CN113603683A - 用于抗微生物治疗的经取代苯基噁唑烷酮 - Google Patents
用于抗微生物治疗的经取代苯基噁唑烷酮 Download PDFInfo
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- CN113603683A CN113603683A CN202111073361.5A CN202111073361A CN113603683A CN 113603683 A CN113603683 A CN 113603683A CN 202111073361 A CN202111073361 A CN 202111073361A CN 113603683 A CN113603683 A CN 113603683A
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- phenyl
- cycloalkyl
- alkyl radical
- esi
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- NCTCGHLIHJJIBK-UHFFFAOYSA-N 3-phenyl-1,3-oxazolidin-2-one Chemical class O=C1OCCN1C1=CC=CC=C1 NCTCGHLIHJJIBK-UHFFFAOYSA-N 0.000 title description 4
- 238000011203 antimicrobial therapy Methods 0.000 title description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 239000003814 drug Substances 0.000 claims abstract description 11
- 238000011282 treatment Methods 0.000 claims abstract description 11
- 230000000813 microbial effect Effects 0.000 claims abstract description 9
- 208000015181 infectious disease Diseases 0.000 claims abstract description 8
- 241000187479 Mycobacterium tuberculosis Species 0.000 claims abstract description 5
- 230000002924 anti-infective effect Effects 0.000 claims abstract description 4
- -1 p-toluenesulfonyl Chemical group 0.000 claims description 128
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 120
- 150000001875 compounds Chemical class 0.000 claims description 85
- 229910052757 nitrogen Inorganic materials 0.000 claims description 63
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 61
- 150000003254 radicals Chemical class 0.000 claims description 54
- 229910052739 hydrogen Inorganic materials 0.000 claims description 41
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 40
- 125000003118 aryl group Chemical group 0.000 claims description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims description 26
- 229910052731 fluorine Inorganic materials 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 23
- 229910052717 sulfur Inorganic materials 0.000 claims description 23
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 22
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 22
- 239000012453 solvate Substances 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 239000000126 substance Substances 0.000 claims description 18
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 14
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 10
- 150000003852 triazoles Chemical class 0.000 claims description 10
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 70
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 abstract description 19
- 125000001424 substituent group Chemical group 0.000 abstract description 10
- 125000002950 monocyclic group Chemical group 0.000 abstract description 6
- 125000002619 bicyclic group Chemical group 0.000 abstract description 3
- 125000003003 spiro group Chemical group 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 434
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 265
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 211
- 238000005160 1H NMR spectroscopy Methods 0.000 description 165
- 239000000243 solution Substances 0.000 description 145
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 124
- 239000000203 mixture Substances 0.000 description 122
- 239000011541 reaction mixture Substances 0.000 description 121
- 239000007787 solid Substances 0.000 description 106
- 238000004809 thin layer chromatography Methods 0.000 description 103
- 239000012043 crude product Substances 0.000 description 100
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 94
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 92
- 238000010898 silica gel chromatography Methods 0.000 description 89
- 239000012044 organic layer Substances 0.000 description 67
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 55
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 54
- 235000019270 ammonium chloride Nutrition 0.000 description 47
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 45
- 229910001868 water Inorganic materials 0.000 description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
- 238000004896 high resolution mass spectrometry Methods 0.000 description 40
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 40
- 230000015572 biosynthetic process Effects 0.000 description 37
- 238000003786 synthesis reaction Methods 0.000 description 36
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 239000000047 product Substances 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 28
- 235000019439 ethyl acetate Nutrition 0.000 description 28
- 229910000027 potassium carbonate Inorganic materials 0.000 description 28
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 26
- 238000010791 quenching Methods 0.000 description 26
- 239000012299 nitrogen atmosphere Substances 0.000 description 25
- 239000003921 oil Substances 0.000 description 25
- 235000019198 oils Nutrition 0.000 description 24
- ZRADTEUZDXCFDL-CBINBANVSA-N C12COCC(CC1)N2C1=C(C=C(C=C1F)N1C(O[C@H](C1)CN=[N+]=[N-])=O)F Chemical compound C12COCC(CC1)N2C1=C(C=C(C=C1F)N1C(O[C@H](C1)CN=[N+]=[N-])=O)F ZRADTEUZDXCFDL-CBINBANVSA-N 0.000 description 23
- 238000000746 purification Methods 0.000 description 23
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 22
- FVEFYOOMDFKAQO-GASCZTMLSA-N N1([C@@H](CC[C@@H]1C(=O)OCC)C(=O)OCC)C(=O)OCC1=CC=CC=C1 Chemical compound N1([C@@H](CC[C@@H]1C(=O)OCC)C(=O)OCC)C(=O)OCC1=CC=CC=C1 FVEFYOOMDFKAQO-GASCZTMLSA-N 0.000 description 22
- UHRQFGGHAVRLMI-UHFFFAOYSA-N OC(=O)C12CCC(CSC1)N2Cc1ccccc1 Chemical compound OC(=O)C12CCC(CSC1)N2Cc1ccccc1 UHRQFGGHAVRLMI-UHFFFAOYSA-N 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 22
- 239000012267 brine Substances 0.000 description 21
- 239000000706 filtrate Substances 0.000 description 21
- 150000004702 methyl esters Chemical class 0.000 description 21
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
- 239000000725 suspension Substances 0.000 description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 20
- 239000012298 atmosphere Substances 0.000 description 20
- 239000001257 hydrogen Substances 0.000 description 20
- 229910052938 sodium sulfate Inorganic materials 0.000 description 20
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 20
- 239000007832 Na2SO4 Substances 0.000 description 19
- MCBNBQYJKAGMNT-NSHDSACASA-N NC[C@@H](CN1C(C=C2F)=CC(F)=C2N2C=CSCC=C2)OC1=O Chemical compound NC[C@@H](CN1C(C=C2F)=CC(F)=C2N2C=CSCC=C2)OC1=O MCBNBQYJKAGMNT-NSHDSACASA-N 0.000 description 18
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 18
- YVOQRJKNEJFAOH-UHFFFAOYSA-N FC1=C(C(=CC(=C1)[N+](=O)[O-])F)N1CC2CCC(C1)O2 Chemical compound FC1=C(C(=CC(=C1)[N+](=O)[O-])F)N1CC2CCC(C1)O2 YVOQRJKNEJFAOH-UHFFFAOYSA-N 0.000 description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 17
- GUQNFKAJTYVMGI-RTYFJBAXSA-N C12COCC(CC1)N2C1=C(C=C(C=C1F)N1C(O[C@H](C1)CO)=O)F Chemical compound C12COCC(CC1)N2C1=C(C=C(C=C1F)N1C(O[C@H](C1)CO)=O)F GUQNFKAJTYVMGI-RTYFJBAXSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 16
- GTGBUEGDGYIKKT-CBINBANVSA-N C12COCC(CC1)N2C1=C(C=C(C=C1F)N1C(O[C@H](C1)CN)=O)F Chemical compound C12COCC(CC1)N2C1=C(C=C(C=C1F)N1C(O[C@H](C1)CN)=O)F GTGBUEGDGYIKKT-CBINBANVSA-N 0.000 description 15
- FVXXVOVEPSUIIL-LLVKDONJSA-N OC[C@@H](CN1C(C=C2F)=CC(F)=C2N2C=CSCC=C2)OC1=O Chemical compound OC[C@@H](CN1C(C=C2F)=CC(F)=C2N2C=CSCC=C2)OC1=O FVXXVOVEPSUIIL-LLVKDONJSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 15
- 239000000460 chlorine Substances 0.000 description 14
- 238000009472 formulation Methods 0.000 description 14
- 239000000284 extract Substances 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- DUWUBESHZTWXER-RTYFJBAXSA-N C12CSCC(CC1)N2C1=C(C=C(C=C1F)N1C(O[C@H](C1)CO)=O)F Chemical compound C12CSCC(CC1)N2C1=C(C=C(C=C1F)N1C(O[C@H](C1)CO)=O)F DUWUBESHZTWXER-RTYFJBAXSA-N 0.000 description 12
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 11
- 239000012141 concentrate Substances 0.000 description 11
- LDUSEIANLSWKPY-GASCZTMLSA-N diethyl (2s,5r)-1-benzylpyrrolidine-2,5-dicarboxylate Chemical compound CCOC(=O)[C@H]1CC[C@@H](C(=O)OCC)N1CC1=CC=CC=C1 LDUSEIANLSWKPY-GASCZTMLSA-N 0.000 description 11
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 11
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 10
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 10
- 230000022886 mitochondrial translation Effects 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 239000011591 potassium Substances 0.000 description 10
- 229910052700 potassium Inorganic materials 0.000 description 10
- 238000002953 preparative HPLC Methods 0.000 description 10
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 9
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- LVSZUBXEXIFENX-UHFFFAOYSA-N FC1=C(C(=CC(=C1)[N+](=O)[O-])F)N1C2CSCC1CC2 Chemical compound FC1=C(C(=CC(=C1)[N+](=O)[O-])F)N1C2CSCC1CC2 LVSZUBXEXIFENX-UHFFFAOYSA-N 0.000 description 9
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 9
- 235000019345 sodium thiosulphate Nutrition 0.000 description 9
- FZYAUXQPZLZAFX-UHFFFAOYSA-N 1,5-thiazocane Chemical compound C1CNCCCSC1 FZYAUXQPZLZAFX-UHFFFAOYSA-N 0.000 description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
- CYLRBPYXPVSJSG-BPCQOVAHSA-N C12CSCC(CC1)N2C1=C(C=C(C=C1)N1C(O[C@H](C1)CN)=O)F Chemical compound C12CSCC(CC1)N2C1=C(C=C(C=C1)N1C(O[C@H](C1)CN)=O)F CYLRBPYXPVSJSG-BPCQOVAHSA-N 0.000 description 8
- RBTSLGWWKBZJJF-CBINBANVSA-N C12CSCC(CC1)N2C1=C(C=C(C=C1F)N1C(O[C@H](C1)CN)=O)F Chemical compound C12CSCC(CC1)N2C1=C(C=C(C=C1F)N1C(O[C@H](C1)CN)=O)F RBTSLGWWKBZJJF-CBINBANVSA-N 0.000 description 8
- LJLAAONYXAGVSH-PIMMBPRGSA-N C12CSCC(CC1)N2C1=C(C=C(C=C1F)N1C(O[C@H](C1)CNC(CCC)=O)=O)F Chemical compound C12CSCC(CC1)N2C1=C(C=C(C=C1F)N1C(O[C@H](C1)CNC(CCC)=O)=O)F LJLAAONYXAGVSH-PIMMBPRGSA-N 0.000 description 8
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 8
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 8
- OQFUNFPIPRUQAE-UHFFFAOYSA-N 1,4-thiazepane Chemical compound C1CNCCSC1 OQFUNFPIPRUQAE-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- RUBQQRMAWLSCCJ-UHFFFAOYSA-N 1,2-difluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(F)=C1 RUBQQRMAWLSCCJ-UHFFFAOYSA-N 0.000 description 6
- IOQDNRYTTAIWTH-UHFFFAOYSA-N 3,3-bis(bromomethyl)-1-(4-methylphenyl)sulfonylazetidine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1CC(CBr)(CBr)C1 IOQDNRYTTAIWTH-UHFFFAOYSA-N 0.000 description 6
- NTVCMEJZWNSEFW-ICSRJNTNSA-N 4-(diaminomethylideneamino)-n-[[(2s)-1-[(2s)-3-hydroxy-2-(naphthalen-2-ylsulfonylamino)propanoyl]pyrrolidin-2-yl]methyl]butanamide Chemical compound NC(N)=NCCCC(=O)NC[C@@H]1CCCN1C(=O)[C@H](CO)NS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 NTVCMEJZWNSEFW-ICSRJNTNSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- IAKIVCGNRCJQHH-UHFFFAOYSA-N 4h-1,4-thiazepin-5-one Chemical compound O=C1NC=CSC=C1 IAKIVCGNRCJQHH-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- KFBLRGVHVVZXDH-HNNXBMFYSA-N C(CCC)(=O)NC[C@H]1CN(C(O1)=O)C1=CC(=C(C=C1)N1CCSCCC1)F Chemical compound C(CCC)(=O)NC[C@H]1CN(C(O1)=O)C1=CC(=C(C=C1)N1CCSCCC1)F KFBLRGVHVVZXDH-HNNXBMFYSA-N 0.000 description 6
- PKBFXBGEEQVXFG-UHFFFAOYSA-N C12CN(CC(CC1)O2)C1=C(C=C(C=C1)N1C(OC(C1)CN)=O)F Chemical compound C12CN(CC(CC1)O2)C1=C(C=C(C=C1)N1C(OC(C1)CN)=O)F PKBFXBGEEQVXFG-UHFFFAOYSA-N 0.000 description 6
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Classifications
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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- A61P31/06—Antibacterial agents for tuberculosis
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- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
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- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
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- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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- C—CHEMISTRY; METALLURGY
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/08—Bridged systems
Abstract
本发明涉及新型噁唑烷酮(式I):
Description
本申请是申请号为2016800542271、申请日为2016年7月15日、发明名称为“用于抗微生物治疗的经取代苯基噁唑烷酮”的中国发明专利申请的分案申请,原申请为国际申请号为PCT/US2016/042486的中国国家阶段申请,该国际申请要求申请日为2015年7月17日,申请号为62/193,963的美国申请的优先权。
发明领域
本发明总体上涉及具有抗菌活性的化合物,并且更具体地,涉及具有抗结核性质的化合物。特别地,本发明涉及可用于治疗有需要的患者中的结核病的经取代的苯基噁唑烷酮化合物。
以下引用或依赖的所有文件明确地通过引用并入本文。
发明背景
利奈唑胺是首创新药,并于2000年被批准用于多种临床应用,包括治疗由金黄色葡萄球菌/耐甲氧西林金黄色葡萄球菌、耐万古霉素肠球菌和肺炎链球菌(Pen-S)引起的医院内和社区获得性肺炎和皮肤感染。利奈唑胺表现出针对结核分枝杆菌(包括多重耐药(MDR)和广泛耐药(XDR)菌株在内)的体外抑菌活性,最低抑菌浓度(MIC)低于1μg/ml。然而,它在小鼠结核病模型中仅显示出一般的活性。尽管如此,利奈唑胺已经在联合治疗方案中被超适应症用于治疗多重耐药结核病。
目前在临床开发中的噁唑烷酮在长期给药(即超过一个月)后,在动物中显示骨髓毒性,这被认为与线粒体蛋白质合成(MPS)抑制有关,其安全边际很窄或没有安全边际。由于这类化合物的抗微生物作用模式是抑制微生物蛋白质合成,所以这些化合物表现出的MPS抑制及随之而来的骨髓毒性被认为是机制特异性的。这些噁唑烷酮通常显示高清除率,因此需要在临床治疗TB或其正在开发用于的其他适应症中施用高剂量(例如,每天500mg至1600mg)以实现有效暴露。因此,确定用于TB治疗的新一代噁唑烷酮将是非常合乎需要的,其将显示出改善的针对TB的效力和功效、降低的系统清除率以将日剂量降低至500mg以下,以及减少的MPS抑制和相关的骨髓毒性,使长期施用时的安全边际得到改善。
发明概述
本发明涉及式I的新型噁唑烷酮:
或其药学上可接受盐、水合物或溶剂合物,其中,
R独立地为OR1、OC(O)R2、OC(O)NHR2、OS(O2)R2、NHS(O)2R2、NR3R4、NHC(O)R5;
R’和R”独立地为H、F、Cl或OMe;
每个R1独立地为H、C1-C6烷基、C3-C8环烷基,其中所述烷基、环烷基任选地被1至4个选自以下的基团取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基;
每个R2独立地为C1-C6烷基、C3-C8环烷基、杂环基、杂芳基或芳基,其中所述烷基、环烷基、杂环基、杂芳基或芳基任选地被1至4个选自以下的基团取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6酰氧基、CF3、NO2、CN和NH2;
R3和R4各自独立地为H、C1-C6烷基、C3-C8环烷基、杂环基、杂芳基、芳基;或者R3和R4跟与之相连的氮一起形成具有1至3个选自O、S或N的附加杂原子的4至8元杂环基或杂芳基,其中所述烷基、环烷基、杂环基、杂芳基或芳基任选地被1至4个选自以下的基团取代:卤素、C1-C6烷基、C1-C6烷氧基、CF3、NO2、CN;
每个R5独立地为C1-C6烷基、C3-C8环烷基、C1-C6烷氧基、杂芳基、芳基,其中所述烷基、环烷基、杂环基、杂芳基或芳基任选地被1至4个选自以下的基团取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6酰氧基、CF3、NO2、CN和NH2;
环A选自:
其中,
R6和R7各自独立地为H、F、CH3、CH2CH3、CF3、苯基;
X=O、S、SO、SO2;
Y=O、S、SO、SO2和NR8;
m为1或2;
n为1或2;
p为1或2;
q为1或2;
R8独立地为H、C1-C4烷基、C3-C6环烷基、COCH3和对甲苯磺酰基,其中所述烷基,环烷基任选地被1至4个选自以下的基团取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6酰氧基、CF3、NO2、CN和NH2。
在另一个方面中,本发明提供了药物组合物,其包含至少一种式I化合物或其盐、水合物或溶剂合物,和一种或多种药学上可接受的载体和/或添加剂。
在另一个方面中,本发明提供了通过向有需要的患者施用治疗有效量的式I化合物或其盐、水合物或溶剂合物而治疗人类中微生物感染的方法。
在另一个方面中,本发明包括式I或其盐、水合物或溶剂合物的药物组合物,其进一步包含一种或多种另外的抗感染治疗物。
在又一个方面中,本发明涉及根据式I所示的化合物或其药学上可接受盐、水合物或溶剂合物,其用作人类中的抗结核(TB)治疗剂。
发明详述
本发明的一个方面是提供如上所示和所述的根据式I所示的新化合物。特别地,本发明的化合物是可用于有效对抗许多人类和兽类病原体的抗微生物剂,包括革兰氏阳性好氧细菌、结核分枝杆菌、鸟分枝杆菌等。因此,本发明提供了根据式I所示的新化合物,以及其药学上可接受的盐、水合物或溶剂合物。公式I中的变量值在以下段落中提供。
下表1通过指示其结构,以及其分别如以下实施例9和10中所述进行测试时针对结核分枝杆菌H37Rv菌株的体外活性和体外MPS抑制活性,而显示了本发明化合物的一些具体实例。如下表1中所示,有效的抗结核药剂表现出低MIC值(MIC低于1μg/mL的特定化合物)。相反地,IC50的高MPS抑制指示减小的线粒体蛋白质的体外合成活性,并且指示降低的体内骨髓抑制毒性。在本发明的某些实施方式中,具有最佳治疗指数的化合物是显示出与MPS抑制相对较高的IC50结合的相对较低MIC值的那些化合物。表1中提供了本发明的代表性化合物(其中条目“NA”(即“不适用”)表示未测量特定值):
表1
定义
除非另有说明,否则用于本文的“烷基”包括具有指定碳原子数的支链和直链饱和脂族烃基。在整个申请中使用常用的烷基缩写,例如甲基可以通过包括“Me”或CH3的常规缩写来表示,或者是一个不带有定义的末端基团的延伸键的符号,例如乙基通过“Et”或CH2CH3来表示,丙基通过“Pr”或CH2CH2CH3来表示,丁基可通过“Bu”或CH2CH2CH2CH3等来表示。“C1-6烷基”(或“C1-C6烷基”)是指具有指定碳原子数的支链或直链烷基,包括所有异构体。C1-6烷基包括所有的己基烷基和戊基烷基异构体,以及正、异、仲和叔丁基、正和异丙基、乙基和甲基。如果未提供数目,则旨在用于直链或支链烷基的为1-10个碳原子。C1-6烷基可以是未取代的或者被1-3个氟或1-3个氯原子取代。
“环烷基”是指不含杂原子的C3-10碳环。例如,环烷基包括环丙基、环丁基、环戊基、环己基、环庚基、十氢萘基等。
“芳基”是指含有6-12个碳原子的单环和双环芳族环。芳基的实例包括但不限于苯基、萘基、茚基等。芳基还包括与芳基稠合的单环。实例包括四氢萘基、茚满基等。
除非另有说明,否则“杂环基”是指含有1-2个选自N、O和S的杂原子的4-、5-、6-、7-或8-元单环饱和环,其中连接点可以是碳或氮。“杂环基”的实例包括但不限于哌啶基、哌嗪基、吗啉基、吡咯烷基、噁唑烷基、咪唑烷基等。该术语还包括非芳族的部分不饱和单环,例如通过氮连接的2-或4-吡啶酮或N-取代的(1H,3H)-嘧啶-2,4-二酮(N-取代的尿嘧啶)。杂环基还可以包括带电形式的此类部分,例如哌啶鎓。
“杂芳基”是指具有5-10个原子并含有1-3个选自N、O和S的杂原子的单环或双环芳族环或环系。实例包括但不限于噁二唑基、噻二唑基、吡咯基、呋喃基、三嗪基、噻吩基、嘧啶基(pyrimidyl)、嘧啶基(pyrimidinyl)、哒嗪基、吡嗪基、异噁唑基、三唑基、异噻唑基、吡唑基、咪唑基、吡啶基(pyridyl)、吡啶基(pyridinyl)、噁唑基、噻唑基、四唑基等。杂芳基还包括与非芳族或部分芳族的杂环稠合的芳族杂环基团,以及与环烷基环稠合的芳族杂环基团。杂芳基另外的实例包括但不限于咪唑并吡啶基、咪唑并哒嗪基、吡唑并吡唑基、吲唑基、噻吩并吡唑基、吡唑并吡啶基和咪唑并噻唑基。杂芳基还包括带电荷的此类基团,如吡啶鎓。在一个实施方式中,杂芳基为三唑基、咪唑基、噁二唑基、吡唑基、噁唑基和吡啶基。
除非另有说明,否则“杂环烷基”包括与如上所述的杂环基的碳或氮原子键合的支链和直链饱和脂族烃基。
“卤素(或卤)”包括氟、氯、溴和碘。在一个实施方式中,卤素为氯或氟。
在环(例如芳基、杂芳基环或饱和杂环)中的任何原子上允许被指定的取代基取代,条件是这样的环取代在化学上是允许的并且产生稳定的化合物。可以制备和分离“稳定的”化合物,并且其结构和性质保持或可被导致在一段时间内保持基本不变,以允许该化合物用于所述目的。
当变量(例如R、Rx等)在任何组成或公式中出现一次以上时,其每次出现时的定义与其在每个其它情况下出现时的定义无关。另外,只有当此类组合产生稳定的化合物时才允许取代基和/或变量的组合。
在选择本公开的化合物时,本领域普通技术人员将认识到各种取代基,即R1、R2、R等,要依照化学结构连接性和稳定性的一般原则来选择。
术语“取代的”用于包括指定取代基带来的多个取代度。当要求多个取代基时,取代的化合物可以独立地被一个或多个公开的取代基所取代。独立地被取代意味着(两个或更多个)取代基可以相同或不同。
当取代基或变量具有多个定义时,该取代基或变量被定义为选自由指定定义所组成的组。
盐:
结构式I的化合物还涵盖药学上可接受的盐。本发明的化合物可以以药学上可接受的盐的形式施用。术语“药学上可接受的盐”是指由药学上可接受的碱或酸(包括无机或有机碱或酸)制备的盐。碱性化合物的药学上可接受的盐是指本发明化合物的无毒盐,其通常通过将游离碱与合适的有机或无机酸混合而制备。本发明的碱性化合物的代表性盐包括但不限于以下:乙酸盐、抗坏血酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、右旋樟脑磺酸盐、碳酸盐、克拉维酸盐、柠檬酸盐、依地酸盐、乙二磺酸盐、依托酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、氢溴酸盐、盐酸盐、乳糖酸盐、月桂酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化盐、甲基硝酸盐、甲基硫酸盐、甲磺酸盐、磷酸盐/二磷酸盐、聚半乳糖醛酸盐、丙酸盐、水杨酸盐、硬脂酸盐、硫酸盐、碱式乙酸盐、琥珀酸盐、鞣酸盐、酒石酸盐、茶氯酸盐(teoclate)、硫氰酸盐、甲苯磺酸盐、三乙基碘化盐、戊酸盐等。由式I所涵盖的酸的合适的药学上可接受的盐包括但不限于由无机碱(包括铝、铵、钙、铜、铁、亚铁、锂、镁、三价锰、二价锰、钾、钠、锌等)形成的盐。衍生自药学上可接受的有机无毒碱的盐包括以下的盐:伯胺、仲胺和叔胺、环胺、二环己胺和碱性离子交换树脂、例如精氨酸、甜菜碱、咖啡因、胆碱、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺,氨基葡糖胺、组氨酸、哈胺、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。
式I化合物的溶剂合物和水合物也包括在本发明中。
本发明还公开了如下所述的合成式I化合物的方法。
本发明的一个值得关注的方面涉及根据式I所示的化合物或其药学上可接受的盐、水合物或溶剂合物,其可用于治疗人类微生物感染的方法。
