CN116041330A - 一种含苯并氮杂环侧链的三氮唑醇类抗真菌化合物及其制备方法与用途 - Google Patents
一种含苯并氮杂环侧链的三氮唑醇类抗真菌化合物及其制备方法与用途 Download PDFInfo
- Publication number
- CN116041330A CN116041330A CN202310136176.9A CN202310136176A CN116041330A CN 116041330 A CN116041330 A CN 116041330A CN 202310136176 A CN202310136176 A CN 202310136176A CN 116041330 A CN116041330 A CN 116041330A
- Authority
- CN
- China
- Prior art keywords
- compound
- side chain
- cdcl
- nmr
- benzoazacyclic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000000843 anti-fungal effect Effects 0.000 title claims abstract description 26
- 229940121375 antifungal agent Drugs 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims description 13
- 150000001875 compounds Chemical class 0.000 title abstract description 107
- FQKFPGMGQXQHLP-UHFFFAOYSA-N 1-hydroxytriazole Chemical compound ON1C=CN=N1 FQKFPGMGQXQHLP-UHFFFAOYSA-N 0.000 title description 4
- -1 triazole alcohol compound Chemical class 0.000 claims abstract description 97
- 239000003814 drug Substances 0.000 claims abstract description 63
- 229940079593 drug Drugs 0.000 claims abstract description 49
- 241000233866 Fungi Species 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 6
- 208000015181 infectious disease Diseases 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 206010017533 Fungal infection Diseases 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- 208000031888 Mycoses Diseases 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical group N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 abstract description 20
- 230000000694 effects Effects 0.000 abstract description 13
- 206010018910 Haemolysis Diseases 0.000 abstract description 9
- 230000008588 hemolysis Effects 0.000 abstract description 9
- 238000000338 in vitro Methods 0.000 abstract description 9
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 230000035945 sensitivity Effects 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 73
- 238000003786 synthesis reaction Methods 0.000 description 73
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 36
- 229940125797 compound 12 Drugs 0.000 description 36
- IBODDUNKEPPBKW-UHFFFAOYSA-N 1,5-dibromopentane Chemical compound BrCCCCCBr IBODDUNKEPPBKW-UHFFFAOYSA-N 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- VXWVFZFZYXOBTA-UHFFFAOYSA-N 5-bromo-1h-indole Chemical compound BrC1=CC=C2NC=CC2=C1 VXWVFZFZYXOBTA-UHFFFAOYSA-N 0.000 description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 17
- 241000222122 Candida albicans Species 0.000 description 16
- 241000699670 Mus sp. Species 0.000 description 15
- 229940095731 candida albicans Drugs 0.000 description 15
- 239000007788 liquid Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 13
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 13
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 229960004884 fluconazole Drugs 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 206010059866 Drug resistance Diseases 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 210000003743 erythrocyte Anatomy 0.000 description 9
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 9
- 229960004740 voriconazole Drugs 0.000 description 9
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 8
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- NJBRNNOGZPVNNR-UHFFFAOYSA-N 1-[[2-(2,4-difluorophenyl)oxiran-2-yl]methyl]-1,2,4-triazole;methanesulfonic acid Chemical compound CS(O)(=O)=O.FC1=CC(F)=CC=C1C1(CN2N=CN=C2)OC1 NJBRNNOGZPVNNR-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- XCHRPVARHBCFMJ-UHFFFAOYSA-N 1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl)ethanone Chemical compound FC1=CC(F)=CC=C1C(=O)CN1N=CN=C1 XCHRPVARHBCFMJ-UHFFFAOYSA-N 0.000 description 6
- DWAQDRSOVMLGRQ-UHFFFAOYSA-N 5-methoxyindole Chemical compound COC1=CC=C2NC=CC2=C1 DWAQDRSOVMLGRQ-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 239000012980 RPMI-1640 medium Substances 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000010171 animal model Methods 0.000 description 6
- 229940091771 aspergillus fumigatus Drugs 0.000 description 6
- 230000002538 fungal effect Effects 0.000 description 6
- 241001225321 Aspergillus fumigatus Species 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 102100021695 Lanosterol 14-alpha demethylase Human genes 0.000 description 5
- 101710146773 Lanosterol 14-alpha demethylase Proteins 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 5
- 229940125961 compound 24 Drugs 0.000 description 5
- 235000011187 glycerol Nutrition 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 5
- 229920000053 polysorbate 80 Polymers 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- GTQHJCOHNAFHRE-UHFFFAOYSA-N 1,10-dibromodecane Chemical group BrCCCCCCCCCCBr GTQHJCOHNAFHRE-UHFFFAOYSA-N 0.000 description 4
- WGAXVZXBFBHLMC-UHFFFAOYSA-N 1,9-dibromononane Chemical compound BrCCCCCCCCCBr WGAXVZXBFBHLMC-UHFFFAOYSA-N 0.000 description 4
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 4
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- YTAOBBFIOAEMLL-REQDGWNSSA-N Luliconazole Chemical compound ClC1=CC(Cl)=CC=C1[C@H](CS\1)SC/1=C(\C#N)N1C=NC=C1 YTAOBBFIOAEMLL-REQDGWNSSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 238000003113 dilution method Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 229960004130 itraconazole Drugs 0.000 description 4
- 229960000570 luliconazole Drugs 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 3
- SGRHVVLXEBNBDV-UHFFFAOYSA-N 1,6-dibromohexane Chemical compound BrCCCCCCBr SGRHVVLXEBNBDV-UHFFFAOYSA-N 0.000 description 3
- MYTGFBZJLDLWQG-UHFFFAOYSA-N 5-chloro-1h-indole Chemical compound ClC1=CC=C2NC=CC2=C1 MYTGFBZJLDLWQG-UHFFFAOYSA-N 0.000 description 3
- YTYIMDRWPTUAHP-UHFFFAOYSA-N 6-Chloroindole Chemical compound ClC1=CC=C2C=CNC2=C1 YTYIMDRWPTUAHP-UHFFFAOYSA-N 0.000 description 3
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 3
- 241000222173 Candida parapsilosis Species 0.000 description 3
- 241000222178 Candida tropicalis Species 0.000 description 3
- 201000007336 Cryptococcosis Diseases 0.000 description 3
- 241000221204 Cryptococcus neoformans Species 0.000 description 3
- 101000745711 Homo sapiens Cytochrome P450 3A4 Proteins 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 229940055022 candida parapsilosis Drugs 0.000 description 3
- 239000006285 cell suspension Substances 0.000 description 3
- 238000004296 chiral HPLC Methods 0.000 description 3
- 229940121657 clinical drug Drugs 0.000 description 3
- 229940126208 compound 22 Drugs 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 102000044284 human CYP3A4 Human genes 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 231100000053 low toxicity Toxicity 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 206010040872 skin infection Diseases 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 2
- CMSMOCZEIVJLDB-CQSZACIVSA-N (2r)-n,n-bis(2-chloroethyl)-2-oxo-1,3,2$l^{5}-oxazaphosphinan-2-amine Chemical compound ClCCN(CCCl)[P@@]1(=O)NCCCO1 CMSMOCZEIVJLDB-CQSZACIVSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical compound C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
- DVLFYONBTKHTER-UHFFFAOYSA-N 3-(N-morpholino)propanesulfonic acid Chemical compound OS(=O)(=O)CCCN1CCOCC1 DVLFYONBTKHTER-UHFFFAOYSA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- OZFPSOBLQZPIAV-UHFFFAOYSA-N 5-nitro-1h-indole Chemical compound [O-][N+](=O)C1=CC=C2NC=CC2=C1 OZFPSOBLQZPIAV-UHFFFAOYSA-N 0.000 description 2
- YYFFEPUCAKVRJX-UHFFFAOYSA-N 6-fluoro-1h-indole Chemical compound FC1=CC=C2C=CNC2=C1 YYFFEPUCAKVRJX-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 241000675278 Candida albicans SC5314 Species 0.000 description 2
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 229940126639 Compound 33 Drugs 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000037026 Invasive Fungal Infections Diseases 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 2
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 229940125851 compound 27 Drugs 0.000 description 2
- 229940127204 compound 29 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- SMZORVKKJCIPCG-UHFFFAOYSA-N iodo(trimethyl)-$l^{4}-sulfane Chemical compound CS(C)(C)I SMZORVKKJCIPCG-UHFFFAOYSA-N 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 229960004125 ketoconazole Drugs 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- 208000007288 14-alpha Demethylase Inhibitors Diseases 0.000 description 1
- 239000002615 14-alpha demethylase Inhibitor Substances 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- ZUNFPBNHELLPPP-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[2-(dimethylamino)ethyl]benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCCN(C)C)C=CC=1 ZUNFPBNHELLPPP-UHFFFAOYSA-N 0.000 description 1
- ILINOHVVKWYAFM-UHFFFAOYSA-N 5,6-dichloro-1h-indole Chemical compound C1=C(Cl)C(Cl)=CC2=C1NC=C2 ILINOHVVKWYAFM-UHFFFAOYSA-N 0.000 description 1
- STVHMYNPQCLUNJ-UHFFFAOYSA-N 5-bromo-1h-indazole Chemical compound BrC1=CC=C2NN=CC2=C1 STVHMYNPQCLUNJ-UHFFFAOYSA-N 0.000 description 1
