CN104892581B - 具有杀菌活性的2‑甲基‑4‑氨基‑5‑(取代‑1,2,3‑三唑基)甲基嘧啶衍生物、其制备方法及应用 - Google Patents
具有杀菌活性的2‑甲基‑4‑氨基‑5‑(取代‑1,2,3‑三唑基)甲基嘧啶衍生物、其制备方法及应用 Download PDFInfo
- Publication number
- CN104892581B CN104892581B CN201410082965.XA CN201410082965A CN104892581B CN 104892581 B CN104892581 B CN 104892581B CN 201410082965 A CN201410082965 A CN 201410082965A CN 104892581 B CN104892581 B CN 104892581B
- Authority
- CN
- China
- Prior art keywords
- compound
- yield
- nmr
- pure product
- dmso
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- -1 2-methyl-4-amino-5-(substituted-1,2,3-triazolyl)methylpyridine Chemical class 0.000 title claims abstract description 12
- 230000000844 anti-bacterial effect Effects 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 240000008067 Cucumis sativus Species 0.000 claims abstract description 12
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 10
- 150000002367 halogens Chemical class 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 9
- 235000007688 Lycopersicon esculentum Nutrition 0.000 claims abstract description 6
- 235000002637 Nicotiana tabacum Nutrition 0.000 claims abstract description 6
- 206010039509 Scab Diseases 0.000 claims abstract description 6
- 241000209140 Triticum Species 0.000 claims abstract description 6
- 235000021307 Triticum Nutrition 0.000 claims abstract description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 6
- 240000007594 Oryza sativa Species 0.000 claims abstract description 5
- 235000007164 Oryza sativa Nutrition 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 235000009566 rice Nutrition 0.000 claims abstract description 5
- 239000004480 active ingredient Substances 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 244000061176 Nicotiana tabacum Species 0.000 claims abstract 2
- 240000003768 Solanum lycopersicum Species 0.000 claims abstract 2
- 239000000417 fungicide Substances 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 230000000855 fungicidal effect Effects 0.000 claims 1
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 abstract description 10
- 125000001424 substituent group Chemical group 0.000 abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 5
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 150000002466 imines Chemical class 0.000 abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 3
- 150000007942 carboxylates Chemical class 0.000 abstract description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 2
- 229910052717 sulfur Inorganic materials 0.000 abstract description 2
- 239000007787 solid Substances 0.000 description 111
- 239000000047 product Substances 0.000 description 100
- 238000000921 elemental analysis Methods 0.000 description 66
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 41
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 40
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 35
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000003054 catalyst Substances 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 150000007530 organic bases Chemical class 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- HRZOZFYDZBEQQQ-UHFFFAOYSA-N 5-(azidomethyl)-2-methylpyrimidin-4-amine Chemical compound CC1=NC=C(CN=[N+]=[N-])C(N)=N1 HRZOZFYDZBEQQQ-UHFFFAOYSA-N 0.000 description 5
- 241000233866 Fungi Species 0.000 description 5
- 0 Cc1ncc(C[n]2nnc(C*(c3cc([N+]([O-])=O)cc(*)c3)=O)c2)c(N)n1 Chemical compound Cc1ncc(C[n]2nnc(C*(c3cc([N+]([O-])=O)cc(*)c3)=O)c2)c(N)n1 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 241000227653 Lycopersicon Species 0.000 description 4
- 241000208125 Nicotiana Species 0.000 description 4
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 101710088194 Dehydrogenase Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 241000212749 Zesius chrysomallus Species 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 235000010378 sodium ascorbate Nutrition 0.000 description 3
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 3
- 229960005055 sodium ascorbate Drugs 0.000 description 3
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 2
- 241000223600 Alternaria Species 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 241000123650 Botrytis cinerea Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- ZSLZBFCDCINBPY-ZSJPKINUSA-N acetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- CPEKAXYCDKETEN-UHFFFAOYSA-N benzoyl isothiocyanate Chemical compound S=C=NC(=O)C1=CC=CC=C1 CPEKAXYCDKETEN-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940126540 compound 41 Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 1
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 1
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- FNHHVPPSBFQMEL-KQHDFZBMSA-N (3S)-5-N-[(1S,5R)-3-hydroxy-6-bicyclo[3.1.0]hexanyl]-7-N,3-dimethyl-3-phenyl-2H-1-benzofuran-5,7-dicarboxamide Chemical compound CNC(=O)c1cc(cc2c1OC[C@@]2(C)c1ccccc1)C(=O)NC1[C@H]2CC(O)C[C@@H]12 FNHHVPPSBFQMEL-KQHDFZBMSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- STPKWKPURVSAJF-LJEWAXOPSA-N (4r,5r)-5-[4-[[4-(1-aza-4-azoniabicyclo[2.2.2]octan-4-ylmethyl)phenyl]methoxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound O[C@H]1C(CCCC)(CCCC)CS(=O)(=O)C2=CC=C(N(C)C)C=C2[C@H]1C(C=C1)=CC=C1OCC(C=C1)=CC=C1C[N+]1(CC2)CCN2CC1 STPKWKPURVSAJF-LJEWAXOPSA-N 0.000 description 1
- VTWKXBJHBHYJBI-SOFGYWHQSA-N (ne)-n-benzylidenehydroxylamine Chemical compound O\N=C\C1=CC=CC=C1 VTWKXBJHBHYJBI-SOFGYWHQSA-N 0.000 description 1
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 1
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 1
- MHSLDASSAFCCDO-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylpyrazol-3-yl)-3-(4-pyridin-4-yloxyphenyl)urea Chemical compound CN1N=C(C(C)(C)C)C=C1NC(=O)NC(C=C1)=CC=C1OC1=CC=NC=C1 MHSLDASSAFCCDO-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- JCERKCRUSDOWLT-UHFFFAOYSA-N 1-bromopropan-1-ol Chemical compound CCC(O)Br JCERKCRUSDOWLT-UHFFFAOYSA-N 0.000 description 1
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 1
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 description 1
- VCUXVXLUOHDHKK-UHFFFAOYSA-N 2-(2-aminopyrimidin-4-yl)-4-(2-chloro-4-methoxyphenyl)-1,3-thiazole-5-carboxamide Chemical compound ClC1=CC(OC)=CC=C1C1=C(C(N)=O)SC(C=2N=C(N)N=CC=2)=N1 VCUXVXLUOHDHKK-UHFFFAOYSA-N 0.000 description 1
- QEBYEVQKHRUYPE-UHFFFAOYSA-N 2-(2-chlorophenyl)-5-[(1-methylpyrazol-3-yl)methyl]-4-[[methyl(pyridin-3-ylmethyl)amino]methyl]-1h-pyrazolo[4,3-c]pyridine-3,6-dione Chemical compound C1=CN(C)N=C1CN1C(=O)C=C2NN(C=3C(=CC=CC=3)Cl)C(=O)C2=C1CN(C)CC1=CC=CN=C1 QEBYEVQKHRUYPE-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 1
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 1
- DFRAKBCRUYUFNT-UHFFFAOYSA-N 3,8-dicyclohexyl-2,4,7,9-tetrahydro-[1,3]oxazino[5,6-h][1,3]benzoxazine Chemical compound C1CCCCC1N1CC(C=CC2=C3OCN(C2)C2CCCCC2)=C3OC1 DFRAKBCRUYUFNT-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- WFOVEDJTASPCIR-UHFFFAOYSA-N 3-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]-n-[[2-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound N=1N=C(C=2C=CN=CC=2)N(C)C=1CNC(C=1)=CC=CC=1C(=O)NCC1=CC=CC=C1C(F)(F)F WFOVEDJTASPCIR-UHFFFAOYSA-N 0.000 description 1
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 1
- MPMKMQHJHDHPBE-RUZDIDTESA-N 4-[[(2r)-1-(1-benzothiophene-3-carbonyl)-2-methylazetidine-2-carbonyl]-[(3-chlorophenyl)methyl]amino]butanoic acid Chemical compound O=C([C@@]1(N(CC1)C(=O)C=1C2=CC=CC=C2SC=1)C)N(CCCC(O)=O)CC1=CC=CC(Cl)=C1 MPMKMQHJHDHPBE-RUZDIDTESA-N 0.000 description 1
- DQAZPZIYEOGZAF-UHFFFAOYSA-N 4-ethyl-n-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]piperazine-1-carboxamide Chemical compound C1CN(CC)CCN1C(=O)NC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(C#C)=C1 DQAZPZIYEOGZAF-UHFFFAOYSA-N 0.000 description 1
- VKLKXFOZNHEBSW-UHFFFAOYSA-N 5-[[3-[(4-morpholin-4-ylbenzoyl)amino]phenyl]methoxy]pyridine-3-carboxamide Chemical compound O1CCN(CC1)C1=CC=C(C(=O)NC=2C=C(COC=3C=NC=C(C(=O)N)C=3)C=CC=2)C=C1 VKLKXFOZNHEBSW-UHFFFAOYSA-N 0.000 description 1
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 1
- ZTLMHGOWADYAHM-UHFFFAOYSA-N 5-phenyl-3h-1,3,4-thiadiazole-2-thione Chemical compound S1C(S)=NN=C1C1=CC=CC=C1 ZTLMHGOWADYAHM-UHFFFAOYSA-N 0.000 description 1
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 1
- GDUANFXPOZTYKS-UHFFFAOYSA-N 6-bromo-8-[(2,6-difluoro-4-methoxybenzoyl)amino]-4-oxochromene-2-carboxylic acid Chemical compound FC1=CC(OC)=CC(F)=C1C(=O)NC1=CC(Br)=CC2=C1OC(C(O)=O)=CC2=O GDUANFXPOZTYKS-UHFFFAOYSA-N 0.000 description 1
