CN117229210A - 十氢异喹啉类化合物及其制备方法和用途 - Google Patents
十氢异喹啉类化合物及其制备方法和用途 Download PDFInfo
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- CN117229210A CN117229210A CN202210643184.8A CN202210643184A CN117229210A CN 117229210 A CN117229210 A CN 117229210A CN 202210643184 A CN202210643184 A CN 202210643184A CN 117229210 A CN117229210 A CN 117229210A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 53
- -1 Decahydroisoquinoline compound Chemical class 0.000 title claims abstract description 29
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 claims abstract description 15
- 239000003112 inhibitor Substances 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 104
- 150000001875 compounds Chemical class 0.000 claims description 103
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 64
- 239000002904 solvent Substances 0.000 claims description 57
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- 239000003513 alkali Substances 0.000 claims description 31
- 239000000243 solution Substances 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 238000004440 column chromatography Methods 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 20
- 239000011261 inert gas Substances 0.000 claims description 20
- 230000002829 reductive effect Effects 0.000 claims description 20
- 238000010992 reflux Methods 0.000 claims description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 238000005406 washing Methods 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 13
- 239000012074 organic phase Substances 0.000 claims description 13
- 229940002612 prodrug Drugs 0.000 claims description 13
- 239000000651 prodrug Substances 0.000 claims description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 239000012453 solvate Substances 0.000 claims description 12
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 238000004587 chromatography analysis Methods 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 238000007865 diluting Methods 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- 239000003208 petroleum Substances 0.000 claims description 7
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 7
- FMCAFXHLMUOIGG-JTJHWIPRSA-N (2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-JTJHWIPRSA-N 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 6
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 6
- 235000011009 potassium phosphates Nutrition 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 6
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 5
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims description 5
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 5
- FMCAFXHLMUOIGG-IWFBPKFRSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-IWFBPKFRSA-N 0.000 claims description 4
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical group C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 4
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 claims description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- RPNNPZHFJPXFQS-UHFFFAOYSA-N methane;rhodium Chemical compound C.[Rh] RPNNPZHFJPXFQS-UHFFFAOYSA-N 0.000 claims description 4
- AIHIHVZYAAMDPM-UHFFFAOYSA-N oxiran-2-ylmethyl 3-nitrobenzenesulfonate Chemical compound [O-][N+](=O)C1=CC=CC(S(=O)(=O)OCC2OC2)=C1 AIHIHVZYAAMDPM-UHFFFAOYSA-N 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- BWKMGYQJPOAASG-VIFPVBQESA-N (3s)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=CC=C2CN[C@H](C(=O)O)CC2=C1 BWKMGYQJPOAASG-VIFPVBQESA-N 0.000 claims description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 3
- 239000012535 impurity Substances 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 238000006386 neutralization reaction Methods 0.000 claims description 3
- 230000003472 neutralizing effect Effects 0.000 claims description 3
- 238000004537 pulping Methods 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 3
- IOKGWQZQCNXXLD-UHFFFAOYSA-N tert-butyl n-(3-bromopropyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCBr IOKGWQZQCNXXLD-UHFFFAOYSA-N 0.000 claims description 3
- 150000001728 carbonyl compounds Chemical class 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 239000012065 filter cake Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- 230000009545 invasion Effects 0.000 abstract description 5
- 230000004071 biological effect Effects 0.000 abstract description 4
- 208000030820 Ebola disease Diseases 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 110
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 85
- 230000015572 biosynthetic process Effects 0.000 description 52
- 238000003786 synthesis reaction Methods 0.000 description 52
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- 210000004027 cell Anatomy 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 241001112090 Pseudovirus Species 0.000 description 13
- 238000004809 thin layer chromatography Methods 0.000 description 11
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- 230000000694 effects Effects 0.000 description 10
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
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- 230000005764 inhibitory process Effects 0.000 description 7
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
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- 238000012216 screening Methods 0.000 description 6
- 108010052285 Membrane Proteins Proteins 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
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- 231100000135 cytotoxicity Toxicity 0.000 description 5
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- PINPOEWMCLFRRB-LURJTMIESA-N (1s)-1-(4-chlorophenyl)ethanamine Chemical compound C[C@H](N)C1=CC=C(Cl)C=C1 PINPOEWMCLFRRB-LURJTMIESA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 102100021696 Syncytin-1 Human genes 0.000 description 3
- 241000711975 Vesicular stomatitis virus Species 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- QVSVMNXRLWSNGS-UHFFFAOYSA-N (3-fluorophenyl)methanamine Chemical compound NCC1=CC=CC(F)=C1 QVSVMNXRLWSNGS-UHFFFAOYSA-N 0.000 description 2
- YMVFJGSXZNNUDW-UHFFFAOYSA-N (4-chlorophenyl)methanamine Chemical compound NCC1=CC=C(Cl)C=C1 YMVFJGSXZNNUDW-UHFFFAOYSA-N 0.000 description 2
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 2
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Abstract
本发明提供了一种式I所述的十氢异喹啉类化合物及其制备方法和用途。本发明的十氢异喹啉类化合物为埃博拉侵入抑制剂，作用于EBOV‑GP靶点，具有较强的生物活性和较好的选择性，可作为EBOV‑GP抑制剂的应用和其在制备治疗埃博拉病等相关药物中的应用。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种(3S,4aS,8aS)-2-[3-(取代氨基)-2-取代-丙基]十氢异喹啉-3-甲酰胺类化合物、其制备方法及其作为EBOV-GP抑制剂的用途和其在制备用于预防和/或治疗埃博拉的药物中的用途。
背景技术
埃博拉病毒(EBOV)是一种高致死性的病毒，尚缺乏有效的治疗药物。虽有一款疫苗(Ervebo) 和两款中和抗体(Inmazeb、Ebanga)通过FDA审批，但疫苗仅针对18岁以上成人用于预防，且存在不良反应及运输储存等问题，而接受抗体Inmazeb、Ebanga治疗的患者在临床实验中28天平均生存率仅为65.5％和64.9％。
埃博拉病毒侵入时，组织蛋白酶介导的包膜糖蛋白(GP)裂解是埃博拉病毒侵入宿主细胞关键步骤。EBOV-GP由GP1、GP2亚基组成，其中GP1起吸附作用，GP2参与病毒和宿主细胞膜的融合。EBOV-GP抑制剂通过与包膜蛋白结合，改变蛋白构象，阻碍其与组织蛋白酶结合，使GP1上糖冠部分不能顺利脱除，影响后续GP1和GP2分离及GP2成熟释放，干扰病毒与宿主细胞融合。
有鉴于此，特提出本发明。
发明内容
假病毒(pseudovirus)技术是国内外筛选评价埃博拉活性化合物的主要手段之一。EBOV 具有高致死性及缺乏有效治疗方法，必须在生物安全4级(BSL-4)实验室中进行实验，而在全球范围内，只有很少的科研机构可以使用真正的EBOV病毒(infectious virus)进行研究。因此，开发了一种膜蛋白假病毒“替代”系统，该假病毒感染细胞的亲嗜性和感染能力完全由外源膜蛋白的种类和活性决定。
本发明根据包膜病毒的相似性，通过埃博拉膜蛋白的假病毒技术进行高通量筛选，发现新型十氢异喹啉类化合物具有抗病毒活性，可应用于埃博拉病毒感染的治疗。
本发明的目的之一在于提供一种十氢异喹啉类化合物。
本发明的目的之二在于提供一种所述十氢异喹啉类化合物的制备方法。
本发明的目的之三在于提供一种包含所述十氢异喹啉类化合物的药物组合物。
本发明的目的之四在于提供一种所述十氢异喹啉类化合物或药物组合物在制备EBOV-GP抑制剂中的应用。
