CN116102537A - 一种喹啉酮类衍生物及其制备方法和用途 - Google Patents
一种喹啉酮类衍生物及其制备方法和用途 Download PDFInfo
- Publication number
- CN116102537A CN116102537A CN202211407887.7A CN202211407887A CN116102537A CN 116102537 A CN116102537 A CN 116102537A CN 202211407887 A CN202211407887 A CN 202211407887A CN 116102537 A CN116102537 A CN 116102537A
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- Prior art keywords
- compound
- quinolinone derivative
- methyl
- pharmaceutically acceptable
- solvate
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- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title description 8
- 201000008827 tuberculosis Diseases 0.000 claims abstract description 21
- 230000001355 anti-mycobacterial effect Effects 0.000 claims abstract description 11
- 239000002532 enzyme inhibitor Substances 0.000 claims abstract description 8
- 229940125532 enzyme inhibitor Drugs 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 235
- 238000006243 chemical reaction Methods 0.000 claims description 69
- -1 methoxy, hydroxy Chemical group 0.000 claims description 63
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 239000003814 drug Substances 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 24
- 229940079593 drug Drugs 0.000 claims description 21
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 18
- 239000012453 solvate Substances 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 11
- 241000187479 Mycobacterium tuberculosis Species 0.000 claims description 11
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 5
- 201000009671 multidrug-resistant tuberculosis Diseases 0.000 claims description 5
- 125000004011 3 membered carbocyclic group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 208000015355 drug-resistant tuberculosis Diseases 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 2
- 229940126062 Compound A Drugs 0.000 claims description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 20
- 230000002365 anti-tubercular Effects 0.000 abstract description 9
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- 239000002994 raw material Substances 0.000 description 61
- 238000001308 synthesis method Methods 0.000 description 51
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 19
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 7
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
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- 239000006228 supernatant Substances 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
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- 102000004190 Enzymes Human genes 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 241001049988 Mycobacterium tuberculosis H37Ra Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 3
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- 229910052757 nitrogen Inorganic materials 0.000 description 3
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- FFRYUAVNPBUEIC-UHFFFAOYSA-N quinoxalin-2-ol Chemical compound C1=CC=CC2=NC(O)=CN=C21 FFRYUAVNPBUEIC-UHFFFAOYSA-N 0.000 description 3
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- PTTUMBGORBMNBN-UHFFFAOYSA-N 1,2,3-trifluoro-5-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(F)=C(F)C(F)=C1 PTTUMBGORBMNBN-UHFFFAOYSA-N 0.000 description 2
- KOFLVDBWRHFSAB-UHFFFAOYSA-N 1,2,4,5-tetrahydro-1-(phenylmethyl)-5,9b(1',2')-benzeno-9bh-benz(g)indol-3(3ah)-one Chemical compound C1C(C=2C3=CC=CC=2)C2=CC=CC=C2C23C1C(=O)CN2CC1=CC=CC=C1 KOFLVDBWRHFSAB-UHFFFAOYSA-N 0.000 description 2
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- ZCJKTGPZLLGECQ-UHFFFAOYSA-N 4-chloro-2,6-difluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=C(Cl)C=C1F ZCJKTGPZLLGECQ-UHFFFAOYSA-N 0.000 description 1
- XUHYQIQIENDJER-BYPYZUCNSA-N 5-[(2s)-pyrrolidin-2-yl]-2h-tetrazole Chemical compound C1CCN[C@@H]1C1=NNN=N1 XUHYQIQIENDJER-BYPYZUCNSA-N 0.000 description 1
- UTTJAIFHRUAFED-UHFFFAOYSA-N 5-hydroxy-3,4-dihydro-2(1h)-quinolinone Chemical compound N1C(=O)CCC2=C1C=CC=C2O UTTJAIFHRUAFED-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- CFCWRLAINATSJN-UHFFFAOYSA-N 8-fluoro-4-hydroxy-1h-quinolin-2-one Chemical compound C1=CC=C2C(O)=CC(=O)NC2=C1F CFCWRLAINATSJN-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- RVHMNSYRSSOONW-UHFFFAOYSA-N FC=1C=CC(=C2CCC(NC=12)=O)OCC1(CCNCC1)O Chemical compound FC=1C=CC(=C2CCC(NC=12)=O)OCC1(CCNCC1)O RVHMNSYRSSOONW-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 241001646725 Mycobacterium tuberculosis H37Rv Species 0.000 description 1
- 108700035964 Mycobacterium tuberculosis HsaD Proteins 0.000 description 1
- LWLSVNFEVKJDBZ-UHFFFAOYSA-N N-[4-(trifluoromethoxy)phenyl]-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide Chemical compound FC(OC1=CC=C(C=C1)NC(=O)N1CCC(CC1)CC1=CC(=CC=C1)OC1=NC=C(C=C1)C(F)(F)F)(F)F LWLSVNFEVKJDBZ-UHFFFAOYSA-N 0.000 description 1
- NSGDYZCDUPSTQT-UHFFFAOYSA-N N-[5-bromo-1-[(4-fluorophenyl)methyl]-4-methyl-2-oxopyridin-3-yl]cycloheptanecarboxamide Chemical compound Cc1c(Br)cn(Cc2ccc(F)cc2)c(=O)c1NC(=O)C1CCCCCC1 NSGDYZCDUPSTQT-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- JIMXXGFJRDUSRO-UHFFFAOYSA-N adamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC2CC1(C(=O)O)C3 JIMXXGFJRDUSRO-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 229940101006 anhydrous sodium sulfite Drugs 0.000 description 1
- 229940124976 antitubercular drug Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- AQNQQHJNRPDOQV-UHFFFAOYSA-N bromocyclohexane Chemical compound BrC1CCCCC1 AQNQQHJNRPDOQV-UHFFFAOYSA-N 0.000 description 1
- BRTFVKHPEHKBQF-UHFFFAOYSA-N bromocyclopentane Chemical compound BrC1CCCC1 BRTFVKHPEHKBQF-UHFFFAOYSA-N 0.000 description 1
- WEDIIKBPDQQQJU-UHFFFAOYSA-N butane-1-sulfonyl chloride Chemical compound CCCCS(Cl)(=O)=O WEDIIKBPDQQQJU-UHFFFAOYSA-N 0.000 description 1
- WKIXWKIEOCQGAF-UHFFFAOYSA-N butane-2-sulfonyl chloride Chemical compound CCC(C)S(Cl)(=O)=O WKIXWKIEOCQGAF-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 230000036978 cell physiology Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229960000285 ethambutol Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960003350 isoniazid Drugs 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- NCBZRJODKRCREW-UHFFFAOYSA-N m-anisidine Chemical compound COC1=CC=CC(N)=C1 NCBZRJODKRCREW-UHFFFAOYSA-N 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
- QLNWXBAGRTUKKI-UHFFFAOYSA-N metacetamol Chemical compound CC(=O)NC1=CC=CC(O)=C1 QLNWXBAGRTUKKI-UHFFFAOYSA-N 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- KPBSJEBFALFJTO-UHFFFAOYSA-N propane-1-sulfonyl chloride Chemical compound CCCS(Cl)(=O)=O KPBSJEBFALFJTO-UHFFFAOYSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- 230000008791 toxic response Effects 0.000 description 1