- XASOHFCUIQARJT-UHFFFAOYSA-N 8-methoxy-6-[7-(2-morpholin-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one Chemical compound C(N1C(=O)C2=C(OC)C=C(C=3N4C(=NC=3)C=C(C=C4)OCCN3CCOCC3)C=C2CC1)C(F)(F)F XASOHFCUIQARJT-UHFFFAOYSA-N 0.000 description 1
- 241000223602 Alternaria alternata Species 0.000 description 1
- LNTIKAHDNWYAGL-UHFFFAOYSA-N Br.CC#C Chemical compound Br.CC#C LNTIKAHDNWYAGL-UHFFFAOYSA-N 0.000 description 1
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 1
- PKMUHQIDVVOXHQ-HXUWFJFHSA-N C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O Chemical compound C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O PKMUHQIDVVOXHQ-HXUWFJFHSA-N 0.000 description 1
- QXJHBXQVWHZTOS-UHFFFAOYSA-N Cc1nc(N)c(C[n]2nnc(CSc3nnc(-c(cc4)ccc4F)[s]3)c2)cn1 Chemical compound Cc1nc(N)c(C[n]2nnc(CSc3nnc(-c(cc4)ccc4F)[s]3)c2)cn1 QXJHBXQVWHZTOS-UHFFFAOYSA-N 0.000 description 1
- IGZDPQDQRVTLBQ-UHFFFAOYSA-N Cc1nc(N)c(C[n]2nnc(CSc3nnc(-c(ccc([N+]([O-])=O)c4)c4Cl)[o]3)c2)cn1 Chemical compound Cc1nc(N)c(C[n]2nnc(CSc3nnc(-c(ccc([N+]([O-])=O)c4)c4Cl)[o]3)c2)cn1 IGZDPQDQRVTLBQ-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 1
- 241000223195 Fusarium graminearum Species 0.000 description 1
- 241000461774 Gloeosporium Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 1
- AVYVHIKSFXVDBG-UHFFFAOYSA-N N-benzyl-N-hydroxy-2,2-dimethylbutanamide Chemical compound C(C1=CC=CC=C1)N(C(C(CC)(C)C)=O)O AVYVHIKSFXVDBG-UHFFFAOYSA-N 0.000 description 1
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- GNVMUORYQLCPJZ-UHFFFAOYSA-M Thiocarbamate Chemical compound NC([S-])=O GNVMUORYQLCPJZ-UHFFFAOYSA-M 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 229940126545 compound 53 Drugs 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 229940125900 compound 59 Drugs 0.000 description 1
- 229940126179 compound 72 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical class [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000021186 dishes Nutrition 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- BJXYHBKEQFQVES-NWDGAFQWSA-N enpatoran Chemical compound N[C@H]1CN(C[C@H](C1)C(F)(F)F)C1=C2C=CC=NC2=C(C=C1)C#N BJXYHBKEQFQVES-NWDGAFQWSA-N 0.000 description 1
- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000034659 glycolysis Effects 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 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
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- YCJZWBZJSYLMPB-UHFFFAOYSA-N n-(2-chloropyrimidin-4-yl)-2,5-dimethyl-1-phenylimidazole-4-carboxamide Chemical compound CC=1N(C=2C=CC=CC=2)C(C)=NC=1C(=O)NC1=CC=NC(Cl)=N1 YCJZWBZJSYLMPB-UHFFFAOYSA-N 0.000 description 1
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000012015 potatoes Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960002363 thiamine pyrophosphate Drugs 0.000 description 1
- 235000008170 thiamine pyrophosphate Nutrition 0.000 description 1
- 239000011678 thiamine pyrophosphate Substances 0.000 description 1
- YXVCLPJQTZXJLH-UHFFFAOYSA-N thiamine(1+) diphosphate chloride Chemical compound [Cl-].CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N YXVCLPJQTZXJLH-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Classifications
-
- 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
- C07D403/06—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 carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
- A01N43/647—Triazoles; Hydrogenated triazoles
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
- A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
- A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
- A01N47/12—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof containing a —O—CO—N< group, or a thio analogue thereof, neither directly attached to a ring nor the nitrogen atom being a member of a heterocyclic ring
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
- A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
- A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
- A01N47/34—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N< containing the groups, e.g. biuret; Thio analogues thereof; Urea-aldehyde condensation products
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Agronomy & Crop Science (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种具有杀菌活性的2‑甲基‑4‑氨基‑5‑(取代‑1,2,3‑三唑基)甲基嘧啶衍生物、其制备方法及应用，结构式其中，R1表示氢或I；X表示O、NH或S；Y表示苯甲酰胺硫羰基或取代苯甲酰胺硫羰基、2‑苯基‑1,3,4‑噻（噁）二唑‑5‑基或2‑取代苯基‑1,3,4‑噻（噁）‑5‑基、苯甲（乙酮）亚胺基或取代苯甲（乙酮）亚胺基；在Y所涉及的苯环上的取代基主要为：H、卤素、硝基、氰基、CF3、C1‑4烷基、甲氧基、C1‑2羧酸基或羧酸酯基。本发明化合物对小麦赤霉病菌、水稻纹枯病菌、黄瓜灰霉病菌、番茄早疫病菌、烟草赤星病菌和黄瓜炭疽病菌具有显著防效，可用作杀菌活性成分。
Description
技术领域
本发明涉及2-甲基-4-氨基-5-(取代-1,2,3-三唑基)甲基嘧啶衍生物、其制备方法及其应用。
背景技术
丙酮酸脱氢酶系是生物体内能量代谢调控过程中的一类重要酶系，它连接着糖酵解得到的丙酮酸转化为三羧酸循环的底物乙酰辅酶A的过程。基于其重要的生化特点，丙酮酸脱氢酶系完全可作为农药靶标进行研究。近年来，本发明人以微生物中丙酮酸脱氢酶系为靶标，设计合成了具有作为杀菌剂应用价值的新型结构化合物。例如，A类（贺红武等，中国发明专利，申请号为201110268908.7）化合物则显示了优异的杀菌活性。
发明内容
本发明的目的在于探索具有杀菌活性的新型化合物，并提供了一种具有杀菌活性的2-甲基-4-氨基-5-(取代-1,2,3-三唑基)甲基嘧啶衍生物、其制备方法及应用。
本发明在A类化合物基础上进一步优化了Y的结构类型，提出了一种具有杀菌活性的新型化合物，其具有通式（I）的结构：
其中，R1表示氢或I；X表示O、NH或S；Y表示苯甲酰胺硫羰基或取代苯甲酰胺硫羰基、2-苯基-1,3,4-噻（噁）二唑-5-基或2-取代苯基-1,3,4-噻（噁）-5-基、苯甲（乙酮）亚胺基或取代苯甲（乙酮）亚胺基；在Y所涉及的苯环上的取代基主要为：H、卤素、硝基、氰基、CF3、C1-4烷基、甲氧基、C1-2羧酸基或羧酸酯基；取代基在苯环任意位置上的单取代或多取代，取代基相同或不同。
化合物（I）包括以通式（I-1）表示的[1-（2-甲基-4-氨基嘧啶-5-甲基）-1H-1,2,3-三唑]-4-甲基-（取代苯甲酰基）硫代氨基甲酸酯（硫脲）化合物、以通式（I-2）表示的N-（（1-（（2-甲基-4-氨基嘧啶-5-基）甲基）-1H-1,2,3-三唑-4-基）甲基）-2-取代苯基-1,3,4-噻（噁）-5-基硫醚化合物、以通式（I-3）表示的O-[1-（2-甲基-4-氨基嘧啶-5-甲基）-1H-1,2,3-三唑-4-基]取代苯甲（乙酮）肟醚化合物。
本发明所提出的通式（I-1）、通式（I-2）、通式（I-3）的化合物结构均未见报道，通式（I-1）、通式（I-2）、通式（I-3）的结构分别定义如下：
通式（I-1）中，X为氧或NH；R1的定义与通式（I）的R1定义相同；R2为：H、卤素、硝基、甲氧基或C1-4烷基；R3为：H、卤素、硝基、氰基、CF3、C1-4烷基或甲氧基；R2与R3位置可互换。
通式（I-2）中，X为氧或S；R1的定义与通式（I）的R1定义相同；R2为：H、卤素、硝基或C1-4烷基；R3为：H、卤素、硝基、CF3、甲氧基或C1-4烷基；R2与R3位置可互换。
通式（I-3）中，R1的定义与通式（I）的R1定义相同；R2为H、硝基或卤素；R3为：H、卤素、硝基、C1-4烷基或甲氧基；R2与R3位置可换；R4为H或甲基。
本发明具有通式（I）结构的化合物对小麦赤霉病菌、水稻纹枯病菌、黄瓜灰霉病菌、番茄早疫病菌、烟草赤星病菌和黄瓜炭疽病菌具有显著的防效，可用作杀菌剂的活性成分。
具有通式（I-1）结构的化合物的制备方法，是在催化剂和有机碱或仅在催化剂的存在下，使化合物（II）与炔中间体（III）在-10～80℃温度下反应12-24小时关环生成，A法。反应式如下：
上述反应式（1）中，通式（III）中R1、R2、R3、X的定义与通式（I-1）中R1、R2、R3、X的定义相同。
上述A法反应中，化合物（II）、中间体（III）、催化剂和有机碱的摩尔比为1：（0.8-1.2）：（0.01-0.15）：2；反应溶剂采用有机溶剂：二氯甲烷、二氧六环、二氯乙烷、丙酮、叔丁醇、水、苯、乙酸乙酯、四氢呋喃、乙腈、N,N-二甲基甲酰胺或二甲基亚砜；催化剂为：CuI、CuBr(PPh3)3、CuSO4·5H2O:抗坏血酸钠、CuBr或Cu(OAc)2；有机碱为：三乙胺、二异丙基乙基胺、吡啶或六氢吡啶。
具有通式（I-2）结构的化合物的制备方法，是在催化剂和有机碱或仅在催化剂的存在下，使化合物（II）与中间体（IV）在-10～80℃温度下反应12-24小时关环生成，B法。反应式如下：
上述反应式（2）中，通式（IV）中R1、R2、R3、X的定义与通式（I-2）中R1、R2、R3、X的定义相同。
上述B法反应中，化合物（II）、中间体（IV）、催化剂和有机碱的摩尔比为1：（0.8-1.2）：（0.01-0.15）：2；反应溶剂采用有机溶剂：二氯甲烷、二氧六环、二氯乙烷、丙酮、叔丁醇：水、苯、乙酸乙酯、四氢呋喃、乙腈、N,N-二甲基甲酰胺或二甲基亚砜；催化剂为：CuI、CuBr(PPh3)3、CuSO4·5H2O:抗坏血酸钠、CuBr或者Cu(OAc)2；有机碱为：三乙胺、二异丙基乙基胺、吡啶或六氢吡啶。
具有通式（I-2）结构的化合物的制备方法，是在催化剂和有机碱或仅在催化剂的存在下，使化合物（II）与中间体（V）在-10～80℃温度下反应12-24小时关环生成，C法。反应式如下：
上述反应式（3）中，通式（V）中R1、R2、R3、R4的定义与通式（I-3）中R1、R2、R3、R4的定义相同。
上述C法反应中，化合物（II）、中间体（V）、催化剂和有机碱的摩尔比为1：（0.8-1.2）：（0.01-0.15）：2；反应溶剂采用有机溶剂：二氯甲烷、二氧六环、二氯乙烷、丙酮、叔丁醇：水、苯、乙酸乙酯、四氢呋喃、乙腈、N,N-二甲基甲酰胺或二甲基亚砜；催化剂为：CuI、CuBr(PPh3)3、CuSO4·5H2O:抗坏血酸钠、CuBr或者Cu(OAc)2；有机碱为：三乙胺、二异丙基乙基胺、吡啶或六氢吡啶。
具体实施方式
下面通过实施例具体地说明本发明化合物（I），包括化合物（I-1）、（I-2）、（I-3）的制备方法，这些实施例仅对本发明进行说明，而不是对本发明进行限制。
下述实施例中采用的化合物（II）可参见文献1中记载的方法进行制备。
实施例1：中间体III-1的制备
在装有干燥管、低温温度计、恒压滴液漏斗的100mL三颈瓶中加入0.28g炔丙醇（5mmol）、0.5g三乙胺（5mmol）和10mL乙腈，在低温恒温反应浴中冷却至4℃，缓慢加入10mL的苯甲酰异硫氰酸酯的乙腈溶液，其中苯甲酰异硫氰酸酯为5mmol；维持反应液温度低于5℃，待苯甲酰异硫氰酸酯的乙腈溶液滴加完毕后，转移至室温反应，TLC（薄层色谱）监测。反应结束后，依次用5%稀盐酸、饱和碳酸氢钠溶液及饱和食盐水洗涤至溶液呈中性。然后用二氯甲烷（15mL×3次）萃取水相，经合并有机相、无水硫酸钠干燥过夜、抽滤、滤液浓缩即得粗产品，经硅胶柱层析梯度淋洗（石油醚：乙酸乙酯=3:1）即得纯品。
R1、R2、R3、X为其他取代基的中间体III按中间体III-1类似方法制得。
实施例2：中间体IV-1的制备
于50mL圆底烧瓶中加入4.0mmol的5-苯基-1,3,4-噻二唑-2-硫醇、4.0mmol碳酸钾粉末，溶于15mL干燥二甲基亚砜，室温下滴加入4.8mmol溴丙醇，于室温下搅拌反应，TLC（薄层色谱）监测反应至原料点消失，停止反应后，将体系倾入100mL水中，充分搅拌，有大量固体析出，抽滤得粗品IV-1，无需提纯。
R1、R2、R3、X为其他取代基的中间体IV按中间体IV-1类似方法制得。
实施例3：中间体V-1的制备
分别将5mmol苯甲醛肟、5mmol溴丙炔溶于20mL无水乙腈，然后加入5mmol氢氧化钠，回流反应8小时，TLC（薄层色谱）监测反应完全。减压除去乙腈，然后依次经稀盐酸、饱和碳酸氢钠溶液、饱和食盐水洗涤，用乙酸乙酯（20mL×3次）萃取水相，经合并有机相、无水硫酸钠干燥，浓缩得粗产品，丙酮重结晶得中间体V-1。
R1、R2、R3、R4为其他取代基的中间体V按中间体V-1类似方法制得。
实施例4：化合物1的制备
将1mmol2-甲基-4-氨基-5-叠氮甲基嘧啶和1mmol O-丙炔基苯甲酰基氨基硫代甲酸酯溶于20mL四氢呋喃中，加入2mmol三乙胺和0.1mmol碘化亚铜CuI，在60-70℃搅拌反应10-15小时，TLC（薄层色谱）监测反应至完全，加水有固体析出，经减压过滤、水洗、烘干的粗品。用N,N-二甲基甲酰胺和水重结晶，得黄色固体状的目标化合物，产率88%，mp：120-122℃。
元素分析/%：计算值：C,53.25;H,4.47;N,25.57;S,8.36;实测值：C,53.09;H,4.74;N,25.33;S,8.04;1H NMR(400MHz,CDCl3):δ2.49(s,3H,CH3),5.35(s,2H,CH2),5.44(s,2H,CH2),5.66(s,2H,NH2),7.41-8.03(m,5H,Ar-H),7.72(s,1H,CH),8.19(s,1H,CH);13CNMR(100MHz,DMSO-d6):δ25.2,46.9,57.9,108.2,125.0,128.8,129.2,133.5,142.0,156.4,161.6,165.5,167.2,179.3.IR(KBr):1277(C=S),1702(C=O),3150(N-H),3512cm-1.ESI-MS(m/z):384(M++1).
化合物2-20按化合物1类似方法制得，结构鉴定数据如下：
化合物2
所得纯品为黄色固体，产率87%，m.p.115-116℃;。元素分析/%：计算值：C,48.86;H,3.86;N,23.46;S,7.67;实测值：C,48.83;H,4.20;N,23.57;S,7.82;1H NMR(400MHz,CDCl3):δ2.50(s,3H,CH3),5.36(s,2H,CH2),5.45(s,2H,CH2),5.58(s,2H,NH2),7.28-7.85(m,4H,Ar-H),7.46(s,1H,CH),8.19(s,1H,CH).IR(KBr):1265(C=S),1717(C=O),3145(N-H),3544cm-1.ESI-MS(m/z):418(M++1).
