CN104876880A - Diaryl ether derivatives as well as preparation method and application thereof - Google Patents
Diaryl ether derivatives as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN104876880A CN104876880A CN201510210449.5A CN201510210449A CN104876880A CN 104876880 A CN104876880 A CN 104876880A CN 201510210449 A CN201510210449 A CN 201510210449A CN 104876880 A CN104876880 A CN 104876880A
- Authority
- CN
- China
- Prior art keywords
- acid
- dmso
- pyrimidine
- alkynyl
- nmr
- 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.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 150000001987 diarylethers Chemical class 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 12
- 208000030507 AIDS Diseases 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- -1 nitro, amino, hydroxyl Chemical group 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 claims description 3
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- FFHWGQQFANVOHV-UHFFFAOYSA-N dimethyldioxirane Chemical compound CC1(C)OO1 FFHWGQQFANVOHV-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims description 2
- 229940049920 malate Drugs 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- VKJKEPKFPUWCAS-UHFFFAOYSA-M potassium chlorate Chemical compound [K+].[O-]Cl(=O)=O VKJKEPKFPUWCAS-UHFFFAOYSA-M 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910001927 ruthenium tetroxide Inorganic materials 0.000 claims description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 3
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 125000004185 ester group Chemical group 0.000 claims 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
- 125000002769 thiazolinyl group Chemical group 0.000 claims 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 1
- FICRUKJPZRGCSI-UHFFFAOYSA-N [Mg].C(C=1C(C(=O)OCCCCCCCC)=CC=CC1)(=O)OCCCCCCCC.C(C1=CC=CC=C1)(=O)OOC(C1=CC=CC=C1)=O Chemical class [Mg].C(C=1C(C(=O)OCCCCCCCC)=CC=CC1)(=O)OCCCCCCCC.C(C1=CC=CC=C1)(=O)OOC(C1=CC=CC=C1)=O FICRUKJPZRGCSI-UHFFFAOYSA-N 0.000 claims 1
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims 1
- 229940033355 lauric acid Drugs 0.000 claims 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims 1
- 229960005181 morphine Drugs 0.000 claims 1
- 230000003647 oxidation Effects 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 claims 1
- 150000002978 peroxides Chemical class 0.000 claims 1
- JRKICGRDRMAZLK-UHFFFAOYSA-N peroxydisulfuric acid Chemical compound OS(=O)(=O)OOS(O)(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-N 0.000 claims 1
- 150000003016 phosphoric acids Chemical class 0.000 claims 1
- 239000000651 prodrug Substances 0.000 claims 1
- 229940002612 prodrug Drugs 0.000 claims 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 229950004288 tosilate Drugs 0.000 claims 1
- 241000700605 Viruses Species 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 7
- 230000003013 cytotoxicity Effects 0.000 abstract description 5
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 5
- 238000002474 experimental method Methods 0.000 abstract description 5
- 241000713772 Human immunodeficiency virus 1 Species 0.000 abstract description 4
- 150000004677 hydrates Chemical class 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 abstract description 2
- 239000002243 precursor Substances 0.000 abstract description 2
- 239000012453 solvate Substances 0.000 abstract description 2
- 230000008827 biological function Effects 0.000 abstract 1
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- 230000010076 replication Effects 0.000 abstract 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 38
- 239000011734 sodium Substances 0.000 description 34
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- 238000002844 melting Methods 0.000 description 19
- 230000008018 melting Effects 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 15
- 241000725303 Human immunodeficiency virus Species 0.000 description 7
- 230000036436 anti-hiv Effects 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 230000000120 cytopathologic effect Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 102100034343 Integrase Human genes 0.000 description 4
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 4
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 4
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 3
- 229960003804 efavirenz Drugs 0.000 description 3
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 3
- 229960002049 etravirine Drugs 0.000 description 3
- PYGWGZALEOIKDF-UHFFFAOYSA-N etravirine Chemical compound CC1=CC(C#N)=CC(C)=C1OC1=NC(NC=2C=CC(=CC=2)C#N)=NC(N)=C1Br PYGWGZALEOIKDF-UHFFFAOYSA-N 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 229960000689 nevirapine Drugs 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical group OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 2
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 description 2
- 125000006310 cycloalkyl amino group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- CGBYTKOSZYQOPV-ASSBYYIWSA-N 5-chloro-3-[[3-[(e)-2-cyanoethenyl]-5-methylphenyl]-methoxyphosphoryl]-1h-indole-2-carboxamide Chemical compound C1([P@](=O)(C=2C3=CC(Cl)=CC=C3NC=2C(N)=O)OC)=CC(C)=CC(\C=C\C#N)=C1 CGBYTKOSZYQOPV-ASSBYYIWSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- MCPUZZJBAHRIPO-UHFFFAOYSA-N Lersivirine Chemical compound CCC1=NN(CCO)C(CC)=C1OC1=CC(C#N)=CC(C#N)=C1 MCPUZZJBAHRIPO-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 229960001413 acetanilide Drugs 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229960005319 delavirdine Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- BRDYCNFHFWUBCZ-UHFFFAOYSA-N dodecaneperoxoic acid Chemical compound CCCCCCCCCCCC(=O)OO BRDYCNFHFWUBCZ-UHFFFAOYSA-N 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- FZERHIULMFGESH-UHFFFAOYSA-N methylenecarboxanilide Natural products CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-N o-dicarboxybenzene Natural products OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- ZVIWEYTXPYNLGB-UHFFFAOYSA-M potassium;4-[[2-[[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-1,2,4-triazol-3-yl]sulfanyl]acetyl]amino]-3-chlorobenzoate Chemical compound [K+].ClC1=CC(C(=O)[O-])=CC=C1NC(=O)CSC1=NN=C(Br)N1C(C1=CC=CC=C11)=CC=C1C1CC1 ZVIWEYTXPYNLGB-UHFFFAOYSA-M 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 229960002814 rilpivirine Drugs 0.000 description 1
- YIBOMRUWOWDFLG-ONEGZZNKSA-N rilpivirine Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-ONEGZZNKSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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Abstract
本发明属于医药技术领域，具体涉及如通式Ⅰ的二芳醚类衍生物及其药用盐，其水合物和溶剂化物，其多晶或共晶，其同样生物功能的前体和衍生物，其制备方法以及含有一个或多个此类化合物的组合物在治疗艾滋病等相关药物中的应用。药理实验结果表明，该类化合物具有显著的抗HIV-1病毒活性，可以有效的抑制HIV-1病毒感染的MT-4细胞的复制，并且具有较低的细胞毒性。 The present invention belongs to the technical field of medicine, and specifically relates to diaryl ether derivatives such as general formula I and pharmaceutically acceptable salts thereof, hydrates and solvates thereof, polycrystals or cocrystals thereof, precursors and derivatives thereof with the same biological function , its preparation method and the application of the composition containing one or more such compounds in the treatment of AIDS and other related drugs. The results of pharmacological experiments show that the compound has significant anti-HIV-1 virus activity, can effectively inhibit the replication of HIV-1 virus-infected MT-4 cells, and has low cytotoxicity.
Description
技术领域 technical field
本发明属于医药技术领域，具体涉及一种二芳醚类衍生物及其制备方法和在治疗艾滋病等相关药物中的应用。 The invention belongs to the technical field of medicine, and specifically relates to a diaryl ether derivative, a preparation method thereof, and an application in treating AIDS and other related medicines.
背景技术 Background technique
艾滋病（AIDS）即获得性免疫缺陷综合征（Acquired immune deficiency syndrome）是由人类免疫缺陷病毒（Human immunodeficiency virus, HIV）所导致的流行性传染病。 AIDS (Acquired Immune Deficiency Syndrome) is an epidemic infectious disease caused by Human Immunodeficiency Virus (HIV).
逆转录酶（Reverse transcriptase, RT）在HIV从mRNA逆转录成DNA的过程中起了决定性作用，因此成为抗艾滋病药物设计的重要靶点之一。 Reverse transcriptase (Reverse transcriptase, RT) plays a decisive role in the process of HIV reverse transcription from mRNA to DNA, so it has become one of the important targets for the design of anti-AIDS drugs.
在现有的抗HIV药物研究中，非核苷类逆转录酶抑制剂（NNRTIs）因其高效低毒等优点而成为各国药物化学家关注的热点之一。目前，经美国FDA批准上市的抗HIV逆转录酶抑制剂有五种：奈维拉平（Nevirapine）、德拉韦定（Delavirdine）、依非韦伦（Efavirenz）、依曲韦林（Etravirine）、利匹韦林（Rilpivirine）。另外，RDEA806、IDX899、UK-453061正在进行临床研究。研究显示，经典的NNRTIs只作用于HIV-1，而对HIV-2病毒无效。 In the existing anti-HIV drug research, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have become one of the hotspots of medicinal chemists in various countries because of their high efficiency and low toxicity. Currently, there are five anti-HIV reverse transcriptase inhibitors approved by the US FDA: Nevirapine, Delavirdine, Efavirenz, Etravirine, Rilpivirine. In addition, RDEA806, IDX899, and UK-453061 are undergoing clinical research. Studies have shown that classic NNRTIs only act on HIV-1, but are ineffective against HIV-2 virus.