- 239000000814 tuberculostatic agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D471/02—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 two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pulmonology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
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Abstract
本发明提供了一种喹啉酮类衍生物,具有式I所示结构。其具有优异的抗结核分枝杆菌活性,作为一种新型DprE1酶抑制剂,毒性可控,抗结核活性和药代动力学性质优异,具有非常好的临床应用前景。
Description
技术领域
本发明属于化学医药领域,具体涉及一种喹啉酮类衍生物及其制备方法和用途。
背景技术
结核病是由结核分枝杆菌感染引起的慢性传染病,为全球十大致死性疾病之一。其中四分之一的结核病死亡是由耐药结核造成的。到目前为止,对药物敏感结核病的治疗仍然沿用上世纪70年代的四种药物:异烟肼、利福平、吡嗪酰胺和乙胺丁醇。自2012年以来,贝达喹啉和德拉玛尼先后被美国FDA和欧洲EMA批准上市,但由于贝达喹啉和德拉玛尼不明确的毒性反应和疗效,目前备受争议,仍然没有被用作一线抗结核药物。因此,开发具有新型化学结构和作用模式的抗结核分枝杆菌药物被认为是目前重要的研究方向。
结核分枝杆菌具有特征性的、复杂的细胞壁结构,涉及与细胞生理学和发病机理有关的多种功能。而分枝杆菌内特有的DprE1关键酶与结核分枝杆菌细胞壁生物合成相关,对于结核分枝杆菌的存活至关重要。在过去几年内,研究发现的DprE1酶抑制剂(如BTZ和OPC-167832)通过与DprE1酶共价或非共价结合,能够导致分枝杆菌死亡。这些化合物都显示出抗结核功效,为设计DprE1酶抑制剂和治疗结核病提供了有力证据。
不过,现有的DprE1酶抑制剂的抗结核活性等性质仍有待进一步提高,进一步研究毒性可控、抗结核活性更好、药代动力学性质更优、具有更好成药前景的喹啉酮类化合物,以期获得更好的临床治疗效果,具有重要的意义。
发明内容
本发明的目的在于提供一种具有优异的抗结核活性的新型DprE1酶抑制剂。
本发明提供了式I所示喹啉酮类衍生物或其药学上可接受的盐、溶剂合物:
其中,环A为芳基、芳杂环基或并芳杂环基;L为O或NR7;L’、L”分别独立选自无、CO、SO2、NH或(CH2)m,m为1~3的整数;M1、M2分别独立选自N或CH;
R1、R2、R3分别独立选自H、卤素、C1~C3烷氧基、羟基、-NR11R12或R2、R3连接形成3~7元环;R11为H或C1~C3烷基,R12为C1~C3烷基或-CO-R13,R13为卤素取代或未取代的C1~C3烷基;
R4为-H或-OH;
其中,Ra、Rb、Rc分别独立选自卤素、硝基、其中,R’、R”分别独立选自:H、-CO-Rs或-SO2-Rs;R”’为-O-Rs或Rs、Rp、Rq分别独立选自H、C1~C3的烷基,或Rp、Rq连接成环;
Rd为卤素、卤素取代或未取代的C1~C3烷基、C3~C6环烷基或C3~C6杂环烷基;
R7为C1~C3的烷基。
更进一步地,上述R1、R2、R3分别独立选自H、F、甲氧基、羟基、-NR11R12或R1、R2连接形成三元环;R11为H或甲基,R12为甲基或-CO-R13,R13为1~3个F取代或未取代的甲基。
更进一步地,上述R1为H、F或甲氧基,R2为H或-NR11R12,R3为H,或R2和R3连接形成饱和3元碳环;R11为H或甲基,R12为甲基或-CO-R13,R13为甲基或-CF3。
更进一步地,上述喹啉酮类衍生物具有式II-A所示结构:
优选地,R1为H或F,R2为H且R3为H,或R2、R3连接形成饱和3元碳环。
更进一步地,上述喹啉酮类衍生物具有式II-B所示结构:
其中R3为H;
优选地,R1为H或F,R2为-NR11R12;R11为H或甲基,R12为甲基或-CO-R13,R13为甲基或-CF3。
更进一步地,上述喹啉酮类衍生物具有式II-C或式II-D所示结构:
其中,R2和R3均为H;
优选地,R1为H、F或甲氧基。
更进一步地,上述喹啉酮类衍生物具有式II-E或式II-F所示结构:
其中,R1、R2、R3均为H。
进一步地,上述L为O或N-CH3。
进一步地,上述L’为CO、SO2、NH或CH2。
进一步地,上述L”为无。
进一步地,上述M1和M2中至少一个为CH。
更进一步地,上述M1为CH,M2为N。
更进一步地,上述M1为CH,M2为CH。
更进一步地,上述M1为N,M2为CH。
进一步地,上述R5为-H或Ra、Rb、Rc取代的芳基。
更进一步地,上述Ra、Rb、Rc为卤素。
更进一步地,上述Ra、Rb、Rc分别独立选自F或Cl;优选地,Ra、Rb为F,Rc为Cl。
更进一步地,上述Ra、Rb为F,Rc选自Cl、硝基、其中,R’、R”分别独立选自:H、-CO-Rs或-SO2-Rs;R”’为-O-Rs或Rs、Rp、Rq分别独立选自H、甲基,或Rp、Rq连接成三元环;
所述Rd为Cl、F取代或未取代的C1~C3烷基、C3~C6环烷基或C6杂环烷基,所述杂环烷基的杂原子为N和/或O。
进一步地,上述喹啉酮类衍生物具有式III-A或式III-B所示结构:
更进一步地,上述喹啉酮类衍生物具有如下结构:
进一步地,上述喹啉酮类衍生物具有式III-C所示结构:
更进一步地,上述喹啉酮类衍生物具有如下结构:
进一步地,上述喹啉酮类衍生物具有式III-D所示结构:
更进一步地,上述喹啉酮类衍生物具有如下结构:
本发明还提供了上述喹啉酮类衍生物的合成方法,包括如下步骤:将化合物A和化合物B在无机碱作用下,70~90℃反应4~8h,得式I化合物;
反应式如下:
其中,R0为-OH或-NH-R7。
本发明还提供了上述的喹啉酮类衍生物或其药学上可接受的盐或溶剂合物作为DprE1酶抑制剂的用途。
本发明还提供了上述的喹啉酮类衍生物或其药学上可接受的盐或溶剂合物在制备治疗结核病的药物中的用途,优选地,所述结核病是耐药结核病。
进一步地,上述药物是抗结核分枝杆菌的药物,优选地,所述结核分枝杆菌是耐药性结核分枝杆菌。
本发明的有益效果:本发明化合物具有优异的抗结核分枝杆菌活性,作为一种新型DprE1酶抑制剂,毒性可控,抗结核活性和药代动力学性质优异,具有非常好的临床应用前景。
本发明中,“取代”是指分子中的1个、2个或多个氢原子被其它不同的原子或分子所替换,包括该分子中同位原子或异位原子上的1个、2个或多个取代。
本发明中,碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,所述C1~C6的烷基或C1~6烷基是指C1、C2、C3、C4、C5、C6的烷基,即具有1~6个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、己基等。类似的,C1~C6的烷氧基是指C1、C2、C3、C4、C5、C6的烷氧基。
本发明中,“盐”是将化合物或其立体异构体,与无机和/或有机酸和/或碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的金属离子盐(钠盐、钾盐等)盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明中,“其溶剂合物”指化合物与溶剂形成溶剂合物,其中,所述溶剂包括(但并不限于):水、乙醇、甲醇、异丙醇、丙二醇、四氢呋喃、二氯甲烷。
本发明中,“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
“卤素”为氟、氯、溴或碘。
“烷基”是烷烃分子中少掉一个氢原子而成的烃基,例如甲基-CH3,乙基-CH3CH2、丙基、异丙基等。
“芳基”指具有共轭的π电子体系的全碳单环或稠合多环基团,例如苯基、萘基。
“芳杂环基”指包含一个到多个杂原子的具有共轭的π电子体系的单环或稠合多环。含有至少一个选自N、O或S的环杂原子,其余环原子是C,另外具有完全共轭的π电子***。例如苯并吡嗪基。
“并芳杂环基”指上述芳基或芳杂环基与另一环状结构共用两个相邻的碳原子或杂原子形成的基团。
“杂环”指饱和或不饱和的环状烃,环状烃可以是单环也可以是多环,且携带至少一个环杂原子(包括但不限于O、S或N),其余为C。例如,“3~8元杂环”指碳原子和杂原子的总数为3~8的杂环。
“环烷基”指饱和的环状烃取代基;环状烃可以是单环也可以是多环。例如,“3-8元环烷基”指碳原子数为3~8的环烷基。
“杂环烷基”指饱的环状烃取代基;环状烃可以是单环也可以是多环,且携带至少一个环杂原子(包括但不限于O、S或N)。例如,“3~8元杂环基”指碳原子和杂原子的总数为3~8的杂环基。
“桥环烃”可分为二环桥环烃及多环桥环烃。二环桥环烃由两个脂环共用两个以上碳原子所构成;多环桥环烃由三个以上的脂环共用两个以上碳原子组成。“桥环烃基”是桥环烃的分子中少掉一个氢原子而成的烃基;“多环桥环烃基”是多环桥环烃的分子中少掉一个氢原子而成的烃基。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明所用原料与设备均为已知产品,通过购买市售产品所得。
实施例1、
化合物A1 5-((1-(4-氯-2,6-二氟苯基)-4-羟基哌啶-4-基)甲氧基)-3,4-二氢喹啉-2(1H)-酮
化合物A1的合成路线如下:
第一步:
在三口烧瓶中加入250mL干燥四氢呋喃,并将原料1(28.23g,200mmol)和原料2(35.56g,240mmol)溶解其中,用冰盐浴冷却混合体系至0℃。在恒压滴液漏斗中慢慢滴加入110mL浓度为2mol/L的六甲基二硅基氨基钠的四氢呋喃溶液。反应放热,控制滴加速度使反应温度保持在0-2℃。滴毕,反应混合液保温于0℃搅拌10min后撤去冰盐浴并任其自然升温至室温并于室温搅拌反应3h。TLC监测反应完成,将反应液于减压下旋去绝大部分溶剂,在所得剩余物中加入冰水,慢慢加入饱和柠檬酸水溶液小心将体系调至呈中性后,加入二氯甲烷萃取三次,合并有机相,并依次用水、饱和食盐水洗涤。分出有机相并用无水硫酸钠干燥,抽滤并旋干滤液,拌样柱层析纯化,得浅黄色油状目标物中间体3 43.2g(收率84%)。
第二步:
在两颈烧瓶中加入135mL浓硫酸,用冰盐浴将硫酸冷却至0℃。将中间体3(43.0g,167mmol)溶解于40mL二氯甲烷中,通过滴液漏斗在30min时间里将所得溶液慢慢滴加到上述硫酸溶液中,控制滴加速度,使反应液温度保持在0-5℃。滴毕,反应混合液保温于0℃搅拌10min后撤去冰盐浴并任其自然升温至室温并于室温搅拌反应2h。TLC监测反应完成,将反应液在30℃于减压下旋去绝大部分低沸点溶剂二氯甲烷,将所得剩余物加入碎冰中。搅拌混合液,待大量固体物析出,静止沉淀20min,用隔板漏斗过滤出固体物。将固体物转至烧杯中并加入水充分洗涤,待滤液pH值接近7,此时滤饼接近浅黄色至类白色。将滤饼取出并于真空干燥箱中并用五氧化二磷干燥,得浅黄色固体中间体4 28.7g(收率:89%)。
第三步:
溶解中间体4 23.0g于100mL冰醋酸中,搅拌溶解后加入4.6g 10%钯碳。氮气置换5次后再用氢气置换一次,于氢气氛围中加热至110℃反应3d。TLC检测反应完毕,减压蒸去醋酸溶剂,用PE:EA=2:1稀释反应体系,先用硅藻土抽滤,滤液旋干后,加入碳酸氢钠或碳酸钠水溶液,调至体系pH至约为7。将混合液超声10min,抽滤出滤饼,并多次用水洗滤饼。抽滤出滤饼并干燥,然后用DCM润洗几次滤饼得滤液。滤液旋干经硅胶柱层析分离得中间体521.6g,收率92.9%。
第四步:
称取21.0g中间体5,溶解在300mL干燥二氯甲烷中,于-30℃冷浴中将混合溶液冷至-15℃并于该条件下慢慢滴加入400mL BBr3。控制滴加速度,使体系温度保持在-10℃以下。加完后保持低温搅拌30min后,将冷浴撤去并将反应体系自然升温至室温,搅拌3h。TLC监测显示反应很彻底,将体系在减压下室温旋去溶剂及低沸点物质,所得剩余物加入200mL碎冰中,搅拌至碎冰完全溶解。加入二氯甲烷萃取,分液。水相再用二氯甲烷萃取三次,合并有机相,并用水、饱和食盐水洗涤。分出有机相并用无水硫酸钠干燥,抽滤并旋干滤液,拌样柱层析纯化即得白色固体中间体6 16.2g,收率83%。
第五步:
将中间体6(100mg,0.55mmol)溶于6mL无水DMF中,加入无水碳酸钾(114mg,0.825mmol),常温搅拌5min后缓慢加入原料7(171mg,0.66mmol),升温至80℃反应6h。TLC监测反应完全,将反应液冷却至室温,加入适量冰水,用乙酸乙酯萃取三次,合并有机相,水洗,再用饱和食盐水洗涤,无水硫酸钠干燥后过滤,滤液减压浓缩至干,进一步用硅胶层析柱分离得目标化合物A1,淡黄色固体24mg,收率10%。1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),7.34–7.19(m,2H),7.00(t,J=9.7Hz,1H),6.58(dd,J=9.1,3.7Hz,1H),4.69(s,1H),3.77(s,2H),3.38(m,J=10.5,9.1,4.6Hz,2H),3.03–2.87(m,4H),2.46(s,2H),1.79(dt,J=12.3,6.4Hz,2H),1.63(d,J=12.9Hz,2H).HR-MS:m/z 463.1015(M+Na)+.
实施例2、
化合物A2 5-((1-(4-氯-2,6-二氟苯基)-4-羟基哌啶-4-基)甲氧基)-3,4-二氢喹啉-2(1H)-酮
参照化合物A1的合成方法,将原料1换成3-甲氧基苯胺,得化合物A2,白色固体,收率15%。1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),7.26(d,J=8.8Hz,2H),7.07(t,J=8.1Hz,1H),6.59(d,J=8.2Hz,1H),6.48(d,J=7.9Hz,1H),4.69(s,1H),3.78(s,2H),3.36(d,J=12.0Hz,2H),2.97(d,J=11.7Hz,2H),2.87(t,J=7.7Hz,2H),2.42(dd,J=8.4,6.9Hz,2H),1.81(dt,J=12.4,6.4Hz,2H),1.63(d,J=12.8Hz,2H).HR-MS:m/z 445.1107(M+Na)+.
实施例3、
化合物A3 4-((1-(4-氯-2,6-二氟苯基)-4-羟基哌啶-4-基)甲氧基)喹啉-2(1H)-酮
以4-羟基喹啉-2(1H)-酮和原料7为原料,参照化合物A1第五步合成方法,得化合物A3,淡黄色固体,收率20%。1H NMR(400MHz,DMSO-d6)δ11.33(s,1H),7.95(d,J=8.1Hz,1H),7.51(t,J=7.6Hz,1H),7.28(d,J=8.7Hz,2H),7.18(t,J=7.7Hz,1H),5.87(s,1H),4.89(s,1H),3.95(s,2H),3.41(d,J=11.4Hz,2H),3.01(d,J=11.5Hz,2H),1.87–1.66(m,4H).HR-MS:m/z443.0947(M+Na)+.
实施例4、
化合物A4 4-((1-(4-氯-2,6-二氟苯基)-4-羟基哌啶-4-基)甲氧基)-8-氟喹啉-2(1H)-酮
以8-氟-4-羟基喹啉-2(1H)-酮和7为原料,参照化合物A1第五步合成方法,得化合物A4,淡黄色固体,收率18%。1H NMR(400MHz,DMSO-d6)δ11.38(s,1H),7.79(d,J=8.1Hz,1H),7.44(dd,J=11.1,8.0Hz,1H),7.28(d,J=8.8Hz,2H),7.18(td,J=8.1,4.9Hz,1H),4.92(s,1H),3.97(s,2H),3.00(d,J=11.5Hz,2H),2.00(q,J=7.3Hz,2H),1.76(q,J=13.3,12.0Hz,4H).