化合物3
所得纯品为黄色固体，产率84%，m.p.139-141℃。元素分析/%：计算值：C,48.86;H,3.86;N,23.46;S,7.67;实测值：C,49.24;H,3.96;N,23.53;S,7.74;1H NMR(400MHz,CDCl3):δ2.49(s,3H,CH3),5.38(s,2H,CH2),5.44(s,2H,CH2),5.66(s,2H,NH2),7.35-7.99(m,4H,Ar-H),7.72(s,1H,CH),8.05(s,1H,CH).IR(KBr):1270(C=S),1722(C=O),3147(N-H),3454cm-1.ESI-MS(m/z):418(M++1).
化合物4
所得纯品为黄色固体，产率78%，m.p.124-125℃。元素分析/%：计算值：C,48.86;H,3.86;N,23.46;S,7.67;实测值：C,49.02;H,4.05;N,23.33;S,7.75;1H NMR(400MHz,CDCl3):δ2.49(s,3H,CH3),5.36(s,2H,CH2),5.43(s,2H,CH2),5.63(s,2H,NH2),7.39-7.97(m,4H,Ar-H),7.71(s,1H,CH),8.20(s,1H,CH);13C NMR(100MHz,DMSO-d6):δ25.2,46.8,58.1,108.2,125.0,128.1,131.0,138.4,141.7,156.3,161.5,164.6,167.6,180.3.IR(KBr):1277(C=S),1708(C=O),3110(N-H),3452cm-1.ESI-MS(m/z):418(M++1).
化合物5
所得纯品为浅黄色固体，产率73%，m.p.156-157℃。元素分析/%：计算值：C,54.39;H,4.82;N,24.67;S,8.07;实测值：C,54.69;H,4.99;N,24.65;S,7.62;1H NMR(400MHz,CDCl3):δ2.49(s,3H,CH3),2.62(s,3H,CH3),5.36(s,2H,CH2),5.41(s,2H,CH2),5.67(s,2H,NH2),7.22-7.96(m,4H,Ar-H),7.71(s,1H,CH),8.20(s,1H,CH).IR(KBr):1270(C=S),1702(C=O),3150(N-H),3512cm-1.ESI-MS(m/z):398(M++1).
化合物6
所得纯品为黄色固体，产率83%，m.p.123-125℃。元素分析/%：计算值：C,54.39;H,4.82;N,24.67;S,8.07;实测值：C,54.17;H,4.73;N,23.55;S,8.01;1H NMR(400MHz,CDCl3):δ2.51(s,3H,CH3),2.65(s,3H,CH3),5.38(s,2H,CH2),5.43(s,2H,CH2),5.54(s,2H,NH2),7.32-7.93(m,4H,Ar-H),7.71(s,1H,CH),8.08(s,1H,CH).IR(KBr):1253(C=S),1709(C=O),3118(N-H),3452cm-1.ESI-MS(m/z):398(M++1).
化合物7
所得纯品为浅黄色固体，产率71%，m.p.146-148℃。元素分析/%：计算值：C,50.87;H,4.02;N,24.43;S,7.99;实测值：C,51.04;H,4.29;N,24.32;S,7.66;1H NMR(400MHz,CDCl3):δ2.49(s,3H,CH3),5.36(s,2H,CH2),5.46(s,2H,CH2),5.60(s,2H,NH2),7.11-7.93(m,4H,Ar-H),7.52(s,1H,CH),8.20(s,1H,CH).IR(KBr):1253(C=S),1729(C=O),3148(N-H),3453cm-1.ESI-MS(m/z):402(M++1).
化合物8
所得纯品为黄色固体，产率76%，m.p.132-133℃。元素分析/%：计算值：C,50.87;H,4.02;N,24.43;S,7.99;实测值：C,50.92;H,4.34;N,24.40;S,7.80;1H NMR(400MHz,CDCl3):δ2.50(s,3H,CH3),5.36(s,2H,CH2),5.43(s,2H,CH2),5.62(s,2H,NH2),7.07-8.06(m,4H,Ar-H),7.71(s,1H,CH),8.20(s,1H,CH).IR(KBr):1253(C=S),1721(C=O),3111(N-H),3454cm-1.ESI-MS(m/z):402(M++1).
化合物9
所得纯品为黄色固体，产率70%，m.p.134-136℃。元素分析/%：计算值：C,44.16;H,3.49;N,21.21;S,6.94;实测值：C,44.44;H,3.77;N,31.38;S,6.84;1H NMR(400MHz,CDCl3):δ2.50(s,3H,CH3),5.36(s,2H,CH2),5.45(s,2H,CH2),5.61(s,2H,NH2),7.33-7.80(m,4H,Ar-H),7.66(s,1H,CH),8.20(s,1H,CH).IR(KBr):1270(C=S),1721(C=O),3145(N-H),3453cm-1.ESI-MS(m/z):463(M++1).
化合物10
所得纯品为黄色固体，产率77%，m.p.141-142℃。元素分析/%：计算值：C,48.68;H,3.60;N,23.38;S,7.65;实测值：C,48.32;H,3.86;N,23.62;S,7.54;1H NMR(400MHz,CDCl3):δ2.49(s,3H,CH3),5.36(s,2H,CH2),5.42(s,2H,CH2),5.59(s,2H,NH2),6.92-7.71(m,4H,Ar-H),7.71(s,1H,CH),8.20(s,1H,CH).IR(KBr):1265(C=S),1725(C=O),3139(N-H),3440cm-1.ESI-MS(m/z):420(M++1).
化合物11
所得纯品为黄色固体，产率50%，m.p.73-75℃。素分析/%：计算值：C,44.11;H,3.27;N,24.21;S,6.93;实测值：C,44.25;H,3.42;N,24.22;S,6.82;1H NMR(600MHz,DMSO-d6):δ2.29(s,3H,CH3),5.44(s,2H,CH2),5.49(s,2H,CH2),6.98(s,2H,NH2),7.99-8.27(m,3H,Ar-H),8.38(s,1H,CH);13C NMR(100MHz,DMSO-d6):δ25.3,46.8,109.3,122.4,125.2,125.5,132.0,132.6,135.4,141.1,142.9,149.4,156.2,161.4,163.5,194.5.IR(KBr):1243(C=S),1603(C=O),3369(N-H)cm-1.EI-MS(m/z,%):462(M+,2).
化合物12
所得纯品为黄色固体，产率56%，m.p.62-64℃。元素分析/%：计算值：C,45.14;H,3.34;N,21.68;S,7.09;实测值：C,45.25;H,3.56;N,21.95;S,7.25;1H NMR(600MHz,DMSO-d6):δ2.30(s,3H,CH3),5.38(s,2H,CH2),5.47(s,2H,CH2),6.98(s,2H,NH2),7.53-7.81(m,3H,Ar-H),8.25(s,1H,CH).IR(KBr):1245(C=S),1604(C=O),3366(N-H)cm-1.EI-MS(m/z,%):451(M+,2).
化合物13
所得纯品为黄色固体，产率87%，m.p.96-98℃。元素分析/%：计算值：C,51.46;H,4.77;N,22.11;S,7.23;实测值：C,51.62;H,4.59;N,22.95;S,6.98;1H NMR(400MHz,DMSO-d6):δ2.30(s,3H,CH3),3.78(s,3H,OCH3),3.81(s,3H,OCH3),5.34(s,2H,CH2),5.45(s,2H,CH2),6.94(s,2H,NH2),7.05(d,1H,J=8.8Hz,Ar-H),7.41(s,1H,Ar-H),7.56(d,1H,J=7.2Hz,Ar-H),8.22(s,1H,CH);13C NMR(100MHz,DMSO-d6):δ25.3,46.7,55.5,55.7,57.6,111.0,111.6,121.4,123.3,124.9,142.2,148.4,153.1156.0,160.9,161.4,165.2,166.9,180.3.IR(KBr):1271(C=S),1706(C=O),3365(N-H)cm-1.EI-MS(m/z,%):462(M+,2).
化合物14
所得纯品为黄色固体，产率44%，m.p.>260℃。元素分析/%：计算值：C,43.13;H,3.19;N,26.63;S,6.77;实测值：C,43.35;H,3.42;N,26.12;S,6.53;1H NMR(600MHz,DMSO-d6):δ2.29(s,3H,CH3),5.50(s,2H,CH2),5.52(s,2H,CH2),7.00(s,2H,NH2),8.30(s,1H,CH),8.87(s,1H,Ar-H),9.03(s,1H,Ar-H).IR(KBr):1277(C=S),1726(C=O),3362(N-H)cm-1.EI-MS(m/z,%):473(M+,4).
化合物15
所得纯品为黄色固体，产率34%，m.p.206-208℃。元素分析/%：计算值：C,51.46;H,4.77;N,22.11;S,7.23;实测值：C,51.27;H,4.49;N,22.22;S,7.38;1H NMR(400MHz,DMSO-d6):δ2.29(s,3H,CH3),3.78(s,3H,OCH3),3.81(s,3H,OCH3),5.34(s,2H,CH2),5.48(s,2H,CH2),6.98(s,2H,NH2),7.04(d,1H,J=8.4Hz,Ar-H),7.41(d,1H,J=1.8Hz,Ar-H),7.56(d,1H,J=8.4Hz,Ar-H).IR(KBr):1271(C=S),1706(C=O),3369(N-H)cm-1.EI-MS(m/z,%):443(M+,4).
化合物16
所得纯品为黄色固体，产率77%，m.p.141-142℃。元素分析/%：计算值：C,48.68;H,3.60;N,23.38;S,7.65;实测值：C,48.32;H,3.86;N,23.62;S,7.54;1H NMR(400MHz,CDCl3):δ2.49(s,3H,CH3),5.36(s,2H,CH2),5.42(s,2H,CH2),5.59(s,2H,NH2),6.92-7.71(m,4H,Ar-H),7.71(s,1H,CH),8.20(s,1H,CH).IR(KBr):1265(C=S),1725(C=O),3139(N-H),3440cm-1.EI-MS(m/z,%):420(M++1,100).
化合物17
所得纯品为黄色固体，产率33%，m.p.230-232℃。元素分析/%：计算值：C,45.14;H,3.34;N,21.68;S,7.09;实测值：C,45.22;H,3.11;N,21.88;S,7.20;1H NMR(400MHz,DMSO-d6):δ2.32(s,3H,CH3),5.39(s,2H,CH2),5.51(s,2H,CH2),7.06(s,2H,NH2),7.53-7.81(m,3H,Ar-H),8.25(s,1H,CH).IR(KBr):1271(C=S),1712(C=O),3426(N-H)cm-1.EI-MS(m/z,%):451(M+,2).
化合物18
所得纯品为黄色固体，产率30%，m.p.191-193℃。元素分析/%：计算值：C,40.09;H,3.17;N,19.25;S,6.30;实测值：C,40.20;H,3.45;N,19.18;S,6.16;1H NMR(600MHz,DMSO-d6):δ2.29(s,3H,CH3),4.49(s,2H,CH2),5.43(s,2H,CH2),6.97(s,2H,NH2),7.16-7.85(m,3H,Ar-H),7.97(s,1H,CH).IR(KBr):1285(C=S),1715(C=O),3364(N-H)cm-1.EI-MS(m/z,%):509(M+,2).
化合物19
所得纯品为黄色固体，产率40%，m.p.138-140℃。元素分析/%：计算值：C,47.89;H,3.57;N,21.72;S,7.10;实测值：C,47.05;H,3.64;N,21.67;S,7.38;1H NMR(600MHz,DMSO-d6):δ2.30(s,3H,CH3),5.25(s,2H,CH2),5.45(s,2H,CH2),6.95(s,2H,NH2),7.49-7.79(m,4H,Ar-H),8.01(s,1H,CH),8.03(s,1H,CH).IR(KBr):1323(C=S),1656(C=O),3376(N-H)cm-1.EI-MS(m/z,%):451(M+,2).
化合物20
所得纯品为黄色固体，产率37%，m.p.>260℃。元素分析/%：计算值：C,52.93;H,3.95;N,27.43;S,7.85;实测值：C,52.78;H,3.72;N,27.12;S,7.55;1H NMR(400MHz,DMSO-d6):δ2.50(s,3H,CH3),4.52(s,2H,CH2),5.51(s,2H,CH2),7.11(s,2H,NH2),7.96(m,4H,Ar-H),8.00(s,1H,CH),9.28(s,1H,CH).IR(KBr):1271(C=S),1712(C=O),3426(N-H)cm-1.EI-MS(m/z,%):408(M+,2).