本发明的目的之五在于提供一种所述十氢异喹啉类化合物或药物组合物在制备用于预防和/或治疗埃博拉的药物中的应用。
为了实现本发明的上述目的，特采用以下技术方案：
本发明第一方面提供了一种式I化合物、其异构体、药学上可接受的盐、酯、前药或溶剂合物，
其中：
X1和X2各自独立地选自H、取代或未取代的C1-C6烷基、取代或未取代的C6-C12芳基，所述取代的取代基选自卤素、-OH、-SH、-O(C1-C6烷基)、-S(C1-C6烷基)、C1-C6烷基；特别地，X1和X2各自独立地选自H、取代或未取代的C1-C4烷基、取代或未取代的苯基，所述取代的取代基选自卤素、-OH、-SH、-O(C1-C6烷基)、-S(C1-C6烷基)、C1-C6烷基；或者
X1和X2彼此连接并和与其相连的碳原子形成C3-C6亚环烷基；
Y选自H、-OH、卤素或氧代(＝O)；
Z选自H、C1-C6烷基、C3-C8环烷基、取代或未取代的C6-C12芳基、5-7元杂芳基；特别地，Z选自H、C1-C4烷基、C3-C6环烷基、取代或未取代的苯基、5-6元杂芳基；更特别地选自H、甲基、乙基、叔丁基、环己基、取代或未取代的苯基，所述取代的取代基选自卤素、-OH、-SH、-O(C1-C6烷基)、-S(C1-C6烷基)、C1-C6烷基；
R选自H、C1-C4烷基；特别选自H、甲基、乙基、异丙基；
m为0、1、2、3或4，优选为0、1、2或3；
A环选自C3-C8环烷基、C6-C12芳基、5-7元杂芳基、3-10元杂环基；特别地，A环选自C3-C6环烷基、C6-C12芳基、5-6元杂芳基、3-10元杂环基；更特别地，A环选自环戊基、环己基、环庚基、苯基、萘基、吡啶基；
(R1)n表示n个R1取代，n为0、1、2、3、4或5，优选为0、1或2；
R1各自独立地选自卤素、-NO2、-CN、C1-C6烷基、-OH、-O(C1-C6烷基)、-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)2、-COOH、-C(＝O)O(C1-C6烷基)、-C(＝O)NH(C1-C6烷基)、-C(＝O)N(C1-C6烷基)2、-OC(＝O)(C1-C6烷基)、-NHC(＝O)(C1-C6烷基)、-C(＝O)(C1-C6烷基)；或者
相邻的两个R1和与其相连的A环一起形成[C6-C12芳环]并[5-6元杂芳环]，特别地，相邻的两个R1和与其相连的A环一起形成苯并[5元氮杂芳环]，更特别地，相邻的两个R1和与其相连的A环一起形成苯并吡咯基团；
其中所述杂芳基、杂环基或杂芳环各自独立地含有1、2、3或4个选自N、O和S中的杂原子。
在一些实施方式中，X1和X2各自独立地选自H、C1-C4烷基、羟基取代的C1-C4烷基、苯基；或者
X1和X2彼此连接并和与其相连的碳原子形成C3-C6亚环烷基；
Y选自H、-OH或卤素；
Z选自H、C1-C4烷基、C3-C6环烷基、苯基，更优选自H、甲基、乙基、叔丁基、环己基、苯基；
R选自H、C1-C4烷基；优选选自H、甲基、乙基；
A环选自环己基、苯基、吡啶基；
R1各自独立地选自氨基、卤素、-O(C1-C6烷基)、-NO2、-CN、-C(＝O)O(C1-C6烷基)；
或者，相邻的两个R1和与其相连的A环一起形成苯并[5元氮杂芳环]，更特别地，相邻的两个R1和与其相连的A环一起形成苯并吡咯基团。
在一些实施方式中，式I化合物选自如下式I-a化合物：
其中，X1、Z、m、A环和(R1)n的定义与前述相同。
在一些实施方式中，式I化合物选自如下式I-b化合物：
其中，A环和(R1)n的定义与前述相同。
在一些优选实施方式中，式I化合物选自下列化合物：
本发明中的术语定义如下：
所述“卤素”可以为氟、氯、溴或碘。
“C1-Cn烷基”是指具有1-n(n大于1)个碳原子的直链或支链烷基；所述“C1-C6烷基”是指具有1-6个碳原子的直链或支链烷基；其具体实例可以包括甲基、乙基、丙基、正丙基、异丙基、丁基、正丁基、异丁基、叔丁基、1-甲基-丁基、1-乙基-丁基、戊基、正戊基、异戊基、新戊基、叔戊基、己基、正己基、1-甲基戊基、2-甲基戊基、4-甲基-2-戊基、3,3-二甲基丁基、2-乙基丁基以及类似基团，但不限于此。“C1-C4烷基”的定义类似。
所述“C3-C8环烷基”是指包含3-8个环碳原子的完全饱和的1价环状烃类化合物基团，其具体实例包括环丙基、环丁基、环戊基、环己基。C3-C6环烷基的定义类似。
所述“3-10元杂环基”是指环上含有1至4个选自氮、氧、硫中的杂原子的3-10元杂环烷基团，其具体实例包括环氧乙烷、四氢咪唑、四氢呋喃。
所述“C6-C12芳基”是指具有6至12个碳原子的单环或多环芳基；其具体实例包括苯基、萘基。
所述“5-6元杂芳基”是指环上含有1至4个选自氮、氧、硫中的杂原子的环原子数为5-6的芳族基团，其具体实例包括吡啶、哒嗪、嘧啶、吡咯等。
所述“C3-C6亚环烷基”是指从前述定义的“C3-C6环烷基”再去掉任意位置的一个氢原子后的2价取代基，其具体实例包括亚环丙基亚环丁基/>等。
本申请中，各取代基与母核的连接关系以连接位点满足价态需求。例如，吡啶基，其与母核的连接可以是2位、3位或4位，即吡啶基可以表示2-吡啶基、3-吡啶基、4-吡啶基。其他基团类似。
“药学上可接受的盐”包括式I化合物的阴离子盐和阳离子盐，例如式I化合物与酸或碱形成的盐；所述酸包括无机酸、有机酸；优选地，所述无机酸包括盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸；优选地，所述有机酸包括甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、柠檬酸、枸橼酸、酒石酸、碳酸、苦味酸、甲磺酸、乙磺酸、对甲苯磺酸、谷氨酸、双羟萘酸；所述碱包括钠、钾、钙、铝、锂和铵的氢氧化物、碳酸盐、碳酸氢盐等。
本申请所涉及的化合物及其前药、可药用盐、酯可具有异构体或消旋体，例如光学异构体(包括非对映异构体和对映异构体)、阻转异构体、几何异构体(顺反异构体)、构象异构体、互变异构体以及它们的混合物等，但不限于此。这些异构体也包含在本发明的权利要求所限定的范围中。
本发明第二方面提供了一种所述的化合物、其异构体、药学上可接受的盐、酯、前药或溶剂合物的制备方法，包括以下步骤：
(1)按照如下路线制备中间体Ⅳ：
以化合物Ⅱ(S)-(-)-1,2,3,4-四氢异喹啉-3-羧酸为原料，溶解在溶剂A中，缓慢滴加含三光气的溶液；滴毕，惰性气体保护下，回流反应2-5小时；反应毕，稍冷，减压浓缩，蒸除大部分溶剂A，残留物用石油醚打浆，真空干燥；所得化合物溶解在溶剂B中，冰水浴下，缓慢滴加叔丁胺；滴毕，撤去冰浴，室温下搅拌过夜；反应液用2N HCl洗涤，合并水相，调pH至8-9，并加少量碎冰控制温度；接着用二氯甲烷萃取，浓缩，石油醚洗涤，真空干燥，得化合物Ⅲ；
将化合物Ⅲ加入高压反应釜中，加溶剂C溶解，并加入催化剂；惰性气体置换3次，氢气置换3次，调节至合适压力，油浴加热至80～180℃反应过夜；反应毕，冷却，泄压，滤除催化剂，减压浓缩，柱色谱纯化得中间体Ⅳ；
其中，所述溶剂A、溶剂B和溶剂C各自独立地为选自丙酮、乙腈、甲苯、二氯甲烷、四氢呋喃、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙醇、异丙醇、正丁醇、异丁醇中的一种或者多种；
所用催化剂为选自湿钯-炭、干钯-炭、钌-炭、钌-氧化铝、铑炭、铑-氧化铝、雷尼镍、二氧化铂中的一种或者多种；
所述化合物Ⅱ、三光气、叔丁胺的摩尔比例为1:1:1.5-1:1.5:4，最优摩尔比例为1:1.2:2；
(2)中间体Ⅳ按照如下三种路线之一制备目标化合物Ⅰ：
路线一：
步骤1：将中间体Ⅳ溶于溶剂D，加入反应物Ⅴ间硝基苯磺酸缩水甘油酯(R型或S型)，在碱性条件下，惰性气体保护，油浴加热至50～120℃，反应2-5小时；反应毕，反应液用乙酸乙酯稀释，依次用碳酸氢钠水溶液、饱和食盐水洗涤；有机相用无水硫酸钠干燥，减压浓缩，柱色谱纯化得化合物Ⅵ；
步骤2：将化合物Ⅵ溶于溶剂E，加入对应的胺Ⅶ，惰性气体保护，回流反应过夜；反应毕，减压浓缩，选用合适的显色剂，色谱法纯化，得目标化合物Ia；
其中，所述溶剂D和溶剂E各自独立地为选自丙酮、乙腈、甲苯、二氯甲烷、四氢呋喃、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、水、甲醇、乙醇、异丙醇、正丁醇、异丁醇中的一种或者多种；
所用的碱为选自下述无机碱和有机碱中的一种或多种，无机碱：碳酸钠、碳酸钾、碳酸铯、磷酸钾、氢氧化钠、氢氧化钾、钠氢，有机碱：N,N-二甲基氨基吡啶、三乙胺、二异丙基乙基胺、三丁胺、叔丁醇钾中；
所述中间体Ⅳ、反应物Ⅴ、碱的摩尔比例为1:1:1-1:1.5:2，最优摩尔比例为1:1.1:1.2；
所述化合物Ⅵ、胺Ⅶ的摩尔比例为1:1-1:2，最优摩尔比例为1:1.2。
路线二：
步骤1：中间体Ⅳ用溶剂F溶解后，接着先后加入碱、苄溴，惰性气体保护下，加热至50～120℃，反应过夜；反应毕，反应液用乙酸乙酯稀释，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，柱色谱分离得化合物Ⅷ；
步骤2：将浓硫酸用溶剂G稀释后，加入化合物Ⅷ，惰性气体保护下，回流反应过夜；反应毕，将反应液倾倒入水中，二氯甲烷萃取除杂质；接着，水相加入碱中和，再用二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，浓缩，柱色谱分离，得化合物Ⅸ；
步骤3：将化合物Ⅸ溶解在溶剂H中，先后加入1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐、1-羟基苯并三唑、二异丙基乙基胺，室温下搅拌30分钟后，加入相应的胺，继续室温搅拌1小时；反应液用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱色谱分离得化合物Ⅹ；
步骤4：将化合物Ⅹ加入反应瓶中，加溶剂I溶解，并加入催化剂；惰性气体置换3次，氢气置换3次，调节至合适压力，油浴加热至50～100℃，反应3-10小时；反应毕，冷却，泄压，滤除催化剂，减压浓缩，柱色谱纯化得化合物Ⅺ；
步骤5：将化合物Ⅺ溶于溶剂I，加入反应物Ⅴ间硝基苯磺酸缩水甘油酯(R型或S型)，在碱性条件下，惰性气体保护，油浴加热至50～120℃，反应2-5小时；反应毕，反应液用乙酸乙酯稀释，依次用碳酸氢钠水溶液、饱和食盐水洗涤；有机相用无水硫酸钠干燥，减压浓缩，柱色谱纯化得化合物Ⅻ；
步骤6：将化合物Ⅻ溶于溶剂K，加入对应的胺Ⅶ，惰性气体保护，回流反应过夜；反应毕，减压浓缩，选用合适的显色剂，色谱法纯化，得目标化合物Ib；
其中，所述溶剂F、溶剂G、溶剂H、溶剂I、溶剂J和溶剂K各自独立地为选自丙酮、乙腈、甲苯、二氯甲烷、四氢呋喃、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、水、甲醇、乙醇、异丙醇、正丁醇、异丁醇中的一种或者多种；
所用的碱为选自下述无机碱和有机碱中的一种或多种，无机碱：碳酸钠、碳酸钾、碳酸铯、磷酸钾、氢氧化钠、氢氧化钾、钠氢，有机碱：N,N-二甲基氨基吡啶、三乙胺、二异丙基乙基胺、三丁胺、叔丁醇钾；
所用催化剂为湿钯-炭、干钯-炭、钌-炭、钌-氧化铝、铑炭、铑-氧化铝、雷尼镍、二氧化铂中的一种或者多种。
路线三：
步骤1：中间体Ⅳ、N-Boc-3-氨基丙基溴、碱和溶剂L，回流反应过夜；反应毕，滤除碱，并用乙酸乙酯洗涤滤饼，浓缩滤液，色谱分离；将产物溶于4M HCl/二氧六环，室温下搅拌；反应毕，减压浓缩，残留物用水溶解，接着用碱中和，二氯甲烷萃取，浓缩得化合物XIII；
步骤2：化合物XIII用溶剂M溶解，加入羰基化合物XIV和路易斯酸，惰性气体保护，回流反应3-10小时；LC-MS跟踪反应至反应完全；
步骤3：室温下，在步骤2反应液中加入还原剂，室温搅拌1-6小时；反应毕，加入饱和碳酸氢钠溶液淬灭；乙酸乙酯/水分液，合并有机相，干燥浓缩，色谱分离得化合物Ic；
其中，所述溶剂L和溶剂M各自独立地为选自丙酮、乙腈、甲苯、二氯甲烷、四氢呋喃、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、水、甲醇、乙醇、异丙醇、正丁醇、异丁醇中的一种或者多种；
所用的碱为选自下述无机碱和有机碱中的一种或多种，无机碱：碳酸钠、碳酸钾、碳酸铯、磷酸钾、氢氧化钠、氢氧化钾、钠氢，有机碱：N,N-二甲基氨基吡啶、三乙胺、二异丙基乙基胺、三丁胺、叔丁醇钾；
所用路易斯酸为乙酸、四氯化钛、钛酸四异丙酯中的一种或者多种；
所用还原剂为四氢锂铝、硼氢化钠、氰基硼氢化钠中的一种或者多种；
以上各路线中所涉及的取代基分别如上所述。
本发明第三方面提供了一种药物组合物，其包括选自式I化合物、其异构体、药学上可接受的盐、酯、前药和溶剂合物中的一种或多种，以及任选存在的药学上可接受的载体。
药学上可接受的载体是指药学领域常规的药物载体，例如：稀释剂，如水等；填充剂，如淀粉、蔗糖等；粘合剂，如纤维素衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮；湿润剂，如甘油；崩解剂，如琼脂、碳酸钙和碳酸氢钠；吸收促进剂，如季铵化合物；表面活性剂，如十六烷醇；吸附载体，如高岭土和皂粘土；润滑剂，如滑石粉、硬脂酸钙和硬脂酸镁和聚乙二醇等。另外，还可以在上述药物组合物中加入其它辅剂，如香味剂和甜味剂等。
本发明第四方面提供了上述化合物或上述药物组合物在制备EBOV-GP抑制剂中的应用。
本发明第五方面提供了上述化合物或上述药物组合物在制备用于预防和/或治疗埃博拉的药物中的应用。
有益效果：
本发明从多样性小分子化合物库中筛选出一类全新的拟肽类化合物，作为抗埃博拉先导化合物，运用基于结构的药物设计，在特定位置引入不同取代基和特殊成药性基团，获得一系列埃博拉侵入抑制剂候选苗头化合物，对埃博拉病毒具有较强的生物活性和较好的选择性。通过对该类化合物的研究，可为相关病毒的爆发应急储备备选化合物，提升国家应对重大公共卫生事件的能力。
此外，本发明所设计的目标分子均为手性分子，包括三或四个手性中心。通过本发明的合成和活性测试研究，可阐明这些新型手性分子与靶标的相互作用机制，揭示手性立体异构体的微观作用与宏观药理活性之间的关系。
该类化合物为埃博拉侵入抑制剂，作用于EBOV-GP靶点，具有较强的生物活性和较好的选择性。
在上文中已经详细地描述了本发明，但是上述实施方式本质上仅是例示性，且并不欲限制本发明。此外，本文并不受前述现有技术或发明内容或以下实施例中所描述的任何理论的限制。
具体实施方式
下面结合实施例对本发明作进一步的说明，需要说明的是，提供以下实施例仅出于说明目的并不构成对本发明要求保护范围的限制。
除特殊说明外，在实施例中所采用的原料、试剂、方法等均为本领域常规的原料、试剂、方法。
本发明中，室温指环境温度，为10℃-35℃。过夜是指8-15小时。回流是指常压下溶剂回流温度。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。MS的测定用Finnigan LCQ/Deca(ESI)质谱仪。高效液相色谱法(HPLC)分析使用Gilson-215高压液相色谱仪。
薄层层析硅胶板使用烟台黄海HSGF 254或青岛GF 254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.2mm,薄层层析分离纯化产品采用的规格是0.4mm -0.5mm。硅胶柱色谱法一般使用烟台黄海硅胶200-300目硅胶为载体。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括二氯甲烷/甲醇体系和石油醚/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自上海皓鸿生物医药科技有限公司、毕得医药等公司。实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。
实施例1-1：(S)-1,2,3,4-四氢异喹啉-3-甲酰叔丁胺III的合成
在2L三口瓶中，加入化合物Ⅱ(S)-(-)-1,2,3,4-四氢异喹啉-3-羧酸(80.0g，452mmol) 和四氢呋喃400mL，慢慢滴加含三光气(64.0g，218mmol)的四氢呋喃溶液300mL。滴毕，氮气保护下回流反应2h。稍冷，浓缩除去大部分溶剂，加入石油醚打浆，真空干燥得64g化合物XV，淡黄色固体。
在2L三口瓶中，加入64g化合物XV与二氯甲烷700mL，冰水浴，缓慢滴加叔丁胺180mL，室温搅拌过夜。反应毕，反应液用2N HCl洗涤，合并水相，小心用氢氧化钠调 pH至8-9(酸碱中和放热，注意控制温度)。二氯甲烷萃取，浓缩。石油醚洗涤，真空干燥得55.0g白色固体Ⅲ，两步总收率52.4％。1H NMR(400MHz,DMSO-d6)δ7.38(s,1H),7.10 (d,J＝2.8Hz,3H),7.03(d,J＝2.6Hz,1H),3.92–3.79(m,2H),3.30(dd,J＝10.3,4.6Hz,1H), 2.84(dd,J＝16.2,4.6Hz,1H),2.66(dd,J＝16.2,10.2Hz,1H),2.54(s,1H),1.28(s,9H).