实施例5、
化合物A5 N-(3-((1-(4-氯-2,6-二氟苯基)-4-羟基哌啶-4-基)甲氧基)苯基)-2,2,2-三氟-N-甲基乙酰胺
以2,2,2-三氟-N-(3-羟基苯基)-N-甲基乙酰胺和7为原料,参照化合物A1第五步合成方法,得化合物A5,红棕色油状物,收率15.3%。1H NMR(400MHz,DMSO-d6)δ7.38(t,J=8.1Hz,1H),7.30–7.21(m,2H),7.13–7.03(m,2H),6.98(d,J=7.9Hz,1H),4.75(s,1H),3.83(s,2H),3.40(s,3H),3.29(s,2H),2.98(dd,J=9.8,5.3Hz,2H),1.80(dt,J=12.4,6.2Hz,2H),1.63(d,J=12.8Hz,2H).
实施例6、
化合物A6 1-(4-氯-2,6-二氟苯基)-4-((3-(甲胺基)苯氧基)甲基)哌啶-4-醇
将化合物A5(23mg,0.048mmol)溶于四氢呋喃中,加入氢氧化钠(8mg,0.19mmol)水溶液(1mL),常温反应8h。TLC监测反应完全,加入适量水,用乙酸乙酯萃取三次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后过滤,滤液减压浓缩至干,进一步用硅胶层析柱分离得目标化合物A6,白色固体8mg,收率43%。1H NMR(400MHz,DMSO-d6)δ7.37–7.19(m,2H),6.96(t,J=8.0Hz,1H),6.13(dd,J=8.1,2.2Hz,2H),6.09(t,J=2.2Hz,1H),5.59(q,J=5.1Hz,1H),4.63(s,1H),3.70(s,2H),3.38(d,J=10.9Hz,2H),2.96(d,J=11.5Hz,2H),2.65(d,J=5.0Hz,3H),1.80(m,J=12.6,4.6Hz,2H),1.58(d,J=12.9Hz,2H).HR-MS:m/z405.1157(M+Na)+.
实施例7、
化合物A7 N-(3-((1-(4-氯-2,6-二氟苯基)-4-羟基哌啶-4-基)甲氧基)苯基)-1-(二氟-l3-甲基)-l2-氟甲酰胺
以2,2,2-三氟-N-(3-羟基苯基)乙酰胺和7为原料,参照化合物A1第五步合成方法,得化合物A7,红棕色油状物,收率18%.1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),7.36(t,J=2.2Hz,1H),7.34–7.23(m,4H),6.84(dd,J=8.0,2.4Hz,1H),4.73(s,1H),3.79(s,2H),2.97(d,J=11.5Hz,2H),1.80(m,J=12.7,4.6Hz,2H),1.62(d,J=12.9Hz,2H),1.24(d,J=7.9Hz,2H).HR-MS:m/z 487.0815(M+Na)+.
实施例8、
化合物A8 N-(3-((1-(4-氯-2,6-二氟苯基)-4-羟基哌啶-4-基)甲氧基)苯基)乙酰胺
以N-(3-羟基苯基)乙酰胺和7为原料,参照化合物A1第五步合成方法,得化合物A8,白色固体,收率18%。1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),7.35(t,J=2.2Hz,1H),7.26(d,J=8.9Hz,2H),7.17(t,J=8.1Hz,1H),7.06(d,J=8.1Hz,1H),6.63(dd,J=8.1,2.4Hz,1H),4.70(s,1H),3.74(s,2H),3.38(d,J=11.5Hz,2H),2.96(d,J=11.6Hz,2H),2.03(s,3H),1.79(dt,J=12.4,6.4Hz,2H),1.60(d,J=12.9Hz,2H).
实施例9、
化合物A9 1-(4-氯-2,6-二氟苯基)-4-((喹喔啉-5-氧基)甲基)哌啶-4-醇
以喹喔啉-5-醇和7为原料,参照化合物A1第五步合成方法,得化合物A9,淡黄色固体,收率12%。1H NMR(400MHz,DMSO-d6)δ8.95(q,J=1.9Hz,2H),7.77(t,J=8.2Hz,1H),7.65(d,J=8.4Hz,1H),7.34(d,J=7.8Hz,1H),7.28(d,J=8.9Hz,2H),4.80(d,J=7.6Hz,1H),4.04(s,2H),3.42(t,J=10.8Hz,2H),3.01(d,J=11.5Hz,2H),1.99(m,J=12.5,4.8Hz,2H),1.70(d,J=12.8Hz,2H).HR-MS:m/z 428.0948(M+Na)+.
实施例10、
A10 1-(4-氯-2,6-二氟苯基)-4-((喹喔啉-2-氧基)甲基)哌啶-4-醇
以2-羟基喹喔啉和7为原料,参照化合物A1第五步合成方法,得化合物A10,淡黄色固体,收率15%。1H NMR(400MHz,DMSO-d6)δ8.26(s,1H),7.92(d,J=8.6Hz,1H),7.81(dd,J=7.9,1.5Hz,1H),7.61(m,J=8.7,7.2,1.6Hz,1H),7.40–7.34(m,1H),7.29–7.21(m,2H),4.74(s,1H),4.31(s,2H),3.25(t,J=11.4Hz,2H),2.93(d,J=11.5Hz,2H),1.79(m,J=12.7,4.4Hz,2H),1.61(d,J=13.1Hz,2H).HR-MS:m/z 428.0951(M+Na)+.
实施例11、
化合物A11 1-(4-氯-2,6-二氟苯基)-4-((7-甲氧基-1,5-萘啶-4-基)氧基)甲基)哌啶-4-醇
以7-甲氧基-1,5萘啶-4-醇和7为原料,参照化合物A1第五步合成方法,得化合物A11,淡黄色固体,收率15%。1H NMR(400MHz,DMSO-d6)δ8.36(d,J=1.7Hz,1H),7.87(d,J=7.8Hz,1H),7.77(d,J=2.4Hz,1H),7.31–7.20(m,2H),6.13(d,J=7.8Hz,1H),4.83(s,1H),4.28(s,2H),3.98(d,J=1.2Hz,3H),3.27(d,J=3.4Hz,2H),2.93(d,J=11.7Hz,2H),1.81(dd,J=13.0,8.6Hz,2H),1.48(d,J=12.6Hz,2H).HR-MS:m/z 436.1234(M+H)+.
实施例12、
化合物A12 1-(4-氯-2,6-二氟苯基)-4-((3-羟基苯基)(甲基)氨基)甲基)哌啶-4-醇
以3-羟基-N-甲基苯胺和7为原料,参照化合物A1第五步合成方法,得化合物A12,淡黄色固体,收率10%。1H NMR(400MHz,DMSO-d6)δ8.92(s,1H),7.24(d,J=9.0Hz,2H),6.90(t,J=8.1Hz,1H),6.27–6.22(m,1H),6.20(d,J=2.3Hz,1H),6.02(dd,J=7.8,2.0Hz,1H),4.43(s,1H),3.24(s,2H),2.93(s,3H),2.89(d,J=12.0Hz,4H),1.71–1.60(m,2H),1.53(d,J=12.7Hz,2H).HR-MS:405.1158(M+Na)+.
实施例13、
化合物A13 5-((1-(4-氯-2,6-二氟苯基)-3-羟基哌啶-3-基)甲氧基)-3,4-二氢喹啉-2(1H)-酮
化合物A13的合成步骤如下:
将原料8(100mg,0.614mmol)溶于6mL无水DMF中,加入无水碳酸钾(127mg,0.921mmol),常温搅拌5min后缓慢加入原料9(191mg,0.7368mmol),升温至80℃反应6h。TLC监测反应完全,将反应液冷却至室温,加入适量冰水,用乙酸乙酯萃取三次,合并有机相,水洗,再用饱和食盐水洗涤,无水硫酸钠干燥后过滤,滤液减压浓缩至干,进一步用硅胶层析柱分离得目标化合物A13,淡黄色固体42mg,收率16%。1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),7.30–7.21(m,2H),7.05(t,J=8.1Hz,1H),6.57(d,J=8.3Hz,1H),6.47(d,J=7.9Hz,1H),4.78(s,1H),3.98(s,2H),3.22(d,J=11.8Hz,1H),3.03(d,J=5.6Hz,2H),2.94(d,J=11.8Hz,1H),2.87–2.75(m,2H),2.38(m,J=7.7,2.2Hz,2H),1.96–1.87(m,1H),1.77(s,1H),1.63–1.46(m,2H).HR-MS:m/z 445.1109(M+Na)+.
实施例14、
化合物A14 1-(4-氯-2,6-二氟苯基)-3-((喹喔啉-5-氧基)甲基)哌啶-3-醇
以喹喔啉-5-醇和9为原料,参照化合物A13的合成方法,得化合物A14,淡黄色固体,收率10%。1H NMR(400MHz,DMSO-d6)δ8.93(d,J=1.8Hz,1H),8.89(d,J=1.9Hz,1H),7.75(t,J=8.2Hz,1H),7.62(dd,J=8.4,1.1Hz,1H),7.31(dd,J=7.9,1.2Hz,1H),7.23–7.14(m,2H),4.87(s,1H),4.26(s,2H),3.37(d,J=11.9Hz,1H),3.05(d,J=4.8Hz,2H),3.02(d,J=11.6Hz,1H),2.14–2.05(m,1H),1.87–1.77(m,1H),1.68–1.51(m,2H).HR-MS:m/z:428.0948(M+Na)+.
实施例15、
化合物A15 1-(4-氯-2,6-二氟苯基)-3-((喹喔啉-2-氧基)甲基)哌啶-3-醇
以2-羟基喹喔啉和9为原料,参照化合物A13的合成方法,得化合物A15,淡黄色固体,收率13%。1H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.01(dd,J=8.2,1.4Hz,1H),7.83(dd,J=8.3,1.4Hz,1H),7.75(ddd,J=8.3,6.9,1.5Hz,1H),7.64(ddd,J=8.3,7.0,1.5Hz,1H),7.27–7.18(m,2H),4.95(s,1H),4.55(s,2H),3.26(d,J=11.8Hz,1H),3.06(s,2H),2.98(d,J=11.8Hz,1H),1.97(d,J=12.9Hz,1H),1.83–1.73(m,1H),1.63(td,J=8.7,4.2Hz,1H),1.59–1.48(m,1H).
实施例16、
化合物A16 1-(4-氯-2,6-二氟苯基)-3-((7-甲氧基-1,5-萘啶-4-基)氧基)甲基)哌啶-3-醇
以7-甲氧基-1,5萘啶-4-醇和9为原料,参照化合物A13的合成方法,得化合物A16,淡黄色固体,收率17%。1H NMR(400MHz,DMSO-d6)δ8.36(d,J=2.0Hz,1H),7.87(d,J=7.8Hz,1H),7.77(d,J=2.5Hz,1H),7.31–7.17(m,2H),6.13(d,J=7.8Hz,1H),4.83(s,1H),4.28(s,2H),3.98(d,J=1.2Hz,3H),3.26(d,J=12.7Hz,2H),2.93(d,J=11.7Hz,2H),1.81(dd,J=13.1,8.6Hz,2H),1.48(d,J=12.6Hz,2H).
实施例17、
化合物A17 5-((4-((4-氯-2,6-二氟苯基)氨基)-1-羟基环己基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
化合物A17的合成步骤如下:
将中间体6(100mg,0.55mmol)溶于6mL无水DMF中,加入无水碳酸钾(114mg,0.825mmol),常温搅拌5min后缓慢加入原料10(181mg,0.66mmol),升温至80℃反应6h。TLC监测反应完全,将反应液冷却至室温,加入适量冰水,用乙酸乙酯萃取三次,合并有机相,水洗,再用饱和食盐水洗涤,无水硫酸钠干燥后过滤,滤液减压浓缩至干,进一步用硅胶层析柱分离得目标化合物A17,淡黄色固体,收率10%。1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),7.36(d,J=7.2Hz,2H),6.98(t,J=9.7Hz,1H),6.53(dd,J=9.1,3.8Hz,1H),5.76(s,1H),4.46(s,1H),3.67(s,2H),3.57(s,2H),2.88(t,J=7.6Hz,2H),2.44(t,J=7.7Hz,2H),2.43–2.31(m,2H),1.66(t,J=12.4Hz,2H),1.51(d,J=12.9Hz,2H).HR-MS:m/z 455.1342(M+H)+.