- LPTVWZSQAIDCEB-UHFFFAOYSA-N 5-bromo-1h-pyrrolo[2,3-b]pyridine Chemical compound BrC1=CN=C2NC=CC2=C1 LPTVWZSQAIDCEB-UHFFFAOYSA-N 0.000 description 1
- MFZQJIKENSPRSJ-UHFFFAOYSA-N 5-chloro-1h-pyrrolo[2,3-b]pyridine Chemical compound ClC1=CN=C2NC=CC2=C1 MFZQJIKENSPRSJ-UHFFFAOYSA-N 0.000 description 1
- CGCHCLICSHIAAM-UHFFFAOYSA-N 5-iodo-1h-indazole Chemical compound IC1=CC=C2NN=CC2=C1 CGCHCLICSHIAAM-UHFFFAOYSA-N 0.000 description 1
- GZWWDKIVVTXLFL-UHFFFAOYSA-N 5-methoxy-1h-indazole Chemical compound COC1=CC=C2NN=CC2=C1 GZWWDKIVVTXLFL-UHFFFAOYSA-N 0.000 description 1
- YPKBCLZFIYBSHK-UHFFFAOYSA-N 5-methylindole Chemical compound CC1=CC=C2NC=CC2=C1 YPKBCLZFIYBSHK-UHFFFAOYSA-N 0.000 description 1
- MAWGHOPSCKCTPA-UHFFFAOYSA-N 6-bromo-1h-indole Chemical compound BrC1=CC=C2C=CNC2=C1 MAWGHOPSCKCTPA-UHFFFAOYSA-N 0.000 description 1
- ONYNOPPOVKYGRS-UHFFFAOYSA-N 6-methylindole Natural products CC1=CC=C2C=CNC2=C1 ONYNOPPOVKYGRS-UHFFFAOYSA-N 0.000 description 1
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical group NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 102000004328 Cytochrome P-450 CYP3A Human genes 0.000 description 1
- 108010081668 Cytochrome P-450 CYP3A Proteins 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 108010049047 Echinocandins Proteins 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 101000737796 Homo sapiens Cerebellar degeneration-related protein 2 Proteins 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 101150066553 MDR1 gene Proteins 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 241000222126 [Candida] glabrata Species 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 208000032343 candida glabrata infection Diseases 0.000 description 1
- 201000003984 candidiasis Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000003208 gene overexpression Methods 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 231100000334 hepatotoxic Toxicity 0.000 description 1
- 230000003082 hepatotoxic effect Effects 0.000 description 1
- 102000056262 human PPIG Human genes 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000007793 ph indicator Substances 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- 150000004291 polyenes Chemical class 0.000 description 1
- 229960001589 posaconazole Drugs 0.000 description 1
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003239 susceptibility assay Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing 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
- A61P31/10—Antimycotics
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (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)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明属于医药领域，公开了结构如式I所示的含苯并氮杂环侧链的三氮唑醇类化合物，其外消旋体、R型异构体、S型异构体、药学上可接受的盐，R1和R2分别独立的代表氢、甲基、甲氧基、氟、氯、溴、碘、硝基；n为2～10的整数；X代表N、CH；Y代表N、CH。本发明化合物的体外抗真菌活性优于临床药物，对临床唑类药物的耐药真菌株敏感性好，且对真菌14α‑去甲基化酶(CYP51)选择性高，毒副作用小；高浓度下未表现出溶血作用，安全性好，具有制备抗真菌药物的用途。本发明还公开了所述的含苯并氮杂环侧链的三氮唑醇类化合物或其外消旋体、R型异构体、S型异构体、药学上可接受的盐在制备抗真菌药物中的用途。
Description
技术领域
本发明属于抗真菌药物领域，具体涉及一种含苯并氮杂环侧链的三氮唑醇类抗真菌化合物及其制备方法与在制备防治真菌感染药物中的应用。
背景技术
由于免疫抑制剂、广谱抗生素等的大量使用，深部真菌感染的发生率大幅度上升，已成为一种具有较高致死率的临床常见病。目前，临床上用于抗真菌的药物种类有限，主要是唑类、多烯类、棘白菌素类，且部分药物存在抗菌谱窄、副作用大等问题。而一线抗深部真菌感染药物如氟康唑、伊曲康唑、伏立康唑等由于大量应用，耐药性问题严重，常常不能满足临床需要。因此，开发高效、广谱和低毒，特别是对临床耐药株敏感的新型抗真菌药物具有重要意义。
14α-去甲基化酶(CYP51)是临床上用来治疗侵袭性真菌感染的主要靶点。唑类药物是一类代表性的CYP51酶抑制剂，是临床上使用最广泛的抗真菌药物，包括氟康唑、伊曲康唑、伏立康唑等。但受耐药作用的影响，唑类药物抗菌效果逐步下降，各类菌株对抗菌药物产生耐药作用的机制复杂而多变。因此，对唑类药物结构进行合理修饰，开发新型唑类CYP51靶向小分子抑制剂是解决问题的重要途径之一。构效关系研究表明唑类侧链与CYP51底物进出通道中的氨基酸残基相互作用，不同的疏水性和氢键作用可能会使小分子在提高药效力、逆转耐药性和治愈霉菌感染等方面具有优势。例如伊曲康唑和泊沙康唑由于具有长侧链结构，不仅能有效治疗念珠菌病，还能治疗曲霉病和隐球菌病。因此，设计不同类型及长度侧链的唑类CYP51抑制剂是开发新型唑类药物的一个有效途径。
发明内容
本发明的目的在于解决临床上抗真菌药物的不足，提供高效、广谱和低毒的抗真菌药物。本发明基于氟康唑核心骨架合成了一种新型含苯并氮杂环侧链的三氮唑醇类抗真菌化合物或其药学上可接受的盐。
本发明的目的是通过以下技术方案实现的：
结构如式I所示的含苯并氮杂环侧链的三氮唑醇类化合物，其外消旋体、R型异构体、S型异构体、药学上可接受的盐：
其中：R1和R2分别独立的代表氢、甲基、甲氧基、氟、氯、溴、碘、硝基；
nX为代2表～N1、0C的H整；数；
Y代表N、CH。
优选的，R1代表氢、甲基、甲氧基、氟、氯、溴、碘、硝基；R2代表氢、甲基、甲氧基、氟、氯、溴、硝基；
n为2～10的整数；
X代表N、CH；
Y代表N、CH。
更优选的，R1代表氢、甲基、甲氧基、氯、溴、硝基、碘；R2代表氢、氟、氯、溴；
n为2～4的整数；
X代表N、CH；
Y代表N、CH。
具体的，结构如下所示的含苯并氮杂环侧链的三氮唑醇类化合物，其外消旋体、R型异构体、S型异构体、药学上可接受的盐：
所述的药学上可接受的盐包括但不限于式I所示的化合物的盐酸盐、硫酸盐、磷酸盐、马来酸盐、富马酸盐、枸橼酸盐、甲磺酸盐、对甲苯磺酸盐、酒石酸或醋酸盐。
本发明的另一目的是提供一种所述的含苯并氮杂环侧链的三氮唑醇类化合物的制备方法，合成路线为：
其中，R1、R2、n、X、Y如前所述；
具体包括如下步骤：
步骤(1)、制备1-(2,4-二氟苯基)-2-(1H-1,2,4-三唑-1-基)乙烷-1-酮(化合物H3)：化合物H1与化合物H2的摩尔比为1:1.3，化合物H1与碳酸钾的摩尔比为1:1.3，化合物H1与TEBA的摩尔比为37：1，反应溶剂为二氯甲烷，反应温度为室温(25±5℃)，反应时间为10-20小时；
步骤(2)、制备1-[2-(2,4-二氟苯基)-2,3-环氧丙基]-1H-1,2,4-三唑甲烷磺酸盐(化合物H4)：化合物H3与三甲基氧化硫碘的摩尔比为1:1，化合物H3与三甲基十六烷基溴化铵的摩尔比为40:1，化合物H3与氢氧化钠的摩尔比为1:3，化合物H3与甲烷磺酸的摩尔比为1:1，反应溶剂为甲苯，反应温度为60℃，反应时间时间为3-5小时；
步骤(3)、制备化合物H7：式H5所示的杂环胺与式H6所示的二溴烷烃的摩尔比为1:3，式H5所示的的杂环胺与氢化钠的摩尔比为1:2.5，反应溶剂为二甲亚砜，反应温度为室温(25±5℃)，反应时间为5-10小时，得到化合物H7；
步骤(4)、制备化合物H8：化合物H7与碳酸钾的摩尔比为1:2，化合物H7与哌嗪的摩尔比为1:6，反应溶剂为乙腈，反应温度为室温(25±5℃)，反应时间为15-20小时，得到化合物H8；
步骤(5)、制备式I所示的含苯并氮杂环侧链的三氮唑醇类化合物：化合物H4与化合物H8的摩尔比为1:1.25，化合物H4与三乙胺的摩尔比为1:3.3，反应溶剂为乙醇，反应温度为80℃，反应时间为10-20小时，得到含苯并氮杂环侧链的三氮唑醇类化合物。
本发明所述的含苯并氮杂环侧链的三氮唑醇类化合物对多种念珠菌、烟曲霉和隐球菌均表现出良好的活性，对临床唑类药物的耐药真菌株敏感性好，且部分体外抗真菌活性优于临床药物，对真菌14α-去甲基化酶(CYP51)选择性高，毒副作用小；高浓度下未表现出溶血作用，安全性好；且本发明化合物不易使真菌产生耐药性，显著优于氟康唑。说明本发明化合物具有良好的开发应用前景。
本发明的另一个目的是提供所述的含苯并氮杂环侧链的三氮唑醇类化合物或其外消旋体、R型异构体、S型异构体、药学上可接受的盐在制备抗真菌药物中的用途。
优选的，所述的用途为在制备治疗真菌感染引起的浅部或深部感染疾病药物中的用途。
所述的真菌为不耐药真菌或耐药真菌。优选的，所述的真菌为不耐药真菌或耐药的念珠菌属、隐球菌属、曲霉菌属真菌。具体的，所述的真菌包括但不限于标准菌：白色念珠菌、近平滑念珠菌、热带念珠菌、季也蒙念珠菌、光滑念珠菌、新型隐球菌、烟曲霉菌。白色念珠菌临床分离株：CA24D，CA102，CA901，CA112869；外排泵过表达株：YEM13，YEM15。
本发明的另一个目的是提供一种药物，它是以所述的含苯并氮杂环侧链的三氮唑醇类化合物或其外消旋体、R型异构体、S型异构体、药学上可接受的盐添加药学上可接受的辅料制成的常见药用制剂。
所述的药学上可接受的辅料为香料、甜味剂、稀释剂、液体或固体填料等常用药用辅料。
所述的药用制剂为片剂、粉剂、胶囊、糖浆、针剂，液剂、悬浮剂。
本发明所述的含苯并氮杂环侧链的三氮唑醇类化合物或其外消旋体、R型异构体、S型异构体、药学上可接受的盐在临床上的给药方式可以采用注射、口服等方式。
附图说明
图1是化合物24的手性HPLC色谱图。
图2是化合物S-24的手性HPLC色谱图。
图3是受试药物抗耐药性考察结果。
图4是化合物对白色念珠菌SC5314(A)和白色念珠菌耐药株24D(B)全身感染模型的治疗作用；其中，*p<0.05，***p<0.001。
图5是化合物对白色念珠菌SC5314皮肤感染模型治疗作用。
具体实施方式
下面通过具体实施方式对本发明的技术方案作进一步说明。
实施例1
1-(2,4-二氟苯基)-2-(1H-1,2,4-三唑-1-基)乙烷-1-酮(化合物H3)的合成
将化合物H2(4.49g，0.065mol)、TEBA(0.25g，1.350mmol)、K2CO3(8.0g，0.065mol)悬浮于CH2Cl2(50mL)中，于0℃滴加化合物H1(9.5g，0.05mol)的CH2Cl2(50mL)悬浮液，滴加完毕，室温反应20小时，滤除残渣，减压回收溶剂，得到化合物H3粗品(7.350g)。将粗品倒入冰水(300mL)中，加入1mol/L盐酸(100mL)使粗品全部溶解，静置分层除去不溶油状物，水相用NaHCO3(5g)中和，至pH8-9，得到白色沉淀(化合物H3，6.96g,62.4％)。
1H NMR(500MHz,CDCl3)δ8.22(s,1H),8.08–8.02(m,1H),8.01(s,1H),7.09–7.03(m,1H),7.00–6.96(m,1H),5.60(d,J＝3.4Hz,2H).13C NMR(125MHz,CDCl3)δ187.66,167.88(d,J＝12.7Hz),165.81(d,J＝12.7Hz),164.23(d,J＝12.7Hz),162.18(d,J＝12.8Hz),151.97,144.89,133.20(dd,J＝10.8,4.4Hz),119.02(dd,J＝14.1,3.5Hz),113.24(dd,J＝21.7,3.1Hz),106.14–103.96(m),58.50(d,J＝13.6Hz).
1-[2-(2,4-二氟苯基)-2,3-环氧丙基]-1H-1,2,4-三唑甲烷磺酸盐(化合物H4)的合成取2′,4′-二氟-2-(1H-1,2,4-三唑-1-基)苯乙酮5.2g(0.023mol)、三甲基氧化硫碘5.1g(0.023mol)和三甲基十六烷基溴化铵0.210g(0.577mmol)，放入100mL三颈瓶中，加入甲苯40mL和20％的氢氧化钠溶液10mL，60℃加热搅拌3小时，分离出甲苯层，水层用甲苯萃取，合并甲苯液，水洗至中性，回收绝大部分甲苯后向残留液中加入甲烷磺酸2.200g(0.023mol)与20mL乙酸乙酯配成的溶液，振摇均匀，冷却充分，抽滤，固体用乙酸乙酯洗涤，干燥后无水乙醇重结晶，得到白色固体(化合物H4)3.950g，收率51.1％。
1H NMR(500MHz,D2O)δ9.12(s,1H),8.38(s,1H),7.08–7.13(m,1H),6.88(t,J＝10.7Hz,1H),6.81(t,J＝8.5Hz,1H),5.02(d,J＝15.0Hz,1H),4.58(d,J＝15.0Hz,1H),3.19(d,J＝4.1Hz,1H),3.03(d,J＝4.0Hz,1H),2.68(s,3H).
5-溴-1-(5-溴戊基)-1H-吲哚(化合物L3)的合成
在50mL三颈瓶中，加入5-溴吲哚(化合物L1，1.000g，5.155mmol)、NaH(0.300g，12.500mmol)、无水DMSO(20mL)，室温搅拌1小时，向反应液中加入1,5-二溴戊烷(化合物L2，2.500g，15.300mmol)，室温下继续搅拌反应10小时，此时TLC检测反应完全。向反应液中缓慢滴加水淬灭反应，乙酸乙酯萃取，有机相无水硫酸钠干燥；硅胶柱层析(洗脱剂为乙酸乙酯:石油醚＝1:10V/V)得到淡黄色油状物(化合物L3)1.100g，收率61.2％。
1H NMR(500MHz,CDCl3)δ7.78(d,J＝1.2Hz,1H),7.34–7.27(m,1H),7.22(d,J＝8.7Hz,1H),7.12(d,J＝2.9Hz,1H),6.46(d,J＝2.8Hz,1H),4.13(t,J＝7.0Hz,2H),3.39(t,J＝6.7Hz,2H),1.91–1.84(m,4H),1.50–1.44(m,2H).13C NMR(125MHz,CDCl3)δ134.59,130.28,128.91,124.28,123.46,112.61,110.76,100.77,46.37,33.33,32.25,29.41,25.57.
5-溴-1-(5-(哌嗪-1-基)戊基)-1H-吲哚(化合物L4)的合成
将化合物L3(1.100g,3.180mmol)、K2CO3(0.870g,6.360mmol)、哌嗪(1.640g,19.100mmol)置于乙腈(30mL)中，室温搅拌10小时。TLC检测反应完全，抽滤，将滤液浓缩，硅胶柱层析(洗脱剂为二氯甲烷:甲醇＝10:1V/V)得到黄色油状物(化合物L4)0.750g，收率68.3％。
1H NMR(500MHz,CDCl3)δ7.76(d,J＝1.5Hz,1H),7.32–7.24(m,1H),7.21(d,J＝8.7Hz,1H),7.10(d,J＝3.0Hz,1H),6.43(d,J＝2.6Hz,1H),4.10(t,J＝7.1Hz,2H),2.90(t,J＝4.8Hz,4H),2.44–2.40(m,4H),2.31–2.25(m,2H),2.09(s,1H),1.88–1.82(m,2H),1.55–1.48(m,2H),1.34-1.28(m,2H).13C NMR(125MHz,CDCl3)δ134.61,130.22,128.90,124.16,123.38,112.50,110.78,100.58,59.00,54.49,46.49,46.01,30.09,26.24,24.89.
1-(5-(5-溴-1H-吲哚-1-基)戊基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物12)的合成
取1-[2-(2,4-二氟苯基)-2,3-环氧丙基]-1H-1,2,4-三唑甲烷磺酸盐(化合物H4,220mg,0.662mmol)、5-溴-1-(5-(哌嗪-1-基)戊基)-1H-吲哚(化合物L4,200mg,0.828mmol)、三乙胺(0.300mL，2.162mmol)，溶于30mL无水乙醇中，加热回流10小时。反应结束后，蒸干溶剂，硅胶柱层析(洗脱剂为二氯甲烷:甲醇＝100:1V/V)得产物(化合物12)0.230g，淡黄色油状物，产率59.1％。
1H NMR(500MHz,CDCl3)δ8.17(s,1H),7.82(s,1H),7.76(d,J＝1.2Hz,1H),7.59–7.55(m,1H),7.30(d,J＝3.2Hz,1H),7.20(d,J＝8.7Hz,1H),7.09(d,J＝2.9Hz,1H),6.84(dd,J＝13.1,6.0Hz,2H),6.44(d,J＝2.5Hz,1H),5.30(s,1H),4.60–4.47(m,2H),4.09(t,J＝7.0Hz,2H),3.08(d,J＝13.5Hz,1H),2.68(d,J＝13.6Hz,1H),2.32(br,10H),1.86–1.80(m,2H),1.49–1.43(m,2H),1.31–1.25(m,2H).13C NMR(125MHz,CDCl3)δ163.73(d,J＝12.2Hz),161.74(d,J＝12.0Hz),159.93(d,J＝11.8Hz),157.97(d,J＝11.6Hz),151.07,144.66,134.61,130.23,129.32(dd,J＝9.2,6.0Hz),128.89,126.25(dd,J＝12.9,3.6Hz),124.19,123.40,112.53,111.56(dd,J＝20.5,3.0Hz),110.77,104.31(t,J＝26.3Hz),100.62,71.95(d,J＝5.3Hz),62.26(d,J＝3.25Hz),58.07,56.39(d,J＝4.66Hz),54.21,53.16,46.46,30.01,26.28,24.76；HRMS(ESI)m/z:calcd for C28H34BrF2N6O[M+H]+,587.1946,found,587.1939.