实施例1-2：(3S,4aS,8aS)-十氢异喹啉-3-甲酰叔丁胺IV的合成
将Rh/C(1.0g，5％w/w)与异丙醇500mL加入高压反应釜中，再加入化合物Ⅲ(52.0g， 224mmol)。反应釜用氮气置换3次，氢气置换3次，调节压力至30个大气压，130℃下反应16h。反应毕，冷却，泄压，反应液用硅藻土助滤，浓缩。柱色谱分离得白色固体IV 44.1g，收率82.6％。1H NMR(400MHz,DMSO-d6)δ7.10(s,1H),2.91(dd,J＝11.2,3.1Hz,1H), 2.66(qd,J＝12.8,2.6Hz,2H),1.78–1.16(m,22H).13C NMR(101MHz,DMSO-d6)δ173.20, 60.91,51.24,50.07,35.58,34.32,31.94,29.91,28.92,26.44,24.88,20.80.
实施例1-3：(3S,4aS,8aS)-2-[(S)-环氧乙烷-2-甲基]十氢异喹啉-3-甲酰叔丁胺VI-1的合成
在250mL反应瓶中依次加入化合物Ⅳ(3.00g，12.6mmol)，二异丙基乙胺(1.95g，15.1mmol)及DMF 50mL，最后加入(R)-间硝基苯磺酸缩水甘油酯V-1(3.59g，13.8mmol)。氮气保护下，100℃下反应5h。TLC跟踪反应。反应毕，反应液用碳酸氢钠溶液稀释，乙酸乙酯萃取。合并有机相，水洗，干燥，浓缩，柱色谱分离，得2.41g淡黄色油状液体Ⅵ-1，收率64.8％。1HNMR(400MHz,CDCl3)δ6.56(s,1H),3.04(dt,J＝6.7,3.4Hz,1H),2.94(dd, J＝11.3,2.1Hz,1H),2.82–2.76(m,1H),2.53(dd,J＝10.6,3.6Hz,1H),2.46(dd,J＝5.0,2.6 Hz,1H),2.33(ddd,J＝17.2,13.8,5.3Hz,2H),2.23(dd,J＝11.4,3.4Hz,1H),1.81–1.75(m, 1H),1.71(d,J＝3.6Hz,1H),1.62–1.52(m,2H),1.52–1.46(m,2H),1.41–1.35(m,2H),1.33 –1.26(m,11H),1.25–1.14(m,2H).13C NMR(101MHz,CDCl3)δ173.90,77.48,77.16,76.84, 69.27,58.97,58.83,50.43,49.51,46.51,35.94,33.08,30.92,30.69,28.70,28.62,26.40,25.70, 20.37.
实施例1-4：(3S,4aS,8aS)-2-[(R)-环氧乙烷-2-甲基]十氢异喹啉-3-甲酰叔丁胺VI-2的合成
在100mL反应瓶中依次加入化合物Ⅳ(1.67g，7.01mmol)，二异丙基乙胺(1.09g，8.41mmol)及DMF 30mL，最后加入(S)-间硝基苯磺酸缩水甘油酯V-2(2.00g，7.71mmol)。氮气保护下，100℃下反应5h。TLC跟踪反应。反应毕，反应液用碳酸氢钠溶液稀释，乙酸乙酯萃取。合并有机相，水洗，干燥，浓缩，柱色谱分离，得1.52g淡黄色固体Ⅵ-2，收率73.6％。1HNMR(400MHz,CDCl3)δ6.58(s,1H),2.96(dd,J＝12.2,8.1Hz,2H),2.88(dd,J ＝11.7,2.0Hz,1H),2.74–2.69(m,1H),2.63(dd,J＝5.3,2.6Hz,1H),2.57(dd,J＝10.9,3.4 Hz,1H),2.19(dd,J＝11.7,3.3Hz,1H),2.06(dd,J＝14.4,4.6Hz,1H),1.80–1.66(m,4H), 1.56(dd,J＝8.6,3.3Hz,1H),1.52–1.46(m,2H),1.41–1.31(m,13H),1.26–1.19(m,2H).
实施例1：(3S,4aS,8aS)-2-[(R)-3-苄氨基-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺1的合成
在25mL反应瓶中依次加入化合物Ⅵ-1(294mg，1.0mmol)，乙醇10mL及苄胺(214mg，2.0mmol)，氮气保护下，回流反应过夜。TLC，化合物Ⅵ-1已反应完毕。将反应液直接减压浓缩，色谱分离，得淡黄色油状物1 120mg，收率29.9％。1H NMR(400MHz,CD3OD) δ7.36(ddd,J＝25.2,16.9,7.2Hz,5H),3.88(dt,J＝20.7,8.4Hz,3H),3.03(d,J＝11.4Hz,1H), 2.79–2.57(m,3H),2.47(dd,J＝13.2,8.6Hz,1H),2.22–2.10(m,2H),1.92(dd,J＝24.5,12.7 Hz,1H),1.83–1.54(m,6H),1.48–1.21(m,15H).13C NMR(101MHz,CD3OD)δ175.08, 128.47,128.18,127.22,69.21,66.09,60.27,58.71,52.95,52.86,50.50,36.12,33.37,30.71,30.61,27.38,26.10,25.20,20.00.
实施例2：(3S,4aS,8aS)-2-[(R)-3-苄基乙氨基-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺2的合成
制备方法参照实施例1，将苄胺换成N-乙基苄胺，得到化合物2。1H NMR(600MHz,CD3OD)δ7.28(ddd,J＝39.6,15.7,7.0Hz,5H),4.59(s,2H),3.87–3.58(m,3H),2.86(d,J＝11.5Hz,1H),2.66–2.56(m,2H),2.53(dd,J＝11.3,3.1Hz,1H),2.41(s,2H),2.31–2.07(m,2H),1.87(dd,J＝24.6,12.9Hz,1H),1.79–1.71(m,2H),1.64–1.51(m,3H),1.42(ddd,J＝16.4,7.0,3.3Hz,2H),1.36–1.25(m,12H),1.08(t,J＝6.8Hz,3H).13C NMR(151MHz, CD3OD)δ175.31,128.90,127.90,126.78,69.23,64.74,64.36,60.66,58.46,58.12,50.39,48.05,36.02,33.36,30.68,29.22,27.30,27.27,26.06,25.54,25.16,19.99.
实施例3：(3S,4aS,8aS)-2-[(R)-3-环己基甲氨基-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺3的合成
制备方法参照实施例1，将苄胺换成环己基甲胺，得到化合物3。1H NMR(400MHz,CDCl3)δ5.93(s,1H),3.95(s,1H),3.37–3.18(m,2H),2.82–2.67(m,3H),2.58(dd,J＝11.4,3.1Hz,1H),2.45(dd,J＝13.5,5.6Hz,1H),2.36(d,J＝12.1Hz,1H),2.21(dd,J＝22.8,9.6Hz, 1H),2.03–1.82(m,3H),1.71(dd,J＝23.4,8.5Hz,6H),1.55–1.40(m,4H),1.38–1.14(m, 18H),1.07–0.95(m,2H).13C NMR(126MHz,CDCl3)δ174.11,70.39,66.15,60.42,55.67, 53.85,51.45,37.00,36.13,33.40,31.32,31.24,31.04,29.85,28.79,26.52,26.38,25.92,20.55.
实施例4：(3S,4aS,8aS)-2-[(R)-3-(4-氨基苄基)氨基-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺4 的合成
制备方法参照实施例1，将苄胺换成4-(氨甲基)苯胺，得到化合物4。1H NMR(400MHz, CDCl3)δ7.09(d,J＝8.1Hz,2H),6.63(d,J＝8.3Hz,2H),6.47(s,1H),3.84(dd,J＝9.9,7.7Hz, 1H),3.72–3.56(m,4H),2.89(d,J＝11.2Hz,1H),2.66(d,J＝10.7Hz,1H),2.60–2.55(m, 1H),2.48(ddd,J＝16.2,12.4,9.2Hz,2H),2.10(dd,J＝11.5,3.0Hz,1H),1.98(d,J＝12.5Hz, 1H),1.89–1.63(m,5H),1.53(dd,J＝22.5,7.7Hz,5H),1.40–1.19(m,13H).13C NMR(151 MHz,CDCl3)δ173.79,145.48,129.34,115.10,70.02,65.97,60.22,58.39,53.32,52.74,50.68, 35.88,33.30,30.99,30.88,28.61,26.36,25.60,20.29.
实施例5：(3S,4aS,8aS)-2-{(R)-3-[(1H-吲哚-5-甲胺)-2-羟基丙基]}十氢异喹啉-3-甲酰叔丁胺 5的合成
制备方法参照实施例1，将苄胺换成(1H-吲哚-5-)甲胺，得到化合物5。1H NMR(400MHz, CD3OD)δ7.52(s,1H),7.35(d,J＝8.3Hz,1H),7.21(d,J＝3.1Hz,1H),7.11(d,J＝9.3Hz, 1H),6.41(d,J＝2.8Hz,1H),3.83(d,J＝11.3Hz,3H),3.35(s,2H),2.88(d,J＝10.8Hz,1H), 2.67–2.48(m,3H),2.38(dd,J＝13.0,9.2Hz,1H),2.07(dd,J＝11.5,2.9Hz,1H),2.00(d,J＝ 12.8Hz,1H),1.91–1.80(m,1H),1.74–1.65(m,2H),1.59(d,J＝11.5Hz,1H),1.54–1.45(m, 3H),1.42–1.14(m,15H).13C NMR(101MHz,CD3OD)δ176.60,137.22,130.31,129.67, 126.17,123.41,121.60,112.37,102.47,70.65,67.60,61.84,59.91,55.24,54.16,51.95,50.00, 37.54,34.84,32.21,32.12,28.92,27.58,26.64,21.49.
实施例6：(3S,4aS,8aS)-2-[(R)-3-(4-甲氧基苄基氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺6的合成
制备方法参照实施例1，将苄胺换成4-甲氧基苄胺，得到化合物6。1H NMR(400MHz,CDCl3)δ7.55(dd,J＝8.7,2.9Hz,2H),6.91–6.83(m,2H),6.13(d,J＝11.8Hz,1H),4.24–4.05(m,3H),3.78(d,J＝1.5Hz,3H),3.41(d,J＝13.1Hz,1H),3.34–3.06(m,1H),2.96(dd,J＝12.1,3.9Hz,1H),2.82(d,J＝11.1Hz,1H),2.60–2.34(m,2H),2.01(d,J＝22.1Hz,1H),1.77–1.66(m,1H),1.54–0.97(m,20H).13C NMR(101MHz,CDCl3)δ173.91,160.15,131.66,124.28,114.24,69.45,65.33,64.09,60.45,55.31,51.49,40.88,36.83,33.75,32.89,29.80,28.61, 25.46,21.12.
实施例7：(3S,4aS,8aS)-2-[(R)-3-(3-甲氧基苄基氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺 7的合成
制备方法参照实施例1，将苄胺换成3-甲氧基苄胺，得到化合物7。1H NMR(400MHz,CDCl3)δ7.23(t,J＝8.0Hz,1H),6.93(d,J＝5.0Hz,2H),6.79(dd,J＝8.1,1.9Hz,1H),6.36(s, 1H),3.89–3.78(m,6H),2.94(d,J＝10.9Hz,1H),2.77(s,1H),2.61–2.48(m,3H),2.08(dd,J ＝26.9,11.9Hz,2H),1.86–1.72(m,2H),1.68–1.45(m,6H),1.34(s,12H),1.28–1.14(m, 3H).13C NMR(151MHz,CDCl3)δ173.70,159.79,129.48,120.64,113.73,112.93,70.05,66.05, 60.10,58.60,55.22,53.58,52.90,50.78,35.88,33.29,30.95,30.87,28.61,26.36,25.55,20.25.
实施例8：(3S,4aS,8aS)-2-[(R)-3-(4-氰基苄基氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺8 的合成
制备方法参照实施例1，将苄胺换成4-氰基苄胺，得到化合物8。1H NMR(400MHz,CDCl3)δ7.58(d,J＝8.1Hz,2H),7.43(d,J＝8.1Hz,2H),6.28(s,1H),3.84(s,2H),2.84(d,J＝11.3Hz,1H),2.55(dddd,J＝34.8,19.4,11.8,4.9Hz,4H),2.12(dd,J＝11.5,3.1Hz,1H),1.97(dd,J＝12.7,1.9Hz,1H),1.88–1.66(m,4H),1.63–1.46(m,4H),1.42–1.13(m, 15H).13C NMR(101MHz,CDCl3)δ173.75,145.68,132.28,128.79,118.99,110.84,77.48, 77.16,76.84,70.05,66.08,59.75,58.30,53.42,53.04,50.88,35.86,33.33,30.98,30.91,28.65, 26.38,25.63,20.31.
实施例9：(3S,4aS,8aS)-2-[(R)-3-(3-氰基苄基氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺9 的合成
制备方法参照实施例1，将苄胺换成3-氰基苄胺，得到化合物9。1H NMR(400MHz，CDCl3)δ8.10(d,J＝7.2Hz,1H),7.96(s,1H),7.64(d,J＝7.8Hz,1H),7.53(t,J＝7.8Hz,1H), 6.07(s,1H),4.20(q,J＝12.2Hz,2H),4.00(s,1H),3.57(s,1H),3.47–3.36(m,1H),3.01(d,J ＝11.1Hz,1H),2.74–2.67(m,1H),2.61–2.47(m,2H),2.17(dd,J＝12.1,3.1Hz,1H),1.63– 1.55(m,1H),1.46–1.31(m,15H),1.30–1.15(m,5H).13C NMR(126MHz,CDCl3)δ173.65, 135.09,133.77,132.41,129.83,118.29,112.73,69.82,65.98,60.52,53.70,51.68,51.49,50.69, 35.79,32.94,30.59,30.38,29.69,28.69,26.29,25.17,20.03.