实施例5：化合物21的制备
将1mmol2-甲基-4-氨基-5-叠氮甲基嘧啶和1mmol丙炔基苯甲酰基硫脲溶于20mL乙腈中，加入2mmol二异丙基乙基胺和0.1mmol碘化亚铜，在30-40℃搅拌反应10-15小时，TLC（薄层色谱）监测反应至完全，加水有固体析出，经减压过滤、水洗、烘干，得到粗品。用N,N-二甲基甲酰胺和水重结晶，得目标化合物，为浅黄色固体，产率70%，mp：124-126℃。
元素分析/%：计算值：C,53.39;H,4.74;N,29.30;S,8.38;实测值：C,53.04;H,4.65;N,29.27;S,8.35;1H NMR(400MHz,CDCl3):δ2.49(s,3H,CH3),5.35(s,2H,CH2),5.44(s,2H,CH2),5.66(s,2H,NH2),7.41-8.03(m,5H,Ar-H),7.72(s,1H,CH),8.19(s,1H,CH).IR(KBr):1265(C=S),1692(C=O),3150(N-H),3410cm-1.EI-MS(m/z,%):383(M++1,100).
化合物22-40按化合物21类似方法制得，其结构鉴定数据如下：
化合物22
所得纯品为黄色固体，产率87%，m.p.115-116℃。元素分析/%：计算值：C,48.98;H,4.11;N,26.88;S,7.69;实测值：C,49.20;H,4.36;N,26.79;S,7.74;1H NMR(400MHz,CDCl3):δ2.50(s,3H,CH3),5.36(s,2H,CH2),5.45(s,2H,CH2),5.58(s,2H,NH2),7.28-7.85(m,4H,Ar-H),7.46(s,1H,CH),8.19(s,1H,CH).IR(KBr):1250(C=S),1717(C=O),3145(N-H),3544cm-1.EI-MS(m/z,%):417(M++1,100).
化合物23
所得纯品为黄色固体，产率85%，m.p.159-161℃。元素分析/%：计算值：C,48.98;H,4.11;N,26.88;S,7.69;实测值：C,48.99;H,4.43;N,26.52;S,7.39;1H NMR(400MHz,CDCl3):δ2.49(s,3H,CH3),5.38(s,2H,CH2),5.44(s,2H,CH2),5.66(s,2H,NH2),7.35-7.99(m,4H,Ar-H),7.72(s,1H,CH),8.05(s,1H,CH).IR(KBr):1250(C=S),1722(C=O),3147(N-H),3454cm-1.EI-MS(m/z,%):417(M++1,100).
化合物24
所得纯品为黄色固体，产率77%，m.p.124-125℃;元素分析/%：计算值：C,48.98;H,4.11;N,26.88;S,7.69;实测值：C,48.92;H,4.54;N,27.11;S,7.50;1H NMR(400MHz,CDCl3):δ2.49(s,3H,CH3),5.36(s,2H,CH2),5.43(s,2H,CH2),5.63(s,2H,NH2),7.39-7.97(m,4H,Ar-H),7.71(s,1H,CH),8.20(s,1H,CH).IR(KBr):1250(C=S),1708(C=O),3110(N-H),3452cm-1.EI-MS(m/z,%):417(M++1,100).
化合物25
所得纯品为浅黄色固体，产率80%，m.p.156-157℃。元素分析/%：计算值：C,54.53;H,5.08;N,28.26;S,8.09;实测值：C,49.68;H,4.85;N,28.40;S,8.14;1H NMR(400MHz,CDCl3):δ2.49(s,3H,CH3),2.62(s,3H,CH3),5.36(s,2H,CH2),5.41(s,2H,CH2),5.67(s,2H,NH2),7.22-7.96(m,4H,Ar-H),7.71(s,1H,CH),8.20(s,1H,CH).IR(KBr):1270(C=S),1702(C=O),3150(N-H),3512cm-1.EI-MS(m/z,%):397(M++1,100).
化合物26
所得纯品为黄色固体，产率80%，m.p.120-122℃。元素分析/%：计算值：C,54.53;H,5.08;N,28.26;S,8.09;实测值：C,54.31;H,5.11;N,28.17;S,8.22;1H NMR(400MHz,CDCl3):δ2.51(s,3H,CH3),2.65(s,3H,CH3),5.38(s,2H,CH2),5.43(s,2H,CH2),5.54(s,2H,NH2),7.32-7.93(m,4H,Ar-H),7.71(s,1H,CH),8.08(s,1H,CH).IR(KBr):1270(C=S),1709(C=O),3118(N-H),3452cm-1.EI-MS(m/z,%):397(M++1,100).
化合物27
所得纯品为浅黄色固体，产率90%，m.p.141-143℃。元素分析/%：计算值：C,50.99;H,4.28;N,27.98;S,8.01;实测值：C,50.76;H,4.06;N,27.84;S,8.26;1H NMR(400MHz,CDCl3):δ2.49(s,3H,CH3),5.36(s,2H,CH2),5.46(s,2H,CH2),5.60(s,2H,NH2),7.11-7.93(m,4H,Ar-H),7.52(s,1H,CH),8.20(s,1H,CH).IR(KBr):1270(C=S),1729(C=O),3148(N-H),3453cm-1.EI-MS(m/z,%):401(M++1,100).
化合物28
所得纯品为黄色固体，产率78%，m.p.152-153℃。元素分析/%：计算值：C,50.99;H,4.28;N,27.98;S,8.01;实测值：C,51.03;H,4.01;N,27.84;S,8.26;1H NMR(400MHz,CDCl3):δ2.50(s,3H,CH3),5.36(s,2H,CH2),5.43(s,2H,CH2),5.62(s,2H,NH2),7.10-8.06(m,4H,Ar-H),7.71(s,1H,CH),8.20(s,1H,CH).IR(KBr):1270(C=S),1721(C=O),3111(N-H),3454cm-1.EI-MS(m/z,%):401(M++1,100).
化合物29
所得纯品为黄色固体，产率86%，m.p.134-136℃。元素分析/%：计算值：C,44.26;H,3.71;N,24.29;S,6.95;实测值：C,44.04;H,3.97;N,24.11;S,6.83;1H NMR(400MHz,CDCl3):δ2.50(s,3H,CH3),5.36(s,2H,CH2),5.45(s,2H,CH2),5.61(s,2H,NH2),7.33-7.80(m,4H,Ar-H),7.66(s,1H,CH),8.20(s,1H,CH).IR(KBr):1270(C=S),1721(C=O),3145(N-H),3453cm-1.EI-MS(m/z,%):462(M++1,100).
化合物30
所得纯品为黄色固体，产率65%，m.p.165-167℃。元素分析/%：计算值：C,48.80;H,3.85;N,26.78;S,7.66;实测值：C,48.65;H,3.82;N,26.88;S,7.82;1H NMR(400MHz,CDCl3):δ2.49(s,3H,CH3),5.36(s,2H,CH2),5.42(s,2H,CH2),5.59(s,2H,NH2),6.92-7.71(m,4H,Ar-H),7.71(s,1H,CH),8.20(s,1H,CH).IR(KBr):1270(C=S),1725(C=O),3139(N-H),3440cm-1.EI-MS(m/z,%):419(M++1,100).
化合物31
所得纯品为黄色固体，产率42%，m.p.240-242℃。元素分析/%：计算值：C,44.21;H,3.49;N,27.29;S,6.94;实测值：C,44.55;H,3.67;N,27.46;S,6.62;1H NMR(600MHz,DMSO-d6):δ2.29(s,3H,CH3),4.48(s,2H,J=6.0Hz,CH2),5.48(s,2H,CH2),6.97(s,2H,NH2),7.68(d,1H,J=8.4Hz,Ar-H),8.02(s,1H,CH),8.21(d,1H,J=8.4Hz,Ar-H),8.32(s,1H,Ar-H),9.23(s,1H,CH).IR(KBr):1355(C=S),1679(C=O),3218(N-H)cm-1.EI-MS(m/z,%):461(M+,2).
化合物32
所得纯品为黄色固体，产率50%，m.p.186-188℃。元素分析/%：计算值：C,45.24;H,3.57;N,24.83;S,7.10;实测值：C,45.02;H,3.30;N,24.00;S,7.46;1H NMR(400MHz,DMSO-d6):δ2.29(s,3H,CH3),4.48(s,2H,J=6.0Hz,CH2),5.63(s,2H,CH2),7.08(s,2H,NH2),7.48(s,2H,Ar-H),7.68(s,1H,Ar-H),8.02(s,1H,Ar-H),8.32(s,1H,Ar-H),9.23(s,1H,CH).IR(KBr):1299(C=S),1666(C=O),3363(N-H)cm-1.EI-MS(m/z,%):450(M+,2).
化合物33
所得纯品为黄色固体，产率62%，m.p.208-209℃。元素分析/%：计算值：C,51.57;H,5.01;N,25.32;S,7.25;实测值：C,51.22;H,5.47;N,25.04;S,7.48;1H NMR(400MHz,DMSO-d6):δ2.30(s,3H,CH3),3.82(s,6H,OCH3),4.47(s,2H,CH2),5.42(s,2H,CH2),6.97(s,2H,NH2),7.04(s,2H,Ar-H),7.60(s,2H,Ar-H),8.02(s,1H,Ar-H),8.32(s,1H,Ar-H),9.12(s,1H,CH);13C NMR(100MHz,DMSO-d6):δ27.4,34.7,47.2,56.0,113.7,127.1,128.9,130.0,131.0,132.3,134.4,135.1,138.3,140.6,160.3,161.1,165.3,169.2,192.4.IR(KBr):1267(C=S),1695(C=O),3334(N-H)cm-1.EI-MS(m/z,%):442(M+,2).
化合物34
所得纯品为黄色固体，产率44%，m.p.181-183℃。元素分析/%：计算值：C,43.22;H,3.41;N,29.65;S,6.79;实测值：C,42.48;H,3.47;N,29.76;S,6.52;1H NMR(400MHz,DMSO-d6):δ2.28(s,3H,CH3),4.57(s,2H,CH2),5.42(s,2H,CH2),6.93(s,2H,NH2),8.07(s,1H,CH),8.95(s,1H,Ar-H),9.07(s,2H,Ar-H),9.75(s,1H,CH).IR(KBr):1344(C=S),1672(C=O),3414(N-H)cm-1.EI-MS(m/z,%):472(M+,2).
化合物35
所得纯品为黄色固体，产率34%，m.p.191-193℃。元素分析/%：计算值：C,51.57;H,5.01;N,25.32;S,7.25;实测值：C,50.60;H,5.42;N,25.17;S,7.05;1H NMR(400MHz,DMSO-d6):δ2.32(s,3H,CH3),3.75(s,3H,OCH3),3.78(s,3H,OCH3),4.85(s,2H,CH2),5.48(s,2H,CH2),6.97(s,2H,NH2),6.67-7.34(m,3H,Ar-H),8.13(s,1H,CH),11.00(s,1H,NH),11.76(s,1H,NH).IR(KBr):1288(C=S),1631(C=O),3432(N-H)cm-1.EI-MS(m/z,%):442(M+,5).
化合物36
所得纯品为黄色固体，产率97%，m.p.228-230℃。元素分析/%：计算值：C,48.80;H,3.85;N,26.78;S,7.66;实测值：C,48.63;H,3.73;N,26.13;S,7.48;1H NMR(400MHz,DMSO-d6):δ2.30(s,3H,CH3),4.48(d,2H,J=5.2Hz,CH2),5.43(s,2H,CH2),6.94(s,2H,NH2),7.14-7.71(m,3H,Ar-H),8.00(s,1H,CH),8.83(s,1H,CH);13C NMR(100MHz,DMSO-d6):δ25.2,46.6,67.0,104.2,104.5,104.8,111.6,111.8,120.2,120.4,123.0,131.8,131.9,144.8,158.5,158.6,161.0,161.1,161.4,162.1,162.2,162.8,164.7.IR(KBr):1432(C=S),1663(C=O),3309(N-H)cm-1.EI-MS(m/z,%):442(M+,5).
化合物37
所得纯品为黄色固体，产率45%，m.p.164-166℃。元素分析/%：计算值：C,45.24;H,3.57;N,24.83;S,7.10;实测值：C,45.60;H,3.44;N,24.13;S,7.36;1H NMR(400MHz,DMSO-d6):δ2.32(s,3H,CH3),4.39(s,2H,CH2),5.51(s,2H,CH2),7.06(s,2H,NH2),7.53-7.81(m,3H,Ar-H),8.25(s,1H,CH).IR(KBr):1431(C=S),1644(C=O),3428(N-H)cm-1.EI-MS(m/z,%):450(M+,2).
化合物38
所得纯品为黄色固体，产率为30%，m.p.206-208℃。元素分析/%：计算值：C,40.17;H,3.37;N,22.04;S,6.31;实测值：C,40.32;H,3.55;N,22.77;S,6.19;1H NMR(400MHz,DMSO-d6):δ2.30(s,3H,CH3),4.43(s,2H,CH2),5.44(s,2H,CH2),6.98(s,2H,NH2),7.16-7.85(m,4H,Ar-H),8.00(s,1H,CH),8.91(s,1H,CH).IR(KBr):1389(C=S),1664(C=O),3335(N-H)cm-1.EI-MS(m/z,%):508(M+,2).