实施例2
1-(4-(10-(6-氯-1H-吲哚-1-基)癸基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物1)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,10-二溴癸烷替换实施例1中的1,5-二溴戊烷、等摩尔6-氯吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物1，淡黄色油状物，产率为51.9％。
1H NMR(600MHz,CDCl3)δ8.15(s,1H),7.80(s,1H),7.58–7.51(m,2H),7.32(s,1H),7.11–7.02(m,2H),6.85–6.78(m,1H),6.42(d,J＝3.0Hz,1H),5.31(s,1H),4.56–4.49(m,2H),4.05(t,J＝7.8Hz,2H).3.07(d,J＝13.6Hz,2H),2.67(d,J＝13.6Hz,1H),2.35(br,10H),1.84–1.78(m,2H),1.42(t,J＝16.9Hz,2H),1.30(br,12H).13C NMR(150MHz,CDCl3)δ163.53(d,J＝12.1Hz),161.88(d,J＝12.1Hz),159.75(d,J＝11.7Hz),158.12(d,J＝11.7Hz),151.02,144.64,136.34,129.30(dd,J＝9.3,5.9Hz),128.50,127.32,127.05,126.25(dd,J＝12.9,3.5Hz),121.73,119.84,111.53(dd,J＝20.5,3.1Hz),109.38,104.29(t,J＝26.3Hz),101.11,71.90(d,J＝5.4Hz),62.25(d,J＝14.4Hz),58.54,56.38(d,J＝4.8Hz),54.23,53.17,46.52,30.12,29.44,29.40,29.38,29.16,27.44,26.91,26.66；HRMS(ESI)m/z:calcd for C33H44ClF2N6O[M+H]+,613.3288,found,613.3226.
实施例3
2-(2,4-二氟苯基)-1-(4-(10-(5-甲氧基-1H-吲哚-1-基)癸基)哌嗪-1-基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物2)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,10-二溴癸烷替换实施例1中的1,5-二溴戊烷、等摩尔5-甲氧基吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物2，淡黄色油状物，产率为53.4％。
1H NMR(600MHz,CDCl3)δ8.09(s,1H),7.80(s,1H),7.53–7.47(m,1H),7.23(d,J＝8.8Hz,1H),7.08(dd,J＝17.4,2.5Hz,2H),6.87(dd,J＝8.8,2.3Hz,1H),6.83–6.77(m,2H),6.40(d,J＝2.9Hz,1H),4.58(br,2H),4.07(t,J＝7.1Hz,2H),3.86(s,3H),3.11(d,J＝13.6Hz,1H),2.81(br,11H),1.84–1.76(m,2H),1.70(br,2H),1.26(br,12H).13C NMR(150MHz,CDCl3)δ163.61(d,J＝12.1Hz),161.95(d,J＝12.3Hz),159.56(d,J＝11.7Hz),157.93(d,J＝11.7Hz),153.83,151.33,144.54,131.31,129.48(dd,J＝9.2,5.8Hz),128.83,128.33,125.14(d,J＝7.8Hz),111.67,111.66(dd,J＝20.5,2.9Hz),110.10,104.32(t,J＝26.4Hz),102.52,100.31,73.88(d,J＝3.0Hz),62.30(d,J＝3.5Hz),57.60,55.89(d,J＝3.0Hz),52.22,51.63,46.55,45.86,30.26,29.70,29.26,29.22,29.12,29.03,26.91,26.88；HRMS(ESI)m/z:calcd for C34H47F2N6O2[M+H]+,609.3728,found,609.3721.
实施例4
1-(4-(10-(5-氯-1H-吲哚-1-基)癸基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物3)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,10-二溴癸烷替换实施例1中的1,5-二溴戊烷、等摩尔5-氯吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物3，淡黄色油状物，产率为49.9％。
1H NMR(600MHz,CDCl3)δ8.15(s,1H),7.80(s,1H),7.59(d,J＝1.2Hz,1H),7.58–7.52(m,1H),7.25(d,J＝8.7Hz,1H),7.15(dd,J＝8.7,1.6Hz,1H),7.11(d,J＝3.0Hz,1H),6.86–6.78(m,2H),6.42(d,J＝3.0Hz,1H),5.31(s,1H),4.58–4.48(m,2H),4.08(t,J＝7.1Hz,2H),3.07(d,J＝13.5Hz,1H),2.67(d,J＝13.6Hz,1H),2.31(br,10H),1.85–1.77(m,2H),1.40(br,2H),1.26(br,12H).13C NMR(150MHz,CDCl3)δ163.54(d,J＝12.0Hz),161.88(d,J＝12.1Hz),159.75(d,J＝11.7Hz),158.12(d,J＝11.8Hz),151.04,144.64,134.36,129.50,129.31(dd,J＝9.3,5.9Hz),129.06,126.36–126.14(m),124.88,121.57,120.23,111.53(dd,J＝20.5,3.1Hz),110.34,104.29(t,J＝26.3Hz),100.54,71.91(d,J＝4.98Hz),62.25(d,J＝3.7Hz),58.53,56.37(d,J＝4.83Hz),54.22,53.18,46.59,30.19,29.43,29.39,29.37,29.16,27.44,26.91,26.66；HRMS(ESI)m/z:calcd for C33H44ClF2N6O[M+H]+,613.3228,found,613.3224.
实施例5
1-(4-(10-(5-溴-1H-吲哚-1-基)癸基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物4)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,10-二溴癸烷替换实施例1中的1,5-二溴戊烷，其他条件均不变，得到化合物4，淡黄色油状物，产率为45.8％。
1H NMR(600MHz,CDCl3)δ8.15(s,1H),7.79(s,1H),7.75(d,J＝1.8Hz,1H),7.57–7.52(m,1H),7.28–7.26(m,1H),7.21(d,J＝8.7Hz,1H),7.09(d,J＝3.1Hz,1H),6.84–6.79(m,2H),6.42(d,J＝3.0Hz,1H),4.58–4.46(m,2H),4.08(t,J＝7.1Hz,2H),3.07(d,J＝13.5Hz,1H),2.68(d,J＝13.6Hz,1H),2.31(br,10H),1.86–1.76(m,2H),1.47–1.39(m,2H),1.34(br,12H).13CNMR(150MHz,CDCl3)δ163.54(d,J＝12.1Hz),161.89(d,J＝12.0Hz),159.74(d,J＝11.8Hz),158.10(d,J＝11.8Hz),151.03,144.63,134.62,130.19,129.31(dd,J＝9.3,5.9Hz),128.92,126.16(dd,J＝12.9,3.6Hz),124.10,123.34,112.45,111.54(dd,J＝20.5,3.1Hz),110.81,104.53–104.06(m),100.48,72.01(d,J＝5.4Hz),62.25(d,J＝3.6Hz),58.44,56.35(d,J＝4.9Hz),54.04,53.08,46.57,30.17,29.41,29.38,29.36,29.15,27.41,26.89,26.49；HRMS(ESI)m/z:calcd for C33H44BrF2N6O[M+H]+,657.2728,found,657.2724.
实施例6
1-(4-(9-(5-溴-1H-吲哚-1-基)壬基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物5)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,9-二溴壬烷替换实施例1中的1,5-二溴戊烷，其他条件均不变，得到化合物5，淡黄色油状物，产率为53.6％。
1H NMR(600MHz,CDCl3)δ8.16(s,1H),7.80(s,1H),7.75(d,J＝1.5Hz,1H),7.59–7.52(m,1H),7.27(d,J＝1.7Hz,1H),7.20(d,J＝8.7Hz,1H),7.09(d,J＝3.0Hz,1H),6.85–6.79(m,2H),6.42(d,J＝2.5Hz,1H),4.56–4.48(m,2H),4.08(t,J＝7.1Hz,2H),3.07(d,J＝13.5Hz,1H),2.67(d,J＝13.6Hz,1H),2.31(br,10H),1.86–1.73(m,2H),1.40(br,2H),1.25(br,10H).13CNMR(150MHz,CDCl3)δ163.53(d,J＝12.1Hz),161.92(d,J＝11.9Hz),159.75(d,J＝11.7Hz),158.12(d,J＝11.7Hz),151.04,144.65,134.61,130.19,129.30(dd,J＝9.3,5.9Hz),128.92,126.27(dd,J＝12.9,3.4Hz),124.11,123.35,112.46,111.54(dd,J＝20.6,3.0Hz),110.81,104.64–104.01(m),100.49,71.84(d,J＝5.2Hz),62.23(d,J＝3.7Hz),58.53,56.37(d,J＝4.9Hz),54.28,53.20,46.57,30.17,29.38,29.33,29.12,27.42,26.89,26.70；HRMS(ESI)m/z:calcd for C32H42BrF2N6O[M+H]+,643.2566,found,643.2562.
实施例7
2-(2,4-二氟苯基)-1-(4-(9-(5-甲氧基-1H-吲哚-1-基)壬基)哌嗪-1-基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物6)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,9-二溴壬烷替换实施例1中的1,5-二溴戊烷、等摩尔5-甲氧基吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物6，淡黄色油状物，产率为61.4％。
1H NMR(500MHz,CDCl3)δ8.18(s,1H),7.83(s,1H),7.63–7.57(m,1H),7.25(d,J＝8.8Hz,1H),7.15–7.06(m,2H),6.93–6.88(m,1H),6.85(t,J＝9.9Hz,2H),6.44–6.43(d,J＝2.5Hz,1H),5.33(s,1H),4.60–4.51(m,2H),4.10(t,J＝7.0Hz,2H),3.89(s,3H),3.10(d,J＝13.4Hz,1H),2.70(d,J＝13.6Hz,1H),2.35(br,10H),1.84(br,2H),1.44(br,2H),1.29(br,10H).13CNMR(125MHz,CDCl3)δ163.70(d,J＝12.6Hz),161.75(d,J＝12.0Hz),159.95(d,J＝11.7Hz),157.99(d,J＝12.6Hz),153.90,151.08,144.66,131.36,129.34(dd,J＝9.3,6.0Hz),128.87,128.27,126.28(dd,J＝12.8,3.6Hz),111.73,111.55(dd,J＝20.6,3.0Hz),110.08,104.30(t,J＝26.3Hz),102.57,100.35,71.97(d,J＝4.5Hz),62.30(d,J＝3.654Hz),58.51,56.40(d,J＝4.7Hz),55.91,54.24,53.18,46.58,30.29,29.40,29.37,29.17,27.43,26.97,26.63；HRMS(ESI)m/z:calcd for C33H45F2N6O2[M+H]+,595.3576,found,595.3569.
实施例8
1-(4-(9-(6-氯-1H-吲哚-1-基)壬基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物7)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,9-二溴壬烷替换实施例1中的1,5-二溴戊烷、等摩尔6-氯吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物7，淡黄色油状物，产率为58.6％。
1H NMR(600MHz,CDCl3)δ8.15(s,1H),7.79(s,1H),7.53(dd,J＝17.8,7.9Hz,2H),7.32(s,1H),7.06(d,J＝14.3Hz,1H),6.84–6.77(m,2H),6.45(s,1H),5.31(s,1H),4.57–4.45(m,10H),4.05(t,J＝6.9Hz,2H),3.07(d,J＝13.6Hz,1H),2.67(d,J＝13.6Hz,1H),2.49–2.18(br,16H),1.85–1.76(m,2H),1.48–1.37(m,2H),1.37–1.19(br,10H).13C NMR(150MHz,CDCl3)δ163.53(d,J＝12.0Hz),161.88(d,J＝12.1Hz),159.75(d,J＝11.7Hz),158.11(d,J＝11.7Hz),151.03,144.63,136.34,129.31(dd,J＝9.2,5.9Hz),128.50,127.32,127.05,126.23(dd,J＝12.8,3.5Hz),121.73,119.84,111.53(dd,J＝20.5,2.9Hz),109.37,104.29(t,J＝26.3Hz),101.11,71.92(d,J＝5.3Hz),62.25(d,J＝3.6Hz),58.49,56.38,54.19,53.16,46.50,30.11,29.36,29.33,29.11,27.40,26.88,26.60；HRMS(ESI)m/z:calcd for C32H42ClF2N6O[M+H]+,599.3077,found,599.3072.
实施例9
1-(4-(9-(5-氯-1H-吲哚-1-基)壬基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物8)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,9-二溴壬烷替换实施例1中的1,5-二溴戊烷、等摩尔5-氯吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物8，淡黄色油状物，产率为63.6％。
1H NMR(600MHz,CDCl3)δ8.11(s,1H),7.80(s,1H),7.58(d,J＝1.2Hz,1H),7.56–7.50(m,1H),7.25(d,J＝8.7Hz,1H),7.16–7.13(m,1H),7.11(d,J＝3.0Hz,1H),6.84–6.78(m,2H),6.42(d,J＝3.1Hz,1H),4.58–4.53(m,2H),4.08(t,J＝7.0Hz,2H),3.09(d,J＝13.7Hz,1H),2.73(d,J＝13.7Hz,1H),2.53(br,10H),1.80(t,J＝7.0Hz,2H),1.53(br,2H),1.25(br,10H).13C NMR(150MHz,CDCl3)δ163.58(d,J＝12.2Hz),161.93(d,J＝12.2Hz),159.64(d,J＝11.7Hz),158.01(d,J＝11.8Hz),151.23,144.58,134.37,129.50,129.39(dd,J＝9.3,5.9Hz),129.09,125.66(d,J＝16.4Hz),124.86,121.56,120.23,111.62(dd,J＝20.6,2.9Hz),110.36,104.74–103.93(m),100.57,72.93(d,J＝5.7Hz),62.26(d,J＝3.6Hz),58.02,56.10(d,J＝4.38Hz),53.01,52.67,46.56,30.14,29.71,29.20,29.12,29.03,27.10,26.82；HRMS(ESI)m/z:calcd for C32H42ClF2N6O[M+H]+,599.3077,found,599.3076.