发明内容 Contents of the invention
本发明的目的在于提出一种逆转录酶抑制剂二芳醚类衍生物，具体涉及通式Ⅰ所述二芳醚类衍生物及其药用盐，其水合物和溶剂化物，其多晶和共晶，其同样生物功能的前体和衍生物。 The object of the present invention is to propose a kind of reverse transcriptase inhibitor diaryl ether derivatives, specifically related to the diaryl ether derivatives described in general formula I and pharmaceutically acceptable salts thereof, hydrates and solvates thereof, polymorphs and Co-crystals, their equally biologically functional precursors and derivatives.
本发明所提供的二芳醚类衍生物，具有如下结构式Ⅰ： The diaryl ether derivatives provided by the present invention have the following structural formula I:
其中，R1和R2分别独立选自氢，氰基，硝基，氨基，羟基，卤素，任选被取代的C1~6烷基，任选被取代的C2~6烯基，任选被取代的C2~6炔基或C1~6烷氧基； Wherein, R and R are independently selected from hydrogen , cyano, nitro, amino, hydroxyl, halogen, optionally substituted C 1 ~6 alkyl, optionally substituted C 2~6 alkenyl, any Choose substituted C 2~6 alkynyl or C 1~6 alkoxy;
R3选自氢，氰基，硝基，氨基，羟基，卤素，磺酸基，羧基，酯基，C1~6烷基，C1~6烷氧基，C1~6烷巯基，C3~6环烷基，C3~6环烷氧基，C3~6环烷氨基，C2~6烯基，C2~6炔基，取代的C2~6烯基或取代的C2~6炔基； R3 is selected from hydrogen, cyano, nitro, amino, hydroxyl, halogen, sulfonic acid, carboxyl, ester, C 1~6 alkyl, C 1~6 alkoxy, C 1 ~6 alkylmercapto, C 3~6 cycloalkyl, C 3~6 cycloalkoxy, C 3~6 cycloalkylamino, C 2~6 alkenyl, C 2~6 alkynyl, substituted C 2~6 alkenyl or substituted C 2~6 alkynyl groups;
Ar为单取代或多取代的芳环，芳环上的取代基选自氢，氰基，硝基，氨基，羟基，卤素，磺酸基，羧基，酯基，C1~6烷基，C1~6烷氧基，C1~6烷巯基，C3~6环烷基，C3~6环烷氧基，C3~6环烷氨基，C2~6烯基，C2~6炔基，取代的C2~6烯基或取代的C2~6炔基。 Ar is a monosubstituted or polysubstituted aromatic ring, and the substituents on the aromatic ring are selected from hydrogen, cyano, nitro, amino, hydroxyl, halogen, sulfonic acid, carboxyl, ester, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 alkylmercapto, C 3~6 cycloalkyl, C 3~6 cycloalkoxy , C 3~6 cycloalkylamino, C 2~6 alkenyl, C 2~6 Alkynyl, substituted C 2~6 alkenyl or substituted C 2~6 alkynyl.
本发明中，所述二芳醚类衍生物的药用盐包括盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、醋酸盐、甲磺酸盐、对甲苯磺酸盐、酒石酸盐、柠檬酸盐、富马酸盐或苹果酸盐。 In the present invention, the pharmaceutically acceptable salts of the diaryl ether derivatives include hydrochloride, hydrobromide, sulfate, phosphate, acetate, methanesulfonate, p-toluenesulfonate, tartrate, Citrate, fumarate or malate.
本发明还提出二芳醚类衍生物的制备方法，其制备的反应通式如下： The present invention also proposes the preparation method of diaryl ether derivatives, and the general reaction formula of its preparation is as follows:
具体操作步骤如下： The specific operation steps are as follows:
以上述结构式Ⅱ所示的化合物为原料，在溶剂中，与氧化剂反应，制得化合物Ⅰ； Using the compound represented by the above structural formula II as a raw material, reacting with an oxidizing agent in a solvent to prepare compound I;
所述的溶剂为水、二氯甲烷、氯仿、乙酸乙酯、甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、乙腈、四氢呋喃、硝基甲烷、醋酐、萘烷、N,N-二甲基甲酰胺中的一种或者多种； Described solvent is water, methylene chloride, chloroform, ethyl acetate, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, acetonitrile, tetrahydrofuran, nitromethane, acetic anhydride, decalin , one or more of N,N-dimethylformamide;
所述的氧化剂为双氧水、过氧化叔丁醇、间氯过氧苯甲酸、过氧乙酸、三氟过氧乙酸、过氧十二酸、高锰酸钾、重铬酸钾、高碘酸钠、高碘酸、次氯酸钠、次氯酸、氯酸钾、卤素、过硫酸氢钾复合盐、过二硫酸四丁基铵、四氧化钌、硝酸、氧气、N-甲基氧化吗啡、过氧化苯二甲酸镁盐、二甲基双环氧乙烷中的一种或者多种； The oxidizing agent is hydrogen peroxide, tert-butyl alcohol peroxide, m-chloroperoxybenzoic acid, peracetic acid, trifluoroperoxyacetic acid, peroxydodecanoic acid, potassium permanganate, potassium dichromate, sodium periodate , periodic acid, sodium hypochlorite, hypochlorous acid, potassium chlorate, halogen, potassium persulfate compound salt, tetrabutylammonium peroxodisulfate, ruthenium tetroxide, nitric acid, oxygen, N-methylmorphine oxide, phthalic acid peroxide One or more of magnesium salt and dimethyldioxirane;
所述的氧化剂与化合物Ⅱ的摩尔比为1:1~3:1，优选2.1:1~2.6:1； The molar ratio of the oxidizing agent to compound II is 1:1~3:1, preferably 2.1:1~2.6:1;
反应温度为0~50℃，优选20~40℃； The reaction temperature is 0~50°C, preferably 20~40°C;
反应时间为1~24h，优选5-10h。 The reaction time is 1~24h, preferably 5-10h.
本发明还涉及一种药物组合物，该组合物含有有效剂量的上述化合物和相关的药用载体，以及所述化合物或组合物在制备预防和治疗艾滋病药物中的应用。 The present invention also relates to a pharmaceutical composition, which contains an effective dose of the above compound and related pharmaceutical carriers, and the application of the compound or composition in the preparation of AIDS prevention and treatment drugs.
本发明基于二芳醚类衍生物与逆转录酶结合模式，结合计算机辅助药物设计，在中间嘧啶环与右翼的硫乙酰胺基链接子上引入氧原子，新引入的氧原子可与高度保守氨基酸残基Tyr318形成氢键，从而增强目标分子与逆转录酶的结合力，进一步提高目标化合物的抗病毒活性。生物活性测试表明，所有化合物均具有较强抗HIV-1病毒活性和较小的细胞毒性，具有较高的选择性指数。 The present invention is based on the combination mode of diaryl ether derivatives and reverse transcriptase, combined with computer-aided drug design, introduces an oxygen atom on the middle pyrimidine ring and the right-wing thioacetamide linker, and the newly introduced oxygen atom can be combined with a highly conserved amino acid Residue Tyr318 forms a hydrogen bond, thereby enhancing the binding force between the target molecule and reverse transcriptase, and further improving the antiviral activity of the target compound. Biological activity tests show that all compounds have strong anti-HIV-1 virus activity and low cytotoxicity, and have high selectivity index.
具体实施方式 Detailed ways
通过下述实施实例可以更好地理解本发明内容，但是不能限制本发明的内容。 The content of the present invention can be better understood through the following implementation examples, but the content of the present invention cannot be limited.
实施例1：终产物Ⅰ的合成 Embodiment 1: the synthesis of final product I
20~40℃下，将硫醚Ⅱ加入到溶剂中，搅拌溶解，然后加入氧化剂，搅拌5-10h。TLC显示反应完全。依次用饱和亚硫酸钠溶液、饱和碳酸钠溶液、水、饱和食盐水洗涤，有机相经无水硫酸钠干燥过夜。过滤，浓缩，甲苯重结晶，得到所需固体。 At 20~40℃, add thioether II into the solvent, stir to dissolve, then add oxidant, and stir for 5-10h. TLC showed the reaction was complete. It was washed successively with saturated sodium sulfite solution, saturated sodium carbonate solution, water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration, and recrystallization from toluene gave the desired solid.
