CN111777638A - Quinoline compound, preparation method, pharmaceutical composition and application thereof - Google Patents
Quinoline compound, preparation method, pharmaceutical composition and application thereof Download PDFInfo
- Publication number
- CN111777638A CN111777638A CN202010692200.3A CN202010692200A CN111777638A CN 111777638 A CN111777638 A CN 111777638A CN 202010692200 A CN202010692200 A CN 202010692200A CN 111777638 A CN111777638 A CN 111777638A
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- Prior art keywords
- alkyl
- substituted
- unsubstituted
- alkoxy
- group
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- -1 Quinoline compound Chemical class 0.000 title claims description 70
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 199
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 239000002207 metabolite Substances 0.000 claims abstract description 26
- 230000009385 viral infection Effects 0.000 claims abstract description 8
- 208000036142 Viral infection Diseases 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 234
- 229910052736 halogen Inorganic materials 0.000 claims description 94
- 150000002367 halogens Chemical class 0.000 claims description 94
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 62
- 229910052739 hydrogen Inorganic materials 0.000 claims description 56
- 239000001257 hydrogen Substances 0.000 claims description 56
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 50
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 50
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 45
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 45
- 125000003545 alkoxy group Chemical group 0.000 claims description 44
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 29
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 26
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 24
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 24
- 239000000460 chlorine Substances 0.000 claims description 24
- 229910052801 chlorine Inorganic materials 0.000 claims description 24
- 229910052731 fluorine Inorganic materials 0.000 claims description 24
- 239000011737 fluorine Substances 0.000 claims description 24
- 150000002431 hydrogen Chemical class 0.000 claims description 24
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 21
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 21
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 21
- 229910052794 bromium Inorganic materials 0.000 claims description 21
- 239000011630 iodine Substances 0.000 claims description 21
- 229910052740 iodine Inorganic materials 0.000 claims description 21
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 20
- 241000700605 Viruses Species 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 16
- 241000711573 Coronaviridae Species 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 8
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 8
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 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 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- 206010035664 Pneumonia Diseases 0.000 claims description 5
- 206010022000 influenza Diseases 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 4
- 241001115402 Ebolavirus Species 0.000 claims description 4
- 241000991587 Enterovirus C Species 0.000 claims description 4
- 241000709721 Hepatovirus A Species 0.000 claims description 4
- 241000711798 Rabies lyssavirus Species 0.000 claims description 4
- 241000700584 Simplexvirus Species 0.000 claims description 4
- 241000907316 Zika virus Species 0.000 claims description 4
- 229910052805 deuterium Inorganic materials 0.000 claims description 4
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 201000009182 Chikungunya Diseases 0.000 claims description 3
- 201000003075 Crimean-Congo hemorrhagic fever Diseases 0.000 claims description 3
- 241000725619 Dengue virus Species 0.000 claims description 3
- 201000004315 EAST syndrome Diseases 0.000 claims description 3
- 241000711549 Hepacivirus C Species 0.000 claims description 3
- 241000700721 Hepatitis B virus Species 0.000 claims description 3
- 241000712431 Influenza A virus Species 0.000 claims description 3
- 241000713196 Influenza B virus Species 0.000 claims description 3
- 241000712902 Lassa mammarenavirus Species 0.000 claims description 3
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 9
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 364
- 238000003786 synthesis reaction Methods 0.000 description 102
- 230000015572 biosynthetic process Effects 0.000 description 101
- 238000005160 1H NMR spectroscopy Methods 0.000 description 100
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 91
- 238000006243 chemical reaction Methods 0.000 description 66
- 239000000243 solution Substances 0.000 description 41
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 210000004027 cell Anatomy 0.000 description 22
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- 230000002829 reductive effect Effects 0.000 description 18
- 238000004440 column chromatography Methods 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 14
- 229910019142 PO4 Inorganic materials 0.000 description 14
- 239000010452 phosphate Substances 0.000 description 14
- 238000012360 testing method Methods 0.000 description 13
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 229960004171 hydroxychloroquine Drugs 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 229940125782 compound 2 Drugs 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- 229910001629 magnesium chloride Inorganic materials 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical class [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 238000001308 synthesis method Methods 0.000 description 6
- 210000003501 vero cell Anatomy 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 5
- 235000010290 biphenyl Nutrition 0.000 description 5
- 239000004305 biphenyl Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 231100000135 cytotoxicity Toxicity 0.000 description 5
- 230000003013 cytotoxicity Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
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- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 3
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
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- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 108010072147 type V-S pancreatic trypsin Proteins 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
A compound shown as a general formula I, pharmaceutically acceptable salts thereof, or metabolites thereof, and a preparation method, a pharmaceutical composition and application thereof.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a quinoline compound, a preparation method, a pharmaceutical composition and application thereof.
Background
Hydroxychloroquine is an antimalarial drug of great interest for the last 50 years. The sulfate form of hydroxychloroquine, namely hydroxychloroquine sulfate, is one of the most commonly used drugs for clinically treating rheumatic diseases at present, particularly systemic lupus erythematosus and rheumatoid arthritis. In a related mechanism research experiment, hydroxychloroquine has anti-inflammatory and immunomodulatory activity, which can reduce the production of inflammatory factors. For example, in vitro experiments have shown that hydroxychloroquine inhibits the production of interleukin 1(IL-1), interleukin 6(IL-2), Tumor Necrosis Factor (TNF), and interferon gamma (IFN γ) by monocytes. In addition, hydroxychloroquine also has antiviral, antibacterial and anticancer effects, and especially has been attracting much attention against viral infections. In vitro tests show that hydroxychloroquine has inhibitory activity on MERS-CoV, SARS-CoV-2, rabies virus, poliovirus, hepatitis A virus, Zika virus, Ebola virus, herpes simplex virus and the like. Recently, under the severe situation of increasing numbers of patients and deaths in COVID-19 in the United states, the FDA in the United states issued an emergency grant at 29/3 of 2020 allowing hydroxychloroquine to be used for the treatment of COVID-19. However, toxicological test results indicate that long-term administration of hydroxychloroquine can cause retinopathy and irreversible damage to the nervous system. Therefore, the search for the hydroxychloroquine derivative with high safety and good activity is of great significance for the development of medicaments for treating rheumatic diseases, resisting virus infection and the like.
Disclosure of Invention
The invention provides a novel quinoline compound, a preparation method, a pharmaceutical composition and application thereof.
In one aspect, the invention provides a compound of formula I, a pharmaceutically acceptable salt thereof, or a metabolite thereof,
wherein X is O or NH;
y is O or NH;
R1is hydroxy, halogen, cyano, unsubstituted or R1-1Substituted C1-6Alkyl, unsubstituted or R1-2Substituted C1-6Alkoxy radical, C3-10Cycloalkyl, -NR1-3R1-4、-(C＝O)R1-5、-(C＝O)OR1-6、-(C＝O)NR1-7R1-8、-S(＝O)2NR1-9R1-10or-O (C ═ O) R1-11；
R1-1Is halogen;
R1-2is halogen;
R1-3～R1-11independently selected from hydrogen or C1-4An alkyl group;
R2is C1-6An alkyl group;
R3is hydrogen, C1-18Alkoxy radical- (C1-6Alkyl) -, unsubstituted or R3-1Substituted C1-6Alkyl, unsubstituted or R3-2Substituted C6-10Aryl radical, R3-3(C＝O)OCH2-、R3-4(C＝O)SCH2CH2-、
R3-1Is halogen or hydroxy;
R3-2is deuterium, halogen, hydroxy, cyano, nitro, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, -NR3-2-1R3-2-2、-(C＝O)NR3-2-3R3-2-4、-S(＝O)2NR3-2-5R3-2-6、-(C＝O)R3-2-7OR, - (C ═ O) OR3 -2-8or-O (C ═ O) R3-2-9；
R3-2-1～R3-2-9Independently selected from hydrogen or C1-4An alkyl group;
R3-3、R3-4and R3-5Independently selected from C1-6Alkyl or C1-6An alkoxy group;
R3-6is C1-6An alkyl group;
R3-7is hydrogen or halogen;
R3-8is C1-8Alkyl or benzyl;
R3-9is unsubstituted or R3-9-1Substituted C1-6Alkyl radical, C1-6alkoxy-C1-6Alkyl, or, NR3-9-2R3-9-3-(C1-6Alkyl) -;
R3-9-1is hydroxy, halogen or C1-4An alkyl group;
R3-9-2and R3-9-3Independently selected from hydrogen or C1-4An alkyl group;
R3-10is hydrogen or C1-6An alkyl group;
R3-11is C1-6An alkyl group;
R3-12is C1-6An alkyl group;
n is an integer of 1-6;
R4is hydrogen, unsubstituted or R4-1Substituted C1-6Alkyl, unsubstituted or R4-2Substituted C6-10Aryl radical, R4-3(C＝O)OCH2-、R4-4(C＝O)SCH2CH2-、
R4-1Is halogen or hydroxy;
R4-2is deuterium, halogen, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl or C1-4A haloalkoxy group;
R4-3、R4-4and R4-5Independently selected from C1-6Alkyl or C1-6An alkoxy group;
R4-6is C1-6An alkyl group;
R4-7is hydrogen or halogen;
R4-8is hydrogen, C1-8Alkyl or benzyl;
R4-9is unsubstituted or R4-9-1Substituted C1-6Alkyl radical, C1-6alkoxy-C1-6Alkyl or NR4-9-2R4-9-3-(C1-6Alkyl) -;
R4-9-1is hydroxy, halogen or C1-4Alkyl groups of (a);
R4-9-2and R4-9-3Independently selected from hydrogen or C1-4Alkyl groups of (a);
R5is hydrogen, unsubstituted or R5-1Substituted C1-6Alkyl, or C3-10A cycloalkyl group;
R5-1is hydroxy, halogen, amino or cyano.
In one embodiment, the compound of formula I is in a stereoisomeric form.
In one embodiment, when X is O, R3Is hydrogen, C1-18Alkoxy radical- (C1-6Alkyl) -, unsubstituted or R3-1Substituted C1-6Alkyl, unsubstituted or R3-2Substituted C6-10Aryl radical, R3-3(C＝O)OCH2-、R3-4(C＝O)SCH2CH2-、
In one embodiment, when X is NH, R3Is composed of
In one embodiment, when Y is O, R4Is hydrogen, unsubstituted or R4-1Substituted C1-6Alkyl, unsubstituted or R4-2Substituted C6-10Aryl radical, R4-3(C＝O)OCH2-、R4-4(C＝O)SCH2CH2-、
In one embodiment, when R1When the halogen is fluorine, chlorine, bromine or iodine;
in one embodiment, when R1Is unsubstituted or R1-1Substituted C1-6When it is alkyl, said R1-1Is one or more, when there are more than one R1-1When R is said1-1May be the same or different;
in one embodiment, when R1Is unsubstituted or R1-1Substituted C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
in one embodiment, when R1Is unsubstituted or R1-2Substituted C1-6At alkoxy, said R1-2Is one or more, when there are more than one R1-2When R is said1-2May be the same or different;
in one embodiment, when R1Is unsubstituted or R1-2Substituted C1-6At alkoxy, said C1-6Alkoxy is C1-4An alkoxy group;
in one embodiment, when R1Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl being C3-6A cycloalkyl group;
in one embodiment, when R1-1When the halogen is fluorine, chlorine, bromine or iodine;
in one embodiment, when R1-2When the halogen is fluorine, chlorine, bromine or iodine;
in one embodiment, when R1-3Is C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, propyl, butyl or isopropyl;
in one embodiment, when R1-4Is C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, propyl, butyl or isopropyl;
in one embodiment, when R2Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
in one embodiment, when R3Is C1-18Alkoxy radical- (C1-6Alkyl) -said C1-18Alkoxy radical C1-6Alkyl is CH3(CH2)15O-(C1-4Alkyl) -;
in one embodiment, when R3Is unsubstituted or R3-1Substituted C1-6When it is alkyl, said R3-1Is one or more, when there are more than one R3-1When R is said3-1May be the same or different;
in one embodiment, when R3Is unsubstituted or R3-1Substituted C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
in one embodiment, when R3Is unsubstituted or R3-2Substituted C6-10When aryl is said to R3-2Is one or more, when there are more than one R3-2When R is said3-2May be the same or different;
in one embodiment, when R3Is unsubstituted or R3-2Substituted C6-10When aryl, said C6-10Aryl is phenyl or naphthyl;
in one embodiment, when R3-1When the halogen is fluorine, chlorine, bromine or iodine;
in one embodiment, when R3-2When the halogen is fluorine, chlorine, bromine or iodine;
in one embodiment, when R3-2Is C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, propyl, butyl or isopropyl;
in one embodiment, when R3-2Is C1-4When halogenated alkyl, said C1-4Haloalkyl is-CF3；
In one embodiment, when R3-2Is C1-4At alkoxy, said C1-4Alkoxy is methoxy, ethoxy, propoxy, butoxy or isopropoxy;
in one embodiment, when R3-2Is C1-4When halogenated alkoxy, said C1-4haloalkoxy-OCF3；
In one embodiment, when R3-2-1～R3-2-9Independently is C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, propyl, isopropyl or butyl;
in one embodiment, when R3-3、R3-4And R3-5Independently selected from C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
in one embodiment, when R3-3、R3-4And R3-5Independently selected from C1-6At alkoxy, said C1-6Alkoxy is C1-4An alkoxy group;
in one embodiment, when R3-6Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
in one embodiment, when R3-7When halogen is used, the halogen is fluorine, chlorine, bromine or iodine;
in one embodiment, when R3-8Is C1-8When alkyl, said C1-8Alkyl is C1-6An alkyl group;
in one embodiment, when R3-9Is unsubstituted or R3-9-1Substituted C1-6When it is alkyl, said R3-9-1Is one or more, when there are more than one R3-9-1When is in use, theR of (A) to (B)3-9-1May be the same or different;
in one embodiment, when R3-9Is unsubstituted or R3-9-1Substituted C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
in one embodiment, when R3-9Is C1-6alkoxy-C1-6When alkyl, said C1-6alkoxy-C1-6Alkyl is C1-4alkoxy-C1-4An alkyl group;
in one embodiment, when R3-9Is NR3-9-2R3-9-3-(C1-6Alkyl) -, said NR3-9-2R3-9-3-(C1-6Alkyl) -is NR3-9-2R3-9-3-(C1-4Alkyl) -;
in one embodiment, when R3-9-1Is C1-4When alkyl, said C1-4Alkyl is methyl, ethyl or propyl;
in one embodiment, when R3-9-2And R3-9-3Independently selected from C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, isopropyl, propyl or butyl;
in one embodiment, when R3-10Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
in one embodiment, when R3-11Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
in one embodiment, when R3-12Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
in one embodiment, when R4Is unsubstituted or R4-1Substituted C1-6When it is alkyl, said R4-1Is one or more, when there are more than one R4-1When R is said4-1May be the same or different;
in one embodiment, when R4Is not takenIs substituted or R4-1Substituted C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
in one embodiment, when R4-1When the halogen is fluorine, chlorine, bromine or iodine;
in one embodiment, when R4Is unsubstituted or R4-2Substituted C6-10When aryl is said to R4-2Is one or more, when there are more than one R4-2When R is said4-2May be the same or different;
in one embodiment, when R4Is unsubstituted or R4-2Substituted C6-10When aryl, said C6-10Aryl is phenyl;
in one embodiment, when R4-2When the halogen is fluorine, chlorine, bromine or iodine;
in one embodiment, when R4-2Is C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, propyl, butyl or isopropyl;
in one embodiment, when R4-2Is C1-4When halogenated alkyl, said C1-4Haloalkyl is-CF3；
In one embodiment, when R4-2Is C1-4At alkoxy, said C1-4Alkoxy is methoxy, ethoxy, propoxy, butoxy or isopropoxy;
in one embodiment, when R4-2Is C1-4When halogenated alkoxy, said C1-4haloalkoxy-OCF3；
In one embodiment, when R4-3、R4-4And R4-5Independently selected from C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
in one embodiment, when R4-3、R4-4And R4-5Independently selected from C1-6At alkoxy, said C1-6Alkoxy is C1-4Alkoxy radicalA group;
in one embodiment, when R4-6Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
in one embodiment, when R4-7When halogen is used, the halogen is fluorine, chlorine, bromine or iodine;
in one embodiment, when R4-8Is C1-8When alkyl, said C1-8Alkyl is C1-6An alkyl group;
in one embodiment, when R4-9Is unsubstituted or R4-9-1Substituted C1-6When it is alkyl, said R4-9-1Is one or more, when there are more than one R4-9-1When R is said4-9-1May be the same or different;
in one embodiment, when R4-9Is unsubstituted or R4-9-1Substituted C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
in one embodiment, when R4-9Is C1-6alkoxy-C1-6When alkyl, said C1-6alkoxy-C1-6Alkyl is C1-4alkoxy-C1-4An alkyl group;
in one embodiment, when R4-9Is NR4-9-2R4-9-3-(C1-6Alkyl) -, said NR4-9-2R4-9-3-(C1-6Alkyl) -is NR4-9-2R4-9-3-(C1-4Alkyl) -;
in one embodiment, when R4-9-1Is C1-4When alkyl, said C1-4Alkyl is methyl, ethyl or propyl;
in one embodiment, when R4-9-2And R4-9-3Independently selected from C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, isopropyl, propyl or butyl;
in one embodiment, when R5Is unsubstituted or R5-1Substituted C1-6When alkyl is present, theR is as described5-1Is one or more, when there are more than one R5-1When R is said5-1May be the same or different;
in one embodiment, when R5Is unsubstituted or R5-1Substituted C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
in one embodiment, when R5-1When the halogen is fluorine, chlorine, bromine or iodine.
In one embodiment, when R5Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl being C3-6A cycloalkyl group.
In one embodiment, when R1Is unsubstituted or R1-1Substituted C1-6When it is alkyl, said R1-1The number of (a) is 1, 2 or 3;
in one embodiment, when R1Is unsubstituted or R1-1Substituted C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl;
in one embodiment, when R1Is unsubstituted or R1-2Substituted C1-6At alkoxy, said R1-21, 2 or 3;
in one embodiment, when R1Is unsubstituted or R1-2Substituted C1-6At alkoxy, said C1-6Alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butyloxy, sec-butoxy or tert-butoxy;
in one embodiment, when R1Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
in one embodiment, when R1is-NR1-3R1-4When said is-NR1-3R1-4is-NH2Or (b) or (c),
In one embodiment, when R2Is C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, butyl, isopropyl, isobutyl or sec-butyl;
in one embodiment, when R3Is C1-18Alkoxy radical- (C1-6Alkyl) -said C1-18Alkoxy radical- (C1-6Alkyl) -is CH3(CH2)15O-CH2CH2-, or, CH3(CH2)15O-CH2CH2CH2-；
In one embodiment, when R3Is unsubstituted or R3-1Substituted C1-6When it is alkyl, said R3-1The number of (a) is 1, 2 or 3;
in one embodiment, when R3Is unsubstituted or R3-1Substituted C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl or tert-butyl;
in one embodiment, when R3Is unsubstituted or R3-2Substituted C6-10When aryl is said to R3-2The number of (a) is 1, 2, 3 or 4;
in one embodiment, when R3-3、R3-4And R3-5Independently selected from C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl;
in one embodiment, when R3-3、R3-4And R3-5Independently selected from C1-6At alkoxy, said C1-6Alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy;
in one embodiment, when R3-6Is C1-6When alkyl, said C1-6The alkyl is methyl,Ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl or tert-butyl;
in one embodiment, when R3-7When halogen is used, the halogen is fluorine or chlorine;
in one embodiment, when R3-8Is C1-8When alkyl, said C1-8Alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or hexyl, preferably methyl, isopropyl, isobutyl, sec-butyl or hexyl;
in one embodiment, when R3-9Is unsubstituted or R3-9-1Substituted C1-6When it is alkyl, said R3-9-1The number of (a) is 1, 2 or 3;
in one embodiment, when R3-9Is unsubstituted or R3-9-1Substituted C1-6When alkyl, said C1-6Alkyl of (a) is methyl, ethyl, propyl, butyl, isopropyl or isobutyl;
in one embodiment, when R3-9Is C1-6alkoxy-C1-6When alkyl, said C1-6alkoxy-C1-6Alkyl is
In one embodiment, when R3-9Is NR3-9-2R3-9-3-(C1-6Alkyl) -, said NR3-9-2R3-9-3-(C1-6Alkyl) -is
In one embodiment, when R3-10Is C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl or butyl;
in one embodiment, when R3-11Is C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl or butyl;
in one embodiment, when R3-12Is C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl or butyl;
in one embodiment, when R4Is unsubstituted or R4-1Substituted C1-6When it is alkyl, said R4-1The number of (a) is 1, 2 or 3;
in one embodiment, when R4Is unsubstituted or R4-1Substituted C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl or tert-butyl;
in one embodiment, when R4Is unsubstituted or R4-2Substituted C6-10When aryl is said to R4-2The number of (a) is 1, 2, 3 or 4;
in one embodiment, when R4-3、R4-4And R4-5Independently selected from C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl;
in one embodiment, when R4-3、R4-4And R4-5Independently selected from C1-6At alkoxy, said C1-6Alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy;
in one embodiment, when R4-6Is C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl or tert-butyl;
in one embodiment, when R4-7When halogen is used, the halogen is fluorine or chlorine;
in one embodiment, when R4-8Is C1-8When alkyl, said C1-8Alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or hexyl, preferably methyl, isopropyl, isobutyl, sec-butyl or hexyl;
at one isIn embodiments, when R4-9Is unsubstituted or R4-9-1Substituted C1-6When it is alkyl, said R4-9-1The number of (a) is 1, 2 or 3;
in one embodiment, when R4-9Is unsubstituted or R4-9-1Substituted C1-6When alkyl, said C1-6Alkyl of (a) is methyl, ethyl, propyl, butyl, isopropyl or isobutyl;
in one embodiment, when R4-9Is C1-6alkoxy-C1-6When alkyl, said C1-6alkoxy-C1-6Alkyl is
In one embodiment, when R4-9Is NR4-9-2R4-9-3-(C1-6Alkyl) -, said NR4-9-2R4-9-3-(C1-6Alkyl) -is
In one embodiment, when R5Is unsubstituted or R5-1Substituted C1-6When it is alkyl, said R5-1The number of (a) is 1, 2 or 3;
in one embodiment, when R5Is unsubstituted or R5-1Substituted C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl;
in one embodiment, when R5Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In one embodiment, when R1Is unsubstituted or R1-1Substituted C1-6When it is alkyl, said R1-1Substituted C1-6Alkyl is-CF3；
In one embodiment, when R1Is unsubstituted or R1-2Substituted C1-6At alkoxy, said R1-2Substituted C1-6Alkoxy is-OCF3；
In one embodiment, when R3Is unsubstituted or R3-1Substituted C1-6When it is alkyl, said R3-1Substituted C1-6Alkyl is-CH2CCl3or-CH2CF3；
In one embodiment, when R3Is unsubstituted or R3-2Substituted C6-10When aryl is said to R3-2Substituted C6-10Aryl is
In one embodiment, when R3-9Is unsubstituted or R3-9-1Substituted C1-6When it is alkyl, said R3-9-1Substituted C1-6Alkyl is
In one embodiment, when R4Is unsubstituted or R4-1Substituted C1-6When it is alkyl, said R4-1Substituted C1-6Alkyl is-CH2CCl3or-CH2CF3；
In one embodiment, when R4Is unsubstituted or R4-2Substituted C6-10When aryl is said to R4-2Substituted C6-10Aryl is
In one embodiment, when R4-9Is unsubstituted or R4-9-1Substituted C1-6When it is alkyl, said R4-9-1Substituted C1-6Alkyl is
In one embodiment, when R5Is unsubstituted or R5-1Substituted C1-6When it is alkyl, said R5-1Substituted C1-6Alkyl is
In one embodiment, when R5Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In one embodiment, R1Is halogen, unsubstituted or R1-1Substituted C1-6Alkyl, unsubstituted or R1-2Substituted C1-6Alkoxy, or, -NR1-3R1-4；
In one embodiment, R3Is C1-18Alkoxy radical- (C1-6Alkyl) -, unsubstituted or R3-1Substituted C1-6Alkyl, unsubstituted or R3-2Substituted C6-10Aryl radical, R3-3(C＝O)OCH2-、R3-4(C＝O)SCH2CH2-、
In one embodiment, R3-1Is halogen;
in one embodiment, R3-2Is halogen, hydroxy, cyano, nitro, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, -NR3-2-1R3-2-2、-(C＝O)NR3-2-3R3-2-4、-S(＝O)2NR3-2-5R3-2-6、-(C＝O)R3-2-7OR, - (C ═ O) OR3-2-8；
In one embodiment, R3-2-3～R3-2-6Is hydrogen;
in one embodiment, R3-2-7And R3-2-8Is C1-4An alkyl group;
in one embodiment, R3-9-1Is a hydroxyl group;
in one embodiment, R3-9-2And R3-9-3Independently selected from C1-4An alkyl group;
in one embodiment, R4Is hydrogen, unsubstituted or R4-1Substituted C1-6Alkyl, unsubstituted or R4-2Substituted C6-10Aryl radical, R4-3(C＝O)OCH2-、R4-4(C＝O)SCH2CH2-、
In one embodiment, R4-1Is halogen;
in one embodiment, R4-2Is halogen, C1-4Alkoxy radical, C1-4Haloalkyl, or, C1-4A haloalkoxy group;
in one embodiment, R5-1Is a hydroxyl group.