实施例10
2-(2,4-二氟苯基)-1-(4-(6-(5-甲氧基-1H-吲哚-1-基)己基)哌嗪-1-基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物9)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,6-二溴己烷替换实施例1中的1,5-二溴戊烷、等摩尔5-甲氧基吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物9，淡黄色油状物，产率为43.4％。
1H NMR(500MHz,CDCl3)δ8.18(s,1H),7.82(s,1H),7.61–7.56(m,1H),7.24(d,J＝8.8Hz,1H),7.14–7.05(m,2H),6.92–6.80(m,3H),6.42(d,J＝2.0Hz,1H),5.31(s,1H),4.59–4.49(m,2H),4.09(t,J＝6.9Hz,2H),3.88(s,3H),3.09(d,J＝13.5Hz,1H),2.70(d,J＝13.6Hz,1H),2.34(br,10H),1.80(br,2H),1.43(br,2H),1.31(br,4H).13C NMR(125MHz,CDCl3)δ163.74(d,J＝12.1Hz),161.75(d,J＝11.8Hz),159.95(d,J＝11.7Hz),157.99(d,J＝11.7Hz),153.92,151.07,144.66,131.33,129.34(dd,J＝9.3,5.9Hz),128.89,128.27,126.27(dd,J＝12.8,3.7Hz),111.75,111.55(dd,J＝20.5,2.9Hz),110.06,104.59–103.99(m),102.59,100.41,71.98(d,J＝5.2Hz),62.29(d,J＝3.7Hz),58.26,56.37(d,J＝4.78Hz),55.90,54.24,53.15,46.47,30.18,27.06,26.84,26.51；HRMS(ESI)m/z:calcdfor C30H39F2N6O2[M+H]+,53.3097,found,553.3099.
实施例11
1-(4-(6-(6-氟-1H-吲哚-1-基)己基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1，2，4-三唑-1-基)丙烷-2-醇(化合物10)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,6-二溴己烷替换实施例1中的1,5-二溴戊烷、等摩尔6-氟吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物10，淡黄色油状物，产率为42.6％。
1H NMR(600MHz,CDCl3)δ8.15(s,1H),7.80(s,1H),7.57–7.52(m,2H),7.06(d,J＝3.1Hz,1H),6.99(dd,J＝10.0,1.9Hz,1H),6.89–6.80(m,3H),6.46(d,J＝3.1Hz,1H),4.57–4.49(m,2H),4.05(t,J＝7.0Hz,2H),3.08(d,J＝13.5Hz,1H),2.67(d,J＝13.6Hz,1H),2.41(br,10H),1.84–1.78(m,2H),1.43(br,2H),1.31(br,4H).13C NMR(150MHz,CDCl3)δ163.55(d,J＝12.2Hz),161.89(d,J＝12.0Hz),160.43,159.72(d,J＝11.8Hz),158.86,158.08(d,J＝11.8Hz),151.07,144.64,135.89(d,J＝12.0Hz),129.30(dd,J＝9.3,5.9Hz),128.40–128.03(m),126.11(dd,J＝12.4,3.2Hz),124.92,121.60(d,J＝10.2Hz),111.79–111.40(m),107.95(d,J＝24.5Hz),104.32(t,J＝26.3Hz),101.11,95.71(d,J＝26.1Hz)72.02(d,J＝5.1Hz),62.20(d,J＝3.6Hz),58.10,56.30(d,J＝4.8Hz),53.93,53.00,46.44,29.93,26.98,26.75,26.25；HRMS(ESI)m/z:calcd for C29H36F3N6O[M+H]+,541.2897,found,541.2899.
实施例12
1-(4-(6-(5-溴-1H-吲哚-1-基)己基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1，2，4-三唑-1-基)丙烷-2-醇(化合物11)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,6-二溴己烷替换实施例1中的1,5-二溴戊烷，其他条件均不变，得到化合物11，淡黄色油状物，产率为65.6％。
1H NMR(500MHz,CDCl3)δ8.17(s,1H),7.82(s,1H),7.76(s,1H),7.62–7.52(m,1H),7.28(d,J＝8Hz,1H),7.21(d,J＝8.7Hz,1H),7.09(d,J＝2.7Hz,1H),6.84(br,2H),6.43(d,J＝2.4Hz,1H),5.32(s,1H),4.60–4.46(m,2H),4.09(t,J＝6.9Hz,2H),3.08(d,J＝13.5Hz,1H),2.68(d,J＝13.6Hz,1H),2.28(br,10H),1.88–1.73(m,2H),1.41(br,2H),1.29(br,4H).13C NMR(125MHz,CDCl3)δ163.72(d,J＝12.0Hz),161.73(d,J＝12.1Hz),159.93(d,J＝11.7Hz),157.97(d,J＝11.8Hz),151.06,144.67,134.61,130.22,129.32(dd,J＝9.3,6.0Hz),128.94,126.28(dd,J＝12.8,3.5Hz),124.15,123.39,112.50,111.56(dd,J＝20.5,3.0Hz),110.81,104.31(t,J＝26.3Hz),100.56,71.88(d,J＝5.5Hz),62.25(d,J＝3.6Hz),58.26,56.37(d,J＝4.78Hz),54.28,53.18,46.49,30.08,27.03,26.80,26.56；HRMS(ESI)m/z:calcd for C29H36BrF2N6O[M+H]+,601.2097,found,601.2097.
实施例13
2-(2,4-二氟苯基)-1-(4-(5-(5-甲氧基-1H-吲哚-1-基)戊基)哌嗪-1-基)-3-(1H-1，2，4-三唑-1-基)丙烷-2-醇(化合物13)的合成
参照实施例1化合物12的合成方法，采用等摩尔5-甲氧基吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物13，淡黄色油状物，产率为39.4％。
1H NMR(500MHz,CDCl3)δ8.18(s,1H),7.82(s,1H),7.55–7.60(m,1H),7.23(d,J＝8.8Hz,1H),7.12(d,J＝2.0Hz,1H),7.07(d,J＝2.8Hz,1H),6.92–6.79(m,3H),6.42(d,J＝2.7Hz,1H),5.31(s,1H),4.61–4.48(m,2H),4.09(t,J＝6.9Hz,2H),3.88(s,3H),3.09(d,J＝13.4Hz,1H),2.68(d,J＝13.6Hz,1H),2.36(br,10H),1.81-1.87(m,2H),1.43-1.49(m,2H),1.27-1.33(m,2H).13C NMR(125MHz,CDCl3)δ163.73(d,J＝12.1Hz),161.74(d,J＝12.0Hz),159.94(d,J＝11.8Hz),157.98(d,J＝11.7Hz),153.91,151.06,144.67,131.29,129.32(dd,J＝9.2,5.9Hz),128.88,128.25,126.28(dd,J＝12.9,3.5Hz),111.77,111.56(dd,J＝20.6,3.0Hz),110.05,104.31(t,J＝26.3Hz),102.55,100.44,71.90(d,J＝5.4Hz),62.27(d,J＝3.6Hz),58.17,56.39(d,J＝4.9Hz),55.89,54.28,53.19,46.46,30.14,26.37,24.85；HRMS(ESI)m/z:calcd for C29H37F2N6O2[M+H]+,539.2941,found,539.2945.
实施例14
1-(4-(5-(6-氟-1H-吲哚-1-基)戊基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物14)的合成
参照实施例1化合物12的合成方法，采用等摩尔6-氟吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物14，淡黄色油状物，产率为55.6％。
1H NMR(500MHz,CDCl3)δ8.18(s,1H),7.82(s,1H),7.62–7.48(m,2H),7.07(d,J＝3.0Hz,1H),7.01(d,J＝8.4Hz,1H),6.91–6.80(m,3H),6.48(d,J＝2.5Hz,1H),5.27(s,1H),4.52(dd,J＝18.7,7.8Hz,2H),4.06(t,J＝6.9Hz,2H),3.09(d,J＝13.4Hz,1H),2.68(d,J＝13.6Hz,1H),2.31(br,10H),1.90–1.77(m,2H),1.52–1.41(m,2H),1.36–1.23(m,2H).13CNMR(125MHz,CDCl3)δ163.73(d,J＝12.5Hz),161.74(d,J＝12.1Hz),160.63,159.94(d,J＝11.7Hz),158.74,157.97(d,J＝11.8Hz),151.06,144.67,135.93(d,J＝11.9Hz),129.32(dd,J＝9.1,6.0Hz),128.17–128.12(m),126.27(dd,J＝12.9,3.4Hz),124.95,121.62(d,J＝10.2Hz),111.57(dd,J＝20.5,2.8Hz),108.36–107.47(m),104.73–103.98(m),101.18,95.70(d,J＝26.2Hz),71.88(d,J＝4.78Hz),62.24(d,J＝3.52Hz),58.11,56.38(d,J＝4.5Hz),54.26,53.18,46.44,29.90,26.34,24.79；HRMS(ESI)m/z:calcd for C28H34F3N6O[M+H]+,527.2741,found,527.2744.
实施例15
1-(4-(4-(5-溴-1H-吲哚-1-基)丁基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物15)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,4-二溴丁烷替换实施例1中的1,5-二溴戊烷，其他条件均不变，得到化合物15，淡黄色油状物，产率为49.8％。
1H NMR(600MHz,CDCl3)δ8.14(s,1H),7.79(s,1H),7.73(d,J＝1.7Hz,1H),7.57–7.51(m,1H),7.26(dd,J＝8.7,1.8Hz,1H),7.18(d,J＝8.7Hz,1H),7.06(d,J＝3.1Hz,1H),6.85–6.78(m,2H),6.41(d,J＝3.0Hz,1H),4.56–4.47(m,2H),4.08(t,J＝7.0Hz,2H),3.06(d,J＝13.5Hz,1H),2.66(d,J＝13.6Hz,1H),2.35(br,10H),1.84–1.77(m,2H),1.47–1.38(m,2H).13C NMR(150MHz,CDCl3)δ163.54(d,J＝12.1Hz),161.88(d,J＝12.1Hz),159.74(d,J＝11.8Hz),158.10(d,J＝11.78Hz),151.01,144.64,134.56,130.23,129.29(dd,J＝9.3,5.9Hz),128.86,126.17(dd,J＝12.9,3.6Hz),124.17,123.39,112.52,111.55(dd,J＝20.5,3.1Hz),110.77,104.50–104.07(m),100.67,71.94(d,J＝5.5Hz),62.22(d,J＝3.8Hz),57.57,56.34(d,J＝4.9Hz),54.16,53.06,46.35,27.95,24.00；HRMS(ESI)m/z:calcd for C27H32BrF2N6O[M+H]+,573.1789,found,573.1787.
实施例16
2-(2,4-二氟苯基)-1-(4-(3-(5-甲氧基-1H-吲哚-1-基)丙基)哌嗪-1-基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物16)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,3-二溴丙烷替换实施例1中的1,5-二溴戊烷、等摩尔5-甲氧基吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物16，淡黄色油状物，产率为51.4％。
1H NMR(600MHz,CDCl3)δ8.16(s,1H),7.81(s,1H),7.58–7.53(m,1H),7.23(d,J＝8.9Hz,1H),7.09(d,J＝2.3Hz,1H),7.04(d,J＝3.0Hz,1H),6.87–6.81(m,3H),6.39(d,J＝2.6Hz,1H),5.26(s,1H),4.58–4.48(m,2H),4.13(t,J＝6.6Hz,2H),3.86(s,3H),3.09(d,J＝13.6Hz,1H),2.68(d,J＝13.6Hz,1H),2.35(br,8H),2.24–2.18(m,2H),1.95–1.90(m,2H).13C NMR(150MHz,CDCl3)δ163.56(d,J＝12.1Hz),161.90(d,J＝12.1Hz),159.75(d,J＝11.7Hz),158.11(d,J＝11.7Hz),153.89,151.06,144.66,131.34,129.30(dd,J＝9.3,5.9Hz),128.79,128.37,126.30–126.11(m),111.75,111.57(dd,J＝20.6,3.1Hz),110.10,104.57–104.02(m),102.45,100.57,71.92(d,J＝4.4Hz),62.22(d,J＝3.8Hz),56.34(d,J＝4.8Hz),55.85,54.64,54.29,53.01,43.83,27.15；HRMS(ESI)m/z:calcd forC27H33F2N6O2[M+H]+,511.2633,found,511.2631.
实施例17
1-(4-(3-(6-溴-1H-吲哚-1-基)丙基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物17)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,3-二溴丙烷替换实施例1中的1,5-二溴戊烷、等摩尔6-溴吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物17，淡黄色油状物，产率为53.2％。
1H NMR(600MHz,CDCl3)δ8.16(s,1H),7.81(s,1H),7.59–7.53(m,2H),7.46(d,J＝8.4Hz,1H),7.18(d,J＝9.3Hz,1H),7.04(d,J＝3.1Hz,1H),6.85–6.80(m,2H),6.44(d,J＝3.1Hz,1H),5.28(s,1H),4.58–4.49(m,2H),4.13(t,J＝6.4Hz,2H),3.11(d,J＝13.5Hz,1H),2.70(d,J＝13.6Hz,1H),2.35(br,8H),2.21–2.12(m,2H),1.96–1.84(m,2H).13C NMR(150MHz,CDCl3)δ163.55(d,J＝12.0Hz),161.90(d,J＝12.1Hz),159.77(d,J＝11.8Hz),158.13(d,J＝11.8Hz),151.04,144.65,137.02,129.31(dd,J＝9.3,5.9Hz),128.46,127.19,126.24(dd,J＝12.8,3.6Hz),122.43,122.05,115.02,112.58,111.56(dd,J＝20.6,3.1Hz),104.70–103.95(m),101.44,71.91(d,J＝5.4Hz),62.25(d,J＝3.8Hz),56.40(d,J＝4.8Hz),54.37,54.21,52.99,43.49,27.18；HRMS(ESI)m/z:calcd for C26H30BrF2N6O[M+H]+,559.1633,found,559.1629.