以不同的硫醚Ⅱ用上述方法分别制得目标化合物，部分结果如下： The target compounds were prepared by the above method with different thioethers II, and some results are as follows:
室温下，将2-{[4-(4-氰基-2,6-二甲基苯酚)嘧啶-2-基]硫基}乙酰苯胺（5.53 mmol）加入到60 mL二氯甲烷中，搅拌溶解，然后加入间氯过氧苯甲酸（12.16 mmol），搅拌9h。TLC显示反应完全。依次用饱和亚硫酸钠溶液（20 mL × 2）、饱和碳酸钠溶液（20 mL × 2）、水（20 mL × 2）、饱和食盐水（20 mL × 2）洗涤，有机相经无水硫酸钠干燥过夜。过滤，浓缩，甲苯重结晶，得到所需固体。 At room temperature, add 2-{[4-(4-cyano-2,6-dimethylphenol)pyrimidin-2-yl]thio}acetanilide (5.53 mmol) into 60 mL of dichloromethane, stir Dissolved, then added m-chloroperoxybenzoic acid (12.16 mmol), stirred for 9h. TLC showed the reaction was complete. Wash successively with saturated sodium sulfite solution (20 mL × 2), saturated sodium carbonate solution (20 mL × 2), water (20 mL × 2), saturated brine (20 mL × 2), and dry the organic phase over anhydrous sodium sulfate overnight. Filtration, concentration, and recrystallization from toluene gave the desired solid.
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白色粉状固体；收率72%; 熔点：136.9–137.8℃; 1H NMR (400 MHz, DMSO-d 6) δ = 2.06 (s, 6H, 2CH 3), 4.54 (s, 2H, CH 2), 7.09 (t, J = 7.4 Hz, 1H, Ph’ H 4), 7.32 (t, J = 7.8 Hz, 2H, Ph’ H 3,5), 7.44 (d, J = 8.0 Hz, 2H, Ph’ H 2,6), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5), 7.64 (s, 2H, PhH 3,5), 9.00 (d, J = 5.6 Hz, 1H, pyrimidine H 6), 10.35 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d 6) δ = 15.66, 57.14, 109.29, 110.92, 118.45, 119.17, 124.15, 128.93, 132.29, 132.85, 138.16, 152.14, 159.55, 161.04, 164.19, 168.14; IR (KBr): ν? = 3347 (s; ν(N-H)), 2223 (s; ν(C≡N)), 1683 (s; ν(C=O)), 1326 (s; ν(S=O)), 1124 cm-1 (s; ν(S=O)); MS (ESI+) m/z 445 (M+Na)+; HRMS calcd for C21H18N4O4S [M+Na]+: 445.0946, found: 445.0930; HPLC: tR = 9.45 min, 97.35%。 White powdery solid; yield 72%; melting point: 136.9–137.8°C; 1 H NMR (400 MHz, DMSO- d 6 ) δ = 2.06 (s, 6H, 2C H 3 ), 4.54 (s, 2H, CH 2 ), 7.09 (t, J = 7.4 Hz, 1H, Ph ' H 4 ), 7.32 (t, J = 7.8 Hz, 2H, Ph ' H 3,5 ), 7.44 (d, J = 8.0 Hz, 2H, Ph ' H 2,6 ), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5 ), 7.64 (s, 2H, Ph H 3,5 ), 9.00 (d, J = 5.6 Hz, 1H, pyrimidine H 6 ), 10.35 (s, 1H, N H ); 13 C NMR (100 MHz, DMSO- d 6 ) δ = 15.66, 57.14, 109.29, 110.92, 118.45, 119.17, 124.15, 128.93, 132.29, 113.85.1 , 159.55, 161.04, 164.19, 168.14; IR (KBr): ν ? = 3347 (s; ν (NH)), 2223 (s; ν (C≡N)), 1683 (s; ν (C=O)) , 1326 (s; ν (S=O)), 1124 cm -1 (s; ν (S=O)); MS (ESI+) m/z 445 (M+Na) + ; HRMS calcd for C 21 H 18 N 4 O 4 S [M+Na] + : 445.0946, found: 445.0930; HPLC: t R = 9.45 min, 97.35%.
。 .
操作同上。白色粉状固体；收率74%; 熔点：136.6–137.4℃; 1H NMR (400 MHz, DMSO-d 6) δ = 2.06 (s, 6H, 2CH 3), 2.27 (s, 3H, CH 3), 4.52 (s, 2H, CH 2), 6.91 (d, J = 7.2 Hz, 1H, Ph’ H 4), 7.17-7.24 (m, 2H, Ph’ H 5,6), 7.29 (s, 1H, Ph’ H 2), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5), 7.62 (s, 2H, PhH 3,5), 9.00 (d, J = 5.6 Hz, 1H, pyrimidine H 6), 10.26 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d 6) δ = 15.65, 21.14, 57.08, 109.27, 110.91, 116.33, 118.45, 119.62, 124.81, 128.74, 132.26, 132.84, 138.12, 138.18, 152.12, 159.49, 161.04, 164.20, 168.11; MS (ESI+) m/z 459 (M+Na)+; HRMS calcd for C22H20N4O4S [M+Na]+: 459.1103, found: 459.1086; HPLC: tR = 9.98 min, 96.25%。 The operation is the same as above. White powdery solid; yield 74%; melting point: 136.6–137.4°C; 1 H NMR (400 MHz, DMSO- d 6 ) δ = 2.06 (s, 6H, 2C H 3 ), 2.27 (s, 3H, CH 3 ), 4.52 (s, 2H, CH 2 ), 6.91 (d, J = 7.2 Hz, 1H, Ph ' H 4 ), 7.17-7.24 (m, 2H, Ph ' H 5,6 ), 7.29 (s , 1H, Ph ' H 2 ), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5 ), 7.62 (s, 2H, Ph H 3,5 ), 9.00 (d, J = 5.6 Hz, 1H, pyrimidine H 6 ), 10.26 (s, 1H, N H ); 13 C NMR (100 MHz, DMSO- d 6 ) δ = 15.65, 21.14, 57.08, 109.27, 110.91, 116.33, 118.45, 119.62, 124.81, 118.72, 6 132.84, 138.12, 138.18, 152.12, 159.49, 161.04, 164.20, 168.11; MS (ESI+) m/z 459 (M+Na) + ; HRMS calcd for C 22 H 20 N 4 O 4 S [M+Na] + : 459.1103, found: 459.1086; HPLC: tR = 9.98 min, 96.25%.
。 .
操作同上。白色粉状固体；收率77%; 熔点：138.2–138.9℃; 1H NMR (400 MHz, DMSO-d 6) δ = 2.06 (s, 6H, 2CH 3), 2.25 (s, 3H, CH 3), 4.51 (s, 2H, CH 2), 7.10 (d, J = 8.4 Hz, 2H, Ph’ H 3,5), 7.33 (d, J = 8.0 Hz, 2H, Ph’ H 2,6), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5), 7.65 (s, 2H, PhH 3,5), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6), 10.27 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d 6) δ = 15.66, 20.48, 57.13, 109.28, 110.89, 118.45, 119.15, 129.27, 132.29, 132.85, 133.17, 135.68, 152.14, 159.26, 161.01, 164.19, 168.13; MS (ESI+) m/z 459 (M+Na)+; HRMS calcd for C22H20N4O4S [M+Na]+: 459.1103, found: 459.1099; HPLC: tR = 9.94 min, 96.77%。 The operation is the same as above. White powdery solid; yield 77%; melting point: 138.2–138.9°C; 1 H NMR (400 MHz, DMSO- d 6 ) δ = 2.06 (s, 6H, 2C H 3 ), 2.25 (s, 3H, CH 3 ), 4.51 (s, 2H, CH 2 ), 7.10 (d, J = 8.4 Hz, 2H, Ph ' H 3,5 ), 7.33 (d, J = 8.0 Hz, 2H, Ph ' H 2,6 ), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5 ), 7.65 (s, 2H, Ph H 3,5 ), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6 ), 10.27 (s , 1H, N H ); 13 C NMR (100 MHz, DMSO- D 6 ) Δ = 15.66, 20.48, 57.13, 109.28, 110.89, 118.45, 119.15, 129.27, 132.85, 133.17, 135.68, 152.26, 161.011111.011 , 164.19, 168.13; MS (ESI+) m/z 459 (M+Na) + ; HRMS calcd for C 22 H 20 N 4 O 4 S [M+Na] + : 459.1103, found: 459.1099; HPLC: t R = 9.94 min, 96.77%.
。 .