In one embodiment, certain groups of the compounds of formula I are defined as follows (undefined groups are as described in any of the preceding schemes):
x is O or NH;
y is O or NH;
R1is halogen, unsubstituted or R1-1Substituted C1-6Alkyl, unsubstituted or R1-2Substituted C1-6Alkoxy, or, -NR1- 3R1-4；
R1-1Is halogen;
R1-2is halogen;
R1-3is hydrogen or C1-4An alkyl group;
R1-4is hydrogen or C1-4An alkyl group;
R2is C1-6An alkyl group;
R3is hydrogen, C1-18Alkoxy radical- (C1-6Alkyl) -, unsubstituted or R3-1Substituted C1-6Alkyl, unsubstituted or R3-2Substituted C6-10Aryl radical, R3-3(C＝O)OCH2-、R3-4(C＝O)SCH2CH2-、
R3-1Is halogen;
R3-2is halogen, hydroxy, cyano, nitro, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, -NR3-2-1R3-2-2、-(C＝O)NR3-2-3R3-2-4、-S(＝O)2NR3-2-5R3-2-6、-(C＝O)R3-2-7OR, - (C ═ O) OR3 -2-8；
R3-2-1And R3-2-2Independently is hydrogen or C1-4An alkyl group;
R3-2-3～R3-2-6is hydrogen;
R3-2-7and R3-2-8Independently is C1-4An alkyl group;
R3-3、R3-4and R3-5Independently selected from C1-6Alkyl or C1-6An alkoxy group;
R3-8is C1-8Alkyl or benzyl;
R3-9is unsubstituted or R3-9-1Substituted C1-6Alkyl radical, C1-6alkoxy-C1-6Alkyl, or, NR3-9-2R3-9-3-(C1-6Alkyl) -;
R3-9-1is a hydroxyl group;
R3-9-2and R3-9-3Independently selected from C1-4An alkyl group;
R3-10is hydrogen or C1-6An alkyl group;
R3-11is C1-6An alkyl group;
R3-12is C1-6An alkyl group;
n is an integer of 1-6;
R4is hydrogen, unsubstituted or R4-1Substituted C1-6Alkyl, unsubstituted or R4-2Substituted C6-10Aryl radical, R4-3(C＝O)OCH2-、R4-4(C＝O)SCH2CH2-、
R4-1Is halogen;
R4-2is halogen, C1-4Alkoxy radical, C1-4Haloalkyl, or, C1-4A haloalkoxy group;
R4-3、R4-4and R4-5Independently selected from C1-6Alkyl or C1-6An alkoxy group;
R4-8is C1-8Alkyl or benzyl;
R4-9is unsubstituted C1-6An alkyl group;
R5is hydrogen, unsubstituted or R5-1Substituted C1-6Alkyl, or, C3-10A cyclopropyl group;
R5-1is a hydroxyl group;
in one embodiment, certain groups of the compounds of formula I are defined as follows (undefined groups are as described in any of the preceding schemes):
x is O or NH;
y is O or NH;
R1is halogen, or unsubstituted or R1-1Substituted C1-6An alkyl group;
R1-1is halogen;
R2is C1-6Alkyl radical；
R3Is hydrogen, C1-18Alkoxy radical- (C1-6Alkyl) -, unsubstituted or R3-1Substituted C1-6Alkyl, unsubstituted or R3-2Substituted C6-10Aryl radical, R3-3(C＝O)OCH2-、R3-4(C＝O)SCH2CH2-、
R3-1Is halogen;
R3-2is halogen, cyano, nitro, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, - (C ═ O) NR3-2-3R3-2-4、-S(＝O)2NR3-2-5R3-2-6、-(C＝O)R3-2-7OR, - (C ═ O) OR3-2-8；
R3-2-3～R3-2-6Is hydrogen;
R3-2-7and R3-2-8Independently is C1-4An alkyl group;
R3-3、R3-4and R3-5Independently selected from C1-6Alkyl or C1-6An alkoxy group;
R3-8is C1-8Alkyl or benzyl;
R3-9is unsubstituted or R3-9-1Substituted C1-6Alkyl radical, C1-6alkoxy-C1-6Alkyl, or, NR3-9-2R3-9-3-(C1-6Alkyl) -;
R3-9-1is a hydroxyl group;
R3-9-2and R3-9-3Independently selected from C1-4An alkyl group;
R3-10is hydrogen or C1-6An alkyl group;
R3-11is C1-6An alkyl group;
R3-12is C1-6An alkyl group;
n is an integer of 1-6;
R4is hydrogen, unsubstituted or R4-1Substituted C1-6Alkyl, unsubstituted or R4-2Substituted C6-10Aryl radical, R4-3(C＝O)OCH2-、R4-4(C＝O)SCH2CH2-、
R4-1Is halogen;
R4-2is halogen, C1-4Alkoxy radical, C1-4Haloalkyl, or, C1-4A haloalkoxy group;
R4-3、R4-4and R4-5Independently selected from C1-6Alkyl or C1-6An alkoxy group;
R4-8is C1-8Alkyl or benzyl;
R4-9is unsubstituted C1-6An alkyl group;
R5is hydrogen or unsubstituted C1-6An alkyl group.
In one embodiment, the compound of formula I is:
wherein, X, Y, R1、R2、R3、R4And R5Is as defined in any one of claims 1 to 6.
In one embodiment, the compound of formula I may be any one of the following compounds:
the invention also provides a preparation method of the compound shown as the general formula I, the pharmaceutically acceptable salt thereof or the metabolite thereof, which comprises the following steps: carrying out substitution reaction on a compound shown as a formula II and a compound shown as a formula III under the action of alkali in a solvent;
wherein, X, Y, R1、R2、R3、R4And R5Is as defined in any of the above claims.
In one embodiment, the solvent may be a solvent conventional in the art, preferably THF, DCM, acetonitrile, 1, 4-dioxane or DMF;
in one embodiment, the base may be an organic base conventional in the art, preferably N-methylimidazole or DIPEA;
in one embodiment, the molar concentration of the compound of formula II in the solvent may be a molar concentration conventional in the art, preferably 0.01-0.05mol/L, such as 0.0186mol/L, 0.01925mol/L, 0.03285 mol/L.
In one embodiment, the molar ratio of the compound represented by the formula III to the compound represented by the formula II may be a molar ratio conventional in the art, and is preferably 0.8:1 to 1.5:1, such as 1:1, 1.1: 1.
In one embodiment, the molar ratio of the base and the compound of formula II may be a molar ratio as is conventional in the art, preferably from 1:1 to 3:1, for example 2: 1.
In one embodiment, the temperature of the substitution reaction may be a temperature conventional in the art, preferably 50 to 90 ℃.
In one embodiment, the progress of the substitution reaction may be monitored by means conventional in the art (e.g. TLC, HPLC or LCMS), preferably for 6 to 12 hours, for example 8 hours.
In one embodiment, after the reaction is completed, it may preferably further include a post-treatment step. The post-treatment conditions and operations may be those conventional in the art, including the steps of: cooling the reaction solution, adding a solvent, extracting to obtain an organic layer, drying, filtering, removing the solvent in the filtrate to obtain a residue, and separating and purifying the residue. The cooling is preferably to room temperature. The solvent is preferably a salt solution, such as a saturated salt solution. The extraction conditions and operations may be those conventional in the art, and the solvent for the extraction is preferably an ester solvent, such as ethyl acetate. The conditions and operations of the filtration can be those conventional in the art. The conditions and operations for removing the solvent can be those conventional in the art, such as evaporating the solvent. The separation and purification is preferably column chromatography separation.
The term "room temperature" as used herein means 20 to 30 ℃ unless otherwise specified.
The invention also provides application of the compound shown as the formula I, pharmaceutically acceptable salt thereof or metabolite thereof in preparing a medicament for preventing or treating virus infection.
Further, the viruses include, but are not limited to, middle east syndrome-associated coronavirus (MERS-CoV), severe acute respiratory syndrome-associated coronavirus (SARS-CoV), influenza a virus, influenza b virus, novel coronavirus pneumonia (covi-19), rabies virus, poliovirus, aids virus, hepatitis a virus, hepatitis c virus, influenza a A H5N1 virus, chikungunya disease, dengue virus, zika virus, lassa virus, congo hemorrhagic fever virus, ebola virus, hepatitis b virus, or herpes simplex virus.
The invention also provides a pharmaceutical composition, which comprises the compound shown in the formula I, pharmaceutically acceptable salt thereof, or metabolite thereof, and a pharmaceutical adjuvant.
In the pharmaceutical composition, the compound shown in formula I, the pharmaceutically acceptable salt thereof, or the metabolite thereof is used in an amount of therapeutically effective amount.
The invention also provides application of the pharmaceutical composition in preparing a medicament for preventing or treating virus infection.
Further, the viruses include, but are not limited to, middle east syndrome-associated coronavirus (MERS-CoV), severe acute respiratory syndrome-associated coronavirus (SARS-CoV), influenza a virus, influenza b virus, novel coronavirus pneumonia (covi-19), rabies virus, poliovirus, aids virus, hepatitis a virus, hepatitis c virus, influenza a A H5N1 virus, chikungunya disease, dengue virus, zika virus, lassa virus, congo hemorrhagic fever virus, ebola virus, hepatitis b virus, or herpes simplex virus.
The pharmaceutical excipients can be those widely used in the field of pharmaceutical production. The excipients are used primarily to provide a safe, stable and functional pharmaceutical composition and may also provide methods for allowing the active ingredient to dissolve at a desired rate after administration to a subject or to promote effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, antiadherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents and sweeteners.
The pharmaceutical compositions of the present invention may be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.
The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implant, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the present invention may also be in a controlled release or delayed release dosage form (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations which can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention with relatively nontoxic acids or bases. When compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting free forms of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting free forms of such compounds with a sufficient amount of an acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, wherein the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming a carbonate or bicarbonate), phosphoric acid (forming a phosphate, monohydrogen phosphate, dihydrogen phosphate), sulfuric acid (forming a sulfate or bisulfate), hydroiodic acid, phosphorous acid, and the like; and salts of organic acids including acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like; the organic acid salt also includes salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt. Preferably, the free form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The free form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
The "pharmaceutically acceptable salts" of the present invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
The term "stereoisomer" refers to isomers resulting from the spatial arrangement of atoms in a molecule, which can be divided into three classes, cis-trans isomers, enantiomers and conformers, and into two broad classes, enantiomers and diastereomers. The cis-trans isomer is an isomer caused by the fact that a double bond or a single bond of a ring-forming carbon atom cannot rotate freely. The enantiomers refer to stereoisomers which are not overlapped with each other in real and mirror images. The conformational isomer refers to a stereoisomer caused by rotation of a single bond, such as chair cyclohexane and boat cyclohexane.
The term "metabolite" refers to a pharmaceutically active product produced by the in vivo metabolism of a compound of formula I or a salt thereof. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc. of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by a method comprising contacting a compound of the invention with a mammal for a period of time sufficient to obtain a metabolite thereof.
Identification of metabolites is typically accomplished by preparing a radiolabeled isotope of a compound of the invention, parenterally administering it at a detectable dose (e.g., greater than about 0.5mg/kg) to an animal, such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from urine, blood or other biological samples. These products are easy to isolate because they are labelled (others are isolated by using antibodies capable of binding to epitopes present in the metabolite). Metabolite structure is determined in a conventional manner, e.g., by MS, LC/MS or NMR analysis. Typically, analysis of metabolites is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolite products are useful in assays for the administration of therapeutic doses of the compounds of the invention, provided that they are not otherwise detectable in vivo. The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioactive isotopes, such as tritium (A), (B), (C3H) Iodine-125 (125I) Or C-14(14C) In that respect All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
It will be understood by those skilled in the art that, in accordance with the convention used in the art, the structural formulae used in the radicals described herein
Means that the corresponding group is connected with other fragments and groups in the compound shown in the formula I through the site.
The "substitution" in the present invention may be one or more, and when there are a plurality of "substitutions", the "substitutions" may be the same or different.
The term "plurality" may list, for example, 2, 3, or 4.
The term "halogen" includes fluorine, chlorine, bromine or iodine.
The term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, and the like.
The term "alkoxy" refers to the group-O-RYWherein R isYIs an alkyl group as defined above.
The above-mentioned preferred conditions may be arbitrarily combined without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
Advantageous effects
The quinoline compound has good treatment effect on virus infection and small toxic and side effects.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1: synthesis of Compound S1
(R) -2- ((4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethyl dimethyl phosphate
To compound 2(500mg, 1.49mmol) was added DCM (10mL), cooled to 0 deg.C and compound 1(215mg, 1.49mmol) was added to the above suspensionTriethylamine (0.25mL,1.64mmol) was then added. The reaction solution was warmed to room temperature and stirred for 3 h. The solvent was distilled off under reduced pressure, and purified by column chromatography to give compound S1(370mg, 56%).1H NMR(500MHz,Chloroform-d)8.48(d,J＝5.7Hz,1H),7.87(d,J＝2.3Hz,1H),7.79(d,J＝8.4Hz,1H),7.26(dd,J＝8.4,2.2Hz,1H),7.05(d,J＝5.7Hz,1H),4.51(d,J＝9.3Hz,1H),4.10(ddt,J＝11.2,8.6,6.5Hz,1H),4.00(ddt,J＝11.2,8.6,6.5Hz,1H),3.85–3.76(m,1H),3.73(d,J＝11.0Hz,6H),2.90(dt,J＝12.9,6.4Hz,1H),2.73(dt,J＝12.9,6.5Hz,1H),2.67–2.58(m,1H),2.61–2.51(m,2H),2.52–2.43(m,1H),1.67–1.54(m,1H),1.57–1.51(m,1H),1.51(ddt,J＝6.2,2.7,1.5Hz,1H),1.52–1.42(m,1H),1.15(d,J＝6.2Hz,3H),1.06(t,J＝7.2Hz,3H).
The following synthesis methods of the compounds S2 to S20 in examples 2 to 20 were the same as those of the compound S1 in example 1, and only the corresponding raw materials were replaced.
Example 2: synthesis of Compound S2
(R) -2- ((4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethyl diethyl phosphate
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.7Hz,1H),7.87(d,J＝2.3Hz,1H),7.79(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.04(d,J＝5.5Hz,1H),4.51(d,J＝9.3Hz,1H),4.22–3.94(m,6H),3.62–3.51(m,1H),3.01(dt,J＝12.7,6.4Hz,1H),2.77–2.45(m,5H),1.67–1.56(m,1H),1.57–1.46(m,2H),1.50–1.40(m,1H),1.37–1.30(m,6H),1.14(d,J＝6.2Hz,3H),1.06(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)145.91,145.70,143.75,131.71,127.08,125.07,123.75,123.18,99.76,64.87,64.83,64.27,64.22,54.30,53.95,53.90,48.27,47.57,31.56,24.31,20.39,16.10,16.06,12.06.
Example 3: synthesis of Compound S3
(R) -2- ((4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethyl bis (2,2, 2-trichloroethyl) phosphate
1H NMR(300MHz,DMSO-d6)8.45(d,J＝5.7Hz,1H),7.87(d,J＝2.1Hz,1H),7.79(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.00(d,J＝5.5Hz,1H),5.03(dd,J＝9.3,8.4Hz,2H),4.80(dd,J＝9.3,8.5Hz,2H),4.45(d,J＝9.3Hz,1H),4.09(ddt,J＝11.2,8.6,6.5Hz,1H),3.99(ddt,J＝11.0,8.4,6.4Hz,1H),3.62–3.50(m,1H),3.02(dt,J＝12.9,6.5Hz,1H),2.71(dq,J＝12.1,7.2Hz,1H),2.60–2.40(m,4H),1.69–1.57(m,1H),1.58–1.39(m,3H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)146.03,145.94,143.98,131.37,127.13,124.66,123.65,123.18,99.76,95.77,95.72,70.77,70.72,70.68,64.93,64.88,54.34,53.96,53.91,48.27,47.57,31.55,24.32,20.35,12.03.
Example 4: synthesis of Compound S4
(R) -2- ((4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethyl bis (2,2, 2-trifluoroethyl) phosphate
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.87(d,J＝2.3Hz,1H),7.79(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.05(d,J＝5.7Hz,1H),4.69(dp,J＝13.0,8.9Hz,2H),4.57(dp,J＝13.0,8.9Hz,2H),4.45(d,J＝9.5Hz,1H),4.09(ddt,J＝11.2,8.6,6.5Hz,1H),3.99(ddt,J＝11.0,8.4,6.4Hz,1H),3.86–3.74(m,1H),3.13(dt,J＝12.7,6.4Hz,1H),2.74–2.46(m,5H),1.69–1.57(m,1H),1.55–1.44(m,2H),1.47–1.36(m,1H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)145.94,145.47,143.98,131.50,127.12,125.91,125.86,124.66,123.77,123.72,123.67,123.18,121.62,121.57,119.48,119.43,99.76,65.06,65.02,64.97,64.93,64.88,64.85,64.80,64.75,64.63,64.58,64.54,64.42,64.37,64.32,54.30,53.96,53.91,48.27,47.57,31.53,24.32,20.35,12.03.
Example 5: synthesis of Compound S5
(S) -2- ((4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethyl dimethyl phosphate
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.7Hz,1H),7.87(d,J＝2.3Hz,1H),7.79(d,J＝8.5Hz,1H),7.26(dd,J＝8.4,2.2Hz,1H),7.06(d,J＝5.7Hz,1H),4.51(d,J＝9.3Hz,2H),4.05(dt,J＝8.5,6.4Hz,2H),3.73(d,J＝10.8Hz,5H),3.62–3.51(m,1H),2.78(t,J＝6.5Hz,2H),2.64(q,J＝7.2Hz,2H),2.58–2.50(m,2H),1.58–1.46(m,4H),1.15(d,J＝6.2Hz,3H),1.06(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)145.83,145.71,143.63,131.64,127.08,125.07,123.68,123.18,99.54,64.94,64.89,55.74,55.70,54.30,54.00,53.95,48.22,47.58,31.59,24.31,20.40,12.06.
Example 6: synthesis of Compound S6
(S) -2- ((4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethylbis (2,2, 2-trifluoroethyl) phosphate
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.87(d,J＝2.3Hz,1H),7.79(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.05(d,J＝5.7Hz,1H),4.69(dp,J＝13.0,8.9Hz,2H),4.57(dp,J＝13.0,8.9Hz,2H),4.45(d,J＝9.5Hz,1H),4.09(ddt,J＝11.2,8.6,6.5Hz,1H),3.99(ddt,J＝11.0,8.4,6.4Hz,1H),3.86–3.74(m,1H),3.13(dt,J＝12.7,6.4Hz,1H),2.74–2.46(m,5H),1.69–1.57(m,1H),1.55–1.44(m,2H),1.47–1.36(m,1H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)145.94,145.47,143.98,131.50,127.12,125.91,125.86,124.66,123.77,123.72,123.67,123.18,121.62,121.57,119.48,119.43,99.76,65.06,65.02,64.97,64.93,64.88,64.85,64.80,64.75,64.63,64.58,64.54,64.42,64.37,64.32,54.30,53.96,53.91,48.27,47.57,31.53,24.32,20.35,12.03.
Example 7: synthesis of Compound S7
(R) -2- ((4- ((7-fluoroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethyldiisopropylphosphate
1H NMR(300MHz,DMSO-d6)8.49(d,J＝5.7Hz,1H),8.05(dd,J＝8.4,4.9Hz,1H),7.51(dd,J＝7.9,2.3Hz,1H),7.16(td,J＝8.2,2.2Hz,1H),7.02(d,J＝5.7Hz,1H),4.76–4.63(m,3H),4.10(ddt,J＝11.0,8.4,6.4Hz,1H),4.01(ddt,J＝11.0,8.4,6.4Hz,1H),3.91–3.79(m,1H),3.01(dt,J＝12.7,6.5Hz,1H),2.71(dq,J＝12.1,7.2Hz,1H),2.58(dt,J＝12.1,6.2Hz,1H),2.54–2.40(m,3H),1.65–1.54(m,1H),1.57–1.42(m,3H),1.37(dd,J＝24.9,6.2Hz,12H),1.14(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)162.56,160.54,146.96,145.12,143.67,143.61,124.12,124.06,122.74,122.72,114.17,114.01,112.75,112.59,99.76,71.96,71.91,64.87,64.83,54.30,53.96,53.92,48.27,47.57,31.57,24.31,23.60,23.55,20.39,12.07.
Example 8: synthesis of Compound S8
(R) -2- ((4- ((7-trifluoromethylquinolin-4-yl) amino) pentyl) (ethyl) amino) ethyl diethyl phosphate
1H NMR(300MHz,DMSO-d6)8.54(d,J＝5.7Hz,1H),8.21–8.12(m,2H),7.52(dd,J＝8.4,1.6Hz,1H),7.15(d,J＝5.6Hz,1H),5.18(d,J＝9.3Hz,1H),4.16(ddq,J＝9.8,8.6,7.0Hz,2H),4.13–4.04(m,1H),4.06–3.94(m,3H),3.61–3.49(m,1H),2.93(dt,J＝12.9,6.5Hz,1H),2.68–2.52(m,3H),2.55–2.41(m,2H),1.72–1.60(m,1H),1.56–1.40(m,3H),1.35(td,J＝6.9,0.7Hz,6H),1.12(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)146.66,144.03,143.24,143.23,143.21,143.19,132.12,131.86,131.61,131.35,127.09,124.94,124.02,123.84,123.82,123.81,123.79,122.98,122.95,122.92,122.89,122.80,120.66,120.23,120.20,120.17,120.13,99.76,64.87,64.82,63.88,63.84,54.30,53.93,53.88,48.27,47.57,31.57,24.31,20.38,16.10,16.05,12.03.
Example 9: synthesis of Compound S9
(R) -2- ((4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethyl diphenyl phosphate
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.89–7.80(m,2H),7.39–7.29(m,5H),7.24–7.15(m,7H),4.45(d,J＝9.3Hz,1H),4.13(ddt,J＝11.0,8.4,6.4Hz,1H),4.03(ddt,J＝11.2,8.6,6.5Hz,1H),3.64–3.52(m,1H),2.86(dt,J＝12.7,6.5Hz,1H),2.64(dq,J＝12.1,7.2Hz,1H),2.57–2.42(m,4H),1.69–1.58(m,1H),1.57–1.50(m,1H),1.53–1.46(m,1H),1.50–1.40(m,1H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)150.12,150.06,145.75,145.47,143.98,131.55,129.66,129.65,127.12,124.52,124.47,123.64,123.18,120.12,120.08,99.55,64.81,64.76,54.30,53.93,53.88,48.27,47.57,31.53,24.30,20.35,12.03.
Example 10: synthesis of Compound S10
(R) -2- ((4- ((7-aminoquinolin-4-yl) amino) pentyl) (ethyl) amino) ethyl diphenyl phosphate
1H NMR(300MHz,DMSO-d6)8.30(d,J＝5.7Hz,1H),7.89(d,J＝8.5Hz,1H),7.45(d,J＝2.2Hz,1H),7.39–7.31(m,4H),7.19(ddt,J＝7.3,4.2,1.6Hz,6H),6.72(d,J＝5.7Hz,1H),6.62(dd,J＝8.4,2.2Hz,1H),5.42(d,J＝6.0Hz,1H),5.29(d,J＝6.2Hz,1H),4.73(d,J＝9.3Hz,1H),4.08(dt,J＝8.6,6.5Hz,2H),3.82(ddtd,J＝11.5,9.3,6.2,5.4Hz,1H),2.74(t,J＝6.5Hz,2H),2.60(q,J＝7.2Hz,2H),2.51(t,J＝6.2Hz,2H),1.57–1.40(m,4H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)150.12,150.06,147.31,145.94,144.83,143.55,129.66,129.65,124.47,124.14,120.34,120.19,120.15,110.79,110.11,99.55,64.81,64.76,54.30,53.93,53.88,48.27,47.57,31.53,24.30,20.35,12.03.
