CN106132972B - 用于治疗hcv感染的氨基磷酸酯 - Google Patents
用于治疗hcv感染的氨基磷酸酯 Download PDFInfo
- Publication number
- CN106132972B CN106132972B CN201580000349.8A CN201580000349A CN106132972B CN 106132972 B CN106132972 B CN 106132972B CN 201580000349 A CN201580000349 A CN 201580000349A CN 106132972 B CN106132972 B CN 106132972B
- Authority
- CN
- China
- Prior art keywords
- phenoxy
- fluoro
- compound
- dihydropyrimidine
- phosphoryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 208000015181 infectious disease Diseases 0.000 title abstract description 9
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 118
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- -1 2-morpholinoacetoxy Chemical group 0.000 claims description 147
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 40
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 39
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 14
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 13
- PNHMBKXVXNJADT-UHFFFAOYSA-N 4-morpholin-4-ium-4-ylbutanoate Chemical compound OC(=O)CCCN1CCOCC1 PNHMBKXVXNJADT-UHFFFAOYSA-N 0.000 claims description 12
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 11
- PIJXRNNCIJAUOX-UHFFFAOYSA-N butanoic acid;hydrochloride Chemical compound Cl.CCCC(O)=O PIJXRNNCIJAUOX-UHFFFAOYSA-N 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 7
- YUYHRSGXZZVNMS-UHFFFAOYSA-N 3-morpholin-4-ylpropanoic acid Chemical compound OC(=O)CCN1CCOCC1 YUYHRSGXZZVNMS-UHFFFAOYSA-N 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims description 6
- 229910052698 phosphorus Inorganic materials 0.000 claims description 5
- 125000004437 phosphorous atom Chemical group 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- OIVBLJJLNWEDOU-UHFFFAOYSA-N 3-morpholin-4-ylpropanoic acid;hydrobromide Chemical compound Br.OC(=O)CCN1CCOCC1 OIVBLJJLNWEDOU-UHFFFAOYSA-N 0.000 claims description 2
- KBLUIEOCXFAGJQ-UHFFFAOYSA-N 4-morpholin-4-ylbutanoic acid;hydrobromide Chemical compound Br.OC(=O)CCCN1CCOCC1 KBLUIEOCXFAGJQ-UHFFFAOYSA-N 0.000 claims description 2
- GQWYWIYUQZVZAV-UHFFFAOYSA-N 4-morpholin-4-ylbutanoic acid;hydrochloride Chemical compound Cl.OC(=O)CCCN1CCOCC1 GQWYWIYUQZVZAV-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 2
- HIUZMRURQCPBET-UHFFFAOYSA-N S(C)(=O)(=O)O.N1(CCOCC1)CCCC(=O)O Chemical compound S(C)(=O)(=O)O.N1(CCOCC1)CCCC(=O)O HIUZMRURQCPBET-UHFFFAOYSA-N 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 239000011159 matrix material Substances 0.000 claims description 2
- 229960005475 antiinfective agent Drugs 0.000 claims 2
- 239000004599 antimicrobial Substances 0.000 claims 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 229940122604 HCV protease inhibitor Drugs 0.000 claims 1
- 229940124772 HCV-NS5B polymerase inhibitor Drugs 0.000 claims 1
- 101800001014 Non-structural protein 5A Proteins 0.000 claims 1
- 208000036142 Viral infection Diseases 0.000 claims 1
- 125000003710 aryl alkyl group Chemical group 0.000 claims 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims 1
- 239000002955 immunomodulating agent Substances 0.000 claims 1
- 229940121354 immunomodulator Drugs 0.000 claims 1
- 230000002584 immunomodulator Effects 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- 230000009385 viral infection Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 16
- 150000002148 esters Chemical class 0.000 abstract description 9
- 229940002612 prodrug Drugs 0.000 abstract description 3
- 239000000651 prodrug Substances 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 125000000217 alkyl group Chemical group 0.000 description 33
- 238000002360 preparation method Methods 0.000 description 30
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- VIWZVFVJPXTXPA-UHFFFAOYSA-N N-(2-Carboxymethyl)-morpholine Chemical compound OC(=O)CN1CCOCC1 VIWZVFVJPXTXPA-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 125000005842 heteroatom Chemical group 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 230000002194 synthesizing effect Effects 0.000 description 9
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 8
- 239000012981 Hank's balanced salt solution Substances 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 7
- 125000004104 aryloxy group Chemical group 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 150000002430 hydrocarbons Chemical class 0.000 description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 description 6
- 229960002063 sofosbuvir Drugs 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 125000006575 electron-withdrawing group Chemical group 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 4
- OXOWTLDONRGYOT-UHFFFAOYSA-M 4-(dimethylamino)butanoate Chemical compound CN(C)CCCC([O-])=O OXOWTLDONRGYOT-UHFFFAOYSA-M 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000002015 acyclic group Chemical group 0.000 description 3
- 229960003767 alanine Drugs 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 229930195734 saturated hydrocarbon Natural products 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 125000002103 4,4'-dimethoxytriphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)(C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H])C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- DMULVCHRPCFFGV-UHFFFAOYSA-N N,N-dimethyltryptamine Chemical compound C1=CC=C2C(CCN(C)C)=CNC2=C1 DMULVCHRPCFFGV-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000012317 TBTU Substances 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000005456 alcohol based solvent Substances 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 125000001769 aryl amino group Chemical group 0.000 description 2
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000013553 cell monolayer Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 230000005595 deprotonation Effects 0.000 description 2
- 238000010537 deprotonation reaction Methods 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 2
- 229960004801 imipramine Drugs 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 238000000386 microscopy Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- UHHKSVZZTYJVEG-UHFFFAOYSA-N oxepane Chemical compound C1CCCOCC1 UHHKSVZZTYJVEG-UHFFFAOYSA-N 0.000 description 2
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 2
- 150000008298 phosphoramidates Chemical class 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 230000005588 protonation Effects 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 description 1
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 1
- YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- APMLPUDURDVGTF-UHFFFAOYSA-N 2-pyrrolo[2,3-b]pyridin-1-ylethanamine Chemical compound C1=CN=C2N(CCN)C=CC2=C1 APMLPUDURDVGTF-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- XLZYKTYMLBOINK-UHFFFAOYSA-N 3-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C(=O)C=2C=CC(O)=CC=2)=C1 XLZYKTYMLBOINK-UHFFFAOYSA-N 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 1
- UIKUBYKUYUSRSM-UHFFFAOYSA-N 3-morpholinopropylamine Chemical compound NCCCN1CCOCC1 UIKUBYKUYUSRSM-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- OXOWTLDONRGYOT-UHFFFAOYSA-N 4-(dimethylamino)butanoic acid Chemical compound CN(C)CCCC(O)=O OXOWTLDONRGYOT-UHFFFAOYSA-N 0.000 description 1
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 description 1
- NMILGIZTAZXMTM-UHFFFAOYSA-N 4-propylmorpholine Chemical compound CCCN1CCOCC1 NMILGIZTAZXMTM-UHFFFAOYSA-N 0.000 description 1
- 125000003341 7 membered heterocyclic group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000003341 Bronsted base Substances 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 1
- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- AQZGPSLYZOOYQP-UHFFFAOYSA-N Diisoamyl ether Chemical compound CC(C)CCOCCC(C)C AQZGPSLYZOOYQP-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 108090000331 Firefly luciferases Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical compound CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 101100288143 Rattus norvegicus Klkb1 gene Proteins 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000003998 acyclic ketones Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 238000011095 buffer preparation Methods 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical group C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 125000001721 carboxyacetyl group Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- DMSZORWOGDLWGN-UHFFFAOYSA-N ctk1a3526 Chemical group NP(N)(N)=O DMSZORWOGDLWGN-UHFFFAOYSA-N 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 150000003997 cyclic ketones Chemical class 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- TXFOLHZMICYNRM-UHFFFAOYSA-N dichlorophosphoryloxybenzene Chemical compound ClP(Cl)(=O)OC1=CC=CC=C1 TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- MKZUDFZKTZOCRS-UHFFFAOYSA-N diphosphono hydrogen phosphate;1h-pyrimidine-2,4-dione Chemical class O=C1C=CNC(=O)N1.OP(O)(=O)OP(O)(=O)OP(O)(O)=O MKZUDFZKTZOCRS-UHFFFAOYSA-N 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- ROBXZHNBBCHEIQ-BYPYZUCNSA-N ethyl (2s)-2-aminopropanoate Chemical compound CCOC(=O)[C@H](C)N ROBXZHNBBCHEIQ-BYPYZUCNSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003870 intestinal permeability Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- XJGVXQDUIWGIRW-UHFFFAOYSA-N loxapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2OC2=CC=C(Cl)C=C12 XJGVXQDUIWGIRW-UHFFFAOYSA-N 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 229940078552 o-xylene Drugs 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- PJGSXYOJTGTZAV-UHFFFAOYSA-N pinacolone Chemical compound CC(=O)C(C)(C)C PJGSXYOJTGTZAV-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000012899 standard injection Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical group [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- 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
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
-
- 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
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Virology (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种式(I)化合物或其药学上可接受的盐、酯或其前药以及含有这类化合物的药物制剂。本发明也提供了使用此处提供的一个或多个化合物治疗HCV感染的方法。
Description
相关申请的交叉参考
本申请要求2015年2月6日提交的国际专利申请PCT/CN2015/072391的优先权。据此通过引用将上述申请的内容完整地并入。
发明背景
丙型肝炎病毒(HCV)感染是一个严重的健康问题，感染HCV会导致慢性肝脏疾病，如肝硬化和肝癌。HCV感染人群众多，据估计，约占全世界人口的2-15％。根据美国疾病控制中心估计，仅美国就有四百五十万感染者。按照世界卫生组织的统计，全世界有超过2亿的感染者，每年至少新增300万-400万感染者。在感染人群中，约 20％患者可以自动清除HCV病毒，但其余患者体内驻扎的HCV病毒将会伴随他们一生。10-20％的慢性感染者最终发展成肝硬化或肝癌。HCV疾病为非肠道传播，它通过污染的血液和血液制品、污染针头、性传播或直接由被感染或携带者母亲传播给其子女。当前用于HCV感染的治疗仅限于单独使用重组干扰素α或与核苷类似物利巴韦林联合的免疫疗法，但疗效有限。此外，还没有批准的HCV疫苗。因此，迫切需要能够有效治疗HCV感染的改进药物。本发明提供了一种有望满足该需求的化合物。
发明概述
本发明提供了一种式I化合物
其中，
R1是芳基或杂芳基；
每一个R2和R3独立地选自于氢、烷基、杂芳基，当R2和R3中的一个为氢或烷基时，另一个必须为杂芳基；或
R2、R3与它们相连的氮原子一起组成一个5‐7元的杂环，且可含有1‐2个除与 R2、R3相连的氮原子外的杂原子，所述的杂原子独立地选自于O、S或NR6；所述的R6为氢、烷基、酰基、芳基或杂芳基；所述的杂环可以在它的碳原子上被烷基、卤素或烷氧羰基取代；或
R4是氢或烷基；
R5是氢或烷基；
X是一个键、O、NH或N‐烷基；和
n是1、2、3或4。
在本发明的一方面，R1是芳基或杂芳基。例如，R1可以是苯基，所述苯基可被 1‐3个独立选自于卤素或烷基的取代基取代。
在本发明的一方面，R1是苯基或萘基。
在本发明的另一方面，R2是氢，R3是杂芳基。例如，R3可以是吡啶或异喹啉。R3的具体例子包括
在本发明的一方面，R2、R3与它们相连的氮原子一起组成一个5‐6元的杂环，且可含有1‐2个除与R2、R3相连的氮原子外的杂原子，所述的杂原子独立地选自于 O、S或NR6；所述的R6为氢、烷基或酰基；所述的杂环可以在它的碳原子上被1个或多个烷氧羰基取代；具体的例子中杂环可以是
在本发明的一方面，R2、R3与它们相连的氮原子一起组成一个取代或未取代的杂芳基；具体的例子中杂芳基可以是
在本发明的另一方面，R4是甲基或乙基。
在本发明的另一方面，R5是甲基、乙基或异丙基。
在本发明的另一方面，X是一个键、O、NH或N‐烷基。
在本发明的另一方面，磷原子是手性的，且至少有90％(如至少97％)的S立体异构体。
在本发明的另一方面，n是1、2、3或4。
在本发明的另一方面，本发明中的化合物是式I化合物药学上可接受的盐。这种盐的例子包括醋酸盐、4‐甲苯磺酸盐、氢溴酸盐或盐酸盐。
本发明中的化合物的具体例子包括但不限于，
((S)‐(((2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐4‐甲基‐3‐(2‐吗啡啉乙酰氧基)四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐L‐丙氨酸异丙酯；
((S)‐(((2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐4‐甲基‐3‐(2‐吗啡啉乙酰氧基)四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐L‐丙氨酸异丙酯4‐甲基苯磺酸盐；
(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位3‐吗啡啉丙酸酯；
(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位3‐吗啡啉丙酸酯 4‐甲基苯磺酸盐；
(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位4‐吗啡啉丁酸酯；
(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位4‐吗啡啉丁酸酯 4‐甲基苯磺酸盐；
(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位4‐(二甲基氨基)丁酸酯；
(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位4‐(吡啶‐2‐位氨基) 丁酸酯盐酸盐；
(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位4‐(异喹啉‐1‐位氨基)丁酸酯盐酸盐；
((S)‐(((2R,3R,4R,5R)‐3‐(2‐(7H‐吡咯[2,3‐b]吡啶‐7‐位)乙酰氧基)‐5‐(2,4‐二酮‐ 3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐4‐甲基四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐L‐丙氨酸异丙酯；
(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位4‐(1H‐吡咯[2,3‐b] 吡啶‐1‐位)丁酸酯；
((S)‐(((2R,3R,4R,5R)‐3‐(2‐(1H‐吡咯[2,3‐b]吡啶‐1‐位)乙酰氧基)‐5‐(2,4‐二酮‐ 3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐4‐甲基四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐L‐丙氨酸异丙酯；
((S)‐(((2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐4‐甲基‐3‐((3‐吗啡啉丙酰)氧基)四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐L‐缬氨酸甲酯；
(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐2‐((((S)‐(((S)‐1‐乙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐氟‐4‐甲基四氢呋喃‐3‐位3‐吗啡啉丙酸酯；