化合物39
所得纯品为黄色固体，产率40%，m.p.230-232℃。元素分析/%：计算值：C,48.00;H,3.80;N,24.88;S,7.12;实测值：C,48.18;H,3.95;N,24.44;S,7.55;1H NMR(400MHz,DMSO-d6):δ2.29(s,3H,CH3),4.52(s,2H,CH2),5.39(s,2H,CH2),6.91(s,2H,NH2),7.85(s,2H,Ar-H),8.02(s,2H,Ar-H),8.04(s,1H,CH),9.26(s,1H,CH).IR(KBr):1336(C=S),1631(C=O),3423(N-H)cm-1.EI-MS(m/z,%):450(M+,2).
化合物40
所得纯品为黄色固体，产率35%，m.p.193-195℃。元素分析/%：计算值：C,53.06;H,4.21;N,30.94;S,7.87;实测值：C,53.14;H,4.06;N,30.01;S,7.65;1H NMR(400MHz,DMSO-d6):δ2.40(s,3H,CH3),4.51(s,2H,CH2),5.46(s,2H,CH2),7.02(s,2H,NH2),7.99(m,4H,Ar-H),7.99(s,2H,Ar-H),9.28(s,1H,CH).IR(KBr):1285(C=S),1663(C=O),3416(N-H)cm-1.EI-MS(m/z,%):407(M+,2).
实施例6：化合物41的制备
于50mL圆底烧瓶中加入2.0mmol2-甲基-4-氨基-5-叠氮甲基嘧啶、2.0mmol三乙胺、10mL无水乙腈、2.1mmol5-苯基-（1,3,4-噻二唑）-2-硫基丙炔，搅拌溶解，再加入0.1mmol的CuI，室温下搅拌反应，TLC（薄层色谱）监测反应至完全，加水搅拌有固体析出，抽滤、水洗、烘干的粗品经乙醇重结晶，得目标化合物，为白色固体，产率91%，mp：121-123℃。
1H NMR(600MHz,DMSO-d6)δ(ppm):2.32(s,3H,CH3),4.65(s,2H,-SCH2-),5.44(s,2H,CH2),7.04(s,2H,NH2),7.58-7.97(m,5H,H-Ph),8.16(s,1H,pyrimidin-5-yl-H);IR(KBr):ν3385(N-H),3140,2361,2356,1663,1594,1574,1471,1430,1224,1195,1120,1064,995,837,814,780,706;HRMS(calcd.)[M+Na]+:419.0837(419.0740).
化合物42-74按化合物41类似方法制得，其结构鉴定数据如下：
化合物42
所得纯品为黄色固体，产率90%，m.p.128-130℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.29(s,3H,CH3),4.63(s,2H,-SCH2-),5.42(s,2H,CH2),6.93(s,2H,NH2),7.57-8.25(m,4H,1H,H3,5and6-Ph,pyrimidin-5-yl-H);IR(KBr):3337(N-H),3196,2369,2359,2100,1600,1564(N=O),1466,1345(N=O),1260,1228,1194,1121,1089,1048,855,807,725。
化合物43
所得纯品为黄色固体，产率91%;m.p.137-139℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.28(s,3H,CH3),4.66(s,2H,-SCH2-),5.41(s,2H,CH2),6.91(s,2H,NH2),8.14(s,1H,pyrimidin-5-yl-H),8.20-8.43(m,4H,H2,3,5and6-Ph);IR(KBr):3400(N-H),3142,2363,2354,1632,1595,1558,1521(N=O),1463,1346(N=O),1190,1115,1069,855,808,790,708;HRMS(calcd.)[M+Na]+:464.0688(464.0695).
化合物44
所得纯品为白色固体，产率91%;m.p.157-160℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.29(s,3H,CH3),4.63(s,2H,-SCH2-),5.43(s,2H,CH2),6.97(s,2H,NH2),7.55-7.95(m,4H,H3,4,5and6-Ph),8.14(s,1H,pyrimidin-5-yl-H);IR(KBr):3379(N-H),3140,2364,2355,1660,1595,1572,1478,1431,1196,1120,1091,1050,814,779,762,729;HRMS(calcd.)[M+Na]+:453.0447(453.0393).
化合物45
所得纯品为白色固体，产率91%;m.p.169-171℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.30(s,3H,CH3),4.62(s,2H,-SCH2-),5.42(s,2H,CH2),6.93(s,2H,NH2),6.93-7.40(m,4H,H2,3,5and6-Ph),8.13(s,1H,pyrimidin-5-yl-H);IR(KBr):3334(N-H),3162,2364,2359,1664,1593,1571,1472,1426,1222,1197,1118,1094,1068,1054,839,813,782,729。
化合物46
所得纯品为黄色固体，产率92%;m.p.117-120℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.29(s,3H,CH3),4.63(s,2H,-SCH2-),5.42(s,2H,CH2),6.93(s,2H,NH2),7.93-8.19(m,4H,1H,H3,4,5and6-Ph,pyrimidin-5-yl-H);IR(KBr):3411(N-H),3144,2453,2353,1662,1647,1596,1572,1528(N=O),1465,1432,1352(N=O),1196,1118,1065,996,857,809,789,726;HRMS(calcd.)[M+Na]+:464.0688(464.0676).
化合物47
所得纯品为白色固体，产率93%;m.p.133-135℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.29(s,3H,CH3),4.63(s,2H,-SCH2-),5.42(s,2H,CH2),6.93(s,2H,NH2),7.07-7.63(m,3H,H3,5and6-Ph),8.13(s,1H,pyrimidin-5-yl-H);IR(KBr):3327(N-H),3167,2394,2354,1658,1593,1568,1474,1426,1373,1194,1148,1118,1089,1051,864,813,777,731。
化合物48
所得纯品为白色固体，产率93%;m.p.137-139℃;1H NMR(600MHz,DMSO-d6)δ(ppm):2.29(s,3H,CH3),4.61(s,2H,-SCH2-),5.43(s,2H,CH2),6.96(s,2H,NH2),7.41-7.44(m,2H,H2,6-Ph),7.99-8.00(m,2H,H3,5-Ph),8.13(s,1H,pyrimidin-5-yl-H);IR(KBr):3334(N-H),3150,2432,2354,1665,1609,1594,1573,1501,1473,1426,1357,1228,1192,1119,1066,845,814,781,732;HRMS(calcd.)[M+Na]+:437.0743(437.0713)。
化合物49
所得纯品为白色固体，产率91%;m.p.115-117℃;1H NMR(600MHz,DMSO-d6)δ(ppm):2.28(s,3H,CH3),4.65(s,2H,-SCH2-),5.41(s,2H,CH2),6.94(s,2H,NH2),7.96-7.98(m,2H,H2,6-Ph),8.13-8.15(m,3H,H3,5-Ph,pyrimidin-5-yl-H);IR(KBr):3389(N-H),3069,2400,2354,1664,1595,1558,1505,1468,1416,1324,1197,1166,1111,1077,1058,857,812,791;HRMS(calcd.)[M+Na]+:487.0711(487.0722).
化合物50
所得纯品为黄色固体，产率85%;m.p.144-147℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.30(s,3H,CH3),4.65(s,2H,-SCH2-),5.43(s,2H,CH2),6.91(s,2H,NH2),7.55-7.78(m,3H,H2,4and6-Ph),8.15(s,1H,pyrimidin-5-yl-H);IR(KBr):3364(N-H),3222,2363,2354,1633,1598,1561,1531(N=O),1470,1346,(N=O)1283,1235,1180,1102,991,865,811,750,720。
化合物51
所得纯品为黄色固体，产率88%;m.p.151-153℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.28(s,3H,CH3),4.67(s,2H,-SCH2-),5.42(s,2H,CH2),6.94(s,2H,NH2),7.87(s,1H,H1-Ph),8.15(s,1H,pyrimidin-5-yl-H),8.35-8.63(m,3H,H4,5and6-Ph);IR(KBr):3370(N-H),2355,2335,1629,1597,1557,1528(N=O),1462,1433,1352(N=O),1229,1198,1113,1058,972,871,811,789,744,709;HRMS(calcd.)[M+Na]+:464.0688(464.0638)。
化合物52
所得纯品为白色固体，产率90%;m.p.139-141℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.31(s,3H,CH3),4.63(s,2H,-SCH2-),5.48(s,2H,CH2),7.02(s,2H,NH2),7.40-7.99(m,4H,H3,4,5and6-Ph),8.15(s,1H,pyrimidin-5-yl-H);IR(KBr):3401(N-H),3132,2440,2356,1666,1600,1564,1493,1477,1437,1337,1222,1183,1118,1054,814,790,771,736;HRMS(calcd.)[M+Na]+:437.0743(437.0700).
化合物53
所得纯品为黄色固体，产率为70%;m.p.170-171℃;元素分析/%：计算值：C,42.95;H,3.18;N,23.57;S,13.49;实测值：C,43.36;H,3.39;N,23.21;S,13.14;1HNMR(400MHz,DMSO-d6(ppm):2.28(s,3H,CH3),4.62(s,2H,-SCH2-),5.41(s,2H,CH2),6.91(s,2H,NH2),7.54-7.58(m,2H,H-Ph),7.84-7.89(m,2H,H-Ph),8.02(s,1H,1,2,3-triazol-4-yl-H);8.14(s,1H,pyrimidin-5-yl-H),13CNMR(100MHz,DMSO-d6)δ(ppm):25.4,26.9,47.0,109.7,120.9,124.4,128.5,131.8,133.6,134.6,142.6,148.1,156.3,161.6,164.3。
化合物54
所得纯品为浅黄色固体，产率52%;m.p.180-182℃;元素分析/%：计算值：C,50.69;H,4.25;N,26.27;S,15.04;实测值：C,50.42;H,4.46;N,26.24;S,15.15;1H NMR(400MHz,DMSO-d6)δ(ppm):2.29(s,3H,CH3),3.84(s,3H,OCH3),4.61(s,2H,-SCH2-),5.42(s,2H,CH2),6.94(s,2H,NH2),7.13(d,2H,J=10.8Hz,Ar-H),7.89(d,2H,J=10.8Hz,Ar-H),8.14(s,1H,pyrimidin-5-yl-H)。
化合物55
所得纯品为浅黄色固体，产率71%;m.p.209-211℃;元素分析/%：计算值：C,52.66;H,4.42;N,27.30;S,15.62;实测值：C,52.68;H,4.49;N,27.27;S,15.48;1H NMR(400MHz,DMSO-d6)δ(ppm):2.28(s,3H,CH3),2.38(s,3H,CH3),4.61(s,2H,-SCH2-),5.40(s,2H,CH2),6.93(s,2H,NH2),7.39(d,2H,J=8.0Hz,Ar-H),7.84(d,2H,J=8.0Hz,Ar-H),7.98(s,1H,1,2,3-triazol-4-yl-H),8.14(s,1H,pyrimidin-5-yl-H)。
化合物56
所得纯品为棕色固体，产率62%;m.p.155-156℃;元素分析/%：计算值：C,52.66;H,4.42;N,27.30;S,15.62;实测值：C,51.90;H,4.85;N,26.66;S,15.39;1H NMR(600MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),2.61(s,3H,CH3),4.75(s,2H,-SCH2-),5.52(s,2H,CH2),7.05(s,2H,NH2),7.55-7.59(m,2H,Ar-H),7.86-7.90(m,2H,Ar-H),8.08(s,1H,1,2,3-triazol-4-yl-H),8.25(s,1H,pyrimidin-5-yl-H)。
化合物57
所得纯品为浅黄色固体，产率74%;m.p.149-151℃;1H NMR(600MHz,DMSO-d6)δ(ppm):2.29(s,3H,CH3),2.57(s,3H,CH3),4.64(s,2H,-SCH2-),5.42(s,2H,CH2),6.95(s,2H,NH2),7.41(d,2H,J=27.0Hz,H-Ph),7.49(d,H,H-Ph),7.85(d,2H,J=7.2Hz,Ar-H),7.90(s,1H,1,2,3-triazol-4-yl-H),8.06(s,1H,pyrimidin-5-yl-H)。
化合物58
所得纯品为黄色固体，产率93%;m.p.162-164℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.32(s,3H,CH3),4.64(s,2H,-SCH2-),5.42(s,2H,CH2),7.00(s,2H,NH2),7.52-7.99(m,3H,H3,5and6-Ph),8.13(s,1H,pyrimidin-5-yl-H);IR(KBr):3356(N-H),3132,2355,2332,2097,1629,1594,1559(N=O),1467,1345(N=O),1260,1227,1193,1089,1050,883,806,729。
化合物59
所得纯品为黄色固体，产率90%;m.p.143-145℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.31(s,3H,CH3),4.63(s,2H,-SCH2-),5.44(s,2H,CH2),6.97(s,2H,NH2),7.91-8.18(m,4H,1H,H3,4,5and6-Ph,pyrimidin-5-yl-H);13C NMR(100MHz,DMSO-d6)δ(ppm):25.11,26.86,46.78,108.35,123.92,124.56,127.74,128.48,142.25,149.15,155.89,161.45,163.98,164.51,167.18;HRMS(calcd.)[M+H]+:426.1097(426.1102).