Example 11: synthesis of Compound S11
(R) -2- ((4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethyl bis (4-methoxyphenyl) phosphate
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.30–7.21(m,2H),7.14–7.08(m,4H),6.96–6.90(m,4H),4.45(d,J＝9.3Hz,1H),4.14(m,2H),4.03(m,1H),3.79(s,5H),3.64–3.52(m,1H),2.84(dt,J＝12.9,6.4Hz,1H),2.75–2.61(m,3H),2.58–2.46(m,2H),1.73–1.62(m,1H),1.62–1.52(m,1H),1.53–1.41(m,2H),1.14(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)154.22,148.32,148.26,145.75,143.98,131.33,127.26,124.40,123.61,123.18,119.93,119.89,114.27,114.25,99.55,64.81,64.76,55.38,54.30,53.96,53.91,48.27,47.56,31.55,24.32,20.35,12.03.
Example 12: synthesis of Compound S12
(S) -2- ((4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethyl bis (4-methoxyphenyl) phosphate
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.30–7.21(m,2H),7.14–7.08(m,4H),6.96–6.90(m,4H),4.45(d,J＝9.3Hz,1H),4.14(m,2H),4.03(m,1H),3.79(s,5H),3.64–3.52(m,1H),2.84(dt,J＝12.9,6.4Hz,1H),2.75–2.61(m,3H),2.58–2.46(m,2H),1.73–1.62(m,1H),1.62–1.52(m,1H),1.53–1.41(m,2H),1.14(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)154.22,148.32,148.26,145.75,143.98,131.33,127.26,124.40,123.61,123.18,119.93,119.89,114.27,114.25,99.55,64.81,64.76,55.38,54.30,53.96,53.91,48.27,47.56,31.55,24.32,20.35,12.03.
Example 13: synthesis of Compound S13
(R) -2- ((4- ((7-fluoroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethyl diphenyl phosphate
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),8.15(dd,J＝8.5,5.0Hz,1H),7.68(dd,J＝7.9,2.3Hz,1H),7.39–7.31(m,4H),7.26–7.16(m,7H),7.13(d,J＝5.5Hz,1H),4.71(d,J＝9.3Hz,1H),4.13(ddt,J＝11.0,8.4,6.4Hz,1H),4.03(ddt,J＝11.2,8.6,6.5Hz,1H),3.64–3.52(m,1H),2.90(dt,J＝12.9,6.5Hz,1H),2.73–2.63(m,2H),2.61–2.52(m,2H),2.55–2.45(m,1H),1.69–1.57(m,1H),1.59–1.48(m,2H),1.51–1.39(m,1H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)162.60,160.59,150.12,150.06,146.73,144.88,143.88,143.82,129.66,129.65,124.47,124.08,124.02,122.74,122.72,120.19,120.15,114.29,114.12,112.89,112.73,99.55,64.81,64.76,54.30,53.93,53.88,48.27,47.57,31.53,24.30,20.35,12.03.
Example 14: synthesis of Compound S14
(R) -2- ((4- ((7- (dimethylamino) quinolin-4-yl) amino) pentyl) (ethyl) amino) ethyl diphenyl phosphate
1H NMR(300MHz,DMSO-d6)8.23(d,J＝5.7Hz,1H),7.98(d,J＝8.4Hz,1H),7.45(d,J＝2.3Hz,1H),7.39–7.31(m,4H),7.19(tt,J＝7.9,1.4Hz,6H),6.75(dd,J＝8.4,2.2Hz,1H),6.67(d,J＝5.7Hz,1H),4.35(d,J＝9.3Hz,1H),4.08(dt,J＝8.6,6.5Hz,2H),3.96–3.85(m,1H),2.98(s,5H),2.76(t,J＝6.5Hz,2H),2.66–2.58(m,2H),2.55–2.48(m,2H),1.58–1.43(m,4H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)150.12,150.06,146.08,145.01,143.71,143.19,129.66,129.65,124.47,124.15,120.12,120.08,119.47,112.20,107.86,99.55,64.81,64.76,54.30,53.93,53.88,48.27,47.56,40.40,31.53,24.30,20.35,12.03.
Example 15: synthesis of Compound S15
(R) -2- ((4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethyl bis (4-trifluoromethylphenyl) phosphate
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.88–7.81(m,2H),7.51–7.45(m,2H),7.41(t,J＝7.7Hz,1H),7.39–7.27(m,4H),7.22(d,J＝5.7Hz,1H),7.20–7.14(m,2H),4.45(d,J＝9.3Hz,1H),4.14(ddt,J＝11.2,8.6,6.5Hz,1H),4.03(ddt,J＝11.2,8.6,6.5Hz,1H),3.61–3.49(m,1H),3.04(dt,J＝12.7,6.5Hz,1H),2.70(dq,J＝12.1,7.2Hz,1H),2.64–2.54(m,2H),2.56–2.43(m,2H),1.65(dp,J＝12.9,6.5Hz,1H),1.62–1.52(m,1H),1.56–1.42(m,2H),1.13(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)151.08,151.02,150.21,150.16,145.92,145.86,143.83,131.76,131.51,131.40,131.25,130.99,129.07,127.27,127.12,126.89,126.86,126.83,126.79,125.11,124.98,124.52,124.21,123.96,123.70,123.65,123.44,123.17,122.97,122.84,120.83,120.69,119.92,119.88,119.85,119.82,119.69,119.65,117.92,117.88,116.94,116.91,116.88,116.87,116.84,116.81,99.57,64.75,64.71,54.33,53.96,53.91,48.27,47.56,31.56,24.38,20.33,12.03.
Example 16: synthesis of Compound S16
(R) -2- ((4- ((7-chloroquinolin-4-yl) (cyclopropyl) amino) pentyl) (ethyl) amino) ethyl diphenyl phosphate
1H NMR(300MHz,DMSO-d6)8.66(d,J＝5.7Hz,1H),7.94(d,J＝2.4Hz,1H),7.60(d,J＝8.4Hz,1H),7.45(dd,J＝8.4,2.2Hz,1H),7.39–7.31(m,5H),7.23–7.15(m,6H),6.83(d,J＝5.5Hz,1H),4.08(dt,J＝8.5,6.4Hz,2H),3.56–3.46(m,1H),2.83(t,J＝6.5Hz,2H),2.59(q,J＝7.2Hz,2H),2.51(dq,J＝11.5,6.0Hz,3H),1.71–1.56(m,4H),1.36–1.27(m,2H),1.19(d,J＝6.6Hz,2H),1.05(t,J＝7.2Hz,3H),1.03–0.93(m,2H).13C NMR(125MHz,DMSO-d6)150.12,150.06,144.48,143.68,139.58,132.21,129.66,129.65,128.63,127.13,125.35,124.47,124.33,120.12,120.08,106.55,64.81,64.76,54.34,53.96,53.91,52.70,48.27,31.90,27.84,24.46,19.24,12.03,8.27.
Example 17: synthesis of Compound S17
(R) -2- ((4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethyl bis (4-trifluoromethoxyphenyl) phosphate
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.88–7.81(m,2H),7.32(dd,J＝8.4,2.2Hz,1H),7.16–7.03(m,8H),4.45(d,J＝9.3Hz,1H),4.14(ddt,J＝11.0,8.4,6.4Hz,1H),4.03(ddt,J＝11.2,8.6,6.6Hz,1H),3.59–3.48(m,1H),2.96(dt,J＝12.8,6.5Hz,1H),2.70–2.55(m,2H),2.57–2.50(m,1H),2.54–2.43(m,2H),1.64(dp,J＝13.0,6.6Hz,1H),1.53–1.30(m,4H),1.13(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)148.20,148.15,145.99,145.92,144.13,144.05,143.96,143.87,143.83,131.40,127.26,124.52,123.83,123.66,123.17,121.69,121.16,121.15,121.14,121.13,121.11,119.98,119.94,119.55,117.40,99.57,64.75,64.71,54.33,53.94,53.90,48.27,47.56,31.56,24.43,20.33,12.03.
Example 18: synthesis of Compound S18
(R) -2- ((4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethylbis (4-fluorophenyl) phosphate
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.87(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.25–7.15(m,5H),7.14–7.06(m,4H),4.45(d,J＝9.3Hz,1H),4.08(dt,J＝8.4,6.4Hz,2H),3.64–3.52(m,1H),2.77(t,J＝6.5Hz,2H),2.61(q,J＝7.3Hz,2H),2.51(t,J＝6.2Hz,2H),1.59–1.41(m,4H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)158.48,156.46,149.44,149.42,149.39,149.36,145.75,145.52,143.98,131.33,127.26,124.51,123.62,123.18,120.76,120.72,120.70,120.66,116.16,116.14,116.00,115.98,99.55,64.81,64.76,54.30,53.96,53.91,48.27,47.56,31.55,24.32,20.35,12.03.
Example 19: synthesis of Compound S19
(R) -2- ((4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethyl bis (4-acetoxybenzyl) phosphate
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.42(dt,J＝8.4,1.0Hz,4H),7.27(dd,J＝8.5,2.3Hz,1H),7.16(d,J＝5.6Hz,1H),7.07–7.00(m,4H),5.08(ddt,J＝11.7,8.6,1.1Hz,2H),5.01(ddt,J＝11.5,8.4,0.9Hz,2H),4.45(d,J＝9.3Hz,1H),4.09(ddt,J＝11.0,8.4,6.4Hz,1H),3.99(ddt,J＝11.0,8.4,6.4Hz,1H),3.55(ddtd,J＝11.6,9.3,6.2,5.4Hz,1H),2.95(dt,J＝12.8,6.5Hz,1H),2.84(dt,J＝12.7,6.4Hz,1H),2.68–2.52(m,2H),2.52–2.42(m,2H),2.26(s,4H),1.75–1.63(m,3H),1.62–1.40(m,3H),1.13(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13CNMR(125MHz,DMSO-d6)170.66,149.74,145.92,145.61,143.83,133.18,133.12,131.40,127.99,127.95,127.26,124.52,123.66,123.17,122.70,99.57,69.44,69.39,64.87,64.82,54.33,53.94,53.90,48.27,47.56,31.56,24.38,21.08,20.33,12.03.
Example 20: synthesis of Compound S20
(S) -2- ((4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethylbis (4-acetoxybenzyl) phosphate
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.42(dt,J＝8.4,1.0Hz,4H),7.27(dd,J＝8.5,2.3Hz,1H),7.16(d,J＝5.6Hz,1H),7.07–7.00(m,4H),5.08(ddt,J＝11.7,8.6,1.1Hz,2H),5.01(ddt,J＝11.5,8.4,0.9Hz,2H),4.45(d,J＝9.3Hz,1H),4.09(ddt,J＝11.0,8.4,6.4Hz,1H),3.99(ddt,J＝11.0,8.4,6.4Hz,1H),3.55(ddtd,J＝11.6,9.3,6.2,5.4Hz,1H),2.95(dt,J＝12.8,6.5Hz,1H),2.84(dt,J＝12.7,6.4Hz,1H),2.68–2.52(m,2H),2.52–2.42(m,2H),2.26(s,4H),1.75–1.63(m,3H),1.62–1.40(m,3H),1.13(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13CNMR(125MHz,DMSO-d6)170.66,149.74,145.92,145.61,143.83,133.18,133.12,131.40,127.99,127.95,127.26,124.52,123.66,123.17,122.70,99.57,69.44,69.39,64.87,64.82,54.33,53.94,53.90,48.27,47.56,31.56,24.38,21.08,20.33,12.03.
Example 21: synthesis of Compound (5)
The method comprises the following steps: synthesis of Compound 4
Compound 3(2g, 11.2mmol) was dissolved in DCM (20mL), sodium periodate (5.1g, 22.4mmol) was added and dissolved in water (4mL), and the reaction was refluxed for 2h, and a white solid appeared in the reaction solution. TLC monitoring until the raw material reaction is complete. Cooled to 0 deg.C and about 4g MgSO were added4Stirring was continued for 15min, and filtration gave a filtrate which was concentrated to give compound 4 as an oil (1.0g, 85%).1H NMR(500MHz,Chloroform-d)5.42-4.60(2H,m,broad),4.29(s,3H).
Step two: synthesis of Compound 5
Compound 4(1g, 9.4mmol) was dissolved in anhydrous DCM (15mL) and the reaction was cooled to-60 ℃. Dimethylphosphoryl chloride (1mL, 9.4mol) was added slowlySlowly added dropwise to the above suspension followed by the slow addition of triethylamine (1.5mL, 10.34 mmol). The reaction solution is heated to room temperature and stirred for reaction for 3 hours. The reaction was cooled to 0 deg.C, 4-nitrophenol (1.4g, 10.34mmol) was added, and triethylamine (1.5mL, 10.34mmol) was added slowly. The reaction solution is heated to room temperature and stirred for reaction for 3 hours. The solvent was distilled off under reduced pressure, and column chromatography purification was performed to give compound 5(1.7g, 56%).1H NMR(500MHz,Chloroform-d)8.16–8.10(m,2H),7.39–7.33(m,2H),5.73(dd,J＝8.1,6.2Hz,1H),4.37(d,J＝6.2Hz,2H),3.76(s,2H),3.60(d,J＝10.8Hz,3H).
Example 22: synthesis of Compound S21
Methyl 2- (((2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (methoxy) phosphoryl) oxy) -2-hydroxyacetate
Acetonitrile (15mL) was added to compound 2(1g, 3.03mmol), compound 5(1.1g, 3.65mmol) and magnesium chloride (288mg, 3.30mmol) at room temperature, the reaction mixture was warmed to 70 ℃, stirred for 10min, DIPEA (1.3mL, 7.58mmol) was added, stirring was continued for 1h, the reaction was stopped, ethyl acetate (80mL) was added to dilute the reaction mixture, the organic phase was washed with 5% diluted citric acid (40mL), saturated ammonium chloride (40mL), saturated potassium carbonate (2 × 40mL), saturated saline (40mL), dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and then purified by column chromatography to give compound S21(914mg, 60%).1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.7Hz,1H),7.87(d,J＝2.1Hz,1H),7.79(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.05(d,J＝5.7Hz,1H),6.26–6.18(m,2H),4.45(d,J＝9.3Hz,1H),4.10(ddt,J＝11.0,8.4,6.4Hz,1H),4.00(ddt,J＝11.2,8.6,6.5Hz,1H),3.77–3.71(m,5H),3.63–3.51(m,1H),2.97(dt,J＝12.8,6.5Hz,1H),2.74(dt,J＝12.7,6.5Hz,2H),2.66–2.47(m,4H),1.64–1.36(m,4H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.29,173.23,145.94,145.47,143.84,131.58,126.89,124.99,123.68,123.18,99.76,87.69,87.64,64.91,64.86,55.93,55.88,54.30,53.93,53.88,52.83,48.27,47.57,31.57,24.31,20.38,12.03.
Example 23: synthesis of Compound (8)
The method comprises the following steps: synthesis of Compound (7)
Redistilled compound 6(1g, 11.4mmol) was dissolved in anhydrous dichloromethane (10mL), methanol (2mL) was added, the reaction was stirred at room temperature overnight, and the TLC plate reaction was completed and was directly put to the next reaction without purification.
Step two: synthesis of Compound (8)
Compound 7(1.1g, 9.4mmol) was dissolved in anhydrous DCM (15mL) and the reaction was cooled to-60 ℃. Dimethylphosphoryl chloride (1mL, 9.4mol) was slowly added dropwise to the above suspension, followed by triethylamine (1.5mL, 10.34mmol) slowly. The reaction solution is heated to room temperature and stirred for reaction for 3 hours. The reaction was cooled to 0 deg.C, 4-nitrophenol (1.4g, 10.34mmol) was added, and triethylamine (1.5mL, 10.34mmol) was added slowly. The reaction solution is heated to room temperature and stirred for reaction for 3 hours. The solvent was distilled off under reduced pressure, and column chromatography purification was performed to give compound 8(2.2g, 72%).1H NMR(500MHz,Chloroform-d)8.17–8.10(m,2H),7.39–7.33(m,2H),5.50(d,J＝8.1Hz,1H),4.20(s,3H),3.74(s,3H),3.32(s,3H).
Example 24: synthesis of Compound S22
Methyl 2- (((2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (methoxy) phosphoryl) oxy) -2-methoxyacetate
To compound 2(1g, 3.03mmol), compound 8(1.2g, 3.65mmol) and magnesium chloride (288mg, 3.30mmol) was added acetonitrile (15mL) at room temperature. The reaction mixture was warmed to 70 ℃ and stirred for 10min, and DIPEA (1.3mL, 7.58mmol) was added. After stirring for 1 hour, the reaction was stopped and ethyl acetate (80mL) was added to dilute the reaction. The organic phase was pickled with 5% dilute citric acidWashing (40mL), washing with saturated ammonium chloride (40mL), washing with saturated potassium carbonate (2 × 40mL), washing with saturated brine (40mL), drying over anhydrous sodium sulfate, filtering, evaporating off the solvent under reduced pressure, and purifying by column chromatography to give compound S22(1.0g, 65%).1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.7Hz,1H),7.87(d,J＝2.1Hz,1H),7.79(d,J＝8.5Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.05(d,J＝5.5Hz,1H),6.07(d,J＝8.1Hz,1H),4.45(d,J＝9.3Hz,1H),4.10(ddt,J＝11.0,8.4,6.4Hz,1H),4.00(ddt,J＝11.0,8.4,6.4Hz,1H),3.77–3.71(m,6H),3.64–3.52(m,1H),3.30(s,2H),2.93(dt,J＝12.8,6.4Hz,1H),2.69–2.40(m,5H),1.67–1.56(m,1H),1.57–1.47(m,1H),1.50–1.44(m,2H),1.48–1.39(m,1H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)172.32,172.26,145.94,145.47,143.84,131.58,126.95,124.97,123.67,123.18,99.76,93.07,93.02,64.96,64.92,55.93,55.88,55.60,55.57,54.30,53.93,53.88,53.76,48.27,47.57,31.57,24.31,20.36,12.03..
Example 25: synthesis of Compound 10
To compound 9(2.2g, 14.41mmol) was added DCM (25mL) and cooled to-78 ℃. Phosphorus oxychloride was slowly added dropwise (0.64mL, 6.86mol) to the above suspension followed by the slow addition of triethylamine (2.0mL, 14.41 mmol). The reaction solution is heated to room temperature and stirred for reaction for 2 hours. The reaction was cooled to 0 deg.C, 4-nitrophenol (1.82g, 6.86mmol) was added, and triethylamine (2.0mL, 14.41mmol) was added slowly. The reaction solution is heated to room temperature and stirred for reaction for 3 hours. The solvent was distilled off under reduced pressure, and column chromatography purification was performed to give compound 10(1.6g, 66%).1H NMR(500MHz,Chloroform-d)8.16–8.10(m,2H),7.38–7.32(m,2H),4.97(p,J＝5.8Hz,1H),4.74(d,J＝6.4Hz,1H),3.72(dq,J＝11.2,5.5Hz,1H),3.64(dq,J＝10.3,7.0Hz,1H),3.56–3.40(m,3H),1.39(d,J＝5.5Hz,3H),1.25–1.15(m,9H).
Example 26: synthesis of Compound S23
Acetonitrile (15mL) was added to compound 2(1g, 3.03mmol), compound 10(1.3g, 3.65mmol) and magnesium chloride (288mg, 3.30mmol) at room temperature, the reaction solution was warmed to 70 ℃, stirred for 10min, DIPEA (1.3mL, 7.58mmol) was added, stirring was continued for 1h, the reaction was stopped, ethyl acetate (80mL) was added to dilute the reaction solution, the organic phase was washed with 5% diluted citric acid (40mL), saturated ammonium chloride (40mL), saturated potassium carbonate (2 × 40mL), saturated saline (40mL), dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and then purified by column chromatography to give compound S23(1.4g, 75%).1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.2Hz,1H),7.79(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.06(d,J＝5.7Hz,1H),4.45(d,J＝9.3Hz,1H),4.22(dq,J＝10.1,7.0Hz,2H),4.11–3.87(m,7H),3.64–3.52(m,3H),2.73–2.55(m,2H),2.55–2.45(m,2H),2.49–2.41(m,1H),1.71–1.59(m,1H),1.59–1.46(m,2H),1.49–1.39(m,1H),1.35(d,J＝6.8Hz,6H),1.24(t,J＝7.0Hz,6H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)172.83,172.77,145.94,145.75,143.98,131.37,127.12,124.52,123.64,123.18,99.55,62.67,62.62,61.16,54.30,53.82,53.77,53.02,52.97,48.27,47.56,31.55,24.32,20.35,17.54,17.49,14.39,12.03.
The following synthetic methods of the compounds S24 to S30 in examples 27 to 33 were the same as the synthetic method of the compound S23, and only the corresponding raw materials were replaced.
Example 27: synthesis of Compound S24
1H NMR(300MHz,DMSO-d6)8.45(d,J＝5.7Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.32(dd,J＝8.4,2.2Hz,1H),7.29–7.18(m,10H),7.04(d,J＝5.7Hz,1H),4.51–4.42(m,2H),4.10–3.83(m,7H),3.60–3.48(m,1H),3.22(ddt,J＝13.9,7.7,1.0Hz,2H),3.13(d,J＝7.5Hz,2H),2.99(ddt,J＝14.0,7.8,0.9Hz,2H),2.74(dt,J＝12.8,6.4Hz,1H),2.66(dq,J＝12.1,7.2Hz,1H),2.63–2.52(m,2H),2.54–2.40(m,2H),1.66–1.33(m,4H),1.26(t,J＝7.0Hz,6H),1.14(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)171.90,171.84,145.99,145.93,143.83,136.04,136.00,131.40,129.74,129.15,127.36,127.26,124.43,123.64,123.15,99.57,62.76,62.72,61.27,55.06,55.01,54.32,53.82,53.77,48.04,47.55,36.43,36.38,31.57,24.43,20.33,14.14,12.03.
Example 28: synthesis of Compound S25
1H NMR(500MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),8.06(dd,J＝8.5,5.0Hz,1H),7.50(dd,J＝8.0,2.2Hz,1H),7.14(td,J＝8.2,2.3Hz,1H),7.02(d,J＝5.7Hz,1H),4.71(d,J＝9.3Hz,1H),4.23–3.82(m,10H),2.93(dt,J＝12.7,6.5Hz,1H),2.69–2.44(m,6H),1.65(ddd,J＝13.4,12.5,6.5Hz,1H),1.59–1.41(m,3H),1.35(d,J＝6.8Hz,6H),1.24(t,J＝6.9Hz,6H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)172.85,172.79,162.60,160.59,146.73,145.21,143.88,143.82,124.08,124.02,122.74,122.72,114.39,114.23,112.89,112.73,99.55,62.67,62.62,61.16,54.30,53.82,53.77,53.02,52.97,48.27,47.56,31.53,24.32,20.35,17.54,17.49,14.39,12.03.
Example 29: synthesis of Compound S26
1H NMR(300MHz,DMSO-d6)8.54(d,J＝5.7Hz,1H),8.42(d,J＝8.4Hz,1H),8.30(d,J＝1.8Hz,1H),7.55(dd,J＝8.4,1.6Hz,1H),7.05(d,J＝5.7Hz,1H),5.18(d,J＝9.3Hz,1H),4.22(dq,J＝10.1,7.0Hz,2H),4.10–3.87(m,7H),3.82(d,J＝7.3Hz,2H),3.54(ddtd,J＝11.6,9.3,6.1,5.4Hz,1H),2.83(dt,J＝12.9,6.4Hz,1H),2.72–2.53(m,3H),2.53–2.44(m,1H),1.65(dp,J＝12.9,6.4Hz,1H),1.57–1.40(m,3H),1.36(d,J＝6.8Hz,6H),1.23(t,J＝6.9Hz,6H),1.12(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)172.94,172.88,146.66,144.38,143.24,143.22,143.20,143.19,132.02,131.76,131.50,131.25,127.23,125.08,124.04,123.86,123.84,123.82,123.81,122.99,122.96,122.94,122.93,122.90,120.80,120.22,120.19,120.16,120.13,99.55,62.67,62.62,61.16,54.30,53.82,53.77,53.02,52.97,48.27,47.56,31.55,24.32,20.35,17.54,17.49,14.39,12.03.