本发明的另一个值得关注的方面是治疗需要此种治疗的人类患者中的微生物感染的方法,其包括向所述患者施用治疗有效量的式I化合物或其药学上可接受的盐、水合物或溶剂合物。
在另一个方面中,本发明提供了式I或其盐、水合物或溶剂合物的药物组合物,其进一步包含一种或多种另外的抗感染剂。
在又一个方面中,本发明涉及根据式I所示的化合物或其药学上可接受的盐、水合物或溶剂合物,其用作人类中的抗结核(TB)剂。
尽管本发明的化合物可能作为原料化学品而被施用,但是优选将其以药物组合物提供。因此,根据另一个方面,本发明提供了一种药物组合物,其包含式(I)化合物或其药学上可接受的盐或溶剂合物,连同一种或多种其药学上的载体,并且任选地包含一种或多种其它治疗成分。在与制剂的其他成分相容的方面,载体(一种或多种)必须是“可接受的”,并且对其接受者无害。
该制剂包括适于口服、肠胃外(包括皮下、皮内、肌内、静脉内和关节内)、直肠和局部(包括皮肤、口腔、舌下和眼内)施用的制剂。最合适的途径可能取决于接受者的状况和病症。片剂、胶囊剂、眼内局部制剂和胃肠外溶液在氨基糖苷类中是常见的。制剂可以方便地以单位剂量形式提供,并且可以通过制药领域中公知的任何方法制备。所有方法包括使式(I)化合物或其药学上可接受的盐或溶剂合物(“活性成分”)与构成一种或多种辅助成分的载体混合的步骤。通常,制剂的制备是通过将活性成分与液体载体或细分的固体载体或两者均匀且紧密地混合,然后如果需要,将产品成型为所需的制剂。
适于口服施用的本发明制剂可以以离散的单元提供,例如各自含有预定量的活性成分的胶囊、扁囊剂或片剂;以粉末或颗粒提供;以水性液体或非水性液体中的溶液或悬液提供;或者以水包油液体乳剂或油包水液体乳剂提供。活性成分也可以以丸剂、膏剂或糊剂提供。
可以通过任选地与一种或多种辅助成分压制或模制来制备片剂。可以通过在合适的机器中压制任选地与粘合剂、润滑剂、惰性稀释剂、润滑、表面活性或分散剂混合的自由流动形式的活性成分(如粉末或颗粒),制备压制片剂。可以通过将用惰性液体稀释剂润湿的粉状化合物的混合物在合适的机器上模塑而制备模制片剂。片剂可以任选地经包衣或刻痕,并且可以经配制以提供其中活性成分的持续、延迟或受控制的释放。
用于肠胃外施用的制剂包括水性和非水性的无菌注射溶液,其可含有抗氧化剂、缓冲剂、抑菌剂和使制剂与预期接受者的血液等渗的溶质。用于肠胃外施用的制剂还包括水性和非水性的无菌混悬液,其可以包括悬浮剂和增稠剂。该制剂可以呈现于多剂量容器(例如密封的安瓿和小瓶)的单位剂量中,并且可以在冷冻干燥(冻干)条件下贮存,仅需要在即用之前添加无菌液体载体,例如盐水、磷酸盐缓冲盐水(PBS)等。现配注射溶液和悬液可以由前述类型的无菌粉末、颗粒和片剂制备。
优选的单位剂量制剂是含有如下文所述的有效剂量或其适当部分的活性成分的制剂。
应当理解,除了以上特别提及的成分之外,本发明的制剂还可以包括本领域中就所讨论的制剂类型而言的其它常规试剂,例如适于口服施用的制剂可以包括调味剂。
缩略语
在整个以下合成方案和实施例中,除非另有说明,否则使用具有以下含义的缩略语:
Ac为乙酸酯或乙酰基;
aq.为水性的;
Ar为芳基;
Bn为苄基;
BnNH2为苄胺;
Boc为叔丁基氨甲酰基;
br为宽;
Bu为丁基;
tBu为叔丁基;
n-BuLi为正丁基锂;
CbzCl为氯甲酸苄酯;
CFU为菌落形成单位;
CO2为二氧化碳;
COX-1为环氧合酶I;
cPr为环丙基;
DCM为二氯甲烷;
DIPEA为N,N-二异丙基乙胺;
DMAP为4-二甲氨基吡啶
DMEM为达尔伯克改良伊格尔培养基
DMF为N,N-二甲基甲酰胺;
DMSO为二甲基亚砜;
ELISA为酶联免疫吸附测定
ESI为电喷雾离子化;
Et为乙基;
Et3N为三乙胺;
Et2O为乙醚;
EtOH为乙醇,
EtOAc为乙酸乙酯;
FBS为胎牛血清
Halo为卤素(例如氟或氯);
1H-NMR为质子核磁共振;
13C-NMR为碳核磁共振;
H9C2为来自大鼠心脏成肌细胞的细胞系
HPLC为高效液相色谱;
HRMS为高分辨质谱;
Hz为赫兹;
i为异;
IC50为半数最大抑制浓度;
Kg为千克;
M为摩尔;
Me为甲基;
μg为微克;
MeCN为乙腈;
MeOH为甲醇;
MsCl是甲磺酰氯;
MHz为兆赫兹;
mm为毫米;
μL为微升;
mM为毫摩尔;
μM为微摩尔;
mmol为毫摩尔;
MABA为微孔板阿尔玛蓝测定;
MIC为最小抑制浓度;
MPS为线粒体蛋白质合成;
m/z为质荷比;
n为正位的;
NEAA为非必需氨基酸
nm为纳米;
nPr为正丙基;
p为对位的;
PE为石油醚;
Ph为苯基;
Pr为丙基;
rt为室温;
sec为仲;
SDH-A为琥珀酸脱氢酶-A
tert为叔;
TFA为三氟乙酸;
TsCl为对甲苯磺酰氯;
TMSI为三甲基碘硅烷;
TPP为三苯基膦;
TsNH2为对甲苯磺酰胺;
Tosyl为对甲苯磺酰基;
THF为四氢呋喃;
TLC为薄层色谱。
实施例
在以下实施例中说明了制备本发明的代表性化合物的合成方法。起始原料是可商购的,或者可以根据本领域已知的或如本文所示的步骤制备。以下实施例旨在协助说明本发明,并且无意于也不应当将其解释为限制其范围。
实施例1
[1,4]硫氮杂环庚烷(1a)的制备
步骤1:二氢-2H-噻喃-4(3H)-酮肟(1a-1)的合成
向二氢-2H-噻喃-4(3H)-酮(10g,0.086mol)和盐酸羟胺(10.4g,0.15mol)在H2O(100mL)和乙醇(40mL)中的溶液中加入乙酸钠(13.1g,0.16mol)。将混合物回流4小时,真空除去有机溶剂并在冰浴中冷却残余物,通过过滤获得8.92g固体,收率为79%。1H-NMR(400MHz,CDCl3)δ:2.88(m,2H),2.80(m,2H),2.74(m,2H),2.57(m,2H)。
步骤2:1,4-硫氮杂环庚-5-酮(1a-2)的合成
在115℃下加热二氢-2H-噻喃-4(3H)-酮肟(4.01g,0.03mol)在多聚磷酸中的混合物15分钟,并冷却至室温,加入冰水,然后用EtOAc萃取混合物5次。合并的有机层经Na2SO4干燥,并在真空下浓缩以得到2.4g棕色固体状的产物,收率为60%。1H-NMR(400MHz,CDCl3)δ:6.79(brs,1H),3.63(m,2H),2.94(m,2H),2.74(m,4H)。
步骤3:1,4-硫氮杂环庚烷(1a)的合成
在0℃下向1,4-硫氮杂环庚-5-酮(2.07g,15.7mmol)在干燥THF中的溶液中加入LiAlH4(0.66g,17.3mmol),然后将混合物在室温下搅拌4小时。将H2O(0.7mL)、15%NaOH(0.7mL)和H2O(2.1mL)先后加至反应。过滤混合物以得到1.77g产物,收率为96%。1H-NMR(400MHz,CDCl3)δ:3.07(m,2H),2.98(m,2H),2.75(m,4H),1.93(m,2H)。
实施例2
1,5-硫氮杂环辛烷盐酸化物(1b)的制备
步骤1:3,3'-(苄基氮烷二基)二丙酸二甲酯(1b-1)的合成
室温下将苄胺(10.7g,0.1mol)在MeOH(50mL)中的溶液滴加至丙烯酸甲酯(18.9g,.022mol)在MeOH(100mL)中的溶液。将所得混合物回流8小时,并真空蒸发以以定量收率得到27.9g产物。1H-NMR(400MHz,CDCl3)δ:7.28(m.,5H),3.64(s,2H),3.59(s,6H),2.80(m,4H),2.47(m,4H)。
步骤2:3,3'-(苄基氮烷二基)双(丙-1-醇)(1b-2)的合成
在0℃下向3,3'-(苄基氮烷二基)二丙酸二甲酯(4.47g,16.0mmol)在干燥THF中的溶液中加入LiAlH4(0.77g,20.2mmol),然后将混合物在室温下搅拌24小时。将MeOH(1.5mL)、15%NaOH(1.0mL)和H2O(1.0mL)先后加至反应。过滤混合物以得到3.4g产物,收率为91%。1H-NMR(400MHz,CDCl3)δ:7.31(m,5H),3.68(t,J=5.6Hz,5.6Hz,4H),3.57(s,2H),2.63(t,J=6.4Hz,6.0Hz,4H),1.76(m,4H)。
步骤3:N-苄基-3-溴-N-(3-溴丙基)丙-1-胺(1b-3)的合成
在0℃下向3,3'-(苄基氮烷二基)双(丙-1-醇)(447mg,2.0mmol)在干燥CH2Cl2中的溶液中滴加PBr3,然后将混合物在室温下搅拌12小时。用水稀释反应混合物并用CH2Cl2萃取。合并的有机层用饱和NaHCO3和盐水洗涤,经Na2SO4干燥并浓缩。获得0.43g黄色油状的产物,收率为61%。1H-NMR(400MHz,CDCl3)δ:7.27(m,5H),3.56(s,2H),3.44(t,J=6.8Hz,6.4Hz,4H),2.58(t,J=6.4Hz,6.4Hz,4H),2.02(m,4H)。
步骤4:5-苄基-1,5-硫氮杂环辛烷(1b-4)的合成
向N-苄基-3-溴-N-(3-溴丙基)丙-1-胺(1.0g,2.9mmol)在乙醇中的溶液中加入Na2S·9H2O(697mg,2.9mmol)。将混合物回流18小时。然后将混合物冷却至室温,并真空除去溶剂。向残余物中加入H2O和Et2O。用Et2O萃取水层,并且合并的有机层用盐水洗涤,经Na2SO4干燥并在真空下浓缩。不经纯化使用粗产物。
步骤5:1,5-硫氮杂环辛烷盐酸化物(1b)的合成
在0℃下向5-苄基-1,5-硫氮杂环辛烷(8.6g,39mmol)在CH2Cl2中的溶液中加入(6.15g,43mmol)。将混合物在室温下搅拌6小时。真空蒸发溶剂并将残余物在MeOH中回流3小时。将混合物浓缩并用Et2O洗涤。不经纯化使用粗产物。
实施例3
(1R,5S)-3-硫杂-6-氮杂双环[3.1.1]庚烷(1c)的制备
步骤1:2,4-二溴戊二酸二乙酯(1c-1)的合成
在100℃下向二氢-2H-吡喃-2,6(3H)-二酮(11.4g,0.1mol)和PBr3(0.1mL)的溶液中滴加Br2(32g,0.2mol),将混合物在100℃下搅拌7小时并冷却至室温。将HCl/EtOH(10mL)加至反应混合物并在室温下搅拌过夜。EtOH蒸发后,将Et2O加至残余物并用饱和NaHCO3和盐水洗涤,经Na2SO4干燥,浓缩以得到32g产物,其不经纯化而用于下一步骤。
步骤2:(2R,4S)-1-苄基氮杂环丁烷-2,4-二甲酸二乙酯(1c-2)的合成
将(2R,4S)-2,4-二溴戊二酸二乙酯(54g,156mmol)、苄胺(17g,159mmol)和K2CO3(25.9g,187.2mmol)在甲苯中的混合物回流24小时。该混合物用盐水洗涤,经干燥并浓缩。通过硅胶层析纯化粗产物以得到18.39g产物,收率为41%。HRMS(ESI):C16H22NO4的m/z[M+H]+计算值:292.1549;实测值:292.1542。
步骤3:((2R,4S)-1-苄基氮杂环丁烷-2,4-二基)二甲醇(1c-3)的合成
在室温下向(2R,4S)-1-苄基氮杂环丁烷-2,4-二甲酸二乙酯(0.8g,2.75mmol)在EtOH/MeOH(9:1;10mL)中的溶液中加入CaCl2(0.92g,8.25mmol)。然后向所得经搅拌的混合物中逐份加入NaBH4(0.63g,16.5mmol)。将反应混合物在室温下搅拌过夜。随后加入H2O(5mL),并将混合物搅拌30分钟。然后将混合物真空浓缩,并在H2O(10mL)和CH2Cl2(10mL)之间分配。用CH2Cl2(2×10mL)萃取水层,并合并有机层,用盐水(10mL)洗涤,经Na2SO4干燥,并真空浓缩以得到0.25g黄色油状的产物。该产物不经进一步纯化而用于下一步骤。MS(ESI):m/z[M+H]+:208.1477。
步骤4:(2R,4S)-2,4-双(羟甲基)氮杂环丁烷-1-甲酸苄酯(1c-4)的合成
向((2R,4S)-1-苄基氮杂环丁烷-2,4-二基)二甲醇(0.52g,2.9mmol)在MeOH(10mL)中的溶液中加入Pd(OH)2(0.13g),并将混合物在室温,H2下搅拌2小时。将悬液过滤通过硅藻土短封垫并用另外的MeOH洗脱。真空除去溶剂。将残余物溶于无水CH2Cl2(30mL)中。向所得溶液中加入DIPEA(0.37g,2.9mmol),然后滴加CbzCl(0.44g,2.56mmol)。将混合物在室温下搅拌2小时,然后用H2O(50mL)淬灭。有机层用盐水洗涤,经Na2SO4干燥并浓缩。通过硅胶层析(CH2Cl2中5%MeOH)纯化粗产物以得到0.33g黄色油状的产物,收率为45%。
步骤5:(2R,4S)-2,4-双(((甲磺酰基)氧基)甲基)氮杂环丁烷-1-甲酸苄酯(1c-5)的合成
向(2R,4S)-2,4-双(羟甲基)氮杂环丁烷-1-甲酸苄酯(51mg,0.2mmol)在CH2Cl2(15mL)中的溶液中加入Et3N(61mg,0.6mmol),然后滴加MsCl(70mg,0.6mmol)。将混合物在室温下搅拌5小时,并且反应混合物用1N HCl和盐水洗涤,经Na2SO4干燥并浓缩。通过硅胶层析(CH2Cl2中5%MeOH)纯化粗产物以得到65mg黄色油状的产物,收率为80%。
HRMS(ESI):C15H22NO8S2的m/z[M+H]+计算值:408.0787;实测值:408.0780。
步骤6:(2R,4S)-2,4-双(溴甲基)氮杂环丁烷-1-甲酸苄酯(1c-6)的合成
回流(2R,4S)-2,4-双(((甲磺酰基)氧基)甲基)氮杂环丁烷-1-甲酸苄酯(65mg,0.16mmol)和LiBr(139mg,1.6mmol)在丙酮(15mL)中的混合物10小时。蒸发反应混合物,向残余物中加入H2O(20mL)和Et2O(20mL)。用Et2O(2×20mL)萃取水层,并用盐水(10mL)洗涤经合并有机层,经Na2SO4干燥并在真空下浓缩以得到51mg黄色油状的产物,收率为85%。HRMS(ESI):C13H15Br2NO2的m/z[M+H]+计算值:375.9548;实测值:375.9558。
步骤7:(1R,5S)-3-硫杂-6-氮杂双环[3.1.1]庚烷-6-甲酸苄酯(1c-7)的合成
向(2R,4S)-2,4-双(溴甲基)氮杂环丁烷-1-甲酸苄酯(0.77g,2.05mmol)在DMF(5mL)中的溶液中加入Na2S·9H2O(0.59g,2.46mmol)。将混合物在室温下搅拌45分钟。向溶液中加入H2O(20mL)和EtOAc(25mL)。用EtOAc(2×20mL)萃取水层,并用盐水(10mL)洗涤合并的有机层,经Na2SO4干燥并在真空下浓缩。通过硅胶层析(PE中20–30%EtOAc)纯化粗产物以得到0.15g无色油状的产物,收率为28.7%。HRMS(ESI):C13H17NO2S的m/z[M+H]+计算值:250.0902;实测值:250.0900。
步骤8:(1R,5S)-3-硫杂-6-氮杂双环[3.1.1]庚烷碘化物(1c)的合成
在0℃,Ar下向(1R,5S)-3-硫杂-6-氮杂双环[3.1.1]庚烷-6-甲酸苄酯(0.19g,0.8mmol)在无水CH2Cl2(20mL)中的溶液中加入TMSI(0.39g,1.9mmol)。将所得混合物在室温下搅拌2小时,并将MeOH(5mL)滴加至反应。将所得溶液另外搅拌0.5小时,然后蒸发以除去溶剂。用PE/EtOAc(2:1)洗涤残余物以得到0.24g棕色固体状的粗产物,其不经纯化被使用。
实施例4
(1R,5S)-3-硫杂-8-氮杂双环[3.2.1]辛烷碘化物(1d)的制备
步骤1:顺式-1-苄基吡咯烷-2,5-二甲酸二乙酯(1d-1)的合成
在室温下向经搅拌的2,5-二溴己二酸二乙酯(10.8g,30mmol)和苄胺(3.2g,30mmol)在甲苯(45mL)和H2O(9mL)中的溶液中加入K2CO3(5g,36mmol)。在Ar下将混合物回流20小时,然后倒入H2O(30mL)中。用EtOAc(2×20mL)萃取水层,合并的有机层用盐水(20mL)洗涤,经Na2SO4干燥,并通过硅胶层析(PE中10–20%EtOAc)纯化以得到6.1g黄色油状的产物,收率为67%。
1H-NMR(400MHz,CDCl3)δ:7.35–7.22(m,5H),4.06–4.00(m,4H),3.97(s,2H),3.46(brs,2H),2.08–2.04(m,4H),1.19(t,J=7.1Hz,6H)。HRMS(ESI):C17H24NO4的m/z[M+H]+计算值:306.1705;实测值:306.1695。
步骤2:顺式-吡咯烷-1,2,5三甲酸1-苄2,5-二乙酯(1d-2)的合成
向顺式-1-苄基吡咯烷-2,5-二甲酸二乙酯(5.4g,17.7mmol)在MeOH(100mL)中的溶液中加入10%Pd/C(0.54g),并将混合物在室温,H2下在帕尔摇床(Parr Shaker)中以50psi振摇4小时。将悬液过滤通过硅藻土短封垫并用另外的MeOH洗脱。真空除去溶剂。将残余物溶于无水CH2Cl2(50mL)中,并冷却至0℃。向所得溶液中加入Et3N(2.2g,21.6mmol),然后滴加CbzCl(3.7g,21.6mmol)。将混合物在室温下搅拌过夜,然后用H2O(50mL)淬灭。有机层用盐水洗涤,经Na2SO4干燥并浓缩。通过硅胶层析(PE中5–20%EtOAc)纯化粗产物以得到5.22g黄色油状的产物,收率为84%。1H-NMR(400MHz,CDCl3)δ:7.33–7.29(m,5H),5.19–5.10(m,2H),4.47(m,1H),4.40(m,1H),4.22(q,J=7.2Hz,2H),4.09(q,J=6.8Hz,2H),2.25–2.14(m,4H),1.28(t,J=6.8Hz,3H),1.17(t,J=6.8Hz,3H)。HRMS(ESI):C18H24NO6的m/z[M+H]+计算值:350.1604;实测值:350.1649。
步骤3:顺式-2,5-双(羟甲基)吡咯烷-1-甲酸苄酯(1d-3)的合成
在室温下向顺式-吡咯烷-1,2,5三甲酸1-苄2,5-二乙酯(5.75g,16.4mmol)在EtOH/MeOH(10:1;300mL)中的溶液中加入CaCl2(5.5g,49.2mmol)。然后向所得经搅拌的混合物中逐份加入NaBH4(3.75g,98.4mmol)。将反应混合物在室温下搅拌过夜。随后加入H2O(50mL),并将混合物搅拌30分钟。然后将混合物真空浓缩,并在H2O(100mL)和EtOAc(100mL)之间分配。用EtOAc(2×50mL)萃取水层,并合并有机层,用盐水(10mL)洗涤,经Na2SO4干燥,并真空浓缩以得到4.57g无色油状的产物。该产物不经进一步纯化而用于下一步骤。
1H-NMR(400MHz,CDCl3)δ:7.39–7.33(m,5H),5.16(s,2H),4.09–3.82(m,4H),3.56(d,J=8.1Hz,2H),2.91(brs,2H),2.04–1.97(m,4H)。HRMS(ESI):C14H19NNaO4的m/z[M+Na]+计算值:288.1206;实测值:288.1196。
步骤4:顺式-2,5-双(对甲苯磺酰氧甲基)吡咯烷-1-甲酸苄酯(1d-4)的合成
将化合物顺式-2,5-双(羟甲基)吡咯烷-1-甲酸苄酯(4.35g,16.4mmol)、Et3N(3.65g,36.1mmol)和DMAP(4.01g,32.8mmol)在CH2Cl2(50mL)中的溶液冷却至0℃。向该混合物中一次性加入对甲苯磺酰氯(6.88g,36.1mmol)并将所得混合物在室温下搅拌过夜。然后混合物用水和盐水洗涤,经Na2SO4干燥并在真空下浓缩。通过快速柱层析(PE中30–40%EtOAc)纯化残余物以得到8.97g半固体状的产物,收率为95%。
1H-NMR(400MHz,CDCl3)δ:7.73(brs,4H),7.36–7.29(m,9H),5.03–4.96(m,2H),4.15–3.89(m,6H),2.44(s,6H),1.87–1.83(m,4H)。13C-NMR(100MHz,CDCl3)δ(旋转异构体):165.30,154.49,144.90,135.88,132.61,129.90,128.55,128.19,127.89,69.16,68.87,67.28,57.30,56.56,26.61,25.44,21.63。HRMS(ESI):C28H32NO8S2的m/z[M+H]+计算值:574.1564;实测值:574.1547。
步骤5:(1R,5S)-3-硫杂-8-氮杂双环[3.2.1]辛烷-8-甲酸苄酯(1d-5)的合成
向顺式-2,5-双(对甲苯磺酰氧甲基)吡咯烷-1-甲酸苄酯(4.1g,7.1mmol)在乙醇(25mL)和H2O(25mL)中的溶液中加入Na2S·9H2O(5.12g,21.3mmol)。将混合物回流5小时。然后将混合物冷却至室温,并真空除去溶剂。向残余物中加入H2O(20mL)和EtOAc(25mL)。用EtOAc(2×20mL)萃取水层,并且合并的有机层用盐水(10mL)洗涤,经Na2SO4干燥并在真空下浓缩。通过硅胶层析(PE中20–30%EtOAc)纯化粗产物以得到1.38g无色油状的产物,收率为73%。
1H-NMR(400MHz,CDCl3)δ:7.37–7.30(m,5H),5.16(s,2H),4.52–4.47(m,2H),3.22(d,J=11.6Hz,1H),3.11(d,J=10.8Hz,1H),2.12(d,J=12.8Hz,2H),2.06(d,J=1.2Hz,4H)。13C-NMR(100MHz,CDCl3)δ:152.95,136.59,128.40,127.93,127.80,66.73,53.94,32.72,32.08,28.82,27.99。HRMS(ESI):C14H18NO2S的m/z[M+H]+计算值:264.1058;实测值:264.1113。
步骤6:(1R,5S)-3-硫杂-8-氮杂双环[3.2.1]辛烷碘化物(1d)的合成
在0℃,Ar下向(1R,5S)-3-硫杂-8-氮杂双环[3.2.1]辛烷-8-甲酸苄酯(0.24g,0.91mmol)在无水CH2Cl2(20mL)中的溶液中加入TMSI(0.44g,2.18mmol)。将所得混合物在室温下搅拌0.5小时,并将MeOH(0.26mL)滴加至反应。将所得溶液另外搅拌0.5小时,然后蒸发以除去溶剂。用PE/EtOAc(1:2)洗涤残余物以得到0.21g黄色固体状的产物,收率为91%。Mp:208–210℃。1H-NMR(400MHz,CDCl3)δ:8.92(brs,1H),8.72(brs,1H),4.38(s,2H),3.78(d,J=14.0Hz,2H),2.41–2.35(m,4H),2.24–2.22(d,J=7.6Hz,2H)。13C-NMR(100MHz,CDCl3)δ:55.67,31.42,27.23。HRMS(ESI):C6H12NS的m/z[M+H]+计算值:130.0685;实测值:130.0686。
实施例5
2-硫杂-6-氮杂-螺[3.3]庚烷(1e)的制备
步骤1:6-对甲苯磺酰基-2-氧杂-6-氮杂螺[3.3]庚烷(1e-1)的合成
在室温下向KOH(9.04g,161mmol)和3-溴-2,2-双(溴甲基)丙-1-醇(15.3g,47.0mmol)在500mL乙醇中的溶液中加入对甲苯磺酰胺(17.9g,104mmol)并将反应混合物回流20小时。通过蒸发除去溶剂,加入100mL 8%NaOH溶液并将悬液另外搅拌2小时。将混合物过滤并用水冲洗白色滤饼直至洗涤水为中性。干燥滤饼以得到标题产物。收率:6.1g(40.2%)。1H-NMR(400MHz,CDCl3)δ:7.71(d,J=8.0Hz,2H),7.37(d,J=8.0Hz,2H),4.59(s,4H),3.91(s,4H),2.46(s,3H)。HRMS(ESI-TOF+):C12H16NO3S的m/z[M+H]+计算值:254.0825;实测值:254.0851。
步骤2:(3-(溴甲基)-1-对甲苯磺酰基氮杂环丁-3-基)甲醇(1e-2)的合成
在0℃下向6-(对甲苯磺酰基)-2-氧杂-6-氮杂螺[3.3]庚烷(1e-1)(9.79g,38.7mmol)在Et2O(200mL)中的悬液中滴加氢溴酸溶液(AcOH中约33%)。将所得溶液在室温下搅拌30分钟,用1mol/L NaOH将其调整至pH=8。分离各相并用Et2O(3×100mL)萃取水相。合并的有机层经干燥(Na2SO4),过滤并真空浓缩以得到无色固体状的标题化合物。收率:10.0g(77.4%)。1H-NMR(400MHz,CDCl3)δ:7.74(d,J=8.0Hz,2H),7.39(d,J=8.0Hz,2H),3.68(s,2H),3.68(s,2H),3.62(d,J=8.4Hz,2H),3.55(d,J=8.4Hz,2H),3.45(s,2H),2.47(s,3H)。
步骤3:3,3-双(溴甲基)-1-对甲苯磺酰基氮杂环丁烷(1e-3)的合成
将(3-(溴甲基)-1-对甲苯磺酰基氮杂环丁-3-基)甲醇(1e-2)(10.0g,30.0mmol)溶于CH2Cl2中并加入CBr4(16.4g,49.4mmol)。将所得溶液冷却至0℃并加入PPh3(17.9g,104mmol)。将反应混合物在室温下搅拌过夜。减压浓缩混合物并通过硅胶层析(PE中5-10%EtOAc)纯化残余物以得到纯净的标题化合物。收率:8.85g(74.8%)。1H-NMR(400MHz,CDCl3)δ:7.73(d,J=8.0Hz,2H),7.39(d,J=8.0Hz,2H),3.59(s,4H),3.53(s,4H),2.47(s,3H)。
步骤4:6-对甲苯磺酰基-2-硫杂-6-氮杂螺[3.3]庚烷(1e-4)的合成
向3,3-双(溴甲基)-1-对甲苯磺酰基氮杂环丁烷(1e-3)(8.82g,7.9mmol)在CH3CN(90mL)和H2O(9mL)的混合物中的溶液中加入Na2S·9H2O(10.7g,44.7mmol)并将反应混合物在50℃下搅拌4小时,然后将其浓缩至干。加入EtOAc(100mL)和NaHCO3溶液(100mL),并分离各相。用EtOAc(2×100mL)萃取水相。有机相用盐水洗涤,经干燥(Na2SO4),过滤并真空浓缩以得到标题化合物。收率:5.46g(90.1%)。1H-NMR(400MHz,CDCl3)δ:7.71(d J=8.0Hz,2H),7.37(d J=8.0Hz,2H),3.78(s,4H),3.14(s,4H),2.46(s,3H)。HRMS(ESI-TOF+):C12H16NO2S2的m/z[M+H]+计算值:270.0622;实测值:270.0621。
步骤5:2-硫杂-6-氮杂螺[3.3]庚烷(1e)的合成
将6-对甲苯磺酰基-2-硫杂-6-氮杂螺[3.3]庚烷(1e-4)(2.0g,7.9mmol)溶于MeOH(40mL)中。向所得溶液中加入镁粉(1.0g),并将反应混合物在室温下超声约3小时。真空浓缩反应混合物,粗产物不经纯化而用于下一步骤。
实施例6
2-氧杂-6-氮杂-螺[3.3]庚烷(1f)的制备
步骤1:6-对甲苯磺酰基-2-氧杂-6-氮杂螺[3.3]庚烷的合成
如实施例5,步骤1中所述合成此产物。
步骤2:2-氧杂-6-氮杂螺[3.3]庚烷(1f)的合成
将6-对甲苯磺酰基-2-氧杂-6-氮杂螺[3.3]庚烷(6.3g,25.0mmol)溶于MeOH(50mL)中。向所得溶液中加入镁粉(6.0g),并将反应混合物在室温下超声约3小时。真空浓缩反应混合物,粗产物不经纯化而用于下一步骤。
实施例7
N-Boc保护的2,6-二氮杂-螺[3.3]庚烷(1g)的制备
步骤1:(3-(溴甲基)-1-(对甲苯磺酰基)氮杂环丁-3-基)甲醇(1g-1)的合成
在0℃下经15分钟时间向6-(对甲苯磺酰基)-2-氧杂-6-氮杂螺[3.3]庚烷(6.25g,24.7mmol)(根据实施例5步骤1获得)在Et2O(100mL)中的悬液中滴加氢溴酸(AcOH中约33%;4.1mL,24.7mmol)在Et2O(5mL)中的溶液。将所得混合物加温至室温并搅拌45分钟。将所得无色溶液倒入NaHCO3的饱和水溶液(100mL)中。分离有机相并用Et2O(100mL)萃取水相。合并的有机层经干燥(MgSO4),过滤并真空浓缩以得到无色固体状的标题化合物7.74g。粗产物的纯度足以用于进一步的转化。
步骤2:3,3-双(溴甲基)-1-(对甲苯磺酰基)氮杂环丁烷(1g-2)的合成
将以上粗产物1g-1(7.74g,23.1mmol)溶于CH2Cl2(100mL)中并一次性加入CBr4(13.7g,41.2mmol)。将所得溶液冷却至0℃并一次性加入PPh3(26.26g,41.2mmol)。反应混合物转变为暗橙色溶液,将其在0℃下搅拌1.5小时,然后加温至室温并再搅拌8小时。减压浓缩混合物以得到暗橙色油状物,通过层析(己烷:EtOAc 4:1)将其纯化以得到7.61g标题化合物。1H-NMR(400MHz,CDCl3)δ:7.73(d,J=8.4Hz,2H),7.40(d,J=7.6Hz,2H),3.60(s,4H),3.53(s,4H),2.48(s,3H)。
步骤3:2-苄基-6-(对甲苯磺酰基)-2,6-二氮杂螺[3.3]庚烷(1g-3)的合成
将二溴化物1g-2(7.61g,19.1mmol)溶于CH3CN(100mL)中。将苄胺(4.1g,38.3mmol)和DIPEA(12.4g,95.5mmol)加至以上混合物并将反应混合物加热回流3天。然后将微黄色溶液冷却至室温并浓缩至初始体积的约1/6。残余物在CH2Cl2(100mL)和1mol/LNaOH(100mL)之间分配。分离有机相并用CH2Cl2(50mL)萃取水层。合并的有机层经干燥(MgSO4),过滤并真空浓缩。通过层析(己烷:EtOAc:Et3N 1:1:1%至1:2:1%梯度)纯化残余物以得到4.0g标题化合物。1H-NMR(400MHz,CDCl3)δ:7.69(d,J=8.2Hz,2H),7.34(d,J=8.2Hz,2H),7.32-7.11(m,5H),3.82(s,4H),3.47(s,2H),3.13(s,4H),2.44(s,3H)。
步骤4:6-(对甲苯磺酰基)-2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯(1g-5)的合成
将苄基氮杂环丁烷1g-3(2.70g,7.88mmol)溶于MeOH(40mL)中,并将Pd/C(10%钯碳;0.54g)加至以上混合物。建立氢气氛(50PSI),将混合物加热至45℃并在此温度下搅拌48小时。然后将反应混合物冷却至室温并经硅藻土过滤。用MeOH(2×20mL)彻底洗涤滤饼。向以上中间体Ts保护的氮杂环丁烷(1g-4)在MeOH(约80mL)的溶液中加入Boc2O(1.77g,7.88mmol)。将所得溶液在室温下搅拌1小时并真空浓缩。通过层析(己烷:EtOAc 1:1至1:2梯度)纯化残余物以提供纯净的标题化合物。1H-NMR(400MHz,CDCl3)δ:7.71(d,J=7.6Hz,2H),7.37(d,J=8.0Hz,2H),3.85(s,4H),3.84(s,4H),2.46(s,3H),1.39(s,9H)。
步骤5:2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯(1g)的合成
将以上产物1g-5(3.50g,10.0mmol)溶于MeOH(30mL)中。加入Mg粉(1.92g,80.0mmol),并将混合物超声6小时。真空浓缩反应混合物以得到暗灰色固体,其可不经纯化而用于进一步的反应。
实施例8
一般合成方法:噁唑烷酮化合物的制备
以下提供了用于制备(S)-N-((3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代噁唑烷-5-基)甲基)乙酰胺(OTB-114)及其亚砜(OTB-124)的一般步骤。
步骤A:5-(2-氟-4-硝基苯基)-1,5-硫氮杂环辛烷
3,4-二氟硝基苯(4.92g,31mmol)和N,N-二异丙基乙胺(8.81g,68mmol)在CH3CN(30mL)中的溶液在环境温度下用1,5-硫氮杂环辛烷盐酸化物(5.2g,31mol)处理并将反应混合物加热回流24小时。将反应混合物冷却至室温并浓缩。用H2O和CH2Cl2稀释残余物,用CH2Cl2(50mL*3)萃取水层。有机层经Na2SO4干燥,过滤并浓缩。通过硅胶层析色谱(PE/CH2Cl2=10:1)纯化粗产物以得到3.36g(40%)黄色固体状的标题化合物。1H-NMR(400MHz,CDCl3)δ:7.92(m,2H),6.80(t,J=9.2Hz,8.8Hz,1H),3.67(t,J=6.0Hz,5.6Hz,4H),2.72(t,J=5.6Hz,6.0Hz,4H),2.08(m,4H)。
步骤B:(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)氨基甲酸苄酯
向5-(2-氟-4-硝基苯基)-1,5-硫氮杂环辛烷(3.0g,12.5mmol)在MeOH/THF中的溶液中加入10%Pd/C(0.3g),并将混合物在室温,H2下振摇4小时。将悬液过滤通过硅藻土短封垫并用另外的MeOH洗脱。真空除去溶剂。将残余物溶于THF/H2O(50mL)中。向所得溶液中加入NaHCO3(2.12g,25.2mmol),然后滴加CbzCl(2.58g,15.1mmol)。将混合物在室温下搅拌过夜并浓缩。向残余物加入H2O(50mL)并用CH2Cl2萃取。有机层用盐水洗涤,经Na2SO4干燥并浓缩。通过硅胶层析(PE/EtOAc=5:1)纯化粗产物以得到4.6g无色固体状的产物,收率为98%。1H-NMR(400MHz,CDCl3)δ:7.30(m,5H),6.96(m,2H),6.76(s,1H),4.11(m,2H),3.30(m,4H),2.74(m,4H),1.93(m,4H)。
步骤C:(R)-[3-[3-氟-4-(1,5-硫氮杂环辛烷-5-基)苯基]-2-氧代-5-噁唑烷基]甲醇
在N2下将(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)氨基甲酸苄酯(2.44g,6.5mmol)在干燥THF(20mL)中的溶液冷却至-78℃(干冰/丙酮浴)。经10分钟将正丁基锂(己烷中2.5M溶液,2.9mL,7.2mmol)加至反应混合物。在-78℃下将所得淡黄色溶液搅拌50分钟,然后用(R)-(-)-丁酸缩水甘油酯(0.95mL,6.9mmol)滴加处理。将反应混合物在-78℃下另外搅拌30分钟,然后移除冷却浴。使反应混合物加温至环境温度过夜。将饱和NH4Cl水溶液(50mL)加至反应混合物。用EtOAc萃取反应混合物。合并的有机萃取物用盐水洗涤,经Na2SO4干燥,过滤并浓缩。通过硅胶层析(PE/EtOAc=1:2)纯化残余物以得到1.33g无色固体状的产物,收率为59%。1H-NMR(400MHz,CDCl3)δ:7.37(dd,J=14.8Hz,2.4Hz,1H),7.09(dd,J=8.8Hz,2.4Hz,1H),7.00(m,1H),4.73(m,1H),3.95(m,3H),3.76(m,1H),3.35(m,4H),2.74(m,4H),1.97(m,4H)。
步骤D:甲基磺酸(R)-[3-[3-氟-4-(1,5-硫氮杂环辛烷-5-基)苯基]-2-氧代-5-噁唑烷基]甲酯
用冰浴冷却(R)-[3-[3-氟-4-(1,5-硫氮杂环辛烷-5-基)苯基]-2-氧代-5-噁唑烷基]甲醇(1.0g,2.94mmol)在干燥CH2Cl2中的溶液并用Et3N(446mg,4.41mmol)和甲磺酰氯(404mg,3.53mmol)与其反应。将混合物在室温下搅拌2小时,并用H2O、饱和NaHCO3水溶液和盐水洗涤。然后有机层经Na2SO4干燥,过滤并浓缩。产物不经纯化而用于下一步骤。
步骤E:(R)-[3-[3-氟-4-(1,5-硫氮杂环辛烷-5-基)苯基]-2-氧代-5-噁唑烷基]甲基叠氮化物
在室温下用固体NaN3(683mg,10.5mmol)处理甲基磺酸(R)-[3-[3-氟-4-(1,5-硫氮杂环辛烷-5-基)苯基]-2-氧代-5-噁唑烷基]甲酯(859mg,2.1mmol)在干燥DMF中的溶液。冷却至室温,然后将混合物加热至65℃,持续8小时;用H2O淬灭反应混合物并用EtOAc萃取。合并的有机层用H2O和盐水洗涤,经Na2SO4干燥,过滤并浓缩。产物不经纯化而用于下一步骤。
步骤F:(S)-N-((3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代噁唑烷-5-基)甲基)乙酰胺
向(R)-[3-[3-氟-4-(1,5-硫氮杂环辛烷-5-基)苯基]-2-氧代-5-噁唑烷基]甲基叠氮化物(216mg,0.59mmol)在MeOH/THF中的溶液中加入10%Pd/C(22mg),并将混合物在室温,H2下振摇4小时。将悬液过滤通过硅藻土短封垫并用另外的MeOH洗脱。真空除去溶剂。将残余物溶于CH2Cl2中并用Et3N(121mg,1.2mmol)和AcCl(56mg,1.2mmol)处理。用H2O淬灭反应混合物并用CH2Cl2萃取。合并的有机萃取物用盐水洗涤,经Na2SO4干燥,过滤并浓缩。通过硅胶层析(CH2Cl2/MeOH=100:1)纯化残余物以得到0.1g无色固体状的产物,收率为44%。mp78-80℃。(c 0.25,CHCl3)。1H-NMR(400MHz,CDCl3)δ:7.34(m,1H),7.02(m,2H),6.23(m,1H),4.75(m,1H),4.00(t,J=8.8Hz,8.8Hz,1H),3.73(m,2H),3.64(m,1H),3.36(t,J=6.4Hz,6.0Hz,4H),2.73(m,4H),2.04(s,3H),1.97(m,4H)。13C-NMR(125MHz,CDCl3)δ:171.4,155.2(d,J=243.5Hz),154.4,134.5,130.2,119.9,114.3,108.3(d,J=26.8Hz),71.9,48.1,47.8,42.0,31.9,29.7,23.1。HR-MS(ESI-TOF):C18H25O3N3FS的m/z[M+H]+计算值:382.1595;实测值:382.1620。
步骤G:(S)-N-[[3-(3-氟-4-(1-氧化-1,5-硫氮杂环辛-5-基)苯基)-2-氧代-噁唑烷-5-基]甲基]乙酰胺
将偏高碘酸钠(30mg,0.14mmol)在H2O(2mL)中的溶液冷却至0℃。加入(S)-N-((3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代噁唑烷-5-基)甲基)乙酰胺(50mg,0.13mmol),然后加入MeOH(3mL)。将反应混合物在0℃下搅拌2小时并浓缩。将H2O加至残余物并随后用CH2Cl2萃取。合并的有机层用盐水洗涤,经无水Na2SO4干燥,过滤并浓缩。通过硅胶层析(CH2Cl2/MeOH=100:1)纯化残余物以得到39mg无色固体状的产物,收率为75%。mp69-70℃。1H-NMR(400MHz,CDCl3)δ:7.46(dd,J=2.8Hz,14.8Hz,1H),7.14(t,J=9.2Hz,8.8Hz,1H),7.07(m,1H),6.15(m,1H),4.78(m,1H),4.03(t,J=9.2Hz,8.8Hz,1H),3.74(m,3H),3.31(m,1H),3.18(m,4H),2.98(m,2H),2.17(m,4H),2.03(s,3H)。13C-NMR(125MHz,CDCl3)δ:171.0,154.2,134.0,128.5,127.3,122.6,113.9,108.1(d,J=26.9Hz),71.9,53.1,51.7,47.7,42.0,29.7,25.0,23.2。HR-MS(ESI):C18H25O4N3FS的m/z[M+H]+计算值:398.1544;实测值:398.1540。