操作同上。白色粉状固体；收率78%; 熔点：129.8–130.7℃; 1H NMR (400 MHz, DMSO-d 6) δ = 2.06 (s, 6H, 2CH 3), 2.16 (s, 3H, CH 3), 2.17 (s, 3H, CH 3), 4.50 (s, 2H, CH 2), 7.04 (d, J = 8.0 Hz, 1H, Ph’ H 5), 7.16 (d, J = 8.0 Hz, 1H, Ph’ H 6), 7.22 (s, 1H, Ph’ H 2), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5), 7.63 (s, 2H, PhH 3,5), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6), 10.18 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d 6) δ = 15.66, 18.83, 19.59, 57.08, 109.27, 110.90, 116.67, 118.45, 120.29, 129.71, 131.97, 132.28, 132.85, 135.93, 136.58, 152.14, 159.21, 161.03, 164.22, 168.12; MS (ESI+) m/z 473 (M+Na)+; HRMS calcd for C23H22N4O4S [M+Na]+: 473.1259, found: 473.1260; HPLC: tR = 10.33 min, 97.04%。 The operation is the same as above. White powdery solid; yield 78%; melting point: 129.8–130.7°C; 1 H NMR (400 MHz, DMSO- d 6 ) δ = 2.06 (s, 6H, 2C H 3 ), 2.16 (s, 3H, CH 3 ), 2.17 (s, 3H, CH 3 ), 4.50 (s, 2H, CH 2 ), 7.04 (d, J = 8.0 Hz, 1H, Ph ' H 5 ), 7.16 (d, J = 8.0 Hz , 1H, Ph ' H 6 ), 7.22 (s, 1H, Ph ' H 2 ), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5 ), 7.63 (s, 2H, Ph H 3,5 ), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6 ), 10.18 (s, 1H, N H ); 13 C NMR (100 MHz, DMSO- d 6 ) δ = 15.66, 18.83, 19.59, 57.08, 109.27, 110.90, 116.67, 118.45, 120.29, 129.71, 131.97, 132.28, 132.85, 135.93, 136.58, 152.14, 159.21, 161.03, 164.22, 168.12 ; MS (ESI+) M/Z 473 (M+Na) + ; H 22 N 4 O 4 S [M+Na] + : 473.1259, found: 473.1260; HPLC: t R = 10.33 min, 97.04%.
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操作同上。白色粉状固体；收率79%; 熔点：144.3–145.0℃; 1H NMR (400 MHz, DMSO-d 6) δ = 2.06 (s, 6H, 2CH 3), 3.72 (s, 3H, CH 3), 4.49 (s, 2H, CH 2), 6.87 (d, J = 8.8 Hz, 2H, Ph’ H 3,5), 7.35 (d, J = 8.8 Hz, 2H, Ph’ H 2,6), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5), 7.66 (s, 2H, PhH 3,5), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6), 10.23 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d 6) δ = 15.65, 55.22, 57.09, 109.27, 110.87, 114.01, 118.45, 120.71, 131.30, 132.31, 132.85, 152.15, 155.77, 158.96, 161.00, 164.20, 168.13; MS (ESI+) m/z 475 (M+Na)+; HRMS calcd for C22H20N4O5S [M+Na]+: 475.1052, found: 475.1057; HPLC: tR = 9.24 min, 97.49%。 The operation is the same as above. White powdery solid; yield 79%; melting point: 144.3–145.0°C; 1 H NMR (400 MHz, DMSO- d 6 ) δ = 2.06 (s, 6H, 2C H 3 ), 3.72 (s, 3H, CH 3 ), 4.49 (s, 2H, CH 2 ), 6.87 (d, J = 8.8 Hz, 2H, Ph ' H 3,5 ), 7.35 (d, J = 8.8 Hz, 2H, Ph ' H 2,6 ), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5 ), 7.66 (s, 2H, Ph H 3,5 ), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6 ), 10.23 (s , 1H, N H ); 13 C NMR (100 MHz, DMSO- D 6 ) Δ = 15.65, 55.22, 57.09, 109.27, 110.87, 114.01, 118.45, 120.71, 132.31, 132.85, 155.77, 158.96, 161.00 , 164.20, 168.13; MS (ESI+) m/z 475 (M+Na) + ; HRMS calcd for C 22 H 20 N 4 O 5 S [M+Na] + : 475.1052, found: 475.1057; HPLC: t R = 9.24 min, 97.49%.
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操作同上。白色粉状固体；收率81%; 熔点：126.5–127.4℃; 1H NMR (400 MHz, DMSO-d 6) δ = 2.06 (s, 6H, 2CH 3), 4.69 (s, 2H, CH 2), 7.13-7.20 (m, 2H, Ph’ H 4,6), 7.25-7.30 (m, 1H, Ph’ H 5), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5), 7.66 (s, 2H, PhH 3,5), 7.80 (m, 1H, Ph’ H 2), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6), 10.18 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d 6) δ = 15.66, 56.68, 109.29, 110.93, 115.71 (d, J C-C-F = 19.1 Hz), 118.44, 123.20 (d, J C-C-F = 22.0 Hz), 124.53 (d, J C4-F = 3.5 Hz), 125.37 (d, J C3-F = 11.3 Hz), 125.89 (d, J C3-F = 7.5 Hz), 132.31, 132.87, 152.14, 154.29 (d, J C-F = 244.0 Hz), 160.23, 161.03, 164.20, 168.16; MS (ESI+) m/z 463 (M+Na)+; HRMS calcd for C21H17FN4O4S [M+Na]+: 463.0852, found: 463.0850; HPLC: tR = 9.53 min, 96.76%。 The operation is the same as above. White powdery solid; yield 81%; melting point: 126.5–127.4°C; 1 H NMR (400 MHz, DMSO- d 6 ) δ = 2.06 (s, 6H, 2C H 3 ), 4.69 (s, 2H, CH 2 ), 7.13-7.20 (m, 2H, Ph ' H 4,6 ), 7.25-7.30 (m, 1H, Ph ' H 5 ), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5 ), 7.66 (s, 2H, Ph H 3,5 ), 7.80 (m, 1H, Ph ' H 2 ), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6 ), 10.18 (s, 1H, N H ); 13 C NMR (100 MHz, DMSO- d 6 ) δ = 15.66, 56.68, 109.29, 110.93, 115.71 (d, J CCF = 19.1 Hz), 118.44, 123.20 (d, J CCF = 22.0 Hz), 124.53 (d, J C4-F = 3.5 Hz), 125.37 (d, J C3-F = 11.3 Hz), 125.89 (d, J C3-F = 7.5 Hz), 132.31, 132.87 , 152.14, 154.29 (d, J C3-F = 244.0 Hz ), 160.23, 161.03, 164.20, 168.16; MS (ESI+) m/z 463 (M+Na) + ; HRMS calcd for C 21 H 17 FN 4 O 4 S [M+Na] + : 463.0852, found: 463.0850; HPLC: tR = 9.53 min, 96.76%.
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操作同上。白色粉状固体；收率77%; 熔点：128.9–129.5℃; 1H NMR (400 MHz, DMSO-d 6) δ = 2.05 (s, 6H, 2CH 3), 4.56 (s, 2H, CH 2), 6.94 (t, J = 8.4 Hz, 1H, Ph’ H 4), 7.17 (d, J = 8.0 Hz, 1H, Ph’ H 6), 7.34-7.42 (m, 2H, Ph’ H 2,5), 7.56 (d, J = 5.6 Hz, 1H, pyrimidine H 5), 7.63 (s, 2H, PhH 3,5), 9.00 (d, J = 5.6 Hz, 1H, pyrimidine H 6), 10.57 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d 6) δ = 15.66, 57.11, 106.16 (d, J C-C-F = 26.2 Hz), 109.32, 110.81 (d, J C-C-F = 20.8 Hz), 111.00, 115.01 (d, J C4-F = 2.6 Hz), 118.44, 130.74 (d, J C3-F = 9.4 Hz), 132.28, 132.86, 139.85 (d, J C3-F = 11.1 Hz), 152.13, 160.02, 161.11, 163.30 (d, J C-F = 240.6 Hz), 164.14, 168.15; MS (ESI+) m/z 463 (M+Na)+; HRMS calcd for C21H17FN4O4S [M+Na]+: 463.0852, found: 463.0834; HPLC: tR = 9.65 min, 97.98%。 The operation is the same as above. White powdery solid; yield 77%; melting point: 128.9–129.5°C; 1 H NMR (400 MHz, DMSO- d 6 ) δ = 2.05 (s, 6H, 2C H 3 ), 4.56 (s, 2H, CH 2 ), 6.94 (t, J = 8.4 Hz, 1H, Ph ' H 4 ), 7.17 (d, J = 8.0 Hz, 1H, Ph ' H 6 ), 7.34-7.42 (m, 2H, Ph ' H 2, 5 ), 7.56 (d, J = 5.6 Hz, 1H, pyrimidine H 5 ), 7.63 (s, 2H, Ph H 3,5 ), 9.00 (d, J = 5.6 Hz, 1H, pyrimidine H 6 ), 10.57 ( s, 1H, N H ); 13 C NMR (100 MHz, DMSO- d 6 ) δ = 15.66, 57.11, 106.16 (d, J CCF = 26.2 Hz), 109.32, 110.81 (d, J CCF = 20.8 Hz), 111.00, 115.01 (d, J C4-F = 2.6 Hz), 118.44, 130.74 (d, J C3-F = 9.4 Hz), 132.28, 132.86, 139.85 (d, J C3-F = 11.1 Hz), 152.13, 160.02 , 161.11, 163.30 (d, J CF = 240.6 Hz), 164.14, 168.15; MS (ESI+) m/z 463 (M+Na) + ; HRMS calcd for C 21 H 17 FN 4 O 4 S [M+Na] + : 463.0852, found: 463.0834; HPLC: t R = 9.65 min, 97.98%.
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操作同上。白色粉状固体；收率75%; 熔点：124.1–125.0℃; 1H NMR (400 MHz, DMSO-d 6) δ = 2.06 (s, 6H, 2CH 3), 4.52 (s, 2H, CH 2), 7.15 (t, J = 8.8 Hz, 2H, Ph’ H 3,5), 7.45-7.49 (m, 2H, Ph’ H 2,6), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5), 7.65 (s, 2H, PhH 3,5), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6), 10.43 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d 6) δ = 15.67, 57.09, 109.32, 110.97, 115.70 (d, J C-C-F = 22.2 Hz), 118.48, 121.09 (d, J C3-F = 7.9 Hz), 132.33, 132.88, 134.58 (d, J C4-F = 2.4 Hz), 152.17, 159.51, 159.66 (d, J C-F = 239.4 Hz), 161.07, 164.17, 168.17; MS (ESI+) m/z 463 (M+Na)+; HRMS calcd for C21H17FN4O4S [M+Na]+: 463.0852, found: 463.0855; HPLC: tR = 9.52 min, 97.53%。 The operation is the same as above. White powdery solid; yield 75%; melting point: 124.1–125.0°C; 1 H NMR (400 MHz, DMSO- d 6 ) δ = 2.06 (s, 6H, 2C H 3 ), 4.52 (s, 2H, CH 2 ), 7.15 (t, J = 8.8 Hz, 2H, Ph ' H 3,5 ), 7.45-7.49 (m, 2H, Ph ' H 2,6 ), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5 ), 7.65 (s, 2H, Ph H 3,5 ), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6 ), 10.43 (s, 1H, N H ); 13 C NMR (100 MHz, DMSO- d 6 ) δ = 15.67, 57.09, 109.32, 110.97, 115.70 (d, J CCF = 22.2 Hz), 118.48, 121.09 (d, J C3-F = 7.9 Hz), 132.33, 132.88, 134.58 (d, J C4-F = 2.4 Hz), 152.17, 159.51, 159.66 (d, J CF = 239.4 Hz), 161.07, 164.17, 168.17; MS (ESI+) m/z 463 (M+Na) + ; HRMS calcd for C 21 H 17 FN 4 O 4 S [M+Na] + : 463.0852, found: 463.0855; HPLC: t R = 9.52 min, 97.53%.
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操作同上。白色粉状固体；收率76%; 熔点：130.1–130.9℃; 1H NMR (400 MHz, DMSO-d 6) δ = 2.06 (s, 6H, 2CH 3), 4.73 (s, 2H, CH 2), 7.20 (t, J = 7.6 Hz, 1H, Ph’ H 4), 7.32 (t, J = 7.6 Hz, 1H, Ph’ H 5), 7.49 (d, J = 8.0 Hz, 1H, Ph’ H 3), 7.54 (d, J = 5.6 Hz, 1H, pyrimidine H 5), 7.63 (d, J = 8.0 Hz, 1H, Ph’ H 6), 7.69 (s, 2H, PhH 3,5), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6), 9.93 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d 6) δ = 15.69, 56.61, 109.30, 110.95, 118.45, 125.18, 125.68, 126.80, 127.57, 129.68, 132.35, 132.90, 133.93, 152.16, 160.24, 161.02, 164.19, 168.21; MS (ESI+) m/z 479 (M+Na)+; HRMS calcd for C21H17ClN4O4S [M+Na]+: 479.0557, found: 479.0546; HPLC: tR = 9.89 min, 97.92%。 The operation is the same as above. White powdery solid; yield 76%; melting point: 130.1–130.9°C; 1 H NMR (400 MHz, DMSO- d 6 ) δ = 2.06 (s, 6H, 2C H 3 ), 4.73 (s, 2H, CH 2 ), 7.20 (t, J = 7.6 Hz, 1H, Ph ' H 4 ), 7.32 (t, J = 7.6 Hz, 1H, Ph ' H 5 ), 7.49 (d, J = 8.0 Hz, 1H, Ph ' H 3 ), 7.54 (d, J = 5.6 Hz, 1H, pyrimidine H 5 ), 7.63 (d, J = 8.0 Hz, 1H, Ph ' H 6 ), 7.69 (s, 2H, Ph H 3,5 ), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6 ), 9.93 (s, 1H, N H ); 13 C NMR (100 MHz, DMSO- d 6 ) δ = 15.69, 56.61, 109.30, 110.95, 118.45, 125.18, 125.68 , 126.80 , 127.57 , 129.68 , 132.35, 132.90, 133.93, 152.16, 160.24, 161.02, 164.19 , 168.21; O 4 S [M+Na] + : 479.0557, found: 479.0546; HPLC: t R = 9.89 min, 97.92%.
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操作同上。白色粉状固体；收率79%; 熔点：126.2–127.1℃; 1H NMR (400 MHz, DMSO-d 6) δ = 2.05 (s, 6H, 2CH 3), 4.55 (s, 2H, CH 2), 7.15 (d, J = 7.6 Hz, 1H, Ph’ H 4), 7.29 (d, J = 8.0 Hz, 1H, Ph’ H 6), 7.36 (t, J = 8.0 Hz, 1H, Ph’ H 5), 7.56 (d, J = 5.6 Hz, 1H, pyrimidine H 5), 7.62 (s, 2H, PhH 3,5), 7.65 (s, 1H, Ph’ H 2), 9.00 (d, J = 5.6 Hz, 1H, pyrimidine H 6), 10.56 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d 6) δ = 15.68, 57.13, 109.34, 110.04, 117.66, 118.46, 118.67, 123.96, 130.73, 132.30, 132.87, 133.27, 139.55, 152.14, 160.08, 161.13, 164.14, 168.16; MS (ESI+) m/z 479 (M+Na)+; HRMS calcd for C21H17ClN4O4S [M+Na]+: 479.0557, found: 479.0553; HPLC: tR = 10.13 min, 98.60%。 The operation is the same as above. White powdery solid; yield 79%; melting point: 126.2–127.1°C; 1 H NMR (400 MHz, DMSO- d 6 ) δ = 2.05 (s, 6H, 2C H 3 ), 4.55 (s, 2H, CH 2 ), 7.15 (d, J = 7.6 Hz, 1H, Ph ' H 4 ), 7.29 (d, J = 8.0 Hz, 1H, Ph ' H 6 ), 7.36 (t, J = 8.0 Hz, 1H, Ph ' H 5 ), 7.56 (d, J = 5.6 Hz, 1H, pyrimidine H 5 ), 7.62 (s, 2H, Ph H 3,5 ), 7.65 (s, 1H, Ph ' H 2 ), 9.00 (d, J = 5.6 Hz, 1H, pyrimidine H 6 ), 10.56 (s, 1H, N H ); 13 C NMR (100 MHz, DMSO- d 6 ) δ = 15.68, 57.13, 109.34, 110.04, 117.66, 118.46, 118.67, 123.9 , 130.73, 132.30, 132.87, 133.27, 139.55, 152.14, 160.08, 161.13, 164.14, 168.16; MS (ESI + ) m/z 479 (M + Na) + ; HRMS calcd for C21H174ClNS [ M4O +Na] + : 479.0557, found: 479.0553; HPLC: t R = 10.13 min, 98.60%.
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操作同上。白色粉状固体；收率82%; 熔点：132.8–133.6℃; 1H NMR (400 MHz, DMSO-d 6) δ = 2.05 (s, 6H, 2CH 3), 4.54 (s, 2H, CH 2), 7.36 (d, J = 8.8 Hz, 2H, Ph’ H 3,5), 7.47 (d, J = 8.8 Hz, 2H, Ph’ H 2,6), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5), 7.65 (s, 2H, PhH 3,5), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6), 10.51 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d 6) δ = 15.66, 57.11, 109.31, 110.97, 118.45, 120.76, 127.77, 128.87, 132.29, 132.86, 137.09, 152.13, 159.74, 161.06, 164.13, 168.15; MS (ESI+) m/z 479 (M+Na)+; HRMS calcd for C21H17ClN4O4S [M+Na]+: 479.0557, found: 479.0555; HPLC: tR = 10.11 min, 96.28%。 The operation is the same as above. White powdery solid; yield 82%; melting point: 132.8–133.6°C; 1 H NMR (400 MHz, DMSO- d 6 ) δ = 2.05 (s, 6H, 2C H 3 ), 4.54 (s, 2H, CH 2 ), 7.36 (d, J = 8.8 Hz, 2H, Ph ' H 3,5 ), 7.47 (d, J = 8.8 Hz, 2H, Ph ' H 2,6 ), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5 ), 7.65 (s, 2H, Ph H 3,5 ), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6 ), 10.51 (s, 1H, N H ); 13 C NMR ( 100 MHz, DMSO- D 6 ) Δ = 15.66, 57.11, 109.31, 110.97, 118.45, 120.76, 127.77, 128.87, 132.29, 132.86, 152.13, 159.74, 164.13, 168.15; ms (ESI+) m/ Z79 (M+Na) + ; HRMS calcd for C 21 H 17 ClN 4 O 4 S [M+Na] + : 479.0557, found: 479.0555; HPLC: t R = 10.11 min, 96.28%.
