR10;ff)-PR11;gg)-(C(PR3)2)r-O-PR12;或hh)-(C(PR3)2)t-N(-K)-PR13;其中,L为直链或支链状的任选被取代基组B中任一项取代的C1-C20亚烷基或者C1-C20亚烯基,K为氢原子、或任选被取代基组A中任一项取代的C1-C20烷基,PR0为任选被取代基组A中任一项取代的C1-C20烷基或者C1-C20烯基,PR1为任选被取代基组A中任一项取代的C3-C8碳环基、杂环基、C1-C20烷基氨基、C1-C20烷基硫基,PR2为任选被取代基组A中任一项取代的C1-C20烷基、C3-C8碳环基、杂环基、或三(C1-C20烷基)甲硅烷基,PR3各自独立地为氢原子、C1-C20烷基或羟基,或者相邻碳原子上的2个PR3任选地共同形成亚烯基或亚烷基,PR4各自独立地为任选被取代基组A中任一项取代的C1-C20烷基、C3-C8碳环基、杂环基、C1-C20烷基氨基、或三(C1-C20烷基)甲硅烷基,PR5各自独立地为羟基或苄氧基;PR6为任选被取代基组A中任一项取代的C3-C8碳环基或杂环基,PR7各自独立地为任选被取代基组A中任一项取代的C1-C20烷基,PR8为任选被取代基组A中任一项取代的C1-C20烷氧基,PR9为任选被取代基组A中任一项取代的C1-C20烷氧基、C1-C20烷基氨基、C3-C8碳环氧基、杂环氧基、C3-C8碳环氨基、或杂环氨基,以及PR8及PR9任选与相邻的磷原子共同形成任选被取代基组A中任一项取代的杂环,PR10为任选被取代基组A中任一项取代的C1-C20烷基、C3-C8碳环基、或杂环基,PR11为任选被取代基组A中任一项取代的C1-C20烷基、C1-C20烯基、C1-C20炔基、C3-C8碳环基、或杂环基,PR12各自独立地为氢原子、或任选被取代基组A中任一项取代的C1-C20烷基,PR13为任选被取代基组A中任一项取代的C1-C20烷基磺酰基,p为2~3的整数,q为1~2的整数,r为2~4的整数,t为2~4的整数,取代基组A包括:氧代基、C1-C20烷基、C1-C20烯基、C1-C20卤代烷基、C1-C20羟基烷基、氨基、C1-C20烷基氨基、C3-C8碳环基、杂环基、碳环烷基、C3-C8螺环、C1-C20烷基羰基、卤素、羟基、羧基、C1-C20烷基羰基氨基、C1-C20烷基羰基氨基C1-C20烷基、C1-C20烷基羰氧基、C1-C20烷氧基羰基、C1-C20烷氧基羰基C1-C20烷基、C1-C20烷氧基羰氧基、C1-C20烷基氨基羰氧基、C1-C20烷基氨基C1-C20烷基、C1-C20烷氧基、氰基、硝基、叠氮基、C1-C20烷基磺酰基、三(C1-C20烷基)甲硅烷基、及磷酰基,取代基组B包括:C3-C8螺环、卤素。 - 根据权利要求1所述的化合物或其互变异构体、溶剂化物、前药、同位素标记物、以及药学上可接受的盐,其中环A选自
X3、X4、X5各自独立地为CR5R5’、S、O、SO、SO2或NR6,其中R5、R5’和R6各自独立地选自H、卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基、C1-C20烷基羰基、C1-C20烷氧基羰基、C1-C20烷基羰基氧基、C1-C20烷氧基羰基氧基、苄氧基羰基、苄氧基羰基氧基;n为选自0、1、2、3、4的整数。 - 根据权利要求1所述的化合物或其互变异构体、溶剂化物、前药、同位素标记物、以及药学上可接受的盐,其中环A选自环丙烷环、环丁烷环、环戊烷环、环己烷环、环庚烷环、环辛烷环、氮杂环丙烷环、氮杂环丁烷环、四氢吡咯环、哌啶环、氮杂环庚烷环、氮杂环辛烷环、氧杂环丙烷环、氧杂环丁烷环、四氢呋喃环、四氢吡喃环、氧杂环庚烷环、氧杂环辛烷环、硫杂环丙烷环、硫杂环丁烷环、四氢噻吩环、四氢噻喃环、硫杂环庚烷环、硫杂环辛烷环、四氢咪唑环、四氢吡唑环、四氢噁唑环、四氢异噁唑环、四氢噻唑环、四氢异噻唑环、哌嗪环、吗啉环、二噁烷环、噻噁烷环、二噻烷环,其任选地被一个或多个选自以下的基团取代:卤素、氧代基、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基、C1-C20烷基羰基、C1-C20烷氧基羰基、C1-C20烷基羰基氧基、C1-C20烷氧基羰基氧基、苄氧基羰基、苄氧基羰基氧基。