((S)‐(((2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐4‐甲基‐3‐(((3‐吗啡啉丙基)氨基甲酰)氧)四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐L‐丙氨酸异丙酯；
((S)‐(((2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐4‐甲基‐3‐(((3‐吗啡啉丙基)氨基甲酰)氧)四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐L‐丙氨酸乙酯；
((S)‐(((2R,3R,4R,5R)‐3‐(((2‐(1H‐吡咯[2,3‐b]吡啶‐1‐位)乙基)氨基甲酰)氧)‐5‐ (2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐4‐甲基四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐L‐丙氨酸异丙酯；
(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位3‐吗啡啉丙酸酯盐酸盐；
(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位3‐吗啡啉丙酸酯氢溴酸盐；
(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位3‐吗啡啉丙酸酯甲磺酸盐；
(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位4‐吗啡啉丁酸酯盐酸盐；
(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位4‐吗啡啉丁酸酯氢溴酸盐；
(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位4‐吗啡啉丁酸酯甲磺酸盐；
((S)‐(((2R,3R,4R,5R)‐3‐(2‐(1H‐吡咯[2,3‐b]吡啶‐1‐位)乙酰氧基)‐5‐(2,4‐二酮‐ 3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐4‐甲基四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐L‐丙氨酸异丙酯盐酸盐；
((S)‐(((2R,3R,4R,5R)‐3‐(2‐(1H‐吡咯[2,3‐b]吡啶‐1‐位)乙酰氧基)‐5‐(2,4‐二酮‐ 3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐4‐甲基四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐L‐丙氨酸异丙酯氢溴酸盐；和
((S)‐(((2R,3R,4R,5R)‐3‐(2‐(1H‐吡咯[2,3‐b]吡啶‐1‐位)乙酰氧基)‐5‐(2,4‐二酮‐ 3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐4‐甲基四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐L‐丙氨酸异丙酯甲磺酸盐。
在另一方面，本发明提供了一种包含至少一个上述的化合物与药学上可接受的基质组成的药用制剂。所述的药用制剂可用于治疗人类HCV感染。
在另一方面，本发明还提供了治疗HCV感染的方法，该方法包括给予HCV感染病人一种本发明的化合物或其药学上可接受的盐。一方面，该方法还可进一步给予 HCV感染病人另一种不同于本发明化合物的其他抗病毒试剂。
在另一方面，本发明还与本发明中的化合物用途有关，用于制造一种治疗HCV 感染的药物。
相比于已经报道的可潜在治疗HCV感染的其他化合物，本发明中的化合物有意想不到的优势，在临床应用上本发明中的化合物是更理想的。这些优势包括但不限于：能形成药学上可接受的盐使得化合物的水溶性和稳定性提高、显示了类似的或更好的药学作用，因此本发明中的化合物更容易做成制剂用于临床治疗。
本发明的具体描述
如果无另外说明，这里引用的所有术语具有与那些本领域的熟练人员理解本发明相同的含义。
如本文所使用的用语“一(a)”或“一(an)”实体是指一个或多个所述实体，例如，一化合物是指一个或多个化合物或者至少一个化合物。同样地，术语“(a)”(或“an”)、“一个或多个”以及“至少一个”在本文可互换使用。
如无其他与特定的含义相背的，以复数形式表示的词语也包括一个单数词语的含义。例如，词语“化合物”也指“一个化合物”，除非一个单数可能与特定的含义相背。
如本文所使用的术语“任选的”或“任选地”是指其后描述的事件或情况可以出现但不是必须出现，并且该描述包括该事件或情况出现的例子和不出现的例子。例如，“任选的键”是指该键可以存在或不存在，并且该键包括单键、双键或三键。又比如，一个“任选取代的”基团是指该基团可以被适当的取代基取代或不被取代。
术语“P*”是指磷原子是手性的，且它有一个相应的Cahn‐Ingold‐Prelog命名的“R”或“S”，它有可接受的常见含义。
如本文所使用的术语“纯化的”是指一个给定的化合物的纯度。例如，当给定化合物是组分中的一个主要成分时该化合物被纯化，意即至少50％重量比纯度。因此，“纯化的”包括至少50％重量比纯度，至少60％重量比纯度，至少70％纯度，至少80％纯度，至少85％纯度，至少90％纯度，至少92％纯度，至少94％纯度，至少 96％纯度，至少97％纯度，至少98％纯度，至少99％纯度，至少99.5％纯度，至少 99.9％纯度，其中“基本上纯的”包括至少97％纯度，至少98％纯度，至少99％纯度，至少99.5％纯度，至少99.9％纯度。
如本文所使用的术语“代谢物”是指给予一个客体需要的药物后在体内产生的一个化合物。
如本文所使用的术语“大约”(也可表示为～)是指援引的数值是一个在标准实验误差内变化的部分范围。
如本文所使用的术语“基本上无水的”是指一种物质最多含10％的水，优选最多1％的水，更优选最多0.5％的水，最优选最多0.1％的水，所述百分数指重量百分数。
如本文所使用的术语“前药”是指一个药物分子的生物转化衍生物，它在体内经过酶或化学的转化释放出活性母药，然后活性母药发挥期望的药效。关于前药也有其他的描述，例如J.Rautio等的文献(Nat Rev Drug Discov.,2008Mar；7(3):255‐70)，据此通过引用将上述文献完整地并入。
一种溶剂或反相溶剂(在反应、结晶等中使用或晶格和/或吸收的溶剂)包括至少一个C1‐C8的醇，C2‐C8的醚，C3‐C7的酮，C3‐C7的酯，C1‐C2的氯碳化合物，C2‐ C7的腈，其他溶剂，C5‐C12的饱和碳氢化合物，C6‐C12的芳基碳氢化合物。C1‐C8的醇是指一种直链/支链和/或环状/非环状的有那样的数量的碳的醇。C1‐C8的醇包括但不限于，甲醇、乙醇、正丙醇、异丙醇、异丁醇、己醇和环己醇。C2‐C8的醚指一种直链/支链和/或环状/非环状的有那样的数量的碳的醚。C2‐C8的醚包括但不限于，二甲醚、二乙醚、二异丙醚、二丁醚、甲基叔丁基醚(MTBE)，四氢呋喃和二氧六环。 C3‐C7的酮指一种直链/支链和/或环状/非环状的有那样的数量的碳的酮。C3‐C7的酮包括但不限于，丙酮、甲基乙基酮、丙酮、丁酮、甲基叔丁基酮、甲基丁基酮和环己酮。C3‐C7的酯指一种直链/支链和/或环状/非环状的有那样的数量的碳的酯。C3‐C7的酯包括但不限于，乙酸乙酯、乙酸丙酯、乙酸正丁酯等。C1‐C2的氯碳化合物指一种有那样的数量的碳的氯碳化合物。C1‐C2的氯碳化合物包括但不限于，氯仿、二氯甲烷(DCM)、四氯化碳、1,2‐二氯乙烷和四氯乙烷。C2‐C7的腈指一种直链/支链和/或环状/非环状的有那样的数量的碳的腈。C2‐C7的腈包括但不限于，乙腈、丙腈等。其他的溶剂指通常在有机化学中使用的溶剂，包括但不限于，二乙二醇、二甘醇二甲醚 (二乙二醇二甲醚)、1,2‐二甲氧基‐乙烷、二甲基甲酰胺、二甲基亚砜、乙二醇、丙三醇、六甲基磷酰胺、六甲基亚磷酰三胺、N‐甲基‐2‐吡咯烷酮、硝基甲烷、吡啶、三乙胺和乙酸。C5‐C12的饱和碳氢化合物指一种直链/支链和/或环状/非环状的碳氢化合物。C5‐C12的饱和碳氢化合物包括但不限于，正戊烷、石油醚(石油英)、正己烷、正庚烷、环己烷和环庚烷。C6‐C12的芳基碳氢化合物指取代和未取代的有苯基在其骨架上的碳氢化合物。优选的碳氢化合物包括苯、二甲苯、甲苯、氯苯、邻二甲苯、间二甲苯、对二甲苯，更优选的是甲苯。
如本文所使用的术语“卤素”包括氯、溴、碘和氟。
术语“封端基团”指表现出下列特点的化学基团。“基团”衍生自一个“保护的化合物”。该基团对伯羟基的选择性超过仲羟基、可以在与氨基磷酸酯(pH2‐8)的稳定性一致的条件下加上并赋予所得产物显著不同的物理性质，因此，允许3’‐磷酰胺‐5’‐新基团的产品更容易从未反应的目标化合物中分离。这个基团必须选择性的反应并以良好的收率得到保护的产物，且该产物在设计的反应中是稳定的(见Protective Groups in OrganicSynthesis,3nd ed.T.W.Greene and P.G.M.Wuts,John Wiley&Sons, New York,N.Y.,1999)。基团的例子包括但不限于：苯甲酰基、乙酰基、苯基取代的苯甲酰基、四氢吡喃、三苯甲基、DMT(4,4’‐二甲氧基三苯甲基)、MMT(4‐单甲氧基三苯甲基)、三甲氧基三苯甲基、苯基呫吨基(9‐苯基氧杂蒽‐9‐位)、苯基硫杂呫吨基(9‐苯基硫杂蒽‐9‐位)或9‐(p‐甲氧基苯基)氧杂蒽‐9‐位(MOX)等；C(O)‐烷基、 C(O)Ph、C(O)芳基、CH2O‐烷基、CH2O‐芳基、SO2‐烷基、SO2‐芳基、叔丁基二甲基硅基、叔丁基二苯基硅基。缩醛，如MOM或THP等等被认为是可能的基团。氟代化合物也是涵盖的，目前它们能够连接到化合物上且能够通过传递一个氟固相提取基质选择性脱除。具体例子包括氟化三苯甲基类似物、三苯甲基类似物1‐[4‐ (1Η,1H,2H,2H‐全氟癸基)苯基]‐1,1‐二苯基甲醇。还涵盖三苯甲基、BOC、FMOC、CBz等其他氟代类似物。磺酰氯(如对甲苯磺酰氯)可在5’位置选择性反应。可选择性形成酯诸如乙酸酯和苯甲酸酯。二羧基酸酐诸如琥珀酸酐和其衍生物可与游离羧酸产生酯键，这种例子包括但不限于，草酰基、丙二酰基、琥珀酰基、戊二酰基、己二酰基、庚二酰基、辛二酰基、壬二酰基、癸二酰基、邻苯二甲酰基、异邻苯二甲酰基、对邻苯二甲酰基等。游离羧酸极大地增加了极性且还可将其用于将反应产物萃取到温和碱性水相(如碳酸氢钠溶液)中。磷酰胺基团在酸性介质中是相对稳定的，因此还可使用需要酸性反应条件的基团(如四氢吡喃基)。
术语“保护基团”衍生自“保护化合物”，具有其常见和普通的含义，意即至少一个保护基或封端基结合到至少一个允许化学修饰至少一个其他官能团的官能团 (如‐OH、‐NH2等)上。保护基团的实例包括但不限于，苯甲酰基、乙酰基、苯基取代的苯甲酰基、四氢吡喃基、三苯甲基、DMT(4,4’‐二甲氧基三苯甲基)、MMT(4‐单甲氧基三苯甲基)、三甲氧基三苯甲基、苯基呫吨基(9‐苯基氧杂蒽‐9‐位)、苯基硫杂呫吨基(9‐苯基硫杂蒽‐9‐位)或9‐(p‐甲氧基苯基)氧杂蒽‐9‐位(MOX)等；C(O)‐烷基、C(O)Ph、C(O)芳基、C(O)O(低级烷基)、C(O)O(低级亚烷基)芳基(如，‐C(O) OCH2Ph)、C(O)O芳基、CH2O‐烷基、CH2O‐芳基、SO2‐烷基、SO2‐芳基、包含至少一个硅原子的保护基团，诸如叔丁基二甲基硅基、叔丁基二苯基硅基、Si(低级烧基)2OSi (低级烧基)2OH(如，‐Si(iPr)2OSi(iPr)2OH)。
如本文所用的术语“保护的化合物”，如无另外指明，指含有“保护基团”并且能够与含有需被保护的官能团的化合物反应的化合物。
如本文所用的术语“离去基团”，具有对于本领域技术人员而言相同的意思(Advanced Organic Chemistry:reactions,mechanisms and structure—FourthEdition by Jerry March,John Wiley and Sons Ed.；1992pages 351‐357)，它是底物分子的一部分并与之连接的基团；在底物分子进行取代反应的反应中(例如亲核试剂)，离去基团随之被取代。离去基团的例子包括但不限于：卤素(F、Cl、Br和I)，优选Cl、Br或 I；甲苯磺酸酯基、甲磺酸酯基、三氟甲基磺酸酯基、乙酸酯基、、樟脑磺酸酯基、芳氧基和至少一个吸电子基团取代的芳氧基(例如对硝基苯氧基、2‐氯苯氧基、4‐氯苯氧基、2,4‐二硝基苯氧基、五氟苯氧基等)等。术语“吸电子基团”此处具有其通常含义。吸电子基团的例子包括但不限于卤素、‐NO2、‐C(O)(低级烷基)、‐C(O)(芳基)‐ C(O)O(低级烷基)、C(O)O(芳基)等。
如本文所用的术语“碱性试剂”是能够使羟基去质子化的化合物。碱性试剂的例子包括但不限于(低级烷)氧化物((低级烷基)OM)并联合醇溶剂，其中(低级烷)氧化物包括但不限于MeO‐、EtO‐、nPrO‐、iPrO‐、tBuO‐、iAmO‐(异戊氧化物)等，且其中M是碱金属阳离子，例如Li+，Na+,K+等。醇溶剂包括(低级烷基)OH，例如 MeOH、EtOH、nPrOH、iPrOH、tBuOH、iAmOH等。还可以使用非‐烷氧基碱，例如氢化钠、六甲基二甲硅基胺钠、六甲基二甲硅基胺锂、二异丙基酰胺锂、氢化钙、碳酸钠、碳酸钾、碳酸铯、DBU、DBN、Grignard试剂，例如(低级烷基)Mg(卤素)，其包括但不限于MeMgCl、MeMgBr、tBuMgCl、tBuMgBr等。
术语“碱”(包括术语“碱性试剂”)，是指能够将含质子的化合物去质子化的化合物，即Bronsted碱。除了上述援引例子，碱的其他例子包括但不限于吡啶、三甲基吡啶、2,6‐(低级烷基)‐吡啶、二甲基‐苯胺、咪唑、N‐甲基‐咪唑、吡唑、N‐甲基‐吡唑、三乙胺、二异丙基乙基胺等。
术语“吸电子基团”具有其平常含义。吸电子基团的例子包括但不限于卤素 (F、Cl、Br或I)、‐NO2、‐C(O)(低级烷基)、‐C(O)(芳基)、‐C(O)O(低级烷基)、‐C(O)O(芳基)等。
术语“共晶”包括4、RP‐4或SP‐4与盐结合的共晶，所述盐包括药学上可接受的盐。
如本文所用的术语“盐”是指含阳离子和阴离子的化合物，其可通过可接受质子部位的质子化和/或可供质子部位的去质子化来产生。值得注意的是，可接受质子部位的质子化导致形成阳离子类物质，其电荷通过生理阴离子的存在而平衡，而可供质子部位的去质子化导致形成阴离子类物质，其电荷通过生理阳离子的存在而平衡。