Example 30: synthesis of Compound S27
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.88–7.81(m,2H),7.27(dd,J＝8.4,2.2Hz,1H),7.09(d,J＝5.7Hz,1H),4.45(d,J＝9.3Hz,1H),4.15(dt,J＝11.5,6.0Hz,2H),4.09–3.99(m,3H),3.98–3.89(m,1H),3.87(d,J＝7.1Hz,2H),3.79(dd,J＝7.2,6.5Hz,2H),3.60–3.48(m,1H),3.03(dt,J＝12.8,6.4Hz,1H),2.66–2.52(m,5H),2.48(dt,J＝12.2,6.2Hz,1H),2.08–1.94(m,J＝6.7Hz,2H),1.73–1.37(m,9H),1.36–1.22(m,2H),1.13(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H),0.97–0.87(m,18H).13C NMR(125MHz,DMSO-d6)172.35,172.30,145.92,145.86,143.83,131.40,127.27,124.52,123.65,123.17,99.57,65.22,62.67,62.62,57.87,57.82,54.33,53.81,53.76,48.27,47.56,31.56,30.66,29.92,29.87,24.38,20.33,19.11,18.50,18.47,13.80,12.03.
Example 31: synthesis of Compound S28
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.2Hz,1H),7.79(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.06(d,J＝5.7Hz,1H),4.45(d,J＝9.3Hz,1H),4.22(dq,J＝10.1,7.0Hz,2H),4.11–3.87(m,7H),3.64–3.52(m,3H),2.73–2.55(m,2H),2.55–2.45(m,2H),2.49–2.41(m,1H),1.71–1.59(m,1H),1.59–1.46(m,2H),1.49–1.39(m,1H),1.35(d,J＝6.8Hz,6H),1.24(t,J＝7.0Hz,6H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)172.83,172.77,145.94,145.75,143.98,131.37,127.12,124.52,123.64,123.18,99.55,62.67,62.62,61.16,54.30,53.82,53.77,53.02,52.97,48.27,47.56,31.55,24.32,20.35,17.54,17.49,14.39,12.03.
Example 32: synthesis of Compound S29
1H NMR(300MHz,DMSO-d6)8.65(d,J＝5.7Hz,1H),7.95(d,J＝2.3Hz,1H),7.55(d,J＝8.4Hz,1H),7.46(dd,J＝8.4,2.2Hz,1H),7.18(d,J＝5.6Hz,1H),4.22(dq,J＝9.9,7.0Hz,2H),4.11–3.96(m,5H),3.93(ddt,J＝11.0,8.4,6.4Hz,1H),3.79(d,J＝7.4Hz,2H),3.35(dqd,J＝8.2,6.6,5.6Hz,1H),2.90(s,3H),2.95–2.86(m,1H),2.71–2.47(m,5H),1.75–1.52(m,4H),1.34(d,J＝6.8Hz,6H),1.24(t,J＝7.0Hz,6H),1.17(d,J＝6.6Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)172.94,172.88,147.64,144.60,143.40,132.24,128.53,127.13,124.82,124.30,104.76,62.67,62.62,61.16,54.34,53.82,53.77,53.70,53.02,52.97,48.27,33.71,31.44,24.60,19.39,17.54,17.49,14.39,12.03.
Example 33: synthesis of Compound S30
1H NMR(300MHz,DMSO-d6)8.66(d,J＝5.7Hz,1H),7.95(d,J＝2.3Hz,1H),7.55(d,J＝8.4Hz,1H),7.46(dd,J＝8.4,2.2Hz,1H),7.15(d,J＝5.7Hz,1H),4.22(dq,J＝10.1,7.0Hz,2H),4.15–3.89(m,8H),3.91–3.79(m,1H),3.72(dt,J＝12.8,6.8Hz,1H),3.66(d,J＝7.3Hz,2H),3.55(dt,J＝12.8,6.8Hz,1H),3.42–3.33(m,1H),3.08(dt,J＝12.9,6.5Hz,1H),2.71(dt,J＝12.8,6.4Hz,1H),2.69–2.57(m,1H),2.60–2.45(m,3H),1.72–1.49(m,4H),1.37(d,J＝6.8Hz,6H),1.27–1.18(m,9H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)172.94,172.88,146.62,144.58,143.43,132.21,128.64,127.19,125.13,124.40,105.23,62.67,62.62,61.16,59.76,54.34,53.82,53.77,53.25,53.02,52.97,48.27,47.75,31.76,24.57,18.88,17.54,17.49,14.39,12.03.
Example 34: (methoxy (4-nitrophenoxy) phosphoryl) -L-alanine methyl ester
To compound 11(2.0g, 14.40mmol) was added DCM (25mL) and cooled to-78 ℃. Methyl dichlorophosphate (1.5mL, 14.40mmol) was added to the suspension, followed by the slow addition of triethylamine (2.0mL, 14.40 mmol). The reaction solution is heated to room temperature and stirred for reaction for 3 hours. The reaction was cooled to 0 deg.C, 4-nitrophenol (1.82g, 13.09mmol) was added, and triethylamine (2.0mL, 14.40mmol) was added slowly. The reaction solution is heated to room temperature and stirred for reaction for 3 hours. The solvent was distilled off under reduced pressure, and column chromatography purification was performed to give compound 12(3.3g, 72%).1H NMR(500MHz,Chloroform-d)8.01–7.94(m,2H),7.53–7.47(m,2H),4.57(d,J＝7.4Hz,1H),4.09–4.00(m,1H),3.73–3.66(m,6H),1.36(d,J＝6.8Hz,3H).
Example 35: synthesis of Compound S31
((2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (methoxy) phosphoryl) -L-alanine methyl ester
Acetonitrile (15mL) was added to compound 2(1g, 3.03mmol), compound 12(1.2g, 3.65mmol) and magnesium chloride (288mg, 3.30mmol) at room temperature, the reaction solution was warmed to 70 ℃, stirred for 10min, DIPEA (1.3mL, 7.58mmol) was added, stirring was continued for 1h, the reaction was stopped, ethyl acetate (80mL) was added to dilute the reaction solution, the organic phase was washed with 5% diluted citric acid (40mL), saturated ammonium chloride (40mL), saturated potassium carbonate (2 × 40mL), saturated saline (40mL), dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and then purified by column chromatography to give compound S31(1.1g, 68%).1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.7Hz,1H),7.87(d,J＝2.1Hz,1H),7.79(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.07(d,J＝5.7Hz,1H),4.45(d,J＝9.3Hz,1H),4.31(d,J＝7.3Hz,1H),4.12–3.90(m,3H),3.69–3.59(m,6H),3.62–3.51(m,1H),2.93(dt,J＝13.0,6.5Hz,1H),2.80(dt,J＝12.9,6.4Hz,1H),2.71–2.46(m,4H),1.72–1.54(m,2H),1.55–1.40(m,2H),1.38(d,J＝6.8Hz,3H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)172.86,172.81,145.94,145.47,143.84,131.77,126.84,125.12,123.68,123.18,99.76,64.51,64.47,54.30,53.94,53.89,53.87,53.83,52.59,51.87,51.82,48.27,47.57,31.57,24.31,20.38,17.09,17.04,12.03.
The synthesis methods of the compounds S32 to S76 in the following examples 36 to 80 were the same as the synthesis method of the compound S31, and only the corresponding raw materials were replaced.
Example 36: synthesis of Compound S32
((2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (ethoxy) phosphoryl) -L-valine methyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.87(d,J＝2.3Hz,1H),7.79(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.01(d,J＝5.6Hz,1H),4.45(d,J＝9.3Hz,1H),4.36(d,J＝7.1Hz,1H),4.18–3.98(m,3H),3.94(ddt,J＝11.0,8.4,6.4Hz,1H),3.80(t,J＝6.8Hz,1H),3.71(s,2H),3.64–3.52(m,1H),3.09(dt,J＝12.7,6.5Hz,1H),2.74–2.43(m,5H),2.21–2.08(m,J＝6.6Hz,1H),1.73–1.61(m,1H),1.60–1.46(m,2H),1.49–1.37(m,2H),1.30–1.23(m,3H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H),0.95(dd,J＝25.0,6.7Hz,6H).13C NMR(125MHz,DMSO-d6)172.71,172.65,145.94,145.47,143.98,131.55,127.12,124.66,123.67,123.18,99.76,64.55,64.50,63.00,62.95,57.04,56.99,54.30,53.87,53.83,52.65,48.27,47.57,31.53,30.00,29.95,24.30,20.35,18.52,18.50,16.22,16.17,12.03.
Example 37: synthesis of Compound S33
((2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (2,2, 2-trifluoroethoxy) phosphoryl) -L-alanine methyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.87(d,J＝2.3Hz,1H),7.79(d,J＝8.4Hz,1H),7.32(dd,J＝8.4,2.2Hz,1H),7.02(d,J＝5.6Hz,1H),4.74–4.62(m,1H),4.64–4.49(m,1H),4.45(d,J＝9.3Hz,1H),4.22(d,J＝7.3Hz,1H),4.12–3.99(m,2H),4.02–3.90(m,1H),3.67(s,2H),3.64–3.52(m,1H),2.96(dt,J＝12.8,6.4Hz,1H),2.72(dq,J＝12.1,7.2Hz,1H),2.60(dt,J＝12.9,6.5Hz,1H),2.58–2.42(m,3H),1.67–1.55(m,2H),1.51(dtd,J＝13.3,6.7,5.6Hz,1H),1.46–1.33(m,5H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)172.86,172.81,145.94,145.47,143.98,131.50,127.12,125.91,125.86,124.66,123.77,123.72,123.67,123.18,121.62,121.57,119.48,119.43,99.76,64.83,64.79,64.62,64.57,64.55,64.50,64.40,64.35,64.19,64.14,54.30,53.87,53.83,52.60,51.94,51.89,48.27,47.57,31.53,24.32,20.35,16.91,16.87,12.03.
Example 38: synthesis of Compound S34
((2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (2,2, 2-trichloroethoxy) phosphoryl) -L-valine methyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.2Hz,1H),7.79(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.09(d,J＝5.6Hz,1H),5.00(dd,J＝9.3,8.6Hz,1H),4.83(dd,J＝9.2,8.5Hz,1H),4.45(d,J＝9.3Hz,1H),4.22(d,J＝7.1Hz,1H),4.06(ddt,J＝11.2,8.6,6.5Hz,1H),3.94(ddt,J＝11.0,8.4,6.4Hz,1H),3.81(t,J＝6.8Hz,1H),3.69(s,2H),3.62–3.50(m,1H),2.91(dt,J＝12.9,6.5Hz,1H),2.68(dq,J＝12.1,7.2Hz,1H),2.63–2.54(m,2H),2.55–2.38(m,2H),2.14(dp,J＝13.4,6.6Hz,1H),1.66–1.56(m,1H),1.59–1.51(m,1H),1.54–1.47(m,1H),1.51–1.41(m,2H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H),0.92(dd,J＝25.1,6.6Hz,6H).13C NMR(125MHz,DMSO-d6)172.70,172.65,145.94,145.93,143.98,131.37,127.13,124.52,123.64,123.18,99.55,95.77,95.72,70.68,70.64,64.55,64.50,57.02,56.97,54.33,53.89,53.84,52.61,48.27,47.57,31.55,30.10,30.06,24.32,20.35,18.52,18.50,12.03.
Example 39: synthesis of Compound S35
((2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (methoxy) phosphoryl) -L-leucine methyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.87(d,J＝2.3Hz,1H),7.79(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.07(d,J＝5.6Hz,1H),4.45(d,J＝9.3Hz,1H),4.12–3.89(m,4H),3.68–3.52(m,6H),2.98(dt,J＝12.7,6.4Hz,1H),2.76–2.62(m,2H),2.60–2.49(m,2H),2.44(dt,J＝12.2,6.3Hz,2H),1.82–1.40(m,7H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H),0.90(dd,J＝25.0,6.9Hz,6H).13C NMR(125MHz,DMSO-d6)172.82,172.76,145.94,145.47,143.98,131.55,127.12,124.66,123.67,123.18,99.76,64.58,64.53,54.30,53.94,53.89,53.87,53.83,53.60,53.56,52.52,48.27,47.57,40.36,40.31,31.53,24.96,24.94,24.30,22.34,20.35,12.03.
Example 40: synthesis of Compound S36
((2- (((S) -4- ((7-fluoroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (ethoxy) phosphoryl) -L-valine methyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),8.12(dd,J＝8.4,5.2Hz,1H),7.54(dd,J＝8.0,2.2Hz,1H),7.16(td,J＝8.2,2.2Hz,1H),7.04(d,J＝5.5Hz,1H),4.71(d,J＝9.3Hz,1H),4.18(d,J＝7.3Hz,1H),4.17–4.00(m,3H),3.94(ddt,J＝11.0,8.4,6.4Hz,1H),3.81–3.74(m,2H),3.71(s,2H),3.64–3.52(m,1H),2.97(dt,J＝12.7,6.5Hz,1H),2.74–2.41(m,5H),2.24–2.11(m,J＝6.6Hz,1H),1.64(dp,J＝13.0,6.4Hz,1H),1.60–1.49(m,1H),1.51–1.35(m,2H),1.30–1.23(m,3H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H),0.96(dd,J＝25.1,6.6Hz,6H).13C NMR(125MHz,DMSO-d6)172.71,172.65,162.60,160.59,146.92,144.88,143.88,143.82,124.08,124.01,122.74,122.72,114.33,114.17,112.89,112.73,99.76,64.55,64.50,63.00,62.95,57.04,56.99,54.30,53.87,53.83,52.63,48.27,47.57,31.53,29.96,29.91,24.30,20.35,18.52,18.50,16.22,16.17,12.03.
Example 41: synthesis of Compound S37
((2- (((R) -4- ((7-Methoxyquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (isopropoxy) phosphoryl) -L-alanine methyl ester
1H NMR(300MHz,DMSO-d6)8.40(d,J＝5.7Hz,1H),7.93(dt,J＝8.3,0.6Hz,1H),7.07–7.00(m,2H),6.66(d,J＝5.6Hz,1H),4.55(dhept,J＝8.1,6.2Hz,1H),4.39(d,J＝9.3Hz,1H),4.13–3.90(m,3H),3.82(s,2H),3.69–3.57(m,3H),3.16(d,J＝7.3Hz,1H),3.01(dt,J＝12.7,6.4Hz,1H),2.68(dq,J＝12.1,7.2Hz,1H),2.63–2.53(m,2H),2.56–2.42(m,4H),1.66–1.54(m,2H),1.58–1.37(m,2H),1.27(d,J＝6.1Hz,3H),1.21(dd,J＝7.4,6.5Hz,6H),1.14(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)172.86,172.81,159.78,146.29,145.24,143.82,124.38,121.66,113.67,107.73,99.76,72.08,72.03,64.55,64.50,55.23,54.30,53.87,53.83,52.57,51.93,51.88,48.27,47.57,31.53,24.31,23.62,23.57,20.35,16.95,16.90,12.03.
Example 42: synthesis of Compound S38
((2- (((R) -4- ((7-trifluoromethoxyquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (tert-butoxy) phosphoryl) -L-alanine methyl ester
1H NMR(300MHz,DMSO-d6)8.38(d,J＝5.7Hz,1H),7.87(d,J＝8.4Hz,1H),7.32(d,J＝2.4Hz,1H),7.18(dd,J＝8.4,2.4Hz,1H),6.97(d,J＝5.6Hz,1H),4.51(d,J＝9.3Hz,1H),4.12–3.90(m,3H),3.92–3.80(m,1H),3.66(s,3H),3.66(d,J＝7.3Hz,1H),2.85(dt,J＝12.9,6.5Hz,1H),2.68(dq,J＝12.1,7.2Hz,1H),2.61–2.50(m,2H),2.53–2.44(m,1H),2.47–2.37(m,1H),1.65–1.53(m,1H),1.55–1.44(m,2H),1.48–1.39(m,1H),1.38–1.33(m,12H),1.14(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)172.99,172.93,149.33,149.24,149.15,149.07,146.36,145.61,144.01,124.25,123.77,121.66,121.63,120.29,120.27,119.48,117.34,113.24,113.22,99.55,78.38,78.34,64.32,64.27,54.30,53.89,53.84,52.56,51.93,51.88,48.27,47.56,31.55,29.42,29.37,24.32,20.35,16.94,16.89,12.03.
Example 43: synthesis of Compound S39
((2- (((R) -4- ((7-chloroquinolin-4-yl) (methyl) amino) pentyl) (ethyl) amino) ethoxy) (isopropoxy) phosphoryl) -L-alanine methyl ester
1H NMR(300MHz,DMSO-d6)8.65(d,J＝5.7Hz,1H),7.93(d,J＝2.3Hz,1H),7.58(d,J＝8.4Hz,1H),7.46(dd,J＝8.4,2.2Hz,1H),7.18(d,J＝5.7Hz,1H),4.55(dhept,J＝8.1,6.2Hz,1H),4.12–4.03(m,1H),4.06–3.90(m,2H),3.80(d,J＝7.3Hz,1H),3.67(s,2H),3.30–3.20(m,1H),2.91(s,2H),2.84(dt,J＝12.7,6.5Hz,1H),2.71(dq,J＝12.1,7.2Hz,1H),2.61(dt,J＝12.7,6.5Hz,1H),2.60–2.46(m,3H),1.77–1.62(m,2H),1.65–1.52(m,4H),1.36(d,J＝6.8Hz,3H),1.27(d,J＝6.1Hz,3H),1.21(dd,J＝11.9,6.4Hz,6H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)172.86,172.81,147.64,144.60,143.15,132.41,128.53,127.15,124.82,124.54,104.78,72.02,71.97,64.55,64.50,54.33,53.87,53.83,53.69,52.60,51.95,51.91,48.27,33.71,31.43,24.49,23.62,23.57,19.39,16.95,16.90,12.03.
Example 44: synthesis of Compound S40
((2- (((R) -4- ((7-chloroquinolin-4-yl) (cyclopropyl) amino) pentyl) (ethyl) amino) ethoxy) (tert-butoxy) phosphoryl) -L-alanine methyl ester
1H NMR(300MHz,DMSO-d6)8.66(d,J＝5.7Hz,1H),7.94(d,J＝2.2Hz,1H),7.59(d,J＝8.4Hz,1H),7.45(dd,J＝8.4,2.2Hz,1H),7.30(d,J＝5.5Hz,1H),4.12–3.98(m,2H),3.96(ddt,J＝11.2,8.4,6.5Hz,1H),3.78(d,J＝7.3Hz,1H),3.68–3.57(m,3H),3.05(dt,J＝12.7,6.5Hz,1H),2.70(dq,J＝12.1,7.2Hz,1H),2.62–2.40(m,6H),1.70–1.49(m,4H),1.43–1.28(m,14H),1.31–1.23(m,3H),1.05(t,J＝7.2Hz,3H),0.93(ddd,J＝10.7,9.8,5.8Hz,2H).13C NMR(125MHz,DMSO-d6)173.01,172.95,144.48,143.39,139.58,132.24,128.53,127.12,125.35,124.43,106.56,78.38,78.34,64.32,64.27,54.37,53.89,53.84,52.77,52.57,51.93,51.88,48.27,31.90,29.42,29.37,27.84,24.46,19.24,16.94,16.89,12.03,8.27.
Example 45: synthesis of Compound S41
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (phenoxy) phosphoryl) -L-alanine ethyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.87(d,J＝2.3Hz,1H),7.79(d,J＝8.4Hz,1H),7.42–7.34(m,2H),7.28(dd,J＝8.4,2.2Hz,1H),7.24–7.15(m,2H),7.12–7.05(m,2H),4.45(d,J＝9.3Hz,1H),4.22(dq,J＝9.9,6.9Hz,1H),4.14–3.92(m,5H),3.81–3.70(m,1H),2.89(dt,J＝12.8,6.5Hz,1H),2.73(dt,J＝12.9,6.5Hz,1H),2.67–2.57(m,2H),2.61–2.50(m,2H),1.67–1.55(m,1H),1.57–1.46(m,1H),1.47–1.34(m,2H),1.33(d,J＝6.7Hz,3H),1.24(t,J＝6.9Hz,3H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13CNMR(125MHz,DMSO-d6)172.87,172.81,152.23,152.17,145.75,145.47,143.98,131.37,129.44,129.42,127.12,124.62,124.52,123.64,123.18,120.59,120.55,99.55,64.51,64.46,61.16,54.30,53.93,53.88,52.07,52.03,48.27,47.57,31.53,24.32,20.35,16.95,16.90,14.39,12.03.
Example 46: synthesis of Compound S42
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (phenoxy) phosphoryl) -L-alanine methyl ester
1H NMR(300MHz,DMSO-d6)8.45(d,J＝5.7Hz,1H),7.87(d,J＝2.3Hz,1H),7.79(d,J＝8.4Hz,1H),7.38(td,J＝7.2,6.7,1.4Hz,3H),7.27(dd,J＝8.4,2.2Hz,1H),7.24–7.16(m,1H),7.17–7.11(m,2H),4.45(d,J＝9.3Hz,1H),4.14–3.99(m,2H),4.02–3.92(m,1H),3.72–3.64(m,3H),3.64–3.52(m,1H),2.96(dt,J＝12.7,6.4Hz,1H),2.67(dq,J＝12.1,7.2Hz,1H),2.59(dt,J＝12.9,6.4Hz,1H),2.53–2.44(m,2H),2.46–2.38(m,1H),1.66–1.55(m,2H),1.57–1.38(m,6H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)172.97,172.92,152.23,152.17,145.75,145.47,143.98,131.55,129.44,129.42,127.12,124.62,124.52,123.64,123.18,120.59,120.55,99.55,64.51,64.46,54.30,53.90,53.85,52.61,51.93,51.88,48.27,47.57,31.53,24.30,20.35,16.93,16.89,12.03.
Example 47: synthesis of Compound S43
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (phenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.87(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.42–7.34(m,2H),7.32(dd,J＝8.4,2.2Hz,1H),7.20(tt,J＝7.4,1.4Hz,1H),7.19–7.12(m,3H),5.00(hept,J＝6.1Hz,1H),4.45(d,J＝9.3Hz,1H),4.14–4.05(m,2H),4.08–3.99(m,1H),4.02–3.92(m,1H),3.64–3.52(m,1H),3.04(dt,J＝12.9,6.5Hz,1H),2.74–2.46(m,4H),2.47–2.38(m,1H),1.70–1.58(m,1H),1.58–1.47(m,2H),1.50–1.40(m,1H),1.38(d,J＝6.6Hz,3H),1.23(dd,J＝25.1,6.2Hz,6H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.01,172.95,152.23,152.17,145.75,145.52,143.98,131.37,129.44,129.42,127.12,124.62,124.51,123.65,123.18,120.59,120.55,99.55,68.20,64.51,64.46,54.30,53.93,53.88,52.50,52.46,48.27,47.56,31.55,24.32,21.59,20.35,17.11,17.06,12.03.
Example 48: synthesis of Compound S44
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (phenoxy) phosphoryl) -L-alanine 2-methoxyethyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.88–7.81(m,2H),7.42–7.34(m,2H),7.27(dd,J＝8.4,2.2Hz,1H),7.23–7.16(m,2H),7.17–7.08(m,3H),4.45(d,J＝9.3Hz,1H),4.35–4.21(m,2H),4.14–3.92(m,4H),3.64–3.52(m,1H),3.54–3.40(m,2H),3.39(s,2H),3.04(dt,J＝12.7,6.4Hz,1H),2.74–2.65(m,1H),2.64(dd,J＝12.9,6.4Hz,1H),2.64–2.54(m,2H),2.53–2.45(m,1H),1.72–1.61(m,1H),1.63–1.50(m,2H),1.50–1.41(m,1H),1.41(d,J＝6.7Hz,3H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.03,172.97,152.23,152.17,145.75,143.98,131.33,129.44,129.42,127.26,124.62,124.51,123.61,123.18,120.59,120.55,99.55,70.73,65.03,64.51,64.46,58.99,54.30,53.93,53.88,52.15,52.11,48.27,47.56,31.55,24.32,20.35,17.42,17.38,12.03.