实施例18、
化合物A18 4-((4-((4-氯-2,6-二氟苯基)氨基)-1-羟基环己基)甲氧基)喹啉-2(1H)-酮
以4-羟基喹啉-2(1H)-酮和10为原料,参照化合物A17的合成方法,得化合物A18,淡黄色固体,收率12%。1H NMR(400MHz,DMSO-d6)δ7.84–7.79(m,1H),7.25(t,J=7.8Hz,1H),7.16(d,J=8.0Hz,2H),6.76(d,J=8.4Hz,1H),6.62(s,2H),6.54(t,J=7.5Hz,1H),4.70(d,J=7.9Hz,1H),4.56(s,1H),3.99(s,2H),3.76(m,1H),1.65(m,5H),1.43(m,2H).
实施例19、
化合物A19 4、-((4-氯-2,6-二氟苯基)氨基)-1-((喹喔啉-5-氧基)甲基)环己烷-1-醇
以喹喔啉-5-醇和10为原料,参照化合物A17的合成方法,得化合物A19,淡黄色固体,收率11%。1H NMR(400MHz,DMSO-d6)δ9.00–8.86(m,2H),7.76(t,J=8.1Hz,1H),7.64(d,J=8.4Hz,1H),7.30(d,J=7.8Hz,1H),7.18(d,J=8.1Hz,2H),4.78–4.68(m,1H),4.58(s,1H),3.97(s,2H),3.60–3.37(m,1H),1.71(p,J=12.5,12.0Hz,7H).HR-MS:m/z 442.1101(M+Na)+.
实施例20、
化合物A20 4-((4-氯-2,6-二氟苯基)氨基)-1-((喹喔啉-2-氧基)甲基)环己烷-1-醇
以2-羟基喹喔啉和10为原料,参照化合物A17的合成方法,得化合物A20,淡黄色固体,收率10%。1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.01(d,J=8.2Hz,1H),7.84(dd,J=8.5,1.5Hz,1H),7.79–7.73(m,1H),7.64(m,J=8.4,6.9,1.5Hz,1H),7.23–7.13(m,2H),4.77–4.65(m,1H),4.59(s,1H),4.25(s,2H),1.71(t,J=11.8Hz,6H),1.56(d,J=12.5Hz,2H).HR-MS:m/z 442.1180(M+Na)+.
实施例21、
化合物B1 8-氟-5-((4-羟基哌啶-4-基)甲氧基)-3,4-二氢喹啉-2(1H)-酮
化合物B1的合成步骤如下:
第一步:
将中间体6(0.1g,0.55mmol)和无水碳酸钾(0.092g,0.66mmol)溶解在4mL DMF中,搅拌半小时后,加入原料11(0.14g,0.66mmol),反应液在80℃的条件下反应,6-8h后,反应完毕。停止反应,将水加入反应液中,用乙酸乙酯萃取。干燥,减压干燥浓缩有机相,硅胶柱层析分离。即得中间体12,100mg,收率46%。
第二步:
将中间体12(50mg,0.275mmol)溶于甲醇,加入5mL的浓盐酸,常温反应2h后反应完全。减压蒸馏旋干反应液,加入少量碱水,用乙酸乙酯萃取。干燥,减压浓缩有机相,硅胶柱层析分离得化合物B1。即得A7(化合物F1),36mg白色固体,收率90%。1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),7.07–6.96(m,1H),6.58(dd,J=9.1,3.7Hz,1H),5.17(s,1H),3.77(s,2H),3.18(t,J=4.7Hz,2H),3.15–3.07(m,2H),2.91(t,J=7.6Hz,2H),2.48(s,2H),1.92(m,J=13.6,4.7Hz,2H),1.69(d,J=13.9Hz,2H).HR-MS:m/z295.1459(M+H)+.
实施例22、
化合物B2 5-((1-(2,6-二氟-4-硝基苯基)-4-羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
将化合物B1(300mg,1.02mmol)溶于10mL无水DMF中,加入DIEA(337μL,2.04mmol),常温搅拌5min后缓慢加入1,2,3-三氟-5-硝基苯(143μL,1.224mmol),升温至55℃,继续反应10h。TLC监测反应完全,将反应液冷却至室温,加入适量冰水,用乙酸乙酯萃取三次,合并有机相,水洗,再用饱和食盐水洗涤,无水硫酸钠干燥后过滤,滤液减压浓缩至干,进一步用硅胶层析柱分离得目标化合物B2,280mg黄色固体,收率60.8%。1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.06–7.72(m,2H),7.01(t,J=9.7Hz,1H),6.59(dd,J=9.1,3.8Hz,1H),4.82(s,1H),3.78(s,2H),3.51(t,J=12.0Hz,2H),3.34(s,2H),2.91(t,J=7.5Hz,2H),2.50–2.41(m,2H),1.83(m,J=12.7,4.5Hz,2H),1.67(d,J=13.0Hz,2H).HR-MS:m/z 474.1257(M+Na)+.
实施例23、
化合物B3 5-((1-(4-氨基-2,6-二氟苯基)-4-羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
将化合物B2(75mg,0.17mmol)溶于10mL甲醇中,加入10%钯碳(19mg,0.017mmol),减压抽滤,用氢气置换三次,反应体系在氢气环境下常温反应4h。TLC监测反应完全,反应液经硅藻土过滤以除去钯碳,滤饼用甲醇润洗三次,滤液减压浓缩至干,最后经硅胶层析柱分离得化合物B3,50mg白色固体,收率71%。1H NMR(400MHz,DMSO-d6)δ7.00(t,J=9.7Hz,1H),6.58(dd,J=9.1,3.8Hz,1H),6.20–6.06(m,2H),5.39(s,2H),4.56(s,1H),3.75(s,2H),3.28(d,J=11.5Hz,2H),2.92(t,J=7.6Hz,2H),2.77–2.67(m,2H),2.51–2.42(m,2H),1.75(dt,J=12.1,6.3Hz,2H),1.59(d,J=12.7Hz,2H).HR-MS:m/z 444.1499(M+Na)+.
实施例24、
化合物B4 N-(3,5-二氟-4-(4-((8-氟-2-氧代-1,2,3,4-四氢喹啉-5-基)氧基)甲基)-4-羟基哌啶-1-基)苯基)乙酰胺
将化合物B3(15mg,0.036mmol)溶于5mL二氯甲烷中,加入三乙胺(10μL,0.07mmol),0℃条件下搅拌2min,缓慢滴加乙酰氯(4μL,0.04mmol),继续在0℃下搅拌30min,随后自然升至室温继续反应2h。TLC监测反应完全,将反应液减压浓缩旋干,再经硅胶层析柱分离得化合物B4,19mg白色固体,收率33%。1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),10.00(s,1H),7.43–7.18(m,2H),7.00(t,J=9.7Hz,1H),6.58(dd,J=9.1,3.7Hz,1H),4.65(s,1H),3.76(s,2H),3.37(d,J=12.2Hz,2H),2.97–2.83(m,4H),2.49–2.44(m,2H),2.03(s,3H),1.80(m,J=12.5,4.5Hz,2H),1.62(d,J=12.7Hz,2H).
实施例25、
化合物B5 N-(3,5-二氟-4-(4-((8-氟-2-氧代-1,2,3,4-四氢喹啉-5-基)氧基)甲基)-4-羟基哌啶-1-基)苯基)-N-(甲磺酰基)甲磺酰胺
以化合物B3和甲磺酰氯为原料,参照化合物B4的合成方法,得化合物B5,白色固体,收率63%。1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),7.38(d,J=9.4Hz,2H),7.01(t,J=9.7Hz,1H),6.59(dd,J=9.1,3.7Hz,1H),4.74(s,1H),3.78(s,2H),3.54(s,6H),3.43(t,J=11.7Hz,2H),3.11(d,J=11.7Hz,2H),2.92(t,J=7.7Hz,2H),2.46(d,J=10.9Hz,2H),1.90–1.76(m,2H),1.65(d,J=12.9Hz,2H).
实施例26、
化合物B6 5-((1-(3,5-二氟吡啶-4-基)-4-羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以化合物B1和3,4,5-三氟吡啶为原料,参照化合物B2的合成方法,得化合物B6,白色固体,收率40%。1H NMR(400MHz,Chloroform-d)δ8.18–8.08(m,2H),7.62(s,1H),6.93(t,J=9.4Hz,1H),6.48(dd,J=9.1,3.9Hz,1H),3.85(s,2H),3.66–3.53(m,2H),3.45(d,J=12.9Hz,2H),3.01(t,J=7.7Hz,2H),2.66(dd,J=8.4,6.9Hz,2H),2.14(s,1H),1.95–1.80(m,4H).HR-MS:m/z 430.1355(M+Na)+.
实施例27、
化合物B7 3,5-二氟-4-(4-((8-氟-2-氧代-1,2,3,4-四氢喹啉-5-基)氧基)甲基)-4-羟基哌啶-1-基)苯甲酸甲酯
以化合物B1和3,4,5-三氟苯甲酸甲酯为原料,参照化合物B2的合成方法,得化合物B7,白色固体,收率20%。1H NMR(400MHz,Chloroform-d)δ7.58(s,1H),7.55–7.47(m,2H),6.93(t,J=9.4Hz,1H),6.49(dd,J=9.1,3.9Hz,1H),3.89(s,3H),3.85(s,2H),3.56(t,J=11.7Hz,2H),3.29(d,J=12.5Hz,2H),3.02(t,J=7.7Hz,2H),2.66(dd,J=8.4,6.9Hz,2H),2.14(s,1H),1.95–1.78(m,4H).HR-MS:m/z 487.1452(M+Na)+.
实施例28、
化合物B8 8-氟-5-((4-羟基-1-异丁基哌啶-4-基)甲氧基)-3,4-二氢喹啉-2(1H)-酮
将化合物B1(100mg,0.34mmol)溶于4mL无水DMF中,加入DIEA(222mg,0.68mmol),常温搅拌5min后加入溴代异丁烷(45μL,0.408mmol),立即升温至65℃,继续反应4h。TLC监测反应完全,将反应液冷却至室温,加入适量冰水,用乙酸乙酯萃取三次,合并有机相,水洗,再用饱和食盐水洗涤,无水硫酸钠干燥后过滤,滤液减压浓缩至干,进一步用硅胶层析柱分离得目标化合物B8,白色固体21mg,收率18%。1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),7.01(t,J=9.7Hz,1H),6.59(dd,J=9.1,3.7Hz,1H),4.74(s,1H),3.78(s,2H),3.54(s,6H),3.11(d,J=11.7Hz,2H),2.92(t,J=7.7Hz,2H),2.45(s,2H),1.88–1.76(m,1H),1.65(d,J=12.9Hz,2H),1.25(d,J=8.8Hz,6H).
实施例29、
化合物B9 8-氟-5-((4-羟基-1-(戊烷-3-基)哌啶-4-基)甲氧基)-3,4-二氢喹啉-2(1H)-酮
以化合物B1和3-溴戊烷为原料,参照化合物B8的合成方法,得化合物B9,白色固体,收率19%。1H NMR(400MHz,Chloroform-d)δ7.57(s,1H),6.92(t,J=9.4Hz,1H),6.46(dd,J=9.1,3.9Hz,1H),5.30(s,1H),4.66(p,J=6.1Hz,1H),4.01(d,J=13.2Hz,2H),3.80(s,2H),3.27(t,J=12.8Hz,2H),3.04–2.88(m,2H),2.64(dd,J=8.4,7.0Hz,2H),2.04(s,1H),1.74(d,J=13.3Hz,2H),1.62–1.50(m,4H),1.36–1.19(m,2H),0.90(t,J=7.4Hz,6H).