化合物60
所得纯品为黄色固体，产率86%;m.p.126-128℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.31(s,3H,CH3),4.63(s,2H,-SCH2-),5.44(s,2H,CH2),6.97(s,2H,NH2),7.08-7.41(m,4H,H3,4,5and6-Ph),8.11(s,1H,pyrimidin-5-yl-H);IR(KBr):3382(N-H),3141,2355,2334,1660,1595,1572,1468,1431,1359,1196,1120,1091,1071,1051,998,863,815,779,763,729;HRMS(calcd.)[M+H]+:415.0856(415.0831).
化合物61
所得纯品为白色固体，产率93%;m.p.189-191℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.31(s,3H,CH3),4.63(s,2H,-SCH2-),5.44(s,2H,CH2),6.97(s,2H,NH2),6.93-7.40(m,4H,H2,3,5and6-Ph),8.13(s,1H,pyrimidin-5-yl-H);IR(KBr):3337(N-H),3157,2462,2357,1664,1591,1570,1475,1426,1406,1222,1197,1117,1095,1068,1053,1012,839,813,782,729;HRMS(calcd.)[M+H]+:415.0856(415.0890)。
化合物62
所得纯品为黄色固体，产率90%;m.p.171-173℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.31(s,3H,CH3),4.63(s,2H,-SCH2-),5.44(s,2H,CH2),6.97(s,2H,NH2),7.91-8.18(m,4H,1H,H3,4,5and6-Ph,pyrimidin-5-yl-H);IR(KBr):3415(N-H),3145,2353,1648,1597,1569,1527(N=O),1465,1431,1352(N=O),1195,1118,1065,986,857,808,751,725;HRMS(calcd.)[M+H]+:426.1097(426.1082).
化合物63
得纯品为白色固体，产率91%;m.p.173-175℃;1H NMR(600MHz,DMSO-d6)δ(ppm):2.31(s,3H,CH3),4.64(s,2H,-SCH2-),5.45(s,2H,CH2),7.00(s,2H,NH2),7.63-7.97(m,3H,H3,5and6-Ph),8.15(s,1H,pyrimidin-5-yl-H);IR(KBr):3336(N-H),3174,2418,2360,1657,1594,1568,1475,1430,1217,1195,1119,1090,1052,1037,865,832,814,778,732;HRMS(calcd.)[M+Na]+:471.0286(471.0320).
化合物64
所得纯品为白色固体，产率89%;132-134℃;1H NMR(600MHz,DMSO-d6)δ(ppm):2.31(s,3H,CH3),4.63(s,2H,-SCH2-),5.43(s,2H,CH2),7.01(s,2H,NH2),7.40-7.44(m,2H,H2,6-Ph),7.99-8.01(m,2H,H3,5-Ph),8.15(s,1H,pyrimidin-5-yl-H);IR(KBr):3428(N-H),3152,2360,2357,1665,1595,1574,1502,1474,1426,1228,1192,1158,1121,1067,997,956,846,815,782,733;HRMS(calcd.)[M+H]+:399.1152(399.1151).
化合物65
所得纯品为白色固体，产率89%;132-134℃;1H NMR(600MHz,DMSO-d6)δ(ppm):2.29(s,3H,CH3),4.66(s,2H,-SCH2-),5.42(s,2H,CH2),6.98(s,2H,NH2),7.96-7.97(m,2H,H2,6-Ph),8.14-8.16(m,3H,H3,5-Ph,pyrimidin-5-yl-H);IR(KBr):3423(N-H),3069,2360,2357,1665,1595,1559,1508,1468,1416,1325,1198,1167,1110,1077,1058,1015,857,812,792;HRMS(calcd.)[M+H]+:449.1120(449.1133).
化合物66
所得纯品为白色固体，产率88%;m.p.138-140℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.37(s,3H,CH3),4.66(s,2H,-SCH2-),5.47(s,2H,CH2),7.10(s,2H,NH2),7.58-7.95(m,5H,H-Ph),8.18(s,1H,pyrimidin-5-yl-H);HRMS(calcd.)[M+H]+:381.1246(381.1236)。
化合物67
所得纯品为黄色固体，产率87%;m.p.163-165℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.31(s,3H,CH3),4.65(s,2H,-SCH2-),5.43(s,2H,CH2),6.97(s,2H,NH2),7.52-7.75(m,3H,H2,4and6-Ph),8.14(s,1H,pyrimidin-5-yl-H);IR(KBr):3369(N-H),3230,2366,2359,1640,1595,1567,1544(N=O),1472,1351(N=O),1279,1231,1180,1102,990,868,811,750,723。
化合物68
所得纯品为黄色固体，产率90%;m.p.171-173℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.28(s,3H,CH3),4.66(s,2H,-SCH2-),5.43(s,2H,CH2),6.91(s,2H,NH2),7.89(s,1H,H1-Ph),8.14(s,1H,pyrimidin-5-yl-H),8.41-8.65(m,3H,H4,5and6-Ph);IR(KBr):3399(N-H),3132,2362,2355,1660,1593,1562,1527(N=O),1471,1353(N=O),1233,1123,1063,994,868,813,742,710;HRMS(calcd.)[M+H]+:426.1097(426.1069)。
化合物69
所得纯品为白色固体，产率90%;m.p.165-168℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.31(s,3H,CH3),4.62(s,2H,-SCH2-),5.43(s,2H,CH2),7.08(s,2H,NH2),7.41-7.97(m,4H,H3,4,5and6-Ph),8.13(s,1H,pyrimidin-5-yl-H);IR(KBr):3401(N-H),3133,2440,1665,1619,1598,1565,1494,1476,1438,1338,1223,1185,1119,1054,994,959,813,790,770,737;HRMS(calcd.)[M+H]+:399.1152(399.1143).
化合物70
所得纯品为棕色固体，产率72%;m.p.167-168℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.29(s,3H,CH3),4.64(s,2H,-SCH2-),5.42(s,2H,CH2),6.94(s,2H,NH2),7.56(s,2H,H-Ph),7.88(s,2H,H-Ph),8.01(s,1H,1,2,3-triazol-4-yl-H),8.15(s,1H,pyrimidin-5-yl-H)。
化合物71
所得纯品为浅黄色固体，产率88%;m.p.180-181℃;元素分析/%：计算值：C,52.67;H,4.42;N,27.30;O,7.80;S,7.81;实测值：C,52.38;H,4.16;N,27.63;S,7.83;1H NMR(600MHz,DMSO-d6)δ(ppm):2.28(s,3H,CH3),3.84(s,3H,OCH3),4.60(s,2H,-SCH2-),5.40(s,2H,CH2),6.93(s,2H,NH2),7.11(d,2H,J=12Hz,Ar-H),7.88(d,2H,J=12Hz,Ar-H),7.98(s,1H,1,2,3-triazol-4-yl-H),8.15(s,1H,pyrimidin-5-yl-H)。
化合物72
所得纯品为浅黄色固体，产率79%;m.p.215-217℃;1H NMR(400MHz,DMSO-d6)δ(ppm):2.40(s,3H,CH3),2.61(s,3H,CH3),4.73(s,2H,-SCH2-),5.52(s,2H,CH2),7.04(s,2H,NH2),7.52(s,2H,H-Ph),7.95(d,2H,J=5.6Hz,Ar-H),8.08(s,1H,1,2,3-triazol-4-yl-H),8.27(s,1H,pyrimidin-5-yl-H)。
化合物73
所得纯品为棕色固体，产率85%;m.p.152-153℃;元素分析/%：计算值：C,54.81;H,4.60;N,28.41;S,8.13;实测值：C,54.59;H,4.85;N,27.94;S,8.20;1H NMR(600MHz,DMSO-d6)δ(ppm):2.40(s,3H,CH3),2.62(s,3H,CH3),4.75(s,2H,-SCH2-),5.52(s,2H,CH2),7.05(s,2H,NH2),7.56-7.60(m,2H,Ar-H),7.87-7.91(m,2H,Ar-H),8.07(s,1H,1,2,3-triazol-4-yl-H),8.25(s,1H,pyrimidin-5-yl-H)。
化合物74
所得纯品为棕色固体，产率65%;m.p.152-153℃;元素分析/%：计算值：C,54.81;H,4.60;N,28.41;S,8.13;实测值：C,54.89;H,4.38;N,28.86;S,7.85;1H NMR(600MHz,DMSO-d6)δ(ppm):2.29(s,3H,CH3),2.58(s,3H,CH3),4.63(s,2H,-SCH2-),5.41(s,2H,CH2),6.94(s,2H,NH2),7.39-7.50(m,3H,H-Ph),7.85(d,H,J=8.4Hz,Ar-H),7.96(s,1H,1,2,3-triazol-4-yl-H),8.14(s,1H,pyrimidin-5-yl-H)。
实施例7：化合物75的制备
100mL圆底烧瓶中依次加入1mmol2-甲基-4-氨基-5-叠氮甲基嘧啶、1mmol O-炔丙基-4-氟苯乙酮肟醚、2mmol三乙胺，溶于10mL无水四氢呋喃（THF），室温下搅拌，待固体溶解后，加入0.1mmol碘化亚铜，室温下反应10-15小时，TLC（薄层色谱）反应至完全，加水搅拌有固体析出，减压抽滤、水洗、烘干的粗品，用二甲基甲酰胺（DMF）和水重结晶，得黄色固体，产率71%，mp：96-97℃。
元素分析/%：计算值：C,57.46;H,5.11;N,27.59;实测值：C,57.65;H,5.18;N,27.26;1HNMR(600MHz,DMSO-d6):δ2.14(s,3H,CH3),2.29(s,3H,CH3),5.20(s,2H,CH2),5.44(s,2H,CH2),6.95(s,2H,NH2),7.23(d,2H,J=8.4Hz,Ar-H),7.67(s,2H,J=6.0Hz,Ar-H),8.01(s,1H,CH),8.18(s,1H,CH);13C NMR(100MHz,DMSO-d6):δ12.5,25.2,46.7,66.9,108.4,115.2,115.8,124.6,128.1,128.2,132.3,143.5,153.9,156.2,161.5,164.0,167.2.IR(KBr):1663(C=N),3431(N-H)cm-1.EI-MS(m/z,%):355(M+,11).
化合物76-95按化合物75类似方法制得，其结构鉴定数据如下：
化合物76
所得纯品为黄色固体，产率66%，m.p.180-183℃;元素分析/%：计算值：C,49.05;H,4.36;N,23.55;实测值：C,49.23;H,4.54;N,23.91;1H NMR(600MHz,DMSO-d6):δ2.13(s,3H,CH3),2.29(s,3H,CH3),5.20(s,2H,CH2),5.49(s,2H,CH2),7.02(s,2H,NH2),7.56-7.61(m,4H,Ar-H),8.19(s,1H,CH);13C NMR(100MHz,DMSO-d6):δ12.5,25.5,46.7,66.9,111.0,122.6,124.6,127.8,130.0,131.3,134.8,143.5,155.7,161.3,168.7.IR(KBr):1674(C=N),3296(N-H)cm-1.EI-MS(m/z,%):415(M+,7).
化合物77
所得纯品为黄色固体，产率90%，m.p.184-186℃;元素分析/%：计算值：C,54.91;H,4.88;N,26.37;实测值：C,54.45;H,4.75;N,26.18;1H NMR(600MHz,DMSO-d6):δ2.14(s,3H,CH3),2.30(s,3H,CH3),5.20(s,2H,CH2),5.44(s,2H,CH2),6.98(s,2H,NH2),7.47(s,2H,Ar-H),7.64(s,2H,Ar-H),8.19(s,1H,CH);13C NMR(100MHz,DMSO-d6):δ12.5,25.5,46.7,66.9,111.0,122.6,124.6,127.8,130.0,131.3,134.8,143.5,155.7,161.3,168.7.IR(KBr):1676(C=N),3299(N-H)cm-1.EI-MS(m/z,%):371(M+,7).
化合物78
所得纯品为黄色固体，产率73%，m.p.131-132℃;元素分析/%：计算值：C,60.52;H,5.68;N,29.06;实测值：C,59.85;H,5.65;N,29.35;1H NMR(600MHz,DMSO-d6):δ2.15(s,3H,CH3),2.29(s,3H,CH3),5.20(s,2H,CH2),5.44(s,2H,CH2),6.98(s,2H,NH2),7.40(d,2H,J=2.4Hz,Ar-H),7.63(d,2H,J=3.0Hz,Ar-H),8.01(s,1H,Ar-H),8.19(s,1H,CH);13C NMR(100MHz,DMSO-d6):δ12.5,25.2,46.7,66.8,108.3,124.6,125.9,128.4,129.2,135.8,143.5,154.7,156.2,161.5,167.0.IR(KBr):1664(C=N),3327(N-H)cm-1.EI-MS(m/z,%):337(M+,8).
化合物79
所得纯品为黄色固体，产率64%，m.p.154-156℃;元素分析/%：计算值：C,58.84;H,5.76;N,26.69;实测值：C,58.58;H,5.62;N,26.13;1H NMR(600MHz,DMSO-d6):δ2.12(s,3H,CH3),2.29(s,3H,CH3),3.37(s,3H,OCH3),5.16(s,2H,CH2),5.43(s,2H,CH2),6.94(s,2H,NH2),6.96(s,2H,Ar-H),7.58(d,2H,J=3.0Hz,Ar-H),8.17(s,1H,Ar-H);13C NMR(100MHz,DMSO-d6):δ12.4,25.2,46.6,55.1,66.7,108.4,113.8,124.5,127.3,128.2,143.6,156.2,160.1,161.5,167.0,183.0.IR(KBr):1669(C=N),3323(N-H)cm-1.EI-MS(m/z,%):367(M+,10).
化合物80
所得纯品为黄色固体，产率66%，m.p.222-224℃;元素分析/%:计算值：C,53.40;H,4.74;N,29.30;实测值：C,53.61;H,4.31;N,29.12;1H NMR(600MHz,DMSO-d6):δ2.21(s,3H,CH3),2.30(s,3H,CH3),5.27(s,2H,CH2),5.47(s,2H,CH2),6.98(s,2H,NH),7.89(s,2H,Ar-H),8.21(s,1H,CH),8.25(d,2H,J=7.2Hz,Ar-H);IR(KBr):1673(C=N),3302(N-H)cm-1.
化合物81
所得纯品为黄色固体，产率50%，m.p.126-127℃;元素分析/%：计算值：C,57.46;H,5.11;N,27.59;实测值：C,57.15;H,5.12;N,27.32;1H NMR(600MHz,DMSO-d6):δ2.13(s,3H,CH3),2.30(s,3H,CH3),5.20(s,2H,CH2),5.45(s,2H,CH2),6.98(s,2H,NH),7.22-7.46(s,4H,Ar-H),8.04(s,1H,CH),8.17(s,1H,CH);IR(KBr):1639(C=N),3384(N-H)cm-1。
化合物82
所得纯品为黄色固体，产率67%，m.p.188-190℃;元素分析/%：计算值：C,54.91;H,4.88;N,26.37;实测值：54.18;H,4.72;N,26.46;1H NMR(600MHz,DMSO-d6):δ2.14(s,3H,CH3),2.29(s,3H,CH3),5.20(s,2H,CH2),5.45(s,2H,CH2),6.98(s,2H,NH),7.46(s,2H,Ar-H),7.64(s,2H,Ar-H),8.19(s,1H,CH);IR(KBr):1676(C=N),3297(N-H)cm-1.
化合物83
所得纯品为黄色固体，产率64%，m.p.131-133℃;元素分析/%：计算值：C,54.91;H,4.88;N,26.37;实测值：C,54.48;H,4.62;N,26.26;1H NMR(600MHz,DMSO-d6):δ2.15(s,3H,CH3),2.29(s,3H,CH3),5.22(s,2H,CH2),5.44(s,2H,CH2),6.95(s,2H,NH),7.42-7.48(m,2H,Ar-H),7.60(d,1H,J=7.2Hz,Ar-H),7.67(s,1H,Ar-H),8.00(s,1H,CH),8.19(s,1H,CH);IR(KBr):1670(C=N),3389(N-H)cm-1.
化合物84
所得纯品为黄色固体，产率34%，m.p.109-110℃;元素分析/%：计算值：C,53.40;H,4.74;N,29.30;实测值：C,53.11;H,4.69;N,29.57;1H NMR(600MHz,DMSO-d6):δ2.10(s,3H,CH3),2.30(s,3H,CH3),5.12(s,2H,CH2),5.43(s,2H,CH2),6.95(s,2H,NH),7.56(d,1H,J=7.8Hz,Ar-H),7.67(t,1H,J=7.2Hz,Ar-H),7.78(t,1H,J=7.2Hz,Ar-H),8.00(s,1H,CH),8.02(d,1H,J=8.4Hz,Ar-H),8.11(s,1H,CH);IR(KBr):1669(C=N),3385(N-H)cm-1.
化合物85
所得的纯品为白色固体，产率74%，1H NMR(600MHz,DMSO-d6)δ(ppm):2.10(s,3H,CH3),2.32(s,3H,CH3),5.19(s,2H,CH2),5.46(s,2H,CH2),7.00(s,2H,NH2),7.34(s,1H,Ar-H),7.50(s,1H,Ar-H),7.70(s,1H,Ar-H).IR(KBr)υ(cm-1):3414(NH2),2972(CH3),1667(C=N),1646-1227(Ar).
化合物86
所得纯品为黄色固体，产率70%，m.p.190-192℃;元素分析/%：计算值：C,48.99;H,3.85;N,25.00;实测值：C,48.29;H,3.88;N,25.12;1H NMR(600MHz,DMSO-d6):δ2.30(s,3H,CH3),5.25(s,2H,CH2),5.45(s,2H,CH2),6.95(s,2H,NH),7.49-7.79(m,3H,Ar-H),8.01(s,1H,CH),8.22(s,1H,CH),8.39(s,1H,CH);IR(KBr):1676(C=N),3346(N-H)cm-1.
化合物87
所得纯品为黄色固体，产率78%，m.p.185-187℃;元素分析/%：计算值：C,53.71;H,4.51;N,27.40;实测值：C,53.32;H,4.56;N,27.02;1H NMR(600MHz,DMSO-d6):δ2.28(s,3H,CH3),5.18(s,2H,CH2),5.43(s,2H,CH2),6.94(s,2H,NH),7.48(d,2H,J=8.4Hz,Ar-H),7.61(d,2H,J=8.4Hz,Ar-H),7.94(s,2H,CH),8.19(s,1H,CH),8.25(s,1H,CH)。
化合物88
所得纯品为黄色固体，产率86%，m.p.179-181℃;元素分析/%：计算值：C,47.44;H,4.01;N,24.37;实测值：C,46.95;H,4.10;N,24.21;1H NMR(600MHz,DMSO-d6):δ2.31(s,3H,CH3),3.78(s,3H,CH3),5.15(s,2H,CH2),5.47(s,2H,CH2),6.98(s,2H,NH),6.98(s,4H,Ar-H),7.62(d,2H,J=7.8Hz,Ar-H),7.94(s,1H,CH),8.19(s,1H,CH),8.24(s,1H,CH)。
化合物89
所得纯品为黄色固体，产率74%，m.p.168-170℃;元素分析/%：计算值：C,56.30;H,4.72;N,28.72;实测值：C,56.49;H,4.38;N,28.52;1H NMR(600MHz,DMSO-d6):δ2.30(s,3H,CH3),5.18(s,2H,CH2),5.46(s,2H,CH2),6.99(s,2H,NH),7.26(s,2H,Ar-H),7.94(s,1H,CH),8.19(s,1H,CH),8.25(s,1H,CH)。
化合物90
所得纯品为黄色固体，产率30%，m.p.100-101℃;元素分析/%：计算值：C,57.78;H,5.42;N,27.75;实测值：C,57.30;H,5.41;N,27.56;1H NMR(600MHz,DMSO-d6):δ2.31(s,3H,CH3),3.78(s,3H,OCH3),5.15(s,2H,CH2),5.47(s,2H,CH2),6.98(s,4H,Ar+NH),7.54(s,2H,Ar-H),8.17(s,2H,CH)。
化合物91
所得纯品为黄色固体，产率92%，m.p.170-172℃;元素分析/%：计算值：C,C,59.43;H,5.30;N,30.32;实测值：C,59.65;H,5.44;N,30.24;1H NMR(600MHz,DMSO-d6):δ2.29(s,3H,CH3),5.18(s,2H,CH2),5.44(s,2H,CH2),6.95(s,2H,NH2),7.41-7.59(m,5H,Ar-H),8.02(s,1H,CH),8.19(s,1H,CH),8.24(s,1H,CH)。
化合物92
所得纯品为黄色固体，产率65%，m.p.214-216℃;元素分析/%：计算值：C,52.17;H,4.38;N,30.42;实测值：C,51.72;H,4.23;N,30.89;1H NMR(600MHz,DMSO-d6):δ2.29(s,3H,CH3),5.26(s,2H,CH2),5.43(s,2H,CH2),6.96(s,2H,NH),7.86(d,2H,J=9.0Hz,Ar-H),8.22(s,1H,CH),8.27(d,2H,J=8.4Hz,CH),8.42(s,1H,CH)。
化合物93
所得纯品为黄色固体，产率32%，m.p.180-182℃;元素分析/%：计算值：C,52.17;H,4.38;N,30.42;实测值：C,52.73;H,4.45;N,30.08;1H NMR(600MHz,DMSO-d6):δ2.30(s,3H,CH3),5.32(s,2H,CH2),5.46(s,2H,CH2),6.96(s,2H,NH2),7.10(t,1H,J=7.2Hz,Ar-H),7.46(d,1H,J=8.4Hz,Ar-H),7.67(t,1H,J=7.8Hz,Ar-H),7.32(d,1H,J=7.2Hz,Ar-H),7.98(s,1H,CH),7.99(s,1H,CH),8.27(s,1H,CH)。
化合物94
所得纯品为黄色固体，产率46%，m.p.154-155℃;元素分析/%：计算值：C,53.71;H,4.51;N,27.40;实测值：C,53.51;H,4.58;N,27.69;1H NMR(600MHz,DMSO-d6):δ2.29(s,3H,CH3),5.21(s,2H,CH2),5.44(s,2H,CH2),6.94(s,2H,NH),7.44-7.50(m,2H,Ar-H),7.57(d,1H,J=9.0Hz,Ar-H),7.65(s,2H,CH),7.99(s,1H,CH),8.20(s,1H,CH),8.26(s,1H,CH)。
化合物95
所得纯品为黄色固体，产率46%，m.p.154-155℃;元素分析/%：计算值：C,53.71;H,4.51;N,27.40;实测值：C,53.51;H,4.58;N,27.69;1H NMR(600MHz,DMSO-d6):δ2.29(s,3H,CH3),5.21(s,2H,CH2),5.44(s,2H,CH2),6.94(s,2H,NH),7.44-7.50(m,2H,Ar-H),7.57(d,1H,J=9.0Hz,Ar-H),7.65(s,2H,CH),7.99(s,1H,CH),8.20(s,1H,CH),8.26(s,1H,CH)。
实施例8：化合物96的制备
将1mmol2-甲基-4-氨基-5-叠氮甲基嘧啶和1mmol碘代-O-炔丙基-4-氯苯乙酮肟醚溶于5mL无水乙腈，加入0.1mmol碘化亚铜和2mmol三乙胺，室温条件下搅拌反应12小时，加水搅拌有固体析出，抽滤、干燥得黄色固体，产率72%；1H NMR(600MHz,DMSO-d6)δ(ppm):2.16(s,3H,CH3),2.30(s,3H,CH3),5.17(s,2H,CH2),5.45(s,2H,CH2),6.90(s,2H,NH2),7.44(d,2H,J=8.4Hz,Ar-H),7.66(d,2H,J=8.4,Ar-H).
化合物97-104按化合物96类似方法制得，其结构鉴定数据如下：
化合物97
所得纯品为白色固体，产率75%，
1H NMR(600MHz,DMSO-d6)δ(ppm):2.16(s,3H,CH3),2.30(s,3H,CH3),5.16(s,2H,CH2),5.46(s,2H,CH2),6.90(s,2H,NH2),7.22(s,2H,Ar-H),7.70(s,2H,Ar-H).
化合物98
所得纯品为白色固体，产率69%，1H NMR(600MHz,DMSO-d6)δ(ppm):2.13(s,3H,CH3),2.29(s,3H,CH3),5.15(s,2H,CH2),5.43(s,2H,CH2),6.90(s,2H,NH2),7.42(s,2H,Ar-H),7.64(s,2H,Ar-H).
化合物99
所得纯品为白色固体，产率79%，1H NMR(600MHz,DMSO-d6)δ(ppm):2.16(s,3H,CH3),2.31(s,3H,CH3),5.16(s,2H,CH2),5.46(s,2H,CH2),6.96(s,2H,NH2),7.39(s,3H,Ar-H),7.65(s,2H,Ar-H).
化合物100
所得的纯品为白色固体，产率81%，1H NMR(600MHz,DMSO-d6)δ(ppm):2.22(s,3H,CH3),2.33(s,3H,CH3),5.24(s,2H,CH2),5.49(s,2H,CH2),6.94(s,2H,NH2),7.91(d,2H,J=7.8Hz,Ar-H),8.23(d,2H,J=8.4Hz,Ar-H).
化合物101
所得的纯品为白色固体，产率80%，
1H NMR(600MHz,DMSO-d6)δ(ppm):2.16(s,3H,CH3),2.30(s,3H,CH3),5.18(s,2H,CH2),5.44(s,2H,CH2),6.91(s,2H,NH2),7.42(s,1H,Ar-H),7.47(s,1H,Ar-H),7.62(s,1H,Ar-H),7.69(s,1H,Ar-H).EI-MS(m/z,%):497(M+,5.21).