- 根据权利要求1所述的化合物或其互变异构体、溶剂化物、前药、同位素标记物、以及药学上可接受的盐,其中环A选自 其任选地被一个或多个选自以下的基团取代:卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基、C1-C20烷基羰基、C1-C20烷氧基羰基、C1-C20烷基羰基氧基、C1-C20烷氧基羰基氧基、苄氧基羰基、苄氧基羰基氧基。
- 根据权利要求1所述的化合物或其互变异构体、溶剂化物、前药、同位素标记物、以及药学上可接受的盐,其中R1选自:
R7为卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基,m为选自0、1、2、3、4的整数,X1、X2、R3、R3’、R4如权利要求1所定义。 - 根据权利要求1所述的化合物或其互变异构体、溶剂化物、前药、同位素标记物、以及药学上可接受的盐,其中R1选自:
- 根据权利要求1所述的化合物,其为式(XV)、(XVI)、或(XVII)所示的化合物,
或其互变异构体、溶剂化物、前药、同位素标记物、以及药学上可接受的盐,其中R7为卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基,m、n为选自0、1、2、3、4的整数,X1、X2、R2如权利要求1所定义。 - 根据权利要求1所述的化合物,其为下式所示的化合物,
或其互变异构体、溶剂化物、前药、同位素标记物、以及药学上可接受的盐,其中X1、X6、X7、X8选自CH2、O、S、NH、S=O、S(=O)2,X2选自CH或N,R7选自卤素、C1-C20烷基、C1-C20卤代烷基、C1-C20烷氧基,m为选自0、1、2、3、4的整数,R2如权利要求1中所定义。 - 根据权利要求1所述的化合物,其为:
或其互变异构体、溶剂化物、前药、同位素标记物、以及药学上可接受的盐。 - 一种药物组合物,其包含根据权利要求1-9中任一项所述的化合物或其互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐,以及药学上可接受的载体。
- 根据权利要求10所述的药物组合物,其任选地进一步包含一种或多种其它治疗剂,其中所述其它治疗剂选自抗流感病毒剂或疫苗。
- 根据权利要求1-9中任一项所述的化合物或其互变异构体、溶剂化物、前药、同位素标记物、以及药学上可接受的盐和/或根据权利要求10或11所述的药物组合物在制备用于预防和/或治疗由具有帽依赖性核酸内切酶的病毒引起的疾病的药物中的用途。
- 根据权利要求12所述的用途,其中所述疾病选自流感病毒感染引起的疾病。
- 根据权利要求13所述的用途,其中所述流感病毒感染包括甲型流感病毒感染、乙型流感病毒感染、丙型流感病毒感染、丁型流感病毒感染、禽流感病毒感染、猪流感病毒感染。
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CN102803260A (zh) * | 2009-06-15 | 2012-11-28 | 盐野义制药株式会社 | 被取代的多环性氨基甲酰基吡啶酮衍生物 |
CN103228653A (zh) * | 2010-09-24 | 2013-07-31 | 盐野义制药株式会社 | 被取代的多环性氨基甲酰基吡啶酮衍生物的前药 |
CN112876473A (zh) * | 2015-04-28 | 2021-06-01 | 盐野义制药株式会社 | 经取代的多环性吡啶酮衍生物及其前药 |
CN108697715A (zh) * | 2015-12-15 | 2018-10-23 | 盐野义制药株式会社 | 包含帽依赖性核酸内切酶抑制剂及抗流感药的组合的流感治疗用药物 |
CN109721615A (zh) * | 2017-09-18 | 2019-05-07 | 广东东阳光药业有限公司 | 流感病毒复制抑制剂及其用途 |
CN112778330A (zh) * | 2019-11-05 | 2021-05-11 | 上海翰森生物医药科技有限公司 | 含吡啶酮多环类衍生物抑制剂、其制备方法和应用 |
CN114907365A (zh) * | 2021-02-09 | 2022-08-16 | 扬子江药业集团有限公司 | 一种流感病毒抑制剂及其用途 |
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