实施例9
体外抗菌敏感性测定
在96孔微孔板中进行抗微生物敏感性测试。在二甲基亚砜中制备初始药物稀释液(6.4mg/ml),随后在微孔板中的0.1ml 7H9肉汤培养基(BD)中进行两倍稀释。最终药物浓度为约0.008μg/ml。将测试化合物的每个浓度加入到两个孔中。对照孔由细菌和阳性药物(利奈唑胺)组成。将板在37℃下培育。H37Rv的最终细菌滴度为1×106CFU/ml。从培育第7天开始,将20μl的10×Alamar蓝溶液(Life Technologies)和12.5μl的20%吐温80(Sigma-Aldrich)加入到每个孔中,并将板在37℃下进一步培育。在24小时时观察孔并记录所有孔的颜色。视觉MIC被定义为阻止颜色从蓝色变成粉红色的最低药物量。在微孔板荧光计中以底部读取模式测量荧光,激发波长530nm,发射波长590nm。对于荧光MIC,将产生≥90%抑制的最低药物浓度认为是MIC。MIC结果在上表1中提供。
实施例10
体外MPS抑制测试
在384孔板中以1500细胞/孔,在37℃,5%CO2下,在具有10%FBS(Gibco,LifeTechnologies)和1×谷氨酰胺(Gibco,Life Technologies)和NEAA(Gibco,LifeTechnologies)的DMEM(Hyclone,GE LifeSciences)中培育H9C2细胞。培育18小时后加入测试化合物,然后培育5天。通过ELISA测定(MitoBiogenesisTM In-Cell ELISA试剂盒(Colorimetric,Abcam))测量COX-1蛋白(环氧合酶I)和SDH-A(琥珀酸脱氢酶-A)形成减少。MPS测定结果在上表1中提供。
实施例11
根据一般方法合成的具体化合物
OTB-107
(R)-5-[(1H-1,2,3-三唑-1-基)甲基]-3-[3-氟-4-(1,4-硫氮杂环庚-4-基)苯基]噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.94(s,1H),7.75(s,1H),7.17(dd,J=15.2Hz,1.2Hz,1H),6.89(dd,J=8.8Hz,1.6Hz,1H),6.82(t,J=9.6Hz,8.8Hz,1H),5.03(m,1H),4.78(s,2H),4.10(t,J=9.2Hz,8.8Hz,1H),3.87(m,1H),3.68(m,4H),2.87(m,2H),2.68(t,J=6.4Hz,6.0Hz,2H),2.06(m,2H)。13C-NMR(100MHz,CDCl3)δ:153.4,151.0,134.3,124.9,116.8,115.1,108.7(d,J=27.3Hz),70.2,56.1,51.9,51.3,47.4,34.0,31.5,30.3。HR-MS(ESI):C17H21O2N5FS的m/z[M+H]+计算值:378.1395;实测值:378.1396。
OTB-106
(R)-5-[(2H-1,2,3-三唑-2-基)甲基]-3-[3-氟-4-(1,4-硫氮杂环庚-4-基)苯基]噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.65(s,2H),7.27(m,1H),7.01(dd,J=8.8Hz,1.6Hz,1H),6.84(t,J=9.2Hz,9.2Hz,1H),5.11(m.1H),4.85(dd,J=14Hz,4.8Hz,1H),4.74(dd,J=14Hz,6.8Hz,1H),4.05(t,J=9.2Hz,8.8Hz,1H),3.95(m,1H),3.67(m,4H),2.87(m,2H),2.69(t,J=6.4Hz,6.0Hz,2H),2.06(m,2H)。13C-NMR(125MHz,CDCl3)δ:153.7,152.4(d,J=241.8Hz),135.0,134.7,129.1,116.9(d,J=5.1Hz),114.7(d,J=2.9Hz),108.4(d,J=27.4Hz),69.9,56.2,56.1,51.4,48.2,34.1,31.6,30.4。HR-MS(ESI):C17H21O2N5FS的m/z[M+H]+计算值:378.1395;实测值:378.1403。
OTB-109
(S)-3-[3-氟-4-(1,4-硫氮杂环庚-4-基)苯基]-5-[(甲氨基)甲基]噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.30(dd,J=15.6Hz,2.4Hz,1H),7.06(d,J=8.8Hz,1H),6.82(t,J=9.6Hz,9.6Hz,1H),4.83(m,1H),4.02(t,J=8.8Hz,8.4Hz,1H),3.79(t,J=8.0Hz,7.2Hz,1H),3.67(m,4H),2.97(m,2H),2.87(m,2H),2.68(m,2H),2.54(s,3H),2.05(m,2H)。HR-MS(ESI):C16H23O2N3FS的m/z[M+H]+计算值:340.1490;实测值:340.1484。
OTB-108
丁酸(R)-[3-[3-氟-4-(1,4-硫氮杂环庚-4-基)苯基]-2-氧代-5-噁唑烷基]甲酯
1H-NMR(400MHz,CDCl3)δ:7.34(dd,J=15.6Hz,2.4Hz,1H),7.05(dd,J=9.2Hz,2.0Hz,1H),6.89(m,1H),4.84(m,1H),4.37(dd,J=16.0Hz,4.0Hz,1H),4.31(dd,J=12.0Hz,4.8Hz,1H),4.06(t,J=9.2Hz,8.8Hz,1H),3.76(m,1H),3.68(m,4H),2.89(m,2H),2.70(t,J=6.4Hz,6.0Hz,2H),2.34(t,J=7.6Hz,7.2Hz,2H),2.08(m,2H),1.65(m,2H),0.94(t,J=7.6Hz,7.2Hz,3H)。13C-NMR(125MHz,CDCl3)δ:173.3,154.4,152.7(d,J=241.6Hz),134.9(d,J=8.3Hz),129.5(d,J=10.1Hz),117.2(d,J=5.4Hz),114.7(d,J=2.9Hz),108.5(d,J=27.5Hz),70.2,64.1,56.3,51.7,47.5,36.0,34.4,31.9,30.7,18.4,13.7。HR-MS(ESI-TOF):C19H26O4N2FS的m/z[M+H]+计算值:397.1592;实测值:397.1613。
OTB-111
(S)-N-[(3-[3-氟-4-(1,4-硫氮杂环庚-4-基)苯基]-2-氧代-噁唑烷-5-基)甲基]呋喃-2-甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.47(s,1H),7.32(dd,J=16.0Hz,2.0Hz,1H),7.14(d,J=3.2Hz,1H),7.01(dd,J=8.8Hz,1.6Hz,1H),6.87(m,1H),6.81(m,1H),6.52(s,1H),4.82(m,1H),4.04(t,J=9.2Hz,8.8Hz,1H),3.89(m,1H),3.76(m,2H),3.67(m,4H),2.88(m,2H),2.69(t,J=6.4Hz,6.0Hz,2H),2.07(m,2H)。13C-NMR(125MHz,CDCl3)δ:159.0,154.4,152.6(d,J=241.9Hz),147.1,144.5,134.5,129.3,117.2,115.1,114.7,112.3,108.5(d,J=27.4Hz),71.9,56.3,51.7,47.9,41.6,34.1,31.7,30.5。HR-MS(ESI-TOF):C20H23O4N3FS的m/z[M+H]+计算值:420.1388;实测值:420.1400。
OTB-112
(S)-N-[(3-[3-氟-4-(1,4-硫氮杂环庚-4-基)苯基]-2-氧代-噁唑烷-5-基)甲基]噻吩-2-甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.34(m,1H),7.02(m,2H),6.23(m,1H),4.75(m,1H),4.00(t,J=8.8Hz,8.8Hz,1H),3.73(m,2H),3.64(m,1H),3.36(t,J=6.4Hz,6.0Hz,4H),2.73(m,4H),2.04(s,3H),1.97(m,4H)。13C-NMR(125MHz,CDCl3)δ:171.4,155.2(d,J=243.5Hz),154.4,134.5,130.2,119.9,114.3,108.3(d,J=26.8Hz),71.9,48.1,47.8,42.0,31.9,29.7,23.1。HR-MS(ESI-TOF):C18H25O3N3FS的m/z[M+H]+计算值:382.1595;实测值:382.1620。
OTB-115
(S)-N-[[3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)-2-氧代-噁唑烷-5-基]甲基]三甲基乙酰胺
1H-NMR(400MHz,CDCl3)δ:7.34(dd,J=15.6Hz,2.0Hz,1H),7.01(dd,J=8.8Hz,2.4Hz,1H),6.89(m,1H),6.12(m,1H),4.74(m,1H),3.99(t,J=9.2Hz,8.8Hz,1H),3.74(m,1H),3.67(m,6H),2.89(t,J=5.6Hz,5.2Hz,2H),2.70(t,J=6.4Hz,6.4Hz,2H),2.08(m,2H),1.17(s,9H)。13C-NMR(125MHz,CDCl3)δ:179.7,154.6,152.7(d,J=241.6Hz),134.8,129.5,117.2(d,J=5.4Hz),114.7(d,J=2.9Hz),108.5(d,J=27.6Hz),72.1,56.3,51.7,48.0,42.4,39.0,34.4,31.9,30.7,27.7。HR-MS(ESI-TOF):C20H29O3N3FS的m/z[M+H]+计算值:410.1908;实测值:410.1942。
OBD-005
(S)-N-((3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺
1H-NMR(300MHz,CDCl3)δ:7.42-7.23(m,2H),7.01(dd,J=8.9,2.3Hz,1H),6.04(s,1H),4.75(ddd,J=9.0,7.9,4.6Hz,1H),4.00(t,J=9.0Hz,1H),3.79-3.05(m,7H),2.91(dd,J=16.2,10.1Hz,2H),2.70(t,J=6.3Hz,2H),2.28-2.13(m,2H),2.13-1.97(m,2H),1.82-1.25(m,3H),0.92(t,J=7.4Hz,3H),0.01(s,1H)。
LC-MS(ESI):m/z=395.9[M+H]+。
OTB-116
(R)-N-[[3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)-2-氧代-噁唑烷-5-基]甲基]丁烷-1-磺酰胺
1H-NMR(400MHz,CDCl3)δ:7.33(d,J=15.6Hz,1H),7.05(d,J=8.8Hz,1H),6.88(m,1H),4.92(t,J=6.8Hz,6.4Hz,1H),4.78(m,1H),4.02(t,J=9.2Hz,8.8Hz,1H),3.90(m,1H),3.69(m,4H),3.54(m,1H),3.43(m,1H),3.07(m,2H),2.94(m,2H),2.69(m,2H),2.08(m,2H),1.79(m,2H),1.46(m,2H),0.95(t,J=7.2Hz,7.2Hz,3H)。13C-NMR(125MHz,CDCl3)δ:154.2,152.5(d,J=241.8Hz),134.8(d,J=8.3Hz),129.2(d,J=10.5Hz),117.2,115.0,108.6(d,J=27.5Hz),71.5,56.3,53.2,51.6,47.5,45.5,34.1,31.7,30.5,25.6,21.5,13.5。HR-MS(ESI-TOF):C19H29O4N3FS2的m/z[M+H]+计算值:446.1578;实测值:446.1623。
OTB-119
(R)-5-[(1H-1,2,4-三唑-1-基)甲基]-3-[3-氟-4-(1,4-硫氮杂环庚-4-基)苯基]噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:8.24(s,1H),7.96(s,1H),7.22(m,1H),6.97(m,1H),6.89(m,1H),5.02(m,1H),4.54(d,J=4.8Hz,2H),4.10(t,J=9.2Hz,9.2Hz,1H),3.94(m,1H),3.68(m,4H),2.89(m,2H),2.70(m,2H),2.08(m,2H)。HR-MS(ESI-TOF):C17H21O2N5FS的m/z[M+H]+计算值:378.1395;实测值:378.1421。
OTB-412
(S)-((3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)-2-氧代-噁唑烷-5-基)甲基)氨基甲酸甲酯
1H-NMR(400MHz,CDCl3)δ:7.29-7.33(m,1H),7.03-7.05(m,1H),6.82(t,J=8.8Hz,1H),5.10(m,1H),4.73(m,1H),3.99(t,J=9.9Hz,1H),3.69-3.74(m,1H),3.67(s,3H),3.66-3.67(m,4H),3.61(m,1H),3.50-3.55(m,1H),2.87(m,1H),2.68(m,2H),2.04-2.07(m,2H)。13C-NMR(150MHz,CDCl3)δ:157.5,154.3,153.3,151.7,134.8,134.7,129.3,129.2,117.0,117.0,114.7,114.7,108.5,108.4,71.7,56.2,56.2,51.5,47.7,43.7,34.3,31.8,30.6。HR-MS(ESI-TOF):C17H23O4N3FS的m/z[M+H]+计算值:384.1388;实测值:384.1371。
OTB-413
(S)-N-((3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)-2-氧代-噁唑烷-5-基)甲基)环丙烷甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.29-7.33(m,1H),7.03-7.00(m,1H),6.81(t,J=9.6Hz,1H),6.09(m,1H),4.74(m,1H),3.98(t,J=8.8Hz,1H),3.73-3.74(m,1H),3.67-3.71(m,4H),3.62-3.66(m,1H),2.87(t,J=4.8Hz,2H),2.68(t,J=10.0Hz,2H),2.04-2.07(m,2H),1.36-1.43(m,1H),1.05-1.07(m,1H),0.93-0.97(m,2H),0.77-0.78(m,1H)。13C-NMR(150MHz,CDCl3)δ:174.5,154.5,153.3,151.7,134.8,134.7,129.2,129.2,117.0,114.7,108.6,108.4,72.0,56.2,51.5,47.8,42.1,34.3,31.8,30.6,14.7,7.7。HR-MS(ESI-TOF):C19H25O3N3FS的m/z[M+H]+计算值:394.1595;实测值:394.1580。
OTB-414
(S)-N-((3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)-2-氧代噁唑烷-5-基)甲基)环丁烷甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.29-7.34(m,1H),7.03-7.00(m,1H),6.82(t,J=9.6Hz,1H),5.84(m,1H),4.75(m,1H),3.99(t,J=8.8Hz,1H),3.72-3.76(m,1H),3.67-3.71(m,4H),3.63-3.66(m,1H),3.14-3.23(m,2H),2.68(m,1H),1.89-2.35(m,10H)。13C-NMR(150MHz,CDCl3)δ:180.2,176.0,154.5,134.8,134.8,129.2,129.1,117.0,117.0,114.7,114.7,108.5,108.4,72.0,56.2,56.2,51.5,51.5,47.9,42.0,39.7,37.8,34.3,31.8,30.6,25.2,18.4。HR-MS(ESI-TOF):C20H27O3N3FS的m/z[M+H]+计算值:408.1752;实测值:408.1736。
OTB-407
(S)-N-((3-(3,5-二氟-4-(1,4-硫氮杂环庚-4-基)苯基)-2-氧代-噁唑烷-5-基)甲基)乙酰胺
1H-NMR(400MHz,CDCl3)δ:7.07(d,J=10.4Hz,2H),6.08(m,1H),4.76-4.77(m,1H),3.98(t,J=9.2Hz,1H),3.59-3.70(m,3H),3.45-3.48(m,4H),2.89(t,J=6.0Hz,2H),2.77-2.80(m,2H),2.02(s,3H)。13C-NMR(150MHz,CDCl3)δ:171.1,159.8,159.7,158.1,158.1,154.0,133.3,126.0,102.5,102.3,71.9,58.8,54.1,47.5,41.9,36.1,31.8,31.6,23.1。HR-MS(ESI-TOF):C17H22O3N3F2S的m/z[M+H]+计算值:386.1344;实测值:386.1330。
OTB-410
(S)-((3-(3,5-二氟-4-(1,4-硫氮杂环庚-4-基)苯基)-2-氧代-噁唑烷-5-基)甲基)氨基甲酸甲酯
1H-NMR(500MHz,CDCl3)δ:7.09(d,J=10.0Hz,2H),5.09(m,1H),4.76(m,1H),3.99(t,J=9.0Hz,1H),3.74-3.76(m,1H),3.73(s,3H),3.61(m,1H),3.52-3.55(m,1H),3.46-3.47(m,4H),2.90(t,J=6.0Hz,1H),2.78-2.80(m,2H),1.94-1.98(m,2H)。13C-NMR(125MHz,CDCl3)δ:157.5,154.3,153.3,151.7,134.8,134.7,129.3,129.2,117.0,117.0,114.7,114.7,108.4,108.4,71.3,56.2,56.2,51.5,47.8,43.7,34.3,31.8,30.6。HR-MS(ESI-TOF):C17H22O4N3F2S的m/z[M+H]+计算值:402.1297;实测值:402.1287。
OTB-408
(S)-5-((环丙基氨基)甲基)-3-(3,5-二氟-4-(1,4-硫氮杂环庚-4-基)苯基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.07(d,J=10.8Hz,2H),6.06(m,1H),4.76(m,1H),3.96(t,J=8.8Hz,1H),3.66-3.75(m,3H),3.43-3.47(m,3H),2.89(t,J=9.2Hz,2H),2.78-2.80(m,3H),1.94-1.97(m,2H),1.37-1.39(m,1H),0.97(m,1H),0.93(m,1H),0.77-0.79(m,2H)。13C-NMR(150MHz,CDCl3)δ:174.7,159.8,159.7,158.2,158.1,154.0,133.4,126.0,102.6,102.4,72.0,58.8,54.1,47.5,42.0,36.1,31.8,31.6,14.7,7.8,7.7。HR-MS(ESI-TOF):C19H24O3N3F2S的m/z[M+H]+计算值:412.1501;实测值:412.1485。
OTB-409
(S)-5-((环丁基氨基)甲基)-3-(3,5-二氟-4-(1,4-硫氮杂环庚-4-基)苯基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.07(d,J=10.8Hz,2H),5.81(m,1H),4.75(m,1H),3.98(t,J=8.8Hz,1H),3.72-3.76(m,1H),3.64-3.66(m,2H),3.45-3.46(m,3H),3.01(t,J=8.8Hz,1H),2.90(t,J=6.4Hz,2H),2.77-2.80(m,2H),2.13-2.26(m,4H),1.92-1.96(m,3H)。13C-NMR(150MHz,CDCl3)δ:176.0,159.8,159.8,158.2,158.1,154.0,133.3,126.0,102.5,102.3,72.0,58.8,54.1,47.5,41.9,39.7,36.1,31.8,31.6,25.4,25.3,18.1。HR-MS(ESI-TOF):C20H26O3N3F2S的m/z[M+H]+计算值:426.1658;实测值:426.1643。
OTB-411
(R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(3,5-二氟-4-(1,4-硫氮杂环庚-4-基)苯基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.76(d,J=11.2Hz,2H),6.95(d,J=10.4Hz,2H),5.04-5.07(m,1H),4.78(d,J=4.0Hz,2H),4.10(t,J=9.2Hz,1H),3.86-3.90(m,1H),3.44-3.46(m,4H),2.88(t,J=6.4Hz,2H),2.76-2.79(m,2H),1.91-1.97(m,2H)。13C-NMR(125MHz,CDCl3)δ:159.8,159.8,157.9,157.8,153.0,134.6,125.1,102.8,102.5,70.3,58.7,54.0,51.9,47.1,36.1,31.8,31.6。HR-MS(ESI-TOF):C17H20O2N5F2S的m/z[M+H]+计算值:396.1300;实测值:396.1296。
OTB-126
丁酸[(5R)-3-[3-氟-4-(1-氧化-1,4-硫氮杂环庚-4-基)苯基)-2-氧代-噁唑烷-5-基]甲酯
1H-NMR(400MHz,CDCl3)δ:7.45(dd,J=14.8Hz,1.6Hz,1H),7.07(dd,J=8.8Hz,2.4Hz,1H),6.96(t,J=9.2Hz,9.2Hz,1H),4.85(m,1H),4.37(dd,J=12.0Hz,4.0Hz,1H),4.30(dd,J=12.4Hz,4.8Hz,1H),4.07(m,1H),3.78(m,2H),3.40(m,2H),3.19(m,4H),2.98(m,1H),2.72(m,1H),2.33(t,J=7.6Hz,7.2Hz,2H),2.04(m,1H),1.63(m,2H),0.92(t,J=7.6Hz,7.2Hz,3H)。13C-NMR(125MHz,CDCl3)δ:173.2,154.1,154.0(d,J=241.8Hz),136.6,131.4,118.1(d,J=4.3Hz),114.0,(d,J=2.9Hz),107.8(d,J=26.9Hz),70.1,63.9,52.8,49.6,47.2,46.4,43.7,35.8,18.3,16.2,13.6。HR-MS(ESI-TOF):C19H26O5N2FS的m/z[M+H]+计算值:413.1541;实测值:413.1573。
OTB-127
N-[[(5S)-3-(3-氟-4-(1-氧化-1,4-硫氮杂环庚-4-基)苯基)-2-氧代-噁唑烷-5-基]甲基]呋喃-2-甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.47(s,1H),7.42(m,1H),7.14(d,J=3.2Hz,1H),7.04(m,1H),6.87(m,2H),6.51(m,1H),4.85(m,1H),4.05(m,1H),3.81(m,4H),3.38(m,2H),3.15(m,2H),3.04(m,3H),2.70(m,1H),2.03(m,1H)。HR-MS(ESI-TOF):C20H23O5N3FS的m/z[M+H]+计算值:436.1337;实测值:436.1371。
OTB-137
(5R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(3-氟-4-(1-氧化-1,4-硫氮杂环庚-4-基)苯基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.79(s,1H),7.75(s,1H),7.30-7.25(m,1H),6.91-6.89(m,2H),5.07-5.02(m,1H),4.78(d,J=4.0Hz,2H),4.11(t,J=9.2Hz,1H),3.93-3.88(m,1H),3.82-3.76(m,1H),3.43-3.36(m,2H),3.24-2.91(m,4H),2.75-2.69(m,1H),2.04-2.02(m,2H)。HR-MS(ESI):C17H21O3N5FS的m/z[M+H]+计算值:394.1344;实测值:394.1328。
OTB-138
(5R)-5-((2H-1,2,3-三唑-2-基)甲基)-3-(3-氟-4-(1-氧化-1,4-硫氮杂环庚-4-基)苯基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.65(s,2H),7.39(d,J=14.4Hz,1H),7.04-6.98(m,2H),5.15-5.09(m,1H),4.86(dd,J=14.0,4.4Hz,1H),4.75(dd,J=14.0,6.8Hz,1H),4.06(dt,J=9.2,2.4Hz,1H),4.00-3.96(m,1H),3.86-3.82(m,1H),3.46-3.38(m,2H),3.29-3.08(m,3H),3.02-2.96(m,1H),2.76-2.71(m,1H),2.04-2.02(m,2H)。HR-MS(ESI):C17H21O3N5FS的m/z[M+H]+计算值:394.1344;实测值:394.1338。
OTB-140
(5R)-5-((1H-1,2,4-三唑-1-基)甲基)-3-(3-氟-4-(1-氧化-1,4-硫氮杂环庚-4-基)苯基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:8.24(s,1H),7.94(s,1H),7.35(d,J=14.4Hz,1H),7.0-6.96(m,2H),5.02-4.99(m,1H),4.55(d,J=4.4Hz,2H),4.10(dt,J=8.8,2.0Hz,1H),3.99-3.95(m,1H),3.86-3.82(m,1H),3.45-3.38(m,2H),3.29-3.09(m,3H),3.00-2.94(m,1H),2.77-2.71(m,1H),2.07-2.03(m,2H)。HR-MS(ESI):C17H21O3N5FS的m/z[M+H]+计算值:394.1344;实测值:394.1339。
OBD-006
N-(((5S)-3-(3-氟-4-(1-氧化-1,4-硫氮杂环庚-4-基)苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺
1H-NMR(300MHz,CDCl3)δ:7.52(d,J=15.0Hz,1H),7.16(s,1H),7.03(d,J=8.7Hz,1H),5.99(s,1H),4.78(s,1H),4.02(t,J=8.8Hz,2H),3.88-3.56(m,3H),3.55-2.92(m,7H),2.77(s,1H),2.20(t,J=7.1Hz,3H),1.64(dd,J=14.9,7.4Hz,2H),0.91(t,J=7.4Hz,3H)。
LC-MS(ESI):m/z=411.8[M+H]+。
OBD-007
(S)-N-((3-(4-(1,1-二氧化-1,4-硫氮杂环庚-4-基)-3-氟苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺
1H-NMR(300MHz,CDCl3)δ:7.51(d,J=14.7Hz,1H),7.10(d,J=9.9Hz,2H),5.92(s,1H),4.78(s,1H),4.03(t,J=9.0Hz,1H),3.87-3.39(m,7H),3.27(d,J=5.7Hz,2H),2.39(d,J=6.2Hz,2H),2.20(t,J=7.2Hz,2H),1.64(dd,J=14.8,7.4Hz,2H),0.92(t,J=7.3Hz,3H)。
LC-MS(ESI):m/z=427.8[M+H]+。
OTB-110
丁酸(R)-[3-[3-氟-4-(1,5-硫氮杂环辛-5-基)苯基]-2-氧代-5-噁唑烷基]甲酯
1H-NMR(400MHz,CDCl3)δ:7.36(dd,J=14.8Hz,4.0Hz,1H),7.09(dd,J=8.8Hz,2.4Hz,1H),7.04(t,J=10.4Hz,9.2Hz,1H),4.85(m,1H),4.37(m,1H),4.31(m,1H),4.08(m,1H),3.78(m,1H),3.37(m,4H),2.75(m,4H),2.34(t,J=7.6Hz,7.2Hz,2H),1.97(m,4H),1.64(m,2H),0.93(t,7.6Hz,J=7.2Hz,3H)。13C-NMR(125MHz,CDCl3)δ:173.3,155.4(d,J=243.5Hz),154.3,134.5(d,J=8.3Hz),131.1(d,J=10.1Hz),128.2,127.1,120.0(d,J=4.9Hz),114.3(d,J=3.0Hz),108.4(d,J=26.8Hz),70.2,64.0,48.1,47.4,36.0,32.1,29.8,18.4,13.7。HR-MS(ESI-TOF):C20H28O4N2FS的m/z[M+H]+计算值:411.1748;实测值:411.1786。
OTB-113
(R)-5-[(2H-1,2,3-三唑-2-基)甲基]-3-[3-氟-4-(1,5-硫氮杂环辛-5-基)苯基]噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.65(s,2H),7.30(d,J=14.8Hz,1H),7.03(m,2H),5.10(m,1H),4.85(dd,J=14.0Hz,4.8Hz,1H),4.74(dd,J=14.0Hz,7.2Hz,1H),4.06(t,J=9.2Hz,8.8Hz,1H),3.97(m,1H),3.37(t,J=6.0Hz,6.0Hz,4H),2.73(m,4H),1.97(m,4H)。13C-NMR(125MHz,CDCl3)δ:155.2(d,J=243.5Hz),135.2,134.4(d,J=8.1Hz),130.8(d,J=10.3Hz),119.8(d,J=4.9Hz),114.5(d,J=3.1Hz),108.4(d,J=26.6Hz),70.0,56.3,48.3,47.9,31.9,29.6。HR-MS(ESI-TOF):C18H23O2N5FS的m/z[M+H]+计算值:392.1551;实测值:392.1590。
OTB-114
(R)-[3-[3-氟-4-(1,5-硫氮杂环辛-5-基)苯基]-2-氧代-5-噁唑烷基]甲基乙酰胺
1H-NMR(400MHz,CDCl3)δ:7.34(m,1H),7.02(m,2H),6.23(m,1H),4.75(m,1H),4.00(t,J=8.8Hz,8.8Hz,1H),3.73(m,2H),3.64(m,1H),3.36(t,J=6.4Hz,6.0Hz,4H),2.73(m,4H),2.04(s,3H),1.97(m,4H)。13C-NMR(125MHz,CDCl3)δ:171.4,155.2(d,J=243.5Hz),154.4,134.5,130.2,119.9,114.3,108.3(d,J=26.8Hz),71.9,48.1,47.8,42.0,31.9,29.7,23.1。HR-MS(ESI-TOF):C18H25O3N3FS的m/z[M+H]+计算值:382.1595;实测值:382.1620。
OTB-117
(S)-N-[[3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代-噁唑烷-5-基]甲基]呋喃-2-甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.47(s,1H),7.36(d,J=14.4Hz,1H),7.14(d,J=3.2Hz,1H),7.01(m,2H),6.78(m,1H),6.51(m,1H),4.84(m,1H),4.05(t,J=9.2Hz,8.8Hz,1H),3.88(m,1H),3.80(m,2H),3.36(t,J=6.0Hz,6.0Hz,4H),2.73(m,4H),1.96(m,4H)。13C-NMR(125MHz,CDCl3)δ:159.0,155.2(d,J=243.6Hz),154.3,147.1,144.5,134.3,130.9,119.8,115.1,114.3(d,J=3.0Hz),112.3,108.4(d,J=26.8Hz),71.9,47.9,41.5,31.9,29.6。HR-MS(ESI-TOF):C21H25O4N3FS的m/z[M+H]+计算值:434.1544;实测值:434.1581。
OTB-118
(S)-N-[[3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代-噁唑烷-5-基]甲基]噻吩-2-甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.54(m,1H),7.52(m,1H),7.34(m,1H),7.10(m,1H),7.04(m,1H),7.00(m,1H),6.57(t,J=6.0Hz,6.0Hz,1H),4.86(m,1H),4.07(t,J=9.2Hz,8.8Hz,1H),4.07(m,1H),3.82(m,2H),3.36(t,J=6.0Hz,6.0Hz,4H),2.74(m,4H),1.96(m,4H)。13C-NMR(125MHz,CDCl3)δ:162.7,155.2(d,J=243.5Hz),154.5,137.9,130.8,128.7,127.8,119.8,114.5(d,J=3.0Hz),108.5(d,J=26.8Hz),72.1,48.0,42.5,31.9,29.6。HR-MS(ESI-TOF):C21H25O4N4FS2的m/z[M+H]+计算值:450.1316;实测值:450.1356。
OTB-120
(R)-N-[[3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代-噁唑烷-5-基]甲基]丁烷-1-磺酰胺
1H-NMR(400MHz,CDCl3)δ:7.42(d,J=14.4Hz,1H),7.08(m,2H),4.94(m,1H),4.79(m,1H),4.04(t,J=8.8Hz,8.8Hz,1H),3.93(m,1H),3.55(m,1H),3.43(m,5H),3.07(m,2H),2.76(m,4H),2.01(m,4H),1.80(m,2H),1.45(m,2H),0.95(t,J=7.6Hz,7.2Hz,3H)。13C-NMR(125MHz,CDCl3)δ:155.2(d,J=243.6Hz),154.2,134.5,130.7,119.8(d,J=4.9Hz),114.5(d,J=3.0Hz),108.5(d,J=26.8Hz),71.5,53.1,47.9,47.4,45.5,31.9,29.6,25.6,21.5,13.5。HR-MS(ESI-TOF):C20H31O4N3FS2的m/z[M+H]+计算值:460.1735;实测值:460.1778。
OTB-121
(S)-N-[[3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代-噁唑烷-5-基]甲基]三甲基乙酰胺
1H-NMR(400MHz,CDCl3)δ:7.39(d,J=14.4Hz,1H),7.04(m,2H),6.11(m,1H),4.74(m,1H),4.00(t,J=9.2Hz,8.8Hz,1H),3.76(m,1H),3.67(m,2H),3.39(m,4H),2.74(m,4H),1.98(m,4H),1.17(s,9H)。13C-NMR(125MHz,CDCl3)δ:179.6,155.2(d,J=243.6Hz),154.4,134.3(d,J=8.0Hz),130.9(d,J=5.4Hz),128.8,119.8(d,J=4.9Hz),114.2(d,J=2.9Hz),108.2(d,J=26.9Hz),72.0,47.9,47.8,42.2,38.9,31.9,29.6,27.5。HR-MS(ESI-TOF):C21H31O3N3FS的m/z[M+H]+计算值:424.2065;实测值:424.2096。
OBD-001
(R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮
1H-NMR(300MHz,CDCl3)δ:7.76(d,J=17.6Hz,2H),7.41-7.09(m,1H),7.11-6.73(m,2H),5.04(d,J=3.0Hz,1H),4.78(d,J=3.4Hz,2H),4.12(t,J=9.2Hz,1H),3.88(dd,J=9.2,6.1Hz,1H),3.36(t,J=6.0Hz,3H),2.92-2.59(m,4H),2.01(dd,J=27.9,7.3Hz,4H)。
LC-MS(ESI);m/z=391.9[M+H]+。
OBD-003
(S)-N-((3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺
1H-NMR(300MHz,CDCl3)δ:7.50(s,2H),7.03(d,J=6.1Hz,1H),5.99(s,1H),4.77(d,J=5.7Hz,1H),4.02(t,J=9.0Hz,2H),3.70(ddd,J=20.7,15.2,7.7Hz,4H),3.48(s,4H),2.95-2.68(m,4H),2.20(t,J=7.2Hz,3H),2.06(d,J=6.1Hz,4H),1.64(dd,J=14.8,7.4Hz,4H),0.91(t,J=7.4Hz,4H)。
LC-MS(ESI):m/z=409.9[M+H]+。
OBD-008
(R)-5-((1H-1,2,4-三唑-1-基)甲基)-3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮
1H-NMR(300MHz,CDCl3)δ:8.24(s,1H),7.97(s,1H),7.00(s,2H),5.12-4.91(m,1H),4.56(d,J=4.7Hz,2H),4.24-3.83(m,2H),3.38(t,J=6.0Hz,4H),2.95-2.59(m,4H),1.98(s,5H)。
LC-MS(ESI):m/z=391.9[M+H]+。
OTB-124
(S)-N-[[3-(3-氟-4-(1-氧化-1,5-硫氮杂环辛-5-基)苯基)-2-氧代-噁唑烷-5-基]甲基]乙酰胺
1H-NMR(400MHz,CDCl3)δ:7.46(dd,J=2.8Hz,14.8Hz,1H),7.14(t,J=9.2Hz,8.8Hz,1H),7.07(m,1H),6.15(m,1H),4.78(m,1H),4.03(t,J=9.2Hz,8.8Hz,1H),3.74(m,3H),3.31(m,1H),3.18(m,4H),2.98(m,2H),2.17(m,4H),2.03(s,3H)。13C-NMR(125MHz,CDCl3)δ:171.0,154.2,134.0,128.5,127.3,122.6,113.9,108.1(d,J=26.9Hz),71.9,53.1,51.7,47.7,42.0,29.7,25.0,23.2。HR-MS(ESI):C18H25O4N3FS的m/z[M+H]+计算值:398.1544;实测值:398.1540。
OBD-002
(R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(3-氟-4-(1-氧化-1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮
1H-NMR(300MHz,CDCl3)δ:7.92-7.67(m,2H),7.32(d,J=16.8Hz,1H),7.12(t,J=9.0Hz,1H),6.96(d,J=8.1Hz,1H),5.07(s,1H),4.81(d,J=4.0Hz,2H),4.15(t,J=9.0Hz,1H),4.01-3.83(m,1H),3.32(d,J=14.2Hz,5H),3.11-2.87(m,2H),2.59(s,2H),2.19(s,4H)。
LC-MS(ESI):m/z=407.8[M+H]+。
OBD-004
(S)-N-((3-(3-氟-4-(1-氧化-1,5-硫氮杂环辛-5-基)苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺
1H-NMR(300MHz,CDCl3)δ:7.44(dd,J=14.7,2.4Hz,1H),7.19-6.99(m,2H),6.44(s,1H),4.84-4.71(m,1H),4.02(t,J=8.9Hz,1H),3.78(dd,J=9.0,6.6Hz,1H),3.66(t,J=4.6Hz,2H),3.38-3.09(m,6H),2.99(dd,J=12.6,6.3Hz,2H),2.20(dd,J=9.4,5.3Hz,6H),1.71-1.56(m,2H),0.91(dd,J=9.6,5.1Hz,3H)。
LC-MS(ESI):m/z=425.8[M+H]+。
OBD-009
(R)-5-((1H-1,2,4-三唑-1-基)甲基)-3-(3-氟-4-(1-氧化-1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮
1H-NMR(300MHz,CDCl3)δ:8.24(s,1H),7.93(s,1H),7.41-7.20(m,1H),7.19-6.92(m,2H),5.10-4.92(m,1H),4.56(d,J=4.7Hz,2H),4.12(t,J=9.0Hz,1H),3.97(dd,J=9.2,6.2Hz,1H),3.28(dd,J=13.0,6.9Hz,2H),3.12(dd,J=12.5,5.9Hz,4H),3.02-2.83(m,2H),2.22-1.99(m,5H),1.26(d,J=9.4Hz,4H)。
LC-MS(ESI):m/z=407.8[M+H]+。
OTB-227
N-(((5S)-3-(4-(3-硫杂-6-氮杂双环[3.1.1]庚-6-基)-3-氟苯基)-2-氧代-噁唑烷-5-基)甲基)乙酰胺
1H-NMR(400MHz,CDCl3)δ:7.36(d,J=14.4Hz,1H),7.05(d,J=8.4Hz,1H),6.60(t,J=9.2Hz,1H),6.35(brs,1H),4.76-4.74(m,1H),4.56-4.54(m,2H),4.00(t,J=9.2Hz,1H),3.76-3.65(m,2H),3.62-3.57(m,1H),3.43(d,J=12.0Hz,2H),2.93-2.87(m,1H),2.74(d,J=12.0Hz,2H),2.09(s,1H),2.03(s,3H)。13C-NMR(100MHz,CDCl3)δ:171.1,154.5,151.8(d,J=238.5Hz),131.9(d,J=11.8Hz),129.2(d,J=9.5Hz),115.2(d,J=6.2Hz),114.7(d,J=2.8Hz),108.0(d,J=24.9Hz),71.9,60.8,47.8,41.9,29.4,25.3,23.2。HRMS(ESI-TOF+):C17H21FN3O3S的m/z[M+H]+计算值:366.1288;实测值:366.1277。
OTB-501
(R)-3-(4-((1R,5S)-3-硫杂-8-氮杂双环[3.2.1]辛-8-基)-3-氟苯基)-5-(羟甲基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.39(d,J=12.8Hz,1H),7.16(d,J=8.8Hz,1H),6.90(t,J=9.2Hz,1H),4.74(m,1H),4.43(s,2H),3.99-3.96(m,3H),3.79-3.75(m,1H),3.48(d,J=13.2Hz,2H),2.21-2.10(m,6H)。HRMS(ESI):C16H20N2O3FS的m/z[M+H]+计算值:339.1179;实测值:339.1169。
OTB-502
N-(((S)-3-(4-((1R,5S)-3-硫杂-8-氮杂双环[3.2.1]辛-8-基)-3-氟苯基)-2-氧代噁唑烷-5-基)甲基)乙酰胺
1H-NMR(400MHz,CDCl3)δ:7.36(dd,J=15.2,2.4Hz,1H),7.06(dd,J=8.8,1.8Hz,1H),6.83(t,J=9.2Hz,1H),6.18(s,1H),4.77–4.75(m,1H),4.40(s,2H),4.00(t,J=8.8Hz,1H),3.76–3.72(m,2H),3.68-3.62(m,1H),3.37(d,J=12.8Hz,2H),2.26–2.04(m,6H),2.02(s,3H)。13C-NMR(100MHz,CDCl3)δ:171.1,154.5,152.8(d,J=241.7Hz),132.2(d,J=8.6Hz),130.2(d,J=10.4Hz),118.1(d,J=5.0Hz),114.7,108.4(d,J=27.2Hz),71.9,57.4,47.8,42.0,30.2,28.4,23.1。HR-MS(ESI-TOF):C18H23N3O3FS的m/z[M+H]+计算值:380.1444;实测值:380.1435。
OTB-504
(R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(4-((1R,5S)-3-硫杂-8-氮杂双环[3.2.1]辛-8-基)-3-氟苯基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.80(s,1H),7.76(s,1H),7.24(m,1H),6.96(d,J=8.8Hz,1H),6.83(t,J=8.8Hz,1H),5.07–5.04(m,1H),4.79(s,2H),4.40(s,2H),4.11(t,J=8.0Hz,1H),3.90–3.87(m,1H),3.42(d,J=12.8Hz,2H),2.20–2.07(m,6H)。HR-MS(ESI-TOF):C18H21N5O2FS的m/z[M+H]+计算值:390.1400;实测值:390.1385。
OTB-236
N-(((R)-3-(4-((1R,5S)-3-硫杂-8-氮杂双环[3.2.1]辛-8-基)-3-氟苯基)-2-氧代-噁唑烷-5-基)甲基)甲烷磺酰胺
1H-NMR(400MHz,CDCl3)δ:7.47-7.41(m,1H),7.13(d,J=9.6Hz,1H),7.02(t,J=9.6Hz,1H),4.76-4.70(m,1H),4.34(s,2H),4.08(t,J=9.2Hz,1H),3.76(t,J=8.8Hz,1H),3.29-3.26(m,2H),3.11(d,J=12.8Hz,2H),2.93(s,3H),2.11(d,J=12.4Hz,2H),2.02(s,4H)。HR-MS(ESI-TOF):C17H23N3O4FS2的m/z[M+H]+计算值:416.1114;实测值:416.1097。
OTB-237
(((S)-3-(4-((1R,5S)-3-硫杂-8-氮杂双环[3.2.1]辛-8-基)-3-氟苯基)-2-氧代-噁唑烷-5-基)甲基)氨基甲酸甲酯
1H-NMR(400MHz,CDCl3)δ:7.36(d,J=15.2Hz,1H),7.07(d,J=8.8Hz,1H),6.81(t,J=9.2Hz,1H),5.18(brs,1H),4.74(brs,1H),4.39(s,2H),4.01(t,J=8.8Hz,1H),3.76(t,J=7.6Hz,1H),3.69(s,3H),3.56-3.51(m,1H),3.33(d,J=12.8Hz,2H),2.18-2.07(m,6H)。HR-MS(ESI-TOF):C18H23N3O4FS的m/z[M+H]+计算值:396.1393;实测值:396.1388。
OBD-016
N-(((S)-3-(4-((1R,5S)-3-硫杂-8-氮杂双环[3.2.1]辛-8-基)-3-氟苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺
1H-NMR(300MHz,DMSO-d6)δ:8.18(s,1H),7.42(d,J=16.0Hz,1H),7.35-6.88(m,2H),4.71(s,1H),4.35(s,2H),4.07(t,J=8.7Hz,1H),3.77-3.57(m,1H),3.51-3.27(m,2H),3.12(d,J=12.4Hz,2H),2.09(dd,J=20.9,12.2Hz,8H),1.47(dd,J=14.0,7.1Hz,2H),0.80(dd,J=8.0,6.7Hz,3H)。
LC-MS(ESI):m/z=407.9[M+H]+。
OBD-021
(R)-5-((1H-1,2,4-三唑-1-基)甲基)-3-(4-((1R,5S)-3-硫杂-8-氮杂双环[3.2.1]辛-8-基)-3-氟苯基)噁唑烷-2-酮
1H-NMR(300MHz,DMSO-d6)δ:8.57(s,1H),8.01(s,1H),7.36(dd,J=15.8,2.1Hz,1H),7.18-6.92(m,2H),5.06(dd,J=8.9,4.8Hz,1H),4.72-4.52(m,2H),4.36(s,2H),4.17(t,J=9.1Hz,1H),3.84(dt,J=49.3,24.7Hz,1H),3.12(d,J=12.8Hz,2H),2.16(s,1H),2.11(s,1H),2.04(s,4H)。
LC-MS(ESI):m/z=389.9[M+H]+。
OTB-506
N-(((S)-3-(4-((1R,5S)-3-硫杂-8-氮杂双环[3.2.1]辛-8-基)-3-氟苯基)-2-氧代-噁唑烷-5-基)甲基)环丙烷甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.37(d,J=13.6Hz,1H),7.07(d,J=7.6Hz,1H),6.85(brs,1H),6.22(t,J=6.0Hz,1H),4.79–4.73(m,1H),4.41(brs,2H),3.99(t,J=7.2Hz,1H),3.77–3.64(m,3H),3.39(d,J=12.8Hz,2H),2.20–2.09(m,6H),1.43–1.37(m,1H),0.98–0.90(m,2H),0.82–0.75(m,2H)。HR-MS(ESI-TOF):C20H25N3O3FS的m/z[M+H]+计算值:406.1595;实测值:406.1527。
OTB-507
N-(((S)-3-(4-((1R,5S)-3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)-2-氧代-噁唑烷-5-基)甲基)环丁烷甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.45(d,J=12.4Hz,1H),7.17(d,J=8.8Hz,1H),7.05(t,J=8.8Hz,1H)5.95(m,1H),4.78(m,1H),4.51(brs,2H),4.00(t,J=9.2Hz,1H),3.84-3.74(m,3H),3.66(m,2H),3.02(m,1H),2.28-2.15(m,10H),1.95(m,1H),1.85(m,1H)。13C-NMR(100MHz,CDCl3)δ:175.9,154.3,153.0(d,J=242.9Hz),131.2,127.0,118.6(d,J=4.4Hz),114.5(d,J=2.9Hz),108.3(d,J=27.1Hz),71.9,58.2,47.7,41.9,39.6,30.3,28.3,25.4,25.3,18.1。HRMS(ESI);C21H27N3O3SF的m/z[M+H]+计算值:420.1757;实测值:420.1736。
OTB-510
N-(((S)-3-(4-((1R,5S)-3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-2-氧代-噁唑烷-5-基)甲基)乙酰胺
1H-NMR(400MHz,CDCl3)δ:7.08(m,2H),6.00(m,1H),4.76(m,1H),4.24(brs,2H),3.97(t,J=8.8Hz,1H),3.75-3.60(m,3H),3.38(m,2H),2.21(m,2H),2.14(s,4H),2.03(s,3H)。13C-NMR(100MHz,CDCl3)δ:171.2,155.3(dd,J=241.5,9.5Hz),154.1,130.6(t,J=13.6Hz),122.9(t,J=12.4Hz),102.9(dd,J=20.7,11.3Hz),71.9,60.4,47.4,41.9,33.7,29.2,23.1。HRMS(ESI):C18H22N3O3SF2的m/z[M+H]+计算值:398.1350;实测值:398.1329。
OTB-512
(((S)-3-(4-((1R,5S)-3-硫杂-8-氮杂双环[3.2.1]辛-8-基)-3,5-二氟苯基)-2-氧代-噁唑烷-5-基)甲基)氨基甲酸甲酯
1H-NMR(400MHz,CDCl3)δ:7.09(m,2H),5.08(m,1H),4.76(m,1H),4.24(brs,2H),3.98(t,J=8.8Hz,1H),3.75-3.50(m,6H),3.38(m,2H),2.20(m,2H),2.14(s,4H)。13C-NMR(100MHz,CDCl3)δ:157.5,155.3(dd,J=241.6,9.4Hz),153.9,130.7(t,J=13.6Hz),122.9(t,J=12.3Hz),102.9(dd,J=20.7,11.3Hz),71.8,60.4,52.6,47.3,43.6,33.7,29.2。HRMS(ESI):C18H22N3O4SF2的m/z[M+H]+计算值:414.1294;实测值:414.1278。
OTB-511
(R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(4-((1R,5S)-3-硫杂-8-氮杂双环[3.2.1]辛-8-基)-3,5-二氟苯基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.78(s,1H),7.76(s,1H),6.94(d,J=11.6Hz,2H),5.07-5.04(m,1H),4.79(d,J=3.6Hz,2H),4.20(brs,2H),4.09(t,J=8.8Hz,1H),3.88-3.83(m,1H),3.32(d,J=12.8Hz,2H),2.19-2.11(m,6H)。13C-NMR(100MHz,CDCl3)δ:155.3(d,J=242.1Hz),155.2(d,J=242.1Hz),153.1,134.5,129.9(t,J=13.6Hz),125.1,123.3(t,J=12.3Hz),103.3(dd,J=20.7,11.2Hz),70.3,60.4,52.0,47.2,33.8,29.2。HRMS(ESI):C18H20N5O2SF2的m/z[M+H]+计算值:408.1300;实测值:408.1295。
OTB-508
N-(((S)-3-(4-((1R,5S)-3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-2-氧代-噁唑烷-5-基)甲基)环丙烷甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.05(m,2H),6.12(m,1H),4.76(m,1H),4.21(brs,2H),3.95(t,J=9.2Hz,1H),3.72-3.65(m,3H),3.34(m,2H),2.21-2.12(m,6H),1.37(m,1H),0.99-0.75(m,4H)。13C-NMR(100MHz,CDCl3)δ:174.8,155.3(dd,J=241.7,9.5Hz),154.2,130.5(t,J=13.6Hz),123.0(t,J=12.5Hz),103.0(dd,J=20.8,11.4Hz),72.1,60.4,47.5,41.9,33.8,29.2,14.6,7.8,7.7。HRMS(ESI):的C20H24N3O3SF2的m/z[M+H]+计算值:420.1506;实测值:424.1484。
OTB-509
N-(((S)-3-(4-((1R,5S)-3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-2-氧代-噁唑烷-5-基)甲基)环丁烷甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.09(m,2H),5.78(m,1H),4.75(m,1H),4.23(brs,2H),3.97(t,J=8.8Hz,1H),3.73(m,1H),3.65(m,2H),3.36(m,2H),2.99(m,1H),2.27-2.14(m,9H),1.97(m,1H),1.85(m,2H)。13C-NMR(100MHz,CDCl3)δ:176.0,155.3(dd,J=243.4,9.5Hz),154.1,130.6(t,J=13.5Hz),122.9(t,J=12.2Hz),102.9(dd,J=20.7,11.4Hz),72.0,60.4,47.5,41.8,33.7,29.2,25.4,25.3,18.1。HRMS(ESI):C21H26N3O3SF2的m/z[M+H]+计算值:438.1663;实测值:438.1642。
OTB-503
N-(((5S)-3-(3-氟-4-((1R,5S)-3-氧化-3-硫杂-8-氮杂双环[3.2.1]辛-8-基)苯基)-2-氧代-噁唑烷-5-基)甲基)乙酰胺
1H-NMR(400MHz,CDCl3)δ:7.45(dd,J=16.0,2.8Hz,1H),7.12(dd,J=8.8,2.0Hz,1H),6.83(t,J=9.2Hz,1H),6.14(s,1H),4.78–4.77(m,1H),4.61(s,2H),4.00(t,J=8.8Hz,1H),3.77–3.64(m,3H),3.45(d,J=9.6Hz,2H),2.85(d,J=12.4Hz,2H),2.22–2.20(m,2H),2.03(s,3H),1.92–1.88(m,2H)。HR-MS(ESI-TOF):C18H23N3O4FS的m/z[M+H]+计算值:396.1388;实测值:396.1379。
OTB-505
(5R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(3-氟-4-((1R,5S)-3-氧化-3-硫杂-8-氮杂双环[3.2.1]辛-8-基)苯基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.79(s,1H),7.75(s,1H),7.30(dd,J=15.2,2.0Hz,1H),6.98(d,J=8.4Hz,1H),6.79(t,J=9.2Hz,1H),5.07–5.05(m,1H),4.79(s,2H),4.58(s,2H),4.12(t,J=9.2Hz,1H),3.91–3.89(m,1H),3.43(d,J=11.6Hz,2H),2.88–2.81(m,2H),2.21–2.18(m,2H),1.89–1.87(m,2H)。HR-MS(ESI-TOF):C18H21N5O3FS的m/z[M+H]+计算值:406.1349;实测值:406.1339。
OTB-513
N-(((5S)-3-(3,5-二氟-4-((1R,5S)-3-氧化-3-硫杂-8-氮杂双环[3.2.1]辛-8-基)苯基)-2-氧代-噁唑烷-5-基)甲基)环丁烷甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.12(d,J=12.0Hz,2H),5.97(brs,1H),4.77-4.75(m,1H),4.45(s,2H),3.97(t,J=8.8Hz,1H),3.74(t,J=8.4Hz,1H),3.66(t,J=5.2Hz,2H),3.54(d,J=9.2Hz,2H),3.02(m,1H),2.91(d,J=12.0Hz,2H),2.26-2.11(m,6H),1.99-1.92(m,1H),1.87-1.85(m,3H)。HRMS(ESI):C21H26N3O4SF2的m/z[M+H]+计算值:454.1606;实测值:454.1588。
OTB-514
N-(((5S)-3-(3,5-二氟-4-((1R,5S)-3-氧化-3-硫杂-8-氮杂双环[3.2.1]辛-8-基)苯基)-2-氧代-噁唑烷-5-基)甲基)乙酰胺
1H-NMR(400MHz,CDCl3)δ:7.12(d,J=12.0Hz,2H),6.15(brs,1H),4.81-4.75(m,1H),4.45(s,2H),3.98(t,J=8.8Hz,1H),3.74-3.63(m,3H),3.56(d,J=9.2Hz,2H),2.92(d,J=12.4Hz,2H),2.20-2.17(m,2H),2.03(s,3H),1.89-1.83(m,2H)。HRMS(ESI):C18H22N3O4SF2的m/z[M+H]+计算值:414.1293;实测值:414.1275。
OBD-017
N-(((5S)-3-(3-氟-4-((1R,5S)-3-氧化-3-硫杂-8-氮杂双环[3.2.1]辛-8-基)苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺
1H-NMR(300MHz,CDCl3)δ:7.39(dd,J=15.8,2.3Hz,1H),7.03(d,J=6.1Hz,2H),6.78(t,J=9.3Hz,1H),4.72(s,1H),4.55(s,2H),3.94(t,J=8.9Hz,1H),3.81-3.66(m,1H),3.58(s,2H),3.42(d,J=10.3Hz,2H),2.77(d,J=11.9Hz,2H),2.17(dd,J=25.1,17.8Hz,4H),1.84(d,J=7.9Hz,2H),1.56(dd,J=14.5,7.2Hz,2H),0.83(t,J=7.4Hz,3H)。
LC-MS(ESI):m/z=423.8[M+H]+。
OBD-018
(5R)-5-((1H-1,2,4-三唑-1-基)甲基)-3-(3-氟-4-((1R,5S)-3-氧化-3-硫杂-8-氮杂双环[3.2.1]辛-8-基)苯基)噁唑烷-2-酮
1H-NMR(300MHz,DMSO-d6)δ:12.17(s,1H),8.69(d,J=2.9Hz,1H),8.20–8.03(m,1H),7.44(d,J=16.2Hz,1H),7.28-7.02(m,2H),5.08(dd,J=8.5,5.1Hz,1H),4.68-4.52(m,4H),4.20(t,J=9.1Hz,1H),3.91(dd,J=8.7,6.0Hz,1H),3.56(d,J=11.1Hz,2H),2.48(d,J=12.3Hz,2H),2.06(d,J=5.1Hz,2H),1.79(d,J=7.6Hz,2H)。
LC-MS(ESI):m/z=405.8[M+H]+。
OTB-260
(R)-3-(3-氟-4-(2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-5-(羟甲基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.38(d,J=14.0Hz,1H),7.04(d,J=8.0Hz,1H),6.55(t,J=8.8Hz,1H),4.72(brs,1H),4.02(s,4H),3.99-3.89(m,3H),3.76-3.73(m,1H),3.42(s,4H)。13C-NMR(100MHz,CDCl3)δ:154.8,152.2(d,J=240.8Hz),135.9(d,J=11.7Hz),130.2(d,J=9.3Hz),114.6(d,J=5.2Hz),114.5(d,J=3.1Hz),107.6(d,J=23.8Hz),72.8,66.8,62.8,46.7,44.3,36.8。HRMS(ESI):C15H18FN2O3S的m/z[M+H]+计算值:325.1022;实测值:325.1010。
OTB-261
(S)-N-((3-(3-氟-4-(2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代-噁唑烷-5-基)甲基)乙酰胺
1H-NMR(400MHz,CDCl3)δ:7.33(d,J=14.0Hz,1H),6.99(d,J=8.4Hz,1H),6.48(t,J=8.8Hz,1H),6.20(brs,1H),4.75-4.73(m,1H),3.98-3.96(m,5H),3.73-3.66(m,2H),3.62-3.57(m,1H),3.41(s,4H),2.01(s,3H)。HRMS(ESI):C17H21FN3O3S的m/z[M+H]+计算值:366.1288;实测值:366.1274。
OTB-241
(R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(3-氟-4-(2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.79(s,1H),7.75(s,1H),7.22(dd,J=13.6,2.0Hz,1H),6.88(d,J=8.8Hz,1H),6.51(t,J=9.2Hz,1H),5.06-5.00(m,1H),4.78-4.77(m,2H),4.08(t,J=9.2Hz,1H),4.01(s,4H),3.89-3.85(m,1H),3.40(s,4H)。13C-NMR(100MHz,CDCl3)δ:153.6,152.0(d,J=243.1Hz),136.3(d,J=11.1Hz),134.5,129.1(d,J=9.0Hz),125.1,115.0(d,J=3.2Hz),114.5(d,J=5.2Hz),108.1(d,J=23.6Hz),70.4,66.7,52.1,47.7,44.3,36.8。HRMS(ESI):C17H19FN5O2S的m/z[M+H]+计算值:376.1244;实测值:376.1231。
OTB-516
(R)-3-(3,5-二氟-4-(2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-5-(羟甲基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.03(d,J=12.0Hz,2H),4.74-4.70(m,1H),4.18(s,4H),3.98(dd,J=12.8,3.2Hz,1H),3.93-3.85(m,2H),3.75(dd,J=12.4,4.0Hz,1H),3.41(s,4H)。HRMS(ESI):C15H17N2O3SF2的m/z[M+H]+计算值:343.0922;实测值:343.0912。
OTB-515
(S)-N-((3-(3,5-二氟-4-(2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代-噁唑烷-5-基)甲基)乙酰胺
1H-NMR(400MHz,CDCl3)δ:6.98(d,J=11.6Hz,2H),5.99(brs,1H),4.74-4.72(m,1H),4.16(s,4H),3.94(t,J=8.8Hz,1H),3.71-3.65(m,2H),3.61-3.55(m,1H),3.40(s,4H),2.01(s,3H)。13C-NMR(100MHz,CDCl3)δ:171.1,154.2,152.6(dd,J=240.6,11.1Hz),153.1,134.5,128.5(t,J=12.6Hz),124.7(t,J=13.3Hz),102.8(dd,J=18.2,10.7Hz),71.9,68.7,47.6,45.2,42.0,36.5,23.1。HRMS(ESI):C17H20N3O3SF2的m/z[M+H]+计算值:384.1188;实测值:384.1168。
OTB-242
(S)-((3-(3,5-二氟-4-(2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代-噁唑烷-5-基)甲基)氨基甲酸甲酯
1H NMR(400MHz,CDCl3)δ:7.00(d,J=11.6Hz,2H),5.16(brs,1H),4.81–4.67(m,1H),4.16(s,4H),3.94(t,J=8.8Hz,1H),3.68(s,3H),3.56–3.50(m,3H),3.40(s,4H)。HRMS(ESI):C17H20F2N3O4S的m/z[M+H]+计算值:400.1143;实测值:400.1125。
OTB-245
(R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(3,5-二氟-4-(2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)噁唑烷-2-酮
1H NMR(400MHz,CDCl3)δ:7.77(s,1H),7.74(s,1H),6.87(d,J=11.6Hz,2H),5.03–5.01(m,1H),4.77–4.76(m,2H),4.15(s,4H),4.06(t,J=9.2Hz,1H),3.86–3.82(m,1H),3.41(s,4H)。HRMS(ESI):C17H18F2N5O2S的m/z[M+H]+计算值:394.1149;实测值:394.1129。
OTB-243
(S)-N-((3-(3,5-二氟-4-(2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代-噁唑烷-5-基)甲基)环丙烷甲酰胺
1H NMR(400MHz,CDCl3)δ:6.98(d,J=11.6Hz,2H),6.25–6.24(m,1H),4.77–4.71(m,1H),4.16(s,4H),3.92(t,J=8.8Hz,1H),3.71–3.56(m,3H),3.40(s,4H),1.40–1.38(m,1H),1.04–0.87(m,2H),0.82–0.73(m,2H)。HRMS(ESI):C19H22F2N3O3S的m/z[M+H]+计算值:410.1350;实测值:410.1331。
OTB-244
(S)-N-((3-(3,5-二氟-4-(2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代-噁唑烷-5-基)甲基)环丁烷甲酰胺
1H NMR(400MHz,CDCl3)δ:6.99(d,J=11.6Hz,2H),5.83(brs,1H),4.82–4.68(m,1H),4.17(s,4H),3.93(t,J=8.8Hz,1H),3.72–3.64(m,3H),3.40(s,4H),3.03–2.96(m,1H),2.26–1.85(m,6H)。HRMS(ESI):C20H24F2N3O3S的m/z[M+H]+计算值:424.1506;实测值:424.1483
OTB-201
(R)-3-(3-氟-4-(2-氧杂-6-氮杂螺[3.3]庚-6-基)苯基)-5-(羟甲基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.42(dd,J=14.0,2.0Hz,1H),7.03(dd,J=8.8,2.0Hz,1H),6.62(t,J=8.8Hz,1H),4.85(s,4H),4.73(m,1H),4.17(s,4H),4.00-3.95(m,2H),3.93-3.89(m,1H),3.77-3.74(m,1H)。13C-NMR(100MHz,CDCl3)δ:155.2,152.3(d,J=240.7Hz),135.9(d,J=11.3Hz),130.4(d,J=8.9Hz),114.7(d,J=3.0Hz),114.6(d,J=5.6Hz),107.8(d,J=23.8Hz),81.3,73.2,63.1,62.9,46.9,40.1。HRMS(ESI):C15H18FN2O4的m/z[M+H]+计算值:309.1251;实测值:309.1269。
OTB-202
(S)-N-((3-(3-氟-4-(2-氧杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代-噁唑烷-5-基)甲基)乙酰胺
1H-NMR(300MHz,CDCl3)δ:7.35(d,J=14.1Hz,1H),7.00(d,J=8.7Hz,1H),6.51(t,J=9.0Hz,1H),6.03(s,1H),4.84(s,4H),4.74(m,1H),4.12(s,4H),3.99(t,J=8.7Hz,1H),3.73-3.69(m,2H),3.61(m,1H),2.02(s,3H)。13C-NMR(100MHz,CDCl3)δ:171.4,154.8,152.4(d,J=240.8Hz),136.1(d,J=11.9Hz),130.1(d,J=9.2Hz),114.7(d,J=3.1Hz),114.6(d,J=5.0Hz),107.9(d,J=23.6Hz),81.2,72.1,63.1,48.1,42.2,40.1,23.4。HRMS(ESI):C17H21FN3O4的m/z[M+H]+计算值:350.1516;实测值:350.1497。
OTB-203
(R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(3-氟-4-(2-氧杂-6-氮杂螺[3.3]庚-6-基)苯基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.78(s,1H),7.75(s,1H),7.18(d,J=13.6Hz,1H),6.88(d,J=8.8Hz,1H),6.46(t,J=9.2Hz,1H),5.03(m,1H),4.83(s,4H),4.78(m,2H),4.10-4.07(m,5H),3.91-3.85(m,1H)。13C-NMR(100MHz,CDCl3)δ:153.6,152.1(d,J=241.4Hz),136.1(d,J=10.6Hz),134.5,129.2(d,J=9.3Hz),125.1,115.0(d,J=2.9Hz),114.5(d,J=4.7Hz),108.1(d,J=23.7Hz),81.0,70.4,62.9,52.1,47.7,39.8。HRMS(ESI):C17H19FN5O3的m/z[M+H]+计算值:360.1472;实测值:360.1451。
OTB-204
(R)-5-((2H-1,2,3-三唑-2-基)甲基)-3-(3-氟-4-(2-氧杂-6-氮杂螺[3.3]庚-6-基)苯基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.65(s,2H),7.31(d,J=14.4,2.4Hz,1H),6.99(d,J=8.4Hz,1H),6.59(t,J=9.2Hz,1H),5.14-5.07(m,1H),4.88-4.83(m,5H),4.77-4.71(m,1H),4.16(s,4H),4.07-4.02(m,1H),3.98-3.92(m,1H)。13C-NMR(100MHz,CDCl3)δ:158.99,154.38,147.08,144.53,135.18,115.11,114.43,112.30,107.91,107.87,81.04,71.85,70.04,62.91,48.38,48.02,41.57,39.85。HRMS(ESI):C17H19FN5O3的m/z[M+H]+计算值:360.1472;实测值:360.1451。
OTB-205