Example 49: synthesis of Compound S45
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (phenoxy) phosphoryl) -L-alanine 2- (dimethylamino) ethyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.42–7.34(m,2H),7.27(dd,J＝8.4,2.2Hz,1H),7.23–7.15(m,2H),7.17–7.11(m,2H),4.45(d,J＝9.3Hz,1H),4.35(dt,J＝11.4,6.4Hz,1H),4.18(dt,J＝11.3,6.5Hz,1H),4.14–3.92(m,5H),2.86(dt,J＝13.0,6.6Hz,1H),2.79–2.47(m,6H),2.54(s,7H),1.67(dp,J＝12.8,6.4Hz,1H),1.55(dtd,J＝12.4,6.8,5.5Hz,1H),1.52–1.37(m,5H),1.13(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.02,172.97,152.23,152.17,145.75,143.98,131.33,129.44,129.42,127.26,124.62,124.51,123.63,123.18,120.60,120.56,99.55,64.51,64.46,63.05,57.74,54.30,53.93,53.88,52.15,52.11,48.27,47.56,45.01,31.55,24.32,20.35,16.95,16.90,12.03.
Example 50: synthesis of Compound S46
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (phenoxy) phosphoryl) -L-alanine 2-hydroxyethyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.87(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.42–7.32(m,3H),7.28(ddd,J＝8.4,5.1,1.8Hz,3H),7.20(tt,J＝7.2,1.4Hz,1H),4.50(dt,J＝12.3,6.6Hz,1H),4.45(d,J＝9.3Hz,1H),4.23(dt,J＝12.1,6.5Hz,1H),4.14–3.79(m,6H),3.64–3.52(m,1H),3.05(dt,J＝12.8,6.4Hz,1H),2.78–2.46(m,6H),1.70–1.59(m,2H),1.62–1.51(m,2H),1.46(dddd,J＝12.8,7.9,6.4,5.5Hz,1H),1.33(d,J＝6.7Hz,2H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.02,172.96,152.23,152.17,145.75,143.98,131.37,129.44,129.42,127.12,124.62,124.51,123.65,123.18,120.59,120.55,99.55,66.32,64.51,64.46,60.53,54.30,53.93,53.88,52.15,52.11,48.27,47.56,31.55,24.32,20.35,17.42,17.38,12.03.
Example 51: synthesis of Compound S47
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (4-fluorophenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.17–7.03(m,5H),5.01(hept,J＝6.2Hz,1H),4.45(d,J＝9.3Hz,1H),4.14–3.92(m,4H),3.58(ddtd,J＝11.6,9.3,6.2,5.4Hz,1H),3.03(dt,J＝12.8,6.4Hz,1H),2.65(dq,J＝12.1,7.2Hz,1H),2.61–2.40(m,4H),1.72–1.42(m,4H),1.36(d,J＝6.5Hz,3H),1.24(dd,J＝25.0,6.1Hz,6H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,158.48,156.46,151.51,151.49,151.46,151.43,145.75,143.98,131.33,127.26,124.51,123.61,123.18,121.64,121.60,121.57,121.53,116.12,116.10,115.96,115.94,99.55,68.20,64.51,64.46,54.30,53.93,53.88,52.48,52.44,48.27,47.56,31.55,24.32,21.59,20.35,17.11,17.06,12.03.
Example 52: synthesis of Compound S48
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (4-chlorophenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.88–7.81(m,2H),7.45–7.39(m,2H),7.32(dd,J＝8.4,2.2Hz,1H),7.17(d,J＝5.7Hz,1H),7.13–7.07(m,2H),5.01(hept,J＝6.2Hz,1H),4.45(d,J＝9.3Hz,1H),4.18(d,J＝7.3Hz,1H),4.14–3.99(m,2H),4.02–3.92(m,1H),3.61–3.49(m,1H),3.05(dt,J＝12.9,6.5Hz,1H),2.93(dt,J＝12.7,6.4Hz,1H),2.68–2.44(m,4H),1.74–1.62(m,1H),1.60–1.50(m,1H),1.52–1.41(m,2H),1.37(d,J＝6.8Hz,3H),1.24(dd,J＝25.0,6.1Hz,6H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,152.47,152.41,145.75,143.98,131.33,129.34,129.32,129.28,127.26,124.51,123.61,123.18,120.92,120.88,99.55,68.12,64.51,64.46,54.30,53.93,53.88,52.48,52.44,48.27,47.56,31.55,24.32,21.59,20.35,17.11,17.06,12.03.
Example 53: synthesis of Compound S49
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (4-iodophenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.88–7.80(m,2H),7.69–7.63(m,2H),7.32(dd,J＝8.4,2.2Hz,1H),7.16(d,J＝5.7Hz,1H),6.96–6.89(m,2H),5.01(hept,J＝6.2Hz,1H),4.45(d,J＝9.3Hz,1H),4.17(d,J＝7.3Hz,1H),4.14–3.92(m,3H),3.60–3.48(m,1H),3.06(dt,J＝12.9,6.4Hz,1H),2.95(dt,J＝12.7,6.4Hz,1H),2.68–2.44(m,4H),1.74–1.62(m,1H),1.60–1.50(m,1H),1.47(dtdd,J＝12.1,5.8,3.5,1.0Hz,2H),1.36(d,J＝6.8Hz,3H),1.23(dd,J＝25.1,6.2Hz,6H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.02,172.96,152.77,152.71,145.94,145.75,143.98,138.64,138.62,131.33,127.26,124.51,123.61,123.18,122.70,122.66,99.55,85.99,68.12,64.51,64.46,54.33,53.93,53.88,52.47,52.42,48.27,47.56,31.55,24.36,21.59,20.33,17.23,17.18,12.03.
Example 54: synthesis of Compound S50
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (3, 4-dichlorophenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.38(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.21(d,J＝2.2Hz,1H),7.14(d,J＝5.7Hz,1H),7.05(dd,J＝8.4,2.2Hz,1H),5.01(hept,J＝6.2Hz,1H),4.48–4.41(m,2H),4.16–3.92(m,3H),3.61–3.49(m,1H),2.98(dt,J＝12.7,6.5Hz,1H),2.71–2.56(m,2H),2.57–2.43(m,3H),1.73–1.61(m,1H),1.59–1.40(m,6H),1.23(dd,J＝25.1,6.2Hz,6H),1.13(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,150.87,150.81,145.93,145.75,143.98,131.33,130.85,130.83,130.28,130.26,128.58,127.26,124.51,123.63,123.18,120.42,120.38,119.18,119.14,99.55,68.12,64.51,64.46,54.33,53.93,53.88,52.48,52.44,48.27,47.56,31.55,24.32,21.59,20.35,17.11,17.06,12.03.
Example 55: synthesis of Compound S51
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (4-cyanophenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.72–7.66(m,2H),7.30–7.23(m,3H),7.15(d,J＝5.7Hz,1H),5.01(hept,J＝6.2Hz,1H),4.45(d,J＝9.5Hz,1H),4.15–4.05(m,2H),4.08–3.92(m,2H),3.90–3.78(m,1H),2.97(dt,J＝12.7,6.5Hz,1H),2.68–2.41(m,5H),1.69–1.57(m,1H),1.59–1.45(m,2H),1.49–1.38(m,4H),1.24(dd,J＝25.0,6.1Hz,6H),1.13(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,154.00,153.94,145.75,143.98,133.56,133.54,131.33,127.26,124.51,123.63,123.18,120.05,120.01,118.32,104.30,99.55,68.12,64.51,64.46,54.30,53.93,53.88,52.48,52.44,48.27,47.56,31.55,24.32,21.59,20.35,17.11,17.06,12.03.
Example 56: synthesis of Compound S52
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (4-nitrophenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.78(d,J＝5.7Hz,1H),8.18(d,J＝2.3Hz,1H),7.96(dd,J＝8.5,1.3Hz,3H),7.53–7.44(m,3H),7.27(d,J＝5.7Hz,1H),5.01(hept,J＝6.2Hz,1H),4.13–4.00(m,3H),3.96(ddt,J＝11.2,8.6,6.5Hz,1H),3.09(dd,J＝14.3,7.9Hz,1H),2.94(dd,J＝14.3,7.9Hz,1H),2.86(dt,J＝12.9,6.4Hz,1H),2.72–2.57(m,2H),2.56–2.42(m,2H),2.01–1.88(m,1H),1.55–1.44(m,1H),1.48–1.36(m,2H),1.39–1.30(m,4H),1.24(dd,J＝25.0,6.1Hz,6H),1.10–1.00(m,6H).13C NMR(125MHz,DMSO-d6)173.00,172.94,155.29,155.23,145.54,144.47,141.05,134.57,132.15,128.56,127.42,127.34,125.62,125.60,124.69,123.47,119.81,119.77,68.12,64.51,64.46,54.46,53.93,53.88,52.48,52.44,48.27,36.92,34.58,32.11,24.81,21.59,21.38,17.15,17.10,12.03.
Example 57: synthesis of Compound S53
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (4-methylphenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.21–7.13(m,3H),7.17–7.08(m,2H),5.01(hept,J＝6.2Hz,1H),4.45(d,J＝9.3Hz,1H),4.14–3.92(m,4H),3.64–3.53(m,1H),3.10(dt,J＝12.9,6.5Hz,1H),2.72–2.60(m,2H),2.61–2.50(m,2H),2.51–2.42(m,1H),2.32(d,J＝0.7Hz,3H),1.73–1.61(m,1H),1.57–1.46(m,2H),1.50–1.41(m,1H),1.38(d,J＝6.7Hz,3H),1.24(dd,J＝25.0,6.1Hz,6H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,151.92,151.86,145.75,143.98,132.42,131.33,129.58,129.57,127.26,124.51,123.62,123.18,119.57,119.53,99.55,68.20,64.51,64.46,54.30,53.93,53.88,52.50,52.46,48.27,47.56,31.55,24.32,21.59,20.46,20.35,17.11,17.06,12.03.
Example 58: synthesis of Compound S54
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (4-hydroxyphenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.76(s,1H),8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.32(dd,J＝8.4,2.2Hz,1H),7.15(d,J＝5.7Hz,1H),7.00–6.90(m,4H),5.01(hept,J＝6.2Hz,1H),4.45(d,J＝9.3Hz,1H),4.13–3.91(m,3H),3.87(d,J＝7.3Hz,1H),3.64–3.52(m,1H),3.05(dt,J＝12.7,6.5Hz,1H),2.80(dt,J＝12.7,6.5Hz,1H),2.69–2.59(m,1H),2.62–2.52(m,2H),2.53–2.44(m,1H),1.73–1.61(m,1H),1.57–1.40(m,3H),1.36(d,J＝6.7Hz,3H),1.24(dd,J＝25.0,6.1Hz,6H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,152.14,148.11,148.05,145.75,143.98,131.33,127.26,124.51,123.61,123.18,121.18,121.14,116.49,116.47,99.55,68.20,64.51,64.46,54.30,53.93,53.88,52.48,52.44,48.27,47.56,31.55,24.32,21.59,20.35,17.11,17.06,12.03.
Example 59: synthesis of Compound S55
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (4-aminophenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.19(d,J＝5.7Hz,1H),6.86(d,J＝0.9Hz,4H),5.01(hept,J＝6.2Hz,1H),4.90(s,2H),4.45(d,J＝9.3Hz,1H),4.13–4.01(m,3H),3.96(ddt,J＝11.2,8.4,6.5Hz,1H),3.64–3.53(m,1H),2.91(dt,J＝12.8,6.4Hz,1H),2.66(dq,J＝12.1,7.2Hz,1H),2.60–2.41(m,4H),1.70–1.58(m,1H),1.59–1.47(m,2H),1.51–1.41(m,1H),1.42–1.33(m,3H),1.24(dd,J＝25.0,6.1Hz,6H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,148.22,148.16,145.75,143.98,143.77,131.33,127.26,124.51,123.61,123.18,121.50,121.46,116.01,116.00,99.55,68.20,64.51,64.46,54.30,53.93,53.88,52.50,52.46,48.27,47.56,31.55,24.32,21.59,20.35,17.11,17.06,12.03.
Example 60: synthesis of Compound S56
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (3-bromophenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.76(s,1H),8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.32(dd,J＝8.4,2.2Hz,1H),7.15(d,J＝5.7Hz,1H),7.00–6.90(m,4H),4.45(d,J＝9.3Hz,1H),4.13–3.91(m,3H),3.87(d,J＝7.3Hz,1H),3.64–3.52(m,1H),3.05(dt,J＝12.7,6.5Hz,1H),2.80(dt,J＝12.7,6.5Hz,1H),2.69–2.59(m,1H),2.62–2.52(m,2H),2.53–2.44(m,1H),1.73–1.61(m,1H),1.57–1.40(m,3H),1.36(d,J＝6.7Hz,3H),1.24(dd,J＝25.0,6.1Hz,6H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,152.14,148.11,148.05,145.75,143.98,131.33,127.26,124.51,123.61,123.18,121.18,121.14,116.49,116.47,99.55,68.20,64.51,64.46,54.30,53.93,53.88,52.48,52.44,48.27,47.56,31.55,24.32,21.59,20.35,17.11,17.06,12.03.
Example 61: synthesis of Compound S57
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (4-methoxyphenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.45(d,J＝5.7Hz,1H),7.88–7.81(m,2H),7.32(dd,J＝8.4,2.2Hz,1H),7.13(d,J＝5.7Hz,1H),7.03–6.97(m,2H),6.96–6.90(m,2H),5.01(hept,J＝6.2Hz,1H),4.45(d,J＝9.3Hz,1H),4.12(d,J＝7.3Hz,1H),4.12–3.99(m,2H),3.96(ddt,J＝11.2,8.4,6.5Hz,1H),3.79(s,2H),3.61–3.51(m,2H),2.77(dt,J＝12.9,6.4Hz,1H),2.72–2.42(m,5H),1.58–1.38(m,7H),1.24(dd,J＝25.0,6.1Hz,6H),1.13(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,154.22,148.76,148.70,145.75,143.98,131.33,127.26,124.51,123.63,123.18,120.69,120.65,114.33,114.32,99.55,68.12,64.51,64.46,55.38,54.30,53.93,53.88,52.48,52.44,48.27,47.56,31.55,24.32,21.59,20.35,17.11,17.06,12.03.
Example 62: synthesis of Compound S58
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (4-trifluoromethylphenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.71–7.65(m,2H),7.31(dd,J＝8.4,2.2Hz,1H),7.28–7.22(m,2H),7.13(d,J＝5.7Hz,1H),5.01(hept,J＝6.2Hz,1H),4.45(d,J＝9.5Hz,1H),4.14–3.92(m,4H),3.90–3.79(m,1H),2.88(dt,J＝12.8,6.5Hz,1H),2.69–2.45(m,5H),1.63–1.53(m,1H),1.56–1.43(m,2H),1.47–1.36(m,4H),1.23(dd,J＝25.1,6.2Hz,6H),1.14(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,152.63,152.58,145.93,145.75,143.98,131.33,127.27,126.91,126.89,126.88,126.86,126.84,126.83,126.81,126.80,125.13,124.40,124.22,123.96,123.71,123.64,123.45,123.18,122.98,120.84,120.35,120.34,120.32,120.30,120.28,120.26,99.55,68.12,64.51,64.46,54.33,53.93,53.88,52.48,52.43,48.27,47.56,31.56,24.32,21.59,20.35,17.80,17.75,12.03.
Example 63: synthesis of Compound S59
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (4-trifluoromethoxy-phenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.3Hz,1H),7.26(dd,J＝8.4,2.2Hz,1H),7.25–7.19(m,3H),7.04–6.97(m,2H),5.01(hept,J＝6.2Hz,1H),4.45(d,J＝9.3Hz,1H),4.13–4.00(m,2H),3.96(ddt,J＝11.2,8.4,6.5Hz,1H),3.89(d,J＝7.3Hz,1H),3.61–3.49(m,1H),3.09(dt,J＝12.9,6.4Hz,1H),2.77(dt,J＝12.7,6.5Hz,1H),2.66(dq,J＝12.1,7.2Hz,1H),2.61–2.52(m,1H),2.55–2.43(m,2H),1.66–1.56(m,1H),1.59–1.51(m,1H),1.54–1.43(m,2H),1.35(d,J＝6.7Hz,3H),1.23(dd,J＝25.1,6.2Hz,6H),1.13(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.02,172.97,149.31,149.25,145.91,145.86,144.13,144.05,143.96,143.93,143.87,131.40,127.27,124.44,123.83,123.63,123.18,121.69,121.14,121.13,121.12,121.11,121.10,120.68,120.64,119.55,117.40,99.57,68.12,64.51,64.46,54.33,53.93,53.88,52.53,52.48,48.27,47.56,31.56,24.38,21.59,20.33,17.98,17.94,12.03.
Example 64: synthesis of Compound S60
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (4-acetylphenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.72–7.65(m,2H),7.32(dd,J＝8.4,2.2Hz,1H),7.23–7.16(m,2H),7.20–7.12(m,1H),4.45(d,J＝9.3Hz,1H),4.14–3.91(m,4H),3.61–3.49(m,1H),2.92(dt,J＝12.9,6.4Hz,1H),2.71–2.45(m,9H),1.70–1.58(m,1H),1.59–1.40(m,3H),1.38(d,J＝6.8Hz,3H),1.24(dd,J＝25.0,6.1Hz,6H),1.14(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)196.34,173.00,172.94,154.62,154.56,145.93,145.75,143.98,131.33,130.87,130.09,130.07,127.26,124.40,123.64,123.18,119.83,119.79,99.55,68.12,64.51,64.46,54.30,53.93,53.88,52.48,52.44,48.27,47.56,31.55,26.35,24.32,21.59,20.35,17.15,17.10,12.03.
Example 65: synthesis of Compound S61
Methyl 4- (((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (((S) -1-isopropoxy-1-oxoprop-2-yl) amino) phosphoryl) oxy) benzoate
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.91–7.81(m,4H),7.26(dd,J＝8.4,2.6Hz,3H),7.19(d,J＝5.7Hz,1H),5.01(hept,J＝6.2Hz,1H),4.45(d,J＝9.3Hz,1H),4.37(d,J＝7.3Hz,1H),4.14–4.00(m,2H),3.98(ddt,J＝11.2,8.4,6.5Hz,1H),3.90(s,2H),3.61–3.49(m,2H),2.71(dt,J＝12.8,6.5Hz,1H),2.69–2.59(m,1H),2.61–2.52(m,2H),2.50(dq,J＝12.1,7.3Hz,1H),2.46–2.37(m,1H),1.55–1.44(m,2H),1.48–1.38(m,4H),1.42–1.31(m,1H),1.24(dd,J＝25.0,6.1Hz,6H),1.14(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,166.83,154.69,154.63,145.93,145.75,143.98,131.65,131.63,131.33,127.26,124.40,123.64,123.18,122.66,119.84,119.80,99.55,68.12,64.51,64.46,54.30,53.93,53.88,52.48,52.43,52.20,48.27,47.56,31.56,24.32,21.59,20.35,17.80,17.75,12.03.
Example 66: synthesis of Compound S62
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (4-dimethylaminophenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.88–7.81(m,2H),7.27(dd,J＝8.4,2.2Hz,1H),7.21(d,J＝5.6Hz,1H),7.05–6.99(m,2H),6.94–6.88(m,2H),5.01(hept,J＝6.2Hz,1H),4.45(d,J＝9.3Hz,1H),4.13–4.00(m,2H),4.02–3.92(m,1H),3.91(d,J＝7.3Hz,1H),3.61–3.49(m,1H),2.98(dt,J＝12.9,6.5Hz,1H),2.96(s,6H),2.65(dq,J＝12.1,7.3Hz,1H),2.58–2.47(m,3H),2.51–2.43(m,1H),1.73–1.61(m,1H),1.64–1.54(m,1H),1.56–1.44(m,2H),1.29–1.18(m,9H),1.14(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,148.82,148.76,146.10,145.93,145.75,143.98,131.33,127.26,124.40,123.64,123.18,120.56,120.52,114.56,114.54,99.55,68.12,64.51,64.46,54.30,53.93,53.88,52.48,52.44,48.27,47.56,40.23,31.55,24.32,21.59,20.35,17.15,17.10,12.03.
Example 67: synthesis of Compound S63
((S) - (4-Carbamoylphenoxy) (2- (((R) -4- ((7-Chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) phosphoryl) -L-alanine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.2Hz,1H),7.80(d,J＝8.4Hz,1H),7.78–7.72(m,2H),7.27(dd,J＝8.4,2.2Hz,1H),7.20–7.13(m,3H),7.04(s,2H),5.01(hept,J＝6.2Hz,1H),4.45(d,J＝9.3Hz,1H),4.14–3.92(m,4H),3.61–3.49(m,1H),3.12(dt,J＝12.7,6.4Hz,1H),2.68(dq,J＝12.1,7.2Hz,1H),2.64–2.53(m,2H),2.56–2.39(m,2H),1.67–1.55(m,1H),1.58–1.50(m,1H),1.54–1.47(m,1H),1.51–1.41(m,4H),1.24(dd,J＝25.0,6.1Hz,6H),1.14(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,168.73,154.42,154.36,145.93,145.75,143.98,131.33,130.66,129.97,129.95,127.26,124.40,123.64,123.18,119.55,119.51,99.55,68.12,64.51,64.46,54.30,53.93,53.88,52.48,52.44,48.27,47.56,31.55,24.32,21.59,20.35,17.15,17.10,12.03.
Example 68: synthesis of Compound S64
((S) - (4-Aminosulfonylphenoxy) (2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) phosphoryl) -L-alanine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.2Hz,1H),7.80(dd,J＝8.4,1.2Hz,3H),7.38–7.32(m,2H),7.26(dd,J＝8.4,2.2Hz,1H),7.20(d,J＝9.9Hz,1H),7.15(d,J＝5.6Hz,1H),5.01(hept,J＝6.2Hz,1H),4.45(d,J＝9.3Hz,1H),4.21(d,J＝7.3Hz,1H),4.14–4.00(m,2H),3.98(ddt,J＝11.2,8.4,6.5Hz,1H),3.61–3.49(m,1H),3.11(dt,J＝12.7,6.5Hz,1H),2.78(dt,J＝12.8,6.5Hz,1H),2.68–2.47(m,4H),1.66(dp,J＝13.0,6.5Hz,1H),1.58–1.43(m,5H),1.41(dq,J＝12.8,6.4Hz,1H),1.32(d,J＝9.9Hz,1H),1.23(dd,J＝25.1,6.2Hz,6H),1.13(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,155.19,155.13,145.93,145.75,143.98,136.70,131.33,128.37,128.35,127.26,124.40,123.63,123.18,120.35,120.31,99.55,68.12,64.51,64.46,54.33,53.93,53.88,52.48,52.43,48.27,47.56,31.56,24.32,21.59,20.33,17.98,17.94,12.03.
Example 69: synthesis of Compound S65
((S) - (2- (((R) -4- ((7-Fluoroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (phenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),8.08(dd,J＝8.4,4.9Hz,1H),7.59(dd,J＝8.0,2.2Hz,1H),7.42–7.34(m,2H),7.23–7.14(m,4H),7.10(d,J＝5.7Hz,1H),5.01(hept,J＝6.2Hz,1H),4.71(d,J＝9.3Hz,1H),4.14–3.99(m,2H),4.02–3.92(m,1H),3.91–3.80(m,1H),3.78(d,J＝7.3Hz,1H),3.04(dt,J＝12.8,6.5Hz,1H),2.86(dt,J＝12.7,6.5Hz,1H),2.63–2.44(m,4H),1.66–1.56(m,1H),1.59–1.46(m,2H),1.50–1.35(m,4H),1.23(dd,J＝25.1,6.2Hz,6H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.01,172.95,162.63,160.61,152.23,152.17,146.73,145.14,143.88,143.82,129.44,129.42,124.62,124.08,124.01,122.74,122.72,120.59,120.55,114.39,114.23,112.77,112.61,99.55,68.19,64.51,64.46,54.30,53.93,53.88,52.50,52.46,48.27,47.56,31.53,24.32,21.59,20.35,17.11,17.06,12.03.
Example 70: synthesis of Compound S66
((S) - (2- (((R) -4- ((7-trifluoromethylquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (phenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.54(d,J＝5.5Hz,1H),8.43(d,J＝1.6Hz,1H),8.25(d,J＝8.4Hz,1H),7.63(dd,J＝8.4,1.8Hz,1H),7.42–7.34(m,2H),7.26(d,J＝5.7Hz,1H),7.19(tt,J＝7.4,1.5Hz,1H),7.11–7.05(m,2H),5.18(d,J＝9.3Hz,1H),5.01(hept,J＝6.2Hz,1H),4.22(d,J＝7.3Hz,1H),4.14–3.92(m,3H),3.54(ddtd,J＝11.7,9.9,6.2,5.4Hz,1H),3.00(dt,J＝12.9,6.5Hz,1H),2.65–2.43(m,6H),1.68–1.58(m,1H),1.61–1.48(m,1H),1.51–1.38(m,1H),1.34(d,J＝6.8Hz,3H),1.24(dd,J＝25.0,6.1Hz,6H),1.12(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,152.23,152.17,146.57,144.38,143.24,143.22,143.20,143.19,132.02,131.76,131.50,131.25,129.44,129.42,127.23,125.08,124.62,124.04,123.86,123.84,123.82,123.81,122.99,122.96,122.94,122.93,122.90,120.80,120.60,120.56,120.22,120.19,120.16,120.13,99.55,68.12,64.51,64.46,54.30,53.93,53.88,52.48,52.44,48.27,47.56,31.55,24.32,21.59,20.35,17.15,17.10,12.03.