术语“药学上可接受的盐”指盐是药学上可接受的。药学上可接受的盐的例子包括但不限于：(1)酸加成盐，与无机酸形成，如盐酸、氢溴酸、硫酸、硝酸、磷酸等等；或与有机酸形成，如羟基乙酸、丙酮酸、乳酸、丙二酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、3‐(4‐羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1，2‐乙烷‐二磺酸、2‐羟基乙烷磺酸、苯磺酸、4‐氯苯磺酸、2‐萘磺酸、4对甲苯磺酸、樟脑酸、十二烷基硫酸、葡萄糖酸、谷氨酸、水杨酸、顺式‐已二烯二酸等等；或(2)碱加成盐，和上述无机酸的任一种的共轭碱形成，其中共轭碱包含选自Na+、 K+、Mg2+、Ca2+、NHgR”’4‐g+中的阳离子组分，其中R”’是C1‐3烷基，g是选自0、 1、2、3或4的整数。应该理解，所有涉及药学上可接受的盐都包括相同酸加成盐的本文中所定义的溶剂加成形式(溶剂化物)或晶体形式(多晶型物)。
术语“烷基”是指含有1至30个碳原子的非支链或支链、饱和、单价烃基。术语“C1‐M烷基”是指包含1至M个碳原子的烷基，其中M是具有下列数值的整数： 2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、 22、23、24、25、26、27、28、29或30。术语“C1‐4烷基”是指含有1至4个碳原子的烷基。术语“低级烷基”表示包含1至6个碳原子的直链或支链烃基。本文中使用的“C1‐20烷基”是指包含1至20个碳原子的烷基。本文中使用的“C1‐10烷基”是指包含1至10个碳原子的烷基。烷基的例子包括但不限于低级烷基，包括甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基或戊基、异戊基、新戊基、己基、庚基和辛基。术语“(芳)烷基”或“(杂芳基)烷基”是指烷基任选地分别被芳基或杂芳基取代。术语“更低级的烷基”是指包含1至8个碳原子的烷基。这里所用的术语烷氧基指“烷基‐O‐”。
术语“烯基”指具有一个或两个烯双键、优选一个烯双键的、具有2至10个碳原子的不饱和烃链基团。术语“C2‐N烯基”是指包含2至N个碳原子的烯基，其中N 是具有下列数值的整数：3、4、5、6、7、8、9或10。术语“C2‐10烯基”是指包含 2至10个碳原子的烯基。术语“C2‐4烯基”是指包含2至4个碳原子的烯基，例如包括但不限于乙烯基、1‐丙烯基、2‐丙烯基(烯丙基)或2‐丁烯基(巴豆基)。
本文中使用的术语“杂环”是指至少具有一个选自于O、S、N或P的杂原子的单环或多环化合物。杂环化合物可以是芳香族的或非芳香族的、饱和的或不饱和的；它包括单环的3‐8元环、双环或三环融合环系统。例如，杂环化合物包括环乙胺、环氧乙烷、硫杂丙环、氮丙啶、环氧乙烯、噻丙烯、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、氮杂环丁烯、氧杂环丁烯、硫杂环丁烯、吡咯烷、氧杂环戊烷、硫杂环戊烷、吡咯、呋喃、噻吩、哌啶、氧杂环己烷、硫杂环己烷、吡啶、吡喃、噻喃、高哌啶、氧杂环庚烷、硫杂环庚烷、氮杂环庚三烯、氧杂环庚三烯、硫杂环庚三烯、吲哚、喹诺酮、咔唑、吖啶和二苯并氮杂卓。
如无另外说明，本文中使用的术语“芳基”是指取代或未取代的单环或多环融合系统，如苯基(Ph)、联苯基或萘基，术语芳基，如无特别说明，包括取代或未取代的芳基(苯基或取代苯基)。芳基可被一或多个选自以下的部分取代：羟基、F、 Cl、Br、I、氨基、烷基氨基、芳基氨基、烷氧基、芳氧基、硝基、氰基、磺酸基、硫酸酯基、膦酸基、磷酸酯基以及膦酸酯基，其根据需要可保护或不保护，如本领域的技术人员所知，例如，如T.W.Greene及P.G.M.Wuts，“Protective Groups in Organic Synthesis”第三版，John Wiley&Sons，1999中所指导。
本文中使用的术语“杂芳基”是指含碳原子、氢原子以及一个或多个杂原子 (如1‐3个杂原子)的一个单环或多环的芳香环，其中杂原子独立选自于氮、氧和硫。如本领域的技术人员所知，杂芳环相比它们的全碳环有更少的芳香特征。杂芳基的说明性例子包括但不限于吡啶基、哒嗪基、嘧啶基、吡唑基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3,)‐和(1,2,4)‐三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑、噻唑和噁唑。杂芳基可以是未取代的也可以被一个或两个适合的取代基取代。在本发明的实例中，杂芳基是一个单环，其中该环含有2‐5个碳原子和1‐3个杂原子，此处引用为“(C2‐C5)杂芳基”。
除非另有说明，本文中使用的术语"芳氧基"是指取代或未取代的苯氧基(PhO‐ )、对苯基‐苯氧基(p‐Ph‐PhO‐)或萘氧基，优选术语芳氧基是指取代或未取代的苯氧基。芳氧基可被选自下列的一个或多个部分所取代：羟基、F、Cl、Br、I、‐C(O)(低级烷基)、‐C(O)O(低级烷基)、氨基、烷基氨基、芳基氨基、烷氧基、芳氧基、硝基、氰基、磺酸基、硫酸酯基、膦酸基、磷酸酯基以及膦酸酯基，根据需要不保护或保护，这是本领域技术人员所熟知的，例如在T.W.Greene and P.G.Μ.Wuts,“Protective Groups in Organic Synthesis”第三版，John Wiley&Sons，1999中所指导。
术语“制剂”或“剂型”特指包括活性化合物的固体和液体配方且本领域的技术人员将了解活性成分可以不同制剂形式存在，这取决于所需剂量及药代动力学参数。
本文中所用的术语“赋形剂”指的是用于制备药物组合物的化合物，一般安全无毒且生物学或其他方面都不需要，且包括为兽用及人类药用所接受的赋形剂。
术语“结晶的”指的是SP‐4或RP‐4的固体样品当通过X射线粉末衍射或单晶X 射线技术测定时具有结晶特征的情况。
术语“晶体样”指的是SP‐4或Rp‐4的固体样品当通过一种手段(例如肉眼或通过光学或偏振显微镜)测定时具有结晶特征，但当通过另一手段(例如X射线粉末衍射)测定时不具有结晶特征的情况。通过肉眼或通过光学或偏振显微镜肉眼确定固体样品的结晶度的方法公开于USP<695>和<776>中，两篇文献皆以引用方式并入。呈“晶体样”的SP‐4或RP‐4的固体样品在某些条件下可变为晶型的，但当经受其他条件时可变成非晶型的。
术语“无定形的”是指其中Sp‐4或RP‐4的固体样品既不是晶体的也不是晶体样的情形。
下述实施例是为了更好的阐释本发明的某些具体体现而不能被解释为以任何方式限定本发明的范围。
实施例1.制备((S)‐(((2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐4‐甲基‐3‐ (2‐吗啡啉乙酰氧基)四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐L‐丙氨酸异丙酯(I‐1)
化合物1(0.30g,0.57mmol)，化合物2(0.12g,0.68mmol)和DiPEA(0.22g,1.70mmol)溶解在DCM(15mL)中。室温下搅拌5分钟后，加入TBTU(0.22g,0.68mmol)，混合物继续搅拌20hrs。旋干溶剂，EA(100mL)萃取，合并的有机层依次用水洗(2x50 mL)和饱和食盐水洗(50mL)，无水硫酸钠干燥，过滤，浓缩后柱层析纯化得到目标产物 I‐1(0.28g,76％)。
1H‐NMR(400MHz,CDCl3)δ:8.59(s,1H),7.50(d,J＝8.4Hz,1H),7.34(t,J＝8.0Hz,2H),7.23 (d,J＝8.4Hz,2H),7.18(t,J＝7.2Hz,1H),6.19(d,J＝18.8Hz,1H),5.58(d,J＝8.0Hz,1H),5.24 (dd,J1＝9.2Hz,J2＝20.0Hz,1H),5.05‐4.95(m,1H),4.55‐4.50(m,1H),4.34(dd,J1＝1.2Hz,J2＝7.2Hz,1H),4.27‐4.22(m,1H),4.02‐3.92(m,1H),3.85(t,J＝10.4Hz,1H),3.75(t,J＝4.4Hz, 3H),3.37(d,J＝3.6Hz,2H),2.65‐2.58(m,4H),1.40‐1.38(m,6H),1.24(d,J＝6.4Hz,6H).
实施例2.制备((S)‐(((2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐4‐甲基‐3‐ (2‐吗啡啉乙酰氧基)四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐L‐丙氨酸异丙酯4‐甲基苯磺酸盐(I‐2)
化合物I‐1(0.500g,0.76mmol)溶解在DCM(12mL)中，然后加入对甲基苯磺酸(0.145g,0.76mmol)。反应液继续搅拌0.5h后浓缩，重结晶得到目标盐(0.450g)。
1H‐NMR(400MHz,CDCl3)δ:7.71(d,J＝7.2Hz,2H),7.50(d,J＝7.2Hz,1H),7.30‐7.27(m, 2H),7.21‐7.14(m,6H),6.05(brs,1H),5.63(d,J＝7.8Hz,1H),5.30(brs,1H),4.95‐4.91(m, 1H),4.52‐4.28(m,3H),3.95‐3.65(m,6H),3.25‐3.08(m,2H),2.82(s,4H),2.32(s,3H),1.44‐ 1.35(m,6H),1.18(d,J＝6.0Hz,6H).
实施例3.制备(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位3‐吗啡啉丙
酸酯(I‐3)
按照合成化合物I‐1的方法，将2‐吗啡啉乙酸换成3‐吗啡啉乙酸可制备得到化合物I‐3。
1H‐NMR(400MHz,CDCl3)δ:8.43(s,1H),7.57(d,J＝8.0Hz,1H),7.36(t,J＝8.0Hz,2H), 7.26‐7.23(m,2H),7.20(t,J＝7.6Hz,1H),6.24(d,J＝18.8Hz,1H),5.54(d,J＝8.4Hz,1H),5.28 (dd,J1＝9.2Hz,J2＝20.8Hz,1H),5.05‐4.99(m,1H),4.60‐4.55(m,1H),4.34(d,J＝9.6Hz,1H), 4.30‐4.25(m,1H),4.03‐3.95(m,1H),3.87(t,J＝6.4Hz,1H),3.69‐3.67(m,4H),2.74‐2.70(m, 2H),2.65‐2.62(m,2H),2.48(br,4H),1.40‐1.37(m,6H),1.26(d,J＝6.4Hz,6H).
实施例4.制备(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位3‐吗啡啉丙酸酯4‐甲基苯磺酸盐(I‐4)
化合物I‐3(0.500g,0.75mmol)溶解在DCM(12mL)中，然后加入对甲基苯磺酸(0.142g,0.75mmol)。反应液继续搅拌0.5h后浓缩，重结晶得到目标盐(0.465g)。
1H‐NMR(400MHz,CDCl3)δ:10.85(s,1H),7.74(d,J＝8.0Hz,2H),7.48(t,J＝8.4Hz,1H),7.34 (t,J＝8.4Hz,2H),7.30‐7.14(m,5H),6.21‐6.06(m,1H),5.67(d,J＝8.4Hz,1H),5.36‐5.22(m, 1H),5.03‐4.93(m,1H),4.56‐4.32(m,3H),4.13‐3.85(m,6H),3.60‐3.43(m,6H),3.02‐2.99(m, 2H),2.35(s,3H),1.39‐1.32(m,6H),1.21(d,J＝6.4Hz,6H).
实施例5.制备(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位4‐吗啡啉丁酸酯(I‐5)
按照合成化合物I‐1的方法，将2‐吗啡啉乙酸换成4‐吗啡啉乙酸可制备得到化合物I‐5。
1H‐NMR(400MHz,CDCl3)δ:7.53(d,J＝8.4Hz,1H),7.33(t,J＝7.6Hz,2H),7.23‐7.19(m,3H), 6.21(d,J＝18.4Hz,1H),5.57(d,J＝8.0Hz,1H),5.21(dd,J1＝8.8Hz,J2＝20.0Hz,1H),5.04‐ 4.97(m,1H),4.56‐4.51(m,1H),4.33‐4.30(m,1H),4.26‐4.21(m,1H),4.06‐3.96(m,1H), 3.72‐3.70(m,4H),2.48‐2.46(m,4H),2.42‐2.36(m,2H),1.89‐1.81(m,2H),1.38‐1.32(m,6H), 1.24(d,J＝6.4Hz,6H).
实施例6.制备(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位4‐吗啡啉丁酸酯4‐甲基苯磺酸盐(I‐6)
化合物I‐5(0.277g,0.40mmol)溶解在DCM(10mL)中，然后加入对甲基苯磺酸(0.077g,0.40mmol)。反应液继续搅拌0.5h后浓缩，重结晶得到目标盐I‐6(0.310g, 89％)。
1H‐NMR(400MHz,CDCl3)δ:10.44(s,1H),9.05(s,1H),7.73(d,J＝8.0Hz,2H),7.50(t,J＝ 8.4Hz,1H),7.33(t,J＝8.4Hz,2H),7.30‐7.11(m,5H),6.14(d,J＝16.4Hz,1H),5.68(d,J＝ 8.0Hz,1H),5.30‐5.20(m,1H),4.99‐4.96(m,1H),4.45‐4.25(m,4H),3.95‐3.87(m,5H),3.56‐ 3.47(m,2H),3.21‐3.10(m,2H),2.83‐2.69(m,2H),2.51‐2.34(m,2H),2.25(s,3H),2.12‐2.10 (m,2H),1.37‐1.31(m,6H),1.21(d,J＝5.6Hz,6H).
实施例7.制备(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位4‐(二甲基氨基)丁酸酯(I‐7)
按照合成化合物I‐1的方法，将2‐吗啡啉乙酸换成4‐(二甲基氨基)丁酸可制备得到化合物I‐7。
1H‐NMR(400MHz,CDCl3)δ:7.52(d,J＝8.0Hz,1H),7.35(t,J＝7.2Hz,2H),7.23(t,J＝8.4Hz, 2H),7.19(d,J＝7.2Hz,1H),6.22(d,J＝18.8Hz,1H),5.54(d,J＝8.0Hz,1H),5.22(dd,J1＝ 9.2Hz,J2＝20.4Hz,1H),5.03‐4.97(m,1H),4.56‐4.52(m,1H),4.32‐4.31(m,1H),4.26‐4.21(m, 1H),4.13‐4.11(m,1H),4.08‐4.03(m,1H),4.00‐3.95(m,1H),2.50(t,J＝7.2Hz,2H),2.42‐2.36 (m,3H),2.26(s,6H),1.89‐1.81(m,2H),1.37‐1.32(m,6H),1.23(d,J＝6.4Hz,6H).