实施例30、
化合物B10 5-((1-环戊基-4-羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以化合物B1和溴代环戊烷为原料,参照化合物B8的合成方法,得化合物B10,白色固体,收率21%。1H NMR(400MHz,Chloroform-d)δ7.61(s,1H),6.84(t,J=9.4Hz,1H),6.38(dd,J=9.1,3.9Hz,1H),5.05(tt,J=6.1,2.7Hz,1H),3.89(s,2H),3.72(s,2H),3.17(t,J=12.4Hz,2H),2.92(t,J=7.6Hz,2H),2.57(t,J=7.7Hz,2H),2.16–1.91(m,1H),1.78(m,J=16.1,5.3Hz,2H),1.71–1.48(m,8H),1.20(d,J=11.7Hz,2H).
实施例31、
化合物B11 5-((1-环己基-4-羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以化合物B1和溴代环己烷为原料,参照化合物B8的合成方法,得化合物B11,白色固体,收率18%。1H NMR(400MHz,Chloroform-d)δ7.57(s,1H),6.92(t,J=9.4Hz,1H),6.46(dd,J=9.1,3.9Hz,1H),5.30(s,1H),4.66(h,J=5.8,5.4Hz,1H),4.01(d,J=13.1Hz,2H),3.80(s,2H),3.27(t,J=12.8Hz,2H),2.99(t,J=7.7Hz,2H),2.64(dd,J=8.4,7.0Hz,2H),2.04(s,1H),1.74(d,J=13.3Hz,2H),1.61–1.51(m,4H),0.90(t,J=7.4Hz,8H).
实施例32、
化合物B12 8-氟-5-((4-羟基-1-(2-(四氢-2H-吡喃-4-基)乙基)哌啶-4-基)甲氧基)-3,4-二氢喹啉-2(1H)-酮
以化合物B1和4-(2-溴乙基)四氢-2H-吡喃为原料,参照化合物B8的合成方法,得化合物B12,白色固体,收率16%。1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),6.99(t,J=9.7Hz,1H),6.55(dd,J=9.1,3.7Hz,1H),4.54(s,1H),3.81(dd,J=10.9,4.2Hz,2H),3.70(s,2H),3.30–3.20(m,3H),2.90(t,J=7.6Hz,2H),2.76–2.53(m,4H),2.47–2.29(m,5H),1.70(d,J=12.9Hz,2H),1.63–1.50(m,3H),1.40(s,1H),1.24(s,1H),1.15(tt,J=12.1,6.3Hz,2H).HR-MS:m/z 407.2339(M+H)+.
实施例33、
化合物B13 8-氟-5-((4-羟基-1-(2-吗啉乙基)哌啶-4-基)甲氧基)-3,4-二氢喹啉-2(1H)-酮
以化合物B1和4-(2-溴乙基)吗啉为原料,参照化合物B8的合成方法,得化合物B13,白色固体,收率12%。1H NMR(400MHz,Chloroform-d)δ7.61(s,1H),6.92(t,J=9.4Hz,1H),6.45(dd,J=9.1,3.9Hz,1H),3.87(s,2H),3.78–3.68(m,6H),3.67–3.62(m,1H),3.48(d,J=11.2Hz,2H),3.15–3.06(m,1H),2.99(dd,J=8.5,7.0Hz,2H),2.86(t,J=6.2Hz,2H),2.64(dd,J=8.5,6.9Hz,2H),2.61–2.52(m,4H),2.38(s,2H),1.91(d,J=14.2Hz,2H).HR-MS:m/z 408.2292(M+H)+.
实施例34、
化合物B14 5-((1-(4-氯-2,6-二氟苄基)-4-羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以化合物B1和4-氯-2,6-二氟溴苄为原料,参照化合物B8的合成方法,得化合物B14,白色固体,收率7%。1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),7.23–7.11(m,2H),6.99(t,J=9.7Hz,1H),6.54(dd,J=9.1,3.8Hz,1H),4.47(s,1H),3.68(s,2H),2.90(t,J=7.6Hz,2H),2.57(d,J=4.1Hz,1H),2.46(dd,J=8.5,6.9Hz,2H),1.67(t,J=8.4Hz,6H),1.50(q,J=12.2,11.1Hz,1H).HR-MS:m/z 477.1189(M+Na)+.
实施例35、
化合物B15 5-((1-(4-氯-2,6-二氟苯甲酰基)-4-羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
将4-氯-2,6-二氟苯甲酸(25μL,0.21mmol)溶于8mL无水DMF中,依次加入DIEA(75μL,0.42mmol)、HATU(88mg,0.231mmol),常温条件下搅拌10min,随后加入化合物B1(74mg,0.252mmol),继续常温反应2h。TLC监测反应完全,加入适量水,用乙酸乙酯萃取三次,合并有机相,水洗,再用饱和食盐水洗涤,无水硫酸钠干燥后过滤,滤液减压浓缩至干,进一步用硅胶层析柱分离得目标化合物B15,白色固体62mg,收率64%。1H NMR(400MHz,Chloroform-d)δ7.62(s,1H),7.01(m,J=7.2,6.2,2.2Hz,2H),6.92(t,J=9.4Hz,1H),6.45(dd,J=9.1,3.9Hz,1H),4.66(dt,J=13.4,3.3Hz,1H),3.93–3.71(m,2H),3.56(m,J=12.9,3.3Hz,1H),3.39(d,J=13.5Hz,1H),3.30(m,J=12.9,3.3Hz,1H),2.98(t,J=7.7Hz,2H),2.64(t,J=7.7Hz,2H),2.19(s,1H),1.89(dd,J=13.7,2.9Hz,1H),1.82–1.73(m,2H),1.72–1.65(m,1H).HR-MS:m/z 491.0961(M+Na)+.
实施例36、
化合物B16 5-((1-((3r,5r,7r)-金刚烷-1-羰基)-4-羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以金刚烷甲酸和化合物B1为原料,参照化合物B15的合成方法,得化合物B16,白色固体,收率58%。1H NMR(400MHz,Chloroform-d)δ7.67(s,1H),6.92(t,J=9.4Hz,1H),6.45(dd,J=9.1,3.9Hz,1H),4.44–4.25(m,2H),3.79(s,2H),3.29(t,J=12.7Hz,2H),2.99(dd,J=8.4,6.9Hz,2H),2.65(dd,J=8.5,6.9Hz,2H),2.08–1.98(m,9H),1.98–1.90(m,1H),1.78(d,J=13.2Hz,5H),1.65(dt,J=13.1,6.6Hz,4H).
实施例37、
化合物C1 N-(5-(((3R,4R)-1-(4-氯-2,6-二氟苯基)-3,4-二羟基哌啶-4-基)甲氧基)-2-氟苯基)-1-(二氟-l3-甲基)-l2-氟甲酰胺
化合物C1的合成路线如下:
第一步:
将原料13(48g,195.40mmol)、(S)-5-(吡咯烷-2-基)-1H-四唑(5.44g,39.08mmol)和无水乙酸钠(3.21g,39.08mmol)溶于200mL无水DMF中,降温至-40℃,N2保护下加入3/4亚硝基苯(20.93g,195.40mmol)的DMF(300mL)溶液,反应体系在N2保护下于-30℃先反应4h。接下来加入剩下的1/4亚硝基苯,在-30~-40℃N2保护下继续反应6h。加入饱和氯化铵水溶液,用甲基叔丁基醚萃取两次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后过滤,滤液减压浓缩至干得反应中间体。将反应中间体溶于甲醇(240mL)中,反应体系降温至-10℃,加入无水硫酸铜(15.59g,97.70mmol),继续反应2h。TLC监测反应完全,加入适量水稀释反应液,用甲基叔丁基醚萃取三次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后过滤,滤液减压浓缩至干,进一步经硅胶层析柱分离得中间体14,棕色油状物13.1g,收率26%。
第二步:
将中间体14(12g,45.86mmol)和碘化三甲基亚砜(13.12g,59.62mmol)溶于二甲亚砜(145mL)中,N2保护下加入叔丁醇钠(5.73g,59.62mmol),常温搅拌20min。TLC监测反应完全,加入适量水,用乙酸乙酯萃取三次,合并有机相,水洗,再用饱和食盐水洗涤,无水硫酸钠干燥后过滤,滤液减压浓缩至干,进一步用硅胶层析柱分离得消旋体化合物,再经手性柱分离得中间体15,3.6g黄色固体,收率29%。
第三步:
将原料16(60mg,0.27mmol)溶于5mL无水DMF中,加入无水碳酸钾(75mg,0.54mmol),常温搅拌5min后缓慢加入中间体15(82mg,0.297mmol),升温至80℃反应6h。TLC监测反应完全,将反应液冷却至室温,加入适量冰水,用乙酸乙酯萃取三次,合并有机相,水洗,再用饱和食盐水洗涤,无水硫酸钠干燥后过滤,滤液减压浓缩至干,进一步用硅胶层析柱分离得目标化合物C1,10mg棕色油状物,收率7%。1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),7.31–7.21(m,2H),6.77(dd,J=11.8,8.6Hz,1H),6.23(dd,J=7.7,2.8Hz,1H),5.88(dt,J=8.6,3.2Hz,1H),5.07–4.83(m,2H),4.36(s,1H),3.64–3.49(m,1H),3.31–3.19(m,2H),3.18–3.09(m,2H),2.94(dd,J=11.0,5.0Hz,1H),2.84(d,J=11.6Hz,1H).HR-MS:m/z425.0871(M-C2F3O)+.
实施例38、
化合物C2 N-(3-(((3R,4R)-1-(4-氯-2,6-二氟苯基)-3,4-二羟基哌啶-4-基)甲氧基)苯基)-1-(二氟-l3-甲基)-l2-氟甲酰胺
以2,2,2-三氟-N-(3-羟基苯基)乙酰胺和中间体15为原料,参照化合物C1的第三步合成方法,得化合物C2,红棕色油状物,收率8%。1H NMR(400MHz,DMSO-d6)δ8.87(s,1H),7.25(d,J=8.8Hz,2H),6.81(t,J=8.0Hz,1H),6.13(d,J=2.1Hz,1H),6.08(d,J=2.3Hz,1H),5.94(dd,J=7.9,2.1Hz,1H),5.22(t,J=6.0Hz,1H),4.74(s,1H),4.23(s,1H),3.58(s,1H),3.31–3.21(m,1H),3.16(t,J=10.0Hz,2H),3.01(dd,J=13.0,5.2Hz,1H),2.93(d,J=7.9Hz,1H),2.84(d,J=11.0Hz,1H).
实施例39、
化合物C3 5-((3R,4R)-1-(4-氯-2,6-二氟苯基)-3,4-二羟基哌啶-4-基)甲氧基)-3,4-二氢喹啉-2(1H)-酮
以5-羟基-3,4-二氢喹啉-2(1H)-酮和中间体15为原料,参照化合物C1的第三步合成方法,得化合物C3,白色固体,收率20%。1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),7.31–7.23(m,2H),7.08(t,J=8.1Hz,1H),6.59(d,J=8.3Hz,1H),6.49(d,J=8.0Hz,1H),4.86(d,J=6.4Hz,1H),4.51(s,1H),4.04(d,J=8.8Hz,1H),3.75(dt,J=11.0,5.6Hz,1H),3.68(d,J=8.8Hz,1H),3.39–3.31(m,1H),3.21(t,J=10.7Hz,1H),2.97(dd,J=11.0,5.1Hz,1H),2.92–2.80(m,3H),2.43(t,J=7.7Hz,2H),1.92(m,J=13.0,4.8Hz,1H),1.74–1.59(m,1H).、
实施例40、
化合物C4 7-((3R,4R)-1-(4-氯-2,6-二氟苯基)-3,4-二羟基哌啶-4-基)甲氧基)-4-氟-1,1a,3,7b-四氢-2H-环丙烷[c]喹啉-2-酮
以4-氟-7-羟基-1,1a,3,7b-四氢-2H-环丙烷[c]喹啉-2-酮和中间体15为原料,参照化合物C1的第三步合成方法,得化合物C4,淡黄色固体,收率20%。1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),7.31–7.23(m,2H),7.02–6.94(m,1H),6.57(m,J=9.3,5.9,3.8Hz,1H),4.87(dd,J=11.7,6.5Hz,1H),4.54(d,J=4.5Hz,1H),4.07(t,J=8.3Hz,1H),3.81–3.69(m,2H),3.35(d,J=11.6Hz,1H),3.26–3.17(m,1H),2.96(dd,J=11.0,5.1Hz,1H),2.90(d,J=8.3Hz,1H),2.78–2.67(m,1H),2.04(dt,J=8.3,4.4Hz,1H),1.99–1.86(m,1H),1.73(dd,J=19.4,13.5Hz,1H),1.65(m,J=9.2,4.3Hz,1H),0.57(p,J=4.5Hz,1H).HR-MS:m/z491.0961(M+Na)+.