Example 71: synthesis of Compound S67
((S) - (2- (((R) -4- ((7-trifluoromethoxyquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (phenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.38(d,J＝5.7Hz,1H),8.01(d,J＝8.4Hz,1H),7.45(d,J＝2.2Hz,1H),7.42–7.34(m,2H),7.31(dd,J＝8.4,2.2Hz,1H),7.26–7.16(m,3H),7.11(d,J＝5.7Hz,1H),5.01(hept,J＝6.2Hz,1H),4.51(d,J＝9.5Hz,1H),4.14–4.00(m,2H),4.03–3.92(m,2H),3.57-3.53(m,1H),2.84(dt,J＝12.7,6.5Hz,1H),2.73–2.39(m,5H),1.70–1.60(m,1H),1.59(ddd,J＝13.7,6.7,5.5Hz,1H),1.58–1.40(m,5H),1.24(dd,J＝25.0,6.1Hz,6H),1.15(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,152.34,152.29,149.33,149.24,149.15,149.07,146.57,145.41,144.00,129.44,129.42,124.62,124.36,123.77,121.66,121.63,120.59,120.55,120.37,120.36,119.48,117.34,113.05,113.04,99.55,68.12,64.51,64.46,54.30,53.93,53.88,52.48,52.43,48.27,47.56,31.56,24.32,21.59,20.35,17.15,17.10,12.03.
Example 72: synthesis of Compound S68
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) (methyl)) amino) pentyl) (ethyl) amino) ethoxy) (phenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.65(d,J＝5.7Hz,1H),7.95(d,J＝2.1Hz,1H),7.60(d,J＝8.4Hz,1H),7.46(dd,J＝8.4,2.2Hz,1H),7.42–7.35(m,3H),7.29–7.23(m,2H),7.19(tt,J＝7.2,1.5Hz,1H),5.01(hept,J＝6.2Hz,1H),4.14(d,J＝7.3Hz,1H),4.13–3.99(m,2H),4.02–3.92(m,1H),3.36–3.26(m,1H),2.89(dt,J＝12.8,6.4Hz,1H),2.87(s,3H),2.73–2.47(m,5H),1.72–1.43(m,4H),1.36(d,J＝6.8Hz,3H),1.29–1.15(m,9H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,152.23,152.17,147.64,144.60,143.40,132.21,129.44,129.42,128.63,127.13,124.82,124.62,124.30,120.59,120.55,104.76,68.20,64.51,64.46,54.34,53.93,53.88,53.70,52.50,52.46,48.27,33.71,31.44,24.60,21.59,19.39,17.11,17.06,12.03.
Example 73: synthesis of Compound S69
((S) - (2- (((R) -4- ((7-chloroquinolin-4-yl) (cyclopropyl)) amino) pentyl) (ethyl) amino) ethoxy) (phenoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.66(d,J＝5.7Hz,1H),7.94(d,J＝2.3Hz,1H),7.60(d,J＝8.4Hz,1H),7.49–7.42(m,2H),7.42–7.35(m,2H),7.19(ddd,J＝14.6,7.6,1.5Hz,3H),5.01(hept,J＝6.2Hz,1H),4.23(d,J＝7.3Hz,1H),4.14–4.00(m,2H),3.98(ddt,J＝11.2,8.4,6.5Hz,1H),3.63–3.52(m,1H),2.89(dt,J＝12.9,6.5Hz,1H),2.71–2.42(m,6H),1.78–1.68(m,1H),1.69–1.57(m,1H),1.61–1.49(m,2H),1.41(d,J＝6.8Hz,3H),1.34–1.18(m,11H),1.07(t,J＝7.2Hz,3H),0.94(ddd,J＝10.7,9.7,5.7Hz,2H).13C NMR(125MHz,DMSO-d6)173.00,172.94,152.23,152.17,144.48,143.68,139.58,132.21,129.44,129.42,128.63,127.19,125.35,124.62,124.33,120.60,120.56,106.56,68.12,64.51,64.46,54.34,53.93,53.88,52.70,52.48,52.43,48.27,31.90,27.84,24.46,21.59,19.23,17.15,17.10,12.03,8.27.
Example 74: synthesis of Compound S70
((S) - (3-Bromophenyloxy) (2- (((S) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.76(s,1H),8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.32(dd,J＝8.4,2.2Hz,1H),7.15(d,J＝5.7Hz,1H),7.00–6.90(m,4H),4.45(d,J＝9.3Hz,1H),4.13–3.91(m,3H),3.87(d,J＝7.3Hz,1H),3.64–3.52(m,1H),3.05(dt,J＝12.7,6.5Hz,1H),2.80(dt,J＝12.7,6.5Hz,1H),2.69–2.59(m,1H),2.62–2.52(m,2H),2.53–2.44(m,1H),1.73–1.61(m,1H),1.57–1.40(m,3H),1.36(d,J＝6.7Hz,3H),1.24(dd,J＝25.0,6.1Hz,6H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,152.14,148.11,148.05,145.75,143.98,131.33,127.26,124.51,123.61,123.18,121.18,121.14,116.49,116.47,99.55,68.20,64.51,64.46,54.30,53.93,53.88,52.48,52.44,48.27,47.56,31.55,24.32,21.59,20.35,17.11,17.06,12.03.
Example 75: synthesis of Compound S71
((S) - (4-chlorophenoxy) (2- (((S) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.38(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.21(d,J＝2.2Hz,1H),7.14(d,J＝5.7Hz,1H),7.05(dd,J＝8.4,2.2Hz,1H),5.01(hept,J＝6.2Hz,1H),4.48–4.41(m,2H),4.16–3.92(m,3H),3.61–3.49(m,1H),2.98(dt,J＝12.7,6.5Hz,1H),2.71–2.56(m,2H),2.57–2.43(m,3H),1.73–1.61(m,1H),1.59–1.40(m,6H),1.23(dd,J＝25.1,6.2Hz,6H),1.13(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,150.87,150.81,145.93,145.75,143.98,131.33,130.85,130.83,130.28,130.26,128.58,127.26,124.51,123.63,123.18,120.42,120.38,119.18,119.14,99.55,68.12,64.51,64.46,54.33,53.93,53.88,52.48,52.44,48.27,47.56,31.55,24.32,21.59,20.35,17.11,17.06,12.03.
Example 76: synthesis of Compound S72
((S) - (3-Bromophenyloxy) (2- (((S) -4- ((7-fluoroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.54(d,J＝5.7Hz,1H),8.24(d,J＝8.4Hz,1H),7.62(d,J＝2.3Hz,1H),7.31(t,J＝7.8Hz,1H),7.24(t,J＝2.2Hz,1H),7.18(dddd,J＝11.9,7.7,2.2,1.2Hz,2H),7.11(dd,J＝8.4,2.2Hz,1H),6.94(d,J＝5.7Hz,1H),6.21(d,J＝7.3Hz,1H),5.96(d,J＝9.3Hz,1H),5.08(s,2H),5.00-4.90(m,3H),4.12(t,J＝6.4Hz,2H),4.07–3.97(m,1H),3.57(ddtd,J＝11.8,9.4,6.3,5.5Hz,1H),2.89–2.76(m,2H),2.60(q,J＝7.2Hz,2H),2.52(t,J＝6.3Hz,2H),1.68–1.55(m,2H),1.57–1.43(m,2H),1.32(d,J＝6.8Hz,3H),1.24(dd,J＝25.1,6.2Hz,6H),1.17–1.06(m,6H).13C NMR(125MHz,DMSO-d6)173.00,172.94,162.63,160.61,152.12,152.07,146.96,145.23,143.88,143.82,130.71,130.69,127.24,124.08,124.01,122.74,122.72,121.88,121.84,121.75,121.74,119.05,119.01,114.41,114.25,112.89,112.73,99.55,68.12,64.51,64.46,54.33,53.93,53.88,52.48,52.44,48.27,47.56,31.55,24.32,21.59,20.33,17.11,17.06,12.03.
Example 77: synthesis of Compound S73
((S) - (phenoxy) (2- (((S) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.87(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.42–7.34(m,2H),7.32(dd,J＝8.4,2.2Hz,1H),7.20(tt,J＝7.4,1.4Hz,1H),7.19–7.12(m,3H),5.00(hept,J＝6.1Hz,1H),4.45(d,J＝9.3Hz,1H),4.14–4.05(m,2H),4.08–3.99(m,1H),4.02–3.92(m,1H),3.64–3.52(m,1H),3.04(dt,J＝12.9,6.5Hz,1H),2.74–2.46(m,4H),2.47–2.38(m,1H),1.70–1.58(m,1H),1.58–1.47(m,2H),1.50–1.40(m,1H),1.38(d,J＝6.6Hz,3H),1.23(dd,J＝25.1,6.2Hz,6H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.01,172.95,152.23,152.17,145.75,145.52,143.98,131.37,129.44,129.42,127.12,124.62,124.51,123.65,123.18,120.59,120.55,99.55,68.20,64.51,64.46,54.30,53.93,53.88,52.50,52.46,48.27,47.56,31.55,24.32,21.59,20.35,17.11,17.06,12.03.
Example 78: synthesis of Compound S74
((S) - (4-Acetylphenoxy) (2- (((S) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.72–7.65(m,2H),7.32(dd,J＝8.4,2.2Hz,1H),7.23–7.16(m,2H),7.20–7.12(m,1H),4.45(d,J＝9.3Hz,1H),4.14–3.91(m,4H),3.61–3.49(m,1H),2.92(dt,J＝12.9,6.4Hz,1H),2.71–2.45(m,9H),1.70–1.58(m,1H),1.59–1.40(m,3H),1.38(d,J＝6.8Hz,3H),1.24(dd,J＝25.0,6.1Hz,6H),1.14(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)196.34,173.00,172.94,154.62,154.56,145.93,145.75,143.98,131.33,130.87,130.09,130.07,127.26,124.40,123.64,123.18,119.83,119.79,99.55,68.12,64.51,64.46,54.30,53.93,53.88,52.48,52.44,48.27,47.56,31.55,26.35,24.32,21.59,20.35,17.15,17.10,12.03.
Example 79: synthesis of Compound S75
Methyl 4- (((S) - (2- (((S) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) (((S) -1-isopropoxy-1-oxoprop-2-yl) amino) phosphoryl) oxy) benzoate
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.91–7.81(m,4H),7.26(dd,J＝8.4,2.6Hz,3H),7.19(d,J＝5.7Hz,1H),5.01(hept,J＝6.2Hz,1H),4.45(d,J＝9.3Hz,1H),4.37(d,J＝7.3Hz,1H),4.14–4.00(m,2H),3.98(ddt,J＝11.2,8.4,6.5Hz,1H),3.90(s,2H),3.61–3.49(m,2H),2.71(dt,J＝12.8,6.5Hz,1H),2.69–2.59(m,1H),2.61–2.52(m,2H),2.50(dq,J＝12.1,7.3Hz,1H),2.46–2.37(m,1H),1.55–1.44(m,2H),1.48–1.38(m,4H),1.42–1.31(m,1H),1.24(dd,J＝25.0,6.1Hz,6H),1.14(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,166.83,154.69,154.63,145.93,145.75,143.98,131.65,131.63,131.33,127.26,124.40,123.64,123.18,122.66,119.84,119.80,99.55,68.12,64.51,64.46,54.30,53.93,53.88,52.48,52.43,52.20,48.27,47.56,31.56,24.32,21.59,20.35,17.80,17.75,12.03.
Example 80: synthesis of Compound S76
((S) - (3-fluoro-4-chlorophenoxy) (2- (((S) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethoxy) phosphoryl) -L-propylamine isopropyl ester
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86–7.77(m,2H),7.37(dd,J＝8.4,5.0Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.18(d,J＝5.7Hz,1H),6.89(ddd,J＝24.9,8.2,2.2Hz,2H),5.01(hept,J＝6.2Hz,1H),4.45(d,J＝9.3Hz,1H),4.14–3.93(m,3H),3.90(d,J＝7.3Hz,1H),3.61–3.49(m,1H),3.03(dt,J＝12.9,6.5Hz,1H),2.82(dt,J＝12.7,6.5Hz,1H),2.68–2.46(m,4H),1.67–1.55(m,1H),1.59–1.47(m,2H),1.50–1.39(m,1H),1.36(d,J＝6.8Hz,3H),1.24(dd,J＝25.0,6.1Hz,6H),1.13(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)173.00,172.94,158.26,158.24,156.24,156.23,151.88,151.83,151.82,151.76,145.93,145.75,143.98,131.33,129.78,129.76,129.71,129.70,127.26,124.51,123.63,123.18,118.54,118.52,118.50,118.48,116.47,116.31,108.50,108.46,108.34,108.30,99.55,68.12,64.51,64.46,54.30,53.93,53.88,52.48,52.44,48.27,47.56,31.55,24.32,21.59,20.35,17.11,17.06,12.03.
Example 81: synthesis of Compound 14
Diphenyl chlorophosphate (1.5mL, 7.91mmol) was dissolved in anhydrous acetonitrile (20mL) under nitrogen, and a catalytic amount of sodium iodide and Compound 13(2.40g, 15.82mmol) were added to the reaction mixture, followed by heating and refluxing overnight. The reaction was cooled to room temperature, the solvent was evaporated under reduced pressure, the residue was suspended in DCM, cooled to 0 ℃ and 4-nitrophenol (1.10g, 7.91mmol) was added and triethylamine (1.1mL, 7.91mmol) was added slowly. The reaction solution is heated to room temperature and stirred for reaction for 3 hours. The solvent was distilled off under reduced pressure, and column chromatography purification was performed to give compound 14(1.6g, 45%).1H NMR(300MHz,Chloroform-d)8.16–8.09(m,2H),7.42–7.35(m,2H),6.31(dd,J＝8.4,2.4Hz,2H),6.21(dd,J＝8.4,2.4Hz,2H),5.09(hept,J＝6.2Hz,2H),1.32(d,J＝6.1Hz,12H).
Example 82: synthesis of Compound S77
Acetonitrile (15mL) was added to compound 2(1g, 3.03mmol), compound 14(1.6g, 3.65mmol) and magnesium chloride (288mg, 3.30mmol) at room temperature, the reaction solution was warmed to 70 ℃, stirred for 10min, DIPEA (1.3mL, 7.58mmol) was added, stirring was continued for 1h, the reaction was stopped, ethyl acetate (80mL) was added to dilute the reaction solution, the organic phase was washed with 5% diluted citric acid (40mL), saturated ammonium chloride (40mL), saturated potassium carbonate (2 × 40mL), saturated saline (40mL), dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and then purified by column chromatography to give compound S77(1.1g, 55%).1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.11(d,J＝5.7Hz,1H),5.96(dd,J＝8.4,2.4Hz,2H),5.68(dd,J＝8.5,2.5Hz,2H),4.45(d,J＝9.3Hz,1H),4.09(ddt,J＝11.2,8.4,6.4Hz,1H),3.99(ddt,J＝11.2,8.4,6.5Hz,1H),3.55(ddtd,J＝11.6,9.4,6.2,5.4Hz,1H),2.78(dt,J＝12.9,6.5Hz,1H),2.74–2.59(m,2H),2.58(dd,J＝12.1,6.2Hz,1H),2.57–2.48(m,4H),2.44(dt,J＝12.1,6.3Hz,1H),1.61(dq,J＝12.8,6.4Hz,1H),1.58–1.39(m,3H),1.14(s,18H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)174.97,174.94,145.93,145.75,143.98,131.33,127.26,124.51,123.63,123.18,99.55,89.04,89.00,64.96,64.91,54.30,53.96,53.91,48.27,47.56,38.82,31.55,27.07,24.32,20.35,12.03.
The synthesis methods of the compounds S78 to S84 in the following examples S83 to S89 are the same as those of the compound S77, and only the corresponding raw materials need to be replaced.
Example 83: synthesis of Compound S78
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.87(d,J＝2.3Hz,1H),7.79(d,J＝8.4Hz,1H),7.28(dd,J＝8.4,2.2Hz,1H),7.12(d,J＝5.7Hz,1H),6.18(dd,J＝8.5,2.5Hz,2H),5.76(dd,J＝8.5,2.5Hz,2H),4.45(d,J＝9.3Hz,1H),4.09(ddt,J＝11.0,8.4,6.4Hz,1H),3.99(ddt,J＝11.0,8.4,6.4Hz,1H),3.81(s,6H),3.58(ddtd,J＝11.5,9.3,6.2,5.4Hz,1H),3.06(dt,J＝12.9,6.4Hz,1H),2.68(dq,J＝12.1,7.2Hz,1H),2.60–2.45(m,4H),1.61(dq,J＝12.8,6.5Hz,1H),1.58–1.41(m,3H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)153.23,153.20,145.75,145.47,143.98,131.37,127.12,124.51,123.66,123.18,99.55,88.26,88.22,64.96,64.91,54.73,54.30,53.96,53.91,48.27,47.57,31.53,24.32,20.35,12.03.
Example 84: synthesis of Compound S79
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.11(d,J＝5.7Hz,1H),5.96(dd,J＝8.4,2.4Hz,2H),5.68(dd,J＝8.5,2.5Hz,2H),4.45(d,J＝9.3Hz,1H),4.09(ddt,J＝11.2,8.4,6.4Hz,1H),3.99(ddt,J＝11.2,8.4,6.5Hz,1H),3.55(ddtd,J＝11.6,9.4,6.2,5.4Hz,1H),2.78(dt,J＝12.9,6.5Hz,1H),2.74–2.59(m,2H),2.58(dd,J＝12.1,6.2Hz,1H),2.57–2.48(m,4H),2.44(dt,J＝12.1,6.3Hz,1H),1.61(dq,J＝12.8,6.4Hz,1H),1.58–1.39(m,3H),1.14(s,18H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)174.97,174.94,145.93,145.75,143.98,131.33,127.26,124.51,123.63,123.18,99.55,89.04,89.00,64.96,64.91,54.30,53.96,53.91,48.27,47.56,38.82,31.55,27.07,24.32,20.35,12.03.
Example 85: synthesis of Compound S80
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.87(d,J＝2.3Hz,1H),7.79(d,J＝8.4Hz,1H),7.28(dd,J＝8.4,2.2Hz,1H),7.12(d,J＝5.7Hz,1H),6.18(dd,J＝8.5,2.5Hz,2H),5.76(dd,J＝8.5,2.5Hz,2H),4.45(d,J＝9.3Hz,1H),4.09(ddt,J＝11.0,8.4,6.4Hz,1H),3.99(ddt,J＝11.0,8.4,6.4Hz,1H),3.81(s,6H),3.58(ddtd,J＝11.5,9.3,6.2,5.4Hz,1H),3.06(dt,J＝12.9,6.4Hz,1H),2.68(dq,J＝12.1,7.2Hz,1H),2.60–2.45(m,4H),1.61(dq,J＝12.8,6.5Hz,1H),1.58–1.41(m,3H),1.13(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)153.23,153.20,145.75,145.47,143.98,131.37,127.12,124.51,123.66,123.18,99.55,88.26,88.22,64.96,64.91,54.73,54.30,53.96,53.91,48.27,47.57,31.53,24.32,20.35,12.03.
Example 86: synthesis of Compound S81
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.05(d,J＝5.6Hz,1H),6.28(dd,J＝8.4,2.4Hz,2H),6.18(dd,J＝8.4,2.4Hz,2H),5.09(hept,J＝6.2Hz,2H),4.45(d,J＝9.3Hz,1H),4.09(ddt,J＝11.0,8.4,6.4Hz,1H),3.99(ddt,J＝11.0,8.4,6.4Hz,1H),3.61–3.49(m,1H),2.92(dt,J＝12.7,6.5Hz,1H),2.70(dq,J＝12.1,7.2Hz,1H),2.61–2.43(m,4H),1.70–1.58(m,2H),1.61–1.47(m,1H),1.45–1.25(m,13H),1.13(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)152.05,152.02,145.93,145.75,143.98,131.33,127.26,124.51,123.63,123.18,99.55,88.22,88.17,69.96,64.96,64.91,54.30,53.96,53.91,48.27,47.56,31.55,24.32,21.81,20.35,12.03.
Example 87: synthesis of Compound S82
1H NMR(300MHz,DMSO-d6)8.46(d,J＝5.5Hz,1H),8.14(dd,J＝8.4,4.9Hz,1H),7.56(dd,J＝7.9,2.3Hz,1H),7.17(td,J＝8.2,2.3Hz,1H),7.06(d,J＝5.7Hz,1H),6.28(dd,J＝8.4,2.4Hz,2H),6.03(dd,J＝8.6,2.4Hz,2H),5.08(hept,J＝6.2Hz,2H),4.71(d,J＝9.3Hz,1H),4.09(ddt,J＝11.0,8.4,6.4Hz,1H),3.99(ddt,J＝11.0,8.4,6.4Hz,1H),3.94–3.82(m,1H),2.84(dt,J＝12.9,6.5Hz,1H),2.73–2.62(m,2H),2.60–2.48(m,2H),2.51–2.43(m,1H),1.69–1.57(m,1H),1.57–1.44(m,2H),1.48–1.38(m,1H),1.30(dd,J＝25.0,6.1Hz,12H),1.13(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)162.63,160.61,152.05,152.02,146.73,145.23,143.88,143.82,124.08,124.01,122.74,122.72,114.41,114.25,112.89,112.73,99.55,88.22,88.17,69.96,64.96,64.91,54.30,53.96,53.91,48.27,47.56,31.55,24.32,21.81,20.35,12.03.
Example 88: synthesis of Compound S83
1H NMR(300MHz,DMSO-d6)8.58(d,J＝5.5Hz,1H),7.90(d,J＝8.4Hz,1H),7.69(d,J＝2.4Hz,1H),7.35(dd,J＝8.4,2.2Hz,1H),7.10(d,J＝5.7Hz,1H),6.63(s,1H),5.88(d,J＝9.3Hz,1H),5.77(s,4H),4.12(t,J＝6.5Hz,2H),3.63–3.52(m,1H),2.83(td,J＝6.6,1.5Hz,2H),2.64(qd,J＝7.2,1.0Hz,2H),2.52(t,J＝6.3Hz,2H),1.66–1.52(m,2H),1.53(s,14H),1.56–1.44(m,2H),1.15(d,J＝6.2Hz,3H),1.09(t,J＝7.2Hz,6H).13C NMR(125MHz,DMSO-d6))152.61,152.58,146.69,145.63,144.54,144.49,138.29,138.23,138.17,136.19,136.13,136.08,124.20,124.17,124.13,123.98,123.95,123.92,123.77,123.71,122.74,122.71,120.07,120.04,120.01,119.85,119.82,119.79,105.94,103.85,103.80,101.70,101.65,99.57,87.92,87.87,82.78,64.96,64.91,54.33,53.96,53.91,48.27,47.56,31.56,27.65,24.38,20.33,12.03.
Example 89: synthesis of Compound S84
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),8.11(dd,J＝8.4,4.9Hz,1H),7.53(dd,J＝7.9,2.2Hz,1H),7.16(td,J＝8.2,2.3Hz,1H),7.05(d,J＝5.7Hz,1H),5.96(dd,J＝8.4,2.4Hz,2H),5.68(dd,J＝8.5,2.5Hz,2H),4.71(d,J＝9.3Hz,1H),4.09(ddt,J＝11.2,8.4,6.4Hz,1H),3.99(ddt,J＝11.2,8.4,6.5Hz,1H),3.96–3.84(m,1H),3.05(dt,J＝12.7,6.5Hz,1H),2.68(dq,J＝12.1,7.3Hz,1H),2.62–2.54(m,2H),2.57–2.49(m,1H),2.52–2.40(m,1H),1.66–1.54(m,1H),1.56–1.47(m,1H),1.51–1.45(m,1H),1.48–1.38(m,1H),1.13(d,J＝6.2Hz,3H),1.12(s,18H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)174.97,174.94,162.63,160.61,146.73,145.23,143.88,143.82,124.08,124.01,122.74,122.72,114.41,114.25,112.89,112.73,99.55,89.04,89.00,64.96,64.91,54.30,53.96,53.91,48.27,47.56,38.82,31.55,27.07,24.32,20.35,12.03.