实施例8.制备(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位4‐(吡啶‐2‐位氨基)丁酸酯盐酸盐(I‐8)
按照合成化合物I‐1和化合物I‐2的方法，将2‐吗啡啉乙酸换成4‐((叔丁氧羰基)(吡啶‐2‐位)氨基)丁酸、对甲基苯磺酸换成盐酸气可制备得到化合物I‐8。
1H‐NMR(400MHz,CDCl3)δ:8.00(brs,1H),7.66‐7.64(m,1H),7.55(d,J＝8.0Hz,1H),7.33(t, J＝7.6Hz,2H),7.24(t,J＝8.4Hz,2H),7.17(t,J＝7.6Hz,1H),7.02(dd,J1＝5.6Hz,J2＝6.8Hz, 1H),6.22(d,J＝18.4Hz,1H),5.47(dd,J1＝1.2Hz,J2＝20.8Hz,1H),5.20(dd,J1＝9.2Hz,J2＝ 20.8Hz,1H),5.03‐4.94(m,1H),4.57‐4.54(m,1H),4.31‐4.29(m,1H),4.27‐4.22(m,1H),4.01‐ 3.98(m,2H),3.96‐3.88(m,1H),2.51(t,J＝8.4Hz,2H),2.05‐1.96(m,2H),1.38‐1.32(m,6H), 1.22(d,J＝6.4Hz,6H).
实施例9.制备(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位4‐(异喹啉‐1‐位氨基)丁酸酯盐酸盐(I‐9)
按照合成化合物I‐1和化合物I‐2的方法，将2‐吗啡啉乙酸换成4‐((叔丁氧羰基)(异喹啉‐1‐位)氨基)丁酸、对甲基苯磺酸换成盐酸气可制备得到化合物I‐9。
1H‐NMR(400MHz,CDCl3)δ:8.38(d,J＝6.0Hz,1H),8.08(d,J＝1.6Hz,1H),7.92(d,J＝8.4Hz, 1H),7.86(d,J＝8.0Hz,1H),7.72‐7.68(m,1H),7.63‐7.59(m,2H),7.55(d,J＝8.0Hz,1H),7.33 (t,J＝8.8Hz,2H),7.23(t,J＝8.8Hz,2H),7.16(t,J＝7.6Hz,1H),6.21(d,J＝18.4Hz,1H),5.44‐ 5.42(m,1H),5.21‐5.13(m,1H),5.01‐4.94(m,1H),4.56‐4.52(m,1H),4.29‐4.24(m,2H), 4.10‐4.07(m,1H),4.01‐3.93(m,2H),2.60‐2.57(m,2H),2.00‐1.98(m,2H),1.38‐1.34(m,6H), 1.21(d,J＝6.4Hz,6H).
实施例10.制备((S)‐(((2R,3R,4R,5R)‐3‐(2‐(7H‐吡咯[2,3‐b]吡啶‐7‐位)乙酰氧基)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐4‐甲基四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐L‐丙氨酸异丙酯(I‐10)
按照合成化合物I‐1的方法，将2‐吗啡啉乙酸换成2‐(7H‐吡咯[2,3‐b]吡啶‐7‐位)乙酸可制备得到化合物I‐10。
1H‐NMR(400MHz,CDCl3)δ:9.59(brs,1H),7.49(d,J＝8.0Hz,1H),7.31(t,J＝8.4Hz,2H), 7.23‐7.17(m,3H),6.20(d,J＝18.4Hz,1H),5.71(d,J＝7.6Hz,1H),5.03‐4.97(m,1H),4.56‐ 4.51(m,1H),4.47‐4.43(m,1H),4.36‐4.30(m,1H),4.15‐4.09(m,1H),3.98‐3.90(m,2H), 1.40‐1.35(m,6H),1.24(d,J＝6.4Hz,6H).
实施例11.制备(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐2‐((((S)‐(((S)‐1‐异丙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐甲基四氢呋喃‐3‐位4‐(1H‐吡咯 [2,3‐b]吡啶‐1‐位)丁酸酯(I‐11)
按照合成化合物I‐1的方法，将2‐吗啡啉乙酸换成4‐(1H‐吡咯[2,3‐b]吡啶‐1‐位)丁酸可制备得到化合物I‐11。
1H‐NMR(400MHz,CDCl3)δ:9.73(brs,1H),8.30(dd,J1＝4.8Hz,J2＝1.6Hz,1H),7.91(dd,J1＝ 1.6Hz,J2＝8.0Hz,1H),7.54(d,J＝8.0Hz,1H),7.34(t,J＝8.0Hz,2H),7.23‐7.21(m,3H),7.17(t, J＝7.6Hz,1H),7.07(dd,J1＝4.8Hz,J2＝8.0Hz,1H),6.46(d,J＝3.6Hz,1H),6.22(d,J＝18.4Hz, 1H),5.55(d,J＝8.0Hz,1H),5.23(dd,J1＝8.8Hz,J2＝20.4Hz,1H),5.02‐4.92(m,1H),4.57‐4.53 (m,1H),4.40‐4.36(m,2H),4.29‐4.24(m,2H),4.13‐4.08(m,1H),4.03‐3.93(m,1H),2.44(t,J ＝6.8Hz,2H),2.26‐2.20(m,2H),1.38‐1.35(m,6H),1.21(d,J＝6.4Hz,6H).
实施例12.制备((S)‐(((2R,3R,4R,5R)‐3‐(2‐(1H‐吡咯[2,3‐b]吡啶‐1‐位)乙酰氧基)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐4‐甲基四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐L‐丙氨酸异丙酯(I‐12)
按照合成化合物I‐1的方法，将2‐吗啡啉乙酸换成2‐(1H‐吡咯[2,3‐b]吡啶‐1‐位)乙酸可制备得到化合物I‐12。
1H‐NMR(400MHz,CDCl3)δ:8.68(brs,1H),8.29(dd,J1＝4.8Hz,J2＝1.6Hz,1H),7.93(dd,J1＝ 1.6Hz,J2＝7.6Hz,1H),7.47(d,J＝8.8Hz,1H),7.31(t,J＝8.0Hz,2H),7.25‐7.14(m,4H),7.09 (dd,J1＝4.8Hz,J2＝8.0Hz,1H),6.54(d,J＝3.6Hz,1H),6.18(d,J＝18.4Hz,1H),5.50(d,J＝ 8.4Hz,1H),5.20(s,2H),4.96‐4.90(m,1H),4.53‐4.48(m,1H),4.30‐4.23(m,2H),3.94‐3.89 (m,2H),1.36‐1.31(m,6H),1.17(d,J＝6.0Hz,6H).
实施例13.制备((S)‐(((2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐4‐甲基‐3‐ ((3‐吗啡啉丙酰)氧基)四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐L‐缬氨酸甲酯(I‐13)
化合物I‐13按照下列流程制备：
在‐50℃下向苯基二氯磷酸酯(2.005g,9.5mmol)的DCM(15mL)溶液中加入三乙胺(5.235g,51.8mmol)和五氟苯酚(1.595g,8.6mmol)的DCM(20mL)溶液。反应液搅拌 20分钟后滴加化合物13‐1(0.980g,8.6mmo和三乙胺(0.872g,8.6mmol)的DCM(15mL) 溶液。加毕继续在‐50℃搅拌3小时。旋干溶剂，EA(50mL)萃取，合并的有机层依次用水洗(2x50mL)和饱和食盐水洗(50mL)，无水硫酸钠干燥，过滤，浓缩后柱层析纯化得到油状的目标中间体13‐2(3.100g)。
0℃搅拌下，向起始原料13‐3(0.200g,0.77mmol,J.Med.Chem.2005,48,5504‐5508)的无水THF(10mL)溶液中滴加叔丁基氯化镁(1.62mL,1.6mmol)。继续搅拌30分钟后，滴加中间体13‐2(0.350g,0.77mmol)的无水THF(5mL)溶液。0℃继续搅拌1小时后自然升至室温搅拌18小时。加入饱和氯化铵溶液(50mL)淬灭后用EA(2x50mL)萃取。合并的有机层依次用水洗、饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩后柱层析纯化得到目标化合物13‐4(0.165g,40％)。
化合物13‐4(0.165g,0.31mmol)，化合物2(0.051g,0.31mmol)和DiPEA(0.080g,0.62mmol)溶解在DCM(8mL)中。室温下搅拌5分钟后，加入TBTU(0.119g,0.37 mmol)，反应液搅拌20小时。旋干溶剂，EA(50mL)萃取，合并的有机层依次用水洗 (2x30mL)和饱和食盐水洗(30mL)，无水硫酸钠干燥，过滤，浓缩后柱层析纯化得到目标产物I‐13(0.108g,54％)。
1H‐NMR(400MHz,CDCl3)δ:8.12(s,1H),7.52(d,J＝8.0Hz,1H),7.31(t,J＝8.0Hz,2H), 7.23‐7.15(m,3H),6.21(d,J＝19.2Hz,1H),5.52(d,J＝8.4Hz,1H),5.24(dd,J1＝9.2Hz,J2＝ 20.8Hz,1H),4.58‐4.54(m,1H),4.32‐4.23(m,2H),3.81‐3.77(m,1H),3.67‐3.65(m,7H),2.72‐ 2.69(m,2H),2.63‐2.60(m,2H),2.46(br,4H),2.07‐2.02(m,1H),1.37(d,J＝22.4Hz,3H), 0.93‐0.85(m,6H).
实施例14.制备(2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐2‐((((S)‐(((S)‐1‐乙氧基‐1‐酮丙烷‐2‐位)氨基)(苯氧基)磷酰)氧)甲基)‐4‐氟‐4‐甲基四氢呋喃‐3‐位3‐吗啡啉丙酸酯(I‐14)
按照合成化合物I‐13的方法，将化合物13‐1换成L‐丙氨酸乙酯可制备得到化合物I‐14。
1H‐NMR(400MHz,CDCl3)δ:8.45(s,1H),7.53(d,J＝8.0Hz,1H),7.35‐7.32(m,2H),7.26‐ 7.23‐7.16(m,3H),6.21(d,J＝18.8Hz,1H),5.53(d,J＝8.4Hz,1H),5.25(dd,J1＝9.2Hz,J2＝ 20.4Hz,1H),4.57‐4.52(m,1H),4.35‐4.24(m,2H),4.20‐4.11(m,2H),4.06‐3.96(m,1H),3.87‐ 3.81(m,1H),3.69‐3.65(m,4H),2.71‐2.69(m,2H),2.64‐2.61(m,2H),2.42(brs,4H),1.42‐ 1.37(m,6H),1.26(t,J＝7.2Hz,3H).
实施例15.制备((S)‐(((2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐4‐甲基‐3‐ (((3‐吗啡啉丙基)氨基甲酰)氧)四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐L‐丙氨酸异丙酯(I‐15)
化合物I‐15按照下列流程制备：
化合物15‐1(0.144g,1.0mmol)和DiPEA(0.300g,2.3mmol)溶解在DCM(12mL) 中。0℃下分批加入固体三光气(0.158g,0.53mmol)后继续搅拌3小时。旋干溶剂后将残余物重新溶解在DCM(10mL)中。
0℃下将叔丁基氯化镁(0.20ml,0.2mmol)滴加到起始原料1(0.085g,0.16mmol)的无水DCM(10mL)中。搅拌30分钟后，将上述中间体15‐2的DCM(10mL)溶液滴加到反应液中。保温继续搅拌一小时后自然升至室温反应过夜。加入饱和氯化铵溶液(30 mL)淬灭后用EA(2x30mL)萃取。合并的有机层依次用水洗、饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩后柱层析纯化得到目标化合物I‐15(0.068g,61％)。
1H‐NMR(400MHz,CDCl3)δ:7.53(d,J＝8.0Hz,1H),7.34‐7.30(m,2H),7.22(d,J＝8.0Hz, 2H),7.15(t,J＝7.2Hz,1H),6.50(t,J＝5.2Hz,1H),6.22(d,J＝18.8Hz,1H),5.44(d,J＝8.0Hz, 1H),5.09(dd,J1＝9.2Hz,J2＝21.2Hz,1H),5.02‐4.95(m,1H),4.57‐4.53(m,1H),4.33‐4.24(m, 3H),4.05‐3.97(m,1H),3.75‐3.72(m,4H),3.38‐3.31(m,1H),3.29‐3.21(m,1H),2.58‐2.46(m, 6H),1.75‐1.72(m,2H),1.38‐1.32(m,6H),1.22(d,J＝6.0Hz,6H).
实施例16.制备((S)‐(((2R,3R,4R,5R)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐4‐甲基‐3‐ (((3‐吗啡啉丙基)氨基甲酰)氧)四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐L‐丙氨酸乙酯(I‐16)
按照合成化合物I‐15的方法，将化合物1换成((S)‐(((2R,3R,4R,5R)‐5‐(2,4‐二酮‐ 3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐3‐羟基‐4‐甲基四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐L‐丙氨酸乙酯可制备得到化合物I‐16。
1H‐NMR(400MHz,CDCl3)δ:8.29(brs,1H),7.54(d,J＝8.4Hz,1H),7.35‐7.31(m,2H),7.22 (d,J＝8.4Hz,2H),7.16(t,J＝7.6Hz,1H),6.48(t,J＝4.8Hz,1H),6.22(d,J＝18.8Hz,1H), 5.40(d,J＝8.4Hz,1H),5.09(dd,J1＝8.8Hz,J2＝20.8Hz,1H),4.57‐4.53(m,1H),4.28‐4.24(m, 2H),4.18‐4.11(m,3H),4.08‐4.01(m,1H),3.72‐3.70(m,4H),3.41‐3.33(m,1H),3.30‐3.23(m, 1H),2.55‐2.40(m,6H),1.71‐1.65(m,2H),1.39‐1.33(m,6H),1.24(t,J＝7.2Hz,3H).
实施例17.制备((S)‐(((2R,3R,4R,5R)‐3‐(((2‐(1H‐吡咯[2,3‐b]吡啶‐1‐位)乙基)氨基甲酰)
氧)‐5‐(2,4‐二酮‐3,4‐二氢嘧啶‐1(2H)‐位)‐4‐氟‐4‐甲基四氢呋喃‐2‐位)甲氧基)(苯氧基)磷酰)‐ L‐丙氨酸异丙酯(I‐17)
按照合成化合物I‐15的方法，将3‐吗啡啉丙烷‐1‐胺换成2‐(1H‐吡咯[2,3‐b]吡啶‐ 1‐位)乙烷‐1‐胺可制备得到化合物I‐17。
1H‐NMR(400MHz,CDCl3)δ:9.06(brs,1H),8.29(dd,J1＝1.2Hz,J2＝4.8Hz,1H),7.91(dd,J1＝ 1.2Hz,J2＝8.0Hz,1H),7.49(d,J＝8.4Hz,1H),7.34‐7.30(m,2H),7.24‐7.09(m,4H),7.07‐ 7.05(m,1H),6.46(d,J＝3.6Hz,1H),6.14(t,J＝5.2Hz,1H),5.40(d,J＝8.4Hz,1H),5.01‐ 4.94(m,1H),4.53‐4.43(m,3H),4.24‐4.16(m,3H),4.03‐3.97(m,1H),3.68‐3.65(m,2H), 1.37‐1.30(m,6H),1.21(d,J＝6.4Hz,6H).
实施例18.制备化合物I‐3盐酸盐(I‐18)
化合物I‐3(0.500g,0.75mmol)溶解在iPrOH(2mL)中，然后加入浓盐酸(0.09ml,1.12mmol)。反应液继续搅拌1小时后过滤得到目标盐(0.350g)。
1H‐NMR(400MHz,CDCl3)δ:13.16(brs,1H),8.63(s,1H),7.41(d,J＝8.0Hz,2H),7.28(t,J＝ 7.6Hz,2H),7.19‐7.09(m,3H),6.07(d,J＝18.0Hz,1H),5.61(d,J＝6.8Hz,1H),5.21(dd,J1＝ 8.0Hz,J2＝18.4Hz,1H),4.97‐4.88(m,1H),4.41‐4.28(m,3H),4.17‐3.85(m,6H),3.39‐3.09(m, 6H),2.98‐2.69(m,2H),1.34‐1.30(m,6H),1.17(d,J＝6.0Hz,6H).
实施例19.制备化合物I‐3氢溴酸盐(I‐19)
化合物I‐3(0.500g,0.75mmol)溶解在iPrOH(2mL)中，然后加入氢溴酸(0.07ml,1.12mmol)。反应液继续搅拌1小时后过滤得到目标盐(0.400g)。
1H‐NMR(400MHz,CDCl3)δ:11.96(brs,1H),8.56(s,1H),7.41(d,J＝8.0Hz,2H),7.29(t,J＝ 7.6Hz,2H),7.19‐7.10(m,3H),6.07(d,J＝18.8Hz,1H),5.64(dd,J1＝2.0Hz,J2＝8.4Hz,1H), 5.22(dd,J1＝8.4Hz,J2＝17.2Hz,1H),4.97‐4.87(m,1H),4.43‐4.29(m,3H),4.25‐4.12(m,2H), 3.97‐3.82(m,4H),3.42‐3.11(m,6H),2.98‐2.77(m,2H),1.34‐1.29(m,6H),1.17(d,J＝6.4Hz, 6H).
实施例20.制备化合物I‐3甲磺酸盐(I‐20)
化合物I‐3(0.500g,0.75mmol)溶解在iPrOH(2mL)中，然后加入甲磺酸(0.07ml,1.12mmol)。反应液继续搅拌1小时后过滤得到目标盐(0.385g).
1H‐NMR(400MHz,DMSO‐d6)δ:11.56(brs,1H),9.74(s,1H),7.72(d,J＝8.0Hz,2H),7.40(t, J＝8.0Hz,2H),7.22‐7.17(m,3H),6.06‐6.00(m,1H),5.68(dd,J1＝2.0Hz,J2＝8.0Hz,1H),5.33 (br,1H),4.90‐4.81(m,1H),4.34‐4.24(m,3H),3.99‐3.84(m,2H),3.74‐3.63(m,4H),3.40‐ 3.30(m,4H),3.12‐2.99(m,4H),2.36(s,3H),1.37‐1.31(m,6H),1.22(d,J＝6.4Hz,3H),1.17 (d,J＝6.4Hz,3H).
实施例21.制备化合物I‐5盐酸盐(I‐21)
化合物I‐5(0.500g,0.73mmol)溶解在iPrOH(2mL)中，然后加入浓盐酸(0.09ml,1.12mmol)。反应液继续搅拌1小时后过滤得到目标盐(0.370g).
1H‐NMR(400MHz,CDCl3)δ:13.55(brs,1H),7.37(d,J＝8.0Hz,2H),7.26(t,J＝7.6Hz,2H), 7.16‐7.11(m,3H),6.05(d,J＝18.4Hz,1H),5.64(d,J＝7.2Hz,1H),5.15(dd,J1＝8.4Hz,J2＝ 18.8Hz,1H),4.97‐4.89(m,1H),4.30‐4.15(m,4H),3.99‐3.85(m,5H),3.40‐3.35(m,2H), 3.21‐3.10(m,2H),2.80‐2.30(m,4H),2.05‐1.90(m,2H),1.37‐1.31(m,6H),1.17(d,J＝6.0Hz, 6H).
实施例22.制备化合物I‐5氢溴酸盐(I‐22)
化合物I‐5(0.500g,0.73mmol)溶解在iPrOH(2mL)中，然后加入氢溴酸(0.07ml,1.12mmol)。反应液继续搅拌1小时后过滤得到目标盐(0.410g).
1H‐NMR(400MHz,CDCl3)δ:11.56(brs,1H),7.37(d,J＝8.0Hz,2H),7.25(t,J＝8.0Hz,2H), 7.17‐7.10(m,3H),6.07(d,J＝18.4Hz,1H),5.65(d,J＝7.6Hz,1H),5.17‐5.14(m,1H),4.99‐ 4.87(m,1H),4.32‐4.13(m,4H),3.98‐3.83(m,5H),3.43‐3.30(m,2H),3.25‐3.08(m,2H), 2.83‐2.35(m,4H),2.06‐1.93(m,2H),1.37‐1.30(m,6H),1.17(d,J＝6.0Hz,6H).
实施例23.制备化合物I‐5甲磺酸盐(I‐23)
化合物I‐5(0.500g,0.73mmol)溶解在iPrOH(2mL)中，然后加入甲磺酸(0.07ml,1.12mmol)。反应液继续搅拌1小时后过滤得到目标盐(0.370g).
1H‐NMR(400MHz,DMSO‐d6)δ:11.10(brs,1H),9.70(s,1H),7.67(d,J＝8.0Hz,2H),7.36(t, J＝8.0Hz,2H),7.20‐7.13(m,3H),6.06‐6.01(m,1H),5.69(d,J＝7.6Hz,1H),5.26‐5.20(m, 1H),4.92‐4.80(m,1H),4.25‐4.05(m,4H),3.83‐3.65(m,5H),3.42‐3.03(m,4H),2.90‐2.43(m, 4H),2.39(s,3H),2.10‐1.90(m,2H),1.37‐1.31(m,6H),1.17(d,J＝6.0Hz,6H)
实施例24.制备化合物I‐12盐酸盐(I‐24)
化合物I‐12(0.500g,0.73mmol)溶解在iPrOH(2mL)中，然后加入浓盐酸(0.09ml,1.12mmol)。反应液继续搅拌1小时后过滤得到目标盐(0.355g).
1H‐NMR(400MHz,CDCl3)δ:8.39‐8.34(m,3H),7.45‐7.39(m,3H),7.24‐7.20(m,4H),7.10‐ 7.04(m,1H),6.80(d,J＝2.8Hz,1H),6.19(d,J＝18.8Hz,1H),5.43‐5.39(m,2H),5.29(dd,J1＝ 8.4Hz,J2＝18.8Hz,1H),4.98‐4.91(m,1H),4.63‐4.56(m,2H),4.45‐4.43(m,2H),4.03‐3.97 (m,1H),1.36‐1.30(m,6H),1.18(d,J＝6.4Hz,6H).
实施例25.制备化合物I‐12氢溴酸盐(I‐25)
化合物I‐12(0.500g,0.73mmol)溶解在iPrOH(2mL)中，然后加入氢溴酸(0.07ml,1.12mmol)。反应液继续搅拌1小时后过滤得到目标盐(0.390g).
1H‐NMR(400MHz,CDCl3)δ:8.54(d,J＝7.6Hz,1H),8.39‐8.37(m,1H),7.56(t,J＝6.0Hz,2H), 7.48(d,J＝8.0Hz,1H),7.26‐7.20(m,4H),7.12(t,J＝7.2Hz,1H),6.89(s,1H),6.16‐6.05(m, 2H),5.62(d,J＝18.4Hz,1H),5.51(d,J＝8.4Hz,1H),5.32‐5.26(m,2H),5.00‐4.91(m,1H), 4.80‐4.72(m,1H),4.64‐4.60(m,1H),4.51‐4.49(m,1H),4.02‐3.98(m,1H),1.39‐1.32(m,6H), 1.19(d,J＝6.4Hz,6H).
实施例26.制备化合物I‐12甲磺酸盐(I‐26)
化合物I‐12(0.500g,0.73mmol)溶解在iPrOH(2mL)中，然后加入甲磺酸(0.07ml,1.12mmol)。反应液继续搅拌1小时后过滤得到目标盐(0.386g).
1H‐NMR(400MHz,CDCl3)δ:8.54‐8.48(m,2H),7.51‐7.44(m,3H),7.30‐7.21(m,4H),7.14‐ 7.11(m,1H),6.84(d,J＝2.8Hz,1H),6.13(d,J＝18.4Hz,1H),5.65‐5.45(m,2H),5.33‐5.25(m, 1H),5.02‐4.88(m,1H),4.56‐4.53(m,2H),4.45‐4.43(m,2H),3.99‐3.89(m,1H),2.89(s,3H), 1.41‐1.31(m,6H),1.19(d,J＝6.4Hz,6H).
实施例27.Caco‐2透膜性
本试验的目的是利用Caco‐2细胞单层来评价受试化合物的肠透膜性。试验步骤按照实际测试方法描述如下：
1)在37℃水浴中预热HBSS Buffer；
2)从‐20℃冰箱里取出化合物，超声几分钟(不少于1分钟)；
3)溶液制备：
给体溶液缓冲液：含0.3％DMSO和5μM LY的HBSS缓冲液：将150μL DMSO 和50μL LY(5mM)加入到50ml HBSS缓冲液(pH 7.4)中；含0.1％DMSO和5μM LY HBSS 的缓冲液：将50μLDMSO和50μL LY(5mM)加入到50mL HBSS缓冲液(pH7.4)中。
受体溶液缓冲液：制备含0.4％DMSO的缓冲液：将200μL DMSO加入到50ml HBSS缓冲液(pH7.4)中。
4)将细胞培养皿从培养箱中取出，用HBSS缓冲液清洗细胞单层，然后在室温条件下测试TEER值。
5)在4000rpm下将化合物溶液离心5分钟，然后载入到受体室；
6)基于下表列出的溶剂量添加溶液(确保吸取额外的100uL给体样品作为 T0备份)；
7)为了测试顶室LY浓度，从顶室吸取100μL样品注入一个不透明培养皿作为LYT0；
8)37℃预热顶面培养皿和底面培养皿约5分钟，然后将顶面培养皿放到底面培养皿上开始转运；
9)培养皿放在37℃培养箱中90分钟；
10)标曲制备；
11)培养90分钟后将顶面培养皿从底面培养皿中分离；
12)从底面培养皿中吸取100μL样品注入到一个不透明培养皿作为LYT90；
13)用荧光计测量LYT0和LYT90的LY浓度(485nm激发/535nm辐射)；
14)制备LC‐MS/MS样品:
给体样品(1:10稀释)：6μL给体样品+54μL 0.4％DMSO HBSS+60μL ACN(带内标利胆酚或丙咪嗪)；
受体样品：60μL受体样品+60μL CAN(带内标利胆酚或丙咪嗪)。
| 化合物 | Sofosbuvir | I‐1 | I‐3 | I‐5 | I‐8 | I‐12 |
| Papp×106/cm·s‐1(A‐B) | 0.19 | 0.85 | 1.16 | 1.53 | 0.92 | 0.63 |
上表总结表明，许多受试化合物显示了不可预见的优于sofosbuvir的透膜性。
实施例28.热力学水溶性
将足够量的化合物悬浮在水中得到化合物的游离形式的最大终浓度≥10mg·ml-1来测试水溶性。测量pH值前将悬浮液放在25℃下平衡24小时。然后用玻璃纤维C 过滤器将悬浮液过滤到96孔板。滤液稀释101倍。将0.1mg·ml-1DMSO标准溶液做参照，HPLC定量。注射不同体积的标准溶液、稀释溶液和未稀释溶液。按照标准注射中主峰相同保留时间来积分峰，用峰面积来计算溶解度。
相比于报道的有效治疗HCV感染的其他化合物，本发明的化合物显示了不可预见
的更高的溶解度，这使得本发明的化合物可以更理想的用于制备药物制剂和临床治疗感染
HCV的病人。
| 化合物 | Sofosbuvir | I‐2 | I‐4 | I‐6 | I‐8 | I‐9 | I‐18 |
| 溶解度(mg/mL) | 2.0 | 6.0 | 5.2 | 4.7 | >2.0 | >2.0 | >7.0 |
| 化合物 | Sofosbuvir | I‐19 | I‐20 | I‐21 | I‐22 | I‐23 |
| 溶解度(mg/mL) | 2.0 | >7.0 | 3.9 | 5.1 | 4.2 | 3.8 |
实施例29.生物活性
在96孔白色/不透明板内，将1b replicon细胞系按照3000个细胞/孔(50μL)铺板，或在384孔白色/不透明板内，将1b replicon细胞系按照1500个细胞/孔(25μL)铺板。将50μL化合物(2复孔)加入96孔板或25μL化合物(2复孔)加入384孔板， 37℃、5％湿度CO2气体的细胞培养箱内培养4天。培养后，加入Bright‐Glo试剂(96 孔板50μL；384孔板25μL)，萤火虫萤光素酶报告测试HCV复制。相对空白对照计算抑制百分率。
相比于报道的有效治疗HCV感染的其他化合物，本发明的化合物不可预见的显示
了低的EC50值，其小于0.2uM甚至0.15uM或0.10uM。所有受试化合物 (CC50>100uM)相比于市
场上抑制HCV病毒的对照药物(CC50＝63uM)显示了更低的细胞毒性。
| 化合物 | EC50(uM) | 化合物 | EC50(uM) | 化合物 | EC50(uM) |
| I‐1 | 0.312 | I‐2 | 0.235 | I‐3 | 0.156 |
| I‐4 | 0.083 | I‐5 | 0.145 | I‐6 | 0.099 |
| I‐7 | 0.075 | I‐8 | 0.187 | I‐9 | 0.290 |
| I‐10 | 0.133 | I‐11 | 0.539 | I‐12 | 0.082 |
| I‐13 | 3.28 | I‐14 | 0.159 | I‐15 | 4.87 |
| I‐16 | 0.694 | I‐17 | 9.86 | Sofosbuvir | 0.134 |
实施例30.大鼠PK研究
在体内评价了本发明的化合物，口服后测试了肝中活性尿嘧啶三磷酸代谢物的水平。每一个化合物大鼠口服剂量为30mg/kg，肝摘除后肝提取液用于分析其NTP (2’‐脱氧‐2’‐α‐F‐2’‐β‐C‐甲基尿嘧啶三磷酸)水平。下表列出了PK研究结果。
相比于报道的有效治疗HCV感染的其他化合物，本发明的化合物不可预见的显示了比sofosbuvir更高的Cmax值。更重要的是，所有受试化合物在肝内有更高的活性 NTP代谢物药物暴露。
所有上述结果表明，本发明提供了一种有优秀PK性质的新型抗HCV的抑制剂化合物。
上述实例只为说明本发明的技术构思及特点，其目的在于让熟悉本领域的人能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。此处提及的所有出版物据此通过引用完整地并入。凡根据本发明精神实质所做的等效变换或修饰，都应涵盖在本发明的保护范围之内。
Claims (14)
1.一种式(I)的化合物或其药学上可接受的盐，
其中，
R1是芳基、杂芳基、芳基烷基或杂芳基烷基；
R2是氢，R3是或
R2、R3与它们相连的氮原子一起组成杂环，且所述杂环是 其中R6为氢；
R4是甲基；
R5是异丙基；
X是一个键；
n是1、2或3。
2.如权利要求1所述的化合物或其药学上可接受的盐，其特征在于：R1是芳基或杂芳基。
3.如权利要求1所述的化合物或其药学上可接受的盐，其特征在于：R1是苯基或萘基。
4.如权利要求1所述的化合物或其药学上可接受的盐，其特征在于：R2是氢，R3是
5.如权利要求1所述的化合物或其药学上可接受的盐，其特征在于：R2、R3与它们相连的氮原子一起组成杂环，且所述的杂环是
6.如权利要求1所述的化合物或其药学上可接受的盐，其特征在于:R2、R3与它们相连的氮原子一起组成的杂环是
7.如权利要求1所述的化合物或其药学上可接受的盐，其特征在于：磷原子是手性的，且至少有90％的S立体异构体。
8.如权利要求7所述的化合物或其药学上可接受的盐，其特征在于：手性磷原子至少有97％的S立体异构体。
9.如权利要求1-8之一所述的化合物或其药学上可接受的盐，其特征在于：所述药学可接受的盐是醋酸盐、4-甲基苯磺酸盐、甲磺酸盐、盐酸盐或氢溴酸盐。
10.如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，选自：
((S)-(((2R,3R,4R,5R)-5-(2,4-二酮-3,4-二氢嘧啶-1(2H)-位)-4-氟-4-甲基-3-(2-吗啡啉乙酰氧基)四氢呋喃-2-位)甲氧基)(苯氧基)磷酰)-L-丙氨酸异丙酯；
((S)-(((2R,3R,4R,5R)-5-(2,4-二酮-3,4-二氢嘧啶-1(2H)-位)-4-氟-4-甲基-3-(2-吗啡啉乙酰氧基)四氢呋喃-2-位)甲氧基)(苯氧基)磷酰)-L-丙氨酸异丙酯4-甲基苯磺酸盐；
(2R,3R,4R,5R)-5-(2,4-二酮-3,4-二氢嘧啶-1(2H)-位)-4-氟-2-((((S)-(((S)-1-异丙氧基-1-酮丙烷-2-位)氨基)(苯氧基)磷酰)氧)甲基)-4-甲基四氢呋喃-3-位3-吗啡啉丙酸酯；
(2R,3R,4R,5R)-5-(2,4-二酮-3,4-二氢嘧啶-1(2H)-位)-4-氟-2-((((S)-(((S)-1-异丙氧基-1-酮丙烷-2-位)氨基)(苯氧基)磷酰)氧)甲基)-4-甲基四氢呋喃-3-位3-吗啡啉丙酸酯4-甲基苯磺酸盐；
(2R,3R,4R,5R)-5-(2,4-二酮-3,4-二氢嘧啶-1(2H)-位)-4-氟-2-((((S)-(((S)-1-异丙氧基-1-酮丙烷-2-位)氨基)(苯氧基)磷酰)氧)甲基)-4-甲基四氢呋喃-3-位4-吗啡啉丁酸酯；
(2R,3R,4R,5R)-5-(2,4-二酮-3,4-二氢嘧啶-1(2H)-位)-4-氟-2-((((S)-(((S)-1-异丙氧基-1-酮丙烷-2-位)氨基)(苯氧基)磷酰)氧)甲基)-4-甲基四氢呋喃-3-位4-吗啡啉丁酸酯4-甲基苯磺酸盐；
(2R,3R,4R,5R)-5-(2,4-二酮-3,4-二氢嘧啶-1(2H)-位)-4-氟-2-((((S)-(((S)-1-异丙氧基-1-酮丙烷-2-位)氨基)(苯氧基)磷酰)氧)甲基)-4-甲基四氢呋喃-3-位4-(吡啶-2-位氨基)丁酸酯盐酸盐；
((S)-(((2R,3R,4R,5R)-3-(2-(1H-吡咯[2,3-b]吡啶-1-位)乙酰氧基)-5-(2,4-二酮-3,4-二氢嘧啶-1(2H)-位)-4-氟-4-甲基四氢呋喃-2-位)甲氧基)(苯氧基)磷酰)-L-丙氨酸异丙酯；
(2R,3R,4R,5R)-5-(2,4-二酮-3,4-二氢嘧啶-1(2H)-位)-4-氟-2-((((S)-(((S)-1-异丙氧基-1-酮丙烷-2-位)氨基)(苯氧基)磷酰)氧)甲基)-4-甲基四氢呋喃-3-位3-吗啡啉丙酸酯盐酸盐；
(2R,3R,4R,5R)-5-(2,4-二酮-3,4-二氢嘧啶-1(2H)-位)-4-氟-2-((((S)-(((S)-1-异丙氧基-1-酮丙烷-2-位)氨基)(苯氧基)磷酰)氧)甲基)-4-甲基四氢呋喃-3-位3-吗啡啉丙酸酯氢溴酸盐；
(2R,3R,4R,5R)-5-(2,4-二酮-3,4-二氢嘧啶-1(2H)-位)-4-氟-2-((((S)-(((S)-1-异丙氧基-1-酮丙烷-2-位)氨基)(苯氧基)磷酰)氧)甲基)-4-甲基四氢呋喃-3-位3-吗啡啉丙酸酯甲磺酸盐；
(2R,3R,4R,5R)-5-(2,4-二酮-3,4-二氢嘧啶-1(2H)-位)-4-氟-2-((((S)-(((S)-1-异丙氧基-1-酮丙烷-2-位)氨基)(苯氧基)磷酰)氧)甲基)-4-甲基四氢呋喃-3-位4-吗啡啉丁酸酯盐酸盐；