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操作同上。白色粉状固体；收率84%; 熔点：135.1–135.8℃; 1H NMR (400 MHz, DMSO-d 6) δ = 2.06 (s, 6H, 2CH 3), 4.74 (s, 2H, CH 2), 7.40 (d, J = 8.8 Hz, 1H, Ph’ H 5), 7.54 (d, J = 5.6 Hz, 1H, pyrimidine H 5), 7.66-7.69 (m, 4H, PhH 3,5 + Ph’ H 3,6), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6), 10.01 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d 6) δ = 15.70, 56.60, 109.31, 110.00, 118.45, 126.08, 127.73, 129.14, 129.88, 132.24, 132.35, 132.91, 133.14, 152.16, 160.42, 161.04, 164.16, 168.22; MS (ESI+) m/z 513 (M+Na)+; HRMS calcd for C21H16Cl2N4O4S [M+Na]+: 513.0167, found: 513.0169; HPLC: tR = 10.69 min, 97.67%。 The operation is the same as above. White powdery solid; yield 84%; melting point: 135.1–135.8°C; 1 H NMR (400 MHz, DMSO- d 6 ) δ = 2.06 (s, 6H, 2C H 3 ), 4.74 (s, 2H, CH 2 ), 7.40 (d, J = 8.8 Hz, 1H, Ph ' H 5 ), 7.54 (d, J = 5.6 Hz, 1H, pyrimidine H 5 ), 7.66-7.69 (m, 4H, Ph H 3,5 + Ph ' H 3,6 ), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6 ), 10.01 (s, 1H, N H ); 13 C NMR (100 MHz, DMSO- d 6 ) δ = 15.70, 56.60, 109.31, 110.00, 118.45, 126.08, 127.73, 129.14, 129.88, 132.24, 132.35, 132.91, 133.14, 152.16, 161.04, 164.16, 168.22; ms (ESI+) M/Z 513 (m+na) + ; calcd for C 21 H 16 Cl 2 N 4 O 4 S [M+Na] + : 513.0167, found: 513.0169; HPLC: t R = 10.69 min, 97.67%.
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操作同上。白色粉状固体；收率79%; 熔点：126.2–127.0℃; 1H NMR (400 MHz, DMSO-d 6) δ = 2.05 (s, 6H, 2CH 3), 4.55 (s, 2H, CH 2), 7.33-7.36 (m, 1H, Ph’ H 5), 7.56-7.59 (m, 2H, pyrimidine H 5 + Ph’ H 6), 7.63 (s, 2H, PhH 3,5), 7.81 (d, J = 2.4 Hz, 1H, Ph’ H 2), 9.00 (d, J = 5.6 Hz, 1H, pyrimidine H 6), 10.68 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d 6) δ = 15.64, 57.07, 109.31, 111.02, 118.40, 119.27, 120.37, 125.73, 130.93, 131.21, 132.24, 132.83, 138.13, 152.10, 160.17, 161.11, 164.08, 168.12; MS (ESI+) m/z 513 (M+Na)+; HRMS calcd for C21H16Cl2N4O4S [M+Na]+: 513.0167, found: 513.0162; HPLC: tR = 10.73 min, 97.34%。 The operation is the same as above. White powdery solid; yield 79%; melting point: 126.2–127.0°C; 1 H NMR (400 MHz, DMSO- d 6 ) δ = 2.05 (s, 6H, 2C H 3 ), 4.55 (s, 2H, CH 2 ), 7.33-7.36 (m, 1H, Ph ' H 5 ), 7.56-7.59 (m, 2H, pyrimidine H 5 + Ph ' H 6 ), 7.63 (s, 2H, Ph H 3,5 ), 7.81 ( d, J = 2.4 Hz, 1H, Ph ' H 2 ), 9.00 (d, J = 5.6 Hz, 1H, pyrimidine H 6 ), 10.68 (s, 1H, N H ); D 6 ) Δ = 15.64, 57.07, 109.31, 111.02, 118.40, 119.27, 120.37, 125.73, 130.93, 131.21, 132.24, 132.83, 138.13, 152.10, 160.17, 164.08, 168.12; ms (ESI++ /Z) m M+Na) + ; HRMS calcd for C 21 H 16 Cl 2 N 4 O 4 S [M+Na] + : 513.0167, found: 513.0162; HPLC: t R = 10.73 min, 97.34%.
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操作同上。白色粉状固体；收率77%; 熔点：123.2–124.1℃; 1H NMR (400 MHz, DMSO-d 6) δ = 2.05 (s, 6H, 2CH 3), 4.56 (s, 2H, CH 2), 7.33 (s, 1H, Ph’ H 4), 7.48 (s, 2H, Ph’ H 2,6), 7.56 (d, J = 5.6 Hz, 1H, pyrimidine H 5), 7.61 (s, 2H, PhH 3,5), 9.00 (d, J = 5.6 Hz, 1H, pyrimidine H 6), 10.71 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d 6) δ = 15.71, 57.10, 109.39, 111.15, 117.42, 118.45, 123.58, 132.31, 132.88, 134.41, 140.39, 152.16, 160.55, 161.22, 164.13, 168.17; MS (ESI-) m/z 489 (M-H)-; HRMS calcd for C21H16Cl2N4O4S [M+Na]+: 513.0167, found: 513.0162; HPLC: tR = 11.00 min, 97.36%。 The operation is the same as above. White powdery solid; yield 77%; melting point: 123.2–124.1°C; 1 H NMR (400 MHz, DMSO- d 6 ) δ = 2.05 (s, 6H, 2C H 3 ), 4.56 (s, 2H, CH 2 ), 7.33 (s, 1H, Ph ' H 4 ), 7.48 (s, 2H, Ph ' H 2,6 ), 7.56 (d, J = 5.6 Hz, 1H, pyrimidine H 5 ), 7.61 (s, 2H , Ph H 3,5 ), 9.00 (d, J = 5.6 Hz, 1H, pyrimidine H 6 ), 10.71 (s, 1H, N H ); 13 C NMR (100 MHz, DMSO- d 6 ) δ = 15.71, 57.10, 109.39, 111.15, 117.42, 118.45, 123.58, 132.31, 132.88, 134.41, 140.39, 152.16, 160.55, 161.22, 164.13, 168.17; MS (ESI-) M/Z 489 (MH) - ; HRMS CALCD FOR C 21 16 Cl 2 N 4 O 4 S [M+Na] + : 513.0167, found: 513.0162; HPLC: t R = 11.00 min, 97.36%.
。 .
操作同上。白色粉状固体；收率76%; 熔点：136.3–137.1℃; 1H NMR (400 MHz, DMSO-d 6) δ = 2.05 (s, 6H, 2CH 3), 4.53 (s, 2H, CH 2), 7.41 (d, J = 8.8 Hz, 2H, Ph’ H 3,5), 7.49 (d, J = 8.8 Hz, 2H, Ph’ H 2,6), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5), 7.65 (s, 2H, PhH 3,5), 9.00 (d, J = 5.6 Hz, 1H, pyrimidine H 6), 10.51 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d 6) δ = 15.70, 57.16, 109.34, 111.02, 115.88, 118.50, 121.17, 131.83, 132.34, 132.90, 137.53, 152.17, 159.81, 161.10, 164.15, 168.19; MS (ESI+) m/z 523 (M+Na)+; HRMS calcd for C21H17BrN4O4S [M+Na]+: 523.0052, found: 523.0056; HPLC: tR = 10.27 min, 98.48%。 The operation is the same as above. White powdery solid; yield 76%; melting point: 136.3–137.1°C; 1 H NMR (400 MHz, DMSO- d 6 ) δ = 2.05 (s, 6H, 2C H 3 ), 4.53 (s, 2H, CH 2 ), 7.41 (d, J = 8.8 Hz, 2H, Ph ' H 3,5 ), 7.49 (d, J = 8.8 Hz, 2H, Ph ' H 2,6 ), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5 ), 7.65 (s, 2H, Ph H 3,5 ), 9.00 (d, J = 5.6 Hz, 1H, pyrimidine H 6 ), 10.51 (s, 1H, N H ); 13 C NMR ( 100 MHz, DMSO- D 6 ) Δ = 15.70, 57.16, 109.34, 111.02, 115.88, 118.50, 121.17, 131.83, 132.34, 137.53, 152.17, 161.10, 164.15, 168.19 ; (M+Na) + ; HRMS calcd for C 21 H 17 BrN 4 O 4 S [M+Na] + : 523.0052, found: 523.0056; HPLC: t R = 10.27 min, 98.48%.
。 .
操作同上。白色粉状固体；收率78%; 熔点：222.4–223.1℃; 1H NMR (400 MHz, DMSO-d 6) δ = 2.04 (s, 6H, 2CH 3), 4.59 (s, 2H, CH 2), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5), 7.61-7.63 (m, 4H, PhH 3,5 + Ph’ H 3,5), 7.78 (d, J = 8.8 Hz, 2H, Ph’ H 2,6), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6), 10.79 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d 6) δ = 15.69, 57.17, 106.07, 109.35, 111.10, 118.49, 118.91, 119.36, 132.30, 132.89, 133.53, 142.26, 152.15, 160.52, 161.16, 164.11, 168.18; MS (ESI+) m/z 470 (M+Na)+; HRMS calcd for C22H17N5O4S [M+Na]+: 470.0899, found: 470.0890; HPLC: tR = 9.06 min, 98.87%。 The operation is the same as above. White powdery solid; yield 78%; melting point: 222.4–223.1°C; 1 H NMR (400 MHz, DMSO- d 6 ) δ = 2.04 (s, 6H, 2C H 3 ), 4.59 (s, 2H, CH 2 ), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5 ), 7.61-7.63 (m, 4H, Ph H 3,5 + Ph ' H 3,5 ), 7.78 (d, J = 8.8 Hz, 2H, Ph ' H 2,6 ), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6 ), 10.79 (s, 1H, N H ); 13 C NMR (100 MHz, DMSO- d 6 ) δ = 15.69, 57.17, 106.07, 109.35, 111.10, 118.49, 118.91, 119.36, 132.30, 132.89, 133.53, 142.26, 152.15, 160.52, 164.11, 168.18; ms (ESI+) M/ Z470 (M+NA) + ; calcd for C 22 H 17 N 5 O 4 S [M+Na] + : 470.0899, found: 470.0890; HPLC: t R = 9.06 min, 98.87%.
。 .
操作同上。白色粉状固体；收率79%; 熔点：197.6–198.4℃; 1H NMR (400 MHz, DMSO-d 6) δ = 2.04 (s, 6H, 2CH 3), 4.59 (s, 2H, CH 2), 7.20 (d, J = 8.8 Hz, 1H, Ph’ H 3), 7.41 (d, J = 8.4 Hz, 1H, Ph’ H 5), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5), 7.65 (s, 2H, PhH 3,5), 7.99 (d, J = 8.4 Hz, 1H, Ph’ H 6), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6), 10.79 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d 6) δ = 15.69, 57.17, 106.07, 110.25 (d, J C3-F = 9.5 Hz), 111.10, 118.49, 118.91, 120.12 (d, J C-C-F = 22.0 Hz), 124.11 (d, J C3-F = 11.0 Hz), 126.26 (d, J C-C-F = 23.2 Hz), 128.14 (d, J C4-F = 2.9 Hz), 132.30, 133.53, 152.15, 160.52, 161.16, 162.23 (d, J C-F = 246.0 Hz), 164.11, 168.18; MS (ESI+) m/z 488 (M+Na)+; HRMS calcd for C22H16FN5O4S [M+Na]+: 488.0805, found: 488.0799; HPLC: tR = 9.27 min, 96.67%。 The operation is the same as above. White powdery solid; yield 79%; melting point: 197.6–198.4°C; 1 H NMR (400 MHz, DMSO- d 6 ) δ = 2.04 (s, 6H, 2C H 3 ), 4.59 (s, 2H, CH 2 ), 7.20 (d, J = 8.8 Hz, 1H, Ph ' H 3 ), 7.41 (d, J = 8.4 Hz, 1H, Ph ' H 5 ), 7.55 (d, J = 5.6 Hz, 1H, pyrimidine H 5 ), 7.65 (s, 2H, Ph H 3,5 ), 7.99 (d, J = 8.4 Hz, 1H, Ph ' H 6 ), 8.99 (d, J = 5.6 Hz, 1H, pyrimidine H 6 ), 10.79 (s, 1H, N H ); 13 C NMR (100 MHz, DMSO- d 6 ) δ = 15.69, 57.17, 106.07, 110.25 (d, J C3-F = 9.5 Hz), 111.10, 118.49, 118.91, 120.12 ( d, J CCF = 22.0 Hz), 124.11 (d, J C3-F = 11.0 Hz), 126.26 (d, J CCF = 23.2 Hz), 128.14 (d, J C4-F = 2.9 Hz), 132.30, 133.53, 152.15, 160.52, 161.16, 162.23 (d, J CF = 246.0 Hz), 164.11, 168.18; MS (ESI+) m/z 488 (M+Na) + ; HRMS calcd for C 22 H 16 FN 5 O 4 S [M +Na] + : 488.0805, found: 488.0799; HPLC: t R = 9.27 min, 96.67%.
。 .
操作同上。白色粉状固体；收率79%; 熔点：123.7–124.6℃; 1H NMR (400 MHz, DMSO-d 6) δ = 2.05 (s, 6H, 2CH 3), 4.59 (s, 2H, CH 2), 7.57 (d, J = 5.6 Hz, 1H, pyrimidine H 5), 7.60 (s, 2H, PhH 3,5), 7.63 (d, J = 8.0 Hz, 1H, Ph’ H 5), 7.74 (d, J = 8.4 Hz, 1H, Ph’ H 6), 7.96 (d, J = 8.4 Hz, 1H, Ph’ H 4), 8.46 (s, 1H, Ph’ H 2), 9.01 (d, J = 5.6 Hz, 1H, pyrimidine H 6), 10.87 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d 6) δ = 15.68, 57.08, 109.33, 111.13, 113.30, 118.46, 118.81, 125.20, 130.56, 132.31, 132.87, 139.21, 148.03, 152.16, 160.52, 161.19, 164.15, 168.18; MS (ESI+) m/z 490 (M+Na)+; HRMS calcd for C21H17N5O6S [M+Na]+: 490.0797, found: 490.0803; HPLC: tR = 9.39 min, 97.04%。 The operation is the same as above. White powdery solid; yield 79%; melting point: 123.7–124.6°C; 1 H NMR (400 MHz, DMSO- d 6 ) δ = 2.05 (s, 6H, 2C H 3 ), 4.59 (s, 2H, CH 2 ), 7.57 (d, J = 5.6 Hz, 1H, pyrimidine H 5 ), 7.60 (s, 2H, Ph H 3,5 ), 7.63 (d, J = 8.0 Hz, 1H, Ph ' H 5 ), 7.74 (d, J = 8.4 Hz, 1H, Ph ' H 6 ), 7.96 (d, J = 8.4 Hz, 1H, Ph ' H 4 ), 8.46 (s, 1H, Ph ' H 2 ), 9.01 (d, J = 5.6 Hz, 1H, pyrimidine H 6 ), 10.87 (s, 1H, N H ); 13 C NMR (100 MHz, DMSO- d 6 ) δ = 15.68, 57.08, 109.33, 111.13, 113.30, 118.46, 118.81, 125.2 , 130.56, 132.31, 132.87, 139.21, 148.03, 152.16, 160.52 , 161.19 , 164.15, 168.18 ; MS (ESI+) m/z 490 (M+Na) + ; +Na] + : 490.0797, found: 490.0803; HPLC: t R = 9.39 min, 97.04%.
。 .
操作同上。白色粉状固体；收率76%; 熔点：187.1–187.7℃; 1H NMR (400 MHz, DMSO-d 6) δ = 2.04 (s, 6H, 2CH 3), 4.62 (s, 2H, CH 2), 7.57 (d, J = 5.6 Hz, 1H, pyrimidine H 5), 7.62 (s, 2H, PhH 3,5), 7.68 (d, J = 8.8 Hz, 2H, Ph’ H 2,6), 8.22 (d, J = 8.8 Hz, 2H, Ph’ H 3,5), 9.00 (d, J = 5.6 Hz, 1H, pyrimidine H 6), 10.95 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d 6) δ = 15.70, 57.15, 109.36, 111.14, 118.49, 119.12, 125.16, 132.30, 132.90, 142.96, 144.13, 152.15, 160.71, 161.18, 164.12, 168.19; MS (ESI+) m/z 490 (M+Na)+; HRMS calcd for C21H17N5O6S [M+Na]+: 490.0797, found: 490.0792; HPLC: tR = 9.39 min, 97.53%。 The operation is the same as above. White powdery solid; yield 76%; melting point: 187.1–187.7°C; 1 H NMR (400 MHz, DMSO- d 6 ) δ = 2.04 (s, 6H, 2C H 3 ), 4.62 (s, 2H, CH 2 ), 7.57 (d, J = 5.6 Hz, 1H, pyrimidine H 5 ), 7.62 (s, 2H, Ph H 3,5 ), 7.68 (d, J = 8.8 Hz, 2H, Ph ' H 2,6 ) , 8.22 (d, J = 8.8 Hz, 2H, Ph ' H 3,5 ), 9.00 (d, J = 5.6 Hz, 1H, pyrimidine H 6 ), 10.95 (s, 1H, N H ); 13 C NMR ( 100 MHz, DMSO- D 6 ) Δ = 15.70, 57.15, 109.36, 111.14, 118.49, 119.12, 125.16, 132.30, 132.90, 142.96, 144.13, 152.15, 161.18, 164.12 , 168.19; (M+Na) + ; HRMS calcd for C 21 H 17 N 5 O 6 S [M+Na] + : 490.0797, found: 490.0792; HPLC: t R = 9.39 min, 97.53%.
实施例2：抗HIV生物活性测试 Embodiment 2: anti-HIV biological activity test
体外细胞水平的抗HIV病毒活性由比利时Katholleke大学的Rega药物研究所测定，主要包括：对HIV感染的MT-4细胞的抑制活性及细胞毒性两方面。方法如下：使化合物在HIV感染的MT-4细胞中，于感染HIV不同时间，用MTT法测定药物对HIV诱变的细胞病变的保护作用，计算使50%的细胞免于HIV诱导的细胞病变所需的浓度半数有效浓度EC50，毒性测定与抗HIV活性实验平行进行，也是在MT-4细胞培养中，用MTT法测定使50%的未感染细胞发生细胞病变的浓度（CC50），并计算选择性指数SI = CC50/EC50。 The anti-HIV virus activity at the cell level in vitro was determined by the Rega Institute of Pharmacy at Katholleke University in Belgium, mainly including two aspects: inhibitory activity and cytotoxicity to HIV-infected MT-4 cells. The method is as follows: make the compound in HIV-infected MT-4 cells, at different times of HIV infection, use the MTT method to measure the protective effect of the drug on HIV-induced cytopathy, and calculate that 50% of the cells are free from HIV-induced cytopathy The half-effective concentration EC 50 of the required concentration, the toxicity test was carried out in parallel with the anti-HIV activity experiment, also in the MT-4 cell culture, the concentration that caused 50% of uninfected cells to undergo cytopathic changes (CC 50 ) was determined by the MTT method, And calculate the selectivity index SI = CC 50 /EC 50 .
材料与方法： Materials and Methods:
各化合物的抗HIV活性由药物对HIV在细胞中引起的细胞病变的抑制作用效率来监控。采用MT-4细胞进行细胞培养。采用的病毒株有：HIV-1病毒株ⅢB及HIV-2病毒株ROD。 The anti-HIV activity of each compound is monitored by the inhibitory effect of the drug on the cytopathic effect caused by HIV in cells. MT-4 cells were used for cell culture. The virus strains used are: HIV-1 virus strain ⅢB and HIV-2 virus strain ROD.
具体操作如下：将化合物用DMSO或水溶解后在磷酸盐缓冲食盐水溶液稀释，将3×105 MT-4细胞用100 μL各化合物不同浓度此溶液在37℃预培养1h，然后向该化合物中加入100 μL适当的病毒稀释液，将细胞于37℃培养1h。洗涤三次后，将细胞再次分别悬浮于含有或不含有化合物的培养介质中。接着将细胞在5% CO2氛围中，于37℃下再培养7天，并于感染后第三天用含有或不含有化合物的培养介质替换补充培养液。每种培养液条件重复操作两次。对病毒的细胞病变作用每天都用反向光学显微镜监控。典型来讲，本实验中所用的病毒稀释液常常会在病毒感染后第五天导致细胞病变。药物抑制浓度以药物对病毒细胞病变作用产生50%抑制作用而同时对细胞无直接毒性的浓度（CC50）表示。需要强调的是，当化合物水溶性较差，需要DMSO才能溶解时，DMSO比浓度相对于水来讲，一般低于10%（DMSO在MT-4细胞培养介质中最终浓度小于2%）。因为DMSO能影响测试化合物的抗病毒活性，对含有相同浓度DMSO溶液抗病毒活性对比空白实验也应该平行进行。另外，DMSO最终浓度（1/1000）远远低于HIV-1在T细胞中复制所需的浓度。 The specific operation is as follows: the compound is dissolved in DMSO or water and then diluted in phosphate buffered saline solution. 3×10 5 MT-4 cells are pre-incubated with 100 μL of the solution of different concentrations of each compound at 37°C for 1 hour, and then added to the compound Add 100 μL of appropriate virus dilution, and incubate the cells at 37°C for 1 h. After three washes, cells were resuspended in culture medium with or without compound, respectively. Cells were then cultured for an additional 7 days at 37°C in an atmosphere of 5% CO 2 , and the supplemented medium was replaced with medium with or without compound on the third day after infection. Each culture condition was repeated twice. The cytopathic effect on the virus was monitored daily using inverted light microscopy. Typically, the virus dilutions used in this experiment lead to cytopathic effects by day five after virus infection. The inhibitory concentration of the drug is expressed by the concentration (CC 50 ) at which the drug produces 50% inhibitory effect on the cytopathic effect of the virus and has no direct toxicity to the cells. It should be emphasized that when the compound is poorly soluble in water and requires DMSO to dissolve, the specific concentration of DMSO is generally lower than 10% relative to water (the final concentration of DMSO in MT-4 cell culture medium is less than 2%). Because DMSO can affect the antiviral activity of the test compound, the antiviral activity comparison blank experiment containing the same concentration of DMSO solution should also be carried out in parallel. In addition, the final concentration of DMSO (1/1000) was much lower than the concentration required for HIV-1 to replicate in T cells.
本发明用已上市药物奈维拉平（Nevirapine, NVP）、依非韦伦（Efavirenz, EFV）和依曲韦林（Etravirine, ETV）作对照品，部分目标化合物对HIV的抑制活性结果见表1 (Anti-HIV activity and cytotoxicity of compounds 1-19 in MT-4 cells)。 The present invention uses marketed drugs nevirapine (Nevirapine, NVP), efavirenz (EFV) and etravirine (Etravirine, ETV) as reference substances, and the results of the inhibitory activity of some target compounds on HIV are shown in Table 1 (Anti-HIV activity and cytotoxicity of compounds 1-19 in MT-4 cells).
。 .
表1Table 1 [a][a]
[a] All data represent mean values of at least three separate experiments. [b] EC50: effective concentration required to protect 50% of cells against viral cytopathicity in MT-4 cells. [c] CC50: cytotoxic concentration of the compound that reduces the normal uninfected MT-4 cell viability by 50%. [d] SI: selectivity index, ratio CC50/EC50 (WT)。 [a] All data represent mean values of at least three separate experiments. [b] EC 50 : effective concentration required to protect 50% of cells against viral cytopathicity in MT-4 cells. [c] CC 50 : cytotoxic concentration of the compound that reduces the normal uninfected MT-4 cell viability by 50%. [d] SI: selectivity index, ratio CC 50 /EC 50 (WT).
实验结果表明，化学通式中所包含的化合物普遍具有较强的抗HIV-1病毒活性，较小的细胞毒性和较高的选择性指数。 Experimental results show that the compounds contained in the general chemical formula generally have strong anti-HIV-1 virus activity, low cytotoxicity and high selectivity index.
本发明不限于上述实例。 The present invention is not limited to the above examples.
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| KUMARASWAMY GULLAPELLI,等: "SYNTHESIS AND ANTIFUNGAL ACTIVITY OF N (4-1H-BENZO [d] IMIDAZOLE -2YL) PHENYL)-2-(4-HYDROXY-6-SUSTITUTED PYRIMIDIN-2YL THIO /SULFONYL ACETAMIDE DERIVATIVES", 《INT J PHARM BIO SCI》 * |
| ZHIJUN ZHANG,等: "A Novel Nonnucleoside Analogue That Inhibits Human Immunodeficiency Virus Type 1 Isolates Resistant to Current Nonnucleoside Reverse Transcriptase Inhibitors", 《ANTIMICROBIAL AGENTS AND CHEMOTHERAPY》 * |
| 李国秀,等: "HIV-1非核苷类逆转录酶抑制剂的研究进展", 《中国药学杂志》 * |
| 闫任章,等: "非核苷类逆转录酶抑制剂的研究进展", 《中国药学杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105481729A (en) * | 2015-11-30 | 2016-04-13 | 重庆天奕恒化科技有限公司 | DL-homocysteic acid preparation method |
| CN105481729B (en) * | 2015-11-30 | 2018-10-09 | 重庆天奕恒化科技有限公司 | A kind of preparation method of DL- high-cysteic acids |
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