实施例10：(3S,4aS,8aS)-2-[(R)-3-(4-硝基苄基氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺 10的合成
制备方法参照实施例1，将苄胺换成4-硝基苄胺，得到化合物10。1H NMR(400MHz,CDCl3)δ8.17(d,J＝8.5Hz,2H),7.53(d,J＝8.2Hz,2H),6.18(s,1H),4.00–3.83(m,3H),2.90(d,J＝11.5Hz,1H),2.73(d,J＝10.1Hz,1H),2.63–2.48(m,3H),2.17–2.11(m,1H),2.03(d,J＝12.7Hz,1H),1.87–1.47(m,10H),1.37(d,J＝32.7Hz,12H).13C NMR(101MHz,CDCl3)δ173.66,147.23,128.98,123.76,77.48,77.16,76.84,70.19,66.16,59.76,58.45,53.15, 50.99,35.92,33.38,31.03,30.95,28.75,26.43,25.68,20.35.
实施例11：(3S,4aS,8aS)-2-[(R)-3-(4-甲氧羰基苄基氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺11的合成
制备方法参照实施例1，将苄胺换成4-(氨甲基)苯甲酸甲酯，得到化合物11。1HNMR (400MHz,CDCl3)δ8.00(t,J＝7.6Hz,2H),7.41(dd,J＝13.6,8.2Hz,2H),6.24(s,1H),3.95– 3.88(m,5H),3.77–3.66(m,1H),3.48(q,J＝7.0Hz,2H),2.92(d,J＝11.4Hz,1H),2.75(d,J ＝12.7Hz,1H),2.55(ddd,J＝18.2,13.2,6.7Hz,2H),2.27–2.09(m,1H),2.05–1.98(m,2H), 1.64(dd,J＝15.6,7.7Hz,3H),1.51(d,J＝9.1Hz,2H),1.35–1.21(m,14H).13CNMR(101 MHz,CDCl3)δ173.67,166.91,129.90,129.83,128.72,127.01,77.39,77.07,76.75,70.03, 66.00,60.07,53.07,52.95,52.14,52.09,50.98,35.82,33.24,30.83,30.80,28.63,26.30,25.39, 20.12.
实施例12：(3S,4aS,8aS)-2-[(R)-3-(4-氟苄基氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺12 的合成
制备方法参照实施例1，将苄胺换成4-氟苄胺，得到化合物12。1H NMR(400MHz,CDCl3)δ7.38(s,2H),7.01(t,J＝8.3Hz,2H),6.18(s,1H),3.86(s,3H),3.01(s,2H),2.63–2.48(m,3H),2.12(d,J＝10.8Hz,2H),1.82–1.71(m,3H),1.48(s,3H),1.35(s,12H),1.22(d, J＝23.9Hz,4H).13C NMR(126MHz,CDCl3)δ173.13,161.77(d,JC-F＝246.7Hz),129.85,114.90,114.73,69.64,65.57,59.55,52.42,52.20,50.43,35.37,32.78,30.41,30.34,29.20,28.13, 25.82,24.97,19.70.
实施例13：(3S,4aS,8aS)-2-[(R)-3-(3-氟苄基氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺13 的合成
制备方法参照实施例1，将苄胺换成3-氟苄胺，得到化合物13。1H NMR(400MHz,CDCl3)δ7.29(d,J＝7.6Hz,1H),7.10(dd,J＝18.9,8.1Hz,2H),6.94(t,J＝7.5Hz,1H),6.28(s,1H),3.85(d,J＝14.5Hz,3H),2.93(d,J＝11.2Hz,1H),2.76(s,1H),2.63–2.48(m,3H),2.13(d,J＝11.2Hz,1H),2.04(d,J＝12.5Hz,1H),1.79(dd,J＝25.9,14.8Hz,2H),1.66(s,1H), 1.51(dd,J＝13.6,8.4Hz,3H),1.42–1.19(m,15H).13C NMR(126MHz,CDCl3)δ173.63,162.97(d,JC-F＝245.9Hz),129.96,129.90,123.89,115.11(d,JC-F＝18.2Hz),114.10(d,JC-F＝ 21.3Hz),77.29,77.04,76.78,70.08,66.06,59.92,58.53,53.12,52.91,50.82,35.86,33.29, 30.94,30.86,29.70,28.62,26.34,25.56,20.25.
实施例14：(3S,4aS,8aS)-2-[(R)-3-(2-氟苄基氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺14 的合成
制备方法参照实施例1，将苄胺换成2-氟苄胺，得到化合物14。1H NMR(400MHz,CDCl3)δ7.70(s,1H),7.34–7.27(m,1H),7.16(t,J＝7.3Hz,1H),7.06(t,J＝9.0Hz,1H),6.12 (s,1H),4.26(d,J＝11.3Hz,1H),4.08–3.95(m,2H),3.28(s,2H),2.89(s,1H),2.69(d,J＝11.2Hz,1H),2.54(dd,J＝13.5,5.8Hz,1H),2.43(s,1H),2.24–2.16(m,1H),1.75(dd,J＝ 24.3,13.7Hz,2H),1.42(d,J＝12.8Hz,3H),1.37–1.22(m,16H).13C NMR(126MHz,CDCl3) δ172.77,160.65(d,JC-F＝248.0Hz),131.40,129.75(d,JC-F＝7.8Hz),124.00,123.97,114.95 (d,JC-F＝21.5Hz),69.39,65.44,59.82,59.41,52.37,50.78,45.29,35.33,32.65,30.26,30.22, 29.19,28.12,25.79,24.81,19.63.
实施例15：(3S,4aS,8aS)-2-[(R)-3-(4-氯苄基氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺15 的合成
制备方法参照实施例1，将苄胺换成4-氯苄胺，得到化合物15。1H NMR(400MHz,CDCl3)δ7.30(dd,J＝17.0,8.3Hz,4H),6.23(s,1H),3.98–3.68(m,3H),2.97(d,J＝11.5Hz,1H),2.83(d,J＝7.1Hz,1H),2.61–2.47(m,4H),2.10(t,J＝13.6Hz,2H),1.85–1.73(m,2H),1.57(dd,J＝42.9,18.5Hz,7H),1.38(d,J＝31.4Hz,13H).13C NMR(101MHz,CDCl3)δ173.66,133.19,129.93,128.62,105.00,77.37,77.05,76.73,70.08,66.01,59.99,58.73,52.90, 52.79,50.89,35.84,33.27,30.90,30.84,29.71,28.62,26.32,25.48,20.20.
实施例16：(3S,4aS,8aS)-2-[(R)-3-(3-氯苄基氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺16 的合成
制备方法参照实施例1，将苄胺换成3-氯苄胺，得到化合物16。1H NMR(400MHz,CD3OD)δ7.57(s,1H),7.43–7.32(m,3H),4.03(d,J＝12.9Hz,1H),3.90(dd,J＝8.8,3.7Hz,2H),3.13(d,J＝11.6Hz,1H),2.86(d,J＝34.3Hz,2H),2.66(dd,J＝11.0,3.0Hz,1H),2.51(dd,J＝13.5,6.6Hz,1H),2.25(d,J＝13.2Hz,1H),2.17(dd,J＝11.7,3.2Hz,1H),1.81(dt,J＝ 25.5,13.1Hz,2H),1.52(d,J＝11.1Hz,4H),1.42–1.12(m,17H).13C NMR(126MHz,CD3OD)δ174.89,134.13,129.83,129.14,127.88,127.42,69.15,65.99,60.23,53.24,51.95, 50.59,36.16,33.32,30.65,30.44,27.46,26.11,25.22,19.94.
实施例17：(3S,4aS,8aS)-2-[(R)-3-(2-氯苄基氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺17 的合成
制备方法参照实施例1，将苄胺换成2-氯苄胺，得到化合物17。1H NMR(400MHz,CDCl3)δ7.44(d,J＝6.3Hz,1H),7.34(dd,J＝7.2,1.8Hz,1H),7.21(qd,J＝7.4,5.7Hz,2H),6.50(s,1H),3.94(dt,J＝18.6,9.3Hz,3H),2.97(d,J＝11.4Hz,1H),2.79(d,J＝11.1Hz,1H), 2.71–2.62(m,1H),2.60–2.48(m,2H),2.13(dd,J＝19.9,12.2Hz,2H),1.87–1.70(m,3H), 1.68–1.56(m,3H),1.53–1.45(m,3H),1.37–1.30(m,11H),1.29–1.18(m,3H).13C NMR(126MHz,CDCl3)δ172.50,132.88,129.50,128.55,127.73,125.90,68.85,64.87,59.12,57.68, 51.69,49.82,34.81,32.18,29.94,29.84,29.82,27.65,27.62,27.58,25.32,24.51,19.24.
实施例18：(3S,4aS,8aS)-2-[(R)-3-(4-溴苄基氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺18 的合成
制备方法参照实施例1，将苄胺换成4-溴苄胺，得到化合物18。1H NMR(400MHz,CD3OD)δ7.48(t,J＝9.0Hz,2H),7.35(d,J＝8.3Hz,2H),3.91–3.75(m,3H),3.01(d,J＝11.6Hz,1H),2.73(dd,J＝11.6,3.3Hz,1H),2.62(dd,J＝11.1,3.2Hz,2H),2.45(dd,J＝13.3, 8.1Hz,1H),2.14(t,J＝11.1Hz,2H),1.87(dd,J＝24.7,12.3Hz,1H),1.75(d,J＝13.0Hz,1H), 1.59(dd,J＝35.3,13.9Hz,5H),1.44–1.18(m,15H).13C NMR(126MHz,CD3OD)δ176.37, 138.57,132.67,131.98,122.53,70.57,67.51,61.57,60.29,54.24,53.48,51.90,37.50,34.72, 32.08,31.94,28.81,27.47,26.57,21.37.
实施例19：(3S,4aS,8aS)-2-[(R)-3-(6-氯吡啶-3-)甲氨基-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺19的合成
制备方法参照实施例1，将苄胺换成(6-氯吡啶-3-)甲胺，得到化合物19。1H NMR(400 MHz,CD3OD)δ8.40(d,J＝1.9Hz,1H),7.89(dd,J＝8.2,2.3Hz,1H),7.45(d,J＝8.2Hz,1H), 3.87(q,J＝13.6Hz,3H),2.99(d,J＝11.4Hz,1H),2.69(d,J＝8.2Hz,1H),2.64–2.52(m,2H), 2.45(dd,J＝13.2,8.6Hz,1H),2.19–2.06(m,2H),1.95–1.46(m,8H),1.40(dd,J＝16.1,6.5 Hz,3H),1.34(s,9H),1.31–1.15(m,3H).13C NMR(126MHz,CD3OD)δ176.43,151.21, 150.93,141.42,125.43,70.60,67.76,61.43,60.08,54.18,51.89,50.74,37.51,34.75,32.10, 31.98,28.79,27.48,26.64,21.40.
实施例20：(3S,4aS,8aS)-2-[(R)-3-(5-氯吡啶-2-)甲氨基-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺20的合成
制备方法参照实施例1，将苄胺换成(5-氯吡啶-2-)甲胺，得到化合物20。1H NMR(400 MHz,CD3OD)δ8.51(d,J＝2.3Hz,1H),7.83(dd,J＝8.4,2.4Hz,1H),7.48(d,J＝8.4Hz,1H), 3.96–3.82(m,3H),2.99(d,J＝11.5Hz,1H),2.69(dd,J＝11.9,3.9Hz,1H),2.64–2.51(m, 2H),2.45(dd,J＝13.1,9.0Hz,1H),2.17(dd,J＝11.6,3.2Hz,1H),2.12–2.04(m,1H),1.95– 1.85(m,1H),1.77(dt,J＝21.4,12.8Hz,3H),1.64–1.51(m,3H),1.48–1.10(m,16H).13C NMR(126MHz,CD3OD)δ175.11,156.90,147.41,136.63,130.56,123.71,69.29,66.22,60.21, 58.61,53.17,52.96,50.49,36.14,33.39,30.72,30.66,27.38,26.13,25.26,20.05.
实施例21：(3S,4aS,8aS)-2-[(R)-3-(吡啶-4-)甲氨基-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺21 的合成
制备方法参照实施例1，将苄胺换成吡啶-4-甲胺，得到化合物21。1H NMR(500MHz,CD3OD)δ8.48(dd,J＝4.7,1.4Hz,2H),7.48(d,J＝5.8Hz,2H),4.32(s,0H),3.97–3.79(m,3H),3.31(dt,J＝3.2,1.6Hz,1H),2.99(d,J＝10.9Hz,1H),2.74–2.52(m,3H),2.47(dd,J＝13.2,8.9Hz,1H),2.18(dd,J＝11.6,3.3Hz,1H),2.11(d,J＝12.2Hz,1H),1.91(dd,J＝24.5, 12.9Hz,1H),1.80–1.65(m,3H),1.57(ddd,J＝13.3,11.7,6.8Hz,3H),1.44–1.38(m,2H), 1.37–1.22(m,14H).13C NMR(126MHz,CD3OD)δ175.09,148.70,148.53,123.79,122.15, 69.22,66.34,60.09,58.61,52.93,51.67,50.51,36.11,33.36,30.71,30.60,28.36,27.41,26.08, 25.24,20.05.