(S)-N-((3-(3-氟-4-(2-氧杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代-噁唑烷-5-基)甲基)呋喃-2-甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.46(s,1H),7.32(dd,J=14.0,2.4Hz,1H),7.14(d,J=3.2Hz,1H),7.00(d,J=8.4Hz,1H),6.81(t,J=6.4Hz,1H),6.51(d,J=3.2Hz,1H),6.45(t,J=9.2Hz,1H),4.83(brs,5H),4.08(s,4H),4.03(t,J=8.8Hz,1H),3.92-3.85(m,1H),3.79-3.73(m,2H)。13C-NMR(100MHz,CDCl3)δ:159.2,154.6,152.4(d,J=240.8Hz),147.3,144.7,136.5,130.5(d,J=9.4Hz),115.3,114.7(d,J=3.1Hz),112.5,109.9,107.9(d,J=23.9Hz),81.2,72.1,63.1,48.2,41.8,40.1。HRMS(ESI):C20H21FN3O5的m/z[M+H]+计算值:402.1465;实测值:402.1561。
OTB-206
(S)-N-((3-(3-氟-4-(2-氧杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代-噁唑烷-5-基)甲基)噻吩-2-甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.53(d,J=3.2Hz,1H),7.50(d,J=4.8Hz,1H),7.32(d,J=14.0Hz,1H),7.09-6.96(m,2H),6.66(m,1H),6.45(t,J=9.2Hz,1H),4.82(s,4H),4.09-4.01(m,6H),3.81-3.79(m,1H),3.78-3.73(m,2H)。13C-NMR(100MHz,CDCl3)δ:162.9,154.7,152.5(d,J=241.1Hz),150.1,140.8,138.1,130.9,128.9,128.0,114.9(d,J=2.8Hz),114.2(d,J=3.2Hz),108.1(d,J=23.9Hz),81.20 72.2,63.2,48.3,42.7,40.0。HRMS(ESI):C20H21FN3O4S的m/z[M+H]+计算值:418.1237;实测值:418.1331。
OTB-222
(R)-N-((3-(3-氟-4-(2-氧杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代-噁唑烷-5-基)甲基)甲烷磺酰胺
1H-NMR(400MHz,CDCl3)δ:7.44-7.35(m,1H),7.07-6.97(m,1H),6.69-6.59(m,1H),4.98-4.91(m,1H),4.85(s,4H),4.81-4.75(m,1H),4.24-4.14(m,4H),4.13-4.09(m,1H),4.06-3.98(m,1H),3.92-3.86(m,1H),3.63-3.53(m,1H),3.47-3.36(m,1H),3.03(s,3H)。13C-NMR(100MHz,DMSO-d6)δ:154.5,151.7(d,J=237.7Hz),135.9(d,J=11.0Hz),130.5(d,J=9.4Hz),115.2(d,J=5.4Hz),115.1(d,J=2.8Hz),107.3(d,J=23.8Hz),80.2,71.7,62.7,47.6,45.5。HRMS(ESI):C16H21FN3O5S的m/z[M+H]+计算值:386.1186;实测值:386.1185。
OTB-223
(S)-((3-(3-氟-4-(2-氧杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代-噁唑烷-5-基)甲基)氨基甲酸甲酯
1H-NMR(400MHz,CDCl3)δ:7.39(d,J=14.0Hz,1H),7.01(d,J=8.8Hz,1H),6.61(t,J=9.2Hz,1H),5.11(brs,1H),4.84(s,4H),4.73(brs,1H),4.16(s,4H),3.99(t,J=8.8Hz,1H),3.77-3.75(m,1H),3.68(s,3H),3.64-3.60(m,1H),3.55-3.50(m,1H)。HRMS(ESI):C17H21FN3O5的m/z[M+H]+计算值:366.1465;实测值:366.1466。
OTB-238
(S)-N-((3-(3-氟-4-(2-氧杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代-噁唑烷-5-基)甲基)环丙烷甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.35(dd,J=14.0,2.4Hz,1H),7.00(d,J=8.4Hz,1H),6.51(t,J=9.2Hz,1H),6.13(brs,1H),4.84(s,4H),4.75-4.73(m,1H),4.12(s,4H),3.97(t,J=8.8Hz,1H),3.75-3.65(m,3H),1.39-1.36(m,1H),0.97-0.91(m,2H),0.79-0.75(m,2H)。13C-NMR(100MHz,CDCl3)δ:174.8,154.6,151.6(d,J=240.8Hz),136.0(d,J=11.3Hz),129.8(d,J=9.2Hz),114.5(d,J=3.1Hz),114.6(d,J=3.1Hz),114.3(d,J=5.2Hz),107.8(d,J=23.8Hz),81.1,72.1,62.9,47.9,42.0,39.9,14.6,7.7。HRMS(ESI):C19H23FN3O4的m/z[M+H]+计算值:376.1673;实测值:376.1652。
OTB-239
(S)-N-((3-(3-氟-4-(2-氧杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代-噁唑烷-5-基)甲基)环丁烷甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.49(d,J=14.4Hz,1H),7.01(d,J=8.4Hz,1H),6.85(t,J=9.2Hz,1H),5.82(brs,1H),4.86(s,4H),4.76(brs,1H),4.27(s,4H),4.00(t,J=9.2Hz,1H),3.78-3.65(m,3H),3.03-2.99(m,1H),2.26-2.13(m,4H),1.99-1.85(m,2H)。13C-NMR(100MHz,CDCl3)δ:176.0,154.5,152.1(d,J=240.9Hz),136.0(d,J=11.2Hz),129.8(d,J=9.2Hz),114.4(d,J=3.1Hz),114.3(d,J=5.2Hz),107.7(d,J=23.9Hz),81.1,71.9,62.8,47.9,41.9,39.7,25.4,25.3,18.2。HRMS(ESI):C20H25FN3O4的m/z[M+H]+计算值:390.1829;实测值:390.1808。
OTB-229
(R)-3-(3,5-二氟-4-(2-氧杂-6-氮杂螺[3.3]庚-6-基)苯基)-5-(羟甲基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.03(d,J=10.8Hz,2H),4.82(s,4H),4.72(brs,1H),4.28(s,4H),3.99-3.85(m,3H),3.75-3.72(m,1H)。13C-NMR(100MHz,CDCl3)δ:154.6,152.6(dd,J=240.2,10.8Hz),128.9(t,J=12.8Hz),124.3(t,J=13.3Hz),102.8(dd,J=18.2,10.7Hz),81.0,72.9,64.9,62.6,46.3,40.8。HRMS(ESI):C15H17F2N2O4的m/z[M+H]+计算值:327.1156;实测值:327.1135。
OTB-230
(S)-N-((3-(3,5-二氟-4-(2-氧杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代-噁唑烷-5-基)甲基)乙酰胺
1H-NMR(400MHz,CDCl3)δ:6.97(d,J=10.0Hz,2H),6.49(brs,1H),4.81(s,4H),4.75(brs,1H),4.27(s,4H),3.94(t,J=8.8Hz,1H),3.70-3.63(m,3H),2.02(s,3H)。13C-NMR(100MHz,CDCl3)δ:171.2,154.2,152.5(dd,J=240.5,10.9Hz),128.6(t,J=12.6Hz),124.5(t,J=13.4Hz),102.8(dd,J=18.2,10.6Hz),80.9,71.9,64.9,47.5,41.9,40.8,23.1。HRMS(ESI);C17H20F2N3O4的m/z[M+H]+计算值:368.1422;实测值:368.1418。
OTB-231
(S)-((3-(3,5-二氟-4-(2-氧杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代-噁唑烷-5-基)甲基)氨基甲酸甲酯
1H-NMR(400MHz,CDCl3)δ:7.04(d,J=10.8Hz,2H),5.08(brs,1H),4.83(s,4H),4.74(brs,1H),4.34(s,4H),3.96(t,J=9.2Hz,1H),3.72-3.51(m,6H)。13C-NMR(100MHz,CDCl3)δ:157.5,154.0,152.6(dd,J=240.4,10.9Hz),128.7(t,J=12.8Hz),124.5(t,J=13.5Hz),102.8(dd,J=23.3,15.7Hz),80.9,71.7,64.8,52.6,47.4,43.6,40.8。HRMS(ESI):C17H20F2N3O5的计算值:384.1371;实测值:384.1367。
OTB-232
(R)-N-((3-(3,5-二氟-4-(2-氧杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代-噁唑烷-5-基)甲基)甲烷磺酰胺
1H-NMR(400MHz,DMSO-d6)δ:7.8(d,J=12.4Hz,2H),4.74-4.69(m,5H),4.23(s,4H),4.06(t,J=8.8Hz,1H),3.74-3.70(m,1H),3.31-3.27(m,2H),2.94(s,3H)。13C-NMR(100MHz,DMSO-d6)δ:154.3,152.2(dd,J=237.8,11.3Hz),129.5(t,J=13.0Hz),124.4(t,J=13.6Hz),102.9(dd,J=18.2,10.5Hz),80.0,71.8,64.7,47.4,45.5,40.7。HRMS(ESI):C16H20F2N3O5S的m/z[M+H]+计算值:404.1092;实测值:404.1087。
OTB-233
(S)-N-((3-(3,5-二氟-4-(2-氧杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代-噁唑烷-5-基)甲基)环丙烷甲酰胺
1H-NMR(400MHz,CDCl3)δ:6.98(d,J=10.0Hz,2H),6.36(brs,1H),4.82(s,4H),4.75(brs,1H),4.28(s,4H),3.93(t,J=8.8Hz,1H),3.72-3.65(m,3H),1.42-1.40(m,1H),0.96-0.88(m,2H),0.77-0.75(m,2H)。13C-NMR(100MHz,CDCl3)δ:174.9,154.4,152.5(dd,J=240.4,10.3Hz),128.6(t,J=12.7Hz),124.4(t,J=13.4Hz),102.8(dd,J=18.2,10.6Hz),80.9,72.2,64.8,47.6,41.9,40.8,14.5,7.7。HRMS(ESI):C19H22F2N3O4的m/z[M+H]+计算值:394.1578;实测值:394.1575。
OTB-234
(R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(3,5-二氟-4-(2-氧杂-6-氮杂螺[3.3]庚-6-基)苯基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.77(s,1H),7.75(s,1H),6.86(d,J=11.6Hz,2H),5.03-5.02(m,1H),4.81(s,4H),4.77-4.76(m,2H),4.27(s,4H),4.06(t,J=9.2Hz,1H),3.86-3.82(m,1H)。13C-NMR(100MHz,CDCl3)δ:153.2,152.4(dd,J=240.7,11.0Hz),134.5,127.8(t,J=12.8Hz),125.1,124.8(t,J=13.3Hz),103.1(dd,J=18.1,10.7Hz),80.9,70.4,64.8,52.0,47.3,40.8。HRMS(ESI:C17H18F2N5O3的m/z[M+H]+计算值:378.1378;实测值:378.1365。
OTB-240
(S)-N-((3-(3,5-二氟-4-(2-氧杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代-噁唑烷-5-基)甲基)环丁烷甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.00(d,J=12.0Hz,2H),5.87(t,J=6.0Hz,1H),4.82(s,4H),4.77-4.71(m,1H),4.28(s,4H),3.94(t,J=8.8Hz,1H),3.72-3.64(m,3H),3.03-2.99(m,1H),2.26-2.13(m,4H),1.99-1.82(m,2H)。HRMS(ESI):C20H24F2N3O4的m/z[M+H]+计算值:408.1735;实测值:408.1716。
OTB-701
(R)-N-((3-(3-氟-4-(2,6-二氮杂螺[3.3]庚-2-基)苯基)-2-氧代-噁唑烷-5-基)甲基)乙酰胺
1H-NMR(400MHz,CDCl3)δ:7.38(d,J=14.4Hz,1H),7.09(d,J=8.4Hz,1H),6.58(t,J=9.2Hz,1H),4.76(m,2H),4.30(s,4H),4.10(s,4H),3.76(m,1H),3.54(m,2H),1.96(s,3H)。13C-NMR(100MHz,CDCl3)δ:172.6,155.4,153.2,150.8,135.6,130.5,114.4,107.3,72.0,62.2,55.0,48.0,41.7,37.2,21.0。HRMS(ESI):C17H22FN4O3的m/z[M+H]+计算值:349.1671;实测值:349.1662。
OTB-702
(R)-N-((3-(3-氟-4-(6-甲基-2,6-二氮杂螺[3.3]庚-2-基)苯基)-2-氧代-噁唑烷-5-基)甲基)乙酰胺
1H-NMR(400MHz,CDCl3)δ:7.36(d,J=14.4Hz,1H),7.08(d,J=8.8Hz,1H),6.57(t,J=9.2Hz,1H),4.75(m,1H),4.10(t,J=9.2Hz,1H),4.01(s,4H),3.74(m,1H),3,73(s,4H),3.53(m,2H),2.52(s,3H),1.96(s,3H)。13C NMR(100MHz,CDCl3)δ:172.6,155.4,153.2,150.8,136.1,130.3,114.4,107.3,72.0,64.9,62.6,48.0,43.0,41.7,34.8,21.0。HRMS(ESI):C18H24FN4O3的m/z[M+H]+计算值:363.1827,实测值:363.1819。
OTB-704
(R)-N-((3-(3,5-二氟-4-(2,6-二氮杂螺[3.3]庚-2-基)苯基)-2-氧代-噁唑烷-5-基)甲基)乙酰胺
1H-NMR(400MHz,CD3OD)δ:7.12(d,J=9.6Hz,2H),4.76,(m,1H),4.30(s,4H),4.24(s,4H),4.06(m,1H),3.73(m,1H),3.53(m,2H),1.96(s,3H)。13C NMR(100MHz,CD3OD)δ:172.6,155.0,153.7,151.3,129.6,129.4,102.7,102.5,72.0,64.3,55.0,48.0,41.6,38.3,21.0。HRMS(ESI):C17H21F2N4O3的m/z[M+H]+计算值:367.1583,实测值:367.1576.
OTB-705
(R)-N-((3-(3,5-二氟-4-(6-甲基-2,6-二氮杂螺[3.3]庚-2-基)苯基)-2-氧代-噁唑烷-5-基)甲基)乙酰胺
1H-NMR(400MHz,CD3OD)δ:7.12(d,J=10.0Hz,2H),4.75(m,1H),4.22(s,4H),4.05(m,1H),3.78(s,4H),3.73(m,1H),3.53(m,2H),2.55(s,3H),1.96(s,3H)。13C-NMR(100MHz,CD3OD)δ:172.6,155.0,153.7,151.3,129.4,102.8,72.0,64.7,64.6,48.0,42.7,41.7,22.4,21.0。HRMS(ESI):C18H23F2N4O3的m/z[M+H]+计算值:381.1733,实测值:381.1725。
实施例12
本发明附加实施方式的合成
(6)的制备程序:
实验部分
5-氧代硫杂环庚烷-4-甲酸乙酯(2)。
在-30℃下向四氢噻喃-4-酮(100g,862mmol)在Et2O(150mL)中的溶液中加入BF3-Et2O(120mL,948mmol),然后将反应混合物在-30℃和氮气氛下搅拌2小时,之后在-30℃下向混合物中加入2-重氮基乙酸乙酯(147g,1293mmol)在Et2O(100mL)中的溶液,然后将混合物加温至室温并搅拌过夜。用K2CO3淬灭,浓缩溶剂并干燥以得到棕色油状的5-氧代硫杂环庚烷-4-甲酸乙酯(2)(80g,46%)。
硫杂环庚-4-酮(3)。
在180℃下将5-氧代硫杂环庚烷-4-甲酸乙酯(2)(80g,396mmol)和氯化锂(16.6g,396mmol)在DMSO(100mL)和H2O(5滴)中的混合物搅拌2小时。将反应混合物冷却至室温并倒入冰水中,用EA萃取,减压浓缩有机层以得到棕色固体状的硫杂环庚-4-酮(3)(15.9g粗产物,31%)。
(Z)-硫杂环庚-4-酮肟(4)。
向硫杂环庚-4-酮(3)(15.9g,122mmol)在EtOH(150mL)和H2O(50mL)中的溶液中加入NH2OH-HCl(8.47g,122mmol),然后将反应混合物在75℃和氮气氛下搅拌4小时,然后将混合物浓缩并干燥以得到棕色固体状的(Z)-硫杂环庚-4-酮肟(4)(9.97g,56%)。
1,5-硫氮杂环辛-4-酮(5)。
在70℃下将(Z)-硫杂环庚-4-酮肟(4)(9.97g,68.7mmol)和多聚磷酸(50g)的混合物搅拌2小时。将反应混合物冷却至室温并倒入冰水中,使用碳酸钾溶液调整至pH=8,用EA萃取,减压浓缩有机层以得到棕色固体状的1,5-硫氮杂环辛-4-酮(5)(3g粗产物,30%)。
1,5-硫氮杂环辛烷(6)。
在0℃下向1,5-硫氮杂环辛-4-酮(5)(3g,20.7mmol)在THF(100mL)中的溶液中加入THF中的BH3(31mL,31.1mmol),然后回流12小时。用CH3OH(50mL)淬灭反应。将溶剂蒸发以得到白色油状的1,5-硫氮杂环辛烷(6)(1.7g,63%),并且粗产物不经进一步纯化而用于下一反应。
LC-MS(ESI)m/z=132[M+H]+。
步骤1:5-(2-氟-4-硝基苯基)-1,5-硫氮杂环辛烷(8)的制备:
在25℃下向1,5-硫氮杂环辛烷(6)(1g,7.6mmol)和1,2-二氟-4-硝基苯(1.2g,7.6mmol)在DMF(10mL)中的溶液中加入K2CO3(1.05g,7.6mmol),然后将反应混合物在80℃和氮气氛下搅拌2小时,通过TLC监测。减压浓缩混合物,并通过硅胶柱层析(EA:PE=3:1)纯化粗产物以得到黄色固体状的5-(2-氟-4-硝基苯基)-1,5-硫氮杂环辛烷(8)(1.5g,74%)。
LC-MS(ESI)m/z=271[M+H]+。
步骤2:3-氟-4-(1,5-硫氮杂环辛-5-基)苯胺(9):
向5-(2-氟-4-硝基苯基)-1,5-硫氮杂环辛烷(8)(1.5g,5.7mmol)和钯碳(200mg)在MeOH(15mL)中的溶液中,然后将反应混合物在室温和氢气氛下搅拌过夜,通过TLC监测。减压浓缩滤液以得到白色油状的3-氟-4-(1,5-硫氮杂环辛-5-基)苯胺(9)(1.2g,91%),并且粗产物不经进一步纯化而用于下一反应。
LC-MS(ESI)m/z=241[M+H]+。
步骤3:3-氟-4-(1,5-硫氮杂环辛-5-基)苯基氨基甲酸苄酯(10):
在-20℃和氮气氛下将氯甲酸苄酯(1.76g,10.4mmol)加至3-氟-4-(1,5-硫氮杂环辛-5-基)苯胺(9)(1.2g,5.2mmol)和三乙胺(1.05g,10.4mmol)在DCM(200mL)中的悬液中,然后将反应混合物在0℃下搅拌30分钟,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(EA:PE=10:1)纯化粗产物以得到白色固体状的3-氟-4-(1,5-硫氮杂环辛-5-基)苯基氨基甲酸苄酯(10)(740mg,38%)。
LC-MS(ESI)m/z=375[M+H]+。
在-78℃和氮气氛下向3-氟-4-(1,5-硫氮杂环辛-5-基)苯基氨基甲酸苄酯(10)(740mg,1.97mmol)在THF(10mL)中的溶液中加入n-BuLi(1.3ml,2.96mmol),然后将混合物在-78℃下搅拌30分钟,之后将丁酸(R)-环氧乙烷-2-基甲酯(427mg,2.96mmol)在THF中的溶液在-78℃下加至混合物,然后加温至室温并搅拌过夜,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=70:1)纯化粗产物以得到白色固体状的(R)-3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)-5-(羟甲基)噁唑烷-2-酮(11)(382mg,57%)。
LC-MS(ESI)m/z=341[M+H]+。
步骤5:4-甲基苯磺酸(R)-(3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代噁唑烷-5-基)甲酯(12):
在0℃和氮气氛下将4-甲基苯-1-磺酰氯(418mg,2.2mmol)加至(R)-3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)-5-(羟甲基)噁唑烷-2-酮(11)(382mg,1.1mmol)和Et3N(222mg,2.2mmol)在DCM(10mL)中的悬液,并将反应混合物在室温下搅拌过夜,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=50:1)纯化粗产物以得到白色固体状的4-甲基苯磺酸(R)-(3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代噁唑烷-5-基)甲酯(12)(407mg,75%)。
LC-MS(ESI)m/z=495[M+H]+。
步骤6:(R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮(OBD-001):
在25℃下向4-甲基苯磺酸(R)-(3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代噁唑烷-5-基)甲酯(12)(200mg,0.4mmol)和1H-1,2,3-三唑(56mg,0.8mmol)在DMF(5mL)中的溶液中加入K2CO3(110mg,0.8mmol),然后将反应混合物在80℃和氮气氛下搅拌2小时,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(EA:PE=2:1)纯化粗产物以得到白色固体状的(R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮(OBD-001)(70mg,45%)。
1H NMR(301MHz,CDCl3)δ7.76(d,J=17.6Hz,2H),7.41–7.09(m,1H),7.11–6.73(m,2H),5.04(d,J=3.0Hz,1H),4.78(d,J=3.4Hz,2H),4.12(t,J=9.2Hz,1H),3.88(dd,J=9.2,6.1Hz,1H),3.36(t,J=6.0Hz,3H),2.92–2.59(m,4H),2.01(dd,J=27.9,7.3Hz,4H)。
LC-MS(ESI)m/z=391.9[M+H]+。
步骤7:(OBD-002)的制备:
在0℃下向(R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮(OBD-001)(50mg,0.13mmol)在THF(10mL)和10滴水中的溶液中加入过氧单磺酸钾(80mg,0.13mmol),然后将反应混合物在0℃下搅拌2小时,通过TLC监测。用硫代硫酸钠淬灭,并通过硅胶柱层析(DCM:MeOH=80:1)纯化粗产物以得到白色固体状的(OBD-002)(22mg,41%)。
1H NMR(301MHz,CDCl3)δ7.92–7.67(m,2H),7.32(d,J=16.8Hz,1H),7.12(t,J=9.0Hz,1H),6.96(d,J=8.1Hz,1H),5.07(s,1H),4.81(d,J=4.0Hz,2H),4.15(t,J=9.0Hz,1H),4.01–3.83(m,1H),3.32(d,J=14.2Hz,5H),3.11–2.87(m,2H),2.59(s,2H),2.19(s,4H)。
LC-MS(ESI)m/z=407.8[M+H]+。
步骤1:(R)-5-((1H-1,2,4-三唑-1-基)甲基)-3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮(OBD-008):
在25℃下向4-甲基苯磺酸(R)-(3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代噁唑烷-5-基)甲酯(12)(200mg,0.4mmol)和1H-1,2,4-三唑(56mg,0.8mmol)在DMF(5mL)中的溶液中加入K2CO3(110mg,0.8mmol),然后将反应混合物在80℃和氮气氛下搅拌2小时,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(EA:PE=2:1)纯化粗产物以得到白色固体状的(R)-5-((1H-1,2,4-三唑-1-基)甲基)-3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮(OBD-008)(84mg,54%)。
1H NMR(301MHz,CDCl3)δ8.24(s,1H),7.97(s,1H),7.00(s,2H),5.12–4.91(m,1H),4.56(d,J=4.7Hz,2H),4.24–3.83(m,2H),3.38(t,J=6.0Hz,4H),2.95–2.59(m,4H),1.98(s,5H)。
LC-MS(ESI)m/z=391.9[M+H]+。
步骤2:(OBD-009)的制备:
在0℃下向(R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮(OBD-008)(50mg,0.13mmol)在THF(10mL)和10滴水中的溶液中加入过氧单磺酸钾(80mg,0.13mmol),然后将反应混合物在0℃下搅拌2小时,通过TLC监测。用硫代硫酸钠淬灭,并通过硅胶柱层析(DCM:MeOH=80:1)纯化粗产物以得到白色固体状的(OBD-009)(22mg,41%)。
1H NMR(301MHz,CDCl3)δ8.24(s,1H),7.93(s,1H),7.41–7.20(m,1H),7.19–6.92(m,2H),5.10–4.92(m,1H),4.56(d,J=4.7Hz,2H),4.12(t,J=9.0Hz,1H),3.97(dd,J=9.2,6.2Hz,1H),3.28(dd,J=13.0,6.9Hz,2H),3.12(dd,J=12.5,5.9Hz,4H),3.02–2.83(m,2H),2.22–1.99(m,5H),1.26(d,J=9.4Hz,4H)。
LC-MS(ESI)m/z=407.8[M+H]+。
步骤1:(R)-5-(叠氮基甲基)-3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮(13):
在25℃下向4-甲基苯磺酸(R)-(3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代噁唑烷-5-基)甲酯(12)(800mg,1.62mmol)和叠氮化钠(105mg,1.62mmol)在DMF(10mL)中的溶液中加入K2CO3(447g,3.24mmol),然后将反应混合物在80℃和氮气氛下搅拌1小时,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(PE:EA=2:1)纯化粗产物以得到白色固体状的(R)-5-(叠氮基甲基)-3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮(13)(470mg,80%)。
LC-MS(ESI)m/z=366[M+H]+。
步骤2:(S)-5-(氨甲基)-3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮(14):
在25℃下向(R)-5-(叠氮基甲基)-3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮(13)(470mg,1.3mmol)在MeOH(10mL)中的溶液中加入钯碳(100mg),然后将反应混合物在室温和氢气氛下搅拌过夜,通过TLC监测。减压浓缩滤液,并通过硅胶柱层析(DCM:MeOH=50:1)纯化粗产物以得到白色固体状的(S)-5-(氨甲基)-3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮(14)(374mg,85%)。
LC-MS(ESI)m/z=340[M+H]+。
步骤3:(S)-N-((3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺(OBD-005):
在25℃下向(S)-5-(氨甲基)-3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮(14)(374mg,1.1mmol)和丁酸(97mg,1.1mmol)在DCM(10mL)中的溶液中加入HOBt(223mg,1.65mmol)、EDCI(420mg,2.2mmol)和DIPEA(284mg,2.2mmol),然后将反应混合物在25℃和氮气氛下搅拌2小时,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=80:1)纯化粗产物以得到白色固体状的(S)-N-((3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺(OBD-003)(252mg,56%)。
1H NMR(300MHz,CDCl3)δ7.50(s,2H),7.03(d,J=6.1Hz,1H),5.99(s,1H),4.77(d,J=5.7Hz,1H),4.02(t,J=9.0Hz,2H),3.70(ddd,J=20.7,15.2,7.7Hz,4H),3.48(s,4H),2.95–2.68(m,4H),2.20(t,J=7.2Hz,3H),2.06(d,J=6.1Hz,4H),1.64(dd,J=14.8,7.4Hz,4H),0.91(t,J=7.4Hz,4H)。
LC-MS(ESI)m/z=409.9[M+H]+。
步骤4:(OBD-004)的制备:
在0℃下向(S)-N-((3-(3-氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺(OBD-003)(150mg,0.37mmol)在THF(10mL)和10滴水中的溶液中加入过氧单磺酸钾(225mg,0.37mmol),然后将反应混合物在0℃下搅拌2小时,通过TLC监测。用硫代硫酸钠淬灭,并通过制备型HPLC纯化粗产物以得到白色固体状的(OBD-004)(48mg,31%)。
1H NMR(301MHz,CDCl3)δ7.44(dd,J=14.7,2.4Hz,1H),7.19–6.99(m,2H),6.44(s,1H),4.84–4.71(m,1H),4.02(t,J=8.9Hz,1H),3.78(dd,J=9.0,6.6Hz,1H),3.66(t,J=4.6Hz,2H),3.38–3.09(m,6H),2.99(dd,J=12.6,6.3Hz,2H),2.20(dd,J=9.4,5.3Hz,6H),1.71–1.56(m,2H),0.91(dd,J=9.6,5.1Hz,3H)。LC-MS(ESI)m/z=425.8[M+H]+。
步骤1:5-(2,6-二氟-4-硝基苯基)-1,5-硫氮杂环辛烷(8)的制备:
在25℃下向1,5-硫氮杂环辛烷(6)(1g,7.6mmol)和1,2,3-三氟-5-硝基苯(1.35g,7.6mmol)在DMF(10mL)中的溶液中加入K2CO3(2.1g,15.2mmol),然后将反应混合物在80℃和氮气氛下搅拌2小时,通过TLC监测。减压浓缩混合物,并通过硅胶柱层析(EA:PE=3:1)纯化粗产物以得到黄色固体状的5-(2,6-二氟-4-硝基苯基)-1,5-硫氮杂环辛烷(8)(1.64g,75%)。
LC-MS(ESI)m/z=289[M+H]+。
步骤2:3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯胺(9):
向5-(2,6-二氟-4-硝基苯基)-1,5-硫氮杂环辛烷(8)(1.64g,5.7mmol)和钯碳(200mg)在MeOH(15mL)中的溶液中,然后将反应混合物在室温和氢气氛下下搅拌过夜,通过TLC监测。减压浓缩滤液以得到白色油状的3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯胺(9)(1.4g,94%),并且粗产物不经进一步纯化而用于下一反应。
LC-MS(ESI)m/z=259[M+H]+。
步骤3:3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯基氨基甲酸苄酯(10):
在-20℃和氮气氛下将氯甲酸苄酯(1.87g,10.6mmol)加至3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯胺(9)(1.4g,5.3mmol)和三乙胺(1.07g,10.6mmol)在DCM(200mL)中的悬液中,然后将反应混合物在0℃下搅拌30分钟,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(EA:PE=10:1)纯化粗产物以得到白色固体状的3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯基氨基甲酸苄酯(10)(872mg,42%)。
LC-MS(ESI)m/z=393[M+H]+。
步骤4:(R)-3-(3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯基)-5-(羟甲基)噁唑烷-2-酮(11):
在-78℃和氮气氛下向3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯基氨基甲酸苄酯(10)(872mg,2.23mmol)在THF(10mL)中的溶液中加入n-BuLi(1.4ml,3.34mmol),然后将混合物在-78℃下搅拌30分钟,之后将丁酸(R)-环氧乙烷-2-基甲酯(480mg,3.34mmol)在THF中的溶液在-78℃下加至该混合物,然后加温至室温并搅拌过夜,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=70:1)纯化粗产物以得到白色固体状的(R)-3-(3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯基)-5-(羟甲基)噁唑烷-2-酮(11)(519mg,65%)。
LC-MS(ESI)m/z=359[M+H]+。
步骤5:4-甲基苯磺酸(R)-(3-(3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代噁唑烷-5-基)甲酯(12):
在0℃和氮气氛下将4-甲基苯-1-磺酰氯(550mg,2.9mmol)加至(R)-3-(3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯基)-5-(羟甲基)噁唑烷-2-酮(11)(519mg,1.45mmol)和Et3N(292mg,2.9mmol)在DCM(10mL)中的悬液中,并将反应混合物在室温下搅拌过夜,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=50:1)纯化粗产物以得到白色固体状的4-甲基苯磺酸(R)-(3-(3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代噁唑烷-5-基)甲酯(12)(594mg,80%)。
LC-MS(ESI)m/z=513[M+H]+。
步骤6:(R)-5-(叠氮基甲基)-3-(3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮(13):
在25℃下向4-甲基苯磺酸(R)-(3-(3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代噁唑烷-5-基)甲酯(12)(594g,1.2mmol)和叠氮化钠(75mg,1.2mmol)在DMF(10mL)中的溶液中加入K2CO3(160mg,2.4mmol),然后将反应混合物在80℃和氮气氛下搅拌1小时,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(PE:EA=2:1)纯化粗产物以得到白色固体状的(R)-5-(叠氮基甲基)-3-(3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮(13)(400mg,87%)。
LC-MS(ESI)m/z=384[M+H]+。
步骤7:(S)-5-(氨甲基)-3-(3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮(14):
在25℃下向(R)-5-(叠氮基甲基)-3-(3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮(13)(400g,1.04mmol)在MeOH(10mL)中的溶液中加入钯碳(100mg),然后将反应混合物在室温和氮气氛下搅拌过夜,通过TLC监测。减压浓缩滤液,并通过硅胶柱层析(DCM:MeOH=50:1)纯化粗产物以得到白色固体状的(S)-5-(氨甲基)-3-(3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮(14)(331g,89%)。
LC-MS(ESI)m/z=358[M+H]+。
步骤8:(S)-N-((3-(3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺(OBD-026):
在25℃下向(S)-5-(氨甲基)-3-(3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮(14)(165mg,0.46mmol)和丁酸(52mg,0.46mmol)在DCM(10mL)中的溶液中加入HOBt(95mg,0.7mmol)、EDCI(175mg,0.92mmol)和DIPEA(118mg,0.92mmol),然后将反应混合物在25℃和氮气氛下搅拌2小时,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=80:1)纯化粗产物以得到白色固体状的(S)-N-((3-(3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺(OBD-026)(82mg,42%)。
1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.14(d,J=11.1Hz,1H),5.93(s,1H),4.81(s,1H),4.02(t,J=8.9Hz,1H),3.70(s,2H),3.31(s,3H),2.87(s,2H),2.22(s,2H),1.90(s,5H),1.66(d,J=7.3Hz,2H),0.93(t,J=7.4Hz,2H)。
LC-MS(ESI)m/z=428[M+H]+。
步骤9:N-(((S)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺(OBD-027):
在25℃下向(S)-5-(氨甲基)-3-(3,5-二氟-4-(1,5-硫氮杂环辛-5-基)苯基)噁唑烷-2-酮(14)(165mg,0.46mmol)和丁酸(52mg,0.46mmol)在DCM(10mL)中的溶液中加入HOBt(95mg,0.7mmol)、EDCI(175mg,0.92mmol)和DIPEA(118mg,0.92mmol),然后将反应混合物在25℃和氮气氛下搅拌2小时,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=80:1)纯化粗产物以得到白色固体状的N-(((S)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺(OBD-027)(82mg,45%)。
1H NMR(301MHz,CDCl3)δ7.23–6.85(m,2H),6.00(s,1H),4.90–4.66(m,1H),4.17–3.86(m,1H),3.71(s,2H),3.28(s,2H),2.84(s,3H),2.04(s,3H),1.88(s,5H)。
LC-MS(ESI)m/z=400[M+H]+。
合成路线:
实验部分
四氢噻喃-4-酮肟(2)。
向四氢噻喃-4-酮(20g,172mmol)在EtOH(150mL)和H2O(50mL)中的溶液中加入NH2OH-HCl(11.9g,172mmol),然后将反应混合物在75℃和氮气氛下搅拌4小时,然后将混合物浓缩并干燥以得到棕色固体状的四氢噻喃-4-酮肟(2)(14.7g,66%)。
1,4-硫氮杂环庚-5-酮(3)。
将四氢噻喃-4-酮肟(2)(14.7g,112mmol)和多聚磷酸(50g)的混合物在70℃下搅拌2小时。将反应混合物冷却至室温并倒入冰水中,使用碳酸钾溶液调整至pH=8,用EA萃取,减压浓缩有机层以得到棕色固体状的1,4-硫氮杂环庚-5-酮(3)(11.9g粗产物,81%)。
1,4-硫氮杂环庚烷(4)。
在0℃下向1,4-硫氮杂环庚-5-酮(3)(11.9g,105mmol)在THF(100mL)中的溶液中加入THF中的BH3(158mL,158mol),然后回流12小时。用CH3OH(50mL)淬灭反应。将溶剂蒸发以得到白色油状的1,4-硫氮杂环庚烷(4)(10.7g,87%),并且粗产物不经进一步纯化而用于下一反应。
LC-MS(ESI)m/z=118[M+H]+。
步骤1:4-(2-氟-4-硝基苯基)-1,4-硫氮杂环庚烷(6)的制备:
在25℃下向1,4-硫氮杂环庚烷(4)(7g,59.8mmol)和1,2-二氟-4-硝基苯(10.4g,65.8mmol)在DMF(10mL)中的溶液中加入K2CO3(16.5g,119.6mmol),然后将反应混合物在80℃和氮气氛下搅拌2小时,通过TLC监测。减压浓缩混合物,并通过硅胶柱层析(EA:PE=3:1)纯化粗产物以得到黄色固体状的4-(2-氟-4-硝基苯基)-1,4-硫氮杂环庚烷(6)(10g,65%)。
LC-MS(ESI)m/z=257[M+H]+。
步骤2:3-氟-4-(1,4-硫氮杂环庚-4-基)苯胺(7):
向4-(2-氟-4-硝基苯基)-1,4-硫氮杂环庚烷(6)(8g,31.2mmol)和钯碳(500mg)在MeOH(15mL)中的溶液中,然后将反应混合物在室温和氢气氛下搅拌过夜,通过TLC监测。减压浓缩滤液以得到白色油状的3-氟-4-(1,4-硫氮杂环庚-4-基)苯胺(7)(6.4g,93%),并且粗产物不经进一步纯化而用于下一反应。
LC-MS(ESI)m/z=227[M+H]+。
步骤3:3-氟-4-(1,4-硫氮杂环庚-4-基)苯基氨基甲酸苄酯(8):
在-20℃和氮气氛下将氯甲酸苄酯(9.6g,56.6mmol)加至3-氟-4-(1,4-硫氮杂环庚-4-基)苯胺(7)(6.4g,28.3mmol)和三乙胺(5.7g,56.6mmol)在DCM(200mL)中的悬液中,然后将反应混合物在0℃下搅拌30分钟,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(EA:PE=10:1)纯化粗产物以得到白色油状的3-氟-4-(1,4-硫氮杂环庚-4-基)苯基氨基甲酸苄酯(8)(2.34g,23%)。
LC-MS(ESI)m/z=361[M+H]+。
步骤4:(R)-3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)-5-(羟甲基)噁唑烷-2-酮(9):
在-78℃和氮气氛下向3-氟-4-(1,4-硫氮杂环庚-4-基)苯基氨基甲酸苄酯(8)(2.34g,6.5mmol)在THF(10mL)中的溶液中加入n-BuLi(4ml,9.7mmol),然后将混合物在-78℃下搅拌30分钟,之后在-78℃下将丁酸(R)-环氧乙烷-2-基甲酯(1.4g,9.7mmol)在THF中的溶液加至该混合物,然后加温至室温并搅拌过夜,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=70:1)纯化粗产物以得到白色固体状的(R)-3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)-5-(羟甲基)噁唑烷-2-酮(9)(1.16g,55%)。
LC-MS(ESI)m/z=327[M+H]+。
步骤5:4-甲基苯磺酸(R)-(3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)-2-氧代噁唑烷-5-基)甲酯(10):
在0℃和氮气氛下将4-甲基苯-1-磺酰氯(1.4g,7.2mmol)加至(R)-3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)-5-(羟甲基)噁唑烷-2-酮(9)(1.16g,3.6mmol)和Et3N(727mg,7.2mmol)在DCM(10mL)中的悬液中,并将反应混合物在室温下搅拌过夜,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=50:1)纯化粗产物以得到白色固体状的4-甲基苯磺酸(R)-(3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)-2-氧代噁唑烷-5-基)甲酯(10)(1.41g,41%)。
LC-MS(ESI)m/z=481[M+H]+。
步骤1:(R)-5-(叠氮基甲基)-3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)噁唑烷-2-酮(11):
在25℃下向4-甲基苯磺酸(R)-(3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)-2-氧代噁唑烷-5-基)甲酯(10)(1.41g,2.95mmol)和叠氮化钠(190mg,2.95mmol)在DMF(10mL)中的溶液中加入K2CO3(814g,5.9mmol),然后将反应混合物在80℃和氮气氛下搅拌1小时,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(PE:EA=2:1)纯化粗产物以得到白色固体状的(R)-5-(叠氮基甲基)-3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)噁唑烷-2-酮(11)(830mg,80%)。
LC-MS(ESI)m/z=352[M+H]+。
步骤2:(S)-5-(氨甲基)-3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)噁唑烷-2-酮(12):
在25℃下向(R)-5-(叠氮基甲基)-3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)噁唑烷-2-酮(11)(830mg,2.4mmol)在MeOH(10mL)中的溶液中加入钯碳(100mg),然后将反应混合物在室温和氢气氛下搅拌过夜,通过TLC监测。减压浓缩滤液,并通过硅胶柱层析(DCM:MeOH=50:1)纯化粗产物以得到白色固体状的(S)-5-(氨甲基)-3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)噁唑烷-2-酮(12)(654mg,85%)。
LC-MS(ESI)m/z=326[M+H]+。
在25℃下向(S)-5-(氨甲基)-3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)噁唑烷-2-酮(12)(654mg,2mmol)和丁酸(177mg,2mmol)在DCM(10mL)中的溶液中加入HOBt(405mg,3mmol)、EDCI(764mg,4mmol)和DIPEA(516mg,4mmol),然后将反应混合物在25℃和氮气氛下搅拌2小时,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=80:1)纯化粗产物以得到白色固体状的(S)-N-((3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺(OBD-005)(286mg,34%)。
1H NMR(300MHz,CDCl3)δ7.42–7.23(m,2H),7.01(dd,J=8.9,2.3Hz,1H),6.04(s,1H),4.75(ddd,J=9.0,7.9,4.6Hz,1H),4.00(t,J=9.0Hz,1H),3.79–3.05(m,7H),2.91(dd,J=16.2,10.1Hz,2H),2.70(t,J=6.3Hz,2H),2.28–2.13(m,2H),2.13–1.97(m,2H),1.82–1.25(m,3H),0.92(t,J=7.4Hz,3H),0.01(s,1H)。
LC-MS(ESI)m/z=395.9[M+H]+。
步骤4:(OBD-006和OBD-007)的制备:
在0℃下向(S)-N-((3-(3-氟-4-(1,4-硫氮杂环庚-4-基)苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺(OBD-005)(150mg,0.38mmol)在THF(10mL)和10滴水中的溶液中加入过氧单磺酸钾(233mg,0.38mmol),然后将反应混合物在0℃下搅拌2小时,通过TLC监测。用硫代硫酸钠淬灭,并通过制备型HPLC纯化粗产物以得到白色固体状的(OBD-006)(50mg,32%)和白色固体状的(OBD-007)(24mg,15%)。
(OBD-006)
1H NMR(301MHz,CDCl3)δ7.52(d,J=15.0Hz,1H),7.16(s,1H),7.03(d,J=8.7Hz,1H),5.99(s,1H),4.78(s,1H),4.02(t,J=8.8Hz,2H),3.88–3.56(m,3H),3.55–2.92(m,7H),2.77(s,1H),2.20(t,J=7.1Hz,3H),1.64(dd,J=14.9,7.4Hz,2H),0.91(t,J=7.4Hz,3H)。
LC-MS(ESI)m/z=411.8[M+H]+。
(OBD-007)
1H NMR(301MHz,CDCl3)δ7.51(d,J=14.7Hz,1H),7.10(d,J=9.9Hz,2H),5.92(s,1H),4.78(s,1H),4.03(t,J=9.0Hz,1H),3.87–3.39(m,7H),3.27(d,J=5.7Hz,2H),2.39(d,J=6.2Hz,2H),2.20(t,J=7.2Hz,2H),1.64(dd,J=14.8,7.4Hz,2H),0.92(t,J=7.3Hz,3H)。
LC-MS(ESI)m/z=427.8[M+H]+。
R的制备程序:
步骤1:(2S,5R)-1-苄基吡咯烷-2,5-二甲酸二乙酯(2)的制备:
将(2R,5S)-2,5-二溴己二酸二乙酯(1)(100g,278mmol)、BnNH2(44.6g,416mmol)和K2CO3(76.84g,556mmol)在甲苯/H2O中的混合物在110℃下搅拌过夜,通过TLC监测。用EtOAc萃取混合物,用水和盐水洗涤,然后经无水硫酸钠干燥,过滤,并减压浓缩以得到白色油状的(2S,5R)-1-苄基吡咯烷-2,5-二甲酸二乙酯(2)(63.75g,75%)。
LC-MS(ESI)m/z=306[M+H]+。
步骤2:(2S,5R)-吡咯烷-2,5-二甲酸二乙酯(3):
向(2S,5R)-1-苄基吡咯烷-2,5-二甲酸二乙酯(2)(63.75g,209mmol)和钯碳(2g)在MeOH(15mL)中的溶液中加入CH3COOH(5mL),然后将反应混合物在50℃和氢气氛,4atm下搅拌5小时,通过TLC监测。减压浓缩滤液,并且粗产物不经进一步纯化而用于下一反应。
LC-MS(ESI)m/z=216[M+H]+。
步骤3:(2S,5R)-吡咯烷-1,2,5-三甲酸1-苄2,5-二乙酯(4):
在-20℃和氮气氛下向(2S,5R)-吡咯烷-2,5-二甲酸二乙酯(3)(62g,288mmol)和Et3N(58g,577mmol)在DCM(100mL)中的溶液中加入氯甲酸苄酯(98g,577mmol),然后将反应混合物在室温下搅拌5小时,通过TLC监测。用DCM萃取混合物,用水和盐水洗涤,然后经无水硫酸钠干燥,过滤,并减压浓缩以得到白色油状的(2S,5R)-吡咯烷-1,2,5-三甲酸1-苄2,5-二乙酯(4)(80g,80%)。
LC-MS(ESI)m/z=350[M+H]+。
步骤4:(2S,5R)-2,5-双(羟甲基)吡咯烷-1-甲酸苄基(5):
在室温和氮气氛下将CaCl2(76g,688mmol)和NaBH4(43g,1146mmol)加至(2S,5R)-吡咯烷-1,2,5-三甲酸1-苄2,5-二乙酯(4)(80g,229mmol)在EtOH-MeOH(9:1;200mL)中的搅拌溶液中,然后将反应混合物搅拌5小时,通过TLC监测。加入H2O(5mL),并将混合物进一步搅拌15分钟。然后真空浓缩混合物。用EtOAc萃取该混合物,然后经无水硫酸钠干燥,过滤,并减压浓缩以得到白色油状的(2S,5R)-2,5-双(羟甲基)吡咯烷-1-甲酸苄酯(5)(32g,52%)。
LC-MS(ESI)m/z=266[M+H]+。
步骤5:(2S,5R)-2,5-双(对甲苯磺酰氧甲基)吡咯烷-1-甲酸苄酯(6):
在0℃和氮气氛下将4-甲基苯-1-磺酰氯(92g,483mmol)加至(2S,5R)-2,5-双(羟甲基)吡咯烷-1-甲酸苄酯(5)(32g,121mmol)和Et3N在DCM(200mL)中的搅拌溶液中,然后可将反应混合物加温至室温并搅拌5小时,通过TLC监测。用DCM萃取混合物,然后经无水硫酸钠干燥,过滤并减压浓缩,并通过硅胶柱层析(EA:PE=2:1)纯化粗产物以得到白色固体状的(2S,5R)-2,5-双(对甲苯磺酰氧甲基)吡咯烷-1-甲酸苄酯(6)(30g,43%)。
LC-MS(ESI)m/z=574[M+H]+。
步骤6:8-苄基-3-硫杂-8-氮杂-二环[3.2.1]辛烷-1-甲酸酯(7):
在室温下将硫化钠水合物(38g,157mmol)加至(2S,5R)-2,5-双(对甲苯磺酰氧甲基)吡咯烷-1-甲酸苄酯(6)(30g,50mmol)在EtOH(50mL)和水(50mL)中的搅拌溶液中,然后将反应混合物在90℃下搅拌2小时,通过TLC监测。用DCM萃取混合物,然后经无水硫酸钠干燥,过滤并减压浓缩,并通过硅胶柱层析(EA:PE=10:1)纯化粗产物以得到白色固体状的8-苄基-3-硫杂-8-氮杂-二环[3.2.1]辛烷-1-甲酸酯(7)(10g,73%)。
LC-MS(ESI)m/z=264[M+H]+.
步骤7:3-硫杂-8-氮杂-二环[3.2.1]辛烷碘化氢(8):
在0℃和氮气氛下将三甲基碘硅烷(15g,75mmol)加至8-苄基-3-硫杂-8-氮杂-二环[3.2.1]辛烷-1-甲酸酯(7)(10g,38mmol)在DCM(200mL)中的搅拌溶液中,然后使反应混合物加温至室温并搅拌30分钟,通过TLC监测。用DCM萃取混合物,然后经无水硫酸钠干燥,过滤并减压浓缩,并通过硅胶柱层析(DCM:MeOH=15:1)纯化粗产物以得到棕色固体状的3-硫杂-8-氮杂-二环[3.2.1]辛烷碘化氢(8)(8.13g,84%)。
LC-MS(ESI)m/z=130[M+H]+
步骤1:8-(2-氟-4-硝基苯基)-3-硫杂-8-氮杂-二环[3.2.1]辛烷(10)的制备:
在25℃和氮气氛下向3-硫杂-8-氮杂-二环[3.2.1]辛烷碘化氢(8)(5.58g,21.7mmol)和1,2-二氟-4-硝基苯(3.8g,23.8mmol)在DMF(10mL)中的溶液中加入K2CO3(6g,43.4mmol),并将反应混合物在80℃下搅拌2小时,通过TLC监测。减压浓缩混合物,并通过硅胶柱层析(EA:PE=3:1)纯化粗产物以得到黄色固体状的8-(2-氟-4-硝基苯基)-3-硫杂-8-氮杂-二环[3.2.1]辛烷(10)(4.89g,84%)。
LC-MS(ESI)m/z=269[M+H]+。
步骤2:4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯胺(11):
向8-(2-氟-4-硝基苯基)-3-硫杂-8-氮杂-二环[3.2.1]辛烷(10)(4.89g,18.2mmol)和钯碳(200mg)在MeOH(15mL)中的溶液中,然后将反应混合物在室温和氢气氛下搅拌过夜,通过TLC监测。减压浓缩滤液以得到白色油状的4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯胺(11)(4.08g,94%),并且粗产物不经进一步纯化而用于下一反应。
LC-MS(ESI)m/z=239[M+H]+。
步骤3:4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基氨基甲酸苄酯(12):
在0℃和氮气氛下将碳酸,2,5-二氧代-1-吡咯烷基苯甲基酯(6.38g,25.6mmol)加至4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯胺(11)(4.08g,17.1mmol)在THF(30mL)中的悬液中,并将反应混合物在50℃下搅拌5小时,通过TLC监测。减压浓缩混合物,并通过硅胶柱层析(EA:PE=10:1)纯化粗产物以得到白色固体状的4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基氨基甲酸苄酯(12)(4.34g,68%)。
LC-MS(ESI)m/z=373[M+H]+。
在-78℃和氮气氛下向4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基氨基甲酸苄酯(12)(4.34g,11.6mmol)在THF(10mL)中的溶液中加入n-BuLi(7.3ml,17.5mmol),然后将混合物在-78℃下搅拌30分钟,之后在-78℃下将丁酸(R)-环氧乙烷-2-基甲酯(2.5g,17.4mmol)在THF中的溶液加至该混合物,然后加温至室温并搅拌过夜,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=70:1)纯化粗产物以得到白色固体状的(5R)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)-5-(羟甲基)噁唑烷-2-酮(13)(3.03g,77%)。
LC-MS(ESI)m/z=339[M+H]+。
步骤5:4-甲基苯磺酸((R)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)-2-氧代噁唑烷-5-基)甲酯(14):
在0℃和氮气氛下将4-甲基苯-1-磺酰氯(3.41g,17.9mmol)加至(5R)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)-5-(羟甲基)噁唑烷-2-酮(13)(3.03g,8.9mmol)和Et3N(1.8g,17.9mmol)在DCM(10mL)中的悬液中,并将反应混合物在室温下搅拌过夜,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=50:1纯化粗产物以得到)白色固体状的4-甲基苯磺酸((R)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)-2-氧代噁唑烷-5-基)甲酯(14)(3.74g,85%)。
LC-MS(ESI)m/z=493[M+H]+。
步骤6:(5R)-5-((1H-1,2,4-三唑-1-基)甲基)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)噁唑烷-2-酮(OBD-021):
在25℃下向4-甲基苯磺酸((R)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)-2-氧代噁唑烷-5-基)甲酯(14)(500mg,1mmol)和1H-1,2,4-三唑(140mg,2mmol)在DMF(10mL)中的溶液中加入K2CO3(280mg,2mmol),然后将反应混合物在80℃和氮气氛下搅拌2小时,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(EA:PE=2:1)纯化粗产物以得到白色固体状的(5R)-5-((1H-1,2,4-三唑-1-基)甲基)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)噁唑烷-2-酮(OBD-021)(177mg,45%)。
1H NMR(300MHz,DMSO-d6)δ8.57(s,1H),8.01(s,1H),7.36(dd,J=15.8,2.1Hz,1H),7.18–6.92(m,2H),5.06(dd,J=8.9,4.8Hz,1H),4.72–4.52(m,2H),4.36(s,2H),4.17(t,J=9.1Hz,1H),3.84(dt,J=49.3,24.7Hz,1H),3.12(d,J=12.8Hz,2H),2.16(s,1H),2.11(s,1H),2.04(s,4H)。
LC-MS(ESI)m/z=390[M+H]+。
步骤7:(OBD-018)的制备:
在0℃下向(5R)-5-((1H-1,2,4-三唑-1-基)甲基)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)噁唑烷-2-酮(OBD-021)(100mg,0.26mmol)在THF(10mL)和10滴水中的溶液中加入过氧单磺酸钾(157mg,0.26mmol),然后将反应混合物在0℃下搅拌2小时,通过TLC监测。用硫代硫酸钠淬灭,并通过硅胶柱层析(DCM:MeOH=80:1)纯化粗产物以得到白色固体状的(OBD-018)(52mg,50%)。
1H NMR(300MHz,DMSO-d6)δ12.17(s,1H),8.69(d,J=2.9Hz,1H),8.20–8.03(m,1H),7.44(d,J=16.2Hz,1H),7.28–7.02(m,2H),5.08(dd,J=8.5,5.1Hz,1H),4.68–4.52(m,4H),4.20(t,J=9.1Hz,1H),3.91(dd,J=8.7,6.0Hz,1H),3.56(d,J=11.1Hz,2H),2.48(d,J=12.3Hz,2H),2.06(d,J=5.1Hz,2H),1.79(d,J=7.6Hz,2H)。
LC-MS(ESI)m/z=405.8[M+H]+。
步骤1:(5R)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)-5-(叠氮基甲基)噁唑烷-2-酮(15):
在25℃下向4-甲基苯磺酸((R)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)-2-氧代噁唑烷-5-基)甲酯(14)(2g,4mmol)和叠氮化钠(265mg,4mmol)在DMF(10mL)中的溶液中加入K2CO3(1.1g,8mmol),然后将反应混合物在80℃和氮气氛下搅拌1小时,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(PE:EA=2:1)纯化粗产物以得到白色固体状的(5R)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)-5-(叠氮基甲基)噁唑烷-2-酮(15)(1.01g,70%)。
LC-MS(ESI)m/z=364[M+H]+。
步骤2:(5S)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)-5-(氨甲基)噁唑烷-2-酮(OBD-081):
在25℃下向(5R)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)-5-(叠氮基甲基)噁唑烷-2-酮(15)(1.01g,2.8mmol)在MeOH(10mL)中的溶液中加入钯碳(100mg),然后将反应混合物在室温和氢气氛下搅拌过夜,通过TLC监测。减压浓缩滤液,并通过硅胶柱层析(DCM:MeOH=50:1)纯化粗产物以得到白色固体状的(5S)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)-5-(氨甲基)噁唑烷-2-酮(OBD-081)(800mg,85%)。
LC-MS(ESI)m/z=338[M+H]+。
步骤3:N-(((S)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺(OBD-016):
在25℃下向(5S)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)-5-(氨甲基)噁唑烷-2-酮(OBD-081)(200mg,0.59mmol)和丁酸(52mg,0.59mmol)在DCM(10mL)中的溶液中加入HOBt(95mg,0.7mmol)、EDCI(170mg,0.88mmol)和DIPEA(115mg,0.88mmol),然后将反应混合物在25℃和氮气氛下搅拌2小时,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=80:1)纯化粗产物以得到白色固体状的N-(((S)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺(OBD-016)(156mg,65%)。
1H NMR(300MHz,DMSO-d6)δ8.18(s,1H),7.42(d,J=16.0Hz,1H),7.35–6.88(m,2H),4.71(s,1H),4.35(s,2H),4.07(t,J=8.7Hz,1H),3.77–3.57(m,1H),3.51–3.27(m,2H),3.12(d,J=12.4Hz,2H),2.09(dd,J=20.9,12.2Hz,8H),1.47(dd,J=14.0,7.1Hz,2H),0.80(dd,J=8.0,6.7Hz,3H)。
LC-MS(ESI)m/z=407.9[M+H]+。
步骤4:(OBD-017)的制备:
在0℃下向N-(((S)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺(OBD-016)(100mg,0.25mmol)在THF(10mL)和10滴水中的溶液中加入过氧单磺酸钾(157mg,0.26mmol),然后将反应混合物在0℃下搅拌2小时,通过TLC监测。用硫代硫酸钠淬灭,并通过制备型HPLC纯化粗产物以得到白色固体状的(OBD-017)(16mg,15%)。
1H NMR(301MHz,CDCl3)δ7.39(dd,J=15.8,2.3Hz,1H),7.03(d,J=6.1Hz,2H),6.78(t,J=9.3Hz,1H),4.72(s,1H),4.55(s,2H),3.94(t,J=8.9Hz,1H),3.81–3.66(m,1H),3.58(s,2H),3.42(d,J=10.3Hz,2H),2.77(d,J=11.9Hz,2H),2.17(dd,J=25.1,17.8Hz,4H),1.84(d,J=7.9Hz,2H),1.56(dq,J=14.5,7.2Hz,2H),0.83(t,J=7.4Hz,3H)。
LC-MS(ESI)m/z=423.8[M+H]+。
步骤4:(OBD-085)的制备:
在0℃下向(5S)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3-氟苯基)-5-(氨甲基)噁唑烷-2-酮(OBD-081)(100mg,0.29mmol)在THF(10mL)和10滴水中的溶液中加入过氧单磺酸钾(182mg,0.29mmol),然后将反应混合物在0℃下搅拌2小时,通过TLC监测。用硫代硫酸钠淬灭,并通过制备型HPLC纯化粗产物以得到白色固体状的(OBD-085)(28mg,28%)。
1H NMR(400MHz,DMSO-d6)δ7.52(dd,J=16.4,2.2Hz,1H),7.24(dd,J=8.9,2.0Hz,1H),7.13(t,J=9.6Hz,1H),4.58(dd,J=14.1,4.9Hz,3H),4.04(t,J=8.9Hz,1H),3.84(dd,J=8.7,6.5Hz,1H),3.56(d,J=10.0Hz,2H),2.81(dd,J=9.3,4.9Hz,2H),2.46(s,2H),2.17–1.99(m,2H),1.79(dd,J=17.3,9.5Hz,4H)。
LC-MS(ESI)m/z=354[M+H]+。
步骤1:8-(2,6-二氟-4-硝基苯基)-3-硫杂-8-氮杂-二环[3.2.1]辛烷(10)的制备:
在25℃下向3-硫杂-8-氮杂-二环[3.2.1]辛烷碘化氢(8)(5.0g,19.4mmol)和1,2,3-三氟-5-硝基苯(4.13g,23.3mmol)在DMF(10mL)中的溶液中加入K2CO3(5.35g,38.8mmol),然后将反应混合物在80℃和氮气氛下搅拌2小时,通过TLC监测。减压浓缩混合物,并通过硅胶柱层析(EA:PE=3:1)纯化粗产物以得到黄色固体状的8-(2,6-二氟-4-硝基苯基)-3-硫杂-8-氮杂-二环[3.2.1]辛烷(10)(3.6g,65%)。
LC-MS(ESI)m/z=287[M+H]+。
步骤2:4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯胺(11):
碳(200mg)在MeOH(15mL)中的溶液中,然后将反应混合物在室温和氢气氛下搅拌过夜,通过TLC监测。减压浓缩滤液以得到白色油状的4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯胺(11)(2.9g,90%),并且粗产物不经进一步纯化而用于下一反应。
LC-MS(ESI)m/z=257[M+H]+。
步骤3:4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基氨基甲酸苄酯(12):
在0℃和氮气氛下将碳酸,2,5-二氧代-1-吡咯烷基苯甲基酯(5.57g,22.4mmol)加至4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯胺(11)(2.9g,11.2mmol)在THF(30mL)中的悬液中,并将反应混合物在50℃下搅拌5小时,通过TLC监测。减压浓缩混合物,并通过硅胶柱层析(EA:PE=10:1)纯化粗产物以得到白色固体状的4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基氨基甲酸苄酯(12)(3.0g,68%)。
LC-MS(ESI)m/z=391[M+H]+。
步骤4:(5R)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-5-(羟甲基)噁唑烷-2-酮(13):
在-78℃和氮气氛下向4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基氨基甲酸苄酯(12)(3.0g,7.7mmol)在THF(10mL)中的溶液中加入n-BuLi(4.8ml,11.5mmol),然后将混合物在-78℃下搅拌30分钟,之后在-78℃下将丁酸(R)-环氧乙烷-2-基甲酯(1.66g,11.5mmol)在THF中的溶液加至该混合物,然后加温至室温并搅拌过夜,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=70:1)纯化粗产物以得到白色固体状的(5R)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-5-(羟甲基)噁唑烷-2-酮(13)(2.3g,84%)。
LC-MS(ESI)m/z=357[M+H]+。
在0℃和氮气氛下将4-甲基苯-1-磺酰氯(2.45g,13mmol)加至(5R)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-5-(羟甲基)噁唑烷-2-酮(13)(2.3g,6.5mmol)和Et3N(1.3g,13mmol)在DCM(10mL)中的悬液中,并将反应混合物在室温下搅拌过夜,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=50:1)纯化粗产物以得到白色固体状的4-甲基苯磺酸((R)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-2-氧代噁唑烷-5-基)甲酯(14)(2.81g,85%)。
LC-MS(ESI)m/z=511[M+H]+。
步骤6:(5R)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-5-(叠氮基甲基)噁唑烷-2-酮(15):
在25℃下向4-甲基苯磺酸((R)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-2-氧代噁唑烷-5-基)甲酯(14)(2.81g,5.52mmol)和叠氮化钠(360mg,5.52mmol)在DMF(10mL)中的溶液中加入K2CO3(1.52mg,11.04mmol),然后将反应混合物在80℃和氮气氛下搅拌1小时,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(PE:EA=2:1)纯化粗产物以得到白色固体状的(5R)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-5-(叠氮基甲基)噁唑烷-2-酮(15)(1.85g,88%)。
LC-MS(ESI)m/z=382[M+H]+。
步骤7:(5S)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-5-(氨甲基)噁唑烷-2-酮(OBD-083):
在25℃下向(5R)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-5-(叠氮基甲基)噁唑烷-2-酮(15)(1.85g,4.87mmol)在MeOH(10mL)中的溶液中加入钯碳(100mg),然后将反应混合物在室温和氢气氛下搅拌过夜,通过TLC监测。减压浓缩滤液,并通过硅胶柱层析(DCM:MeOH=50:1)纯化粗产物以得到白色固体状的(5S)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-5-(氨甲基)噁唑烷-2-酮(OBD-083)(1.6g,90%)。
1H NMR(400MHz,DMSO)δ7.34–7.15(m,2H),4.59(td,J=11.0,5.0Hz,1H),4.10(s,2H),3.99(t,J=8.9Hz,1H),3.79(dd,J=8.9,6.4Hz,1H),3.11(dd,J=12.6,1.6Hz,2H),2.79(qd,J=13.7,4.9Hz,2H),2.26(dd,J=12.4,3.3Hz,2H),2.01(s,4H),1.72(d,J=59.8Hz,2H)。
LC-MS(ESI)m/z=356[M+H]+。
步骤8:(OBD-087)的制备:
在0℃下向(5S)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-5-(氨甲基)噁唑烷-2-酮(OBD-083)(100mg,0.28mmol)在THF(10mL)和10滴水中的溶液中加入过氧单磺酸钾(173mg,0.28mmol),然后将反应混合物在0℃下搅拌2小时,通过TLC监测。用硫代硫酸钠淬灭,并通过制备型HPLC纯化粗产物以得到白色固体状的(OBD-087)(31mg,30%)。
1H NMR(400MHz,DMSO)δ7.32(t,J=9.4Hz,2H),4.61(dd,J=8.8,6.0Hz,0H),4.34(s,1H),4.02(t,J=8.9Hz,1H),3.82(dd,J=8.9,6.4Hz,1H),3.68(dd,J=12.4,3.7Hz,1H),2.81(qd,J=13.7,4.9Hz,1H),2.58(d,J=11.6Hz,1H),2.12–1.98(m,1H),1.78(q,J=6.9Hz,2H)。
LC-MS(ESI)m/z=372[M+H]+。
步骤9:N-(((S)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺(OBD-029):
在25℃下向(5S)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-5-(氨甲基)噁唑烷-2-酮(OBD-083)(200mg,0.56mmol)和丁酸(52mg,0.59mmol)在DCM(10mL)中的溶液中加入HOBt(95mg,0.7mmol)、EDCI(170mg,0.88mmol)和DIPEA(115mg,0.88mmol),然后将反应混合物在25℃和氮气氛下搅拌2小时,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=80:1)纯化粗产物以得到白色固体状的N-(((S)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺(OBD-029)(119mg,50%)。
1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.22(d,J=12.2Hz,2H),4.73(d,J=3.6Hz,1H),4.07(dd,J=19.1,10.0Hz,3H),3.68(dd,J=9.1,6.2Hz,1H),3.41(s,2H),3.12(d,J=11.3Hz,2H),2.26(dd,J=12.4,3.0Hz,2H),2.05(dd,J=16.8,9.5Hz,6H),1.47(dd,J=14.7,7.3Hz,2H),0.79(t,J=7.4Hz,3H)。
LC-MS(ESI)m/z=426[M+H]+。
步骤10:(OBD-242)的制备:
在0℃下向N-(((S)-3-(4-(3-硫杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-2-氧代噁唑烷-5-基)甲基)丁酰胺(OBD-029)(100mg,0.23mmol)在THF(10mL)和10滴水的溶液中加入过氧单磺酸钾(144mg,0.23mmol),然后将反应混合物在0℃下搅拌2小时,通过TLC监测。用硫代硫酸钠淬灭,并通过制备型HPLC纯化粗产物以得到白色固体状的(OBD-242)(30mg,15%)。
1H NMR(400MHz,DMSO-d6)δ8.19(d,J=5.6Hz,1H),7.28(d,J=12.7Hz,3H),4.77–4.69(m,1H),4.34(s,2H),4.07(t,J=9.0Hz,1H),3.67(d,J=9.0Hz,3H),3.40(dd,J=11.0,5.5Hz,1H),2.56(d,J=11.9Hz,1H),2.06(t,J=7.3Hz,4H),1.82–1.72(m,2H),1.51–1.40(m,2H),0.78(t,J=7.4Hz,3H)。
LC-MS(ESI)m/z=442[M+H]+。
步骤1:(3)的制备:
在25℃下向对甲苯磺酰胺(57g,330mmol)和氢氧化钾(49.8g,890mmol)在乙醇(1000mL)中的溶液中加入3-溴-2,2-双(溴甲基)丙-1-醇(90g,270mmol),然后将反应混合物在100℃下搅拌48小时。减压浓缩混合物,将粗产物倒入氢氧化钾溶液(75mL)中并搅拌2小时,以得到白色固体状的滤饼(3)(10g,59%)。
LC-MS(ESI)m/z=254[M+H]+。
步骤2:(4)的制备:
在40℃下将(3)(10g,39.5mmol)和镁(6.7g)在甲醇(15mL)中的混合物超声1小时,之后减压除去溶剂以得到粘性灰色残余物,加入Et2O和硫酸钠,并在过滤前将所得的灰色混合物剧烈搅拌30分钟。将草酸在乙醇中的溶液加至滤液。立即形成浓稠的白色沉淀物,其为目标产物(4)(3.7g,50%),并且粗产物不经进一步纯化而用于下一反应。
步骤3:(5)的制备:
在25℃下向(4)(3.7g,19.5mmol)和1,2,3-三氟-5-硝基苯(3.81g,21.5mmol)在DMF(10mL)中的溶液中加入K2CO3(5.38g,39mmol),然后将反应混合物在80℃和氮气氛下搅拌2小时,通过TLC监测。减压浓缩混合物,并通过硅胶柱层析(EA:PE=3:1)纯化粗产物以得到黄色固体状的(5)(1.9g,38%)。
LC-MS(ESI)m/z=257[M+H]+。
步骤4:(6)的制备:
向(5)(1.9g,7.4mmol)和钯碳(200mg)在甲醇(15mL)中的溶液中,然后将反应混合物在室温和氢气氛下搅拌过夜,通过TLC监测。减压浓缩滤液以得到白色油状的(6)(1.5g,90%),并且粗产物不经进一步纯化而用于下一反应。
LC-MS(ESI)m/z=227[M+H]+。
步骤5:(7)的制备:
在0℃和氮气氛下将碳酸,2,5-二氧代-1-吡咯烷基苯甲基酯(3.3g,13.3mmol)加至(6)(1.5g,6.7mmol)在THF(30mL)中的悬液中,并将反应混合物在50℃下搅拌5小时,通过TLC监测。减压浓缩混合物,并通过硅胶柱层析(EA:PE=10:1)纯化粗产物以得到白色固体状的(7)(1.6g,68%)。
LC-MS(ESI)m/z=361[M+H]+。
步骤6:(8)的制备:
在-78℃和氮气氛下向(7)(1.6g,4.6mmol)在THF(10mL)中的溶液中加入n-BuLi(2.8ml,6.8mmol),然后将混合物在-78℃下搅拌30分钟,之后在-78℃下将丁酸(R)-环氧乙烷-2-基甲酯(980mg,6.8mmol)在THF中的溶液加至该混合物,然后加温至室温并搅拌过夜,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=70:1)纯化粗产物以得到白色固体状的(8)(1.2g,84%)。
LC-MS(ESI)m/z=327[M+H]+。
步骤7:(9)的制备:
在0℃和氮气氛下将(E)-N1,N1,N2-三甲基二氮烯-1,2-二甲酰胺(443mg,2.6mmol)加至(8)(560mg,1.7mmol)、异噁唑-3-基氨基甲酸叔丁酯(380mg,2.1mmol)和三丁基膦(521mg,2.6mmol)在甲苯(30mL)中的悬液中,然后将反应混合物在60℃下搅拌过夜,通过TLC监测。减压浓缩混合物,并通过硅胶柱层析(EA:PE=10:1)纯化粗产物以得到白色固体状的(9)(309mg,37%)。
LC-MS(ESI)m/z=493[M+H]+。
步骤8:(OBD-061)的制备:
在0℃下向(9)(309g,0.6mmol)在CH2Cl2(10mL)中的溶液中加入三氟乙酸(1mL),然后将混合物在0℃下搅拌30分钟,通过TLC监测。用氯化铵淬灭,用CH2Cl2萃取,减压浓缩有机层,并通过制备型HPLC纯化粗产物以得到白色固体状的(OBD-061)(93mg,38%)。
1H NMR(300MHz,CDCl3)δ8.07(s,1H),7.01(d,J=12.1Hz,2H),5.85(d,J=1.7Hz,1H),4.92(s,1H),4.82(s,4H),4.29(s,4H),3.99(s,2H),3.75(s,2H),3.60(s,2H)
LC-MS(ESI)m/z=392.9[M+H]+。
步骤1:(9)的制备:
在0℃下将4-甲基苯-1-磺酰氯(2.45g,13mmol)加至(8)(2.3g,6.5mmol)和Et3N(1.3g,13mmol)在DCM(10mL)中的悬液中,并将反应混合物在室温和氮气氛下搅拌过夜,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=50:1)纯化粗产物以得到白色固体状的(9)(2.65g,85%)。
LC-MS(ESI)m/z=481[M+H]+。
步骤2:(10)的制备:
在25℃下向(9)(2.65g,5.52mmol)和叠氮化钠(360mg,5.52mmol)in DMF(10mL)中的溶液中加入K2CO3(1.52mg,11.04mmol),然后将反应混合物在80℃和氮气氛下搅拌1小时,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(PE:EA=2:1)纯化粗产物以得到白色固体状的(10)(1.7g,88%)。
LC-MS(ESI)m/z=352[M+H]+。
步骤3:(OBD-062)的制备:
在25℃下向(10)(1.7g,4.86mmol)在MeOH(10mL)中的溶液中加入钯碳(100mg),然后将反应混合物在室温和氢气氛下搅拌过夜,通过TLC监测。减压浓缩滤液,并通过硅胶柱层析(DCM:MeOH=50:1)纯化粗产物以得到白色固体状的(OBD-062)(1.3g,85%)。1H NMR(400MHz,DMSO-d6)δ7.34–6.98(m,2H),4.70(s,4H),4.59(dt,J=11.3,5.1Hz,1H),4.23(d,J=2.2Hz,4H),3.99(dd,J=20.9,12.0Hz,1H),3.78(dd,J=8.9,6.4Hz,1H),2.80(ddd,J=24.5,13.6,4.9Hz,2H),1.99(s,2H)。
LC-MS(ESI)m/z=326.1[M+H]+。
步骤1:(3)的制备:
在25℃下向(1)(3.7g,19.5mmol)和1,2-二氟-4-硝基苯(3.41g,21.5mmol)在DMF(10mL)中的溶液中加入K2CO3(5.38g,39mmol),然后将反应混合物在80℃和氮气氛下搅拌2小时,通过TLC监测。减压浓缩混合物,并通过硅胶柱层析(EA:PE=3:1)纯化粗产物以得到黄色固体状的(3)(1.7g,38%)。
LC-MS(ESI)m/z=239[M+H]+。
步骤2:(4)的制备:
向(3)(1.7g,7.4mmol)和钯碳(200mg)在甲醇(15mL)中的溶液中,然后将反应混合物在室温和氢气氛下搅拌过夜,通过TLC监测。减压浓缩滤液以得到白色油状的(4)(1.4g,90%),并且粗产物不经进一步纯化而用于下一反应。
LC-MS(ESI)m/z=209[M+H]+。
步骤3:(7)的制备:
在0℃和氮气氛下将碳酸,2,5-二氧代-1-吡咯烷基苯甲基酯(3.3g,13.3mmol)加至(6)(1.4g,6.7mmol)在THF(30mL)中的悬液中,并将反应混合物在50℃下搅拌5小时,通过TLC监测。减压浓缩混合物,并通过硅胶柱层析(EA:PE=10:1)纯化粗产物以得到白色固体状的(7)(1.6g,70%)。
LC-MS(ESI)m/z=343[M+H]+。
步骤4:(8)的制备:
在-78℃和氮气氛下向(7)(1.6g,4.7mmol)在THF(10mL)中的溶液中n-BuLi(2.9ml,7.0mmol),然后将混合物在-78℃下搅拌30分钟,之后在-78℃下将丁酸(R)-环氧乙烷-2-基甲酯(1g,7.0mmol)在THF中的溶液加至该混合物,然后加温至室温并搅拌过夜,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=70:1)纯化粗产物以得到白色固体状的(8)(1.2g,84%)。
LC-MS(ESI)m/z=309[M+H]+。
步骤5:(9)的制备:
在0℃和氮气氛下将(E)-N1,N1,N2-三甲基二氮烯-1,2-二甲酰胺(443mg,2.6mmol)加至(8)(523mg,1.7mmol)、异噁唑-3-基氨基甲酸叔丁酯(380mg,2.1mmol)和三丁基膦(521mg,2.6mmol)在甲苯(30mL)中的悬液,然后将反应混合物在60℃下搅拌过夜,通过TLC监测。减压浓缩混合物,并通过硅胶柱层析(EA:PE=10:1)纯化粗产物以得到白色固体状的(9)(298mg,37%)。
LC-MS(ESI)m/z=475[M+H]+。
步骤6:(OBD-056)的制备:
在0℃下向(9)(298mg,0.6mmol)在CH2Cl2(10mL)中的溶液中加入三氟乙酸(1mL),然后将混合物在0℃下搅拌30分钟,通过TLC监测。用氯化铵淬灭,用CH2Cl2萃取,减压浓缩有机层,并通过制备型HPLC纯化粗产物以得到白色固体状的(OBD-056)(84mg,38%)。
1H NMR(301MHz,CDCl3)δ7.39(d,J=14.4Hz,1H),7.25(s,1H),7.04(d,J=8.6Hz,1H),6.83(t,J=8.9Hz,1H),5.14(s,1H),4.73(s,1H),4.39(s,2H),4.00(t,J=8.8Hz,1H),3.84–3.42(m,8H),3.05(dd,J=23.2,11.2Hz,5H),2.13–1.88(m,5H)。
LC-MS(ESI)m/z=375[M+H]+。
步骤1:3-(2,6-二氟-4-硝基苯基)-8-氧杂-3-氮杂-二环[3.2.1]辛烷(3)的制备:
在25℃下向8-氧杂-3-氮杂-二环[3.2.1]辛烷(1)(5.0g,44.2mmol)和1,2,3-三氟-5-硝基苯(8.6g,48.6mmol)在DMF(10mL)中的溶液中加入K2CO3(12.2g,88.4mmol),然后将反应混合物在80℃和氮气氛下搅拌2小时,通过TLC监测。减压浓缩混合物,并通过硅胶柱层析(EA:PE=3:1)纯化粗产物以得到黄色固体状的3-(2,6-二氟-4-硝基苯基)-8-氧杂-3-氮杂-二环[3.2.1]辛烷(3)(9.3g,78%)。
LC-MS(ESI)m/z=271[M+H]+。
步骤2:4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯胺(4)的制备:
向3-(2,6-二氟-4-硝基苯基)-8-氧杂-3-氮杂-二环[3.2.1]辛烷(3)(9.3g,34.4mmol)和钯碳(1g)在MeOH(15mL)中的溶液中,然后将反应混合物在室温和氢气氛下搅拌过夜,通过TLC监测。减压浓缩滤液以得到白色油状的4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯胺(4)(7.8g,95%),并且粗产物不经进一步纯化而用于下一反应。
LC-MS(ESI)m/z=241[M+H]+。
步骤3:4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯基氨基甲酸苄酯(5)的制备:
在0℃和氮气氛下将碳酸,2,5-二氧代-1-吡咯烷基苯甲基酯(12g,48.7mmol)加至4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯胺(4)(7.8g,32.5mmol)在THF(100mL)中的悬液中,并将反应混合物在50℃下搅拌5小时,通过TLC监测。减压浓缩混合物,并通过硅胶柱层析(EA:PE=10:1)纯化粗产物以得到白色固体状的4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯基氨基甲酸苄酯(5)(8.2g,68%)。
LC-MS(ESI)m/z=375[M+H]+。
步骤4:3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯基)-5-(羟甲基)噁唑烷-2-酮(OBD-114)的制备:
在-78℃和氮气氛下向4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯基氨基甲酸苄酯(5)(8.2g,22.1mmol)在THF(10mL)中的溶液中加入n-BuLi(13.8ml,33.1mmol),然后将混合物在-78℃下搅拌30分钟,之后在-78℃下将丁酸(R)-环氧乙烷-2-基甲酯(4.7g,33.1mmol)在THF中的溶液加至该混合物,然后加温至室温并搅拌过夜,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=70:1)纯化粗产物以得到白色固体状的3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯基)-5-(羟甲基)噁唑烷-2-酮(OBD-114)(4.5g,60%)。
LC-MS(ESI)m/z=341[M+H]+。
步骤5:4-甲基苯磺酸(3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯基)-2-氧代噁唑烷-5-基)甲酯(7)的制备:
在0℃和氮气氛下将4-甲基苯-1-磺酰氯(5g,26.6mmol)加至3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯基)-5-(羟甲基)噁唑烷-2-酮(OBD-114)(4.5g,13.3mmol)和Et3N(2.7g,26.6mmol)在DCM(10mL)中的悬液中,并将反应混合物在室温下搅拌过夜,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=50:1)纯化粗产物以得到白色固体状的4-甲基苯磺酸(3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯基)-2-氧代噁唑烷-5-基)甲酯(7)(5.58g,85%)。
LC-MS(ESI)m/z=495[M+H]+。
步骤6:5-((1H-1,2,3-三唑-1-基)甲基)-3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯基)噁唑烷-2-酮(OBD-054)的制备:
在25℃下向4-甲基苯磺酸(3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯基)-2-氧代噁唑烷-5-基)甲酯(7)(300mg,0.6mmol)和1H-1,2,3-三唑(42mg,0.6mmol)在DMF(10mL)中的溶液中加入K2CO3(166mg,1.2mmol),然后将反应混合物在80℃和氮气氛下搅拌1小时,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过制备型HPLC纯化粗产物以得到白色固体状的5-((1H-1,2,3-三唑-1-基)甲基)-3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯基)噁唑烷-2-酮(OBD-054)(82mg,35%)。
1H NMR(300MHz,DMSO-d6)δ8.14(d,J=1.0Hz,1H),7.73(d,J=1.0Hz,1H),7.17(d,J=11.7Hz,2H),5.11(d,J=3.5Hz,1H),4.79(d,J=5.0Hz,2H),4.18(dd,J=23.1,13.7Hz,3H),3.91–3.70(m,1H),3.23(d,J=10.9Hz,3H),2.72(d,J=10.7Hz,3H),2.07–1.61(m,7H)。
LC-MS(ESI)m/z=392[M+H]+。
步骤1:3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯基)-5-(叠氮基甲基)噁唑烷-2-酮(8)的制备:
在25℃下向4-甲基苯磺酸(3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯基)-2-氧代噁唑烷-5-基)甲酯(7)(4g,8mmol)和叠氮化钠(526mg,8mmol)在DMF(10mL)中的溶液中加入K2CO3(2.2mg,16mmol),然后将反应混合物在80℃和氮气氛下搅拌1小时,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(PE:EA=2:1)纯化粗产物以得到白色固体状的3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯基)-5-(叠氮基甲基)噁唑烷-2-酮(8)(2.57g,88%)。
LC-MS(ESI)m/z=366[M+H]+。
步骤2:3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯基)-5-(氨甲基)噁唑烷-2-酮(OBD-115)的制备:
在25℃下向3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯基)-5-(叠氮基甲基)噁唑烷-2-酮(8)(2.57g,7mmol)在MeOH(10mL)中的溶液中加入钯碳(300mg),然后将反应混合物在室温和氢气氛下搅拌过夜,通过TLC监测。减压浓缩滤液,并通过硅胶柱层析(DCM:MeOH=50:1)纯化粗产物以得到白色固体状的3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯基)-5-(氨甲基)噁唑烷-2-酮(OBD-115)(2.1g,85%)。
1H NMR(400MHz,CDCl3)δ7.40–7.20(m,2H),4.62(td,J=10.9,4.9Hz,1H),4.28(s,2H),4.02(t,J=8.9Hz,1H),3.81(dd,J=8.9,6.3Hz,1H),3.27(d,J=10.4Hz,2H),2.81(ddd,J=28.3,18.6,7.7Hz,4H),2.21(s,2H),2.04–1.94(m,2H),1.88–1.71(m,2H)。
LC-MS(ESI)m/z=340[M+H]+。
步骤3:(OBD-048,049,252,253,254)的制备
在25℃下向3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯基)-5-(氨甲基)噁唑烷-2-酮(OBD-115)(200mg,0.59mmol)和R-OH(0.59mmol)在DCM(10mL)中的溶液中加入HOBt(119mg,0.88mmol)、EDCI(225mg,1.18mmol)和DIPEA(152mg,1.18mmol),然后将反应混合物在25℃和氮气氛下搅拌2小时,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=80:1)纯化粗产物以得到白色固体状的(OBD-048,049,252,253,254)。
OBD-048
1H NMR(300MHz,CDCl3)δ7.06(d,J=10.9Hz,2H),5.98(s,1H),4.75(s,1H),4.33(s,2H),3.98(t,J=8.8Hz,1H),3.68(dd,J=19.8,11.0Hz,3H),3.45(d,J=10.9Hz,3H),2.78(d,J=11.1Hz,2H),2.11(d,J=6.6Hz,3H),1.98(d,J=24.1Hz,6H)。
LC-MS(ESI)m/z=426[M+H]+。
OBD-049
1H NMR(301MHz,CDCl3)δ7.06(d,J=11.0Hz,2H),5.15(s,1H),4.75(s,1H),4.32(s,2H),3.97(t,J=9.0Hz,2H),3.80–3.70(m,4H),3.56(d,J=5.9Hz,2H),3.42(s,2H),2.77(d,J=11.1Hz,2H),2.10(d,J=6.4Hz,2H),1.92(d,J=5.0Hz,2H)。
LC-MS(ESI)m/z=397.7[M+H]+。
OBD-252
1H NMR(301MHz,CDCl3)δ7.07(d,J=11.0Hz,2H),6.19(s,1H),4.77(s,1H),4.35(s,2H),3.97(t,J=8.9Hz,1H),3.78–3.62(m,3H),3.46(d,J=10.1Hz,2H),2.79(d,J=11.1 Hz,2H),2.12(d,J=6.5 Hz,2H),1.94(d,J=4.5 Hz,2H),1.43–1.33(m,1H),0.95(dd,J=9.5,4.4 Hz,2H),0.78(d,J=6.4 Hz,2H)。
LC-MS(ESI)m/z=408.1[M+H]+。
OBD-253
1H NMR(301 MHz,CDCl3)δ7.07(d,J=11.0 Hz,2H),5.88(s,1H),4.76(s,1H),4.34(s,2H),3.98(t,J=9.0 Hz,1H),3.79–3.59(m,3H),3.45(d,J=10.8Hz,2H),3.12–2.97(m,1H),2.79(d,J=11.3 Hz,2H),2.38–2.10(m,6H),2.00–1.79(m,4H)。
LC-MS(ESI)m/z=422.1[M+H]+。
OBD-254
1H NMR(301 MHz,CDCl3)δ7.17–6.96(m,2H),6.07(s,1H),4.78(s,1H),4.34(s,2H),3.98(t,J=8.9 Hz,1H),3.82–3.64(m,3H),3.45(d,J=10.0 Hz,2H),2.79(d,J=11.2Hz,2H),2.38–2.06(m,4H),1.98–1.78(m,2H),1.63(dq,J=14.7,7.3 Hz,2H),1.26(s,1H),0.90(t,J=7.4 Hz,3H)。
LC-MS(ESI)m/z=410.1[M+H]+。
步骤1:3-(2-氟-4-硝基苯基)-8-氧杂-3-氮杂-二环[3.2.1]辛烷(3)的制备:
在25℃下向8-氧杂-3-氮杂-二环[3.2.1]辛烷(1)(5.0g,44.2mmol)和1,2-二氟-4-硝基苯(7.7g,48.6mmol)在DMF(10mL)中的溶液中加入K2CO3(12.2g,88.4mmol),然后将反应混合物在80℃和氮气氛下搅拌2小时,通过TLC监测。减压浓缩混合物,并通过硅胶柱层析(EA:PE=5:1)纯化粗产物以得到黄色固体状的3-(2-氟-4-硝基苯基)-8-氧杂-3-氮杂-二环[3.2.1]辛烷(3)(9.1g,82%)。
LC-MS(ESI)m/z=253[M+H]+。
步骤2:4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3-氟苯胺(4)的制备:
向3-(2-氟-4-硝基苯基)-8-氧杂-3-氮杂-二环[3.2.1]辛烷(3)(3)(9.1g,36.2mmol)和钯碳(1g)在MeOH(15mL)中的溶液中,然后将反应混合物在室温和氢气氛下搅拌过夜,通过TLC监测。减压浓缩滤液以得到白色油状的4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3-氟苯胺(4)(7.3g,91%),并且粗产物不经进一步纯化而用于下一反应。
LC-MS(ESI)m/z=223[M+H]+。
步骤3:4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3-氟苯基氨基甲酸苄酯(5)的制备:
在0℃和氮气氛下将碳酸,2,5-二氧代-1-吡咯烷基苯甲基酯(16.4g,65.88mmol)加至4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3-氟苯胺(4)(7.3g,32.9mmol)在THF(100mL)中的悬液中,并将反应混合物在50℃下搅拌5小时,通过TLC监测。减压浓缩混合物,并通过硅胶柱层析(PE:EA=10:1)纯化粗产物以得到白色固体状的4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3-氟苯基氨基甲酸苄酯(5)(7.1g,61%)。
LC-MS(ESI)m/z=357[M+H]+。
步骤4:3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3-氟苯基)-5-(羟甲基)噁唑烷-2-酮(OBD-112)的制备:
在-78℃和氮气氛下向4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3-氟苯基氨基甲酸苄酯(5)(7.1g,20.1mmol)在THF(10mL)中的溶液中加入n-BuLi(12.5ml,30.1mmol),然后将混合物在-78℃下搅拌30分钟,之后在-78℃下将丁酸(R)-环氧乙烷-2-基甲酯(4.3g,30.1mmol)在THF中的溶液加至该混合物,然后加温至室温并搅拌过夜,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=70:1)纯化粗产物以得到白色固体状的3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3-氟苯基)-5-(羟甲基)噁唑烷-2-酮(OBD-112)(3.9g,60%)。
1H NMR(301MHz,DMSO-d6)δ7.46(dd,J=15.4,2.5Hz,1H),7.14(d,J=6.5Hz,1H),7.03–6.84(m,1H),5.18(s,1H),4.64(d,J=3.3Hz,1H),4.31(s,2H),4.00(t,J=9.0Hz,1H),3.81–3.72(m,1H),3.57(d,J=24.9Hz,2H),3.00(d,J=11.2Hz,3H),2.85(d,J=10.9Hz,2H),2.08–1.63(m,5H)。
LC-MS(ESI)m/z=323[M+H]+。
步骤5:4-甲基苯磺酸(3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3-氟苯基)-2-氧代噁唑烷-5-基)甲酯(7)的制备:
在0℃和氮气氛下将4-甲基苯-1-磺酰氯(2.3g,24mmol)加至3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3-氟苯基)-5-(羟甲基)噁唑烷-2-酮(OBD-112)(3.9g,12mmol)和Et3N(1.2g,24mmol)在DCM(10mL)中的悬液中,并将反应混合物在室温下搅拌过夜,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=50:1)纯化粗产物以得到白色固体状的4-甲基苯磺酸(3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3-氟苯基)-2-氧代噁唑烷-5-基)甲酯(7)(4.86g,85%)。
LC-MS(ESI)m/z=477[M+H]+。
步骤6:3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3-氟苯基)-5-(叠氮基甲基)噁唑烷-2-酮(8)的制备:
在25℃下向4-甲基苯磺酸(3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3-氟苯基)-2-氧代噁唑烷-5-基)甲酯(7)(4.86g,10.2mmol)和叠氮化钠(663mg,10.2mmol)在DMF(10mL)中的溶液中加入K2CO3(1.4g,20.4mmol),然后将反应混合物在80℃和氮气氛下搅拌1小时,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(PE:EA=2:1)纯化粗产物以得到白色固体状的3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3-氟苯基)-5-(叠氮基甲基)噁唑烷-2-酮(8)(2.97g,84%)。
LC-MS(ESI)m/z=348[M+H]+。
步骤7:3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3-氟苯基)-5-(氨甲基)噁唑烷-2-酮(OBD-113)的制备:
在25℃下向3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3-氟苯基)-5-(叠氮基甲基)噁唑烷-2-酮(8)(2.97g,8.5mmol)在MeOH(10mL)中的溶液中加入钯碳(300mg),然后将反应混合物在室温和氢气氛下搅拌过夜,通过TLC监测。减压浓缩滤液,并通过硅胶柱层析(DCM:MeOH=50:1)纯化粗产物以得到白色固体状的3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3-氟苯基)-5-(氨甲基)噁唑烷-2-酮(OBD-113)(2.2g,81%)。
1H NMR(301MHz,CDCl3)δ7.53–7.35(m,1H),7.09(d,J=8.9Hz,1H),6.96–6.73(m,1H),4.66(s,1H),4.40(s,1H),4.00(t,J=8.7Hz,1H),3.89–3.74(m,1H),3.06(dd,J=21.9,11.0Hz,6H),2.27–1.85(m,4H)。
LC-MS(ESI)m/z=322[M+H]+。
步骤8:(OBD-110,111)的制备:
在25℃下向3-(4-(8-氧杂-3-氮杂-二环[3.2.1]辛-3-基)-3-氟苯基)-5-(氨甲基)噁唑烷-2-酮(OBD-113)(200mg,0.62mmol)和R-OH(0.62mmol)在DCM(10mL)中的溶液中加入HOBt(126mg,0.96mmol)、EDCI(237mg,1.24mmol)和DIPEA(160mg,1.24mmol),然后将反应混合物在25℃和氮气氛下搅拌2小时,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=80:1)纯化粗产物以得到白色固体状的(OBD-110,111)。
OBD-110
1H NMR(301MHz,CDCl3)δ7.51–7.32(m,1H),7.02(d,J=8.5Hz,1H),6.83(t,J=9.1Hz,1H),6.07(s,1H),4.74(s,1H),4.39(s,2H),4.00(t,J=8.9Hz,1H),3.85–3.49(m,3H),3.05(dd,J=23.2,10.6Hz,4H),2.32–1.67(m,8H)。
LC-MS(ESI)m/z=426[M+H]+。
OBD-111
1H NMR(301MHz,CDCl3)δ7.41(s,1H),7.03(s,1H),6.17(s,0H),5.20–5.02(m,1H),4.85–4.62(m,1H),4.41(s,1H),4.01(s,1H),3.68(s,3H),3.09(d,J=7.9Hz,2H),2.05(d,J=42.7Hz,3H),1.83–1.35(m,3H)。
LC-MS(ESI)m/z=397.7[M+H]+。
步骤1:8-(2,6-二氟-4-硝基苯基)-3-氧杂-8-氮杂-二环[3.2.1]辛烷(3)的制备:
在25℃下向3-氧杂-8-氮杂-二环[3.2.1]辛烷(1)(5.0g,44.2mmol)和1,2,3-三氟-5-硝基苯(8.6g,48.6mmol)在DMF(10mL)中的溶液中加入K2CO3(12.2g,88.4mmol),然后将反应混合物在80℃和氮气氛下搅拌2小时,通过TLC监测。减压浓缩混合物,并通过硅胶柱层析(EA:PE=3:1)纯化粗产物以得到黄色固体状的8-(2,6-二氟-4-硝基苯基)-3-氧杂-8-氮杂-二环[3.2.1]辛烷(3)(9.3g,78%)。
LC-MS(ESI)m/z=271[M+H]+。
步骤2:4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯胺(4)的制备:
向3-(2,6-二氟-4-硝基苯基)-8-氧杂-3-氮杂-二环[3.2.1]辛烷(3)(9.3g,34.4mmol)和钯碳(1g)在MeOH(15mL)中的溶液中,然后将反应混合物在室温和氢气氛下搅拌过夜,通过TLC监测。减压浓缩滤液以得到白色油状的4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯胺(4)(7.8g,95%),并且粗产物不经进一步纯化而用于下一反应。
LC-MS(ESI)m/z=241[M+H]+。
步骤3:4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基氨基甲酸苄酯(5)的制备:
在0℃和氮气氛下将碳酸,2,5-二氧代-1-吡咯烷基苯甲基酯(12g,48.7mmol)加至4-(3-氧杂-8-氮杂-二环[3.2.1]辛-3-基)-3,5-二氟苯胺(4)(7.8g,32.5mmol)在THF(100mL)中的悬液中,并将反应混合物在50℃下搅拌5小时,通过TLC监测。减压浓缩混合物,并通过硅胶柱层析(PE:EA=10:1)纯化粗产物以得到白色固体状的4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基氨基甲酸苄酯(5)(8.2g,68%)。
LC-MS(ESI)m/z=375[M+H]+。
步骤4:(5R)-3-(4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-5-(羟甲基)噁唑烷-2-酮(6)的制备:
在-78℃和氮气氛下向4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基氨基甲酸苄酯(5)(8.2g,22.1mmol)在THF(10mL)中的溶液中加入n-BuLi(13.8ml,33.1mmol),然后将混合物在-78℃下搅拌30分钟,之后在-78℃下将丁酸(R)-环氧乙烷-2-基甲酯(4.7g,33.1mmol)在THF中的溶液加至该混合物,然后加温至室温并搅拌过夜,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=70:1)纯化粗产物以得到白色固体状的(5R)-3-(4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-5-(羟甲基)噁唑烷-2-酮(6)(4.5g,60%)。
LC-MS(ESI)m/z=341[M+H]+。
步骤5:4-甲基苯磺酸((R)-3-(4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-2-氧代噁唑烷-5-基)甲酯(7)的制备:
在0℃和氮气氛下将4-甲基苯-1-磺酰氯(5g,26.6mmol)加至(5R)-3-(4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-5-(羟甲基)噁唑烷-2-酮(6)(4.5g,13.3mmol)和Et3N(2.7g,26.6mmol)在DCM(10mL)中的悬液中,并将反应混合物在室温下搅拌过夜,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=50:1)纯化粗产物以得到白色固体状的4-甲基苯磺酸((R)-3-(4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-2-氧代噁唑烷-5-基)甲酯(7)(5.58g,85%)。
LC-MS(ESI)m/z=495[M+H]+。
步骤6:(5R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)噁唑烷-2-酮(OBD-055)的制备:
在25℃下向4-甲基苯磺酸((R)-3-(4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-2-氧代噁唑烷-5-基)甲酯(7)(300mg,0.6mmol)和1H-1,2,3-三唑(42mg,0.6mmol)在DMF(10mL)中的溶液中加入K2CO3(166mg,1.2mmol),然后将反应混合物在80℃和氮气氛下搅拌1小时,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过制备型HPLC纯化粗产物以得到白色固体状的(5R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)噁唑烷-2-酮(OBD-055)(82mg,35%)。
1H NMR(301MHz,CDCl3)δ7.76(d,J=5.7Hz,2H),6.94(d,J=12.1Hz,2H),5.06(s,1H),4.78(d,J=4.1Hz,1H),4.08(t,J=9.0Hz,1H),3.90(t,J=8.9Hz,4H),3.58(d,J=10.4Hz,2H),2.04(t,J=8.0Hz,4H),1.76(s,2H)。
LC-MS(ESI)m/z=391.8[M+H]+。
步骤1:(5R)-3-(4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-5-(叠氮基甲基)噁唑烷-2-酮(8)的制备:
在25℃下向4-甲基苯磺酸((R)-3-(4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-2-氧代噁唑烷-5-基)甲酯(7)(4g,8mmol)和叠氮化钠(526mg,8mmol)在DMF(10mL)中的溶液中加入K2CO3(2.2g,16mmol),然后将反应混合物在80℃和氮气氛下搅拌1小时,通过TLC监测。用氯化铵淬灭,用EA萃取,减压浓缩有机层,并通过硅胶柱层析(PE:EA=2:1)纯化粗产物以得到白色固体状的(5R)-3-(4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-5-(叠氮基甲基)噁唑烷-2-酮(8)(2.4g,82%)。
LC-MS(ESI)m/z=366[M+H]+。
步骤2:(5S)-3-(4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-5-(氨甲基)噁唑烷-2-酮(9)的制备:
在25℃下向(5R)-3-(4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-5-(叠氮基甲基)噁唑烷-2-酮(8)(2.4g,6.5mmol)在MeOH(10mL)中的溶液中加入钯碳(300mg),然后将反应混合物在室温和氢气氛下搅拌过夜,通过TLC监测。减压浓缩滤液,并通过硅胶柱层析(DCM:MeOH=50:1)纯化粗产物以得到白色固体状的(5S)-3-(4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-5-(氨甲基)噁唑烷-2-酮(9)(1.9g,86%)。
LC-MS(ESI)m/z=340[M+H]+。
步骤3:(OBD-051,052)的制备:
在25℃下向(5S)-3-(4-(3-氧杂-8-氮杂-二环[3.2.1]辛-8-基)-3,5-二氟苯基)-5-(氨甲基)噁唑烷-2-酮(9)(200mg,0.59mmol)和R-OH(0.59mmol)在DCM(10mL)中的溶液中加入HOBt(119mg,0.88mmol)、EDCI(224mg,1.18mmol)和DIPEA(152mg,1.18mmol),然后将反应混合物在25℃和氮气氛下搅拌2小时,通过TLC监测。用氯化铵淬灭,用DCM萃取,减压浓缩有机层,并通过硅胶柱层析(DCM:MeOH=80:1)纯化粗产物以得到白色固体状的(OBD-051,052)。
OBD-051
1H NMR(301MHz,CDCl3)δ6.99(t,J=9.3Hz,2H),5.38(s,1H),4.84–4.69(m,1H),3.98–3.86(m,4H),3.75–3.60(m,4H),2.24–1.97(m,8H)。
LC-MS(ESI)m/z=381.9[M+H]+。
OBD-052
1H NMR(301MHz,CDCl3)δ7.06(d,J=12.4Hz,2H),5.10(s,1H),4.75(s,1H),4.02–3.86(m,4H),3.68(s,2H),3.58(d,J=9.6Hz,2H),2.02(d,J=7.7Hz,2H),1.80(s,4H),0.98(d,J=6.7Hz,3H)。
LC-MS(ESI)m/z=398.0[M+H]+。
实施例13
本发明附加实施方式的合成
以与以上实施例8和12中公开的方式相似的方式,制得了以下化合物:
(((5S)-3-(3-氟-4-((1R,5S)-3-氧化-3-硫杂-8-氮杂双环[3.2.1]辛-8-基)苯基)-2-氧代噁唑烷-5-基)甲基)氨基甲酸甲酯
1H-NMR(400MHz,CDCl3)δ:7.45(d,J=16.4Hz,1H),7.12(d,J=7.6Hz,1H),6.83(t,J=9.2Hz,1H),5.17-5.12(m,1H),4.80-4.74(m,1H),4.62(brs,2H),4.02(t,J=8.4Hz,1H),3.77(t,J=8.0Hz,1H),3.69-3.53(m,4H),3.45(d,J=10.4Hz,2H),2.86(d,J=12.0Hz,2H),2.22(m,2H),1.90-1.88(m,2H)。
HRMS(ESI):C18H23FN3O5S的m/z[M+H]+计算值:412.1344;实测值:412.1359
(((5S)-3-(3,5-二氟-4-((1R,5S)-3-氧化-3-硫杂-8-氮杂双环[3.2.1]辛-8-基)苯基)-2-氧代噁唑烷-5-基)甲基)氨基甲酸甲酯
1H-NMR(400MHz,CDCl3)δ:7.13(d,J=12.4Hz,2H),5.10(m,1H),4.80-4.74(m,1H),4.46(brs,2H),3.98(t,J=8.8Hz,1H),3.76-3.69(m,4H),3.60-3.49(m,3H),2.94(d,J=12.0Hz,2H),2.20-2.18(m,2H),1.87-1.85(m,2H)。
HRMS(ESI):C18H22F2N3O5S的m/z[M+H]+计算值:430.1248;实测值:430.1259
(5R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(3,5-二氟-4-((1R,5S)-3-氧化-3-硫杂-8-氮杂双环[3.2.1]辛-8-基)苯基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.79(s,1H),7.77(s,1H),6.98(d,J=12.0Hz,2H),5.10-5.04(m,1H),4.79(d,J=4.0Hz,2H),4.43(brs,2H),4.10(t,J=9.2Hz,1H),3.91-3.87(m,1H),3.55(d,J=12.4Hz,2H),2.92(d,J=10.4Hz,2H),2.19-2.16(m,2H),1.88-1.83(m,2H)。
HRMS(ESI):C18H20F2N5O3S的m/z[M+H]+计算值:424.1249;实测值:424.1271
(S)-N-((3-(3-氟-4-(2-氧化-2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲基)乙酰胺
1H-NMR(400MHz,CDCl3)δ:7.34(d,J=14.0Hz,1H),7.01(d,J=8.8Hz,1H),6.41(t,J=8.8Hz,1H),6.12(t,J=6.0Hz,1H),4.76-4.73(m,1H),4.01-3.90(m,7H),3.74-3.66(m,2H),3.62-3.56(m,1H),3.45-3.40(m,2H),2.02(s,3H)。
HRMS(ESI):C17H21FN3O4S的m/z[M+H]+计算值:382.1237;实测值:382.1217
(S)-N-((3-(3,5-二氟-4-(2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲基)乙酰胺
HNMR(400MHz,CDCl3)δ:7.03-6.94(m,2H),6.09(t,J=5.6Hz,1H),4.75(q,J=3.2Hz,J=2.8Hz,1H),4.16(s,4H),3.95(t,J=8.8Hz,1H),3.72-3.61(m,3H),3.40(s,4H),2.03(s,3H)。
C17H19F2N3O3S的m/z[M+Na]+计算值:383.1115;实测值:384.0
(S)-((3-(3-氟-4-(2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲基)氨基甲酸甲酯
HNMR(400MHz,CDCl3)δ:7.33(q,J=2.0Hz,J=11.6Hz,2H),7.01(d,J=2.0Hz,1H),6.44(t,J=9.2Hz,1H),5.15(bs,1H),4.77-4.73(m,1H),4.01-3.97(m,4H),3.76-3.52(m,6H),3.42(s,4H)。
C17H20FN3O4S的m/z[M+Na]+计算值:381.1159;实测值:404.1
(S)-((3-(3-氟-4-(2-氧化-2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲基)氨基甲酸甲酯
1H-NMR(400MHz,CDCl3)δ:7.51(d,J=14.4Hz,1H),7.04(d,J=8.4Hz,1H),6.80(t,J=8.8Hz,1H),5.09(brs,1H),4.76(brs,1H),4.16(d,J=13.2Hz,4H),4.01-3.98(m,3H),3.77–3.75(m,1H),3.69(s,3H),3.61-3.55(m,2H),3.46-3.44(m,2H)。
HRMS(ESI);m/z[M+H]+C17H21FN3O5S计算值:398.1186;实测值:398.1166
(R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(3-氟-4-(2-氧化-2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)噁唑烷-2-酮
HNMR(400MHz,CDCl3)δ:7.78(d,J=0.8Hz,1H),7.74(d,J=0.8Hz,1H),7.18(dd,J=13.6,2.4Hz,1H),6.87(dd,J=8.8,1.6Hz,1H),6.37(t,J=9.2Hz,1H),5.04-5.00(m,1H),4.77(d,J=3.6Hz,2H),4.08(t,J=9.2Hz,1H),3.96(dd,J=10.4,1.6Hz,4H),3.92-3.89(m,3H),3.42-3.39(m,2H)。
C17H18FN5O3S的m/z[M+H]+计算值:391.1114;实测值:392.0
(S)-N-((3-(3-氟-4-(2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲基)环丙烷甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.33(d,J=14.0Hz,1H),6.99(d,J=8.8Hz,1H),6.47(t,J=9.2Hz,1H),6.13(brs,1H),4.73(m,1H),3.98-3.95(m,5H),3.73-3.66(m,3H),3.42(s,4H),1.39-1.37(m,1H),0.97-0.91(m,2H),0.78-0.76(m,2H)。
HRMS(ESI):C19H23FN3O3S的m/z[M+H]+计算值:392.1444;实测值:392.1426
(S)-N-((3-(3-氟-4-(2-氧化-2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲基)环丙烷甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.35(d,J=14.0Hz,1H),7.01(d,J=8.4Hz,1H),6.44(t,J=9.2Hz,1H),6.13(brs,1H),4.74(m,1H),4.00-3.91(m,7H),3.75-3.62(m,3H),3.47-3.41(m,2H),1.38-1.37(m,1H),0.97-0.92(m,2H),0.78-0.76(m,2H)。
HRMS(ESI):C19H23FN3O4S的m/z[M+H]+计算值:408.1393;实测值:408.1378
(S)-N-((3-(3-氟-4-(2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲基)环丁烷甲酰胺
HNMR(400MHz,CDCl3)δ:7.76(d,J=8.8Hz,2H),6.92-6.83(m,2H),5.04(m,1H),4.78(q,J=0.8Hz,J=3.2Hz 2H),4.15(t,J=2.4Hz,4H),3.85(t,J=6.0Hz,1H),3.72-3.63(m,3H),3.40(s,4H),3.05-2.99(m,1H),2.24-2.13(m,4H),1.97-1.60(m,2H)。
m/z[M+Na]+C20H24FN3O3S计算值:405.1522;实测值:428.2
(S)-N-((3-(3-氟-4-(2-氧化-2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲基)环丁烷甲酰胺
1H-NMR(400MHz,CDCl3)δ:7.36(d,J=14.4Hz,1H),7.00(d,J=8.0Hz,1H),6.47(t,J=9.2Hz,1H),5.80(brs,1H),4.73(brs,1H),4.00(d,J=12.0Hz,4H),3.95-3.92(m,3H),3.76-3.72(m,1H),3.65-3.62(m,2H),3.47-3.41(m,2H),3.02-2.96(m,1H),2.26-2.13(m,4H),1.98-1.84(m,2H)。
HRMS(ESI):C20H25FN3O4S的m/z[M+H]+计算值:422.1549;实测值:422.1531
(R)-N-((3-(3-氟-4-(2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲基)甲烷磺酰胺
HNMR(400MHz,CDCl3)δ:7.04-6.95(m,2H),5.05(s,1H),4.80-4.77(m,1H),4.15(t,J=2.4Hz,4H),3.97(t,J=8.8Hz,1H),3.86(dd,J=6.4,8.8Hz,1H),3.56(dd,J=3.6,14.4Hz,1H),3.43-3.39(m,5H),3.01(s,3H)。
C16H20FN3O4S2的m/z[M+H]+计算值:401.0879;实测值:402.1
(R)-N-((3-(3-氟-4-(2-氧化-2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲基)甲烷磺酰胺
HNMR(400MHz,CDCl3)δ:7.32(dd,J=14.0,2.4Hz,1H),7.04-7.02(m,1H),6.41(t,J=9.6Hz,1H),4.86-4.77(m,2H),4.04-3.95(m,8H),3.93(dd,J=9.6,3.2Hz,1H),3.43-3.40(m,3H),3.02(s,3H)。
C16H20FN3O5S2的m/z[M+H]+计算值:417.0828;实测值:418.0
(R)-5-((2H-1,2,3-三唑-2-基)甲基)-3-(3-氟-4-(2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)噁唑烷-2-酮
HNMR(400MHz,CDCl3)δ:7.64(s,2H),7.24-7.21(m,1H),6.99(dd,J=8.8,1.6Hz,1H),6.41(t,J=9.6Hz,1H),5.12-5.06(m,1H),4.87-4.82(m,1H),4.75-4.72(m,1H),4.05-4.01(m,1H),3.96-3.93(m,5H),3.40(s,4H)。
C17H18FN5O2S的m/z[M+H]+计算值:375.1165;实测值:376.1
(R)-5-((2H-1,2,3-三唑-2-基)甲基)-3-(3-氟-4-(2-氧化-2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)噁唑烷-2-酮
HNMR(400MHz,CDCl3)δ:7.64(s,2H),7.27-7.23(m,1H),6.99(dd,J=8.8,2.0Hz,1H),6.39(t,J=9.2Hz,1H),5.11-5.06(m,1H),4.87-4.82(m,1H),4.76-4.70(m,1H),4.06-4.03(m,1H),3.98-3.90(m,7H),3.43-3.40(m,2H)。
C17H18FN5O3S的m/z[M+H]+计算值:391.1114;实测值:392.1
甲基氨基甲酸(R)-(3-(3-氟-4-(2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲酯
HNMR(400MHz,CDCl3)δ:7.33(dd,J=2.4,13.6Hz,1H),7.04(dd,J=1.6,8.4Hz,1H),6.44(t,J=9.2Hz,1H),4.88-4.72(m,2H),4.33(t,J=4.0Hz,2H),4.02(t,J=9.2Hz,1H),3.97(d,J=1.6Hz,4H),3.77(dd,J=6.4,8.8Hz,1H),3.42(s,4H),2.80(d,J=4.8Hz,3H)。
C17H20FN3O4S的m/z[M+H]+计算值:381.1159;实测值:382.0
甲基氨基甲酸(R)-(3-(3-氟-4-(2-氧化-2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲酯
HNMR(400MHz,CDCl3)δ:7.35(dd,J=2.0,11.6Hz,1H),7.06(d,J=8.4Hz,1H),6.42(t,J=9.2Hz,1H),4.89-4.70(m,2H),4.42-4.26(m,2H),4.08-3.88(m,7H),3.84-3.71(m,1H),3.47-3.37(m,2H),2.81(m,3H)。
C17H20FN3O5S的m/z[M+H]+计算值:397.1108;实测值:398.0
(S)-N-((3-(3,5-二氟-4-(2-氧化-2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲基)乙酰胺
1H-NMR(400MHz,CDCl3)δ:7.02(d,J=12.0Hz,2H),5.92(brs,1H),4.75-4.74(m,1H),4.16(d,J=12.0Hz,4H),3.97-3.90(m,2H),3.72-3.65(m,4H),3.41-3.37(m,2H),2.02(s,3H)。
HRMS(ESI):C17H20F2N3O4S的m/z[M+H]+计算值:400.1143;实测值:400.1158
(S)-((3-(3,5-二氟-4-(2-氧化-2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲基)氨基甲酸甲酯
1H-NMR(400MHz,CDCl3)δ:7.00(d,J=10.8Hz,2H),5.36(m,1H),4.72(m,1H),4.14(d,J=12.0Hz,4H),3.92(m,3H),3.69(m,1H),3.67(s,3H),3.52(m,2H),3.39(d,J=12.4Hz,2H)。
C17H20F2N3O5S[M+H]+的HRMS(ESI)计算值:416.1086,实测值:416.1073
HNMR(400MHz,CDCl3)δ:7.75(d,J=8.0Hz,2H),6.92-6.83(m,2H),5.05-5.01(m,1H),4.77(d,J=4.0Hz,2H),4.15(dt,J=11.6,2.4Hz,4H),4.05(t,J=9.2Hz,1H),3.92-3.89(m,3H),3.40-3.37(m,2H)。
C17H17F2N5O3S的m/z[M+H]+计算值:409.1020;实测值:410.1
(S)-N-((3-(3,5-二氟-4-(2-氧化-2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲基)环丙烷甲酰胺
1H-NMR(400MHz,CDCl3)δ:6.98(d,J=11.6Hz,2H),6.60(m,1H),4.73(m,1H),4.13(d,J=12.4Hz,4H),3.91(m,3H),3.70(m,1H),3.64(m,2H),3.79(d,J=10.4Hz,2H),1.41(m,1H),0.94(m,1H),0.87(m,1H),0.74(m,2H)
C19H22F2N3O4S[M+H]+的HRMS(ESI)计算值:426.1294,实测值:426.1278
(S)-N-((3-(3,5-二氟-4-(2-氧化-2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲基)环丁烷甲酰胺
1H-NMR(400MHz,CDCl3)δ:6.99(d,J=10.4Hz,2H),6.06(m,1H),4.74(m,1H),4.14(d,J=12.4Hz,4H),3.93(m,3H),3.70(m,1H),3.62(m,2H),3.38(d,J=12.4Hz,2H),3.00(m,1H),2.21(m,1H),2.11(m,3H),1.92(m,1H),1.83(m,1H)
C20H24F2N3O4S[M+H]+的HRMS(ESI)计算值:440.1450,实测值:440.1441
(R)-N-((3-(3,5-二氟-4-(2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲基)甲烷磺酰胺
HNMR(400MHz,CDCl3)δ:7.04-6.95(m,2H),5.05(s,1H),4.80-4.77(m,1H),4.15(t,J=2.4Hz,4H),3.97(t,J=8.8Hz,1H),3.86(dd,J=6.4,8.8Hz,1H),3.56(dd,J=3.6,14.4Hz,1H),3.43-3.39(m,5H),3.01(s,3H)。
m/z[M+H]+C16H19F2N3O4S2计算值:419.0785;实测值:420.1
(R)-N-((3-(3,5-二氟-4-(2-氧化-2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲基)甲烷磺酰胺
HNMR(400MHz,CDCl3)δ:7.03-7.00(m,2H),4.81-4.78(m,2H),4.18-4.14(m,4H),3.98-3.93(m,1H),3.91-3.85(m,3H),3.60-3.41(m,4H),3.40-3.37(m,3H),3.02(s,3H)。
m/z[M+H]+C16H19F2N3O5S2计算值:435.0734;实测值:436.0
甲基氨基甲酸(R)-(3-(3,5-二氟-4-(2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲酯
HNMR(400MHz,CDCl3)δ:7.08-6.91(m,2H),4.91-4.70(m,2H),4.38-4.28(m,2H),4.16(t,J=2.4Hz,4H),3.98(t,J=9.2Hz,1H),3.74(dd,J=6.4,8.8Hz,1H),3.43-3.37(m,4H),2.81(d,J=4.8Hz,3H)。
C17H19F2N3O4S的m/z[M+H]+计算值:399.1064;实测值:400.1
甲基氨基甲酸(R)-(3-(3,5-二氟-4-(2-氧化-2-硫杂-6-氮杂螺[3.3]庚-6-基)苯基)-2-氧代噁唑烷-5-基)甲酯
HNMR(400MHz,CDCl3)δ:7.10-6.95(m,2H),4.89-4.69(m,2H),4.30-4.36(m,2H),4.17(d,J=11.6Hz,4H),4.02-3.89(m,3H),3.74(dd,J=6.4,8.6Hz,1H),3.44-3.33(m,2H),2.81(d,J=4.8Hz,3H)。
C17H19F2N3O5S的m/z[M+H]+计算值:415.1013;实测值:416.0
(R)-5-((1H-1,2,3-三唑-1-基)甲基)-3-(3-氟-4-(2-氧杂-6-氮杂螺[3.3]庚-6-基)苯基)噁唑烷-2-酮
1H-NMR(400MHz,CDCl3)δ:7.65(s,2H),7.31(d,J=14.4,2.4Hz,1H),6.99(d,J=8.4Hz,1H),6.59(t,J=9.2Hz,1H),5.14-5.07(m,1H),4.88-4.83(m,5H),4.77-4.71(m,1H),4.16(s,4H),4.07-4.02(m,1H),3.98-3.92(m,1H)
HRMS(ESI):C17H19FN5O3的m/z[M+H]+计算值:360.1472;实测值:360.1451
将通过以下编号的段落非限制性地进一步描述本发明:
1.式I的化合物:
或其药学上可接受盐、水合物或溶剂合物,其中:
R独立地为OR1、OC(O)R2、OC(O)NHR2、OS(O2)R2、NHS(O)2R2、NR3R4、NHC(O)R5;
R’和R”独立地为H、F、Cl或OMe;
每个R1独立地为H、C1-C6烷基、C3-C8环烷基,其中所述烷基、环烷基任选地被1至4个选自以下的基团取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基;
每个R2独立地为C1-C6烷基、C3-C8环烷基、杂环基、杂芳基或芳基,其中所述烷基、环烷基、杂环基、杂芳基或芳基任选地被1至4个选自以下的基团取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6酰氧基、CF3、NO2、CN和NH2;
R3和R4各自独立地为H、C1-C6烷基、C3-C8环烷基、杂环基、杂芳基、芳基;或者R3和R4跟与之相连的氮一起形成具有1至3个选自O、S或N的附加杂原子的4至8元杂环基或杂芳基,其中所述烷基、环烷基、杂环基、杂芳基或芳基任选地被1至4个选自以下的基团取代:卤素、C1-C6烷基、C1-C6烷氧基、CF3、NO2、CN;
每个R5独立地为C1-C6烷基、C3-C8环烷基、C1-C6烷氧基、杂芳基、芳基,其中所述烷基、环烷基、杂环基、杂芳基或芳基任选地被1至4个选自以下的基团取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6酰氧基、CF3、NO2、CN和NH2;
环A选自:
其中,
R6和R7各自独立地为H、F、CH3、CH2CH3、CF3、苯基;
X=O、S、SO、SO2;
Y=O、S、SO、SO2和NR8;
m为1或2;
n为1或2;
p为1或2;
q为1或2;
R8独立地为H、C1-C4烷基、C3-C6环烷基、COCH3和对甲苯磺酰基,其中所述烷基,环烷基任选地被1至4个选自以下的基团取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6酰氧基、CF3、NO2、CN和NH2。
2.段落1所述的化合物,其中所述化合物由式II表示:
其中,
R独立地为OR1、OC(O)R2、NR3R4、NHS(O)2R2、NHC(O)R5;
R’和R”独立地为H或F;
R1独立地为H、C1-C6烷基、C3-C6环烷基;
R2独立地为C1-C6烷基、C3-C6环烷基;
R3和R4独立地为H、C1-C6烷基、C3-C6环烷基、苯基;或者R3和R4跟与之相连的氮一起以形成吗啉、硫吗啉、哌嗪和三唑;
R5独立地为C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、5或6元杂芳基或苯基;
R6和R7独立地为H、F、CH3、CH2CH3、CF3;
X=O、S、SO、SO2;当X=S、SO、SO2,R’=H,R”=F时,R5不能是CH3;
3.段落1所述的化合物,其中所述化合物由式III表示:
其中,
R独立地为OR1、OC(O)R2、NR3R4、NHS(O)2R2、NHC(O)R5;
R’和R”独立地为H或F;
R1独立地为H、C1-C6烷基、C3-C6环烷基;
R2独立地为C1-C6烷基、C3-C6环烷基;
R3和R4独立地为H、C1-C6烷基、C3-C6环烷基或苯基;或者R3和R4跟与之相连的氮一起以形成吗啉、硫吗啉、哌嗪和三唑;
R5独立地为C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、5或6元杂芳基或苯基;
R6和R7独立地为H、F、CH3、CH2CH3、CF3;
X=O、S、SO、SO2;
4.段落1所述的化合物,其中所述化合物由式IV表示:
其中,
R独立地为OR1、OC(O)R2、NR3R4、NHS(O)2R2、NHC(O)R5;
R’和R”独立地为H或F;
R1独立地为H、C1-C6烷基、C3-C6环烷基;
R2独立地为C1-C6烷基,C3-C6环烷基;
R3和R4独立地为H、C1-C6烷基、C3-C6环烷基、5或6元杂芳基或苯基;或者R3和R4跟与之相连的氮一起以形成吗啉、硫吗啉、哌嗪和三唑;
R5独立地为C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、5或6元杂芳基或苯基;且
X=O、S、SO、SO2。
5.段落1所述的化合物,其中所述化合物由式V表示:
其中,
R独立地为OR1、OC(O)R2、NR3R4、NHS(O)2R2、NHC(O)R5;
R’和R”独立地为H或F;
R1独立地为H、C1-C6烷基、C3-C6环烷基;
R2独立地为C1-C6烷基、C3-C6环烷基;
R3和R4独立地为H、C1-C6烷基、C3-C6环烷基、5或6元杂芳基或苯基;或者R3和R4跟与之相连的氮一起以形成吗啉、硫吗啉、哌嗪和三唑;
R5独立地为C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、5或6元杂芳基或苯基;且
X=O、S、SO、SO2。
6.段落1所述的化合物,其中所述化合物由式VI表示:
7.段落6所述的化合物,其中所述化合物由式VII、式VIII或式IX表示:
其中,
R独立地为OR1、OC(O)R2、NR3R4、NHS(O)2R2、NHC(O)R5;
R’和R”独立地为H或F;
R1独立地为H、C1-C6烷基、C3-C6环烷基;
R2独立地为C1-C6烷基、C3-C6环烷基;
R3和R4独立地为H、C1-C6烷基、C3-C6环烷基、5或6元杂芳基或苯基;或者R3和R4跟与之相连的氮一起以形成吗啉、硫吗啉、哌嗪和三唑;
R5独立地为C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、5或6元杂芳基或苯基;且
X=O、S、SO、SO2。
8.段落1所述的化合物,其中所述化合物由式IIa、IIb、IIIa、IIIb、IVa、IVb、Va、Vb、VIIa、VIIb、VIIIa、VIIIb、IXa或IXb表示:
其中,
R独立地为OH、OCH3、OCH2CH3、OC(O)CH3、NH2、NHCH3、NHC6H5、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、NHS(O)2R2、NHC(O)R5;
R2独立地为C1-C6烷基;
R5独立地为C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、呋喃、噻吩或苯基;在式IIa中,R5不能是CH3;且
X=O、S、SO、SO2。
9.段落1所述的化合物,其中所述化合物是:
10.一种药物组合物,其包含至少一种式I化合物或其盐、水合物或溶剂合物,和一种或多种药学上可接受的载体和/或添加剂。
11.式I或其盐、水合物或溶剂合物的药物组合物,进一步包含一种或多种另外的抗感染治疗物。
12.通过向有需要的患者施用治疗有效量的式I化合物或其盐、水合物或溶剂合物而预防和治疗人类中微生物感染的方法。
13.段落12所述的方法,其中所述微生物感染是由结核分枝杆菌引起的。
***
应当理解的是,本发明不限于上述本发明的特定实施方式,因为可以对特定实施方式进行变化,并且其仍然落入所附权利要求的范围内。
Claims (13)
1.式I的化合物:
或其药学上可接受盐、水合物或溶剂合物,其中:
R独立地为OR1、OC(O)R2、OC(O)NHR2、OS(O2)R2、NHS(O)2R2、NR3R4、NHC(O)R5;
R’和R”独立地为H、F、Cl或OMe;
每个R1独立地为H、C1-C6烷基、C3-C8环烷基,其中所述烷基、环烷基任选地被1至4个选自以下的基团取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基;
每个R2独立地为C1-C6烷基、C3-C8环烷基、杂环基、杂芳基或芳基,其中所述烷基、环烷基、杂环基、杂芳基或芳基任选地被1至4个选自以下的基团取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6酰氧基、CF3、NO2、CN和NH2;
R3和R4各自独立地为H、C1-C6烷基、C3-C8环烷基、杂环基、杂芳基、芳基;或者R3和R4跟与之相连的氮一起形成具有1至3个选自O、S或N的附加杂原子的4至8元杂环基或杂芳基,其中所述烷基、环烷基、杂环基、杂芳基或芳基任选地被1至4个选自以下的基团取代:卤素、C1-C6烷基、C1-C6烷氧基、CF3、NO2、CN;
每个R5独立地为C1-C6烷基、C3-C8环烷基、C1-C6烷氧基、杂芳基、芳基,其中所述烷基、环烷基、杂环基、杂芳基或芳基任选地被1至4个选自以下的基团取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6酰氧基、CF3、NO2、CN和NH2;
环A选自:
其中,
R6和R7各自独立地为H、F、CH3、CH2CH3、CF3、苯基;
X=O、S、SO、SO2;
Y=O、S、SO、SO2和NR8;
m为1或2;
n为1或2;
p为1或2;
q为1或2;
R8独立地为H、C1-C4烷基、C3-C6环烷基、COCH3和对甲苯磺酰基,其中所述烷基,环烷基任选地被1至4个选自以下的基团取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6酰氧基、CF3、NO2、CN和NH2。
2.权利要求1所述的化合物,其中所述化合物由式II表示:
其中,
R独立地为OR1、OC(O)R2、NR3R4、NHS(O)2R2、NHC(O)R5;
R’和R”独立地为H或F;
R1独立地为H、C1-C6烷基、C3-C6环烷基;
R2独立地为C1-C6烷基、C3-C6环烷基;
R3和R4独立地为H、C1-C6烷基、C3-C6环烷基、苯基;或者R3和R4跟与之相连的氮一起以形成吗啉、硫吗啉、哌嗪和三唑;
R5独立地为C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、5或6元杂芳基或苯基;
R6和R7独立地为H、F、CH3、CH2CH3、CF3;
X=O、S、SO、SO2;当X=S、SO、SO2,R’=H,R”=F时,R5不能是CH3。
10.一种药物组合物,其包含至少一种式I化合物或其盐、水合物或溶剂合物,和一种或多种药学上可接受的载体和/或添加剂。
11.式I或其盐、水合物或溶剂合物的药物组合物,进一步包含一种或多种另外的抗感染治疗物。
12.通过向有需要的患者施用治疗有效量的式I化合物或其盐、水合物或溶剂合物而预防和治疗人类中微生物感染的方法。
13.权利要求12所述的方法,其中所述微生物感染是由结核分枝杆菌引起的。
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US20220081403A1 (en) * | 2019-01-18 | 2022-03-17 | Merck Sharp & Dohme Corp. | Oxazolidinone compounds and methods of use thereof as antibacterial agents |
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