化合物102
所得的纯品为白色固体，产率76%，1H NMR(600MHz,DMSO-d6)δ(ppm):2.15(s,3H,CH3),2.31(s,3H,CH3),5.17(s,2H,CH2),5.45(s,2H,CH2),6.91(s,2H,NH2),7.58(s,4H,Ar-H).
化合物103
所得的纯品为白色固体，产率78%，1H NMR(600MHz,DMSO-d6)δ(ppm):2.15(s,3H,CH3),2.31(s,3H,CH3),5.17(s,2H,CH2),5.44(s,2H,CH2),6.91(s,2H,NH2),7.22(d,1H,J=7.8Hz,Ar-H),7.25(d,1H,J=8.4Hz,Ar-H),7.43-7.46(t,2H,J=7.8Hz,7.2Hz,Ar-H),7.65(s,1H,pyrimidine CH).
化合物104
所得的纯品为白色固体，产率74%，1H NMR(600MHz,DMSO-d6)δ(ppm):2.10(s,3H,CH3),2.32(s,3H,CH3),5.19(s,2H,CH2),5.46(s,2H,CH2),7.00(s,2H,NH2),7.34(s,1H,Ar-H),7.50(s,1H,Ar-H),7.70(s,1H,Ar-H).
上述实施例合成的化合物见表1。
表1合成的化合物
本发明具有通式（I）结构的化合物具有优异的杀菌活性，能用于防治小麦赤霉病菌、水稻纹枯病菌、黄瓜灰霉病菌、番茄早疫病菌、烟草赤星病菌和黄瓜炭疽病菌，部分化合物对真菌的防治效果与对照商品化杀菌剂相当或更好。
实施例9杀菌活性试验
以菌丝的生长速率为依据来测定杀菌活性。选取与经济作物、蔬菜类作物、水果类作物有关的六种常见菌类：水稻纹枯病、黄瓜灰霉病、小麦赤霉病、番茄早疫病、烟草赤星病和黄瓜炭疽病作为供试靶标。本发明化合物用丙酮溶解，吐温-80乳化，加入蒸馏水配成一定浓度药液待用。马铃薯200克，葡萄糖15克，琼脂15克，水1000克配成培养基后，于直径9cm的培养皿高温减压灭菌25min，灭菌后趁热将培养基13.5mL和药液1.5mL混合均匀等分到两个培养皿中，水平放置，待冷却后，用灭过菌的取菌器分别从菌种的培养液中取5mm带菌琼脂，放入各培养皿中菌丝面向下，每皿放2-3种菌。设两组空白对照，然后置于无菌恒温干燥箱内48小时，测定菌斑的直径根据空白对照，以直径表示药效：抑制率%=（对照-处理）/对照×100%。
实验材料：
供试菌种：小麦赤霉病菌(Gibberella zeae)、黄瓜灰霉病菌(Botrytiscinerea)、番茄早疫病菌(Alternaria solania)、烟草赤星病菌(Alternaria alternata(Fries)Keissler)、黄瓜炭疽病菌(GloeosporiumorbiculareArs)。
测试结果见表2。
表2部分化合物的测试结果（测试浓度100μg/g）
文中涉及的文献如下：
文献1：Karl M.Erixon,Chester L.Dabalos,Finian J.Leeper.Synthesis andbiological evaluation of pyrophosphate mimics of thiamine pyrophosphate basedon a triazole scaffold.Organic&Biomolecular Chemistry,2008,6,3561-3572.
Claims (4)
1.一种2-甲基-4-氨基-5-(取代-1,2,3-三唑基)甲基嘧啶衍生物，其特征在于，包括具有通式(I-2)结构的化合物：
其中：
X为氧或S；
R1表示氢；
R2表示H、卤素、硝基或C1-4烷基；
R3表示H、卤素、硝基、CF3、甲氧基或C1-4烷基，R2与R3位置可互换。
2.权利要求1所述的通式(I-2)表示的2-甲基-4-氨基-5-(取代-1,2,3-三唑基)甲基嘧啶衍生物的制备方法，其特征是使通式(II)表示的化合物与通式(IV)表示的化合物反应：
通式(IV)中R1、R2、R3、X的定义分别与通式(I-2)中R1、R2、R3、X的定义相同。
3.权利要求1所述的通式(I-2)表示的2-甲基-4-氨基-5-(取代-1,2,3-三唑基)甲基嘧啶衍生物的应用，其特征在于：作为杀菌剂的有效成分。
4.权利要求1所述的通式(I-2)表示的2-甲基-4-氨基-5-(取代-1,2,3-三唑基)甲基嘧啶衍生物的应用，其特征在于：作为对小麦赤霉病菌、水稻纹枯病菌、黄瓜灰霉病菌、番茄早疫病菌、烟草赤星病菌和黄瓜炭疽病菌杀菌剂的有效成分。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410082965.XA CN104892581B (zh) | 2014-03-07 | 2014-03-07 | 具有杀菌活性的2‑甲基‑4‑氨基‑5‑(取代‑1,2,3‑三唑基)甲基嘧啶衍生物、其制备方法及应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410082965.XA CN104892581B (zh) | 2014-03-07 | 2014-03-07 | 具有杀菌活性的2‑甲基‑4‑氨基‑5‑(取代‑1,2,3‑三唑基)甲基嘧啶衍生物、其制备方法及应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104892581A CN104892581A (zh) | 2015-09-09 |
| CN104892581B true CN104892581B (zh) | 2017-02-22 |
Family
ID=54025595
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410082965.XA Active CN104892581B (zh) | 2014-03-07 | 2014-03-07 | 具有杀菌活性的2‑甲基‑4‑氨基‑5‑(取代‑1,2,3‑三唑基)甲基嘧啶衍生物、其制备方法及应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104892581B (zh) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106588887B (zh) * | 2015-10-16 | 2020-09-01 | 华中师范大学 | 化合物及其制备方法和用途 |
| CN105859692B (zh) * | 2016-03-01 | 2018-02-27 | 浙江工业大学 | 一种含嘧啶、噻二唑环和酰胺结构的硫醚类化合物及其应用 |
| CN105859693B (zh) * | 2016-03-01 | 2018-06-26 | 浙江工业大学 | 一种4-苯基-3-((4,6-二甲基嘧啶-2-基硫代)甲基)-5-苄硫基三唑类化合物及其应用 |
| CN106432098B (zh) * | 2016-09-07 | 2018-09-18 | 华中师范大学 | 氨基甲酸酯类化合物及其制备方法和用途 |
| CN108976214B (zh) * | 2017-06-05 | 2020-09-29 | 华中师范大学 | 丙酮酸脱氢酶系抑制剂及其制备方法和用途 |
| CN108218848B (zh) * | 2018-01-22 | 2020-12-18 | 贵州大学 | 一种三氟甲基吡啶联噁二唑（醚）类衍生物及其应用 |
| CN113200924B (zh) * | 2021-05-18 | 2022-11-01 | 南开大学 | 一种4-氨基-5-嘧啶甲酰胺类化合物及其制备方法和应用 |
| CN114957215B (zh) * | 2022-01-13 | 2023-03-21 | 渤海大学 | 亚甲基桥连喹啉和1,2,3-三唑双杂环化合物及其制备方法与应用 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1727343A (zh) * | 2005-07-25 | 2006-02-01 | 华中师范大学 | 具有杀菌活性的取代噻吩并[3',2'∶5,6]吡啶并[4,3－d]嘧啶－4(3H)－酮及制备 |
| CN101289422A (zh) * | 2008-06-06 | 2008-10-22 | 华中师范大学 | 具有杀菌、除草活性的2,3,5,6-四取代-4-氨基吡啶及制备 |
| CN101323617A (zh) * | 2008-07-04 | 2008-12-17 | 华中师范大学 | 具有杀菌活性的2,3,4,7-多取代吡啶并[4,3-d]嘧啶衍生物及制备 |
| CN102993185A (zh) * | 2011-09-13 | 2013-03-27 | 华中师范大学 | 2-甲基-4-氨基-5-（取代-1h-1,2,3-三唑基）甲基嘧啶衍生物的制备及杀菌活性 |
-
2014
- 2014-03-07 CN CN201410082965.XA patent/CN104892581B/zh active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1727343A (zh) * | 2005-07-25 | 2006-02-01 | 华中师范大学 | 具有杀菌活性的取代噻吩并[3',2'∶5,6]吡啶并[4,3－d]嘧啶－4(3H)－酮及制备 |
| CN101289422A (zh) * | 2008-06-06 | 2008-10-22 | 华中师范大学 | 具有杀菌、除草活性的2,3,5,6-四取代-4-氨基吡啶及制备 |
| CN101323617A (zh) * | 2008-07-04 | 2008-12-17 | 华中师范大学 | 具有杀菌活性的2,3,4,7-多取代吡啶并[4,3-d]嘧啶衍生物及制备 |
| CN102993185A (zh) * | 2011-09-13 | 2013-03-27 | 华中师范大学 | 2-甲基-4-氨基-5-（取代-1h-1,2,3-三唑基）甲基嘧啶衍生物的制备及杀菌活性 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104892581A (zh) | 2015-09-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104892581B (zh) | 具有杀菌活性的2‑甲基‑4‑氨基‑5‑(取代‑1,2,3‑三唑基)甲基嘧啶衍生物、其制备方法及应用 | |
| RU2647853C2 (ru) | Способы получения определенных 2-(пиридин-3-ил)тиазолов | |
| RU2647851C2 (ru) | Способы получения некоторых 2-(пиридин-3-ил)тиазолов | |
| CN107501169A (zh) | 一类反式二芳基乙烯类lsd1抑制剂、其制备方法及应用 | |
| CN102993185B (zh) | 2-甲基-4-氨基-5-（取代-1h-1,2,3-三唑基）甲基嘧啶衍生物的制备及杀菌活性 | |
| CN111333634A (zh) | 天然产物Streptochlorin及其衍生物的制备方法和应用 | |
| CN104592144B (zh) | 制备噁唑衍生物的新方法 | |
| CN104292165B (zh) | 含氟和氮杂环的烯烃类化合物及其制备方法和用途 | |
| CN112239464B (zh) | 一种含1,3,4-噁二唑的喹唑啉-4(3h)-酮类衍生物、制备方法及应用 | |
| CN113135856A (zh) | 一类3-三氟甲基-5-氰基吡唑化合物及其制备方法 | |
| CN114213311B (zh) | 一种取代苯甲醛肟酯类化合物及其制备方法和应用 | |
| KR101916901B1 (ko) | 2―아릴카보닐하이드라진카보티오아마이드 유도체 화합물을 포함하는 소포체 스트레스 관련 질환의 예방 또는 치료용 약제학적 조성물 | |
| CN108440506B (zh) | 抗真菌剂-含1,2,3-三氮唑结构的烯醇醚类化合物 | |
| CN113683608B (zh) | 具有杀菌活性的n-取代-2-氨基-4-糖精取代甲基噻唑类化合物、制备方法和应用 | |
| CN106008458A (zh) | 偶氮苯类化合物及其制备方法 | |
| CN111574466B (zh) | 一种含三唑的烯丙基苯甲酸酯类化合物及其制备方法和应用 | |
| CN104974095B (zh) | 2,4,5‑多取代咪唑类化合物及制备方法 | |
| CN116253697B (zh) | 一种二氯萘醌和甲胺类化合物为原料合成醌并噻唑类化合物的方法 | |
| RU2341525C1 (ru) | Замещенные анилиды никотиновой кислоты, обладающие фунгицидной активностью | |
| JP3066594B2 (ja) | アニリン誘導体及びその製造法 | |
| CN117603140A (zh) | 一种含取代联苯结构的吡唑酰基脲或者硫脲类化合物及其制备方法和应用 | |
| CN106234385A (zh) | 一种含苯并吡嗪结构的1,2,4‑三唑衍生物作为杀菌剂的应用 | |
| KR100501146B1 (ko) | 트리아졸 유도체, 그의 제조 방법 및 그를 포함하는농원예용 살균제 조성물 | |
| CN105237451A (zh) | 硫醚类辣根素化合物及其制备方法和应用 | |
| CN115772122A (zh) | 一种苯甲酰胺类化合物及其制备方法和应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20150909 Assignee: Hubei Juhui New Material Industry Technology Research Institute Co.,Ltd. Assignor: CENTRAL CHINA NORMAL University Contract record no.: X2022420000147 Denomination of invention: 2-methyl-4-amino-5 - (substituted 1,2,3-triazolyl) methyl pyrimidine derivatives with bactericidal activity, preparation method and application thereof Granted publication date: 20170222 License type: Common License Record date: 20221228 |
|
| EE01 | Entry into force of recordation of patent licensing contract | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20150909 Assignee: Wuhan Nanwang Environmental Protection Technology Research Co.,Ltd. Assignor: CENTRAL CHINA NORMAL University Contract record no.: X2023980053268 Denomination of invention: 2-methyl-4-amino-5- (substituted 1,2,3-triazolyl) methylpyrimidine derivatives with bactericidal activity, preparation method and application thereof Granted publication date: 20170222 License type: Common License Record date: 20231220 |