实施例22：(3S,4aS,8aS)-2-[(R)-3-(吡啶-3-)甲氨基-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺22 的合成
制备方法参照实施例1，将苄胺换成吡啶-3-甲胺，得到化合物22。1H NMR(500MHz,CD3OD)δ8.62(s,1H),8.47(dd,J＝4.8,1.2Hz,1H),7.94(d,J＝7.8Hz,1H),7.44(dd,J＝7.8, 5.0Hz,1H),4.00–3.85(m,3H),3.04(d,J＝11.5Hz,1H),2.77(s,1H),2.63(dd,J＝11.2,3.0 Hz,2H),2.48(dd,J＝13.3,8.0Hz,1H),2.19–2.13(m,2H),1.87(dd,J＝24.6,12.7Hz,1H), 1.76(d,J＝13.2Hz,1H),1.64–1.48(m,5H),1.44–1.17(m,16H).13C NMR(126MHz, CD3OD)δ174.55,148.87,147.45,137.08,123.39,68.73,65.71,59.69,58.47,52.59,50.08, 49.57,35.66,32.85,30.21,30.09,26.96,25.63,24.79,19.51.
实施例23：(3S,4aS,8aS)-2-[(R)-3-(吡啶-2-)甲氨基-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺23 的合成
制备方法参照实施例1，将苄胺换成吡啶-2-甲胺，得到化合物23。1H NMR(500MHz,CD3OD)δ8.51(d,J＝4.5Hz,1H),7.81(td,J＝7.7,1.7Hz,1H),7.48(d,J＝7.8Hz,1H),7.32(dd,J＝6.9,5.3Hz,1H),4.02–3.82(m,3H),2.99(dd,J＝11.6,1.7Hz,1H),2.68(dd,J＝11.9, 3.9Hz,1H),2.62–2.53(m,2H),2.45(dd,J＝13.2,9.1Hz,1H),2.18(dd,J＝11.6,3.4Hz,1H), 2.09(dd,J＝13.1,2.0Hz,1H),1.95–1.70(m,4H),1.64–1.51(m,3H),1.45–1.23(m, 15H).13C NMR(126MHz,CD3OD)δ175.15,158.25,148.50,137.29,122.82,122.50,69.29, 66.18,60.25,58.56,53.76,52.99,50.49,36.14,33.40,30.73,30.68,27.38,26.13,25.26,20.06.
实施例24：(3S,4aS,8aS)-2-{(R)-2-羟基-3-[(R)-1-(4-氯苯基)乙氨基]丙基}十氢异喹啉-3-甲酰叔丁胺24的合成
制备方法参照实施例1，将苄胺换成(R)-1-(4-氯苯基)乙胺，得到化合物24。1HNMR(500 MHz,CD3OD)δ7.44(s,2H),7.36(d,J＝8.3Hz,2H),4.12(s,1H),3.86(s,1H),3.05(s,1H), 2.83(s,1H),2.63–2.43(m,3H),2.22–1.99(m,3H),1.74(s,2H),1.52(dd,J＝38.3,22.2Hz, 8H),1.40–1.26(m,16H).13C NMR(126MHz,CD3OD)δ174.37,128.30,127.98,68.78,65.30, 59.74,57.01,51.05,50.07,35.65,32.91,30.19,30.01,26.96,25.60,24.71,19.43.
实施例25：(3S,4aS,8aS)-2-{(R)-2-羟基-3-[(S)-1-(4-氯苯基)乙氨基]丙基}十氢异喹啉-3-甲酰叔丁胺25的合成
制备方法参照实施例1，将苄胺换成(S)-1-(4-氯苯基)乙胺，得到化合物25。1HNMR(600 MHz,CD3OD)δ7.35(dd,J＝29.2,8.4Hz,4H),3.89–3.73(m,2H),2.93(d,J＝11.5Hz,1H), 2.58(dd,J＝11.3,3.0Hz,1H),2.46–2.34(m,3H),2.12(dd,J＝11.6,3.3Hz,1H),2.02(d,J＝ 12.9Hz,1H),1.95–1.86(m,1H),1.74(dd,J＝26.1,7.8Hz,3H),1.60–1.52(m,3H),1.44– 1.24(m,20H).13C NMR(126MHz,CD3OD)δ176.59,144.18,134.01,129.78,129.67,70.57, 68.19,61.14,59.99,59.34,52.55,51.91,37.51,34.80,32.13,32.09,28.80,27.48,26.62,21.46.
实施例26：(3S,4aS,8aS)-2-{(R)-2-羟基-3-[(R)-1-(4-氯-3-氟苯基)乙氨基]丙基}十氢异喹啉-3- 甲酰叔丁胺26的合成
制备方法参照实施例1，将苄胺换成(R)-1-(4-氯-3-氟苯基)乙胺，得到化合物26。1HNMR (400MHz,CD3OD)δ7.43(t,J＝7.9Hz,1H),7.30(dd,J＝10.4,1.7Hz,1H),7.18(dd,J＝8.2, 1.3Hz,1H),3.84(dd,J＝8.0,4.3Hz,2H),2.94(d,J＝11.4Hz,1H),2.65–2.53(m,2H),2.44 (dd,J＝13.1,9.5Hz,1H),2.29(dd,J＝11.4,7.3Hz,1H),2.17(dd,J＝11.6,3.3Hz,1H),2.05– 1.98(m,1H),1.91(dd,J＝24.5,12.5Hz,1H),1.86–1.71(m,3H),1.60(dd,J＝16.6,12.6Hz, 3H),1.48–1.30(m,18H).13C NMR(101MHz,CD3OD)δ175.13,159.33,156.87,146.60, 130.28,123.52,118.75,118.58,114.66,114.45,69.24,66.02,60.01,58.35,57.15,51.15,50.46, 36.11,33.39,30.74,30.60,27.37,26.12,25.23,20.05.
实施例27：(3S,4aS,8aS)-2-{(R)-2-羟基-3-[(S)-1-(4-氯-3-氟苯基)乙氨基]丙基}十氢异喹啉-3- 甲酰叔丁胺27的合成
制备方法参照实施例1，将苄胺换成(S)-1-(4-氯-3-氟苯基)乙胺，得到化合物27。1HNMR (500MHz,CD3OD)δ7.42(t,J＝7.9Hz,1H),7.33(dd,J＝10.5,1.8Hz,1H),7.19(dd,J＝8.2, 1.7Hz,1H),3.81(dd,J＝10.2,4.3Hz,2H),2.95(dd,J＝11.6,2.0Hz,1H),2.60(dd,J＝11.3, 3.2Hz,1H),2.46–2.37(m,3H),2.15(dd,J＝11.6,3.3Hz,1H),2.04(dd,J＝13.1,2.1Hz,1H), 1.95(dd,J＝24.6,12.9Hz,1H),1.85–1.72(m,3H),1.65–1.53(m,3H),1.46–1.41(m,2H), 1.40–1.24(m,16H).13C NMR(126MHz,CD3OD)δ175.10,159.09,157.12,146.73,130.23, 123.59,123.57,118.68,118.54,114.72,114.55,69.25,67.08,59.78,58.53,57.76,51.25,50.46, 36.14,33.43,30.78,30.67,27.44,27.39,26.13,25.24,22.46,20.07.
实施例28：(3S,4aS,8aS)-2-{(R)-2-羟基-3-[(R)-1-(3,4-二氯苯基)乙氨基]丙基}十氢异喹啉-3- 甲酰叔丁胺28的合成
制备方法参照实施例1，将苄胺换成(R)-1-(3,4-二氯苯基)乙胺，得到化合物28。1H NMR (400MHz,CD3OD)δ7.55(dd,J＝5.5,2.0Hz,1H),7.46(d,J＝8.3Hz,1H),7.32–7.23(m, 1H),4.61(s,1H),3.86(ddd,J＝30.0,16.5,4.8Hz,1H),3.73–3.43(m,1H),2.79–2.68(m, 1H),2.62–2.49(m,1H),2.46–2.25(m,2H),2.15(dd,J＝24.5,9.3Hz,1H),1.95(d,J＝12.3 Hz,1H),1.80–1.49(m,6H),1.46–1.11(m,18H).13C NMR(126MHz,CD3OD)δ175.08,129.74,129.69,128.11,127.35,126.04,125.13,65.05,63.18,60.21,56.58,50.74,50.53,49.91, 49.53,36.17,33.33,32.93,28.75,26.93,26.83,25.56,24.55,22.97,20.58.
实施例29：(3S,4aS,8aS)-2-{(R)-2-羟基-3-[(S)-1-(3,4-二氯苯基)乙氨基]丙基}十氢异喹啉-3- 甲酰叔丁胺29的合成
制备方法参照实施例1，将苄胺换成(S)-1-(3,4-二氯苯基)乙胺，得到化合物29。1H NMR (400MHz,CD3OD)δ7.58(d,J＝1.9Hz,1H),7.47(dd,J＝8.3,3.1Hz,1H),7.32(dd,J＝8.3, 2.0Hz,1H),4.71–4.52(m,1H),3.93–3.69(m,2H),2.94(d,J＝10.2Hz,1H),2.58(dd,J＝ 11.2,3.2Hz,1H),2.45–2.36(m,2H),2.13(dd,J＝11.7,3.3Hz,1H),2.04(dd,J＝13.2,1.9Hz, 1H),1.90(d,J＝11.5Hz,1H),1.73(dd,J＝22.2,8.1Hz,3H),1.62–1.49(m,3H),1.47–1.16 (m,19H).13C NMR(126MHz,CD3OD)δ174.67,131.54,129.77,128.37,126.27,68.66,66.48, 59.15,58.18,57.13,50.60,50.01,35.64,32.93,30.23,30.18,26.91,25.60,24.71,19.56.
实施例30：(3S,4aS,8aS)-2-{(R)-2-羟基-3-[(S)-1-(4-氯苯基)-2-羟乙氨基]丙基}十氢异喹啉-3- 甲酰叔丁胺30的合成
制备方法参照实施例1，将苄胺换成(S)-1-(4-氯苯基)-2-羟乙胺，得到化合物30。1HNMR (400MHz,CD3OD)δ7.42–7.32(m,4H),3.90–3.75(m,2H),3.62(ddd,J＝18.8,10.8,6.3Hz, 2H),2.92(dd,J＝11.5,1.8Hz,1H),2.64–2.48(m,3H),2.36(dd,J＝12.1,6.6Hz,1H),2.16 (dd,J＝11.6,3.3Hz,1H),2.01–1.74(m,5H),1.61(dd,J＝16.1,12.1Hz,3H),1.48–1.27(m, 16H).13C NMR(101MHz,CD3OD)δ175.22,139.45,132.78,129.12,128.16,69.29,66.09, 65.95,63.98,59.94,58.30,50.91,50.48,36.10,33.40,30.74,30.66,27.38,26.12,25.22,20.05.
实施例31：(3S,4aS,8aS)-2-{(R)-2-羟基-3-[(R)-1-(4-氯苯基)-2-羟乙氨基]丙基}十氢异喹啉-3- 甲酰叔丁胺31的合成
制备方法参照实施例1，将苄胺换成(R)-1-(4-氯苯基)-2-羟乙胺，得到化合物31。1HNMR (400MHz,CD3OD)δ7.41–7.33(m,4H),3.87–3.80(m,1H),3.76(dd,J＝8.5,4.5Hz,1H),3.66(dd,J＝10.8,4.5Hz,1H),3.59(dd,J＝8.5,2.4Hz,1H),2.93(dd,J＝11.5,1.9Hz,1H),2.59(dd,J＝11.2,3.2Hz,1H),2.37(ddd,J＝19.2,10.9,8.0Hz,3H),2.16(dd,J＝11.6,3.3Hz, 1H),2.03–1.97(m,1H),1.96–1.88(m,1H),1.81(dd,J＝32.2,7.1Hz,3H),1.66–1.55(m, 3H),1.47–1.29(m,16H).13C NMR(101MHz,CD3OD)δ175.16,139.22,132.87,129.11, 128.23,69.24,67.01,66.07,64.93,60.31,58.36,51.65,50.47,48.26,48.04,47.83,47.62,47.41, 47.19,46.98,36.09,33.39,30.73,30.66,27.38,26.11,25.23,20.08.
实施例32：(3S,4aS,8aS)-2-[(R)-3-(4-氯苯基异丙氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺32的合成
制备方法参照实施例1，将苄胺换成4-氯苯基异丙胺，得到化合物32。1H NMR(400MHz, CD3OD)δ7.49(d,J＝8.6Hz,2H),7.33(d,J＝8.6Hz,2H),3.78(ddd,J＝9.3,5.1,2.4Hz,1H), 2.94(dd,J＝11.5,1.7Hz,1H),2.59(dd,J＝11.2,3.1Hz,1H),2.43–2.32(m,2H),2.21–2.10 (m,2H),2.03–1.96(m,1H),1.84(ddd,J＝27.5,19.7,7.3Hz,4H),1.60(dd,J＝14.8,10.6Hz, 3H),1.50(d,J＝9.4Hz,6H),1.47–1.39(m,3H),1.38–1.23(m,12H).13CNMR(101MHz, CD3OD)δ175.24,145.36,131.94,127.90,127.51,69.22,66.66,59.88,58.31,55.46,50.48, 46.69,36.09,33.40,30.75,30.67,28.48,27.36,26.93,26.11,25.23,20.06.