实施例41、
化合物D1叔丁基(4R)-4-((8-氟-2-氧代-1,2,3,4-四氢喹啉-5-基)氧基)甲基)-3,4-二羟基哌啶-1-羧酸酯
化合物D1的合成路线如下:
第一步:
将原料17(1g,4.69mmol)溶于甲苯(15mL)中,常温条件下加入三乙胺(716μL,5.16mmol),随后缓慢滴加氯化亚砜(375μL,5.16mmol),常温条件继续搅拌5min后升温至40℃反应30min。TLC监测反应完全,往反应液中加入冰水,乙酸乙酯萃取三遍,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后过滤,滤液减压浓缩至干得粗产物中间体18,无需进一步纯化,直接用于下一步反应。
第二步:
将中间体6(412mg,2.265mmol)溶于无水DMF(15mL)中,加入无水碳酸钾(785mg,5.67mmol),常温搅拌5min后加入中间体18(4.69mmol),立即升温至80℃反应4h。TLC监测反应完全,将反应液冷却至室温,加入适量冰水,用乙酸乙酯萃取三次,合并有机相,水洗,再用饱和食盐水洗涤,无水硫酸钠干燥后过滤,滤液减压浓缩至干,进一步用硅胶层析柱分离得中间体19,731mg白色固体,收率86%。
第三步:
AD-mixβ(935mg,1.2mmol)和甲磺酰胺(77mg,0.8mmol)依次加入到水(10mL)和叔丁醇(10mL)的混合溶液中,常温搅拌10min后降温至0℃,随后加入中间体19(300mg,0.8mmol),0℃反应15h。TLC监测反应完全,加入无水亚硫酸钠(504mg,4mmol),常温搅拌30min后加水稀释,用乙酸乙酯萃取三次,合并有机相,再经1M NaOH洗涤,水洗,无水硫酸钠干燥后过滤,滤液减压浓缩至干,进一步用硅胶层析柱分离得化合物D1,189mg白色固体,收率58%。1H NMR(400MHz,Chloroform-d)δ7.65(s,1H),6.91(t,J=9.4Hz,1H),6.48(dd,J=9.1,3.9Hz,1H),4.20–3.72(m,4H),3.19–3.03(m,1H),2.95(t,J=7.7Hz,3H),2.63(q,J=8.0,7.1Hz,3H),1.66(s,2H),1.47(s,9H).
实施例42、
化合物D2 5-((3R,4R)-1-(2,6-二氟-4-硝基苯基)-3,4-二羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
化合物D2的合成步骤如下:
第一步:
将化合物D1(335mg,0.82mmol)溶于二氯甲烷(8mL)中,加入三氟乙酸(2mL),常温搅拌反应4h。TLC监测反应完毕,将反应液于40℃下减压浓缩至干,再用适量二氯甲烷溶解,减压浓缩至干,反复操作3次,得粗产物中间体20,未经进一步纯化,直接用于下一步反应。
第二步:
将中间体20(300mg,0.97mmol)溶于10mL无水DMF中,加入DIEA(344μL,1.94mmol),常温搅拌5min后缓慢加入1,2,3-三氟-5-硝基苯(原料21)(136μL,1.164mmol),升温至55℃,继续反应10h。TLC监测反应完全,将反应液冷却至室温,加入适量冰水,用乙酸乙酯萃取三次,合并有机相,水洗,再用饱和食盐水洗涤,无水硫酸钠干燥后过滤,滤液减压浓缩至干,进一步用硅胶层析柱分离得目标化合物D2,220mg黄色固体,收率50%。1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.06–7.92(m,2H),7.02(t,J=9.7Hz,1H),6.58(dd,J=9.1,3.7Hz,1H),5.01(d,J=6.3Hz,1H),4.66(s,1H),4.04(d,J=8.8Hz,1H),3.76(dt,J=8.8,6.5Hz,1H),3.70(d,J=8.8Hz,1H),3.45(t,J=12.3Hz,1H),3.26(d,J=17.0Hz,2H),2.87(m,J=7.6,4.6Hz,2H),2.50–2.42(m,3H),1.94(m,J=13.2,4.8Hz,1H),1.78–1.69(m,1H).
实施例43、
化合物D3 5-((3R,4R)-1-(4-氨基-2,6-二氟苯基)-3,4-二羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以化合物D2为原料,参照化合物B3的合成方法,得化合物D3,白色固体,收率60%。1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),7.01(t,J=9.7Hz,1H),6.57(dd,J=9.1,3.7Hz,1H),6.14(d,J=11.5Hz,2H),5.41(s,2H),4.69(d,J=6.5Hz,1H),4.36(s,1H),3.99(d,J=8.7Hz,1H),3.68(m,J=9.9,9.0,4.8Hz,2H),3.31–3.21(m,1H),3.15(t,J=10.4Hz,1H),2.93–2.86(m,1H),2.71(dd,J=10.4,5.1Hz,1H),2.47(d,J=7.8Hz,4H),1.85(dt,J=12.8,6.9Hz,1H).
实施例44、
化合物D4 N-(3,5-二氟-4-((3R,4R)-4-((8-氟-2-氧代-1,2,3,4-四氢喹啉-5-基)氧基)甲基)-3,4-二羟基哌啶-1-基)苯基)乙酰胺
以化合物D3为原料,参照化合物B4的合成方法,得化合物D4,白色固体,收率65%。1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),10.01(s,1H),7.24(d,J=11.3Hz,2H),7.02(t,J=9.7Hz,1H),6.58(dd,J=9.1,3.8Hz,1H),4.80(d,J=6.5Hz,1H),4.46(s,1H),4.01(d,J=8.8Hz,1H),3.78–3.65(m,2H),3.20(t,J=10.5Hz,1H),2.89(dd,J=7.5,5.1Hz,2H),2.80(d,J=11.0Hz,1H),2.47(d,J=7.9Hz,4H),2.03(s,3H),1.95–1.85(m,1H).
实施例45、
化合物D5 5-((3R,4R)-1-(3,5-二氟吡啶-4-基)-3,4-二羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以中间体20和3,4,5-三氟吡啶为原料,参照化合物D2的第二步合成方法,得化合物D5,灰白色固体,收率25%。1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.26(s,2H),7.02(t,J=9.7Hz,1H),6.58(dd,J=9.1,3.7Hz,1H),5.76(s,1H),4.99(d,J=6.3Hz,1H),4.64(s,1H),4.03(d,J=8.8Hz,1H),3.76(dd,J=10.6,5.4Hz,1H),3.69(d,J=8.8Hz,1H),3.41(t,J=12.3Hz,1H),3.27(d,J=11.0Hz,1H),2.87(m,J=7.6,4.6Hz,2H),2.46(t,J=7.7Hz,2H),1.92(m,J=13.0,4.7Hz,1H).HR-MS:m/z 424.1486(M+H)+.
实施例46、
化合物D6 3,5-二氟-4-((3R,4R)-4-((8-氟-2-氧代-1,2,3,4-四氢喹啉-5-基)氧基)甲基)-3,4-二羟基哌啶-1-基)苯甲酸甲酯
以中间体20和3,4,5-三氟苯甲酸甲酯为原料,参照化合物D2的第二步合成方法,得化合物D6,白色固体,收率32%。1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),7.52(d,J=9.2Hz,2H),7.02(t,J=9.8Hz,1H),6.68–6.49(m,1H),4.94(d,J=6.2Hz,1H),4.59(s,1H),4.03(d,J=8.8Hz,1H),3.83(s,3H),3.75(s,1H),3.68(d,J=8.6Hz,1H),3.21–3.09(m,1H),2.87(d,J=7.5Hz,2H),2.50–2.41(m,4H),1.93(t,J=12.8Hz,1H).
实施例47、
化合物D7 3,5-二氟-4-((3R,4R)-4-((8-氟-2-氧代-1,2,3,4-四氢喹啉-5-基)氧基)甲基)-3,4-二羟基哌啶-1-基)-N-甲基苯甲酰胺
化合物D7的合成步骤如下:
第一步:
将化合物D6(200mg,0.42mmol)溶于甲醇(10mL)中,称取NaOH(84mg,2.1mmol),并溶于1mL水中,随后滴加至反应液中,升温至60℃反应3h。TLC监测反应完全,将反应液冷却至室温,用2M盐酸酸化至反应液pH 5-6,减压浓缩至干。再用适量二氯甲烷/甲醇(10/1)混合溶剂溶解,过滤以除去生成的NaCl,滤液减压浓缩旋干得粗产物中间体21,未经进一步纯化,直接用于下一步反应。
第二步:
将中间体21(0.1mmol)溶于DMF中,常温搅拌条件下依次加入DIEA(71μL,0.4mmol)、HATU(42mg.0.11mmol)和甲胺盐酸盐(10mg,0.12mmol),常温反应2h。TLC监测反应完全,加入适量水,用乙酸乙酯萃取三次,合并有机相,水洗,再用饱和食盐水洗涤,无水硫酸钠干燥后过滤,滤液减压浓缩至干,进一步用硅胶层析柱分离得目标化合物D7,15mg白色固体,收率31%。1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.45(q,J=4.5Hz,1H),7.54–7.45(m,2H),7.02(t,J=9.7Hz,1H),6.58(dd,J=9.1,3.7Hz,1H),4.90(s,1H),4.56(s,1H),4.03(d,J=8.8Hz,1H),3.75(dd,J=10.4,5.1Hz,1H),3.68(d,J=8.8Hz,1H),3.24(t,J=11.1Hz,1H),3.17(s,2H),3.08(dd,J=28.7,8.6Hz,1H),2.89(m,J=7.9,7.5,4.8Hz,2H),2.76(d,J=4.4Hz,2H),2.46(d,J=7.7Hz,2H),1.93(m,J=13.1,4.8Hz,1H),1.70(d,J=13.7Hz,1H).
实施例48、
化合物D8 3,5-二氟-4-((3R,4R)-4-((8-氟-2-氧代-1,2,3,4-四氢喹啉-5-基)氧基)甲基)-3,4-二羟基哌啶-1-基)-N-异丙基苯甲酰胺
以中间体21和异丙胺为原料,参照化合物D7的第二步合成方法,得化合物D8,白色固体,收率42%。1H NMR(400MHz,Chloroform-d)δ8.03(s,2H),7.58(s,1H),7.30–7.27(m,1H),6.93(t,J=9.3Hz,1H),6.52(dd,J=9.0,3.9Hz,1H),5.83(s,1H),4.25(d,J=7.6Hz,1H),4.08–3.95(m,3H),3.54–3.40(m,1H),3.34(d,J=8.6Hz,2H),3.16(d,J=12.1Hz,1H),2.97(s,4H),2.89(s,4H),2.69–2.61(m,2H),1.97(d,J=11.9Hz,2H).
实施例49、
化合物D9 N-环丙基-3,5-二氟-4-((3R,4R)-4-((8-氟-2-氧代-1,2,3,4-四氢喹啉-5-基)氧基)甲基)-3,4-二羟基哌啶-1-基)苯甲酰胺
以中间体21和环丙胺为原料,参照化合物D7的第二步合成方法,得化合物D9,白色固体,收率55%。1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.40(d,J=4.2Hz,1H),7.50(d,J=10.0Hz,2H),7.02(t,J=9.7Hz,1H),6.58(dd,J=9.1,3.8Hz,1H),4.90(d,J=6.4Hz,1H),4.55(s,1H),4.09(q,J=5.2Hz,1H),4.03(d,J=8.8Hz,1H),3.75(dt,J=11.1,5.6Hz,1H),3.68(d,J=8.8Hz,1H),3.24(t,J=10.9Hz,1H),3.17(d,J=5.3Hz,2H),3.13–3.00(m,2H),2.88(dd,J=7.5,4.4Hz,1H),2.82(m,J=7.8,3.8Hz,1H),2.46(d,J=7.6Hz,1H),1.93(m,J=13.0,4.7Hz,1H),1.70(d,J=13.5Hz,1H),0.69(m,J=7.1,4.7Hz,2H),0.57–0.49(m,2H).