Example 90: synthesis of Compound 16
To compound 15(2.3g, 14.41mmol) was added DCM (25mL) and cooled to-78 ℃. Phosphorus oxychloride was slowly added dropwise (0.64mL, 6.86mol) to the above suspension followed by the slow addition of triethylamine (2.0mL, 14.41 mmol). The reaction liquid is heated to room temperature and stirred for reaction for 2 hours. The reaction was cooled to 0 deg.C, 4-nitrophenol (1.82g, 6.86mmol) was added, and triethylamine (2.0mL, 14.41mmol) was added slowly. The reaction solution is heated to room temperature and stirred for reaction for 3 hours. The solvent was distilled off under reduced pressure, and purified by column chromatography to give compound 16(1.8g, 50%)。1H NMR(300MHz,Chloroform-d)8.15–8.09(m,2H),7.43–7.36(m,2H),4.40(dddt,J＝43.0,11.3,8.4,6.5Hz,4H),3.41(dt,J＝14.8,6.4Hz,2H),3.24(dt,J＝14.8,6.4Hz,2H),1.25(s,18H).
Example 91: synthesis of Compound S85
Acetonitrile (15mL) was added to compound 2(1g, 3.03mmol), compound 16(1.8g, 3.65mmol) and magnesium chloride (288mg, 3.30mmol) at room temperature, the reaction solution was warmed to 70 ℃, stirred for 10min, DIPEA (1.3mL, 7.58mmol) was added, stirring was continued for 1h, the reaction was stopped, ethyl acetate (80mL) was added to dilute the reaction solution, the organic phase was washed with 5% diluted citric acid (40mL), saturated ammonium chloride (40mL), saturated potassium carbonate (2 × 40mL), saturated saline (40mL), dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and then purified by column chromatography to give compound S85(1.0g, 48%).1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.2Hz,1H),7.80(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.05(d,J＝5.6Hz,1H),4.48–4.28(m,5H),4.09(ddt,J＝11.0,8.4,6.4Hz,1H),3.99(ddt,J＝11.2,8.4,6.5Hz,1H),3.61–3.51(m,1H),3.47(dt,J＝14.8,6.4Hz,2H),3.22(dt,J＝15.0,6.5Hz,2H),3.12(dt,J＝12.9,6.5Hz,1H),2.67(dq,J＝12.1,7.2Hz,1H),2.63–2.53(m,1H),2.57–2.49(m,1H),2.53–2.46(m,1H),2.49–2.40(m,1H),1.66–1.40(m,4H),1.25(s,18H),1.13(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)184.82,145.94,145.75,143.98,131.33,127.26,124.40,123.63,123.18,99.55,66.18,66.15,66.13,66.10,64.92,64.88,54.33,53.96,53.91,48.27,47.56,44.84,33.11,33.06,31.56,28.56,24.32,20.33,12.03.
The following synthetic methods of the compounds S86 to S88 in examples 92 to 94 were the same as the synthetic method of the compound S85, and only the corresponding raw materials were replaced.
Example 92: synthesis of Compound S86
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.05(d,J＝5.5Hz,1H),4.48–4.28(m,5H),4.04(dt,J＝8.5,6.5Hz,2H),3.61–3.51(m,1H),3.49(dt,J＝15.0,6.5Hz,2H),3.22(dt,J＝14.8,6.4Hz,2H),3.01(dq,J＝14.3,7.1Hz,2H),2.92(td,J＝6.5,0.7Hz,2H),2.64(qd,J＝7.2,1.2Hz,2H),2.59(t,J＝6.3Hz,2H),1.66–1.47(m,4H),1.19–1.03(m,18H).13C NMR(125MHz,DMSO-d6)184.69,145.93,145.75,143.98,131.33,127.26,124.51,123.62,123.18,99.55,66.40,66.37,66.36,66.33,64.92,64.88,54.33,53.96,53.91,48.27,47.56,40.50,32.10,32.05,31.55,24.32,20.53,20.35,12.03.
Example 93: synthesis of Compound S87
1H NMR(300MHz,DMSO-d6)8.58(d,J＝5.5Hz,1H),7.89(d,J＝8.4Hz,1H),7.69(d,J＝2.2Hz,1H),7.28(dd,J＝8.4,2.2Hz,1H),7.09(d,J＝5.5Hz,1H),6.63(s,1H),5.88(d,J＝9.3Hz,1H),4.22(t,J＝6.5Hz,4H),4.12(t,J＝6.4Hz,2H),3.60–3.50(m,1H),3.27(t,J＝6.5Hz,4H),2.83(td,J＝6.5,1.6Hz,2H),2.63(qd,J＝7.2,1.7Hz,2H),2.52(t,J＝6.3Hz,1H),1.66–1.52(m,2H),1.56–1.44(m,2H),1.25(s,18H),1.15(d,J＝6.2Hz,3H),1.09(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)184.83,146.69,145.63,144.54,144.49,138.29,138.23,138.17,136.19,136.13,136.08,124.20,124.17,124.13,123.98,123.95,123.92,123.77,123.71,122.74,122.71,120.07,120.04,120.01,119.85,119.82,119.79,105.94,103.85,103.80,101.70,101.65,99.57,66.18,66.15,66.13,66.10,64.92,64.88,54.33,53.96,53.91,48.27,47.56,44.83,33.11,33.06,31.56,28.56,24.43,20.33,12.03.
Example 94: synthesis of Compound S88
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.2Hz,1H),7.80(d,J＝8.4Hz,1H),7.27(dd,J＝8.4,2.2Hz,1H),7.05(d,J＝5.6Hz,1H),4.48–4.28(m,5H),4.09(ddt,J＝11.0,8.4,6.4Hz,1H),3.99(ddt,J＝11.2,8.4,6.5Hz,1H),3.61–3.51(m,1H),3.47(dt,J＝14.8,6.4Hz,2H),3.22(dt,J＝15.0,6.5Hz,2H),3.12(dt,J＝12.9,6.5Hz,1H),2.67(dq,J＝12.1,7.2Hz,1H),2.63–2.53(m,1H),2.57–2.49(m,1H),2.53–2.46(m,1H),2.49–2.40(m,1H),1.66–1.40(m,4H),1.25(s,18H),1.13(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)184.82,145.94,145.75,143.98,131.33,127.26,124.40,123.63,123.18,99.55,66.18,66.15,66.13,66.10,64.92,64.88,54.33,53.96,53.91,48.27,47.56,44.84,33.11,33.06,31.56,28.56,24.32,20.33,12.03.
Example 95: synthesis of Compound 19
The method comprises the following steps: synthesis of diethyl (4-nitrophenyl) phosphate (18)
4-Nitrophenol (1.82g, 13.09mmol) was dissolved in anhydrous DCM (25mL) and cooled to 0 ℃. Compound 17(1.5mL, 14.40mmol) was added to the above solution followed by the slow addition of triethylamine (2.0mL, 14.40 mmol). The reaction solution is heated to room temperature and stirred for reaction for 3 hours. The solvent was distilled off under reduced pressure, and column chromatography purification was performed to give compound 18(1.6g, 42%).1H NMR(500MHz,Chloroform-d)8.01–7.94(m,2H),7.53–7.47(m,2H),4.57(d,J＝7.4Hz,1H),4.09–4.00(m,1H),3.73–3.66(m,6H),1.36(d,J＝6.8Hz,3H).
Step two: 2- ((16 gamma)3Synthesis of (hexadecyl) oxy) ethyl (4-nitrophenyl) phosphate (19)
Compound 18(1.6g, 5.82mmol) was suspended in anhydrous DCM (20mL) and trimethylsilyl bromide (5.6g, 34.92mmol) was added to the above solution under nitrogen and stirred at room temperature for 24 h. The reaction was then concentrated under vacuum to remove excess solvent and trimethyl bromosilane. The residue was then redissolved in anhydrous DCM, cooled to room temperature, a catalytic amount of DMF was added, oxalyl chloride (3mL, 34.92mmol) dissolved in anhydrous DCM (5mL) was slowly added dropwise to the solution, and the reaction was stirred for 6 h. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was redissolved in ether (20 mL). A solution of cetyl alcohol (1.0g, 4.16mmol) and pyridine (2mL) in ether was added slowly to the above solution and monitored by TLC until the reaction was complete. To the reaction solution was added a cold saturated sodium bicarbonate solution, and the mixture was stirred for 1 hour. After hydrolysis was completed, the organic layer was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 19(606mg, 30%)
Example 96: synthesis of Compound S89
2- (((R) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethyl (2- (hexadecyloxy) ethyl) phosphate
Acetonitrile (15mL) was added to compound 2(1g, 3.03mmol), compound 19(1.8g, 3.65mmol) and magnesium chloride (288mg, 3.30mmol) at room temperature, the reaction solution was warmed to 70 ℃, stirred for 10min, DIPEA (1.3mL, 7.58mmol) was added, stirring was continued for 1h, the reaction was stopped, ethyl acetate (80mL) was added to dilute the reaction solution, the organic phase was washed with 5% diluted citric acid (40mL), saturated ammonium chloride (40mL), saturated potassium carbonate (2 × 40mL), saturated saline (40mL), dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and then purified by column chromatography to give compound S89(1.1g, 52%).1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.2Hz,1H),7.80(d,J＝8.4Hz,1H),7.26(dd,J＝8.4,2.2Hz,1H),7.08(d,J＝5.5Hz,1H),4.45(d,J＝9.3Hz,1H),4.19–3.95(m,4H),3.75(dt,J＝12.4,6.2Hz,1H),3.67(dt,J＝12.4,6.2Hz,1H),3.61–3.45(m,2H),3.40(dt,J＝11.9,6.1Hz,1H),3.08(dt,J＝12.9,6.4Hz,1H),2.90(dt,J＝12.9,6.4Hz,2H),2.69–2.55(m,3H),2.58–2.52(m,1H),1.66–1.40(m,6H),1.41–1.28(m,2H),1.32–1.20(m,24H),1.13(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H),0.94–0.84(m,3H).13CNMR(125MHz,DMSO-d6)145.91,145.86,143.93,131.40,127.27,124.44,123.63,123.18,99.57,71.55,70.42,70.37,66.12,66.07,63.87,63.82,54.33,54.05,54.01,48.27,47.56,31.99,31.56,30.06,29.98,29.97,29.94,29.92,29.84,29.81,29.79,29.78,29.64,29.45,26.24,24.32,22.75,20.33,14.10,12.03.
The synthesis methods of the compounds S90 to S92 in the following examples 97 to 99 were the same as the synthesis method of the compound S89, and only the corresponding raw materials were replaced.
Example 97: synthesis of Compound S90
2- (((S) -4- ((7-chloroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethyl (2- (hexadecyloxy) ethyl) phosphate
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.5Hz,1H),7.86(d,J＝2.2Hz,1H),7.80(d,J＝8.4Hz,1H),7.26(dd,J＝8.4,2.2Hz,1H),7.08(d,J＝5.5Hz,1H),4.45(d,J＝9.3Hz,1H),4.19–3.95(m,4H),3.75(dt,J＝12.4,6.2Hz,1H),3.67(dt,J＝12.4,6.2Hz,1H),3.61–3.45(m,2H),3.40(dt,J＝11.9,6.1Hz,1H),3.08(dt,J＝12.9,6.4Hz,1H),2.90(dt,J＝12.9,6.4Hz,2H),2.69–2.55(m,3H),2.58–2.52(m,1H),1.66–1.40(m,6H),1.41–1.28(m,2H),1.32–1.20(m,24H),1.13(d,J＝6.2Hz,3H),1.07(t,J＝7.2Hz,3H),0.94–0.84(m,3H).13C NMR(125MHz,DMSO-d6)145.91,145.86,143.93,131.40,127.27,124.44,123.63,123.18,99.57,71.55,70.42,70.37,66.12,66.07,63.87,63.82,54.33,54.05,54.01,48.27,47.56,31.99,31.56,30.06,29.98,29.97,29.94,29.92,29.84,29.81,29.79,29.78,29.64,29.45,26.24,24.32,22.75,20.33,14.10,12.03.
Example 98: synthesis of Compound S91
2- (((R) -4- ((7-Fluoroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethyl (2- (hexadecyloxy) ethyl) phosphate
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.7Hz,1H),8.12(dd,J＝8.4,4.9Hz,1H),7.54(dd,J＝8.0,2.3Hz,1H),7.17(td,J＝8.2,2.3Hz,1H),7.01(d,J＝5.6Hz,1H),4.19–3.95(m,4H),3.76–3.61(m,2H),3.63–3.52(m,1H),3.55–3.45(m,1H),3.40(dt,J＝11.9,6.1Hz,1H),3.04(dt,J＝12.9,6.5Hz,1H),2.71(dq,J＝11.9,7.2Hz,1H),2.68–2.54(m,2H),2.52–2.41(m,2H),1.68(dp,J＝13.0,6.5Hz,2H),1.61–1.49(m,3H),1.53–1.43(m,2H),1.46–1.20(m,28H),1.14(d,J＝6.2Hz,2H),1.07(t,J＝7.2Hz,3H),0.93–0.84(m,3H).13C NMR(125MHz,DMSO-d6)162.80,160.79,146.90,145.31,143.79,143.73,124.01,123.94,122.74,122.72,114.42,114.26,112.89,112.73,99.57,71.55,70.42,70.37,66.12,66.07,63.87,63.82,54.33,54.05,54.01,48.27,47.56,32.00,31.56,30.06,29.98,29.97,29.94,29.92,29.84,29.81,29.79,29.78,29.64,29.45,26.24,24.32,22.75,20.35,14.10,12.03.
Example 99: synthesis of Compound S92
2- (((S) -4- ((7-Fluoroquinolin-4-yl) amino) pentyl) (ethyl) amino) ethyl (2- (hexadecyloxy) ethyl) phosphate
1H NMR(300MHz,DMSO-d6)8.48(d,J＝5.7Hz,1H),8.12(dd,J＝8.4,4.9Hz,1H),7.54(dd,J＝8.0,2.3Hz,1H),7.17(td,J＝8.2,2.3Hz,1H),7.01(d,J＝5.6Hz,1H),4.19–3.95(m,4H),3.76–3.61(m,2H),3.63–3.52(m,1H),3.55–3.45(m,1H),3.40(dt,J＝11.9,6.1Hz,1H),3.04(dt,J＝12.9,6.5Hz,1H),2.71(dq,J＝11.9,7.2Hz,1H),2.68–2.54(m,2H),2.52–2.41(m,2H),1.68(dp,J＝13.0,6.5Hz,2H),1.61–1.49(m,3H),1.53–1.43(m,2H),1.46–1.20(m,28H),1.14(d,J＝6.2Hz,2H),1.07(t,J＝7.2Hz,3H),0.93–0.84(m,3H).13C NMR(125MHz,DMSO-d6)162.80,160.79,146.90,145.31,143.79,143.73,124.01,123.94,122.74,122.72,114.42,114.26,112.89,112.73,99.57,71.55,70.42,70.37,66.12,66.07,63.87,63.82,54.33,54.05,54.01,48.27,47.56,32.00,31.56,30.06,29.98,29.97,29.94,29.92,29.84,29.81,29.79,29.78,29.64,29.45,26.24,24.32,22.75,20.35,14.10,12.03.
Example 100: test experiment for cytotoxicity and anti-influenza virus drug effect of test compound
Test compound cytotoxicity assay: the cytotoxic effect of the compound on Vero cells is detected by adopting an MTT method, which is also called as an MTT colorimetric method and is a method for detecting the survival and growth of the cells. MTT (yellow thiazole blue) can penetrate through cell membranes to enter cells, amber dehydrogenase in mitochondria of living cells can enable exogenous MTT to be reduced into water-insoluble needle-shaped Formazan crystals and deposited in the cells, the crystals can be dissolved by dimethyl sulfoxide (DMSO), an enzyme linked immunosorbent detector is used for detecting the light absorption value at the wavelength of 490nm/570nm, and the quantity of the living cells can be indirectly reflected.
1) Inoculating Vero cells into a 96-well plate, and adding 100 mu L of cell suspension into each well; the number of cells per well was about 100000 cells in 5% CO2Incubating and culturing at 37 ℃ for 24 h;
2) setting drug concentration gradient, setting 3 multiple wells for each concentration gradient, diluting the drug into corresponding culture medium to desired final concentration, sucking out original culture medium in 96-well plate, adding prepared culture medium containing drug with desired final concentration 100 μ L in 5% CO2Incubating at 37 ℃; simultaneously setting a blank group (only containing 100 mu L of culture medium, no cells and the same subsequent treatment as other wells) and a control group hydroxychloroquine (containing cells and culture medium);
3) 10 μ L of MTT solution (5mg/ml) was added to each well at 44 hours of drug treatment and incubation was continued for 4h (48 hours total drug treated cells);
4) the well was aspirated to remove the medium (if the cells were suspended, the medium was aspirated after centrifugation at 2500rpm for 5 min). Add 150. mu.L of DMSO to each well and shake until the crystals are fully dissolved. Detecting the light absorption value of each hole at OD 490nm on an enzyme-labeling instrument;
5) calculating an inhibition rate: the inhibition ratio is 1- (the OD value of the drug addition agent-the OD value of the blank group)/(the OD value of the control group-the OD value of the blank group) — (the OD value of the control group-the OD value of the drug addition agent)/(the OD value of the control group-the OD value of the blank group);
6) IC calculation Using Graphpad software50A value;
the anti-influenza activity of the compound to be tested is determined by a plaque inhibition method, and the specific operation steps are as follows:
1) vero cells were seeded in 96-well plates (5 × 10)5Cells/well) at 5% CO2Incubating overnight at 37 ℃;
2) the influenza virus strain A/PR/8/34 is diluted to 100PFU/mL virus solution by adopting a serum-free culture medium, the virus solution (0.5 mL/hole) is added into a 96-hole plate, and Vero cells are infected for 1 h;
3) after completion of inoculation and adsorption, the virus culture was discarded and the cells were washed 1 time with PBS (pH 7.2);
3) to a 96-well plate, 80% agar, 1% bovine serum albumin and 3 μ g/mL acetyl trypsin as well as an EMEM medium were added to dilute to desired concentrations of test compound and positive control hydroxychloroquine (8 concentrations were set, 3 duplicate wells per concentration), and additionally, virus control wells (virus-infected cells, no test compound) and normal cell wells (normal cells, no test compound) were set. After the mixture is completely condensed, turning over the mixture up and down, and culturing for 72 h;
4) removing agarose after the culture is finished, and fixing the cell layer for 3min by using 70% ethanol at room temperature; removing ethanol, adding 1mL of crystal violet coloring agent, and dyeing at room temperature for 5 min; removing the crystal violet stain and washing the cells twice with PBS; the number of plaques was then calculated. The plaque inhibition was expressed as a percentage compared to the control against the virus;
5) using GraphPad software with EC50A value;
6) the final Selection Index (SI), SI ═ IC, of the compound was calculated50/EC50；
Specific experimental results are shown in table 1, and the example compounds have low cytotoxicity, good inhibitory activity against influenza virus infection, and good selection index;
TABLE 1 cytotoxicity, anti-influenza Activity and selection index
Example 101: activity assay against novel coronavirus (COVID-19)
The specific operation steps of the activity detection of the novel coronavirus resistant test compound are as follows:
1) vero cells were seeded in 96-well plates (5 × 10)4Cells/well) at 5% CO2Incubating overnight at 37 ℃;
2) adding a novel coronavirus (2019n-Cov) (MOI is 0.05) into a 96-well plate, infecting Vero cells for 2h, and discarding virus liquid;
3) adding a test compound containing a culture medium diluted to a required concentration and hydroxychloroquine of a positive control group into a 96-well plate, setting 8 concentrations, each concentration being 3 multiple wells, and additionally setting a virus control well (cells infected with virus and not containing the test compound) and a normal cell well (normal cells and not containing the test compound); after continuing culturing for 48h, collecting cell supernatant, adopting a lysis buffer solution for lysis, and using the lysis buffer solution for subsequent qRT-PCR determination of RNA copy number;
4) collecting 100. mu.L cell supernatant, and extracting virus RNA according to MiniBEST virus RNA/DNA extraction kit instructions; RNA was eluted using RNase-free water. Reverse transcription was performed using PrimeScript RTReagent kit containing gDNA Eraser, and qRT-PCR was performed using StepOne Plus Real-time PCR system and TB Green PremixEx Taq II.
5) Removing genome DNA in 3 mu L of total RNA by using gDNA scanner, and then synthesizing first strand cDNA in 20 mu L of reaction solution, wherein 2 mu L of cDNA is used as a template for quantitative PCR; using cDNA as a template, and adopting primers used for PCR amplification of a receptor domain of the Spike gene: RBD-F:
5 '-GCTCCATGGCCTAATATTACAAACTTGTGCC 3', RBD-R: 5'-TGCTCTAGACTCAAGTGTCTGTGGATCAC-3', then cloning into pMT/BiP/V5-His vector, and using the vector as plasmid standard after sequencing confirmation;
6) the primer of the quantitative PCR is RBD-qF1: 5'-CAATGGTTTAACAGGCACAGG-3', RBD-qR1:5 ' -CTCAAGTGTCTGTGGATCACG-3; reaction conditions are as follows: pre-denaturation at 95 ℃ for 5min, denaturation at 95 ℃ for 15s, annealing at 54 ℃ for 15s, extension at 72 ℃ for 30s, and reaction cycle number of 40 Cycles;
7) calculating copy number according to standard curve, and calculating EC by GraphPad software50A value;
8) the final Selection Index (SI) of the compound, SI ═ EC, was calculated50/IC50；
Specific experimental results are shown in table 2, and the example compounds have low cytotoxicity, good inhibitory activity on new coronavirus pneumonia and good selection index;
TABLE 2 cytotoxicity, anti-novel coronavirus pneumonia Activity and selection index of test Compounds
Sequence listing
<110> Han Hai New Tuo (Hangzhou) biological medicine Co Ltd
<120> quinoline compound, preparation method, pharmaceutical composition and application thereof
<130>126-2005026IPU
<150>CN202010441916.6
<151>2020-05-22
<160>4
<170>SIPOSequenceListing 1.0
<210>1
<211>3
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<220>
<223>5’-GCTCCATGGCCTAATATTACAAACTTGTGCC3’
<400>1
<210>2
<211>3
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<220>
<223>5’-TGCTCTAGACTCAAGTGTCTGTGGATCAC-3’
<400>2
<210>3
<211>3
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<220>
<223>5’-CAATGGTTTAACAGGCACAGG-3’
<400>3
<210>4
<211>3
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<220>
<223>5’-CTCAAGTGTCTGTGGATCACG-3
<400>4
Claims (12)
1. A compound of formula I, a pharmaceutically acceptable salt thereof, or a metabolite thereof,
wherein X is O or NH;
y is O or NH;
R1is hydroxy, halogen, cyano, unsubstituted or R1-1Substituted C1-6Alkyl, unsubstituted or R1-2Substituted C1-6Alkoxy radical, C3-10Cycloalkyl, -NR1-3R1-4、-(C＝O)R1-5、-(C＝O)OR1-6、-(C＝O)NR1-7R1-8、-S(＝O)2NR1-9R1-10or-O (C ═ O) R1-11；
R1-1Is halogen;
R1-2is halogen;
R1-3～R1-11independently selected from hydrogen or C1-4An alkyl group;
R2is C1-6An alkyl group;
R3is hydrogen, C1-18Alkoxy radical- (C1-6Alkyl) -, unsubstituted or R3-1Substituted C1-6Alkyl, unsubstituted or R3-2Substituted C6-10Aryl radical, R3-3(C＝O)OCH2-、R3-4(C＝O)SCH2CH2-、
R3-1Is halogen or hydroxy;
R3-2is deuterium, halogen, hydroxy, cyano, nitro, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, -NR3-2-1R3-2-2、-(C＝O)NR3-2-3R3-2-4、-S(＝O)2NR3-2-5R3-2-6、-(C＝O)R3-2-7OR, - (C ═ O) OR3-2-8or-O (C ═ O) R3-2-9；
R3-2-1～R3-2-9Independently selected from hydrogen or C1-4An alkyl group;
R3-3、R3-4and R3-5Independently selected from C1-6Alkyl or C1-6An alkoxy group;
R3-6is C1-6An alkyl group;
R3-7is hydrogen or halogen;
R3-8is C1-8Alkyl or benzyl;
R3-9is unsubstituted or R3-9-1Substituted C1-6Alkyl radical, C1-6alkoxy-C1-6Alkyl, or, NR3-9-2R3-9-3-(C1-6Alkyl) -;
R3-9-1is hydroxy, halogen or C1-4An alkyl group;
R3-9-2and R3-9-3Independently selected from hydrogen or C1-4An alkyl group;
R3-10is hydrogen or C1-6An alkyl group;
R3-11is C1-6An alkyl group;
R3-12is C1-6An alkyl group;
n is an integer of 1-6;
R4is hydrogen, unsubstituted or R4-1Substituted C1-6Alkyl, unsubstituted or R4-2Substituted C6-10Aryl radical, R4-3(C＝O)OCH2-、R4-4(C＝O)SCH2CH2-、
R4-1Is halogen or hydroxy;
R4-2is deuterium, halogen, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl or C1-4A haloalkoxy group;
R4-3、R4-4and R4-5Independently selected from C1-6Alkyl or C1-6An alkoxy group;
R4-6is C1-6An alkyl group;
R4-7is hydrogen or halogen;
R4-8is hydrogen, C1-8Alkyl or benzyl;
R4-9is unsubstituted or R4-9-1Substituted C1-6Alkyl radical, C1-6alkoxy-C1-6Alkyl or NR4-9-2R4-9-3-(C1-6Alkyl) -;
R4-9-1is hydroxy, halogen or C1-4Alkyl groups of (a);
R4-9-2and R4-9-3Independently selected from hydrogen or C1-4Alkyl groups of (a);
R5is hydrogen, unsubstituted or R5-1Substituted C1-6Alkyl, or C3-10A cycloalkyl group;
R5-1is hydroxy, halogen, amino or cyano;
optionally, the compound of formula I is in a stereoisomeric form.
2. The compound of formula I, a pharmaceutically acceptable salt thereof, or a metabolite thereof according to claim 1, wherein R is when X is O3Is hydrogen, C1-18Alkoxy radical- (C1-6Alkyl) -, unsubstituted or R3-1Substituted C1-6Alkyl, unsubstituted or R3-2Substituted C6-10Aryl radical, R3-3(C＝O)OCH2-、R3-4(C＝O)SCH2CH2-、
Or, when X is NH, R3Is composed of
And/or, when Y is O, R4Is hydrogen, unsubstituted or R4-1Substituted C1-6Alkyl, unsubstituted or R4-2Substituted C6-10Aryl radical, R4-3(C＝O)OCH2-、R4-4(C＝O)SCH2CH2-、
Or, when Y is NH, R4Is composed of
And/or when R1When the halogen is fluorine, chlorine, bromine or iodine;
and/or when R1Is unsubstituted or R1-1Substituted C1-6When it is alkyl, said R1-1Is one or more, when there are more than one R1-1When R is said1-1The same or different;
and/or when R1Is unsubstituted or R1-1Substituted C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R1Is unsubstituted or R1-2Substituted C1-6At alkoxy, said R1-2Is one or more, when there are more than one R1-2When R is said1-2The same or different;
and/or when R1Is unsubstituted or R1-2Substituted C1-6At alkoxy, said C1-6Alkoxy is C1-4An alkoxy group;
and/or when R1Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl being C3-6A cycloalkyl group;
and/or when R1-1When the halogen is fluorine, chlorine, bromine or iodine;
and/or when R1-2When the halogen is fluorine, chlorine, bromine or iodine;
and/or when R1-3Is C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, propyl, butyl or isopropyl;
and/or when R1-4Is C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, propyl, butyl or isopropyl;
and/or when R2Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R3Is C1-18Alkoxy radical C1-6When alkyl, said C1-18Alkoxy radical C1-6Alkyl is CH3(CH2)15O-(C1-4Alkyl) -;
and/or when R3Is unsubstituted or R3-1Substituted C1-6When it is alkyl, said R3-1Is one or more, when there are more than one R3-1When R is said3-1The same or different;
and/or when R3Is unsubstituted or R3-1Substituted C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R3Is unsubstituted or R3-2Substituted C6-10When aryl is said to R3-2Is one or more, when there are more than one R3-2When R is said3-2The same or different;
and/or when R3Is unsubstituted or R3-2Substituted C6-10When aryl, said C6-10Aryl is phenyl or naphthyl;
and/or when R3-1When the halogen is fluorine, chlorine, bromine or iodine;
and/or when R3-2When it is halogen, said halogen is fluorineChlorine, bromine or iodine;
and/or when R3-2Is C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, propyl, butyl or isopropyl;
and/or when R3-2Is C1-4When halogenated alkyl, said C1-4Haloalkyl is-CF3；
And/or when R3-2Is C1-4At alkoxy, said C1-4Alkoxy is methoxy, ethoxy, propoxy, butoxy or isopropoxy;
and/or when R3-2Is C1-4When halogenated alkoxy, said C1-4haloalkoxy-OCF3；
And/or when R3-2-1～R3-2-9Independently is C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, propyl, isopropyl or butyl;
and/or when R3-3、R3-4And R3-5Independently selected from C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R3-3、R3-4And R3-5Independently selected from C1-6At alkoxy, said C1-6Alkoxy is C1-4An alkoxy group;
and/or when R3-6Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R3-7When halogen is used, the halogen is fluorine, chlorine, bromine or iodine;
and/or when R3-8Is C1-8When alkyl, said C1-8Alkyl is C1-6An alkyl group;
and/or when R3-9Is unsubstituted or R3-9-1Substituted C1-6When it is alkyl, said R3-9-1Is one or more, when there are more than one R3-9-1When R is said3-9-1The same or different;
and/or when R3-9Is unsubstituted or R3-9-1Substituted C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R3-9Is C1-6alkoxy-C1-6When alkyl, said C1-6alkoxy-C1-6Alkyl is C1-4alkoxy-C1-4An alkyl group;
and/or when R3-9Is NR3-9-2R3-9-3-(C1-6Alkyl) -, said NR3-9-2R3-9-3-(C1-6Alkyl) -is NR3-9-2R3 -9-3-(C1-4Alkyl) -;
and/or when R3-9-1Is C1-4When alkyl, said C1-4Alkyl is methyl, ethyl or propyl;
and/or when R3-9-2And R3-9-3Independently selected from C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, isopropyl, propyl or butyl;
and/or when R3-10Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R3-11Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R3-12Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R4Is unsubstituted or R4-1Substituted C1-6When it is alkyl, said R4-1Is one or more, when there are more than one R4-1When R is said4-1The same or different;
and/or when R4Is unsubstituted or R4-1Substituted C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R4-1When the halogen is fluorine, chlorine, bromine or iodine;
and/or whenR4Is unsubstituted or R4-2Substituted C6-10When aryl is said to R4-2Is one or more, when there are more than one R4-2When R is said4-2The same or different;
and/or when R4Is unsubstituted or R4-2Substituted C6-10When aryl, said C6-10Aryl is phenyl;
and/or when R4-2When the halogen is fluorine, chlorine, bromine or iodine;
and/or when R4-2Is C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, propyl, butyl or isopropyl;
and/or when R4-2Is C1-4When halogenated alkyl, said C1-4Haloalkyl is-CF3；
And/or when R4-2Is C1-4At alkoxy, said C1-4Alkoxy is methoxy, ethoxy, propoxy, butoxy or isopropoxy;
and/or when R4-2Is C1-4When halogenated alkoxy, said C1-4haloalkoxy-OCF3；
And/or when R4-3、R4-4And R4-5Independently selected from C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R4-3、R4-4And R4-5Independently selected from C1-6At alkoxy, said C1-6Alkoxy is C1-4An alkoxy group;
and/or when R4-6Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R4-7When halogen is used, the halogen is fluorine, chlorine, bromine or iodine;
and/or when R4-8Is C1-8When alkyl, said C1-8Alkyl is C1-6An alkyl group;
and/or when R4-9Is unsubstituted or R4-9-1Substituted C1-6When it is alkyl, said R4-9-1Is one or more, when there are more than one R4-9-1When R is said4-9-1The same or different;
and/or when R4-9Is unsubstituted or R4-9-1Substituted C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R4-9Is C1-6alkoxy-C1-6When alkyl, said C1-6alkoxy-C1-6Alkyl is C1-4alkoxy-C1-4An alkyl group;
and/or when R4-9Is NR4-9-2R4-9-3-(C1-6Alkyl) -, said NR4-9-2R4-9-3-(C1-6Alkyl) -is NR4-9-2R4 -9-3-(C1-4Alkyl) -;
and/or when R4-9-1Is C1-4When alkyl, said C1-4Alkyl is methyl, ethyl or propyl;
and/or when R4-9-2And R4-9-3Independently selected from C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, isopropyl, propyl or butyl;
and/or when R5Is unsubstituted or R5-1Substituted C1-6When it is alkyl, said R5-1Is one or more, when there are more than one R5-1When R is said5-1The same or different;
and/or when R5Is unsubstituted or R5-1Substituted C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R5-1When the halogen is fluorine, chlorine, bromine or iodine;
and/or when R5Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl being C3-6A cycloalkyl group.
3. The compound of formula I, a pharmaceutically acceptable salt thereof, or a metabolite thereof according to claim 1, wherein when R is1Is unsubstituted or R1-1Substituted C1-6When it is alkyl, said R1-1The number of (a) is 1, 2 or 3;
and/or when R1Is unsubstituted or R1-1Substituted C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl;
and/or when R1Is unsubstituted or R1-2Substituted C1-6At alkoxy, said R1-21, 2 or 3;
and/or when R1Is unsubstituted or R1-2Substituted C1-6At alkoxy, said C1-6Alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butyloxy, sec-butoxy or tert-butoxy;
and/or when R1Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
and/or when R1is-NR1-3R1-4When said is-NR1-3R1-4is-NH2Or (b) or (c),
And/or when R2Is C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, butyl, isopropyl, isobutyl or sec-butyl;
and/or when R3Is C1-18Alkoxy radical- (C1-6Alkyl) -said C1-18Alkoxy radical C1-6Alkyl is CH3(CH2)15O-CH2CH2-, or, CH3(CH2)15O-CH2CH2CH2-；
And/or whenR3Is unsubstituted or R3-1Substituted C1-6When it is alkyl, said R3-1The number of (a) is 1, 2 or 3;
and/or when R3Is unsubstituted or R3-1Substituted C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl or tert-butyl;
and/or when R3Is unsubstituted or R3-2Substituted C6-10When aryl is said to R3-2The number of (a) is 1, 2, 3 or 4;
and/or when R3-3、R3-4And R3-5Independently selected from C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl;
and/or when R3-3、R3-4And R3-5Independently selected from C1-6At alkoxy, said C1-6Alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy;
and/or when R3-6Is C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl or tert-butyl;
and/or when R3-7When halogen is used, the halogen is fluorine or chlorine;
and/or when R3-8Is C1-8When alkyl, said C1-8Alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or hexyl, preferably methyl, isopropyl, isobutyl, sec-butyl or hexyl;
and/or when R3-9Is unsubstituted or R3-9-1Substituted C1-6When it is alkyl, said R3-9-1The number of (a) is 1, 2 or 3;
and/or when R3-9Is unsubstituted or R3-9-1Substituted C1-6When alkyl, said C1-6Alkyl of (A) isMethyl, ethyl, propyl, butyl, isopropyl, or isobutyl;
and/or when R3-9Is C1-6alkoxy-C1-6When alkyl, said C1-6alkoxy-C1-6Alkyl is
And/or when R3-9Is NR3-9-2R3-9-3-(C1-6Alkyl) -, said NR3-9-2R3-9-3-(C1-6Alkyl) -is
And/or when R3-10Is C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl or butyl;
and/or when R3-11Is C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl or butyl;
and/or when R3-12Is C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl or butyl;
and/or when R4Is unsubstituted or R4-1Substituted C1-6When it is alkyl, said R4-1The number of (a) is 1, 2 or 3;
and/or when R4Is unsubstituted or R4-1Substituted C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl or tert-butyl;
and/or when R4Is unsubstituted or R4-2Substituted C6-10When aryl is said to R4-2The number of (a) is 1, 2, 3 or 4;
and/or when R4-3、R4-4And R4-5Independently selected from C1-6When alkyl, said C1-6The alkyl is methyl, ethyl, propyl, isopropyl or butylIsobutyl, sec-butyl or tert-butyl;
and/or when R4-3、R4-4And R4-5Independently selected from C1-6At alkoxy, said C1-6Alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy;
and/or when R4-6Is C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl or tert-butyl;
and/or when R4-7When halogen is used, the halogen is fluorine or chlorine;
and/or when R4-8Is C1-8When alkyl, said C1-8Alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or hexyl, preferably methyl, isopropyl, isobutyl, sec-butyl or hexyl;
and/or when R4-9Is unsubstituted or R4-9-1Substituted C1-6When it is alkyl, said R4-9-1The number of (a) is 1, 2 or 3;
and/or when R4-9Is unsubstituted or R4-9-1Substituted C1-6When alkyl, said C1-6Alkyl of (a) is methyl, ethyl, propyl, butyl, isopropyl or isobutyl;
and/or when R4-9Is C1-6alkoxy-C1-6When alkyl, said C1-6alkoxy-C1-6Alkyl is
And/or when R4-9Is NR4-9-2R4-9-3-(C1-6Alkyl) -, said NR4-9-2R4-9-3-(C1-6Alkyl) -is
And/or when R5Is unsubstituted or R5-1Substituted C1-6When it is alkyl, said R5-1The number of (a) is 1, 2 or 3;
and/or when R5Is unsubstituted or R5-1Substituted C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl;
and/or when R5Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
4. The compound of formula I, a pharmaceutically acceptable salt thereof, or a metabolite thereof according to claim 1, wherein when R is1Is unsubstituted or R1-1Substituted C1-6When it is alkyl, said R1-1Substituted C1-6Alkyl is-CF3；
And/or when R1Is unsubstituted or R1-2Substituted C1-6At alkoxy, said R1-2Substituted C1-6Alkoxy is-OCF3；
And/or when R3Is unsubstituted or R3-1Substituted C1-6When it is alkyl, said R3-1Substituted C1-6Alkyl is-CH2CCl3or-CH2CF3；
And/or when R3Is unsubstituted or R3-2Substituted C6-10When aryl is said to R3-2Substituted C6-10Aryl is
And/or when R3-9Is unsubstituted or R3-9-1Substituted C1-6When it is alkyl, said R3-9-1Substituted C1-6Alkyl is
And/or when R4Is unsubstituted or R4-1Substituted C1-6When it is alkyl, said R4-1Substituted C1-6Alkyl is-CH2CCl3or-CH2CF3；
And/or when R4Is unsubstituted or R4-2Substituted C6-10When aryl is said to R4-2Substituted C6-10Aryl is
And/or when R4-9Is unsubstituted or R4-9-1Substituted C1-6When it is alkyl, said R4-9-1Substituted C1-6Alkyl is
And/or when R5Is unsubstituted or R5-1Substituted C1-6When it is alkyl, said R5-1Substituted C1-6Alkyl is
And/or when R5Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
5. The compound of formula I, a pharmaceutically acceptable salt thereof, or a metabolite thereof, as claimed in claim 1, wherein R is1Is halogen, unsubstituted or R1-1Substituted C1-6Alkyl, unsubstituted or R1-2Substituted C1-6Alkoxy, or, -NR1- 3R1-4；
And/or, R3Is C1-18Alkoxy radical- (C1-6Alkyl) -, unsubstituted or R3-1Substituted C1-6Alkyl, unsubstituted or R3-2SubstitutionC of (A)6-10Aryl radical, R3-3(C＝O)OCH2-、R3-4(C＝O)SCH2CH2-、
And/or, R3-1Is halogen;
and/or, R3-2Is halogen, hydroxy, cyano, nitro, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, -NR3-2-1R3-2-2、-(C＝O)NR3-2-3R3-2-4、-S(＝O)2NR3-2-5R3-2-6、-(C＝O)R3-2-7OR, - (C ═ O) OR3 -2-8；
And/or, R3-2-3～R3-2-6Is hydrogen;
and/or, R3-2-7And R3-2-8Is C1-4An alkyl group;
and/or, R3-9-1Is a hydroxyl group;
and/or, R3-9-2And R3-9-3Independently selected from C1-4An alkyl group;
and/or, R4Is hydrogen, unsubstituted or R4-1Substituted C1-6Alkyl, unsubstituted or R4-2Substituted C6-10Aryl radical, R4-3(C＝O)OCH2-、R4-4(C＝O)SCH2CH2-、
And/or, R4-1Is halogen;
and/or, R4-2Is halogen, C1-4Alkoxy radical, C1-4Haloalkyl, or, C1-4A haloalkoxy group;
and/or, R5-1Is a hydroxyl group.
6. The compound of formula I, a pharmaceutically acceptable salt thereof, or a metabolite thereof according to claim 1, wherein the compound of formula I is according to any one of the following schemes:
the first scheme is as follows:
x is O or NH;
y is O or NH;
R1is halogen, unsubstituted or R1-1Substituted C1-6Alkyl, unsubstituted or R1-2Substituted C1-6Alkoxy, or, -NR1-3R1-4；
R1-1Is halogen;
R1-2is halogen;
R1-3is hydrogen or C1-4An alkyl group;
R1-4is hydrogen or C1-4An alkyl group;
R2is C1-6An alkyl group;
R3is hydrogen, C1-18Alkoxy radical- (C1-6Alkyl) -, unsubstituted or R3-1Substituted C1-6Alkyl, unsubstituted or R3-2Substituted C6-10Aryl radical, R3-3(C＝O)OCH2-、R3-4(C＝O)SCH2CH2-、
R3-1Is halogen;
R3-2is halogen, hydroxy, cyano, nitro, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, -NR3 -2-1R3-2-2、-(C＝O)NR3-2-3R3-2-4、-S(＝O)2NR3-2-5R3-2-6、-(C＝O)R3-2-7OR, - (C ═ O) OR3-2-8；
R3-2-1And R3-2-2Independently is hydrogen or C1-4An alkyl group;
R3-2-3～R3-2-6is hydrogen;
R3-2-7and R3-2-8Independently is C1-4An alkyl group;
R3-3、R3-4and R3-5Independently selected from C1-6Alkyl or C1-6An alkoxy group;
R3-8is C1-8Alkyl or benzyl;
R3-9is unsubstituted or R3-9-1Substituted C1-6Alkyl radical, C1-6alkoxy-C1-6Alkyl, or, NR3-9-2R3-9-3-(C1-6Alkyl) -;
R3-9-1is a hydroxyl group;
R3-9-2and R3-9-3Independently selected from C1-4An alkyl group;
R3-10is hydrogen or C1-6An alkyl group;
R3-11is C1-6An alkyl group;
R3-12is C1-6An alkyl group;
n is an integer of 1-6;
R4is hydrogen, unsubstituted or R4-1Substituted C1-6Alkyl, unsubstituted or R4-2Substituted C6-10Aryl radical, R4-3(C＝O)OCH2-、R4-4(C＝O)SCH2CH2-、
R4-1Is halogen;
R4-2is halogen, C1-4Alkoxy radical, C1-4Haloalkyl, or, C1-4A haloalkoxy group;
R4-3、R4-4and R4-5Independently selected from C1-6Alkyl or C1-6An alkoxy group;
R4-8is C1-8Alkyl or benzyl;
R4-9is not takenSubstituted C1-6An alkyl group;
R5is hydrogen, unsubstituted or R5-1Substituted C1-6Alkyl, or, C3-10A cyclopropyl group;
R5-1is a hydroxyl group;
or, scheme two:
x is O or NH;
y is O or NH;
R1is halogen, or unsubstituted or R1-1Substituted C1-6An alkyl group;
R1-1is halogen;
R2is C1-6An alkyl group;
R3is hydrogen, C1-18Alkoxy radical- (C1-6Alkyl) -, unsubstituted or R3-1Substituted C1-6Alkyl, unsubstituted or R3-2Substituted C6-10Aryl radical, R3-3(C＝O)OCH2-、R3-4(C＝O)SCH2CH2-、
R3-1Is halogen;
R3-2is halogen, cyano, nitro, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, - (C ═ O) NR3-2-3R3-2-4、-S(＝O)2NR3-2-5R3-2-6、-(C＝O)R3-2-7OR, - (C ═ O) OR3-2-8；
R3-2-3～R3-2-6Is hydrogen;
R3-2-7and R3-2-8Independently is C1-4An alkyl group;
R3-3、R3-4and R3-5Independently selected from C1-6Alkyl or C1-6An alkoxy group;
R3-8is C1-8Alkyl or benzyl;
R3-9is unsubstituted or R3-9-1Substituted C1-6Alkyl radical, C1-6alkoxy-C1-6Alkyl, or, NR3-9-2R3-9-3-(C1-6Alkyl) -;
R3-9-1is a hydroxyl group;
R3-9-2and R3-9-3Independently selected from C1-4An alkyl group;
R3-10is hydrogen or C1-6An alkyl group;
R3-11is C1-6An alkyl group;
R3-12is C1-6An alkyl group;
n is an integer of 1-6;
R4is hydrogen, unsubstituted or R4-1Substituted C1-6Alkyl, unsubstituted or R4-2Substituted C6-10Aryl radical, R4-3(C＝O)OCH2-、R4-4(C＝O)SCH2CH2-、
R4-1Is halogen;
R4-2is halogen, C1-4Alkoxy radical, C1-4Haloalkyl, or, C1-4A haloalkoxy group;
R4-3、R4-4and R4-5Independently selected from C1-6Alkyl or C1-6An alkoxy group;
R4-8is C1-8Alkyl or benzyl;
R4-9is unsubstituted C1-6An alkyl group;
R5is hydrogen or unsubstituted C1-6An alkyl group.
7. The compound of formula I, a pharmaceutically acceptable salt thereof, or a metabolite thereof according to any one of claims 1-6, having the structure:
wherein, X, Y, R1、R2、R3、R4And R5Is as defined in any one of claims 1 to 6.
8. The compound of formula I, a pharmaceutically acceptable salt thereof, or a metabolite thereof according to claim 1, wherein the compound of formula I is any one of the following compounds:
9. a process for the preparation of a compound of formula I, a pharmaceutically acceptable salt thereof, or a metabolite thereof as claimed in any one of claims 1 to 8, comprising the steps of: carrying out substitution reaction on a compound shown as a formula II and a compound shown as a formula III under the action of alkali in a solvent;
wherein, X, Y, R1、R2、R3、R4And R5As defined in any one of claims 1 to 8.
10. A pharmaceutical composition comprising a compound of formula I, a pharmaceutically acceptable salt thereof, or a metabolite thereof, as claimed in any one of claims 1-8, and a pharmaceutically acceptable adjuvant.
11. Use of a compound of general formula I, a pharmaceutically acceptable salt thereof, or a metabolite thereof, as claimed in any one of claims 1 to 8, or a pharmaceutical composition as claimed in claim 10, in the manufacture of a medicament for the prophylaxis or treatment of a viral infection.
12. The use of claim 11, wherein the virus is middle east syndrome-associated coronavirus (MERS-CoV), severe acute respiratory syndrome-associated coronavirus (SARS-CoV), influenza a virus, influenza b virus, novel coronavirus pneumonia (covi-19), rabies virus, poliovirus, aids virus, hepatitis a virus, hepatitis c virus, influenza a A H5N1 virus, chikungunya disease, dengue virus, zika virus, lassa virus, congo hemorrhagic fever virus, ebola virus, hepatitis b virus, or herpes simplex virus.
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| US20060040879A1 (en) * | 2004-08-21 | 2006-02-23 | Kosak Kenneth M | Chloroquine coupled nucleic acids and methods for their synthesis |
| CN1829694A (en) * | 2003-07-28 | 2006-09-06 | 阿斯利康(瑞典)有限公司 | Quinoline derivates and their use in therapy |
| CN101374804A (en) * | 2005-12-15 | 2009-02-25 | 阿斯利康(瑞典)有限公司 | Substituted diphenylethers, -amines, -sulfides and -methanes for the treatment of respiratory disease |
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| CN1829694A (en) * | 2003-07-28 | 2006-09-06 | 阿斯利康(瑞典)有限公司 | Quinoline derivates and their use in therapy |
| US20060040879A1 (en) * | 2004-08-21 | 2006-02-23 | Kosak Kenneth M | Chloroquine coupled nucleic acids and methods for their synthesis |
| CN101374804A (en) * | 2005-12-15 | 2009-02-25 | 阿斯利康(瑞典)有限公司 | Substituted diphenylethers, -amines, -sulfides and -methanes for the treatment of respiratory disease |
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| CN114249764A (en) * | 2021-11-10 | 2022-03-29 | 宁波大学 | Intermediate of phosphoramidate prodrug and preparation method and application thereof |
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