实施例33：(3S,4aS,8aS)-2-[(R)-3-(4-氯苯基环丙氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺33的合成
制备方法参照实施例1，将苄胺换成4-氯苯基环丙胺，得到化合物33。1H NMR(400MHz, CD3OD)δ7.41–7.35(m,2H),7.33–7.29(m,3H),3.82–3.69(m,1H),2.90(dd,J＝11.6,1.9 Hz,1H),2.56(ddd,J＝16.1,11.4,3.8Hz,2H),2.45–2.33(m,2H),2.14(dd,J＝11.6,3.3Hz, 1H),2.01(dd,J＝13.0,2.1Hz,1H),1.96–1.72(m,4H),1.60(dd,J＝14.6,10.4Hz,3H),1.47– 1.41(m,2H),1.38–1.27(m,12H),1.10–0.88(m,6H).13C NMR(101MHz,CD3OD)δ175.16, 141.64,131.85,129.12,127.97,127.93,126.97,69.24,66.57,59.93,58.28,50.45,50.01,41.47, 36.09,33.42,30.76,30.67,27.39,26.12,25.23,20.08,16.24,14.64,14.13.
实施例34：(3S,4aS,8aS)-2-[(R)-3-(4-氯苯基异丁氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺34的合成
制备方法参照实施例1，将苄胺换成4-氯苯基异丁胺，得到化合物34。1H NMR(400MHz, CD3OD)δ7.33(q,J＝8.6Hz,4H),3.80(d,J＝4.2Hz,1H),2.91(d,J＝11.5Hz,1H),2.59(dd, J＝11.2,3.1Hz,1H),2.40(dd,J＝13.1,9.3Hz,1H),2.30(t,J＝6.2Hz,2H),2.15(dd,J＝11.6, 3.2Hz,1H),2.01–1.87(m,3H),1.84–1.71(m,3H),1.65–1.54(m,3H),1.48–1.26(m,17H), 1.05(t,J＝7.6Hz,3H),0.76(d,J＝6.8Hz,3H).13C NMR(151MHz,CD3OD)δ174.70,131.91, 129.06,127.38,69.18,68.68,66.47,59.64,57.87,51.43,49.97,35.58,33.35,32.90,30.22,30.18, 26.88,26.85,26.68,25.59,24.74,19.57,18.26,17.76.
实施例35：(3S,4aS,8aS)-2-[(2R)-3-(4-氯苯基苯甲氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺35的合成
制备方法参照实施例1，将苄胺换成4-氯苯基苯甲胺，得到化合物35。1H NMR(400MHz, CD3OD)δ7.42(d,J＝8.4Hz,4H),7.33–7.28(m,4H),7.22(t,J＝7.3Hz,1H),4.84(s,1H), 3.95–3.85(m,1H),3.38(s,1H),2.94(d,J＝11.5Hz,1H),2.63–2.50(m,3H),2.45(dd,J＝11.8,6.7Hz,1H),2.15(dd,J＝11.5,3.2Hz,1H),2.03(dd,J＝13.1,1.8Hz,1H),1.99–1.89(m, 1H),1.88–1.72(m,3H),1.64–1.53(m,3H),1.52–1.18(m,16H).13C NMR(101MHz, CD3OD)δ175.18,143.30,142.69,132.29,128.68,128.21,128.12,126.98,126.86,69.28,66.67, 66.63,59.97,58.31,51.65,50.47,48.27,48.06,47.85,47.63,47.42,47.21,47.00,36.11,33.41, 30.77,30.69,27.45,26.13,25.23,20.08.
实施例36：(3S,4aS,8aS)-2-[(R)-3-(4-氯苯乙氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺36 的合成
制备方法参照实施例1，将苄胺换成4-氯苯乙胺，得到化合物36。1H NMR(500MHz,CD3OD)δ7.30–7.26(m,2H),7.22(d,J＝8.4Hz,2H),3.94–3.81(m,1H),2.98(dd,J＝11.5,1.6Hz,1H),2.91–2.80(m,4H),2.63(ddd,J＝14.5,11.7,3.6Hz,2H),2.54(dd,J＝12.0,7.2Hz,1H),2.42(dd,J＝13.2,9.1Hz,1H),2.17(dd,J＝11.6,3.3Hz,1H),2.06(dd,J＝13.1,1.8 Hz,1H),1.97–1.81(m,2H),1.77(dd,J＝20.6,7.9Hz,2H),1.66–1.52(m,3H),1.46–1.24 (m,15H).13C NMR(126MHz,CD3OD)δ175.16,138.11,131.77,129.96,128.23,69.20,65.98, 60.29,58.55,53.32,50.49,50.38,36.14,34.34,33.38,30.73,30.66,27.41,26.12,25.31,20.08.
实施例37：(3S,4aS,8aS)-2-[(R)-3-(4-氯苯丙氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺37 的合成
制备方法参照实施例1，将苄胺换成4-氯苯丙胺，得到化合物37。1H NMR(400MHz,CD3OD)δ7.26(dd,J＝23.7,8.4Hz,4H),3.90(d,J＝5.2Hz,1H),3.17(d,J＝11.9Hz,1H),2.93–2.63(m,7H),2.49(dd,J＝13.7,6.7Hz,1H),2.24(dd,J＝16.2,7.8Hz,2H),2.05–1.87(m,3H),1.79(dd,J＝14.6,11.7Hz,3H),1.62(dd,J＝21.0,12.6Hz,3H),1.51–1.17(m,15H).13C NMR(126MHz,CD3OD)δ175.07,139.95,131.49,129.58,128.13,69.11,65.67,59.97,59.57,53.15,50.59,36.21,33.26,31.98,30.67,30.59,29.33,27.41,26.10,25.52,20.08.
实施例38：(3S,4aS,8aS)-2-[(R)-3-(4-氯苯丁氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺38 的合成
制备方法参照实施例1，将苄胺换成4-氯苯丁胺，得到化合物38。1H NMR(400MHz,CD3OD)δ7.23(dd,J＝28.1,8.4Hz,4H),3.89(d,J＝3.6Hz,1H),3.06(d,J＝10.2Hz,1H),2.76–2.61(m,6H),2.57(dd,J＝11.9,6.9Hz,1H),2.46(dd,J＝13.3,8.4Hz,1H),2.24–2.10(m,2H),2.00–1.56(m,11H),1.45(dd,J＝9.1,3.5Hz,3H),1.40–1.18(m,12H).13C NMR(151MHz,CD3OD)δ174.62,140.38,130.70,129.25,127.56,68.70,65.42,59.74,58.38,52.94, 50.06,48.50,35.71,34.04,32.88,30.31,30.20,28.11,27.58,27.03,27.00,25.71,24.92,19.68.
实施例39：(3S,4aS,8aS)-2-{(R)-2-羟基-3-[(S)-1-(4-氯苯基)乙氨基]丙基}十氢异喹啉-3-甲酰甲胺39的合成
步骤1：将中间体Ⅳ(10.7g,44.9mmol)溶于100mL DMF，依次加入碳酸钾(12.4g,89.8mmol)、苄溴(8.45g,49.4mmol)，氮气保护下80℃反应过夜。反应毕，用乙酸乙酯稀释，饱和食盐水洗涤，干燥，浓缩，柱色谱分离得白色固体Ⅷ7.70g，收率52.4％。
步骤2：将98％浓硫酸用30mL水及40mL 1,4-二氧六环稀释，加入化合物Ⅷ(7.70g,23.4 mmol)，氮气保护下，回流反应48h。将反应液倾倒入水中，二氯甲烷萃取除杂质。接着，水相加入碱中和，再用二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，浓缩，柱色谱分离，得白色固体Ⅸ4.24g,收率65.9％。1H NMR(400MHz,CD3OD)δ7.58–7.47(m,5H), 4.49(d,J＝13.0Hz,1H),4.38(d,J＝12.6Hz,1H),3.38(dd,J＝11.1,3.6Hz,1H),3.24(d,J＝11.8Hz,1H),3.09(dd,J＝12.8,4.0Hz,1H),2.19(dd,J＝25.4,13.5Hz,1H),2.07–1.88(m, 3H),1.75(dd,J＝21.6,11.2Hz,2H),1.68–1.56(m,2H),1.55–1.21(m,5H).13C NMR(151 MHz,CD3OD)δ171.86,131.23,129.26,128.29,128.23,66.03,58.40,54.57,33.29,31.72,29.27,27.44,24.92,24.10,19.78.
步骤3：将化合物Ⅸ(2.74g,10.0mmol)溶解在30mL二氯甲烷中，依次加入1-乙基 -(3-二甲基氨基丙基)碳化二亚胺盐酸盐(2.49g,13.0mmol)、1-羟基苯并三唑(676mg,5.00mmol)、二异丙基乙基胺(2.58g,20.0mmol)，室温下搅拌30分钟后，加入甲胺盐酸盐(743mg,11.0mmol)，继续室温搅拌1小时。反应液用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱色谱分离得化合物XVI。1H NMR(400MHz,CD3OD)δ7.39–7.29(m,4H),7.25 (d,J＝7.1Hz,1H),3.79(d,J＝13.4Hz,1H),3.00(d,J＝13.4Hz,1H),2.81(s,3H),2.77(dd,J ＝11.4,3.2Hz,1H),2.70(dd,J＝11.6,2.3Hz,1H),2.13–1.99(m,3H),1.85–1.73(m,2H),1.58(dd,J＝10.5,7.7Hz,3H),1.47(ddd,J＝12.7,6.4,3.0Hz,3H),1.30–1.20(m,2H).
步骤4：将化合物XVI(287mg，1.00mmol)加入反应瓶中，加甲醇10mL溶解，并加入30mg 10％的湿钯炭。氮气置换3次，氢气置换3次，调节至合适压力，50℃反应5h。反应毕，冷却，泄压，滤除催化剂，减压浓缩，得化合物XVII粗品140mg，粗收率71.3％。
步骤5：在25mL反应瓶中依次加入化合物XVII(140mg，0.713mmol)，二异丙基乙胺(111mg，0.856mmol)及DMF 5mL，最后加入(R)-间硝基苯磺酸缩水甘油酯V-1(203 mg，0.784mmol)。氮气保护下，100℃下反应5h。TLC跟踪反应。反应毕，反应液用碳酸氢钠溶液稀释，乙酸乙酯萃取。合并有机相，水洗，干燥，浓缩，柱色谱分离，得化合物XVIII。
步骤6：将化合物XVIII(80.0mg,0.317mmol)、(S)-1-(4-氯苯基)乙胺(54.0mg,0.349 mmol)及乙醇10mL，在氮气保护下，回流反应过夜。反应毕，减压浓缩，色谱法纯化，得目标化合物39。1H NMR(500MHz,CD3OD)δ7.51–7.31(m,4H),3.92(s,1H),3.87–3.81 (m,1H),3.00(d,J＝11.6Hz,1H),2.77(d,J＝10.5Hz,3H),2.72(dd,J＝11.4,3.1Hz,1H), 2.51(s,2H),2.39(dd,J＝13.4,7.9Hz,1H),2.20–2.08(m,2H),1.96(dd,J＝24.5,12.9Hz, 1H),1.81–1.55(m,6H),1.50–1.40(m,5H),1.38–1.23(m,6H).13C NMR(126MHz, CD3OD)δ176.38,141.39,132.91,128.54,128.36,69.01,67.04,59.52,58.97,58.08,50.88, 36.04,33.42,30.77,30.67,29.34,26.02,25.18,24.66,21.67,20.06.
实施例40：(3S,4aS,8aS)-2-{(R)-2-羟基-3-[(S)-1-(4-氯苯基)乙氨基]丙基}十氢异喹啉-3-甲酰环己胺40的合成
制备方法参照实施例39，将步骤3中甲胺盐酸盐替换为环己胺，得到化合物40。1HNMR (400MHz,CD3OD)δ7.39(dd,J＝24.9,8.4Hz,4H),3.95–3.81(m,2H),3.65(dd,J＝12.9,9.4 Hz,1H),2.80(d,J＝11.5Hz,1H),2.63(ddd,J＝14.0,11.6,3.0Hz,2H),2.46–2.33(m,2H), 2.17–2.08(m,2H),2.03–1.91(m,1H),1.90–1.51(m,12H),1.47–1.29(m,9H),1.27–1.06 (m,5H).13C NMR(101MHz,CD3OD)δ174.42,143.00,132.46,128.31,69.48,66.48,59.68, 58.75,57.41,51.39,48.14,35.98,33.47,32.40,32.23,30.70,30.39,26.02,25.31,25.16,24.79, 22.57,20.11.
实施例41：(3S,4aS,8aS)-2-{(R)-2-羟基-3-[(S)-1-(4-氯苯基)乙氨基]丙基}十氢异喹啉-3-甲酰苯胺41的合成
制备方法参照实施例39，将步骤3中甲胺盐酸盐替换为苯胺，得到化合物41。1HNMR (400MHz,CD3OD)δ7.63(d,J＝7.8Hz,2H),7.41–7.27(m,6H),7.13(t,J＝7.4Hz,1H),3.88 (dd,J＝12.3,6.6Hz,1H),3.79(q,J＝6.6Hz,1H),3.02(dd,J＝11.6,1.5Hz,1H),2.86(dd,J＝ 11.3,3.1Hz,1H),2.51(dd,J＝13.3,8.9Hz,1H),2.47–2.37(m,2H),2.23(dd,J＝11.7,3.2Hz, 1H),2.14(dd,J＝13.4,1.9Hz,1H),2.09–2.00(m,1H),1.84(dd,J＝13.0,3.2Hz,2H),1.76(d, J＝12.8Hz,1H),1.67–1.54(m,4H),1.46–1.24(m,8H).13C NMR(101MHz,CD3OD)δ 174.05,143.09,138.06,132.44,128.39,128.31,128.23,124.01,120.08,69.36,67.10,60.03, 58.54,57.91,51.03,36.02,33.43,30.72,26.06,25.21,22.24,20.08.