实施例50、
化合物D10 5-((3R,4R)-3,4-二羟基-1-丙酰哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以中间体20和丙酰氯为原料,参照化合物B4的合成方法,得化合物D10,白色固体,收率30%。1H NMR(400MHz,Chloroform-d)δ7.59(s,1H),6.92(t,J=9.7Hz,1H),6.49(dd,J=9.1,3.9Hz,1H),4.69–4.32(m,1H),4.02–3.87(m,2H),3.79(d,J=12.4Hz,1H),3.67(d,J=13.5Hz,1H),3.47–3.19(m,1H),2.94(td,J=7.6,3.0Hz,2H),2.88–2.69(m,2H),2.67–2.57(m,2H),2.47–2.31(m,2H),1.91(t,J=12.4Hz,1H),1.73(ddd,J=20.4,13.2,5.3Hz,1H),1.16(td,J=7.4,4.4Hz,3H).
实施例51、
化合物D11 5-(((3R,4R)-1-丁酰基-3,4-二羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以中间体20和丁酰氯为原料,参照化合物B4的合成方法,得化合物D11,白色固体,收率25%。1H NMR(400MHz,Chloroform-d)δ7.66(s,1H),6.91(td,J=9.4,2.4Hz,1H),6.49(dd,J=9.1,3.9Hz,1H),4.65–4.34(m,1H),4.02–3.86(m,2H),3.80(d,J=12.6Hz,1H),3.68(d,J=13.6Hz,1H),3.51–3.37(m,1H),3.26(dd,J=12.9,10.4Hz,1H),2.93(td,J=7.5,4.1Hz,2H),2.81(dd,J=10.2,5.9Hz,1H),2.61(q,J=7.5Hz,2H),2.34(ddt,J=10.0,7.1,3.9Hz,2H),1.90(t,J=13.2Hz,1H),1.66(dt,J=14.7,6.0Hz,2H),0.97(td,J=7.4,4.8Hz,3H).
实施例52、
化合物D12 5-(((3R,4R)-1-(2-环丙基乙酰基)-3,4-二羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以中间体20和2-环丙基乙酰氯为原料,参照化合物B4的合成方法,得化合物D12,白色固体,收率32%。1H NMR(400MHz,Chloroform-d)δ7.61(s,1H),6.97–6.85(m,1H),6.49(dd,J=9.1,3.9Hz,1H),4.72–4.34(m,1H),4.01–3.87(m,2H),3.86–3.60(m,2H),3.49–3.20(m,1H),2.94(td,J=7.6,3.4Hz,2H),2.89–2.71(m,2H),2.62(q,J=7.4Hz,2H),2.37–2.26(m,2H),1.91(dd,J=16.4,4.7Hz,1H),1.75(td,J=13.2,6.9Hz,1H),1.04(d,J=7.3Hz,1H),0.57(d,J=7.9Hz,2H),0.19(h,J=4.7Hz,2H).
实施例53、
化合物D13 5-(((3R,4R)-1-(2-环己基乙酰基)-3,4-二羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以中间体20和2-环己基乙酰氯为原料,参照化合物B4的合成方法,得化合物D13,白色固体,收率22%。1H NMR(400MHz,Chloroform-d)δ7.62(s,1H),6.92(td,J=9.5,2.5Hz,1H),6.48(dd,J=9.1,3.9Hz,1H),4.70–4.35(m,1H),4.01–3.85(m,2H),3.85–3.64(m,2H),3.51–3.18(m,1H),2.93(q,J=7.3Hz,2H),2.87–2.67(m,2H),2.62(q,J=7.9Hz,2H),2.25(dd,J=9.3,6.8Hz,2H),1.89(dd,J=12.2,9.2Hz,1H),1.81–1.67(m,5H),1.34–1.09(m,5H),1.06–0.85(m,2H).
实施例54、
化合物D14 5-((3R,4R)-1-(3-((二氟-l3-甲基)-l2-芴基)丙酰基)-3,4-二羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以中间体20和4,4,4-三氟丁酰氯为原料,参照化合物B4的合成方法,得化合物D14,白色固体,收率13%。1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),7.01(t,J=9.7Hz,1H),6.56(dd,J=9.1,3.7Hz,1H),5.05(s,1H),4.71(s,1H),4.27(dd,J=12.0,5.1Hz,1H),4.21–4.09(m,1H),4.06–3.97(m,1H),3.67(t,J=8.5Hz,2H),3.62–3.46(m,2H),2.98–2.79(m,2H),2.75–2.53(m,2H),2.44(t,J=7.5Hz,2H),2.38–2.25(m,2H),1.80–1.58(m,2H).
实施例55、
化合物D15 5-(((3R,4R)-3,4-二羟基-1-(丙基磺酰基)哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以中间体20和丙基磺酰氯为原料,参照化合物B4的合成方法,得化合物D15,白色固体,收率28%。1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),7.01(t,J=9.7Hz,1H),6.55(dd,J=9.1,3.8Hz,1H),5.11(d,J=6.0Hz,1H),4.70(s,1H),4.02(d,J=8.8Hz,1H),3.67(dd,J=14.0,7.2Hz,2H),3.47–3.36(m,2H),3.04(m,J=8.8,7.7,5.0Hz,3H),2.94–2.81(m,3H),2.46(d,J=15.5Hz,2H),1.81(dd,J=12.9,4.7Hz,1H),1.74–1.63(m,3H),1.00(t,J=7.4Hz,2H).HR-MS:439.1315(M+Na)+.
实施例56、
化合物D16 5-(((3R,4R)-1-(2-环戊基乙基)-3,4-二羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以中间体20和2-环戊基溴乙烷为原料,参照化合物B8的合成方法,得化合物D16,白色固体,收率32%。1H NMR(400MHz,Chloroform-d)δ7.58(s,1H),6.91(t,J=9.4Hz,1H),6.49(dd,J=9.1,3.9Hz,1H),4.03–3.86(m,3H),2.98(td,J=7.7,4.5Hz,2H),2.82(dd,J=11.0,4.4Hz,1H),2.61(q,J=6.6,5.5Hz,3H),2.46–2.36(m,2),2.33(t,J=10.1Hz,1H),1.88–1.81(m,2H),1.74(dt,J=14.3,8.9Hz,4),1.66–1.56(m,2),1.56–1.44(m,4H),1.15–1.02(m,2H).
实施例57、
化合物D17 5-(((3R,4R)-1-(2-环己基乙基)-3,4-二羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以中间体20和2-环己基溴乙烷为原料,参照化合物B8的合成方法,得化合物D17,白色固体,收率37%。1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),7.00(dd,J=10.4,9.0Hz,1H),6.54(dd,J=9.1,3.8Hz,1H),4.60(d,J=6.7Hz,1H),4.22(s,1H),3.94(d,J=8.8Hz,1H),3.60(t,J=7.9Hz,2H),2.86(m,J=7.6,4.0Hz,2H),2.73–2.61(m,1H),2.46(t,J=7.7Hz,2H),2.32(dd,J=10.0,5.7Hz,2H),2.26–2.11(m,1H),2.08(t,J=10.3Hz,1H),1.76(m,J=13.1,4.4Hz,1H),1.72–1.52(m,6H),1.32(q,J=7.3Hz,2H),1.28–1.04(m,4H),0.89(q,J=10.8,9.7Hz,2H).HR-MS:m/z 421.2498(M+H)+.
实施例58、
化合物D18 5-(((3R,4R)-3,4-二羟基-1-(2-(四氢-2H-吡喃-4-基)乙基)哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以中间体20和4-(2-溴乙基)四氢-2H-吡喃为原料,参照化合物B8的合成方法,得化合物D18,白色固体,收率26%。1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),7.00(t,J=9.7Hz,1H),6.54(dd,J=9.1,3.7Hz,1H),4.64(s,1H),4.27(s,1H),3.95(d,J=8.7Hz,1H),3.86–3.74(m,2H),3.70–3.54(m,3H),3.26(m,J=11.8,2.1Hz,2H),2.86(m,J=7.6,4.0Hz,2H),2.74–2.55(m,1H),2.49–2.31(m,4H),2.18(d,J=37.9Hz,1H),1.78(t,J=12.9Hz,1H),1.63–1.32(m,6H),1.17(m,J=16.2,6.7,4.5Hz,3H).HR-MS:m/z423.2296(M+H)+.
实施例59、
化合物D19 5-(((3R,4R)-3,4-二羟基-1-(2-甲氧基乙基)哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以中间体20和1-溴-2-甲氧基乙烷为原料,参照化合物B8的合成方法,得化合物D19,白色固体,收率10%。1H NMR(400MHz,Chloroform-d)δ7.56(s,1H),6.91(t,J=9.4Hz,1H),6.49(dd,J=9.1,3.9Hz,1H),4.07–3.79(m,3H),3.53(t,J=5.5Hz,2H),3.36(s,3H),2.98(td,J=7.7,4.3Hz,2H),2.90(dd,J=10.6,4.3Hz,1H),2.74–2.58(m,5),2.50–2.41(m,1H),2.37(t,J=10.2Hz,1H),1.86(dd,J=6.8,4.4Hz,2H).
实施例60、
化合物D20 5-((3R,4R)-3,4-二羟基-1-(2-(2-甲氧基乙氧基)乙基)哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以中间体20和1-溴-2-(2-甲氧基乙氧基)乙烷为原料,参照化合物B8的合成方法,得化合物D20,白色油状物,收率10%。1H NMR(400MHz,Chloroform-d)δ7.59(s,1H),6.91(t,J=9.4Hz,1H),6.49(dd,J=9.1,3.9Hz,1H),4.02–3.89(m,3H),3.67–3.59(m,4H),3.58–3.53(m,2H),3.39(s,3H),2.99(td,J=7.6,3.5Hz,2H),2.90(dd,J=11.1,4.3Hz,1H),2.70(t,J=5.7Hz,2H),2.62(t,J=7.7Hz,2H),2.56–2.49(m,1),2.44(t,J=10.1Hz,1H),1.87(q,J=4.4Hz,3H).
实施例61、
化合物D21 5-((3R,4R)-1-(2-环戊基乙酰基)-3,4-二羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以中间体20和2-环戊基乙酰氯为原料,参照化合物B4的合成方法,得化合物D21,白色固体,收率48%。1H NMR(400MHz,Chloroform-d)δ7.59(s,1H),6.90(t,J=9.5Hz,1H),6.45(dt,J=9.0,4.4Hz,1H),5.80(d,J=25.9Hz,1H),4.41(s,2H),4.13(s,1H),4.02(d,J=3.5Hz,1H),3.76(t,J=5.7Hz,1H),3.61(t,J=5.7Hz,1H),3.06–2.93(m,2H),2.64(dd,J=8.4,6.9Hz,2H),2.38(dd,J=15.4,7.2Hz,2H),2.26(td,J=17.3,16.3,8.6Hz,3H),1.86(q,J=8.5,7.2Hz,2H),1.64–1.47(m,4H),1.17(td,J=13.3,10.4,6.3Hz,2H).
实施例62、
化合物D22 5-((3R,4R)-1-(丁基磺酰基)-3,4-二羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以中间体20和丁基磺酰氯为原料,参照化合物B4的合成方法,得化合物D22,白色固体,收率62%。1H NMR(400MHz,Chloroform-d)δ7.60(s,1H),6.92(t,J=9.4Hz,1H),6.49(dd,J=9.1,3.9Hz,1H),4.03–3.90(m,3H),3.78(ddd,J=11.7,5.4,1.9Hz,1H),3.68–3.60(m,1H),3.16(ddd,J=12.2,10.3,4.8Hz,1H),3.03–2.89(m,5H),2.72(d,J=5.9Hz,1H),2.68–2.58(m,3H),1.98–1.90(m,2H),1.87–1.76(m,2H),1.47(h,J=7.4Hz,2H),0.97(t,J=7.4Hz,3H).
实施例63、
化合物D23 5-((3R,4R)-1-((3-氯丙基)磺酰基)-3,4-二羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以中间体20和3-氯丙烷磺酰氯为原料,参照化合物B4的合成方法,得化合物D23,白色固体,收率44%。1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),7.01(dd,J=10.4,9.0Hz,1H),6.54(dd,J=9.1,3.8Hz,1H),5.12(d,J=6.0Hz,1H),4.73(d,J=1.0Hz,1H),4.01(d,J=8.8Hz,1H),3.75(t,J=6.5Hz,2H),3.70–3.61(m,2H),3.43(dd,J=11.1,5.7Hz,2H),3.23–3.15(m,2H),3.12–3.00(m,1H),2.95–2.81(m,3H),2.45(t,J=7.6Hz,2H),2.18–2.04(m,2H),1.83(td,J=13.3,4.8Hz,1H),1.71(d,J=13.9Hz,1H).
实施例64、
化合物D24 5-((3R,4R)-1-(仲丁基磺酰基)-3,4-二羟基哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以中间体20和仲丁基磺酰氯为原料,参照化合物B4的合成方法,得化合物D24,白色固体,收率49%。1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),7.01(dd,J=10.4,9.1Hz,1H),6.55(dd,J=9.1,3.8Hz,1H),5.08(dd,J=6.0,1.1Hz,1H),4.68(d,J=1.1Hz,1H),4.00(d,J=8.8Hz,1H),3.62(dd,J=14.3,6.9Hz,2H),3.47(dt,J=13.0,6.8Hz,2H),3.18–3.05(m,2H),2.96(td,J=11.2,5.2Hz,1H),2.86(td,J=7.6,3.9Hz,2H),2.45(t,J=7.7Hz,2H),1.92–1.72(m,2H),1.67(d,J=13.7Hz,1H),1.42(ddd,J=13.8,9.2,7.3Hz,1H),1.20(d,J=6.8Hz,3H),0.95(t,J=7.5Hz,3H).
实施例65、
化合物D25 5-((3R,4R)-3,4-二羟基-1-((3,3,3-三氟丙基)磺酰基)哌啶-4-基)甲氧基)-8-氟-3,4-二氢喹啉-2(1H)-酮
以中间体20和3,3,3-三氟丙烷-1-磺酰氯为原料,参照化合物B4的合成方法,得化合物D25,白色固体,收率66%。1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),7.01(dd,J=10.5,9.1Hz,1H),6.55(dd,J=9.1,3.7Hz,1H),5.12(d,J=6.0Hz,1H),4.72(d,J=1.0Hz,1H),4.01(d,J=8.8Hz,1H),3.72–3.60(m,2H),3.45(dd,J=11.0,5.4Hz,2H),3.35(dd,J=6.9,4.2Hz,2H),3.16–3.07(m,1H),2.97(t,J=11.0Hz,1H),2.86(td,J=7.6,4.0Hz,2H),2.75–2.63(m,2H),2.45(t,J=7.6Hz,2H),1.83(td,J=13.1,4.7Hz,1H),1.74–1.65(m,1H).
以下通过实验例证明本发明的有益效果。
实验例1、化合物体外抗结核分枝杆菌活性测试
1、化合物体外抗结核分枝杆菌H37Ra活性测试
将H37Ra(ATCC 25177)菌株加入7H9+ADN培养基中,160rpm摇床培养2周生长至对数生长期,稀释调整菌液至1*105CFU/mL左右备用。将待测化合物充分溶于DMSO中,配成10mg/mL的高浓度溶液,于2-8℃条件保存。取样用上述菌液稀释至10-50μg/mL开始,按每个化合物两个复孔加样,8-10个浓度梯度(2倍梯度稀释)依次加入96孔板中,以等量的空白DMSO溶液为空白对照,以不加药的菌液为生长对照,每孔体积200μL。加完板后5% CO2,37℃静置培养5d,检查结核杆菌的生长情况,生长对照孔加入1%的Resazurin溶液培养过夜,观察颜色是否已由蓝色变为红色,此时在剩余所有孔中加入1%的Resazurin溶液培养过夜,采用PE Envision多功能微孔板分析仪测定540/590nm处的荧光值。荧光吸收测得90%以上的菌株死亡率对应的最低药物浓度为该化合物对H37Ra的MIC值,计算公式:死亡率=1-(试验孔荧光值-空白对照荧光值)/(生长对照荧光值-空白对照荧光值)。
化合物对结核分枝杆菌H37Ra的抑制活性如表1所示:
表1化合物抗结核分枝杆菌H37Ra活性结果
注:A:MIC<0.001μM;B:0.001μM≤MIC<0.01μM;C:0.01μM≤MIC<0.1μM;D:0.1μM≤MIC<1μM;E:MIC≥1μM.
表1结果显示,大多数化合物在体外具有明显抑制结核分枝杆菌H37Ra的活性。其中C3、C4、D2和D17抑菌活性与阳性对照OPC-167832相当,MIC值低于0.001μM,展现出显著的抗菌活性。
2、化合物体外抗结核分枝杆菌H37Rv活性测试
化合物溶液制备:待测化合物将以64μg/mL开始进行测试。将化合物以2048μg/mL的浓度溶于DMSO中,作为冷冻原液(-80℃)。将100μL原液加入700μL 7H9 w/o吐温中进行8倍稀释,使其成为800μL的256μg/mL溶液,用于设置孔板。
96孔板设置:培养基为7H9,OD600=0.001类型的培养基,将100μL测试化合物或阳性对照一式两份分别加入两列中(对于一式两份,则加四倍)。从第2列取100μL到第3列并混匀,这作为进行两倍连续稀释,并通过上下吹打8次使其充分混合。连续稀释至第11列,并丢弃最后100μL的溶液。加完药后,在37℃条件下,密封培养7天。检测90%以上的菌株死亡对应的药物浓度,记录MIC值。
主要化合物对结核分枝杆菌H37Rv的抑制活性如表2所示:
表2化合物抗结核分枝杆菌H37Rv活性结果
注:A:MIC<0.1μM;B:0.1μM≤MIC<1μM;C:MIC≥1μM.
表2结果显示,对于抗结核分枝杆菌H37Ra活性较优化合物,体外抗结核分枝杆菌H37Rv活性于阳性化合物一致,均展现出优异的抗结核活性。
3、化合物体外抗耐药结核分枝杆菌(MDR-TB和XDR-TB)活性测试加药:
待测化合物:以DMSO完全溶解,配制成贮存母液,过滤除菌,然后以结核菌Middlebrook 7H9培养液进行系列稀释,临用前以100μL/孔加入96孔培养板,药物终浓度为:1μg/mL,0.5μg/mL,0.25μg/mL,0.125μg/mL,0.0625μg/mL,0.03125μg/mL,0.0156μg/mL,0.0078μg/mL,0.0039μg/mL,0.00019μg/mL,0.0001μg/mL。
对照:均加入含与测试药最高浓度相同浓度的溶剂DMSO。
结核菌:MDR/XDR菌株(Y117,Y16)
取传代1-2次、对数生长期的菌株,磨菌比浊到OD600=1.0(约5×106CFU/mL),取200μL稀释到10mL培养液中后,以连续加样枪100μL/孔(约104CFU/孔)加入培养板;对照组加入与测试化合物等同菌量(D100),1/10菌量(D10)和1/100菌量(D1)。
结果观察:
37℃培养14天时,观察各组菌落生长情况,以无菌落生长的药物组最低浓度作为测试化合物对该菌株的MIC值。
主要化合物对耐药结核分枝杆菌MDR-TB(Y117)和XDR-TB(Y16)的抑制活性如表3所示:
表3化合物抗耐药结核分枝杆菌Y117和Y16活性结果
注:A:MIC100<0.01μg/mL;B:0.01μg/mL≤MIC100<0.05μg/mL;C:0.05μg/mL≤MIC100<0.1μg/mL;D:MIC100≥0.1μg/mL
以上结果表明,化合物C4和D17对于临床分离的结核分枝杆菌展现出显著的杀菌活性,具有良好的临床应用价值。
实验例2、化合物溶解度测试
实验步骤
1.准备纯水
2.样品制备:在792μL水中加入8μL浓度为10mM的对照液和测试化合物原液。
3.样品管在室温下摇晃1h(1000rpm)。
4.制备标曲
4.1制备300μM加标溶液(SS):在194μL MeOH/ACN(4/1)溶液中加入6μL 10mM化合物。
4.2在MeOH/ACN(4/1)溶液中制备标准曲线。
5.对样品进行离心处理(10min-12000rpm)以沉淀未溶解的颗粒。并将上清液转移到新的样品瓶中。
6.用水将上清液稀释10倍和100倍
将10μL上清液加入90μL水中,进行10倍稀释。
将10μL上清液加入990μL水中,进行100倍稀释。
7.LC-MS/MS的样品准备
将5μL样品(无稀释,10倍稀释和100倍稀释)和标准曲线样品加入95μL CAN中,上样分析。
主要化合物溶解度数据如表4所示。
表4化合物溶解度
以上结果显示,相比于阳性对照,化合物D17和D24溶解度显著提升,表明化合物可能具有更优的药代性质,具有潜在临床应用价值。
综上,本发明提供了一种新的喹啉酮类衍生物,具有优异的抗结核分枝杆菌活性,作为一种新型DprE1酶抑制剂,毒性可控,抗结核活性和药代动力学性质优异,具有非常好的临床应用前景。
Claims (13)
1.式I所示喹啉酮类衍生物或其药学上可接受的盐或溶剂合物:
其中,环A为芳基、芳杂环基或并芳杂环基;L为O或NR7;L’、L”分别独立选自无、CO、SO2、NH或(CH2)m,m为1~3的整数;M1、M2分别独立选自N或CH;
R1、R2、R3分别独立选自H、卤素、C1~C3烷氧基、羟基、-NR11R12或R2、R3连接形成3~7元环;R11为H或C1~C3烷基,R12为C1~C3烷基或-CO-R13,R13为卤素取代或未取代的C1~C3烷基;
R4为-H或-OH;
其中,Ra、Rb、Rc分别独立选自卤素、硝基、其中,R’、R”分别独立选自:H、-CO-Rs或-SO2-Rs;R”’为-O-Rs或Rs、Rp、Rq分别独立选自H、C1~C3的烷基,或Rp、Rq连接成环;
Rd为卤素、卤素取代或未取代的C1~C3烷基、C3~C6环烷基或C3~C6杂环烷基;
R7为C1~C3的烷基。
3.如权利要求1或2所述的喹啉酮类衍生物或其药学上可接受的盐或溶剂合物,其特征在于,R1、R2、R3分别独立选自H、F、甲氧基、羟基、-NR11R12或R1、R2连接形成三元环;R11为H或甲基,R12为甲基或-CO-R13,R13为1~3个F取代或未取代的甲基。
4.如权利要求3所述的喹啉酮类衍生物或其药学上可接受的盐或溶剂合物,其特征在于,R1为H、F或甲氧基,R2为H或-NR11R12,R3为H,或R2和R3连接形成饱和3元碳环;R11为H或甲基,R12为甲基或-CO-R13,R13为甲基或-CF3。
12.权利要求1~11任一项所述的喹啉酮类衍生物或其药学上可接受的盐或溶剂合物作为DprE1酶抑制剂的用途。
13.权利要求1~11任一项所述的喹啉酮类衍生物或其药学上可接受的盐或溶剂合物在制备治疗结核病的药物中的用途;优选地,所述药物是抗结核分枝杆菌的药物;更优选地,所述治疗结核病的药物是治疗耐药性结核病的药物,所述结核分枝杆菌是耐药性结核分枝杆菌。
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