实施例18
2-(2,4-二氟苯基)-1-(4-(3-(5-硝基-1H-吲哚-1-基)丙基)哌嗪-1-基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物18)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,3-二溴丙烷替换实施例1中的1,5-二溴戊烷、等摩尔5-硝基吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物18，淡黄色油状物，产率为38.9％。
1H NMR(600MHz,CDCl3)δ8.56(d,J＝2.2Hz,1H),8.14(s,1H),8.08–8.06(m,1H),7.80(s,1H),7.57–7.52(m,1H),7.38(d,J＝9.1Hz,1H),7.23(d,J＝3.6Hz,1H),6.84–6.80(m,2H),6.65(d,J＝3.1Hz,1H),4.58–4.48(m,2H),4.22(t,J＝6.6Hz,2H),3.10(d,J＝13.6Hz,1H),2.69(d,J＝13.6Hz,1H),2.35(br,8H),2.21–2.18(m,2H),1.98–1.94(m,2H).13C NMR(150MHz,CDCl3)δ163.56(d,J＝12.1Hz),161.90(d,J＝12.1Hz),159.74(d,J＝11.7Hz),158.10(d,J＝11.7Hz),151.05,144.66,141.46,138.91,131.09,129.29(dd,J＝9.3,5.9Hz),127.58,126.12(dd,J＝12.9,3.6Hz),118.21,117.07,111.58(d,J＝23.6Hz),109.30,104.66–104.10(m),104.03,72.03(d,J＝5.5Hz),62.22(d,J＝3.8Hz),56.28(d,J＝4.9Hz),54.23,54.14,52.94,43.99,26.94；HRMS(ESI)m/z:calcd for C26H30F2N7O3[M+H]+,526.2373,found,526.2372.
实施例19
1-(4-(3-(5-氯-1H-吲哚-1-基)丙基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物19)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,3-二溴丙烷替换实施例1中的1,5-二溴戊烷、等摩尔5-氯吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物19，淡黄色油状物，产率为59.1％。
1H NMR(600MHz,CDCl3)δ8.15(s,1H),7.80(s,1H),7.59–7.50(m,2H),7.25(d,J＝8.7Hz,1H),7.12(d,J＝8.3Hz,1H),7.08(d,J＝3.0Hz,1H),6.82(t,J＝8.9Hz,2H),6.41(d,J＝3.0Hz,1H),5.25(s,1H),4.58–4.47(m,2H),4.14(t,J＝6.5Hz,2H),3.09(d,J＝13.6Hz,1H),2.69(d,J＝13.6Hz,1H),2.33(br,8H),2.18(br,2H),1.94–1.90(m,2H).13C NMR(150MHz,CDCl3)δ163.56(d,J＝12.1Hz),161.90(d,J＝12.0Hz),159.75(d,J＝11.7Hz),158.11(d,J＝11.7Hz),151.06,144.66,134.43,129.44,129.30(dd,J＝9.3,5.9Hz),129.17,126.19(dd,J＝12.9,3.6Hz),124.96,121.61,120.23,111.58(dd,J＝20.6,3.1Hz),110.38,104.69–104.01(m),100.78,71.95(d,J＝5.5Hz),62.22(d,J＝3.8Hz),56.32(d,J＝4.9Hz),54.45,54.30,52.99,43.79,27.04；HRMS(ESI)m/z:calcd forC26H30ClF2N6O[M+H]+,515.2138,found,515.2135.
实施例20
1-(4-(3-(6-氯-1H-吲哚-1-基)丙基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物20)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,3-二溴丙烷替换实施例1中的1,5-二溴戊烷、等摩尔6-氯吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物20，淡黄色油状物，产率为55.1％。
1H NMR(600MHz,CDCl3)δ8.16(s,1H),7.80(s,1H),7.55(q,J＝8.5Hz,1H),7.50(d,J＝8.4Hz,1H),7.38(s,1H),7.05(dd,J＝6.3,2.2Hz,2H),6.82(t,J＝9.2Hz,2H),6.45(d,J＝3.1Hz,1H),5.27(s,1H),4.57–4.49(m,2H),4.13(t,J＝6.5Hz,2H),3.11(d,J＝13.5Hz,1H),2.70(d,J＝13.6Hz,1H),2.36(br,8H),2.20–2.15(m,2H),1.94–1.89(m,2H).13C NMR(150MHz,CDCl3)δ163.55(d,J＝12.1Hz),161.90(d,J＝12.0Hz),159.77(d,J＝11.8Hz),158.13(d,J＝11.8Hz),151.06,144.66,136.56,129.31(dd,J＝9.3,5.9Hz),128.54,127.36,126.90,126.22(dd,J＝12.8,3.5Hz),121.67,119.88,111.56(dd,J＝20.6,3.1Hz),109.57,104.65–103.92(m),101.39,71.93(d,J＝5.4Hz),62.25(d,J＝3.775Hz),56.38(d,J＝4.8Hz),54.32,54.26,52.98,43.54,27.12；HRMS(ESI)m/z:calcd forC26H30ClF2N6O[M+H]+,515.2138,found,515.2130.
实施例21
2-(2,4-二氟苯基)-1-(4-(3-(5-甲基-1H-吲哚-1-基)丙基)哌嗪-1-基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物21)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,3-二溴丙烷替换实施例1中的1,5-二溴戊烷、等摩尔5-甲基吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物21，淡黄色油状物，产率为47.1％。
1H NMR(600MHz,CDCl3)δ8.16(s,1H),7.81(s,1H),7.58–7.53(m,1H),7.41(s,1H),7.23(d,J＝8.4Hz,1H),7.04–7.00(m,2H),6.83(t,J＝8.8Hz,2H),6.38(d,J＝3.0Hz,1H),5.27(s,1H),4.58–4.48(m,2H),4.14(t,J＝6.7Hz,2H),3.10(d,J＝12.9Hz,1H),2.69(d,J＝13.6Hz,1H),2.45(s,3H),2.35(br,8H),2.24–2.19(m,2H),1.97–1.90(m,2H).13C NMR(150MHz,CDCl3)δ163.56(d,J＝12.1Hz),161.90(d,J＝12.1Hz),159.76(d,J＝11.8Hz),158.12(d,J＝11.8Hz),151.05,144.66,134.36,129.31(dd,J＝9.3,5.9Hz),128.78,128.40,127.95,126.23(dd,J＝12.8,3.6Hz),122.95,120.55,111.57(dd,J＝20.5,3.1Hz),109.04,104.60–104.03(m),100.42,71.90(d,J＝5.5Hz),62.23(d,J＝3.7Hz),56.36(d,J＝4.9Hz),54.69,54.32,53.02,43.74,27.10,21.37；HRMS(ESI)m/z:calcd forC27H33F2N6O[M+H]+,495.2684,found,495.2681.
实施例22
1-(4-(3-(5-溴-1H-吲哚-1-基)丙基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物22)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,3-二溴丙烷替换实施例1中的1,5-二溴戊烷，其他条件均不变，得到化合物22，淡黄色油状物，产率为58.2％。
1H NMR(600MHz,CDCl3)δ8.15(s,1H),7.80(s,1H),7.72(d,J＝1.8Hz,1H),7.57–7.51(m,1H),7.24(dd,J＝8.7,1.7Hz,1H),7.20(d,J＝8.7Hz,1H),7.06(d,J＝3.1Hz,1H),6.85–6.79(m,2H),6.39(d,J＝3.0Hz,1H),4.56–4.48(m,2H),4.12(t,J＝6.6Hz,2H),3.09(d,J＝13.8Hz,1H),2.67(d,J＝13.6Hz,1H),2.33(br,8H),2.19–2.14(m,2H),1.93–1.88(m,2H).13C NMR(150MHz,CDCl3)δ163.53(d,J＝12.0Hz),161.90(d,J＝12.1Hz),159.73(d,J＝11.8Hz),158.09(d,J＝11.8Hz),151.05,144.68,134.67,130.11,129.31(dd,J＝9.3,5.9Hz),129.08,126.16(dd,J＝12.8,3.5Hz),124.12,123.32,112.51,111.59(dd,J＝20.5,3.0Hz),110.88,104.80–103.84(m),100.71,71.93(d,J＝5.4Hz),62.20(d,J＝3.7Hz),56.30(d,J＝4.8Hz),54.40,54.25,52.96,43.74,26.99；HRMS(ESI)m/z:calcd forC26H30BrF2N6O[M+H]+,559.1627,found,559.1630.
实施例23
1-(4-(3-(1H-吲哚-1-基)丙基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物23)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,3-二溴丙烷替换实施例1中的1,5-二溴戊烷、等摩尔吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物23，淡黄色油状物，产率为43.1％。
1H NMR(600MHz,CDCl3)δ8.16(s,1H),7.81(s,1H),7.63(d,J＝7.9Hz,1H),7.56(q,J＝8.6Hz,1H),7.35(d,J＝8.1Hz,1H),7.19(t,J＝7.6Hz,1H),7.10(t,J＝7.4Hz,1H),7.07(d,J＝3.1Hz,1H),6.83(t,J＝8.9Hz,2H),6.48(d,J＝2.7Hz,1H),5.27(s,1H),4.58–4.48(m,2H),4.17(t,J＝6.7Hz,2H),3.10(d,J＝13.2Hz,1H),2.69(d,J＝13.6Hz,1H),2.35(br,8H),2.27–2.16(m,2H),2.00–1.88(m,2H).13C NMR(150MHz,CDCl3)δ163.56(d,J＝12.1Hz),161.90(d,J＝12.0Hz),159.76(d,J＝11.8Hz),158.12(d,J＝11.8Hz),151.06,144.66,135.96,129.32(dd,J＝9.3,5.9Hz),128.51,127.89,126.22(dd,J＝12.9,3.6Hz),121.33,120.92,119.22,111.58(dd,J＝20.5,3.1Hz),109.36,104.77–103.70(m),101.05,71.93(d,J＝5.4Hz),62.23(d,J＝3.8Hz),56.35(d,J＝4.9Hz),54.67,54.31,53.01,43.69,27.09；HRMS(ESI)m/z:calcd for C26H31F2N6O[M+H]+,481.2527,found,481.2523.
实施例24
1-(4-(2-(5-溴-1H-吲哚-1-基)乙基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物24)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,2-二溴乙烷替换实施例1中的1,5-二溴戊烷，其他条件均不变，得到化合物24，淡黄色油状物，产率为63.2％。
1H NMR(600MHz,CDCl3)δ8.14(s,1H),7.80(s,1H),7.74(d,J＝1.7Hz,1H),7.57–7.53(m,1H),7.27(dd,J＝8.7,1.7Hz,1H),7.19(d,J＝8.7Hz,1H),7.11(d,J＝2.4Hz,1H),6.85–6.79(m,2H),6.41(d,J＝2.8Hz,1H),5.20(s,1H),4.56–4.49(m,2H),4.17(br,2H),3.08(d,J＝13.5Hz,1H),2.68(br,3H),2.38(br,8H).13C NMR(150MHz,CDCl3)δ163.57(d,J＝12.1Hz),161.92(d,J＝12.0Hz),159.71(d,J＝11.8Hz),158.08(d,J＝11.7Hz),151.12,144.66,134.55,130.20,129.31(dd,J＝9.1,5.8Hz),129.15,126.09(d,J＝11.7Hz),124.30,123.45,112.68,112.01–111.26(m),110.62,104.93–103.89(m),100.94,72.03(d,J＝11.9Hz),62.20(d,J＝3.7Hz),57.40,56.27(d,J＝4.2Hz),54.20,53.35,44.28；HRMS(ESI)m/z:calcd for C25H28BrF2N6O[M+H]+,545.1471,found,545.1474.
实施例25
(S)-1-(4-(2-(5-溴-1H-吲哚-1-基)乙基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物S-24)
对化合物24手性拆分得到化合物S-24，具体步骤为：色谱柱：Phenomenex Luxcellulose-2(250×4.6mm)；流动相：乙腈/水(70/30)；检测波长：254nm；流速：1mL/min；柱温：25℃。
化合物24、化合物S-24的手性HPLC色谱图分别见图1、图2。
化合物S-24，淡黄色油状物。[α]25D-8.87(C＝0.08in MeOH)；1H NMR(600MHz,CDCl3)δ8.14(s,1H),7.80(s,1H),7.73(d,J＝1.7Hz,1H),7.57–7.52(m,1H),7.26(dd,J＝8.7,1.8Hz,1H),7.17(d,J＝8.7Hz,1H),7.10(d,J＝3.1Hz,1H),6.84–6.79(m,2H),6.40(d,J＝3.1Hz,1H),5.21(s,1H),4.57–4.47(m,2H),4.18–4.11(m,2H),3.07(d,J＝13.5Hz,1H),2.71–2.61(m,3H),2.36(br,8H).13C NMR(150MHz,CDCl3)δ163.55(d,J＝11.9Hz),161.90(d,J＝12.1Hz),159.73(d,J＝11.8Hz),158.09(d,J＝11.8Hz),151.06,144.65,134.57,130.18,129.30(dd,J＝9.3,5.9Hz),129.18,126.13(dd,J＝12.9,3.4Hz),124.25,123.42,112.64,111.60(dd,J＝20.6,3.1Hz),110.63,104.96–103.74(m),100.88,71.99(d J＝5.3Hz),62.19(d,J＝3.8Hz),57.44,56.29(d,J＝4.9Hz),54.25,53.37,44.34；HRMS(ESI)m/z:calcd for C25H28BrF2N6O[M+H]+,545.1471,found,545.1470.