(2R,3R,4R,5R)-5-(2,4-二酮-3,4-二氢嘧啶-1(2H)-位)-4-氟-2-((((S)-(((S)-1-异丙氧基-1-酮丙烷-2-位)氨基)(苯氧基)磷酰)氧)甲基)-4-甲基四氢呋喃-3-位4-吗啡啉丁酸酯氢溴酸盐；
(2R,3R,4R,5R)-5-(2,4-二酮-3,4-二氢嘧啶-1(2H)-位)-4-氟-2-((((S)-(((S)-1-异丙氧基-1-酮丙烷-2-位)氨基)(苯氧基)磷酰)氧)甲基)-4-甲基四氢呋喃-3-位4-吗啡啉丁酸酯甲磺酸盐；
((S)-(((2R,3R,4R,5R)-3-(2-(1H-吡咯[2,3-b]吡啶-1-位)乙酰氧基)-5-(2,4-二酮-3,4-二氢嘧啶-1(2H)-位)-4-氟-4-甲基四氢呋喃-2-位)甲氧基)(苯氧基)磷酰)-L-丙氨酸异丙酯盐酸盐；
((S)-(((2R,3R,4R,5R)-3-(2-(1H-吡咯[2,3-b]吡啶-1-位)乙酰氧基)-5-(2,4-二酮-3,4-二氢嘧啶-1(2H)-位)-4-氟-4-甲基四氢呋喃-2-位)甲氧基)(苯氧基)磷酰)-L-丙氨酸异丙酯氢溴酸盐；
((S)-(((2R,3R,4R,5R)-3-(2-(1H-吡咯[2,3-b]吡啶-1-位)乙酰氧基)-5-(2,4-二酮-3,4-二氢嘧啶-1(2H)-位)-4-氟-4-甲基四氢呋喃-2-位)甲氧基)(苯氧基)磷酰)-L-丙氨酸异丙酯甲磺酸盐。
11.一种药物制剂，其特征在于：包含如权利要求1-10中任一项权利要求所述的化合物和药学上可接受的基质。
12.如权利要求11所述的药物制剂，其特征在于：所述药物制剂是治疗人类HCV病毒感染的药物。
13.如权利要求12所述的药物制剂，其特征在于：所述药物制剂进一步包括一个第二治疗试剂，所述的第二治疗试剂为一个免疫调节剂或一个抗感染试剂。
14.如权利要求13所述的药物制剂，其特征在于：所述的抗感染试剂为一个HCV蛋白酶抑制剂、一个HCV NS5A抑制剂或一个HCV NS5B聚合酶抑制剂。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNPCT/CN2015/072391 | 2015-02-06 | ||
| CN2015072391 | 2015-02-06 | ||
| PCT/CN2015/084044 WO2016123905A1 (en) | 2015-02-06 | 2015-07-15 | Novel phosphoramidates for treatment of hcv infection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106132972A CN106132972A (zh) | 2016-11-16 |
| CN106132972B true CN106132972B (zh) | 2018-08-31 |
Family
ID=56563377
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201580000349.8A Expired - Fee Related CN106132972B (zh) | 2015-02-06 | 2015-07-15 | 用于治疗hcv感染的氨基磷酸酯 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN106132972B (zh) |
| WO (1) | WO2016123905A1 (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20190358214A1 (en) * | 2016-11-17 | 2019-11-28 | Abbvie Inc. | Compositions and Methods for Treating HCV Infection |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010515680A (ja) * | 2007-01-05 | 2010-05-13 | メルク・シャープ・エンド・ドーム・コーポレイション | Ｒｎａ依存性ｒｎａウイルス感染症の治療用としてのヌクレオシドアリールホスホロアミデート |
| AP3515A (en) * | 2010-03-31 | 2016-01-11 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
| US20130018011A1 (en) * | 2011-06-10 | 2013-01-17 | Hassan Javanbakht | Method of treating dengue fever |
| AR092959A1 (es) * | 2012-10-17 | 2015-05-06 | Merck Sharp & Dohme | Derivados de nucleosidos 2-metil sustituidos y metodos de uso de los mismos para el tratamiento de enfermedades virales |
| AU2014225052B2 (en) * | 2013-03-08 | 2016-11-10 | Nanjing Sanhome Pharmaceutical Co., Ltd. | Novel nucleoside phosphoramidate compound and use thereof |
| RU2534613C2 (ru) * | 2013-03-22 | 2014-11-27 | Александр Васильевич Иващенко | Алкил 2-{ [(2r,3s,5r)-5-(4-амино-2-оксо-2н-пиримидин-1-ил)- -гидрокси-тетрагидро-фуран-2-илметокси]-фенокси-фосфориламино} -пропионаты, нуклеозидные ингибиторы рнк-полимеразы hcv ns5b, способы их получения и применения |
-
2015
- 2015-07-15 WO PCT/CN2015/084044 patent/WO2016123905A1/en active Application Filing
- 2015-07-15 CN CN201580000349.8A patent/CN106132972B/zh not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| WO2016123905A1 (en) | 2016-08-11 |
| CN106132972A (zh) | 2016-11-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7413419B2 (ja) | （ｓ）－７－（１－アクリロイルピペリジン－４－イル）－２－（４－フェノキシフェニル）－４，５，６，７－テトラ－ヒドロピラゾロ［１，５－ａ］ピリミジン－３－カルボキサミドの結晶形、その調製、及びその使用 | |
| AU2011307087B2 (en) | Substituted polycyclic carbamoyl pyridone derivative prodrug | |
| JP6581607B2 (ja) | 多環式カルバモイルピリドン化合物の合成 | |
| US9676713B2 (en) | Crystal of pyrrole derivative and method for producing the same | |
| KR20150074187A (ko) | 항 바이러스성 포스포네이트 유사체 및 이의 제조를 위한 방법 | |
| US10870654B2 (en) | Pharmaceutically acceptable salts and polymorphic forms of hydrocodone benzoic acid enol ester and processes for making same | |
| EP3841101B1 (en) | Method for preparing 2-[(3r)-3-methylmorpholin-4-yl]-4-[1-methyl-1h-pyrazol-5-yl)-8-(1h-pyrazol-5-yl)-1,7-naphthyridine | |
| RU2572820C1 (ru) | Новые кристаллические кислотно-аддитивные соли трициклического производного или их гидраты и способ их получения | |
| CN106132972B (zh) | 用于治疗hcv感染的氨基磷酸酯 | |
| TW201829420A (zh) | [(1S)-1-[(2S,4R,5R)-5-(5-胺基-2-酮基-噻唑并[4,5-d]嘧啶-3-基)-4-羥基-四氫呋喃-2-基]丙基]乙酸酯之新穎固態形式 | |
| US20220162185A1 (en) | Crystalline and amorphous forms of n-(5-((4-ethylpiperazin-1-yl)methyl)pyridine-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-2h-indazol-5-yl)pyrimidin-2-amine and its salts, and preparation methods and therapeutic uses thereof | |
| EP4196131A1 (en) | Synthesis of fluorinated nucleotides | |
| JP2016172755A (ja) | 抗ウイルス化合物およびその有用な中間体の調製方法 | |
| US20240239791A1 (en) | Processes for the synthesis of valbenazine | |
| CN106518942B (zh) | 用于治疗hcv感染的新型环磷酯 | |
| EA047328B1 (ru) | КРИСТАЛЛИЧЕСКАЯ ФОРМА (S)-7-(1-АКРИЛОИЛПИПЕРИДИН-4-ИЛ)-2-(4-ФЕНОКСИФЕНИЛ)-4,5,6,7-ТЕТРАГИДРОПИРАЗОЛО[1,5-a]ПИРИМИДИН-3-КАРБОКСАМИДА, ЕЕ ПОЛУЧЕНИЕ И ПРИМЕНЕНИЯ | |
| CN115073518A (zh) | 磷酸双依达拉奉酯类化合物、及其制备方法和用途 | |
| TW201617326A (zh) | （ｓ）－１－（（２ｒ，３ｒ，４ｓ，５ｓ）－５－烯丙－３－甲氧－４－（對甲苯磺醯甲基）四氫呋喃－２－基）－３－氨基丙－２－醇之結晶衍生物 | |
| WO2024153119A1 (en) | Kras g12d inhibitors and uses thereof | |
| KR20110081382A (ko) | 결정성 아데포비어 디피복실 술폰산염 무수물, 그 제조방법 및 이를 포함하는 약제학적 조성물 | |
| CN117229223A (zh) | 一种杂环衍生物及其药物组合物、应用 | |
| EA041344B1 (ru) | КРИСТАЛЛИЧЕСКАЯ ФОРМА (S)-7-(1-АКРИЛОИЛПИПЕРИДИН-4-ИЛ)-2-(4-ФЕНОКСИФЕНИЛ)-4,5,6,7-ТЕТРАГИДРОПИРАЗОЛО[1,5-a]ПИРИМИДИН-3-КАРБОКСАМИДА, ЕЕ ПОЛУЧЕНИЕ И ПРИМЕНЕНИЯ |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180831 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |