CN113845515A - Aromatic heterocyclic structure-containing dimethyl biphenyl diaryl pyrimidine derivative and preparation method and application thereof - Google Patents
Aromatic heterocyclic structure-containing dimethyl biphenyl diaryl pyrimidine derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN113845515A CN113845515A CN202111030896.4A CN202111030896A CN113845515A CN 113845515 A CN113845515 A CN 113845515A CN 202111030896 A CN202111030896 A CN 202111030896A CN 113845515 A CN113845515 A CN 113845515A
- Authority
- CN
- China
- Prior art keywords
- arh
- dmso
- amino
- compound
- 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
- -1 dimethyl biphenyl diaryl pyrimidine derivative Chemical class 0.000 title claims abstract description 59
- 125000006615 aromatic heterocyclic group Chemical group 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title abstract description 53
- 150000001875 compounds Chemical group 0.000 claims abstract description 81
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 239000004305 biphenyl Substances 0.000 claims abstract description 5
- 235000010290 biphenyl Nutrition 0.000 claims abstract description 5
- 230000008827 biological function Effects 0.000 claims abstract description 3
- 239000002243 precursor Substances 0.000 claims abstract description 3
- 239000012453 solvate Substances 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 153
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 129
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 47
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Cs2CO3 Substances [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 47
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 47
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 43
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- RZTDESRVPFKCBH-UHFFFAOYSA-N 1-methyl-4-(4-methylphenyl)benzene Chemical group C1=CC(C)=CC=C1C1=CC=C(C)C=C1 RZTDESRVPFKCBH-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 4
- 239000013078 crystal Substances 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 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
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 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
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-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
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 2
- 230000005496 eutectics Effects 0.000 claims description 2
- 229940049920 malate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 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
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims 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 claims 3
- 239000003937 drug carrier Substances 0.000 claims 1
- 150000004677 hydrates Chemical class 0.000 claims 1
- 239000000651 prodrug Substances 0.000 claims 1
- 229940002612 prodrug Drugs 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 54
- 239000003814 drug Substances 0.000 abstract description 14
- 229940079593 drug Drugs 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 11
- 241000713772 Human immunodeficiency virus 1 Species 0.000 abstract description 8
- 230000003013 cytotoxicity Effects 0.000 abstract description 6
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 6
- 241000725303 Human immunodeficiency virus Species 0.000 abstract description 5
- 238000002474 experimental method Methods 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 abstract description 5
- 238000000338 in vitro Methods 0.000 abstract description 3
- 230000004048 modification Effects 0.000 abstract description 3
- 238000012986 modification Methods 0.000 abstract description 3
- 208000030507 AIDS Diseases 0.000 abstract description 2
- 230000029812 viral genome replication Effects 0.000 abstract description 2
- 150000003384 small molecules Chemical class 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 154
- 238000006243 chemical reaction Methods 0.000 description 129
- 239000000243 solution Substances 0.000 description 88
- 239000000047 product Substances 0.000 description 86
- 239000007787 solid Substances 0.000 description 83
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 54
- 238000001914 filtration Methods 0.000 description 45
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 44
- 238000005160 1H NMR spectroscopy Methods 0.000 description 44
- 238000004128 high performance liquid chromatography Methods 0.000 description 43
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 43
- 238000003756 stirring Methods 0.000 description 43
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 42
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 42
- 238000012512 characterization method Methods 0.000 description 42
- 230000014759 maintenance of location Effects 0.000 description 42
- 238000002844 melting Methods 0.000 description 42
- 230000008018 melting Effects 0.000 description 42
- 239000012074 organic phase Substances 0.000 description 42
- 238000001953 recrystallisation Methods 0.000 description 41
- 239000007858 starting material Substances 0.000 description 41
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 40
- 238000006073 displacement reaction Methods 0.000 description 39
- 239000011541 reaction mixture Substances 0.000 description 39
- 210000004027 cell Anatomy 0.000 description 16
- 230000002401 inhibitory effect Effects 0.000 description 14
- 239000003112 inhibitor Substances 0.000 description 9
- 229940124821 NNRTIs Drugs 0.000 description 8
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 8
- 208000031886 HIV Infections Diseases 0.000 description 7
- 230000000840 anti-viral effect Effects 0.000 description 6
- 230000000120 cytopathologic effect Effects 0.000 description 6
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 5
- 230000036436 anti-hiv Effects 0.000 description 5
- 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 4
- 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 4
- 229960003804 efavirenz Drugs 0.000 description 4
- 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 4
- 229960000689 nevirapine Drugs 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- 241000700605 Viruses Species 0.000 description 3
- 239000002253 acid Substances 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
- 239000001963 growth medium Substances 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000005556 structure-activity relationship Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- KFOAKSUJQFDZJQ-UHFFFAOYSA-N (3-fluoro-2h-pyridin-3-yl)boronic acid Chemical compound OB(O)C1(F)CN=CC=C1 KFOAKSUJQFDZJQ-UHFFFAOYSA-N 0.000 description 2
- PZDAAZQDQJGXSW-UHFFFAOYSA-N 1-fluoro-4-(4-fluorophenyl)benzene Chemical group C1=CC(F)=CC=C1C1=CC=C(F)C=C1 PZDAAZQDQJGXSW-UHFFFAOYSA-N 0.000 description 2
- USJUQEVUEBCLLR-UHFFFAOYSA-N 1h-indol-4-ylboronic acid Chemical compound OB(O)C1=CC=CC2=C1C=CN2 USJUQEVUEBCLLR-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000036142 Viral infection Diseases 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 229960005319 delavirdine Drugs 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- KMEJCVYIVUQTSP-UHFFFAOYSA-N (2,6-difluoropyridin-4-yl)boronic acid Chemical compound OB(O)C1=CC(F)=NC(F)=C1 KMEJCVYIVUQTSP-UHFFFAOYSA-N 0.000 description 1
- ALGDKINLACWIRM-UHFFFAOYSA-N (2,6-dimethylpyridin-4-yl)boronic acid Chemical compound CC1=CC(B(O)O)=CC(C)=N1 ALGDKINLACWIRM-UHFFFAOYSA-N 0.000 description 1
- FNCAXVHODMJGMN-UHFFFAOYSA-N (2-cyanopyrimidin-5-yl)boronic acid Chemical compound OB(O)C1=CN=C(C#N)N=C1 FNCAXVHODMJGMN-UHFFFAOYSA-N 0.000 description 1
- WXGBZJJAGLSBPR-UHFFFAOYSA-N (2-fluoropyridin-4-yl)boronic acid Chemical compound OB(O)C1=CC=NC(F)=C1 WXGBZJJAGLSBPR-UHFFFAOYSA-N 0.000 description 1
- CYAAJADWKHNAHA-UHFFFAOYSA-N (2-methoxypyrimidin-4-yl)boronic acid Chemical compound COC1=NC=CC(B(O)O)=N1 CYAAJADWKHNAHA-UHFFFAOYSA-N 0.000 description 1
- UFYBTLOLWSABAU-UHFFFAOYSA-N (2-methylpyridin-4-yl)boronic acid Chemical compound CC1=CC(B(O)O)=CC=N1 UFYBTLOLWSABAU-UHFFFAOYSA-N 0.000 description 1
- ARAPPZBNPJIAQG-UHFFFAOYSA-N (2-methylpyrimidin-4-yl)boronic acid Chemical compound CC1=NC=CC(B(O)O)=N1 ARAPPZBNPJIAQG-UHFFFAOYSA-N 0.000 description 1
- AQTFSVZONUPBFN-UHFFFAOYSA-N (4-aminopyridin-3-yl)boronic acid Chemical compound NC1=CC=NC=C1B(O)O AQTFSVZONUPBFN-UHFFFAOYSA-N 0.000 description 1
- BHHPDDMECQZQNL-UHFFFAOYSA-N (4-cyanopyridin-3-yl)boronic acid Chemical compound OB(O)C1=CN=CC=C1C#N BHHPDDMECQZQNL-UHFFFAOYSA-N 0.000 description 1
- FJHZOURNTIVCIA-UHFFFAOYSA-N (4-fluoropyridin-3-yl)boronic acid Chemical compound OB(O)C1=CN=CC=C1F FJHZOURNTIVCIA-UHFFFAOYSA-N 0.000 description 1
- YUTPAZKVEOJQCY-UHFFFAOYSA-N (4-methoxypyridin-3-yl)boronic acid Chemical compound COC1=CC=NC=C1B(O)O YUTPAZKVEOJQCY-UHFFFAOYSA-N 0.000 description 1
- ZVCQZLAIBXKVFQ-UHFFFAOYSA-N (4-methylfuran-2-yl)boronic acid Chemical compound CC1=COC(B(O)O)=C1 ZVCQZLAIBXKVFQ-UHFFFAOYSA-N 0.000 description 1
- ASXFMIDIRZPCGK-UHFFFAOYSA-N (4-methylpyridin-3-yl)boronic acid Chemical compound CC1=CC=NC=C1B(O)O ASXFMIDIRZPCGK-UHFFFAOYSA-N 0.000 description 1
- DFUMIZDUIJNUJU-UHFFFAOYSA-N (4-methylthiophen-2-yl)boronic acid Chemical compound CC1=CSC(B(O)O)=C1 DFUMIZDUIJNUJU-UHFFFAOYSA-N 0.000 description 1
- CYEXXDYQJPRMIQ-UHFFFAOYSA-N (5-cyanopyridin-3-yl)boronic acid Chemical compound OB(O)C1=CN=CC(C#N)=C1 CYEXXDYQJPRMIQ-UHFFFAOYSA-N 0.000 description 1
- ZTBRRDJHPKCUIG-UHFFFAOYSA-N (5-ethylpyridin-3-yl)boronic acid Chemical compound CCC1=CN=CC(B(O)O)=C1 ZTBRRDJHPKCUIG-UHFFFAOYSA-N 0.000 description 1
- ISDFOFZTZUILPE-UHFFFAOYSA-N (5-methoxypyridin-3-yl)boronic acid Chemical compound COC1=CN=CC(B(O)O)=C1 ISDFOFZTZUILPE-UHFFFAOYSA-N 0.000 description 1
- REONQWGHSQHTAC-UHFFFAOYSA-N (5-methylpyridin-3-yl)boronic acid Chemical compound CC1=CN=CC(B(O)O)=C1 REONQWGHSQHTAC-UHFFFAOYSA-N 0.000 description 1
- NRIYPIBRPGAWDD-UHFFFAOYSA-N (5-methylthiophen-2-yl)boronic acid Chemical compound CC1=CC=C(B(O)O)S1 NRIYPIBRPGAWDD-UHFFFAOYSA-N 0.000 description 1
- WIKBZUXHNPONPP-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoro-2-iodo-2-(trifluoromethyl)propane Chemical compound FC(F)(F)C(I)(C(F)(F)F)C(F)(F)F WIKBZUXHNPONPP-UHFFFAOYSA-N 0.000 description 1
- DFUGYZQSDFQVPU-UHFFFAOYSA-N 1-benzofuran-3-ylboronic acid Chemical compound C1=CC=C2C(B(O)O)=COC2=C1 DFUGYZQSDFQVPU-UHFFFAOYSA-N 0.000 description 1
- IBCSNLAKMCMGCZ-UHFFFAOYSA-N 1-benzofuran-6-ylboronic acid Chemical compound OB(O)C1=CC=C2C=COC2=C1 IBCSNLAKMCMGCZ-UHFFFAOYSA-N 0.000 description 1
- HABOMNOJYJNVHE-UHFFFAOYSA-N 1h-indol-7-ylboronic acid Chemical compound OB(O)C1=CC=CC2=C1NC=C2 HABOMNOJYJNVHE-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- HFZIXSZWGHOUHU-UHFFFAOYSA-N CN(N1CC(=CC=C1)B(O)O)C Chemical compound CN(N1CC(=CC=C1)B(O)O)C HFZIXSZWGHOUHU-UHFFFAOYSA-N 0.000 description 1
- CTAOQSGVWVWALE-UHFFFAOYSA-N CSC1=C(C=NC=C1)B(O)O Chemical compound CSC1=C(C=NC=C1)B(O)O CTAOQSGVWVWALE-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- PHLLTVDZCKUNJN-UHFFFAOYSA-N [2-(trifluoromethyl)pyridin-4-yl]boronic acid Chemical compound OB(O)C1=CC=NC(C(F)(F)F)=C1 PHLLTVDZCKUNJN-UHFFFAOYSA-N 0.000 description 1
- OEZMIKKBMMAABO-UHFFFAOYSA-N [2-(trifluoromethyl)pyrimidin-5-yl]boronic acid Chemical compound OB(O)C1=CN=C(C(F)(F)F)N=C1 OEZMIKKBMMAABO-UHFFFAOYSA-N 0.000 description 1
- GPOLKFXETWUREM-UHFFFAOYSA-N [4-(trifluoromethyl)pyridin-3-yl]boronic acid Chemical compound OB(O)C1=CN=CC=C1C(F)(F)F GPOLKFXETWUREM-UHFFFAOYSA-N 0.000 description 1
- SFBQNNGMEKUJAN-UHFFFAOYSA-N [5-(trifluoromethyl)pyridin-3-yl]boronic acid Chemical compound OB(O)C1=CN=CC(C(F)(F)F)=C1 SFBQNNGMEKUJAN-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 230000002072 anti-mutant effect Effects 0.000 description 1
- 238000011225 antiretroviral therapy Methods 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- YNCYPMUJDDXIRH-UHFFFAOYSA-N benzo[b]thiophene-2-boronic acid Chemical compound C1=CC=C2SC(B(O)O)=CC2=C1 YNCYPMUJDDXIRH-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 238000011281 clinical therapy Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution 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
- 230000008034 disappearance Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- PZJSZBJLOWMDRG-UHFFFAOYSA-N furan-2-ylboronic acid Chemical compound OB(O)C1=CC=CO1 PZJSZBJLOWMDRG-UHFFFAOYSA-N 0.000 description 1
- CYEFKCRAAGLNHW-UHFFFAOYSA-N furan-3-ylboronic acid Chemical compound OB(O)C=1C=COC=1 CYEFKCRAAGLNHW-UHFFFAOYSA-N 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002825 nitriles Chemical class 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
- 230000003287 optical effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- ABMYEXAYWZJVOV-UHFFFAOYSA-N pyridin-3-ylboronic acid Chemical compound OB(O)C1=CC=CN=C1 ABMYEXAYWZJVOV-UHFFFAOYSA-N 0.000 description 1
- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 description 1
- HZFPPBMKGYINDF-UHFFFAOYSA-N pyrimidin-5-ylboronic acid Chemical compound OB(O)C1=CN=CN=C1 HZFPPBMKGYINDF-UHFFFAOYSA-N 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- KATIRQRAVXTBNY-UHFFFAOYSA-N quinolin-4-ylboronic acid Chemical compound C1=CC=C2C(B(O)O)=CC=NC2=C1 KATIRQRAVXTBNY-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000002441 reversible effect Effects 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
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- ARYHTUPFQTUBBG-UHFFFAOYSA-N thiophen-2-ylboronic acid Chemical compound OB(O)C1=CC=CS1 ARYHTUPFQTUBBG-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000002723 toxicity assay Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61P31/18—Antivirals for RNA viruses for HIV
-
- 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
- C07D239/48—Two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Tropical Medicine & Parasitology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- AIDS & HIV (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a dimethyl biphenyl diaryl pyrimidine derivative containing an aromatic heterocyclic structure, and a preparation method and application thereof. The biphenyl dimethyl diaryl pyrimidine derivative with the compound structure containing the aromatic heterocyclic structure comprises medicinal salt, stereochemical isomer, hydrate and solvate, and precursor and derivative with the same biological function; the invention also comprises a preparation method thereof and application of a composition containing one or more compounds in preparation of related medicaments for treating AIDS and the like. The results of in vitro cell level anti-HIV-1 activity experiments show that the small molecules have stronger anti-HIV-1 bioactivity, can obviously inhibit virus replication in MT-4 cells infected by HIV-1 viruses, and have lower cytotoxicity. And the compound is subjected to salifying modification, so that the water solubility of the original medicine can be effectively improved, and the compound is expected to become a candidate medicine for resisting HIV.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a biphenyl diaryl pyrimidine derivative containing an aromatic heterocyclic structure, and a preparation method and application thereof.
Background
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are widely used in the treatment of human immunodeficiency virus type I (HIV-1) as one of the essential components of highly active antiretroviral therapy (HAART). To date, 6 NNRTIs have been FDA approved and widely used in clinical therapy, and have the respective structural formulae:
Chemical structures of six FDA-approved anti-HIV drugs.
among them, Nevirapine (NVP), Delavirdine (DLV) and Efavirenz (EFV) are the first generation of NNRTIs with highly potent antiviral activity. However, such NNRTIs have a relatively rigid structure, which results in a low genetic barrier; shortly after its widespread use, a series of drug-resistant mutants was induced, including the single mutants K103N, Y181C, Y188L and the double mutant K103N/Y181C (RES 056). While all first generation NNRTIs have demonstrated undesirable antiviral activity against this class of mutants, this result has also directly led to their limited clinical use. In another aspect, second generation NNRTIs include etravirine (ETR,4), rilpivirine (RPV,5), and dorawirine (DOR, 6). Wherein ETR and RPV have a diarylpyrimidine (DAP Y) structural backbone and can be flexibly attached to an attachment pocket. This flexibility of binding can help minimize the loss of binding stability caused by mutations and allow ETR and RPV to have better inhibitory activity against a variety of clinically resistant strains than first generation NNRTIs. However, although the development of viral resistance to ETR and RPV was delayed, mutations in K103N and E138K still emerged and interfered with their clinical effects. Therefore, it is still important to find new inhibitors of the DAPY class with excellent activity against mutants.
Thus, dimethylbiphenyl-DAPY is a novel class of DAPYs designed and synthesized based on the structural skeleton of RPV. Most of the inhibitor molecules showed excellent antiviral activity against WT and mutant. Among them, Compound 7 is more against wild type HIV-1 strain (EC)501nM) and a number of clinically common mutants showed unusual inhibitory activity. However, with the strong hydrophobicity of dimethylbiphenyl, such inhibitor molecules exhibit very poor solubility (S)<1 μ g/mL) and undesirable drug-like characteristics. On the basis of the structure, a series of DAPYs with difluoro-biphenyl structure also come into play, such as:
Representative biphenyl-DAPYs developed by our group with their advantages and drawbacks
of these, both compounds 8 and 9 retained extremely excellent inhibitory activity (EC) against wild-type HIV-1 strains501nM) and improved in the pharmaceutical activity of the inhibitor molecules. Comparison with Compound 7 (S)<1 μ g/mL, pH 2.0), compound 8 had significantly higher solubility (S5.6 μ g/mL, pH 2.0). To further increase the solubility of the inhibitor molecules, this group of subjects used a strategy of introducing heterocycles into the biphenyl fragments, resulting in a series of heteroaryl-biphenyl-DAPYs. Among them, Compound 10 not only has extremely high inhibitory Activity (EC)501nM) and also very high solubility (S611 μ g/mL, pH 2.0). However, the above compounds all lost the inhibitory activity against the double mutant strain and the inhibitory activity against the mutant strain Y188L was also significantly reduced as compared with dimethyl-biphenyl-DAPYs. Therefore, a novel D having high solubility and high inhibitory activity against both WT and mutant strains was soughtAPY is still necessary.
Disclosure of Invention
The invention aims to provide a dimethyl biphenyl diaryl pyrimidine compound with strong biological activity and small cytotoxicity and containing an aromatic heterocyclic structure, and a preparation method and application thereof
The invention provides a dimethyl biphenyl diaryl pyrimidine derivative containing an aromatic heterocyclic structure, which has a structural formula shown as the following formula (I):
wherein R is1Selected from furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, p-aminophenyl, C7～10Aryl heterocyclic radical, optionally substituted furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, C7～10An aromatic heterocyclic group;
the invention provides a dimethyl biphenyl diaryl pyrimidine derivative containing an aromatic heterocyclic structure, which also comprises a medicinal salt, a stereochemical isomer, a hydrate and a solvate thereof, a polycrystal or eutectic crystal and an X-ray diffraction single crystal of a single enantiomer, and a precursor and a derivative thereof with the same biological function.
The medicinal salt of the derivative of the dimethyl biphenyl diaryl pyrimidine containing the aromatic heterocyclic structure comprises hydrochloride, hydrobromide, formate, methanesulfonate, trifluoromethanesulfonate, sulfate, phosphate, acetate, p-toluenesulfonate, tartrate, citrate, succinate, maleate, fumarate or malate.
The invention also provides a preparation method of the dimethyl biphenyl diaryl pyrimidine derivative containing the aromatic heterocyclic structure, which comprises the following specific steps:
in a solvent, compound II (4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile) in Pd (dppf) Cl2Cesium carbonate (Cs)2CO3) Under the action of the acid to obtain the compound through Suzuki-coupling reactionI, the reaction formula for its preparation is as follows:
the reaction conditions were as follows:
the solvent is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, dichloromethane, dichloroethane, toluene, tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, 1, 4-dioxane and ethyl acetate;
the molar ratio of the compound II to the heterocyclic boric acid is 1:1-1: 8;
the compound II is mixed with Pd (dppf) Cl2In a molar ratio of 1:0.01-1: 0.10;
the compound II and Cs2CO3The molar ratio of (1: 1) - (1: 2);
the reaction temperature is 40-180 ℃;
the reaction time is 4-24 h.
The invention also relates to a pharmaceutical composition containing an effective dose of at least one of the compounds and a related medicinal carrier.
The pharmaceutical composition also comprises a pharmaceutical composition prepared by adopting the compound as an active ingredient.
The invention also relates to application of the compound or the composition in preparation of drugs for preventing and treating AIDS.
Based on the structure-activity relationship (SAR) research of biphenyl diaryl pyrimidine derivatives containing aromatic heterocyclic structures and HIV reverse transcriptase, the invention discovers that the dimethyl biphenyl segments can provide a dihedral angle higher than that of difluoro biphenyl, thereby further stabilizing the binding conformation of the inhibitor. At the same time, this particular structure is also an important component which influences the antiviral activity of the inhibitors, in particular the inhibitory activity of the anti-mutant strains. In addition, previous research fully proves that the heterocyclic skeleton can effectively improve the water solubility of the inhibitor molecule, so that the related pharmacy parameters of the inhibitor molecule are optimized. Therefore, fusing these two fragments is a logical strategy for generating novel NNRTIs templates. In this study, we first studied a variety of five-and six-membered unsaturated heterocycles thoroughly to explore deeply their inhibitory activity, SAR and their solubility characteristics. DAPYs having a dimethylbiphenyl structure are expected to effectively retain high inhibitory activity against a variety of clinical mutants because of their higher dihedral angle. The results of in vitro cell level anti-HIV-1 activity experiments show that the series of compounds have remarkable anti-HIV-1 activity and lower cytotoxicity. Meanwhile, salifying modification is carried out on the molecules, and solubility experiments prove that the medicinal salts of the series of compounds show excellent water solubility in various pH ranges, and have good clinical application prospects.
Detailed Description
The invention will be better understood by the following examples of implementation, but is not intended to limit the scope of the invention.
Example 1: preparation of the target product (Ia)
Compound II in Pd (dppf) Cl2And carrying out Suzuki-coupling reaction under the action of cesium carbonate to obtain the compound I. Wherein the solvent is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, dichloromethane, dichloroethane, toluene, tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, 1, 4-dioxane, ethyl acetate, etc.; the reaction temperature is 40-180 ℃, and the reaction time is 4-14 h.
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (1.0mmol), Pd (dppf) Cl2(0.01mmol) and 2-Furanboronic acid (1.2mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. The starting material disappeared and the reaction was complete by TLC (PE/EA: 1/1). The reaction temperature was adjusted to room temperature, and saturated sodium sulfite solution (20 mL. times.2) and saturated sodium carbonate were used in this orderThe solution (20 mL. times.2), water (20 mL. times.2), and a saturated saline solution (20 mL. times.2) were washed, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (Ia).
Characterization of the target product (Ia): a white powdery solid; the yield is 87%; melting point: 228.9-229.1 deg.C (from MeOH).1H NMR(400MHz,DMSO–d6)δ1H NMR(400MHz,DMSO)δ9.60(s,1H,NH),8.89(s,1H, NH),8.04(m,2H,ArH),7.77(m,2H,ArH),7.73(m,1H,ArH),7.55(s,2H,ArH),7.39(m,1H, ArH),6.97(d,J＝4Hz,1H,ArH),6.63(m,1H,ArH),6.39(m,1H,ArH),2.23(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.5,159.8,156.2,153.5,146.1,143.2,137.0,136.4,132.9, 128.9,123.6,120.2,118.4,112.5,106.0,101.8,99.2,18.8.HRMS(ESI-):m/z calcd for C23H18N5O[M-H]-380.1517,found 380.1510.HPLC analysis:retention time＝7.70min；peak area,99.30％％(λ＝254nm).
Example 2: preparation of the target product (Ib)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 2-thiopheneboronic acid (1.2mmol) were added to 1, 4-dioxane (5mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 150 ℃, and the stirring is carried out for 4 hours. The starting material disappeared and the reaction was complete by TLC (PE/EA: 1/1). The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (Ib).
Characterization of the target product (Ib): a white powdery solid; the yield is 81%; melting point: 217.0-217.4 deg.C.1H NMR (400MHz,DMSO–d6)δ9.56(s,1H,NH),8.86(s,1H,NH),8.07-8.02(m,2H,ArH),7.89-7.88 (m,1H,ArH),7.72-7.70(m,2H,ArH),7.66-7.65(m,1H,ArH),7.61-7.60(m,1H,ArH),7.55(s, 2H,ArH),7.38-7.35(m,1H,ArH),6.36(m,1H,ArH),2.32(s,6H,CH3).13C NMR(100MHz, DMSO–d6)δ:162.5,159.8,156.1,146.1,141.7,136.8,136.0,133.7,132.9,127.5,126.7,126.1, 121.0,120.2,118.4,101.7,99.2,18.9.HRMS(ESI-):m/z calcd for C23H18N5S[M-H]-396.1288, found 396.1287.HPLC analysis:retention time＝8.05min；peak area,94.87％％(λ＝254nm)。
Example 3: preparation of the target product (ic)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 3-Furanboronic acid (1.0mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 80 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (ic).
Characterization of the target product (Ic): a white powdery solid; the yield is 87%; melting point: 227.9-228.2 ℃.1H NMR (400MHz,DMSO–d6)δ9.58(s,1H,NH),8.86(s,1H,NH),8.22(s,1H,ArH),8.03(m,2H, ArH),7.77(s,1H,ArH),7.73-7.71(m,2H,ArH),7.46(s,2H,ArH),7.39-7.37(m,1H,ArH), 7.01(s,1H,ArH),6.37(m,1H,ArH),2.21(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ: 13C NMR(101MHz,DMSO)δ162.5,159.8,156.1,146.1,144.7,139.6,136.8,135.8,132.9, 130.4,126.1,125.6,120.2,118.4,109.2,101.7,99.2,18.8.HRMS(ESI-):m/z calcd for C23H18N5O[M-H]-380.1517,found 380.1519.HPLC analysis:retention time＝7.34min；peak area,97.02％(λ＝254nm)。
Example 4: preparation of the target product (Id)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 5-pyrimidineboronic acid (8.0mmol) were added to toluene (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 100 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (Id).
Characterization of the target product (Id): a white powdery solid; the yield is 94%; melting point: 254.0-254.3 deg.C.1H NMR (400MHz,DMSO–d6)δ9.60(s,1H,NH),9.22(m,3H,ArH),8.94(s,1H,NH),8.05-8.04(m, 1H,ArH),7.72(m,2H,ArH),7.67(m,2H,ArH),7.45-7.43(m,2H,ArH),6.40(m,1H,ArH), 2.28(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.4,159.8,157.6,156.2,155.0,146.0, 137.9,137.5,133.4,133.0,132.1,126.9,120.2,118.4,101.8,99.3,18.9.HRMS(ESI-):m/z calcd for C23H18N7[M-H]-392.1629,found 392.1625.HPLC analysis:retention time＝5.08min； peak area,99.39％(λ＝254nm)。
Example 5: preparation of the target product (ie)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 4-pyridineboronic acid (8.0mmol) were added to methanol (6mL) over N2The replacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 24 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (ie).
Characterization of the target product (Ie): a white powdery solid; the yield is 70%; melting point:>300℃。1H NMR(400 MHz,DMSO–d6)δ9.59(s,1H,NH),8.94(s,1H,NH),8.67-8.66(m,2H,ArH),8.03(m,2H, ArH),7.77-7.65(m,6H,ArH),7.38(m,1H,ArH),6.38(m,1H,ArH),2.26(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.4,159.7,156.3,150.7,147.2,146.1,138.1,137.3,135.5, 132.9,126.9,121.6,120.1,118.4,101.8,99.3,18.9.HRMS(ESI-):m/z calcd for C24H19N6[M-H]-391.1677,found 391.1678.HPLC analysis:retention time＝6.00min；peak area,97.47％ (λ＝254nm)。
example 6: preparation of the target product (if)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 3-pyridineboronic acid (4.0mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 14 hours. The starting material disappeared and the reaction was complete by TLC (PE/EA: 1/1). The reaction temperature was adjusted to room temperature, and saturated sodium sulfite solution (20 mL. times.2), saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2), and saturated sodium sulfite were used in this orderAnd brine (20 mL. times.2), and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (if).
Characterization of the target product (If): a white powdery solid; the yield is 94%; melting point: 224.6-224.9 ℃.1H NMR (400MHz,DMSO–d6)δ9.60(s,1H,NH),8.99(s,1H,ArH),8.93(s,1H,NH),8.60(d,J＝4Hz. 1H,ArH),8.13(d,J＝8Hz.1H,ArH),8.05(m,2H,ArH),7.75-7.73(m,2H,ArH),7.58(m,2H, ArH),7.53-7.50(m,1H,ArH),7.41(m,1H,ArH),6.40(m,1H,ArH),2.27(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.5,159.8,156.1,148.8,148.1,146.1,137.4,137.2,135.7, 135.4,134.4,132.9,126.9,124.3,120.2,118.4,101.8,99.3,18.9.HRMS(ESI-):m/z calcd for C24H19N6[M-H]-391.1677,found 391.1672.HPLC analysis:retention time＝8.99min；peak area,99.87％(λ＝254nm)。
Example 7: preparation of the target product (Ig)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.05mmol) and 3-benzofuranboronic acid (4.0mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2), and a saturated brine (20 mL. times.2), and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (ig).
Characterization of the target product (Ig): a white powdery solid; the yield is 70%; melting point: 245.9-246.3 ℃.1H NMR (400MHz,DMSO–d6)δ9.63(s,1H,NH),8.95(s,1H,NH),8.42(s,1H,ArH),8.08-8.02(m, 3H,ArH),7.78-7.69(m,3H,ArH),7.60(s,2H,ArH),7.46-7.39(m,3H,ArH),6.43(m,1H, ArH),2.30(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.5,159.8,156.1,155.7,146.1, 143.0,137.2,136.4,132.9,129.9,127.0,126.2,125.2,123.8,121.4,120.9,120.1,118.4,112.3, 101.8,99.3,18.9.HRMS(ESI-):m/z calcd for C27H20N5O[M-H]-430.1673,found 430.1656. HPLC analysis:retention time＝8.99min；peak area,99.87％(λ＝254nm)。
Example 8: preparation of the target product (ih)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.08mmol) and 2-benzothiopheneboronic acid (8.0mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2), and a saturated brine (20 mL. times.2), and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (ih).
Characterization of the target product (Ih): a white powdery solid; the yield is 92 percent; melting point: 266.7-267.0 ℃.1H NMR (400MHz,DMSO–d6)δ9.61(s,1H,NH),8.94(s,1H,NH),8.05(m,1H,ArH),7.99(d,J＝8 Hz.1H,ArH),7.89(m,1H,ArH),7.87(d,J＝8Hz.1H,ArH),7.74(m,2H,ArH),7.62(s,2H, ArH),7.43-7.35(m,4H,ArH),6.40(m,1H,ArH),2.26(s,6H,CH3).13C NMR(100MHz, DMSO–d6)δ:162.4,159.8,156.2,146.1,143.5,141.0,139.1,137.4,132.9,132.0,126.2,125.3, 125.0,124.2,122.9,120.3,120.2,118.5,101.8,18.8.HRMS(ESI-):m/z calcd for C27H20N5S [M-H]-446.1445,found 446.1444.HPLC analysis:retention time＝5.30min；peak area,98.57％ (λ＝254nm)。
Example 9: preparation of the target product (II)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 6-benzofuranboronic acid (1.2mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 100 ℃, and the stirring is carried out for 4 hours. The starting material disappeared and the reaction was complete by TLC (PE/EA: 1/1). The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (II). :
characterization of the target product (Ii): a white powdery solid; the yield is 92 percent; melting point: 218.3-219.2 ℃.1H NMR (400MHz,DMSO–d6)δ9.58(s,1H,NH),8.89(s,1H,NH),8.12(m,1H,ArH),8.07-8.03(m, 2H,ArH),7.99(m,1H,ArH),7.79-7.65(m,4H,ArH),7.52(s,2H,ArH),7.41-7.39(m,1H, ArH),7.04(d,J＝4Hz,1H,ArH),6.40(m,1H,ArH),2.27(s,6H,CH3).13C NMR(100MHz, DMSO)δ162.6,159.8,156.01,154.4,147.1,146.1,139.1,136.9,136.1,135.7,132.9,128.4, 127.0,123.9,120.2,119.7,118.5,112.0,107.5,101.7,99.3,18.9.HRMS(ESI-):m/z calcd for C27H20N5O[M-H]-430.1673,found 430.1672.HPLC analysis:retention time＝8.80min；peak area,100％(λ＝254nm)。
Example 10: preparation of the target product (Ij)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and indole-4-boronic acid (1.2mmol) were added to methanol (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (ij).
Characterization of the target product (Ij): a white powdery solid; the yield is 90 percent; melting point: 279.4-280.1 ℃.1H NMR (400MHz,DMSO–d6)δ11.30(s,1H,NH),9.61(s,1H,NH),8.90(s,1H,NH),8.05(m,2H, ArH),7.77-7.75(m,2H,ArH),7.51(s,2H,ArH),7.48-7.45(m,2H,ArH),7.42-7.40(m,1H, ArH),7.23(t,J＝8Hz.1H,ArH),7.16(t,J＝8Hz.1H,ArH),6.66(s,1H,ArH),6.42(m,1H, ArH),2.29(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ162.6,159.8,156.1,146.2,139.6, 136.9,136.6,135.8,133.2,132.9,128.2,126.2,126.1,121.8,120.1,118.9,118.5,111.3,101.7, 100.8,99.2,19.0.HRMS(ESI-):m/z calcd for C27H21N6[M-H]-429.1833,found 429.1808. HPLC analysis:retention time＝7.23min；peak area,99.33％(λ＝254nm)。
Example 11: preparation of the target product (Ik)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.08mmol) and 4-quinolineboronic acid (1.2mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 170 ℃, and the stirring is carried out for 4 hours. Detection by TLC (PE/EA: 1/1) showed disappearance of starting material and reactionIt should be complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2), and a saturated brine (20 mL. times.2), and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (ik).
Characterization of the target product (Ik): a white powdery solid; the yield is 90 percent; melting point: 191.0 to 191.6 ℃.1H NMR (400MHz,DMSO–d6)δ9.65(s,1H,ArH),8.99(d,J＝4Hz.2H,ArH),8.15(d,J＝8Hz.1H, ArH),8.06(d,J＝8Hz.1H,ArH),7.99(d,J＝8Hz.1H,ArH),7.85-7.81(m,1H,ArH),7.74(m, 1H,ArH),7.63(t,J＝8Hz.1H,ArH),7.50(d,J＝4Hz.1H,ArH),7.43(m,1H,ArH),7.39(s, 2H,ArH),6.42(m,1H,ArH),2.28(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.5, 159.8,156.4,150.6,148.7,147.8,146.1,137.5,136.9,135.9,133.0,130.1,129.9,129.4,127.3, 126.5,126.0,121.8,120.1,118.4,101.8,99.2,18.8.HRMS(ESI-):m/z calcd for C28H21N6 [M-H]-441.1833,found 441.1827.HPLC analysis:retention time＝7.58min；peak area,96.81％ (λ＝254nm)。
Example 12: preparation of the target product (il)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.10mmol) and indole-7-boronic acid (1.2mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2), and a saturated brine (20 mL. times.2), and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (il).
Characterization of the target product (Il): a white powdery solid; the yield is 77%; melting point: 309.4-310.5 ℃.1H NMR (400MHz,DMSO)δ11.17(s,1H,NH),9.57(s,1H,NH),8.85(s,1H,NH),8.12-7.99(m,2H, ArH),7.90(s,1H,ArH),7.76(m,2H,ArH),7.54-7.46(m,4H,ArH),7.40(t,J＝4Hz.2H,ArH), 6.53(s,1H,ArH),6.39(s,1H,ArH),2.26(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ: 162.6,159.8,157.4,156.0,146.2,140.4,136.6,136.0,135.3,132.8,131.6,128.8,126.7,126.5, 120.8,120.2,118.5,112.3,102.0,101.7,99.3,19.0.HRMS(ESI-):m/z calcd for C27H21N6 [M-H]-429.1833,found 429.1821.HPLC analysis:retention time＝7.42min；peak area,99.50％ (λ＝254nm)。
Example 13: preparation of the target product (Am)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.02mmol) and indole-4-boronic acid (1.6mmol) were added to 1, 4-dioxan (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. The starting material disappeared and the reaction was complete by TLC (PE/EA: 1/1). The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the target compound (im).
Characterization of the target product (Im): a white powdery solid; the yield is 95 percent; melting point: 238.6-239.5 ℃.1H NMR (400MHz,DMSO)δ11.17(s,1H,ArH),9.56(s,1H,NH),8.86(s,1H,NH),8.04(m,2H,ArH), 7.75-7.72(m,3H,ArH),7.65(d,J＝8Hz,1H,ArH),7.50(s,2H,ArH),7.42-7.36(m,3H,ArH), 6.48(s,1H,ArH),6.39(m,1H,ArH),2.26(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ: 162.6,159.8,156.0,146.2,140.2,137.0,136.7,135.6,133.6,133.3,132.9,127.6,126.6,120.9, 120.2,118.7,118.5,109.7,101.7,101.5,99.3,19.0.HRMS(ESI-):m/z calcd for C27H21N6 [M-H]-429.1833,found 429.1832.HPLC analysis:retention time＝7.88min；peak area,99.89％ (λ＝254nm)。
Example 14: preparation of the target product (ln)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 4-methyl-2-thiopheneboronic acid (10.0mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the target compound (ln).
Characterization of the target product (In): a white powdery solid; the yield is 77%; melting point: 208.7-209.3 ℃.1H NMR (400MHz,DMSO–d6)δ9.59(s,1H,NH),8.88(s,1H,NH),8.03(m,2H,ArH),7.72(m,2H, ArH),7.45(s,2H,ArH),7.39(m,1H,ArH),7.35(s,1H,ArH),7.11(s,1H,ArH),6.38(m,1H, ArH),2.27(s,3H,CH3),2.21(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.5,159.8, 156.2,146.1,143.3,138.8,137.2,136.5,132.9,132.5,126.2,125.3,121.1,120.2,118.5,101.8, 99.2,18.8,16.0.HRMS(ESI-):m/z calcd for C24H20N5S[M-H]-410.1445,found 410.1436. HPLC analysis:retention time＝8.91min；peak area,99.06％(λ＝254nm)。
Example 15: preparation of the target product (Io)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 4-methyl-2-furanboronic acid (5.0mmol) were added to 1, 4-dioxan hexacyclic ring (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (Io).
Characterization of the target product (Io): a white powdery solid; the yield is 74 percent; melting point: 238.7-239.0 ℃.1H NMR (400MHz,DMSO–d6)δ9.57(s,1H,NH),8.86(s,1H,NH),8.02(m,2H,ArH),7.70(m,2H, ArH),7.47(s,2H,ArH),7.38(m,1H,ArH),6.82(d,J＝4Hz,1H,ArH),6.36(m,1H,ArH), 6.22(d,J＝4Hz,1H,ArH),2.37(s,3H,CH3),2.21(s,6H,CH3).13C NMR(100MHz,DMSO –d6)δ:162.5,159.8,157.5,156.1,152.06,146.1,136.9,135.9,132.9,129.2,123.1,120.2,118.4, 108.7,106.9,101.7,99.1,40.4,18.8,13.9.HRMS(ESI-):m/z calcd for C24H20N5O[M-H]- 394.1673,found 394.1674.HPLC analysis:retention time＝8.13min；peak area,95.76％(λ＝254 nm)。
Example 16: preparation of the target product (ip)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.02mmol) and 5-Methyl-2-thiopheneboronic acid (6.0mmol) was added to 1, 4-dioxan (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (ip).
Characterization of the target product (Ip): a white powdery solid; the yield is 77%; melting point: 232.4-232.9 ℃.1H NMR (400MHz,DMSO–d6)δ9.57(s,1H,NH),8.86(s,1H,NH),8.02(m,2H,ArH),7.71(m,2H, ArH),7.40(m,3H,ArH),7.30(d,J＝4Hz,1H,ArH),6.84-6.83(m,1H,ArH),6.36(m,1H, ArH),2.49(s,3H,CH3),2.19(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.5,159.8, 156.1,146.1,141.3,139.4,137.1,136.1,132.9,132.5,127.2,125.0,123.8,120.2,118.4,101.7, 99.2,18.8,15.5.HRMS(ESI-):m/z calcd for C24H20N5S[M-H]-410.1445,found 410.1444. HPLC analysis:retention time＝9.00min；peak area,96.38％(λ＝254nm)。
Example 17: preparation of the target product (iq)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.03mmol) and 2-methyl-4-pyridineboronic acid (7.0mmol) were added to 1, 4-dioxan (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 10 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight.Filtration, concentration and recrystallization from methanol gave a solid, the title compound (iq).
Characterization of the target product (Ip): a white powdery solid; the yield is 83 percent; melting point: 193.2-193.5 ℃.1H NMR (400MHz,DMSO–d6)δ9.64(s,1H,NH),8.96(s,1H,NH),8.54(d,J＝4Hz,1H,ArH),8.06 (m,1H,ArH),7.72(m,2H,ArH),7.65(m,1H,ArH),7.63(m,2H,ArH),7.54(m,1H,ArH), 7.40(m,1H,ArH),6.41(m,1H,ArH),2.58(s,3H,CH3),2.28(s,6H,CH3).13C NMR(100 MHz,DMSO–d6)δ:162.4,159.8,159.0,156.3,149.9,147.5,146.1,138.0,137.3,135.8,132.9, 126.8,120.8,120.2,118.7,118.4,101.8,99.2,24.6,18.8.HRMS(ESI-):m/z calcd for C25H21N6 [M-H]-405.1833,found 405.1831.HPLC analysis:retention time＝6.70min；peak area,99.07％ (λ＝254nm)。
Example 18: preparation of the target product (IR)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.10mmol) and 2-fluoro-4-pyridineboronic acid (2.5mmol) were added to 1, 4-dioxan (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. The starting material disappeared and the reaction was complete by TLC (PE/EA: 1/1). The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (ir).
Characterization of the target product (Ir): a white powdery solid; the yield is 81%; melting point: 254.5-254.9 ℃.1H NMR (400MHz,DMSO–d6)δ9.63(s,1H,NH),8.97(s,1H,NH),8.34(d,J＝4Hz,1H,ArH), 8.07-8.05(m,2H,ArH),7.77-7.76(m,2H,ArH),7.73(s,3H,ArH),7.60(s,1H,ArH),7.46-7.43 (m,1H,ArH),6.41(m,1H,ArH),2.28(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:165.8, 163.5,162.3,159.8,153.3(d,JC-F＝8Hz),148.5(d,JC-F＝17Hz),146.0,137.4,133.0,127.1, 120.1,119.9,119.9,118.4,107.0,106.6,101.8,99.3,18.8.HRMS(ESI-):m/z calcd for C24H18FN6[M-H]-409.1582,found 409.1582.HPLC analysis:retention time＝6.61min；peak area,99.93％(λ＝254nm)。HPLC:tR＝6.37min,97.99％,(λ＝254nm)。
Example 19: preparation of the target product (Is)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.02mmol) and 2-trifluoromethyl-4-pyridineboronic acid (3.3mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (is).
Characterization of the product of interest (Is): a white powdery solid; the yield is 76%; melting point: 207.7-208.5 ℃.1H NMR (400MHz,DMSO–d6)δ9.66(s,1H,NH),9.00(s,1H,NH),8.87(d,J＝4Hz,1H,ArH),8.27 (m,1H,ArH),8.12(d,J＝4Hz,1H,ArH),8.08(d,J＝8Hz,1H,ArH),7.81(m,4H,ArH),7.45 (m,2H,ArH),6.43(m,1H,ArH),2.32(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.3, 159.8,156.4,151.2,149.4,147.9(q,JC-F＝33Hz),146.0,137.6,134.1,132.9,127.2,126.4, 124.7,123.6,120.9,120.1,118.4,118.3,101.3,18.8.HRMS(ESI-):m/z calcd for C25H18F3N6 [M-H]-459.1551,found 459.1544.HPLC analysis:retention time＝7.46min；peak area,99.85％ (λ＝254nm)。
Example 20: preparation of the target product (IT)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.03mmol) and 2, 6-dimethyl-4-pyridineboronic acid (1.2mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (it).
Characterization of the target product (It): a white powdery solid; the yield is 80%; melting point: 280.3-281.0 ℃.1H NMR (400MHz,DMSO–d6)δ9.60(s,1H,NH),8.93(s,1H,NH),8.04(m,2H,ArH),7.68(m,2H, ArH),7.60(s,2H,ArH),7.42(s,2H,ArH),7.37(m,1H,ArH),6.38(m,1H,ArH),2.52(s,6H, CH3),2.25(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.4,159.7,158.3,156.3,147.9, 146.1,137.9,137.2,136.1,132.9,126.8,120.1,118.42,118.0,101.7,99.2,24.5,18.8.HRMS (ESI-):m/z calcd for C26H23N6[M-H]-419.1990,found 419.1977.HPLC analysis:retention time ＝7.27min；peak area,99.73％(λ＝254nm)。
Example 21: preparation of the target product (iu)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 2, 6-difluoro-4-pyridineboronic acid (5.0mmol) were added to tetrahydrofuran (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. The starting material disappeared and the reaction was complete by TLC (PE/EA: 1/1). The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (iu).
Characterization of the target product (Iu): a white powdery solid; the yield is 88%; melting point: 260.1-261.0 ℃.1H NMR (400MHz,DMSO–d6)δ9.61(s,1H,NH),8.95(s,1H,NH),8.04-8.02(m,2H,ArH),7.76(m, 3H,ArH),7.59(m,2H,ArH),7.43-7.39(m,2H,ArH),6.38(m,1H,ArH),2.26(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:165.7,165.5,164.5,163.3,163.1,162.0,160.3,158.6,148.2, 139.6,135.2,129.6,122.4,120.6,106.4-106.0(dd,JC-F＝13Hz,JC-F＝13Hz),104.1,21.0. HRMS(ESI-):m/z calcd for C24H17F2N6[M-H]-427.1488,found 427.1482.HPLC analysis: retention time＝7.54min；peak area,97.57％(λ＝254nm)。
Example 22: preparation of the target product (iv)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.02mmol) and 3-fluoro-3-pyridineboronic acid (2.2mmol) were added to 1, 4-dioxan (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. Detected by TLC (PE/EA: 1/1)The material disappeared and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (iv).
Characterization of the target product (Iv): a white powdery solid; the yield is 77%; melting point: 242.4-242.9 ℃.1H NMR (400MHz,DMSO)δ9.61(s,1H,NH),8.94(s,1H,NH),8.90(s,1H,ArH),8.60(d,J＝4Hz, 1H,NH),8.14-8.10(m,1H,ArH),8.06-8.05(m,1H,ArH),7.77-7.74(m,2H,ArH),7.66(s,2H, ArH),7.43(m,2H,ArH),6.41(m,1H,ArH),2.28(s,6H,CH3).13C NMR(100MHz,DMSO –d6)δ:162.4,161.2,159.8,158.7,156.2,146.1,144.3,144.2,137.5(d,JC-F＝26Hz),136.8, 136.7(d,JC-F＝23Hz),133.9,133.0,127.2,121.1(d,JC-F＝19Hz),120.2,118.4,101.8,99.3, 18.8.HRMS(ESI-):m/z calcd for C24H18FN6[M-H]-409.1582,found 409.1576.HPLC analysis: retention time＝6.75min；peak area,98.76％(λ＝254nm)。
Example 23: preparation of the target product (iw)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.05mmol) and 3-fluoro-3-pyridineboronic acid (1.2mmol) were added to 1, 4-dioxan (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. The starting material disappeared and the reaction was complete by TLC (PE/EA: 1/1). The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (iw).
Characterization of the target product (Iw): a white powdery solid; the yield is 95 percent; melting point: 236.9-237.2 ℃.1H NMR (400MHz,DMSO)δ9.61(s,1H,NH),8.96(s,1H,ArH),8.93(s,1H,NH),8.64(d,J＝4Hz,1H, ArH),8.30-8.29(m,1H,ArH),8.06-8.04(m,1H,ArH),7.75(m,2H,ArH),7.66(s,2H,ArH), 7.46-7.40(m,2H,ArH),6.41(m,1H,ArH),2.28(s,6H,CH3).13C NMR(100MHz,DMSO–d6) δ:162.4,159.8,156.2,147.1,146.3,146.1,137.7,137.4,137.2,133.9,133.2,133.0,132.0, 127.2,120.2,118.4,101.8,99.3,18.8.HRMS(ESI-):m/z calcd for C24H18ClN6[M-H]-425.1287, found 425.1281.HPLC analysis:retention time＝7.66min；peak area,99.37％(λ＝254nm)。
Example 24: preparation of the target product (IX)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 3-methyl-5-pyridineboronic acid (1.2mmol) were added to 1, 4-dioxan (5mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 150 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (ix).
Characterization of the target product (ix): a white powdery solid; the yield is 77%; melting point: 257.8-258.2 ℃.1H NMR (400MHz,DMSO–d6)δ9.61(s,1H,NH),9.60(s,1H,NH),8.78(s,1H,ArH),8.45(s,1H, ArH),8.05-8.04(m,2H,ArH),7.96(s,1H,ArH),7.73(m,2H,ArH),7.57(s,2H,ArH), 7.40-7.37(m,1H,ArH),6.41(m,1H,ArH),2.41(s,3H,CH3),2.27(s,6H,CH3).13C NMR(100 MHz,DMSO–d6)δ:162.5,159.8,156.2,149.2,146.1,145.2,137.2,135.6,135.3,134.8,133.5, 133.1,132.9,126.9,120.2,118.4,101.8,99.2,18.9,18.4.HRMS(ESI-):m/z calcd for C25H21N6 [M-H]-405.1833,found 405.1823.HPLC analysis:retention time＝6.86min；peak area,99.62％ (λ＝254nm)。
Example 25: preparation of the target product (Iy)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 3-ethyl-5-pyridineboronic acid (1.0mmol) were added to 1, 4-dioxan (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 80 ℃, and the stirring is carried out for 4 hours. The starting material disappeared and the reaction was complete by TLC (PE/EA: 1/1). The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (iy).
Characterization of the target product (iy): a white powdery solid; the yield is 74 percent; melting point: 204.3-204.7 ℃.1H NMR (400MHz,DMSO–d6)δ9.60(s,1H,NH),8.93(s,1H,NH),8.79(m,1H,ArH),8.47(s,1H, ArH),8.05-8.04(m,2H,ArH),7.98-7.97(m,1H,ArH),7.72(m,2H,ArH),7.58(s,2H,ArH), 7.39(s,1H,ArH),6.40(s,1H,ArH),2.73(q,J＝8Hz,2H,CH2),2.27(s,6H,CH3),1.29(t,J＝ 8Hz,3H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.5,159.8,156.2,148.5,146.1,145.5, 139.6,137.2,135.7,135.4,133.7,132.9,127.3,126.9,120.1,118.4,101.8,99.2,25.8,18.8,15.9. HRMS(ESI-):m/z calcd for C26H23N6[M-H]-419.1990,found 419.1989.HPLC analysis: retention time＝7.49min；peak area,99.81％(λ＝254nm)。
Example 26: preparation of the target product (IZ)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 5-methoxy-3-pyridineboronic acid (8.0mmol) were added to toluene (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 100 ℃, and the stirring is carried out for 4 hours. The starting material disappeared and the reaction was complete by TLC (PE/EA: 1/1). The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (iz).
Characterization of the target product (iz): a white powdery solid; the yield is 77%; melting point: 216.4-217.4 ℃.1H NMR (400MHz,DMSO–d6)δ9.62(s,1H,NH),8.93(s,1H,NH),8.26(d,J＝8Hz,1H,ArH), 8.05-8.04(m,1H,ArH),7.73(m,2H,ArH),7.63(s,2H,ArH),7.42-7.36(m,3H,ArH),7.18(s, 1H,ArH),6.39(m,1H,ArH),3.94(s,3H,OCH3),2.27(s,6H,CH3).13C NMR(100MHz, DMSO–d6)δ:165.0,162.4,159.8,156.2,150.4,147.9,146.1,146.0,137.2,135.5,132.9,126.9, 120.2,118.4,115.4,107.7,101.8,99.3,53.7,18.8.HRMS(ESI-):m/z calcd for C25H21N6O [M-H]-421.1782,found 421.1778.HPLC analysis:retention time＝7.40min；peak area,99.22％ (λ＝254nm)。
Example 27: preparation of target product (Iaa)
Reacting 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amine at room temperaturePhenyl nitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 5-trifluoromethyl-3-pyridineboronic acid (8.0mmol) were added to methanol (6mL) over N2The replacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 24 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2), and a saturated brine (20 mL. times.2), and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (iaa).
Characterization of the target product (iaa): a white powdery solid; the yield is 83 percent; melting point: 268.7-269.2 ℃.1H NMR (400MHz,DMSO–d6)δ9.64(s,1H,NH),9.32(s,1H,ArH),9.00(s,1H,ArH),8.99(s,1H, NH),8.54(s,1H,ArH),8.09-8.07(m,2H,ArH),7.75(s,3H,ArH),7.44(m,2H,ArH),6.44(m, 1H,ArH),2.32(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.4,159.8,156.2,151.9, 146.1,145.1,137.5,136.0,133.6,131.3,128.3,127.3,126.0(q,JC-F＝32Hz),122.8,120.1, 120.1,118.4,101.8,99.3,18.8.HRMS(ESI-):m/z calcd for C25H18F3N6[M-H]-459.1551,found 459.1549.HPLC analysis:retention time＝7.85min；peak area,99.76％(λ＝254nm)。
Example 28: preparation of the target product (Iab)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 5-cyano-3-pyridineboronic acid (4.0mmol) were added to 1, 4-dioxan (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 14 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and a saturated sodium sulfite solution (20 mL. times.2) and a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2), and a saturated saline solution (20 mL. times.2), and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the target compound (iab).
Characterization of the target product (Iab): a white powdery solid; the yield is 81%; melting point: 243.1-243.5 ℃.1H NMR (400MHz,DMSO–d6)δ9.60(s,1H,NH),9.28(s,1H,ArH),9.03(d,J＝4Hz,1H,NH),8.93(s, 1H,NH),8.73-8.72(m,1H,ArH),8.16-7.96(m,2H,ArH),7.90-7.70(m,4H,ArH),7.44(m, 1H,ArH),6.46-6.40(m,1H,ArH),2.28(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.4, 159.8,156.2,151.5,151.2,146.0,137.8,137.4,135.7,133.4,133.0,127.6,127.2,120.2,118.4, 117.5,109.9,101.8,99.3,18.9.HRMS(ESI-):m/z calcd for C25H18N7[M-H]-416.1629,found 416.1623.HPLC analysis:retention time＝5.96min；peak area,98.07％(λ＝254nm)。
Example 29: preparation of the target product (lac)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.05mmol) and 4-fluoro-3-pyridineboronic acid (4.0mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2), and a saturated brine (20 mL. times.2), and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (lac).
Characterization of the target product (lac): a white powdery solid; the yield is 76%; melting point: 227.4-227.9 ℃.1H NMR (400MHz,DMSO–d6)δ9.61(s,1H,NH),8.93(s,1H,NH),8.64(s,1H,ArH),8.36-8.31(m, 1H,ArH),8.07-8.06(m,2H,ArH),7.76(m,2H,ArH),7.57(m,2H,ArH),7.43(m,1H,ArH), 7.30(dd,J＝4Hz,J＝4Hz,1H,ArH),6.42(m,1H,ArH),2.28(s,3H,CH3).13C NMR(100 MHz,DMSO–d6)δ:164.2,162.5,161.8,159.8,156.1,146.1,145.7(d,JC-F＝25Hz),140.5(d, JC-F＝18Hz),137.2,134.3,132.9,126.8,120.2,118.4,110.2,109.9,101.8,99.3,18.9.HRMS (ESI-):m/z calcd for C24H18FN6[M-H]-409.1582,found 409.1584.HPLC analysis:retention time＝6.65min；peak area,99.81％(λ＝254nm)。
Example 30: preparation of the target product (Id)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.08mmol) and 4-methyl-3-pyridineboronic acid (8.0mmol) were added to 1, 4-dioxan (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. The starting material disappeared and the reaction was complete by TLC (PE/EA: 1/1). The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (iad).
Characterization of the target product (iad): a white powdery solid; the yield is 80%; melting point: 250.9-251.4 ℃.1H NMR(400MHz,DMSO–d6)δ9.61(s,1H,NH),8.92(s,1H,NH),8.84(s,1H,ArH),8.05(m, 2H,ArH),8.01(d,J＝4Hz,1H,ArH),7.75-7.74(m,2H,ArH),7.54(s,2H,ArH),7.40(m,1H, ArH),7.35(d,J＝8Hz,1H,ArH),6.41-6.40(m,1H,ArH),2.54(s,3H,CH3),2.26(s,6H,CH3). 13C NMR(100MHz,DMSO–d6)δ:162.5,159.8,157.2,156.1,147.2,146.1,137.1,136.8, 135.5,134.6,132.9,126.8,126.5,123.6,120.2,118.4,101.8,99.3,24.1,18.9.HRMS(ESI-):m/z calcd for C25H21N6[M-H]-405.1833,found 405.1809.HPLC analysis:retention time＝6.79min； peak area,99.60％(λ＝254nm)。
Example 31: preparation of the target product (I ae)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 4-methoxy-3-pyridineboronic acid (1.2mmol) were added to 1, 4-dioxan (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 100 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave solid-the target compound (i ae). :
characterization of the target product (iae): a white powdery solid; the yield is 88%; melting point: 218.6-218.9 ℃.1H NMR (400MHz,DMSO–d6)δ9.57(s,1H,NH),8.88(s,1H,NH),8.55(m,1H,ArH),8.07-8.04(m,3H, ArH),7.73(m,2H,ArH),7.49(s,2H,ArH),7.40(m,1H,ArH),6.93(d,J＝8Hz,1H,ArH), 6.39(m,1H,ArH),3.93(s,3H,OCH3),2.25(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ: 163.5,162.5,159.8,156.1,146.1,145.0,137.9,137.0,136.4,135.4,132.9,129.5,126.3,120.2, 118.4,111.0,101.8,99.3,53.7,18.9.HRMS(ESI-):m/z calcd for C25H21N6O[M-H]-421.1782, found 421.1778.HPLC analysis:retention time＝7.62min；peak area,99.95％(λ＝254nm)。
Example 32: preparation of the target product (iaf)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 4-methylthio-3-pyridineboronic acid (1.2mmol) were added to methanol (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2), and a saturated brine (20 mL. times.2), and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (iaf).
Characterization of the target product (iaf): a white powdery solid; the yield is 92 percent; melting point: 209.6-210.1 ℃.1H NMR (400MHz,DMSO–d6)δ9.59(s,1H,NH),8.91(s,1H,NH),8.85(s,1H,ArH),8.05(m,2H, ArH),8.00(d,J＝8Hz,1H,ArH),7.76-7.74(m,2H,ArH),7.54(s,2H,ArH),7.40(d,J＝8Hz, 2H,ArH),6.41(m,1H,ArH),2.59(s,3H,SCH3),2.26(s,6H,CH3).13C NMR(100MHz, DMSO–d6)δ:162.5,159.8,158.6,156.1,147.5,146.1,137.2,136.8,135.2,134.8,132.9,131.5, 126.4,121.4,120.2,118.4,101.8,99.3,18.9,13.3.HRMS(ESI-):m/z calcd for C25H21N6S [M-H]-437.1554,found 437.1548.HPLC analysis:retention time＝7.88min；peak area,96.02％ (λ＝254nm)。
Example 33: preparation of the target product (I ag)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.08mmol) and 4-amino-3-pyridineboronic acid (1.2mmol) were added to 1, 4-dioxan (6mL)In the middle, through N2The displacement is carried out for three times, the reaction temperature is adjusted to 170 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (I ag).
Characterization of the target product (I ag): a white powdery solid; the yield is 92 percent; melting point: 277.6-278.3 ℃.1H NMR(400MHz,DMSO–d6)δ9.57(s,1H,NH),8.85(s,1H,NH),8.34(s,1H,ArH),8.11-7.98 (m,2H,ArH),7.79-7.73(m,3H,ArH),7.41(s,3H,ArH),6.60(d,J＝8Hz,1H,ArH),6.38(m, 1H,ArH),6.11(s,2H,NH),2.23(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.5, 159.8,159.6,157.5,156.0,146.1,137.2,136.8,136.6,135.8,132.8,125.3,124.2,120.2,118.4, 108.5,101.7,99.2,18.9.HRMS(ESI-):m/z calcd for C24H20N7[M-H]-406.1786,found 406.1786.HPLC analysis:retention time＝5.32min；peak area,99.33％(λ＝254nm)。
Example 34: preparation of the target product (Iah)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.10mmol) and 4-N, N-dimethylamino-3-pyridineboronic acid (1.2mmol) were added to 1, 4-dioxane (6mL) and the mixture was filtered through N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtering, concentrating, recrystallizing with methanol to obtain solid-target productCompound (Iah).
Characterization of the target product (iah): a white powdery solid; the yield is 92 percent; melting point: 289.2-290.1 ℃.1H NMR(400MHz,DMSO–d6)δ9.56(s,1H,NH),8.84(s,1H,NH),8.50(s,1H,ArH),8.10-7.97 (m,2H,ArH),7.86(d,J＝8Hz,1H,ArH),7.75-7.73(m,2H,ArH),7.42-7.38(m,3H,ArH), 6.72(d,J＝12Hz,1H,ArH),6.37(m,1H,ArH),3.08(s,6H,CH3),2.22(s,6H,CH3).13C NMR (100MHz,DMSO–d6)δ:162.5,159.8,158.8,156.0,146.1,145.9,136.8,136.3,135.8,135.5, 132.9,125.4,123.5,120.2,118.4,106.2,101.7,99.3,38.2,19.0.HRMS(ESI-):m/z calcd for C26H24N7[M-H]-434.2099,found 434.2103.HPLC analysis:retention time＝11.40min；peak area,99.22％(λ＝254nm)。
Example 35: preparation of the target product (I ai)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.02mmol) and 4-Nitrophenylboronic acid (1.6mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2), and a saturated brine (20 mL. times.2), and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (I ai).
Characterization of the target product (I ai): a white powdery solid; the yield is 92 percent; melting point: 262.0-263.0 ℃.1H NMR (400MHz,DMSO–d6)δ9.60(s,1H,NH),8.94(s,1H,NH),8.33(d,J＝8Hz,2H,ArH),8.02 (m,3H,ArH),7.75-7.72(m,2H,ArH),7.63(s,2H,ArH),7.41-7.36((m,2H,ArH)),6.46-6.40 (m,1H,ArH),2.27(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.4,159.8,156.2,147.0, 146.8,146.1,137.4,136.1,132.9,128.1,127.4,127.3,124.5,120.1,118.4,101.8,99.3,18.8. HRMS(ESI-):m/z calcd for C25H19N6O2[M-H]-435.1569,found 435.1471.HPLC analysis: retention time＝8.16min；peak area,99.55％(λ＝254nm)。
Example 36: preparation of the target product (Iaj)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 4-trifluoromethyl-3-pyridineboronic acid (10.0mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (iaj).
Characterization of the target product (iaj): a white powdery solid; the yield is 90 percent; melting point: 234.2-234.9 ℃.1H NMR (400MHz,DMSO–d6)δ9.65(s,1H,NH),9.19(s,1H,ArH),8.98(s,1H,NH),8.41(d,J＝4Hz, 1H,ArH),8.08(m,2H,ArH),8.00(d,J＝8Hz,1H,ArH),7.77-7.69(m,4H,ArH),7.45(m,1H, ArH),6.43(m,1H,ArH),2.30(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.4,159.8, 156.2,148.6,146.1,145.5(q,JC-F＝34Hz),139.0,137.5,136.2,133.9,133.0,127.3,123.7, 121.3(q,JC-F＝3Hz),121.0,120.2,118.4,101.9,99.3,18.9.HRMS(ESI+):m/z calcd for C25H18F3N6[M-H]-459.1551,found 459.1532.HPLC analysis:retention time＝7.58min；peak area,99.56％(λ＝254nm)。
Example 37: preparation of the target product (Iak)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 4-cyano-3-pyridineboronic acid (5.0mmol) were added to 1, 4-dioxan (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (Iak).
Characterization of the target product (Iak): a white powdery solid; the yield is 91%; melting point: 245.9-246.6 ℃.1H NMR(400MHz,DMSO–d6)δ9.63(s,1H,NH),9.19(s,1H,ArH),8.97(s,1H,NH),8.41(d,J＝ 4Hz,1H,ArH),8.15(d,J＝4Hz,1H,ArH),8.07-8.06(m,1H,ArH),7.76-7.70(m,4H,ArH), 7.50-7.45(m,2H,ArH),6.42(m,1H,ArH),2.29(s,6H,CH3).13C NMR(100MHz,DMSO–d6) δ:162.3,159.8,156.3,149.6,146.0,139.1,138.3,137.5,135.5,133.5,133.0,131.4,129.5, 127.4,120.2,118.4,118.2,101.8,99.3,18.89.HRMS(ESI-):m/z calcd for C25H18N7[M-H]- 416.1629,found 416.1617.HPLC analysis:retention time＝6.13min；peak area,99.58％(λ＝254 nm)。
Example 38: preparation of the target product (I al)
At room temperature, 4- ((4-bromo-2, 6-dimethyl)Phenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.02mmol) and 4-fluoro-5-methyl-3-pyridineboronic acid boric acid (6.0mmol) were added to 1, 4-dioxane (6mL) and the mixture was cooled with N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (ial).
Characterization of the target product (ial): a white powdery solid; the yield is 92 percent; melting point: 244.5 to 244.8 ℃.1H NMR (400MHz,DMSO–d6)δ1H NMR(400MHz,DMSO)δ9.60(s,1H,NH),8.93(s,1H,NH),8.42 (s,1H,ArH),8.20(d,J＝8Hz,1H,ArH),8.05(m,2H,ArH),7.74(m,2H,ArH),7.56(m,2H, ArH),7.41(m,1H,ArH),6.41(m,1H,ArH),2.36(s,3H,CH3),2.27(s,6H,CH3).13C NMR (100MHz,DMSO–d6)δ:13C NMR(101MHz,DMSO)δ162.8,162.5,160.5,159.8,156.1, 146.1,142.7(d,JC-F＝15Hz),140.8(d,JC-F＝6Hz),137.2,134.4,132.9,126.8,120.12,119.8, 119.5,118.4,101.8,99.3,18.9,14.5.HRMS(ESI-):m/z calcd for C25H20FN6[M-H]-423.1739, found 423.1740.HPLC analysis:retention time＝7.43min；peak area,99.16％(λ＝254nm)。
Example 39: preparation of the target product (I am)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.03mmol) and 2-methyl-4-pyrimidineboronic acid (7.0mmol) were added to 1, 4-dioxan hexacyclic ring (6mL) over N2Replacing for three times, adjusting the reaction temperature to 110 ℃, and stirringAnd (5) 10 h. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and methanol recrystallization provided a solid-the target compound (iam).
Characterization of the target product (I am): a white powdery solid; the yield is 92 percent; melting point: 264.8 to 265.0 ℃.1H NMR(400MHz,DMSO–d6)δ9.57(s,1H,NH),9.07(m,2H,ArH),8.91(m,1H,NH),8.03(m, 2H,ArH),7.72(m,2H,ArH),7.62(m,2H,ArH),7.43(m,1H,ArH),6.38(m,1H,ArH),2.69(s, 3H,CH3),2.25(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:166.5,162.4,159.8,156.2, 155.0,146.1,137.4,133.0,132.4,130.2,126.9,126.6,120.2,118.4,101.8,99.3,25.8,18.9. HRMS(ESI-):m/z calcd for C24H20N7[M-H]-406.1786,found 406.1776.HPLC analysis: retention time＝5.65min；peak area,100％(λ＝254nm)。
Example 40: preparation of the target product (lan)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.10mmol) and 2-methoxy-4-pyrimidineboronic acid (2.5mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (ian).
Characterization of the target product (lan): white colour (Bai)A toner-like solid; the yield is 90 percent; melting point: 238.8-239.5 ℃.1H NMR(400MHz,DMSO–d6)δ9.61(s,1H,NH),9.00-8.93(m,3H,NH,ArH),8.06(m,2H,ArH), 7.77(m,2H,ArH),7.57(m,2H,ArH),7.45(m,1H,ArH),6.42(m,1H,ArH),4.01(s,3H, OCH3),2.27(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:165.0,162.4,159.8,157.6, 156.1,146.1,137.3,137.0,133,0,132.2,127.6,126.2,120.2,118.4,101.8,99.3,55.1,18.9. HRMS(ESI+):m/z calcd for C24H20N7O[M-H]-422.1735,found 422.1725.HPLC analysis: retention time＝6.35min；peak area,99.91％(λ＝254nm)。
Example 41: preparation of the target product (IAo)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.02mmol) and 2-cyano-5-pyrimidineboronic acid (3.3mmol) were added to 1, 4-dioxan hexacyclic ring (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (Io).
Characterization of the target product (Io): a white powdery solid; the yield is 91%; melting point: 258.9-259.4 ℃.1H NMR(400MHz,DMSO–d6)δ9.65(s,1H,NH),9.45(m,2H,ArH),8.99(s,1H,NH),8.07(m, 1H,ArH),7.79(m,4H,ArH),7.51(m,2H,ArH),6.45(m,1H,ArH),2.30(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.3,159.8,156.3,146.0,142.7,139.0,137.7,135.6,133.0, 132.1,130.5,127.4,120.2,118.4,116.8,101.9,99.5,18.9.HRMS(ESI-):m/z calcd for C24H17N8[M-H]-417.1582,found 417.1575.HPLC analysis:retention time＝6.20min；peak area,95.72％(λ＝254nm)。
Example 42: preparation of the target product (iap)
At room temperature, 4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.03mmol) and 2-trifluoromethyl-5-pyrimidineboronic acid (1.2mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (iap).
Characterization of the target product (iap): a white powdery solid; the yield is 92 percent; melting point: 263.6-264.3 ℃.1H NMR(400MHz,DMSO–d6)δ9.63(s,1H,NH),9.48(m,2H,ArH),8.98(s,1H,NH),8.07(m, 1H,ArH),7.78(m,4H,ArH),7.48(m,2H,ArH),6.41(m,1H,ArH),2.30(s,6H,CH3).13C NMR (100MHz,DMSO–d6)δ:162.3,159.8,156.3,154.6-153,5(q,JC-F＝34Hz,JC-F＝36Hz,),146.0, 137.6,135.5,133.0,127.4,124.4,121.7,120.2,119.0,118.4,116.2,101.9,99.2,18.9.HRMS (ESI-):m/z calcd for C24H17F3N7[M+H]+460.1503,found 460.1502.HPLC analysis:retention time＝7.33min；peak area,99.94％(λ＝254nm)。
Implementation 43: salifying transformation and water solubility measurement of compound
And (3) carrying out salifying transformation on the compound, and carrying out water solubility measurement in multiple pH ranges on a salified product by a standard curve method.
Preparing a salified compound: dissolving in solvent completely at room temperature or under heating, adding acid to be salified, and adding N2Stirring for 18-48h under protection until a large amount of solid is separated out. Filtering to obtain the salified compound of the molecule. The solvent is one or more selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, dichloromethane, dichloroethane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, ethyl acetate, n-hexane, cyclohexane and petroleum ether. The following examples of 4-pyridyl substituted compounds specifically illustrate the preparation of hydrochloride and the results of water solubility tests.
4-pyridyl-substituted ie (100mg) was dissolved in 15ml of ethyl acetate at 33 ℃ and 10 drops of acid were added and stirred at 33 ℃ for 24 h. And (4) filtering to obtain a salt-forming compound of the target product after a large amount of solids are separated out. And respectively taking 5-10mg of the compound, sequentially adding buffer solution with pH of 2.0, 7.0 and 7.4 into the compound, stirring the mixture for more than 18 hours at the temperature of 20-25 ℃, filtering supernatant liquid, and testing the water solubility of the compound in various pH ranges by reverse phase HPLC analysis. The water solubility results are as follows:
TABLE 1 Water solubility results for Compound ie and salt-forming complexes thereof
Example 44: anti-HIV biological Activity assay
The anti-HIV virus activity at the cellular level in vitro was determined by the Rega drug research institute of Katholleke university, Belgium, and mainly included: inhibiting activity and cytotoxicity on HIV-infected MT-4 cells. The method comprises the following steps: the protective effect of the drug on HIV-induced cytopathic effects was determined by MTT method in HIV-infected MT-4 cells at different times of HIV infection, and the half-effective concentration EC required to protect 50% of the cells from HIV-induced cytopathic effects was calculated50Toxicity assays were performed in parallel with anti-HIV activity assays, also in MT-4 cell culture, with 50% of uninfected cells being cellularized by MTT assayConcentration of lesions (CC)50) And calculating the selectivity index SI ═ CC50/EC50。
The material and the method are as follows:
the anti-HIV activity of each compound was monitored by the efficacy of the drug in inhibiting the cytopathic effects of HIV in cells. MT-4 cells were used for cell culture. The viral strains used were: HIV-1 strain IIIB and HIV-2 strain ROD.
The specific operation is as follows: dissolving the compound in DMSO or water, diluting in phosphate buffered saline solution, and mixing 3 × 105MT-4 cells were pre-incubated with 100. mu.L of each compound in different concentrations in this solution at 37 ℃ for 1h, and then 100. mu.L of an appropriate viral diluent was added to the compound and the cells were incubated at 37 ℃ for 1 h. After three washes, the cells were resuspended in culture medium with or without compound, respectively. Cells were then incubated at 5% CO2Incubate at 37 ℃ for 7 more days in an atmosphere and replace the supplemented medium with culture medium with or without compound on the third day post infection. The operation was repeated twice for each culture medium condition. Cytopathic effects on the virus were monitored daily with a reverse optical microscope. Typically, the viral dilutions used in this experiment often lead to cytopathic effects the fifth day after viral infection. The inhibitory concentration of the drug is such that the drug produces a 50% inhibition of the viral cytopathic effect while having no direct toxicity to the cells (CC)50) And (4) showing. It is emphasized that, when the compounds are poorly water soluble and require DMSO to dissolve, the DMSO specific concentration is generally less than 10% relative to water (the final concentration of DMSO in the MT-4 cell culture medium is less than 2%). Since DMSO can affect the antiviral activity of the test compound, the antiviral activity of the solutions containing the same concentration of DMSO should also be performed in parallel to the control blank. In addition, the final concentration of DMSO (1/1000) was much lower than the concentration required for HIV-1 replication in T cells.
The invention uses marketed drugs Nevirapine (NVP), Efavirenz (EFV) and Etravirine (ETRAvirine, ETV) as reference substances, and the results of HIV inhibitory activity of part of target compounds are shown in Table 2 (anti-HIV activity and cytotoxicity of compounds Ia-iap in MT-4 cells).
TABLE 2[a]
aAll data represent the mean of at least three independent experiments;bEC50an effective concentration to protect 50% of the cells from viral infection;cCC50the drug concentration when 50% of cells are diseased;dSI selection index, CC50Value and EC50The ratio of the values is used for judging the safety range of the drug effect.
Experimental results show that the compounds contained in the chemical general formula (I) generally have strong anti-HIV-1 virus activity, can remarkably inhibit virus replication in MT-4 cells infected by HIV-1 virus, and have low cytotoxicity and high selectivity index.
It should be noted that, although the above embodiments have been described herein, the scope of the present invention is not limited thereby, and the technical parameters and raw material components which are not described in detail herein can still obtain the same or similar technical effects as the above embodiments when they are changed within the range of the parameters recited in the present invention, and still fall within the scope of the present invention. Therefore, based on the innovative concepts of the present invention, the technical solutions of the present invention can be directly or indirectly applied to other related technical fields by making changes and modifications to the embodiments described herein or by using equivalent structures or equivalent processes performed in the present specification, and are included in the scope of the present invention.
Claims (6)
1. A biphenyl diaryl pyrimidine derivative containing an aromatic heterocyclic structure is characterized in that the structural formula is shown as the following formula (I):
wherein R is1Selected from furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, p-aminophenyl, C7～10Aryl heterocyclic radical, optionally substituted furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, C7～10An aromatic heterocyclic group.
2. The derivatives of dimethyl biphenyl diaryl pyrimidine containing aromatic heterocyclic structure as claimed in claim 1, further comprising pharmaceutically acceptable salts, stereochemically isomeric forms, hydrates and solvates thereof, single crystals of polycrystal or eutectic crystal and single enantiomer thereof, and precursors and derivatives thereof with same biological function.
3. The derivative of dimethyl biphenyl diaryl pyrimidine according to claim 2, wherein the pharmaceutically acceptable salt comprises hydrochloride, hydrobromide, formate, methanesulfonate, trifluoromethanesulfonate, sulfate, phosphate, acetate, p-toluenesulfonate, tartrate, citrate, succinate, maleate, fumarate or malate, and pharmaceutically acceptable prodrugs and derivatives.
4. The method for preparing the dimethyl biphenyl diaryl pyrimidine containing the aromatic heterocyclic structure according to claim 1, which comprises the following steps:
in a solvent, compound II (4- ((4- ((4-bromo-2, 6-dimethylphenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile) in Pd (dppf) Cl2、Cs2CO3The compound I is obtained through Suzuki-coupling reaction under the action of the general formula:
wherein the solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, dichloromethane, dichloroethane, toluene, tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, 1, 4-dioxane and ethyl acetate;
the molar ratio of the compound II to the heterocyclic boric acid is 1:1-1: 8;
compound II with Pd (dppf) Cl2In a molar ratio of 1:0.01-1: 0.10;
compounds II and Cs2CO3The molar ratio of (1: 1) - (1: 2);
the temperature of the Suzuki-coupling reaction is 40-180 ℃, and the reaction time is 4-24 h.
5. A pharmaceutical composition for preventing and treating aids, which comprises the derivatives of dimethyl biphenyl diaryl pyrimidine containing aromatic heterocyclic structure as claimed in any one of claims 1 to 3 and a related pharmaceutically acceptable carrier.
6. The pharmaceutical composition of claim 5, wherein the aromatic heterocycle-containing diarylpyrimidine compound is used as an active ingredient to prepare the pharmaceutical composition.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111030896.4A CN113845515A (en) | 2021-09-03 | 2021-09-03 | Aromatic heterocyclic structure-containing dimethyl biphenyl diaryl pyrimidine derivative and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111030896.4A CN113845515A (en) | 2021-09-03 | 2021-09-03 | Aromatic heterocyclic structure-containing dimethyl biphenyl diaryl pyrimidine derivative and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113845515A true CN113845515A (en) | 2021-12-28 |
Family
ID=78973175
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111030896.4A Pending CN113845515A (en) | 2021-09-03 | 2021-09-03 | Aromatic heterocyclic structure-containing dimethyl biphenyl diaryl pyrimidine derivative and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113845515A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1541215A (en) * | 2001-08-13 | 2004-10-27 | ղɭҩҵ����˾ | HIV inhibiting pyrimidines derivatives |
| CN109053613A (en) * | 2018-07-04 | 2018-12-21 | 复旦大学 | Diaryltriazine compound containing biphenyl structural and its preparation method and application |
| CN112624983A (en) * | 2020-12-14 | 2021-04-09 | 复旦大学 | Biphenyl diaryl pyrimidine derivative containing alkyl structure and preparation method and application thereof |
| CN113105394A (en) * | 2021-03-08 | 2021-07-13 | 复旦大学 | Biphenyl diaryl pyrimidine derivative containing aromatic heterocyclic structure and preparation method and application thereof |
-
2021
- 2021-09-03 CN CN202111030896.4A patent/CN113845515A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1541215A (en) * | 2001-08-13 | 2004-10-27 | ղɭҩҵ����˾ | HIV inhibiting pyrimidines derivatives |
| CN109053613A (en) * | 2018-07-04 | 2018-12-21 | 复旦大学 | Diaryltriazine compound containing biphenyl structural and its preparation method and application |
| CN112624983A (en) * | 2020-12-14 | 2021-04-09 | 复旦大学 | Biphenyl diaryl pyrimidine derivative containing alkyl structure and preparation method and application thereof |
| CN113105394A (en) * | 2021-03-08 | 2021-07-13 | 复旦大学 | Biphenyl diaryl pyrimidine derivative containing aromatic heterocyclic structure and preparation method and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| JEROME GUILLEMONT ET AL.: "Synthesis of Novel Diarylpyrimidine Analogues and Their Antiviral Activity against Human Immunodeficiency Virus Type 1", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| KAIJUN JI ET AL.: "Discovery of biphenyl-substituted diarylpyrimidines as non-nucleoside reverse transcriptase inhibitors with high potency against wild-type and mutant HIV-1", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| YALI SANG ET AL.: "Ligand-Based Design of Nondimethylphenyl-Diarylpyrimidines with Improved Metabolic Stability, Safety, and Oral Pharmacokinetic Profiles", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1910370B1 (en) | A pyridin quinolin substituted pyrrolo [1,2-b] pyrazole monohydrate as tgf-beta inhibitor | |
| EP1569919B1 (en) | Non-nucleoside reverse transcriptase inhibitors | |
| EP2144889B1 (en) | Quinazolin-oxime derivatives as hsp90 inhibitors | |
| DE69013607T2 (en) | Pyrazole derivatives, process for their preparation and use. | |
| CN113105394A (en) | Biphenyl diaryl pyrimidine derivative containing aromatic heterocyclic structure and preparation method and application thereof | |
| PL193898B1 (en) | Dihydropyrimidines | |
| CA3073051A1 (en) | Ahr inhibitors and uses thereof | |
| KR20130046436A (en) | Cyclic n,n'-diarylthioureas and n,n'-diarylureas as androgen receptor antagonists, anti-cancer agent, method for producing and using same | |
| Sławiński et al. | Synthesis, molecular structure, and in vitro antitumor activity of new 4-chloro-2-mercaptobenzenesulfonamide derivatives | |
| CN112920208B (en) | Boric acid-containing indole aryl sulfone derivative and preparation method and application thereof | |
| CA3093984A1 (en) | Calcium salt polymorphs as anti-inflammatory, immunomodulatory and anti-proliferatory agents | |
| JPS6230755A (en) | Distamycin derivatives and manufacture | |
| CN113603708A (en) | Preparation method and application of novel CDK9 inhibitor with macrocyclic framework structure | |
| CA1184910A (en) | Tricyclic cytosine derivatives for combatting circulatory illnesses | |
| HRP20020120A2 (en) | Torsemide polymorphs | |
| CN113461666A (en) | Biphenyl diaryl methyl pyrimidine derivative containing aromatic heterocyclic structure and preparation method thereof | |
| CN112624983B (en) | Biphenyl diaryl pyrimidine derivative containing alkyl structure and preparation method and application thereof | |
| CN113845515A (en) | Aromatic heterocyclic structure-containing dimethyl biphenyl diaryl pyrimidine derivative and preparation method and application thereof | |
| JP2022543183A (en) | Method for synthesizing furoimidazopyridine compound, crystalline form of furoimidazopyridine compound and crystalline form of salt thereof | |
| CN109369623B (en) | Substituted 1,2,3 triazole diaryl pyrimidine derivative and preparation method and application thereof | |
| EP2196453A1 (en) | Novel substituted aryl derivatives, their process of preparation and their therapeutical uses as anti-HIV agents | |
| EP2885300A1 (en) | Tris(hetero)arylpyrazoles and use thereof | |
| CN115260081B (en) | Sulfonamide indole aryl sulfone derivative and preparation method and application thereof | |
| DK141749B (en) | Analogous process for the preparation of pyridinecarboxamidoethylbenzenesulfonylurea compounds. | |
| KR100364941B1 (en) | Novel crystal forms of 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20211228 |
|
| WD01 | Invention patent application deemed withdrawn after publication |