实施例26
1-(4-(2-(5,6-二氯-1H-吲哚-1-基)乙基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物25)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,2-二溴乙烷替换实施例1中的1,5-二溴戊烷、等摩尔5,6-二氯吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物25，淡黄色油状物，产率为53.9％。
1H NMR(500MHz,CDCl3)δ8.14(s,1H),7.79(s,1H),7.65(s,1H),7.54(q,J＝8.8,8.4Hz,1H),7.41(s,1H),7.11(d,J＝2.9Hz,1H),6.86–6.78(m,2H),6.38(d,J＝2.3Hz,1H),5.20(s,1H),4.58–4.46(m,2H),4.10(t,J＝6.3Hz,2H),3.07(d,J＝13.5Hz,1H),2.71–2.61(m,3H),2.36(br,8H).13C NMR(125MHz,CDCl3)δ163.73(d,J＝12.2Hz),161.74(d,J＝12.1Hz),159.90(d,J＝11.8Hz),157.94(d,J＝11.8Hz),151.06,144.64,134.87,130.01,129.30(dd,J＝9.3,5.9Hz),128.10,126.12(dd,J＝12.8,3.6Hz),125.30,123.37,121.79,111.58(dd,J＝20.6,3.1Hz),110.87,104.90–103.66(m),101.01,72.05(d,J＝5.5Hz),62.23(d,J＝3.8Hz),57.42,56.30(d,J＝4.9Hz),54.27,53.36,44.54；HRMS(ESI)m/z:calcd for C25H27Cl2F2N6O[M+H]+,535.1591,found,535.1588.
实施例27
1-(4-(2-(5-硝基-1H-吲哚-1-基)乙基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物26)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,2-二溴乙烷替换实施例1中的1,5-二溴戊烷、等摩尔5-硝基吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物26，黄色油状物，产率为65.1％。
1H NMR(500MHz,CDCl3)δ8.55(s,1H),8.13(s,1H),8.11–8.06(m,1H),7.79(s,1H),7.54(q,J＝8.8,8.4Hz,1H),7.32(d,J＝9.0Hz,1H),7.27(d,J＝2.8Hz,1H),6.86–6.76(m,2H),6.65(d,J＝2.4Hz,1H),5.17(s,1H),4.59–4.43(m,2H),4.27–4.16(m,2H),3.06(d,J＝15.0Hz,1H),2.76–2.64(m,3H),2.38(br,8H).13C NMR(125MHz,CDCl3)δ163.73(d,J＝12.0Hz),161.74(d,J＝12.2Hz),159.89(d,J＝11.7Hz),157.95(d,J＝11.34),151.08,144.64,141.57,138.81,131.27,129.30(dd,J＝9.2,5.9Hz),127.66,126.11(d,J＝15.4Hz),118.19,117.13,111.57(dd,J＝20.6,3.1Hz),109.10,104.55–104.06(m),104.03,72.09(d,J＝5.3Hz),62.22(d,J＝3.6Hz),57.44,56.27(d,J＝4.8Hz),54.26,53.36,44.62；HRMS(ESI)m/z:calcd for C25H28F2N7O3[M+H]+,512.2222,found,512.2221.
实施例28
2-(2,4-二氟苯基)-1-(4-(2-(5-甲氧基-1H-吲哚-1-基)乙基)哌嗪-1-基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物27)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,2-二溴乙烷替换实施例1中的1,5-二溴戊烷、等摩尔5-甲氧基吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物27，淡黄色油状物，产率为49.1％。
1H NMR(600MHz,CDCl3)δ8.15(s,1H),7.80(s,1H),7.59–7.51(m,1H),7.21(d,J＝8.9Hz,1H),7.08(dd,J＝6.6,2.6Hz,2H),6.87(dd,J＝8.8,2.3Hz,1H),6.85–6.79(m,2H),6.39(d,J＝2.5Hz,1H),5.23(s,1H),4.60–4.47(m,2H),4.16(br,2H),3.85(s,3H),3.08(d,J＝13.5Hz,1H),2.74–2.63(m,3H),2.38(br,8H).13C NMR(150MHz,CDCl3)δ163.56(d,J＝12.0Hz),161.90(d,J＝12.1Hz),159.73(d,J＝11.8Hz),158.10(d,J＝11.7Hz),153.99,151.08,144.66,131.19,129.31(dd,J＝9.3,5.9Hz),128.86,128.47,126.23–126.06(m),111.85,111.60(dd,J＝20.5,3.0Hz),109.89,104.14–104.49(m),102.59,100.83,71.98(dJ＝1.51Hz),62.20(d,J＝3.7Hz),57.58,56.30(d,J＝4.7Hz),55.86,54.24,53.39,44.34；HRMS(ESI)m/z:calcd for C26H31F2N6O2[M+H]+,497.2477,found,497.2471.
实施例29
1-(4-(2-(1H-吲哚-1-基)乙基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物28)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,2-二溴乙烷替换实施例1中的1,5-二溴戊烷、等摩尔吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物28，淡黄色油状物，产率为65.2％。
1H NMR(600MHz,CDCl3)δ8.15(s,1H),7.81(s,1H),7.63(d,J＝7.9Hz,1H),7.58–7.52(m,1H),7.33(d,J＝8.2Hz,1H),7.21(t,J＝7.6Hz,1H),7.13–7.09(m,2H),6.86–6.80(m,2H),6.49(d,J＝3.0Hz,1H),5.23(s,1H),4.57–4.48(m,2H),4.22(br,2H),3.09(d,J＝13.5Hz,1H),2.72(br,2H),2.68(d,J＝13.6Hz,1H),2.40(br,8H).13C NMR(150MHz,CDCl3)δ163.57(d,J＝12.1Hz),161.92(d,J＝12.1Hz),159.73(d,J＝11.8Hz),158.10(d,J＝11.7Hz),151.10,144.66,135.84,129.32(dd,J＝9.3,5.9Hz),128.54,127.96,126.11(d,J＝12.9Hz),121.49,121.02,119.38,111.62(dd,J＝20.6,3.0Hz),109.13,104.67–103.95(m),101.34,72.02(d,J＝4.05Hz),62.21(d,J＝3.7Hz),57.49,56.30(d,J＝6.04Hz),54.11,53.37,44.06；HRMS(ESI)m/z:calcd for C25H29F2N6O[M+H]+,467.2371,found,467.2365.
实施例30
1-(4-(2-(1H-吡咯[2,3-b]吡啶-1-基)乙基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物29)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,2-二溴乙烷替换实施例1中的1,5-二溴戊烷、等摩尔7-氮杂吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物29，淡黄色油状物，产率为51.6％。
1H NMR(500MHz,CDCl3)δ8.29(d,J＝4.6Hz,1H),8.15(s,1H),7.89(d,J＝7.8Hz,1H),7.79(s,1H),7.58–7.51(m,1H),7.25(d,J＝2.6Hz,1H),7.08–7.01(m,1H),6.86–6.77(m,2H),6.43(d,J＝3.3Hz,1H),5.26(s,1H),4.58–4.46(m,2H),4.37(t,J＝6.2Hz,2H),3.07(d,J＝13.5Hz,1H),2.82–2.71(m,2H),2.65(d,J＝13.5Hz,1H),2.39(br,8H).13C NMR(125MHz,CDCl3)δ163.70(d,J＝11.9Hz),161.72(d,J＝12.3Hz),159.89(d,J＝11.7Hz),157.92(d,J＝11.7Hz),151.05,147.37,144.66,142.64,129.30(dd,J＝9.3,5.9Hz),128.70,128.32,126.17(dd,J＝12.7,3.6Hz),120.48,115.64,111.58(dd,J＝20.5,3.0Hz),104.67–103.89(m),99.42,71.89(d,J＝5.4Hz),62.17(d,J＝3.8Hz),57.64,56.32(d,J＝4.8Hz),54.26,53.17,41.81；HRMS(ESI)m/z:calcd for C24H28F2N7O[M+H]+,468.2323,found,468.2316.
实施例31
1-(4-(2-(5-氯-1H-吡咯[2,3-b]吡啶-1-基)乙基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物30)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,2-二溴乙烷替换实施例1中的1,5-二溴戊烷、等摩尔5-氯-7-氮杂吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物30，淡黄色油状物，产率为53.6％。
1H NMR(500MHz,CDCl3)δ8.22(s,1H),8.15(s,1H),7.86(s,1H),7.80(s,1H),7.60–7.51(m,1H),7.29(s,1H),6.86–6.77(m,2H),6.38(d,J＝3.6Hz,1H),4.57–4.47(m,2H),4.34(br,2H),3.07(d,J＝13.5Hz,1H),2.73(br,2H),2.66(d,J＝13.5Hz,2H),2.39(d,J＝32.6Hz,8H).13C NMR(125MHz,CDCl3)δ163.77(d,J＝11.08Hz),161.78(d,J＝11.84Hz),159.84(d,J＝12.34Hz),157.93(d,J＝12.5Hz),151.08,145.70,144.66,141.22,129.98,129.31(dd,J＝9.4,5.9Hz),127.79,126.17(d,J＝14.4Hz),123.58,121.12,111.59(dd,J＝20.6,2.6Hz),104.97–103.74(m),99.05,71.92(d,J＝5.9Hz),62.16(d,J＝4.0Hz),57.52,56.30(d,J＝4.4Hz),54.23,53.15,42.00；HRMS(ESI)m/z:calcd for C24H27ClF2N7O[M+H]+,502.1934,found,502.1925.
实施例32
1-(4-(2-(5-溴-1H-吡咯[2,3-b]吡啶-1-基)乙基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物31)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,2-二溴乙烷替换实施例1中的1,5-二溴戊烷、等摩尔5-溴-7-氮杂吲哚替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物31，淡黄色油状物，产率为56.6％。
1H NMR(500MHz,CDCl3)δ8.30(d,1H),8.15(s,1H),8.01(d,J＝1.5Hz,1H),7.80(s,1H),7.55(q,J＝8.9,8.4Hz,1H),7.26(d,J＝2.8Hz,1H),6.85–6.78(m,2H),6.38(d,J＝3.3Hz,1H),5.24(s,1H),4.58–4.45(m,2H),4.34(br,2H),3.07(d,J＝13.5Hz,1H),2.74(br,2H),2.65(d,J＝14.9Hz,1H),2.39(br,8H).13C NMR(125MHz,CDCl3)δ163.72(d,J＝12.4Hz),161.73(d,J＝12.1Hz),159.88(d,J＝11.9Hz),157.92(d,J＝11.6Hz),151.08,145.79,144.66,143.12,130.67,129.82,129.31(dd,J＝9.3,6.0Hz),126.13(d,J＝13.2Hz),122.00,111.68(d,J＝3.0Hz),111.55,104.77–103.95(m),99.03,71.95(d,J＝4.8Hz),62.16(d,J＝3.8Hz),57.48,56.30(d,J＝4.7Hz),54.20,53.14,41.96；HRMS(ESI)m/z:calcd for C24H27BrF2N7O[M+H]+,546.1429,found,546.1421.
实施例33
1-(4-(2-(1H-吲唑-1-基)乙基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物32)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,2-二溴乙烷替换实施例1中的1,5-二溴戊烷、等摩尔吲唑替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物32，黄色油状物，产率为56.7％。
1H NMR(600MHz,CDCl3)δ8.14(s,1H),7.98(s,1H),7.79(s,1H),7.72(d,J＝8.1Hz,1H),7.57–7.51(m,1H),7.41–7.35(m,2H),7.14(t,J＝7.2Hz,1H),6.84–6.78(m,2H),5.23(s,1H),4.55–4.48(m,2H),4.46(t,J＝6.9Hz,2H),3.05(d,J＝13.5Hz,1H),2.83(d,J＝6.0Hz,2H),2.65(d,J＝13.6Hz,1H),2.38(br,8H).13C NMR(150MHz,CDCl3)δ163.54(d,J＝12.0Hz),161.88(d,J＝12.1Hz),159.72(d,J＝11.8Hz),158.09(d,J＝11.6Hz),151.06,144.65,139.55,133.12,129.31(dd,J＝9.3,5.9Hz),126.19,126.12(d,J＝3.4Hz),123.97,121.12,120.52,111.58(dd,J＝20.6,2.9Hz),108.94,105.19–103.61(m),71.94(d,J＝5.3Hz),62.20(d,J＝3.7Hz),57.02,56.30(d,J＝4.9Hz),54.23,53.26,46.68；HRMS(ESI)m/z:calcd for C24H28F2N7O[M+H]+,468.2323,found,468.2319.
实施例34
(S)-1-(4-(2-(1H-吲唑-1-基)乙基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物S-32)
参照实施例25化合物S-24的拆分方法，对化合物32进行手性拆分得到化合物S-32。
黄色油状物；[α]25D-9.40(C＝0.1,MeOH)；1H NMR(500MHz,CDCl3)δ8.17(s,1H),8.01(s,1H),7.82(s,1H),7.75(d,J＝8.1Hz,1H),7.58–7.53(m,1H),7.46–7.38(m,2H),7.18(t,J＝7.3Hz,1H),6.88–6.80(m,2H),5.24(s,1H),4.56–4.49(m,4H),3.09(d,J＝14.5Hz,1H),2.88(br,2H),2.67(d,J＝13.6Hz,1H),2.42(br,8H).13C NMR(125MHz,CDCl3)δ163.74(d,J＝12.2Hz),161.75(d,J＝12.2Hz),159.89(d,J＝11.7Hz),157.92(d,J＝11.8Hz),151.10,144.68,139.56,133.21,129.33(dd,J＝9.3,5.9Hz),126.30,126.11(d,J＝13.1Hz),123.98,121.17,120.60,111.64(dd,J＝20.6,3.3Hz),108.98,104.70–103.90(m),71.97(d,J＝4.6Hz),62.19(d,J＝3.9Hz),57.00,56.29(d,J＝4.9Hz),54.18,53.26,46.58；HRMS(ESI)m/z:calcd for C24H28F2N7O[M+H]+,468.2323,found,468.2325.
实施例35
1-(4-(2-(5-溴-1H-吲唑-1-基)乙基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物33)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,2-二溴乙烷替换实施例1中的1,5-二溴戊烷、等摩尔5-溴吲唑替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物33，黄色油状物，产率为54.7％。
1H NMR(600MHz,CDCl3)δ8.13(s,1H),7.90(s,1H),7.84(s,1H),7.78(s,1H),7.56–7.50(m,1H),7.44–7.40(m,1H),7.27(d,J＝8.9Hz,1H),6.80(q,J＝8.6,8.0Hz,2H),5.20(s,1H),4.55–4.46(m,2H),4.41(t,J＝6.5Hz,2H),3.04(d,J＝13.5Hz,1H),2.80(d,J＝6.0Hz,2H),2.64(d,J＝13.6Hz,1H),2.34(br,8H).13C NMR(150MHz,CDCl3)δ163.53(d,J＝12.0Hz),161.87(d,J＝12.0Hz),159.71(d,J＝11.7Hz),158.07(d,J＝11.8Hz),151.06,144.66,138.34,132.36,129.32(d,J＝5.9Hz),129.26,126.14(dd,J＝12.9,3.4Hz),125.43,123.48,113.60,111.57(dd,J＝20.6,2.9Hz),110.51,104.29(t,J＝26.3Hz),71.96(d,J＝5.3Hz),62.18(d,J＝3.7Hz),57.00,56.28(d,J＝4.8Hz),54.21,53.26,47.00；HRMS(ESI)m/z:calcd for C24H27BrF2N7O[M+H]+,546.1429,found,546.1423.
实施例36
2-(2,4-二氟苯基)-1-(4-(2-(5-甲氧基-1H-吲唑-1-基)乙基)哌嗪-1-基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物34)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,2-二溴乙烷替换实施例1中的1,5-二溴戊烷、等摩尔5-甲氧基吲唑替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物34，黄色油状物，产率为49.6％。
1H NMR(600MHz,CDCl3)δ8.13(s,1H),7.86(s,1H),7.78(s,1H),7.56–7.50(m,1H),7.28(d,J＝6.4Hz,1H),7.04(d,J＝7.5Hz,2H),6.84–6.76(m,2H),5.22(s,1H),4.56–4.46(m,2H),4.41(t,J＝6.8Hz,2H),3.84(s,3H),3.04(d,J＝13.5Hz,1H),2.81(d,J＝6Hz,2H),2.64(d,J＝13.6Hz,1H),2.36(br,8H).13C NMR(150MHz,CDCl3)δ163.53(d,J＝12.1Hz),161.87(d,J＝12.1Hz),159.71(d,J＝11.7Hz),158.08(d,J＝11.8Hz),154.49,151.04,144.64,135.59,132.29,129.30(dd,J＝9.3,5.9Hz),126.15(dd,J＝12.8,3.5Hz),124.18,118.55,111.56(dd,J＝20.5,3.0Hz),109.99,104.28(t,J＝26.3Hz),100.07,71.95(d,J＝5.4Hz),62.19(d,J＝3.7Hz),57.09,56.30(d,J＝4.8Hz),55.66,54.21,53.26,46.90；HRMS(ESI)m/z:calcd for C25H30F2N7O2[M+H]+,498.2429,found,498.2426.
实施例37
1-(4-(2-(5-碘-1H-吲唑-1-基)乙基)哌嗪-1-基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙烷-2-醇(化合物35)的合成
参照实施例1化合物12的合成方法，采用等摩尔1,2-二溴乙烷替换实施例1中的1,5-二溴戊烷、等摩尔5-碘吲唑替换实施例1中的5-溴吲哚，其他条件均不变，得到化合物35，黄色油状物，产率为55.3％。
1H NMR(500MHz,CDCl3)δ8.13(d,J＝2.2Hz,1H),7.90(d,J＝3.5Hz,1H),7.81(s,1H),7.77(d,J＝3.3Hz,1H),7.57–7.49(m,1H),7.46–7.36(m,2H),6.84–6.76(m,2H),5.20(s,1H),4.57–4.45(m,2H),4.37(dt,J＝10.3,5.4Hz,2H),3.04(d,J＝13.5Hz,1H),2.84–2.73(m,2H),2.65(d,J＝16.1Hz,1H),2.35(br,8H).13C NMR(125MHz,CDCl3)δ163.69(d,J＝12.3Hz),161.70(d,J＝12.1Hz),159.89(d,J＝11.7Hz),157.93(d,J＝11.7Hz),151.00,144.62,140.86,133.33,129.38,129.30(dd,J＝9.5,6.1Hz),126.15(dd,J＝12.9,3.7Hz),123.16,122.32,118.54,111.55(dd,J＝20.5,3.1Hz),104.99–103.69(m),91.84,72.00(d,J＝5.5Hz),62.24(d,J＝3.8Hz),57.04,56.32(d,J＝4.9Hz),54.25,53.25,47.04；HRMS(ESI)m/z:calcd for C24H27F2IN7O[M+H]+,594.1290,found,594.1282.
实施例38
(一)化合物体外抗真菌活性实验
依照美国临床标准化委员会(NCCLS)建立真菌敏感性测定方案(M27-A3)的微量液基稀释法执行操作。
标准株：白色念珠菌(Candida albicans)ATCC5314(记为SC5314)、近平滑念珠菌(Candida parapsilosis)ATCC22019(记为C.Par 22019)、热带念珠菌(Candidatropicalis)ATCC750(记为C.tro 750)、季也蒙念珠菌(guilliermondii)ATCC6260(记为C.gui 6260)、光滑念珠菌(candida glabrata)ATCC15126(记为C.gla 15126)、烟曲霉(Aspergillus fumigatus)CGMCC3.7795(记为A.fum)和新型隐球菌(Crytococcusneoformans)CGMCC3.1563(记为C.neo)。
白色念珠菌临床耐药菌：CA24D，CA102，CA901，CA112869。
外排泵过表达株：YEM13：MDR1基因过表达，YEM15：CDR1，CDR2基因过表达。
菌液制备：菌株转接至PDA平板上，35℃培养48小时。挑取5个单克隆菌落重悬于10mL无菌的PBS(pH＝7.3±0.1)中，将混悬液涡旋震荡15秒，血球计数板计数，RPMI 1640培养基调整菌悬液浓度为5×103CFU/mL。
药液配制：取化合物1-化合物35、阳性对照药(氟康唑，伏立康唑，伊曲康唑)溶于二甲亚砜，配成1mg/mL的药物储存液，采用RPMI 1640培养基进行二倍稀释法稀释，得到系列稀释药液。
RPMI 1640培养基：称取34.53g吗啡啉丙磺酸(MOPS)和10.4g RPMI 1640粉末(含有谷氨酰胺，不含碳酸氢盐，有酚红做pH指示剂)溶解于900mL蒸馏水中，搅拌后使用1mol/L的NaOH调整pH为7.2，定容至1L，用0.22μm的滤器过滤除菌，4℃保存，备用。
接种：在96孔板中每孔加入100μL药液、100μL菌悬液。96孔板小心用半透膜封口，上述真菌置于35℃恒温箱中孵育一定时间(念珠菌孵育24小时、隐球菌孵育72小时、烟曲霉菌孵育48小时)；在530nm下检测其吸光度，MIC80定义为抑制80％菌生长的最低浓度。
实验结果：体外抗真菌实验结果如表1和表2所示，表明所有化合物均表现出广谱性、抗耐药性。侧链的长度对化合物的活性具有重要影响，短链化合物表现出优越的活性，其中化合物15-化合物35的体外抗真菌活性强于阳性对照药，说明本发明化合物可用于制备治疗抗真菌感染的药物。
表1.目标化合物的体外抗真菌活性
表2.目标化合物体外抗烟曲霉、隐球菌及耐药株活性
(二)化合物对人源正常细胞毒性
高效的抗真菌药物应具备特异性抗真菌的能力，即只对真菌细胞有抑制或杀伤作用，而对人体正常细胞无毒副作用。因此需对优选化合物进行初步的细胞毒性评价。采用4株人源正常细胞，用MTT法对化合物22，24和S-24进行细胞毒性评价。
细胞系：人脐静脉内皮细胞(HUVEC)、人乳腺上皮细胞(MCF-10A)、人支气管上皮样细胞(16HBE)、人肝细胞(LO2)。
药液配制：取化合物22，24和S-24溶于二甲亚砜，配成20mM的药物储存液，用DMEM培养基系列稀释。
实验方法：细胞采用DMEM培养基培养，取对数生长期细胞，消化后充分吹打呈单细胞悬液，取100μL细胞悬液，按照每孔5000个细胞数接种于透明96孔板中，在37℃、5％CO2的条件下培养24小时。用DMEM培养基稀释药物至所需浓度，每孔加入100μL相应的含药培养基，空白组加入100μL不含药物的DMEM培养基，每个样品浓度设三个平行。在37℃和5％CO2的条件下继续培养48小时，每孔加入20μL MTT(5mg/mL)，在培养箱继续培养4小时。除去上清夜，每孔加入150μL DMSO溶解沉淀，置微量震荡器上荡10分钟使其充分溶解。在BIORAD550型酶标仪上测定570nm处的光密度值。计算细胞存活率，通过Graphpad软件计算药物毒性的IC50。
细胞存活率＝(A实验组-A空白组)/(A溶剂对照组-A空白组)×100％
实验结果：结果如表3所示，化合物22,24和S-24均具有低毒性，S-24的细胞毒活性是其抗真菌活性的1500倍以上(换算成同一单位相除)。以上结果显示化合物22，24和S-24的抗真菌作用具有一定的选择性，对人体正常细胞毒性较小。
表3.目标化合物对人源正常细胞毒性
(三)化合物对小鼠红细胞溶血作用
本发明化合物具有良好的抗真菌活性和低细胞毒性，进一步确认它们对小鼠红细胞的溶血活性。
细胞系：小鼠红细胞(南京森贝伽生物科技有限公司)。
药液配制：取化合物22，24，S-24和阳性对照药(氟康唑，伏立康唑)溶于二甲亚砜，配成10mg/mL的药物储存液，用PBS缓冲液进行系列稀释。
实验方法：1mL小鼠红细胞悬浮在5mL PBS中，1000转/分钟离心3次，获得小鼠红细胞沉淀；将上一步的小鼠红细胞悬浮在PBS中，制备5％v/v的红细胞悬液；将100μL红细胞悬浮液加入到96孔板中，给药组在每孔中加入100μL PBS稀释的系列化合物，含有ddH2O和PBS稀释的Triton 
(1％v/v，100％溶血)孔分别作为空白组和阳性对照，37℃下静置培养1小时。混合物1000转/分钟离心10分钟，上清液转移至96孔板中，OD595测吸光度，计算溶血率。
溶血率＝(给药组-空白组)/(阳性对照-空白组)×100％
实验结果：实验结果如表4所示，与阳性药相比，化合物22，24和S-24均表现出低溶血作用，其中化合物S-24的溶血作用与氟康唑相当，因此本发明化合物具有一定的安全性。
表4.目标化合物对小鼠红细胞溶血作用
(四)化合物对人源CYP3A4抑制作用
三唑类抗真菌药物靶向真菌CYP51蛋白，抑制人类CYP酶，将导致肝毒性副作用，因此选择性靶向真菌CYP51是药物开发的关键。
药液配制：取化合物22、化合物S-24、氟康唑和伏立康唑，分别溶于二甲亚砜，配成10mM的药物储存液。参比抑制剂(酮康唑)溶于二甲亚砜，配成2.5mM的药物储存液。上述药物储存液分别采用DMSO:ACN混合溶剂(v/v:40:60)进行1:2系列稀释。
0.1M K/Mg缓冲液：0.1M磷酸钾缓冲液，含5mM MgCl2。
实验过程：测试代表性化合物对人源CYP3A4酶的体外效力，使用睾酮作为底物。向96孔测定板中加入400μL 0.2mg/mL肝微粒体，然后分别加入30μL系列稀释的受试化合物和参比抑制剂(一式三份)，空白对照组加入等体积的0.1M K/Mg缓冲液(pH 7.4)。每孔加入15μL 320μM的底物溶液(K/Mg缓冲液配制)，37℃预孵育96孔测定板和NADPH溶液5分钟，将15μL预热的8mM NADPH溶液(K/Mg缓冲液配制)加入到测定板中，以启动反应，37℃孵育5分钟，加入180μL含甲苯磺丁脲(200ng/mL)的ACN停止反应；淬火后，摇动板5分钟(600转/分钟)，然后以5000转/分钟离心10分钟；将80μL上清液从每个孔转移到含有120μL超纯水的96孔样品板中，用于LC/MS/MS分析。
选择性指数(Selectivity index，SI)可以指示一定程度上化合物的安全性。
选择性指数＝CYP3A4 IC50/SC5314 MIC80
实验结果如表5所示，化合物22和S-24的IC50分别为0.131μM和0.403μM。化合物S-24(SI＝100.750)的体外安全性优于已上市的唑类药物，如酮康唑(SI＝0.100)、氟康唑(SI＝25.624)，表现出一定的选择性。
表5.目标化合物对人源CYP3A4抑制作用
(五)化合物抗耐药性
白色念珠菌容易产生耐药性，克服耐药性是抗真菌剂的重要属性。为了评价白色念珠菌对S-24的耐药性，以氟康唑为阳性对照，使用微量液基稀释法反复使用受试化合物对白色念珠菌ATCC5314(记为SC5314)进行耐药性研究。
药液配制：分别取化合物S-24和氟康唑，采用二甲亚砜配成10mg/mL的药物储存液，用RPMI 1640培养基进行系列稀释。
实验过程：利用微量液基稀释法测定化合物S-24和氟康唑抗白色念珠菌(SC5314)的MIC80，将0.5×MIC80重复孔中白念珠菌细胞用RPMI 1640培养基调节至5×103CFU/mL，以测量下一代的MIC80，并重复该过程20代。根据传代次数绘制MIC80的倍数变化图。
实验结果：实验结果如图3所示，氟康唑在10代后逐步产生耐药性，而化合物S-24的MIC80未发生明显变化。
(六)小鼠全身感染模型
实验动物：体重在18至22克的ICR小鼠，实验前在符合美国国立卫生研究院实验室动物护理和使用指南的特定无病原体条件下饲养一周，以适应环境，并按照中国药科大学实验动物中心机构动物护理和使用委员会(IACUC)批准的方案进行。
实验菌株：白色念珠菌ATCC5314(记为SC5314)，白色念珠菌耐药株(记为CA24D).