实施例42：(3S,4aS,8aS)-2-{(R)-2-氯-3-[(S)-1-(4-氯苯基)乙氨基]丙基}十氢异喹啉-3-甲酰叔丁胺42的合成
将化合物25(200mg,0.444mmol)溶于二氯甲烷5mL中，加入二氯亚砜(64.5μL,0.444mmol)，回流反应过夜。反应毕，加饱和碳酸氢钠溶液淬灭，分液，浓缩，色谱分离得化合物42。1H NMR(400MHz,CD3OD)δ7.47(d,J＝8.3Hz,2H),7.37(d,J＝8.4Hz,2H), 4.67(s,1H),4.33–4.23(m,1H),3.93(d,J＝6.2Hz,1H),2.99(dd,J＝13.0,3.3Hz,1H),2.75 (d,J＝11.4Hz,1H),2.71–2.58(m,3H),2.40(dd,J＝12.5,4.4Hz,1H),2.13(d,J＝10.1Hz, 1H),1.97(dd,J＝24.4,12.7Hz,1H),1.80–1.67(m,3H),1.60–1.46(m,7H),1.44–1.36(m, 4H),1.32(s,9H).13C NMR(101MHz,CD3OD)δ174.25,142.42,132.73,128.51,128.41,69.09,68.98,60.23,58.06,57.12,51.46,50.55,50.23,35.81,33.35,30.65,30.07,27.46,27.29,25.94, 25.25,20.11.
实施例43：(3S,4aS,8aS)-2-{(R)-2-羟基-3-[(S)-1-(4-氯苯基)乙氨基]丙基}十氢异喹啉-3-甲酰苯胺43的合成
步骤1：中间体Ⅳ(500mg,2.10mmol)溶于15mL乙腈，依次加入碳酸钾(580mg,4.20mmol)、N-Boc-3-氨基丙基溴(549mg,2.31mmol)，氮气保护下回流反应过夜。反应毕，滤去碳酸钾，滤饼用乙酸乙酯洗涤，减压浓缩滤液，柱色谱分离得白色固体390mg,。将上述产物溶于4M HCl/二氧六环，室温下搅拌。反应毕，减压浓缩，残留物用水溶解，接着用5％NaOH溶液中和，二氯甲烷萃取，浓缩得化合物XIII。1H NMR(600MHz,CD3OD)δ 3.38(s,2H),2.97(dd,J＝11.5,2.2Hz,1H),2.77–2.69(m,2H),2.63–2.53(m,2H),2.09– 2.02(m,2H),2.02–1.95(m,1H),1.90(dd,J＝13.0,3.7Hz,1H),1.84–1.71(m,3H),1.70– 1.56(m,4H),1.46–1.29(m,15H).13C NMR(126MHz,CD3OD)δ176.73,69.98,58.54,54.36, 52.15,40.88,37.51,34.81,32.12,31.67,28.84,27.60,26.86,23.67,21.45.
步骤2：化合物XIII(295mg,1.00mmol)用10mL乙醇溶解，加入1-(4-氯苯基)乙酮(170mg,1.10mmol)和钛酸四异丙酯(426mg,1.50mmol)，氮气保护下，回流反应。LC-MS 跟踪反应至反应完全。
步骤3：室温下，在步骤2反应液中加入氰基硼氢化钠(126mg,2.00mmol)，室温搅拌。反应毕，加入饱和碳酸氢钠溶液淬灭。乙酸乙酯/水分液，合并有机相，干燥浓缩，色谱分离得化合物43。1H NMR(500MHz,CD3OD)δ7.62(tt,J＝9.1,2.1Hz,2H),7.48–7.42 (m,2H),4.48(dd,J＝168.5,6.9Hz,1H),3.39(dd,J＝21.5,11.5Hz,1H),3.00–2.78(m,2H), 2.72–2.65(m,1H),2.57(ddd,J＝58.7,34.4,3.6Hz,1H),2.29–2.11(m,1H),2.07–1.99(m, 1H),1.96–1.86(m,1H),1.79(d,J＝6.9Hz,1H),1.76–1.61(m,4H),1.50(ddd,J＝15.5,8.6,5.2Hz,3H),1.46–1.31(m,12H),1.30–1.23(m,2H),1.16–1.00(m,2H),0.98–0.86(m,1H).13C NMR(126MHz,CD3OD)δ175.32,136.14,134.68,129.21,128.52,68.00,67.58,57.68,56.82,56.63,56.16,54.35,50.52,50.32,50.21,44.06,35.28,33.05,32.80,30.28,30.14,29.97, 29.50,27.05,27.00,25.43,25.38,24.54,21.39,21.18,19.33,19.06,17.34.
实施例44：(3S,4aS,8aS)-2-[(S)-3-(4-氯苄基氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺44 的合成
制备方法参照实施例1，将VI-1换成VI-2，将苄胺换成4-氯苄胺，得到化合物44。1HNMR(400MHz,CDCl3)δ7.28(s,4H),6.13(s,1H),3.81(q,J＝13.4Hz,3H),2.83(d,J＝11.5Hz,1H),2.73(dd,J＝11.6,3.4Hz,1H),2.61(d,J＝8.5Hz,1H),2.54–2.41(m,2H),2.23–2.10(m,2H),1.80–1.62(m,3H),1.45(d,J＝9.1Hz,3H),1.40–1.12(m,15H).13C NMR(151MHz,CDCl3)δ173.98,133.06,129.79,128.60,70.10,60.33,59.15,53.00,52.73,50.72,35.76, 33.11,30.74,30.69,28.71,26.21,25.61,20.43.
实施例45：(3S,4aS,8aS)-2-[(S)-3-(4-氟苄基氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺45 的合成
制备方法参照实施例1，将VI-1换成VI-2，将苄胺换成4-氟苄胺，得到化合物45。1HNMR(400MHz,CD3OD)δ7.50(dd,J＝8.4,5.5Hz,2H),7.08(t,J＝8.7Hz,2H),4.00(d,J＝12.8Hz,1H),3.90(dd,J＝10.1,4.6Hz,1H),3.78(d,J＝12.8Hz,1H),2.87–2.68(m,3H),2.58(dd,J＝11.2,2.9Hz,1H),2.44(dd,J＝12.3,9.8Hz,1H),2.16(ddd,J＝14.7,12.0,3.8Hz, 2H),1.94–1.82(m,1H),1.74(d,J＝12.9Hz,1H),1.58–1.46(m,4H),1.40–1.12(m,16H). 13C NMR(126MHz,CD3OD)δ176.05,164.79,162.85,135.03,132.20,132.14,116.29,116.12, 70.86,67.02,61.87,60.15,54.84,53.49,51.93,37.41,34.74,32.06,31.63,28.88,27.40,26.67, 21.36.
实施例46：(3S,4aS,8aS)-2-[(S)-3-(3-氟苄基氨基)-2-羟基丙基]十氢异喹啉-3-甲酰叔丁胺46 的合成
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制备方法参照实施例1，将VI-1换成VI-2，将苄胺换成3-氟苄胺，得到化合物46。1HNMR(400MHz,CD3OD)δ7.39–7.31(m,1H),7.26(d,J＝8.2Hz,2H),7.00(t,J＝7.8Hz, 1H),3.93(dd,J＝30.5,8.6Hz,2H),3.77(d,J＝13.0Hz,1H),2.80(dd,J＝17.8,7.8Hz,2H),2.74–2.65(m,1H),2.56(d,J＝10.2Hz,1H),2.45(t,J＝10.9Hz,1H),2.22–2.08(m,2H),1.97–1.85(m,1H),1.75(d,J＝12.3Hz,1H),1.52(d,J＝11.9Hz,5H),1.40–1.14(m,15H).13C NMR(126MHz,CD3OD)δ176.01,165.37,163.42,142.70,131.23,131.17,125.76,116.70,116.53,115.19,115.03,71.02,67.43,61.98,60.19,55.05,53.89,51.87,37.45,34.76,32.09, 31.61,28.89,27.45,26.73,21.39.
实施例47：(3S,4aS,8aS)-2-{(S)-2-羟基-3-[(S)-1-(4-氯苯基)乙氨基]丙基}十氢异喹啉-3-甲酰叔丁胺47的合成
制备方法参照实施例1，将VI-1换成VI-2，将苄胺换成(S)-1-(4-氯苯基)乙胺，得到化合物47。1H NMR(400MHz,CD3OD)δ7.42(d,J＝8.5Hz,2H),7.38–7.32(m,2H),3.94– 3.82(m,2H),2.79(d,J＝11.3Hz,1H),2.67(dd,J＝12.0,3.2Hz,1H),2.52(dd,J＝11.2,3.1 Hz,1H),2.46–2.33(m,2H),2.17–2.09(m,2H),1.93(dd,J＝24.4,12.8Hz,1H),1.76(dd,J＝21.0,7.9Hz,2H),1.61(ddd,J＝16.6,12.3,3.5Hz,4H),1.48–1.31(m,7H),1.29(s,9H),1.26 –1.15(m,2H).13C NMR(101MHz,CD3OD)δ174.77,142.88,132.49,128.35,69.79,66.35, 59.82,58.65,57.25,51.28,50.38,35.97,33.33,30.69,30.30,27.45,26.04,25.30,22.52,20.07.
抗埃博拉生物活性测试
筛选抑制埃博拉病毒化合物，筛选靶点为埃博拉病毒外膜蛋白GP蛋白(EBOV-GP)的侵入抑制剂。利用带有报告基因的复制缺陷型HIV基因组cDNA质粒与埃博拉病毒GP 蛋白表达质粒，在293T细胞上包装假病毒颗粒(EBOV-GP-HIV)，利用该假病毒感染Huh7 细胞后通过报告基因定量检测EBOV-GP蛋白介导的假病毒侵入活性。报告基因为萤火虫荧光素酶蛋白。化合物细胞毒性采用MTT法测定。通过化合物对对照组VSV-G假病毒的感染活性的抑制，以判断并排除化合物可能的假阳性及脱靶效应。
细胞毒性(MTT法，570nm波长下测定)筛选数据经整理后，以铺种细胞但无化合物对照孔为100％，计算细胞相对存活率(Viability，％)。假病毒侵入活性(FLuc，RLU)筛选数据经整理后，以铺种细胞但无化合物对照孔为100％，计算假病毒相对侵入活性(Infectivity，％)，及假病毒抑制活性(Inhibition＝100％-Infectivity)。
同时，对于活性化合物筛选实验中，我们以水泡口炎病毒(vesicular stomatitisvirus,VSV) 膜蛋白为对照，G蛋白包装的假病毒(VSV-G-HIV)作为无关靶点对照。我们将化合物对EBOV-GP的抑制率与VSV-G的抑制率的比值定义为化合物靶向EBOV-GP的特异性指数(Spec.Index)，该特异性指数越大则说明化合物对埃博拉病毒膜蛋白GP功能的特异性抑制越强。以化合物CC50/EC50比值计算选择指数(SI)。
具体实验步骤如下：
Huh-7细胞获自中国科学院典型培养物保藏中心细胞库(中国上海)。293T细胞系获自ATCC(Manassas,USA)。所有细胞系均在添加了10％胎牛血清(FBS)、37℃、5％CO2 的Dulbecco改良Eagle培养基(DMEM，Thermofisher，上海，中国)中生长。为了生成埃博拉病毒糖蛋白(GP)表达质粒，每种蛋白质的编码序列均从已发表的病毒基因组 (GenBank:NC_002549)中获得，并针对哺乳动物表达进行了优化。我们将优化的GP编码序列与附加的A放在移位位点以确保正确的框架。合成编码序列(Inovogen，China)并插入pcDNA3.1载体，并通过测序验证。为了产生GP蛋白假型HIV病毒体，HIV骨架载体pNL4-3.Luc.R-E-用于假型病毒包装。简而言之，根据制造商的说明，使用 X-tremeGENE DNA HP转染试剂(Roche)将293T细胞与各自的包膜蛋白表达质粒加 pNL4.3LucR-E-质粒共转染。在转染后72小时，收集上清液并通过0.45μm过滤器过滤，然后将过滤后的上清液通过具有100kDa截止值的滤筒超速离心进一步浓缩10倍，分装并最终储存在-80℃下。根据制造商手册(ab218268,Abcam)使用ELISA试剂盒测定假型病毒原液的p24水平。VSV-G假型病毒是用VSV-G表达质粒(Inovogen，中国)以类似方式产生的。
在进行测定前一天，将Huh-7细胞接种在96孔板中(每孔100μL中含有10000个细胞)并孵育过夜。将50μL连续稀释的化合物添加到培养板中并孵育30分钟。然后，在每个孔中加入50μL假型病毒溶液(100ng p24/mL)，并将板进一步孵育2天。细胞在 1×Glo裂解缓冲液(Promega)中裂解，用于荧光素酶报告基因分析。根据制造商的说明，使用Bright-Glo荧光素酶测定系统(Promega)通过生物发光计评估荧光素酶活性。化合物的细胞毒性也通过细胞ATP方法平行测定(没有假型病毒感染)。活力和感染性计算为没有化合物的对照孔的百分比。使用Prism 7的参数回归计算EC50、EC90和CC50值。
本发明用阳性药物托瑞米芬(Toremifene)作对照品，代表活性化合物在Huh7细胞中的抗埃博拉活性和细胞毒性(表1)及特异性抑制(表2)如下所示。
表1
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ND＝Not detected.
表2
EC50:半数有效浓度；CC50:半数致死浓度；SI:选择性指数，SI＝CC50/EC50。
Spec.index:化合物对EBOV-GP的抑制率与VSV-G的抑制率的比值。
实验结果表明，化学通式中所包含的代表化合物具有较好的抗埃博拉病毒活性，较低的细胞毒性和一定的选择性指数。
以上各实施例仅用以举例说明本发明的技术方案，而非对其限制。尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：在没有脱离本发明权利要求所限定的精神和实质的范围内，可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换仍然在本发明权利要求所限定的范围内。
Claims (10)
1.一种式I化合物、其异构体、药学上可接受的盐、酯、前药或溶剂合物，
其中：
X1和X2各自独立地选自H、取代或未取代的C1-C6烷基、取代或未取代的C6-C12芳基，所述取代的取代基选自卤素、-OH、-SH、-O(C1-C6烷基)、-S(C1-C6烷基)、C1-C6烷基；特别地，X1和X2各自独立地选自H、取代或未取代的C1-C4烷基、取代或未取代的苯基，所述取代的取代基选自卤素、-OH、-SH、-O(C1-C6烷基)、-S(C1-C6烷基)、C1-C6烷基；或者
X1和X2彼此连接并和与其相连的碳原子形成C3-C6亚环烷基；
Y选自H、-OH、卤素或氧代(＝O)；
Z选自H、C1-C6烷基、C3-C8环烷基、取代或未取代的C6-C12芳基、5-7元杂芳基；特别地，Z选自H、C1-C4烷基、C3-C6环烷基、取代或未取代的苯基、5-6元杂芳基；更特别地选自H、甲基、乙基、叔丁基、环己基、取代或未取代的苯基，所述取代的取代基选自卤素、-OH、-SH、-O(C1-C6烷基)、-S(C1-C6烷基)、C1-C6烷基；
R选自H、C1-C4烷基；特别选自H、甲基、乙基、异丙基；
m为0、1、2、3或4，优选为0、1、2或3；
A环选自C3-C8环烷基、C6-C12芳基、5-7元杂芳基、3-10元杂环基；特别地，A环选自C3-C6环烷基、C6-C12芳基、5-6元杂芳基、3-10元杂环基；更特别地，A环选自环戊基、环己基、环庚基、苯基、萘基、吡啶基；
(R1)n表示n个R1取代，n为0、1、2、3、4或5，优选为0、1或2；
R1各自独立地选自卤素、-NO2、-CN、C1-C6烷基、-OH、-O(C1-C6烷基)、-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)2、-COOH、-C(＝O)O(C1-C6烷基)、-C(＝O)NH(C1-C6烷基)、-C(＝O)N(C1-C6烷基)2、-OC(＝O)(C1-C6烷基)、-NHC(＝O)(C1-C6烷基)、-C(＝O)(C1-C6烷基)；或者
相邻的两个R1和与其相连的A环一起形成[C6-C12芳环]并[5-6元杂芳环]，特别地，相邻的两个R1和与其相连的A环一起形成苯并[5元氮杂芳环]，更特别地，相邻的两个R1和与其相连的A环一起形成苯并吡咯基团；
其中所述杂芳基、杂环基或杂芳环各自独立地含有1、2、3或4个选自N、O和S中的杂原子。
2.根据权利要求1所述的式I化合物、其异构体、药学上可接受的盐、酯、前药或溶剂合物，其中，
X1和X2各自独立地选自H、C1-C4烷基、羟基取代的C1-C4烷基、苯基；或者
X1和X2彼此连接并和与其相连的碳原子形成C3-C6亚环烷基；
Y选自H、-OH或卤素；
Z选自H、C1-C4烷基、C3-C6环烷基、苯基，更优选自H、甲基、乙基、叔丁基、环己基、苯基；
R选自H、C1-C4烷基；优选选自H、甲基、乙基；
A环选自环己基、苯基、吡啶基；
R1各自独立地选自-NH2、卤素、-O(C1-C6烷基)、-NO2、-CN、-C(＝O)O(C1-C6烷基)；或者，
相邻的两个R1和与其相连的A环一起形成苯并[5元氮杂芳环]，更特别地，相邻的两个R1和与其相连的A环一起形成苯并吡咯基团。
3.根据权利要求1所述的式I化合物、其异构体、药学上可接受的盐、酯、前药或溶剂合物，其中，式I化合物选自如下式I-a化合物：
其中，X1、Z、m、A环和(R1)n的定义同权利要求1。
4.根据权利要求1所述的式I化合物、其异构体、药学上可接受的盐、酯、前药或溶剂合物，其中，式I化合物选自如下式I-b化合物：
其中，A环和(R1)n的定义与同权利要求1。
5.根据权利要求1所述的式I化合物、其异构体、药学上可接受的盐、酯、前药或溶剂合物，其中，式I化合物选自下列化合物：
6.如权利要求1-5中任一项所述的式I化合物、其异构体、药学上可接受的盐、酯、前药或溶剂合物的制备方法，所述方法选自如下三种路线之一：
路线一：
步骤1：将中间体Ⅳ溶于溶剂D，加入反应物Ⅴ间硝基苯磺酸缩水甘油酯(R型或S型)，在碱性条件下，惰性气体保护，油浴加热至50～120℃，反应2-5小时；反应毕，反应液用乙酸乙酯稀释，依次用碳酸氢钠水溶液、饱和食盐水洗涤；有机相用无水硫酸钠干燥，减压浓缩，柱色谱纯化得化合物Ⅵ；
步骤2：将化合物Ⅵ溶于溶剂E，加入对应的胺Ⅶ，惰性气体保护，回流反应过夜；反应毕，减压浓缩，选用合适的显色剂，色谱法纯化，得目标化合物Ia；
其中，所述溶剂D和溶剂E各自独立地为选自丙酮、乙腈、甲苯、二氯甲烷、四氢呋喃、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、水、甲醇、乙醇、异丙醇、正丁醇、异丁醇中的一种或者多种；
所用的碱为选自下述无机碱和有机碱中的一种或多种，无机碱：碳酸钠、碳酸钾、碳酸铯、磷酸钾、氢氧化钠、氢氧化钾、钠氢，有机碱：N,N-二甲基氨基吡啶、三乙胺、二异丙基乙基胺、三丁胺、叔丁醇钾中；
所述中间体Ⅳ、反应物Ⅴ、碱的摩尔比例为1:1:1-1:1.5:2，最优摩尔比例为1:1.1:1.2；
所述化合物Ⅵ、胺Ⅶ的摩尔比例为1:1-1:2，最优摩尔比例为1:1.2；
路线二：
步骤1：中间体Ⅳ用溶剂F溶解后，接着先后加入碱、苄溴，惰性气体保护下，加热至50～120℃，反应过夜；反应毕，反应液用乙酸乙酯稀释，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，柱色谱分离得化合物Ⅷ；
步骤2：将浓硫酸用溶剂G稀释后，加入化合物Ⅷ，惰性气体保护下，回流反应过夜；反应毕，将反应液倾倒入水中，二氯甲烷萃取除杂质；接着，水相加入碱中和，再用二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，浓缩，柱色谱分离，得化合物Ⅸ；
步骤3：将化合物Ⅸ溶解在溶剂H中，先后加入1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐、1-羟基苯并三唑、二异丙基乙基胺，室温下搅拌30分钟后，加入相应的胺，继续室温搅拌1小时；反应液用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱色谱分离得化合物Ⅹ；
步骤4：将化合物Ⅹ加入反应瓶中，加溶剂I溶解，并加入催化剂；惰性气体置换3次，氢气置换3次，调节至合适压力，油浴加热至50～100℃，反应3-10小时；反应毕，冷却，泄压，滤除催化剂，减压浓缩，柱色谱纯化得化合物Ⅺ；
步骤5：将化合物Ⅺ溶于溶剂I，加入反应物Ⅴ间硝基苯磺酸缩水甘油酯(R型或S型)，在碱性条件下，惰性气体保护，油浴加热至50～120℃，反应2-5小时；反应毕，反应液用乙酸乙酯稀释，依次用碳酸氢钠水溶液、饱和食盐水洗涤；有机相用无水硫酸钠干燥，减压浓缩，柱色谱纯化得化合物Ⅻ；
步骤6：将化合物Ⅻ溶于溶剂K，加入对应的胺Ⅶ，惰性气体保护，回流反应过夜；反应毕，减压浓缩，选用合适的显色剂，色谱法纯化，得目标化合物Ib；
其中，所述溶剂F、溶剂G、溶剂H、溶剂I、溶剂J和溶剂K各自独立地为选自丙酮、乙腈、甲苯、二氯甲烷、四氢呋喃、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、水、甲醇、乙醇、异丙醇、正丁醇、异丁醇中的一种或者多种；
所用的碱为选自下述无机碱和有机碱中的一种或多种，无机碱：碳酸钠、碳酸钾、碳酸铯、磷酸钾、氢氧化钠、氢氧化钾、钠氢，有机碱：N,N-二甲基氨基吡啶、三乙胺、二异丙基乙基胺、三丁胺、叔丁醇钾；
所用催化剂为湿钯-炭、干钯-炭、钌-炭、钌-氧化铝、铑炭、铑-氧化铝、雷尼镍、二氧化铂中的一种或者多种；
路线三：
步骤1：中间体Ⅳ、N-Boc-3-氨基丙基溴、碱和溶剂L，回流反应过夜；反应毕，滤除碱，并用乙酸乙酯洗涤滤饼，浓缩滤液，色谱分离；将产物溶于4M HCl/二氧六环，室温下搅拌；反应毕，减压浓缩，残留物用水溶解，接着用碱中和，二氯甲烷萃取，浓缩得化合物XIII；
步骤2：化合物XIII用溶剂M溶解，加入羰基化合物XIV和路易斯酸，惰性气体保护，回流反应3-10小时；LC-MS跟踪反应至反应完全；
步骤3：室温下，在步骤2反应液中加入还原剂，室温搅拌1-6小时；反应毕，加入饱和碳酸氢钠溶液淬灭；乙酸乙酯/水分液，合并有机相，干燥浓缩，色谱分离得化合物Ic；
其中，所述溶剂L和溶剂M各自独立地为选自丙酮、乙腈、甲苯、二氯甲烷、四氢呋喃、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、水、甲醇、乙醇、异丙醇、正丁醇、异丁醇中的一种或者多种；
所用的碱为选自下述无机碱和有机碱中的一种或多种，无机碱：碳酸钠、碳酸钾、碳酸铯、磷酸钾、氢氧化钠、氢氧化钾、钠氢，有机碱：N,N-二甲基氨基吡啶、三乙胺、二异丙基乙基胺、三丁胺、叔丁醇钾；
所用路易斯酸为乙酸、四氯化钛、钛酸四异丙酯中的一种或者多种；
所用还原剂为四氢锂铝、硼氢化钠、氰基硼氢化钠中的一种或者多种，
各路线中所涉及的取代基分别如相应权利要求中所述。
7.根据权利要求6所述的方法，其中，所述中间体Ⅳ由包括如下步骤的制备方法制备：
以化合物Ⅱ(S)-(-)-1,2,3,4-四氢异喹啉-3-羧酸为原料，溶解在溶剂A中，缓慢滴加含三光气的溶液；滴毕，惰性气体保护下，回流反应2-5小时；反应毕，稍冷，减压浓缩，蒸除大部分溶剂A，残留物用石油醚打浆，真空干燥；所得化合物溶解在溶剂B中，冰水浴下，缓慢滴加叔丁胺；滴毕，撤去冰浴，室温下搅拌过夜；反应液用2N HCl洗涤，合并水相，调pH至8-9，并加少量碎冰控制温度；接着用二氯甲烷萃取，浓缩，石油醚洗涤，真空干燥，得化合物Ⅲ；
将化合物Ⅲ加入高压反应釜中，加溶剂C溶解，并加入催化剂；惰性气体置换3次，氢气置换3次，调节至合适压力，油浴加热至80～180℃反应过夜；反应毕，冷却，泄压，滤除催化剂，减压浓缩，柱色谱纯化得中间体Ⅳ；
其中，所述溶剂A、溶剂B和溶剂C各自独立地为选自丙酮、乙腈、甲苯、二氯甲烷、四氢呋喃、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙醇、异丙醇、正丁醇、异丁醇中的一种或者多种；
所用催化剂为选自湿钯-炭、干钯-炭、钌-炭、钌-氧化铝、铑炭、铑-氧化铝、雷尼镍、二氧化铂中的一种或者多种；
所述化合物Ⅱ、三光气、叔丁胺的摩尔比例为1:1:1.5-1:1.5:4，最优摩尔比例为1:1.2:2。
8.一种药物组合物，其包括：选自权利要求1-5中任一项所述的式I化合物、其异构体、药学上可接受的盐、酯、前药和溶剂合物中的一种或多种，以及任选存在的药学上可接受的载体。
9.如权利要求1-5中任一项所述的式I化合物、其异构体、药学上可接受的盐、酯、前药或溶剂合物或权利要求8所述的药物组合物在制备EBOV-GP抑制剂中的应用。
10.如权利要求1-5中任一项所述的式I化合物、其异构体、药学上可接受的盐、酯、前药或溶剂合物或权利要求8所述的药物组合物在制备用于预防和/或治疗埃博拉的药物中的应用。
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