药液配制：化合物S-24、伏立康唑分别采用含1.0％二甲亚砜、1.5％甘油和0.5％吐温80的生理盐水配制成给药溶液。
实验过程：通过尾静脉注射200μL白色念珠菌(SC5314，2×106CFU/mL)建立标准株小鼠感染模型，尾静脉注射200μL白色念珠菌耐药株(CA24D，3×106CFU/mL)建立耐药株小鼠感染模型。造模前一天经腹腔注射200μL环磷酰胺(100mg/Kg)造成免疫缺陷模型。建立模型后，每种模型的小鼠随机均分为四组，每组12只：生理盐水组(空白组，给予含1.0％二甲亚砜、1.5％甘油和0.5％吐温80的生理盐水)、伏立康唑对照组(1.0mg/kg)、S-24低剂量组(1.0mg/kg)和S-24高剂量组(5.0mg/kg)。造模两小时后腹腔给药，每天给药(200μL)1次，连续给药5天，每日观察小鼠存活状态。
实验结果如图4所示，化合物S-24显示出了剂量依赖效应，可延长侵袭性真菌感染小鼠的存活时间。进一步由图4B可知，在白色念珠菌耐药株(CA24D)感染模型中仍然有效，伏立康唑组(9天)的中位生存时间接近空白组(8天)；但在相同剂量(1.0mg/kg)下，S-24低剂量组的中位生存时间(12天)比伏立康唑组更长，这表明化合物S-24在体内对耐药株也保持其有效活性。因此，化合物S-24作为一种新型抑菌剂，对治疗侵袭性真菌感染具有巨大的药用潜力。
(七)小鼠皮肤感染模型
实验动物：体重在18至22克的ICR小鼠，实验前在符合美国国立卫生研究院实验室动物护理和使用指南的特定无病原体条件下饲养一周，以适应环境，并按照中国药科大学实验动物中心机构动物护理和使用委员会(IACUC)批准的方案进行。
实验菌株：白色念珠菌ATCC5314(记为SC5314)。
药液配制：化合物S-24、卢立康唑分别采用含1.0％二甲亚砜、1.5％甘油和0.5％吐温80的生理盐水配制成给药溶液，生理盐水组(含1.0％二甲亚砜，1.5％甘油和0.5％吐温80的生理盐水)。
实验过程：实验开始前一天，小鼠腹腔注射200μL环磷酰胺(100mg/Kg)进行免疫抑制，实验前一天用电动剃毛刀刮除小鼠背部皮毛，实验当天将100μL浓度为1×107CFU/mL的真菌悬液注入小鼠皮下真皮层内，注射部位形成皮丘。小鼠被随机均分为四组，每组6只：生理盐水组(空白组，给予含1.0％二甲亚砜、1.5％甘油和0.5％吐温80的生理盐水)、卢立康唑对照组(1.0mg/kg)、S-24低剂量组(0.5mg/kg)和S-24高剂量组(1.0mg/kg)。实验第二天经皮下注射100μL药物进行治疗，连续用药5天后观察小鼠注射部位是否有红斑、结节、糜烂和溃疡等皮肤感染的特征性临床表现。
实验结果：在整个实验阶段，小鼠没有出现死亡现象。如图5所示，生理盐水组小鼠的真菌感染区域显示加重趋势，而在用S-F24(0.5和1.0mg/kg)或卢立康唑(1.0mg/kg)治疗后伤口不同程度地愈合。相比之下，卢立康唑(1.0mg/kg)组感染明显，相同剂量的化合物S-F24治疗后可逐渐恢复到正常状态阶段。结果表明化合物S-24具有治疗小鼠真菌局部感染的能力。
Claims (10)
1.结构如式I所示的含苯并氮杂环侧链的三氮唑醇类化合物，其外消旋体、R型异构体、S型异构体、药学上可接受的盐：
其中：R1和R2分别独立的代表氢、甲基、甲氧基、氟、氯、溴、碘、硝基；
n为2～10的整数；
X代表N、CH；
Y代表N、CH。
2.根据权利要求1所述的含苯并氮杂环侧链的三氮唑醇类化合物，其特征在于：R1代表氢、甲基、甲氧基、氟、氯、溴、硝基、碘；R2代表氢、甲基、甲氧基、氟、氯、溴、硝基；
n为2～10的整数；
X代表N、CH；
Y代表N、CH。
3.根据权利要求2所述的含苯并氮杂环侧链的三氮唑醇类化合物，其特征在于：R1代表氢、甲基、甲氧基、氯、溴、硝基、碘；R2代表氢、氟、氯、溴；
n为2～4的整数；
X代表N、CH；
Y代表N、CH。
4.结构如下所示的含苯并氮杂环侧链的三氮唑醇类化合物，其外消旋体、R型异构体、S型异构体、药学上可接受的盐：
5.根据权利要求1-4任一项所述的含苯并氮杂环侧链的三氮唑醇类化合物，其特征在于：所述的药学上可接受的盐为盐酸盐、硫酸盐、磷酸盐、马来酸盐、富马酸盐、枸橼酸盐、甲磺酸盐、对甲苯磺酸盐、酒石酸或醋酸盐。
6.一种权利要求1所述的含苯并氮杂环侧链的三氮唑醇类化合物的制备方法，其特征在于：合成路线为：
R1、R2、n、X、Y如权利要求1所述。
7.权利要求1-4任一项所述的含苯并氮杂环侧链的三氮唑醇类化合物或其外消旋体、R型异构体、S型异构体、药学上可接受的盐在制备抗真菌药物中的用途。
8.根据权利要求1所述的用途，其特征在于：所述的用途为在制备治疗真菌感染引起的浅部或深部感染疾病药物中的用途。
9.根据权利要求1所述的用途，其特征在于：真菌为不耐药真菌或耐药真菌。
10.一种药物，其特征在于：它是以权利要求1-4任一项所述的含苯并氮杂环侧链的三氮唑醇类化合物或其外消旋体、R型异构体、S型异构体、药学上可接受的盐添加药学上可接受的辅料制成的常见药用制剂。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310136176.9A CN116041330B (zh) | 2023-02-20 | 2023-02-20 | 一种含苯并氮杂环侧链的三氮唑醇类抗真菌化合物及其制备方法与用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310136176.9A CN116041330B (zh) | 2023-02-20 | 2023-02-20 | 一种含苯并氮杂环侧链的三氮唑醇类抗真菌化合物及其制备方法与用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116041330A true CN116041330A (zh) | 2023-05-02 |
| CN116041330B CN116041330B (zh) | 2024-06-04 |
Family
ID=86121932
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310136176.9A Active CN116041330B (zh) | 2023-02-20 | 2023-02-20 | 一种含苯并氮杂环侧链的三氮唑醇类抗真菌化合物及其制备方法与用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116041330B (zh) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1292378A (zh) * | 1999-09-24 | 2001-04-25 | 中国人民解放军第二军医大学 | 三氮唑醇类抗真菌化合物及其制备方法 |
| CN1324792A (zh) * | 2000-05-24 | 2001-12-05 | 中国人民解放军第二军医大学 | 取代丙基三唑类抗真菌化合物和其盐类以及制备方法 |
| CN1405157A (zh) * | 2002-09-12 | 2003-03-26 | 中国人民解放军第二军医大学 | 新型三氮唑醇类抗真菌化合物及其盐类 |
| CN1539830A (zh) * | 2003-10-28 | 2004-10-27 | 中国人民解放军第二军医大学 | 取代苄胺三氮唑醇类抗真菌化合物及其制备方法 |
| CN101781263A (zh) * | 2010-03-04 | 2010-07-21 | 中国人民解放军第二军医大学 | 氮甲基侧链取代的三唑醇类抗真菌化合物及其制备方法 |
| CN102311399A (zh) * | 2011-07-07 | 2012-01-11 | 中国人民解放军第二军医大学 | 具有含氮侧链的三氮唑醇类抗真菌化合物及其制备方法与应用 |
-
2023
- 2023-02-20 CN CN202310136176.9A patent/CN116041330B/zh active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1292378A (zh) * | 1999-09-24 | 2001-04-25 | 中国人民解放军第二军医大学 | 三氮唑醇类抗真菌化合物及其制备方法 |
| CN1324792A (zh) * | 2000-05-24 | 2001-12-05 | 中国人民解放军第二军医大学 | 取代丙基三唑类抗真菌化合物和其盐类以及制备方法 |
| CN1405157A (zh) * | 2002-09-12 | 2003-03-26 | 中国人民解放军第二军医大学 | 新型三氮唑醇类抗真菌化合物及其盐类 |
| CN1539830A (zh) * | 2003-10-28 | 2004-10-27 | 中国人民解放军第二军医大学 | 取代苄胺三氮唑醇类抗真菌化合物及其制备方法 |
| CN101781263A (zh) * | 2010-03-04 | 2010-07-21 | 中国人民解放军第二军医大学 | 氮甲基侧链取代的三唑醇类抗真菌化合物及其制备方法 |
| CN102311399A (zh) * | 2011-07-07 | 2012-01-11 | 中国人民解放军第二军医大学 | 具有含氮侧链的三氮唑醇类抗真菌化合物及其制备方法与应用 |
Non-Patent Citations (4)
| Title |
|---|
| NA, YOUNG MIN: "Synthesis and activity of novel 1-halogenobenzylindole linked triazole derivatives as antifungal agents", BULLETIN OF THE KOREAN CHEMICAL SOCIETY, vol. 32, no. 1, pages 307 - 310, XP055263570, DOI: 10.5012/bkcs.2011.32.1.307 * |
| NA, YOUNG MIN: "Synthesis and activity of novel indole linked triazole derivatives as antifungal agents", BULLETIN OF THE KOREAN CHEMICAL SOCIETY, vol. 31, no. 11, pages 3467 - 3470 * |
| 楚勇: "新型三氮唑醇类抗真菌药物合成（I）", 中国药物化学杂志, vol. 11, no. 2, pages 80 - 84 * |
| 王志会等: "氮杂吲哚合成", 化学进展, vol. 24, no. 10, pages 1974 - 1982 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116041330B (zh) | 2024-06-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Thamban Chandrika et al. | Alkylated piperazines and piperazine-azole hybrids as antifungal agents | |
| CN102762542B (zh) | 一种抗真菌三唑衍生物 | |
| CN109942546B (zh) | 喹诺酮嘧啶类化合物及其制备方法和应用 | |
| JP2010070503A (ja) | 抗真菌作用２−アミノトリアゾロピリジン誘導体 | |
| US20130252964A1 (en) | Compounds And Methods For Treating Candidiasis And Aspergillus Infections | |
| CN101445488A (zh) | 具抗微生物活性的三唑类化合物及制备方法和医药用途 | |
| CN116041330B (zh) | 一种含苯并氮杂环侧链的三氮唑醇类抗真菌化合物及其制备方法与用途 | |
| EP3060549B1 (en) | Novel antifungal oxodihydropyridinecarbohydrazide derivative | |
| Ogura et al. | Synthesis and antifungal activities of (2R, 3R)-2-aryl-1-azolyl-3-(substituted amino)-2-butanol derivatives as topical antifungal agents | |
| KR20140003497A (ko) | 바이사이클릭 벤젠 유도체로 치환된 신규 항진균성 5,6-디하이드로-4H-피롤로[1,2-a][1,4]벤조디아제핀 및 6H-피롤로[1,2-a][1,4]벤조디아제핀 | |
| CN101323594B (zh) | 卤苄叔胺类双唑抗微生物化合物及其制备方法和医药用途 | |
| CN113999211B (zh) | 一类特异性抗前列腺癌活性的含1,2,3-三氮唑的吲唑骨架衍生物 | |
| CN109485607B (zh) | β-唑类-苯基酮衍生物及其用途 | |
| CN103275024B (zh) | 一种氮唑类抗真菌化合物及其制备方法和用途 | |
| WO2013130738A1 (en) | Compounds and methods for treating malaria | |
| CN106478550B (zh) | 一种ulk1小分子激动剂及其在抗肿瘤药物中的应用 | |
| CN103951625B (zh) | 一种含哌嗪基的1,2,3-三唑类抗真菌化合物及其制备方法和应用 | |
| US11274106B2 (en) | Topoisomerase inhibitors with antibacterial and anticancer activity | |
| CN103483315B (zh) | 7-(3-氨甲基-4-烷氧亚胺基-1-吡咯烷基)-1-[(1r,2s)-2-氟环丙基]喹诺酮羧酸类化合物及其制备方法 | |
| JP2013515756A (ja) | 抗真菌剤として使用するための第２級８−ヒドロキシキノリン−７−カルボキサミド誘導体 | |
| CN102060793B (zh) | 具生物活性的双芳基叔胺唑类化合物及制备方法和医药用途 | |
| CN105899234A (zh) | Dupa-茚并异喹啉缀合物 | |
| CN114181225B (zh) | 一种含笑内酯衍生物及其药物组合物、制备方法和用途 | |
| CN103387548B (zh) | 1,2,3-三唑类抗真菌化合物及其制备方法和应用 | |
| CN103265525B (zh) | 取代噻吩并苯醌类化合物及其制备方法与应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |