CN1694874A - Benzodiazepine derivatives and pharmaceutical compositions containing them - Google Patents
Benzodiazepine derivatives and pharmaceutical compositions containing them Download PDFInfo
- Publication number
- CN1694874A CN1694874A CNA038251906A CN03825190A CN1694874A CN 1694874 A CN1694874 A CN 1694874A CN A038251906 A CNA038251906 A CN A038251906A CN 03825190 A CN03825190 A CN 03825190A CN 1694874 A CN1694874 A CN 1694874A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- phenyl
- benzo
- dihydro
- oxo
- 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.)
- Granted
Links
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 title claims abstract description 26
- 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 title description 2
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 125000003118 aryl group Chemical group 0.000 claims abstract description 137
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 133
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 132
- 239000001257 hydrogen Substances 0.000 claims abstract description 114
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 114
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 111
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 81
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims abstract description 77
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 71
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 57
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 57
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 45
- 150000002367 halogens Chemical class 0.000 claims abstract description 45
- 150000003839 salts Chemical class 0.000 claims abstract description 41
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 39
- -1 heterocyclic radical Chemical class 0.000 claims description 254
- 150000001875 compounds Chemical class 0.000 claims description 232
- 150000003254 radicals Chemical class 0.000 claims description 120
- 238000002360 preparation method Methods 0.000 claims description 113
- 238000000034 method Methods 0.000 claims description 105
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 88
- 239000004202 carbamide Substances 0.000 claims description 78
- 229910052801 chlorine Inorganic materials 0.000 claims description 73
- 239000000460 chlorine Substances 0.000 claims description 72
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 68
- 125000003545 alkoxy group Chemical group 0.000 claims description 65
- 229910052731 fluorine Inorganic materials 0.000 claims description 63
- 239000011737 fluorine Substances 0.000 claims description 63
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 58
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 54
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 49
- 229910052794 bromium Inorganic materials 0.000 claims description 49
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 47
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 42
- 239000000203 mixture Substances 0.000 claims description 42
- 125000001544 thienyl group Chemical group 0.000 claims description 40
- 125000004076 pyridyl group Chemical group 0.000 claims description 39
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 32
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 32
- 125000002541 furyl group Chemical group 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- 125000004598 dihydrobenzofuryl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 29
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 28
- 125000002757 morpholinyl group Chemical group 0.000 claims description 26
- 125000004193 piperazinyl group Chemical group 0.000 claims description 26
- 125000005936 piperidyl group Chemical group 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 21
- SMUQFGGVLNAIOZ-UHFFFAOYSA-N quinaldine Chemical compound C1=CC=CC2=NC(C)=CC=C21 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 claims description 20
- 238000011282 treatment Methods 0.000 claims description 19
- 125000001624 naphthyl group Chemical group 0.000 claims description 17
- 241000700605 Viruses Species 0.000 claims description 12
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 12
- 229940047889 isobutyramide Drugs 0.000 claims description 12
- 125000002971 oxazolyl group Chemical group 0.000 claims description 12
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 12
- HPARLNRMYDSBNO-UHFFFAOYSA-N 1,4-benzodioxine Chemical compound C1=CC=C2OC=COC2=C1 HPARLNRMYDSBNO-UHFFFAOYSA-N 0.000 claims description 11
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- 206010061603 Respiratory syncytial virus infection Diseases 0.000 claims description 10
- 206010022000 influenza Diseases 0.000 claims description 9
- 229960003966 nicotinamide Drugs 0.000 claims description 7
- 239000011570 nicotinamide Substances 0.000 claims description 7
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000005605 benzo group Chemical group 0.000 claims description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 6
- 150000004702 methyl esters Chemical class 0.000 claims description 6
- 229940124530 sulfonamide Drugs 0.000 claims description 6
- 208000015181 infectious disease Diseases 0.000 claims description 5
- 210000000621 bronchi Anatomy 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000003826 tablet Substances 0.000 claims description 4
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 3
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 3
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 claims description 3
- 102000004890 Interleukin-8 Human genes 0.000 claims description 3
- 108090001007 Interleukin-8 Proteins 0.000 claims description 3
- 102000000585 Interleukin-9 Human genes 0.000 claims description 3
- 108010002335 Interleukin-9 Proteins 0.000 claims description 3
- 208000019693 Lung disease Diseases 0.000 claims description 3
- 201000005505 Measles Diseases 0.000 claims description 3
- 208000002606 Paramyxoviridae Infections Diseases 0.000 claims description 3
- 206010034038 Parotitis Diseases 0.000 claims description 3
- 208000009714 Severe Dengue Diseases 0.000 claims description 3
- 241000710886 West Nile virus Species 0.000 claims description 3
- 229960004436 budesonide Drugs 0.000 claims description 3
- 230000001684 chronic effect Effects 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 229960002714 fluticasone Drugs 0.000 claims description 3
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 claims description 3
- 239000003112 inhibitor Substances 0.000 claims description 3
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 claims description 3
- 229940096397 interleukin-8 Drugs 0.000 claims description 3
- 229940118526 interleukin-9 Drugs 0.000 claims description 3
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003199 leukotriene receptor blocking agent Substances 0.000 claims description 3
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 3
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 3
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 claims description 3
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 claims description 3
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 claims description 3
- 230000036266 weeks of gestation Effects 0.000 claims description 3
- 229940051021 yellow-fever virus Drugs 0.000 claims description 3
- ZPQOPVIELGIULI-UHFFFAOYSA-N 1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1 ZPQOPVIELGIULI-UHFFFAOYSA-N 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 241000710772 Yellow fever virus Species 0.000 claims description 2
- 239000007900 aqueous suspension Substances 0.000 claims description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004188 dichlorophenyl group Chemical group 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000006185 dispersion Substances 0.000 claims description 2
- 239000008298 dragée Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000007937 lozenge Substances 0.000 claims description 2
- 125000006501 nitrophenyl group Chemical group 0.000 claims description 2
- 239000012053 oil suspension Substances 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 12
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 229930192474 thiophene Natural products 0.000 claims 1
- 150000003577 thiophenes Chemical class 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 8
- 125000004452 carbocyclyl group Chemical group 0.000 abstract 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 2
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 abstract 1
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 288
- 239000007787 solid Substances 0.000 description 99
- 238000005481 NMR spectroscopy Methods 0.000 description 97
- 239000000463 material Substances 0.000 description 90
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 85
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 50
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 239000002585 base Substances 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- 125000001424 substituent group Chemical group 0.000 description 20
- 125000004122 cyclic group Chemical group 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000001704 evaporation Methods 0.000 description 15
- 239000002253 acid Substances 0.000 description 13
- 241000725643 Respiratory syncytial virus Species 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000003513 alkali Substances 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 230000008020 evaporation Effects 0.000 description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 229960001866 silicon dioxide Drugs 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 125000004043 oxo group Chemical group O=* 0.000 description 5
- 125000003373 pyrazinyl group Chemical group 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000012346 acetyl chloride Substances 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 4
- 239000012964 benzotriazole Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000010276 construction Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 4
- 230000002209 hydrophobic effect Effects 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- MAOBFOXLCJIFLV-UHFFFAOYSA-N (2-aminophenyl)-phenylmethanone Chemical compound NC1=CC=CC=C1C(=O)C1=CC=CC=C1 MAOBFOXLCJIFLV-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
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- 229920002472 Starch Polymers 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 3
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
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- 235000019698 starch Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 2
- IPDOBVFESNNYEE-UHFFFAOYSA-N 1h-indole-7-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=C1NC=C2 IPDOBVFESNNYEE-UHFFFAOYSA-N 0.000 description 2
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical class ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 2
- NSTREUWFTAOOKS-UHFFFAOYSA-N 2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1F NSTREUWFTAOOKS-UHFFFAOYSA-N 0.000 description 2
- LODHFNUFVRVKTH-ZHACJKMWSA-N 2-hydroxy-n'-[(e)-3-phenylprop-2-enoyl]benzohydrazide Chemical compound OC1=CC=CC=C1C(=O)NNC(=O)\C=C\C1=CC=CC=C1 LODHFNUFVRVKTH-ZHACJKMWSA-N 0.000 description 2
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- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229960003115 certolizumab pegol Drugs 0.000 description 1
- 208000029771 childhood onset asthma Diseases 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- NWFNSTOSIVLCJA-UHFFFAOYSA-L copper;diacetate;hydrate Chemical compound O.[Cu+2].CC([O-])=O.CC([O-])=O NWFNSTOSIVLCJA-UHFFFAOYSA-L 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000024835 cytogamy Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- LOZWAPSEEHRYPG-UHFFFAOYSA-N dithiane Natural products C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 229940073621 enbrel Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 125000004407 fluoroaryl group Chemical group 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229940048921 humira Drugs 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 208000022760 infectious otitis media Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 1
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 1
- QTBFPMKWQKYFLR-UHFFFAOYSA-N isobutyl chloride Chemical compound CC(C)CCl QTBFPMKWQKYFLR-UHFFFAOYSA-N 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960005127 montelukast Drugs 0.000 description 1
- XMWFMEYDRNJSOO-UHFFFAOYSA-N morpholine-4-carbonyl chloride Chemical compound ClC(=O)N1CCOCC1 XMWFMEYDRNJSOO-UHFFFAOYSA-N 0.000 description 1
- OFCCYDUUBNUJIB-UHFFFAOYSA-N n,n-diethylcarbamoyl chloride Chemical compound CCN(CC)C(Cl)=O OFCCYDUUBNUJIB-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical group C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000005429 oxyalkyl group Chemical group 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000004540 process dynamic Methods 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229940116176 remicade Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 1
- 229960002586 roflumilast Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000001562 sternum Anatomy 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- QTWBEVAYYDZLQL-UHFFFAOYSA-N thiophene-3-carbonyl chloride Chemical compound ClC(=O)C=1C=CSC=1 QTWBEVAYYDZLQL-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Benzodiazepine derivative of formula (I), and pharmaceutically acceptable salts thereof, are found to be active against RSV. Formula (I) Wherein: - R<1> represents C1-6 alkyl, aryl or heteroaryl; - R<2> represents hydrogen or C1-6 alkyl; - each R<3> is the same or different and represents halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio C1-6 haloalkyl, C1-6 haloalkoxy, amino, mono(C1-6 alkyl)amino, di(C1-6 alkyl)amino, nitro, cyano, -CO2R , -CONR R<II>, -NH-CO-R , -S(O)R , -S(O)2R , -NH-S(O)2R , -S(O)NR R<II> or -S(O)2NR<I>R<II> wherein each R and R<II> is the same or different and represents hydrogen or C1-6 alkyl; - n is from 0 to 3; R<4> represents hydrogen or C1-6 alkyl; - R<6> represents C1-6 alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-(C1-6 alkyl)-, heteroaryl-(C1-6 alkyl)-, carbocyclyl-(C1-6 alkyl)-, heterocyclyl-(C1-6 alkyl)-, aryl-C(O)-C(O)-, heteroaryl-C(O)-C(O)-, carbocyclyl-C(O)-C(O)-, heterocyclyl-C(O)-C(O)- or, -XR<6>; - X represents -CO-, -S(O)- or -S(0)2-; and - R<6> represents C1-6 alkyl, hydroxy, C1-6 alkoxy, C1-6 alkylthio, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-(C1-6 alkyl)-, heteroaryl-(C1-6 alkyl)-, carbocyclyl-(C1-6 alkyl)-, heterocyclyl-(C1-6 alkyl)-, aryl-(C 1-6hydroxyalkyl)-, heteroaryl-(C1-6 hydroxyalkyl)-, carbocyclyl-(C1-6 hydroxyalkyl)-, heterocyclyl-(C 1-6 hydroxyalkyl)-, aryl-(C 1-6alkyl)-O-, heteroaryl-(C 1-6alkyl)-O-, carbocyclyl-(C1-6 alkyl)-O-, heterocyclyl-(C1-6 alkyl)-O- or -NR R<II> wherein each R and R<II> is the same or different and represents hydrogen, C1-6 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, aryl- (C1-6 alkyl)-, heteroaryl-(C1-6 alkyl)-, carbocyclyl-(C1-6 alkyl)- or heterocyclyl-(C1-6 alkyl)-.
Description
The present invention relates to a series of benzodiazepine derivatives of effective anti respiratory syncytial virus (RSV).
RSV is the major cause of all age bracket patient breathing system diseases.Concerning the adult, RSV often causes slight cold symptoms.Concerning the school-ager, it can cause flu and segmental bronchus cough.Concerning the infant, it can cause bronchiolitis (lung's tracheole inflammation) or pneumonia.Find that also it is the common cause of preschool children's middle ear infection (otitis media).The rsv infection of infantile period takes place relevant with childhood asthma.
At present, anti-RSV treatment comprises RSV use monoclonal antibody (being called palivizumab).Palivizumab act as prophylactic treatment RSV rather than therapeutic treatment RSV.Yet although this antibody is usually effective, it costs an arm and a leg.In fact, its high expense can not obtain common use concerning the people of the anti-RSV treatment of many needs.Therefore press for the method that effectively substitutes existing anti-RSV treatment.
Find the effective anti-RSV of general formula (I) benzodiazepine derivative of following uniqueness surprisingly.
Therefore, primary embodiment of the present invention provides acceptable salt on structural formula (I) benzodiazepine derivative or its pharmacology and is used for the treatment of or prevents purposes on the rsv infection medicine in preparation,
Wherein:
-R
1Represent C
1-6Alkyl, aryl or heteroaryl;
-R
2Represent hydrogen or C
1-6Alkyl;
-each R
3Identical or different and represent halogen, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group ,-CO
2R ' ,-CONR ' R " ,-NH-CO-R ' ,-S (O) R ' ,-S (O)
2R ' ,-NH-S (O)
2R ' ,-S (O) NR ' R " or-S (O)
2NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen or C
1-6Alkyl;
-n is 0-3;
-R
4Represent hydrogen or C
1-6Alkyl;
-R
5Represent C
1-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-aryl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-, carbocylic radical-C (O)-C (O)-, heterocyclic radical-C (O)-C (O)-or-XR
6
-X representative-CO-,-S (O)-or-S (O)
2-; And
-R
6Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(
C-6Hydroxyalkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-.Usually, R ' and R " not all are hydrogen.
In the preferred structure formula (I),
-each R
3Identical or different and represent halogen, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group ,-CO
2R ' ,-CONR ' R " ,-NH-CO-R ' ,-S (O) R ' ,-S (O)
2R ' ,-NH-S (O)
2R ' or-S (O) NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen or C
1-6Alkyl;
-R
5Represent C
1-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-XR
6
-X representative-CO-,-S (O)-or-S (O)
2-; And
-R
6Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-or heteroaryl-(C
1-6Alkyl)-.Usually, R ' and R " not all are hydrogen.
C used herein
1-6Alkyl or part are for comprising the straight or branched alkyl or the part of 1-6 carbon atom, for example C
1-4Alkyl or part.C
1-4The example of alkyl and part comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-and the tertiary butyl.For fear of ambiguity, when two alkyl occurring in the group, moieties can be identical or different.
Hydroxyalkyl used herein typically refers to the described alkyl that is replaced by one or more hydroxyls.It is replaced by 1-3 hydroxyl usually.Preferred its replaced by a hydroxyl.Preferred hydroxyalkyl is (monohydroxy) ethyl.
Acyl group used herein is C
2-7Acyl group, for example-CO-R, wherein R is described C
1-6Alkyl.
Aryl used herein is generally C
6-10Aryl, for example phenyl or naphthyl.Be preferably phenyl.Aryl can not be substituted or is substituted in any position.Aryl comprises 0-3 substituting group usually.
Suitable substituent on the aryl comprises halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino ,-CO
2R ' ,-CONR ' R " ,-S (O) R ' ,-S (O)
2R ' ,-S (O) NR ' R " ,-S (O)
2NR ' R " NH-S (O)
2R ' or-NH-CO-R ', wherein each R ' and R are " identical or different and represent hydrogen or C
1-6Alkyl.The example of the suitable substituent on the aryl comprises halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino ,-CO
2R ' ,-CONR ' R " ,-S (O) R ' ,-S (O)
2R ' ,-S (O) NR ' R " ,-NH-S (O)
2R ' or-NH-CO-R ', wherein each R ' and R are " identical or different and represent hydrogen or C
1-6Alkyl.
Preferred substituents on the aryl comprises halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group ,-CO
2R ' ,-S (O) R ' ,-S (O)
2R ' and-S (O)
2NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen or C
1-4Alkyl.The example of the preferred substituents on the aryl comprises halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halo oxyalkyl, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro and cyano group.
Especially preferred substituting group comprises fluorine, chlorine, bromine, iodine, C
1-4Alkyl, C
2-4Acyl group, hydroxyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, C
1-4Halogenated alkoxy, amino, (a C
1-4Alkyl) amino, two (C
1-4Alkyl) amino, nitro ,-CO
2R ' ,-S (O)
2R ' and-S (O)
2NH
2, wherein R ' represents C
1-2Alkyl.Especially preferred substituent example comprises fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro.
Aryl used herein comprises and condenses ring system, and wherein aryl and monocycle carbocylic radical, heterocyclic radical or heteroaryl-condensed are perhaps with monocycle carbocylic radical, the heterocyclic radical or heteroaryl-condensed of fused benzene rings.Usually, described aryl and monocycle carbocylic radical in the ring system, the heterocyclic radical or heteroaryl-condensed of condensing.Preferred such ring system: wherein the monocyclic heterocycles base of aryl and fused benzene rings or heteroaryl-condensed ring system or with the ring system of the monocycle carbocylic radical of fused benzene rings, especially wherein aryl and heterocyclic radical or heteroaryl-condensed ring system.This example that condenses ring system condenses the group of formation benzothienyl or dihydro benzo furyl for phenyl ring wherein and thienyl or with tetrahydrofuran base.The further example of this fused rings is wherein phenyl ring and dioxane base, pyrryl or 2, and 3-dihydro 1-Indanone base condenses the group that forms benzo dioxine base, indyl or 9H-fluorenes-9-ketone group.
Carbocylic radical used herein is generally the saturated or unsaturated monocyclic hydrocarbon ring of the non-aromatics with 3-6 carbon atom.Be preferably stable hydrocarbon ring (being cycloalkyl) with 3-6 carbon atom.Example comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Preferred cyclopentyl or cyclohexyl.Cycloalkyl can not be substituted or is substituted in any position.It comprises 0-3 substituting group usually.
Suitable substituent on the carbocylic radical comprises halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, oxo ,-CO
2R ' ,-CONR ' R " ,-S (O) R ' ,-S (O)
2R ' ,-S (O) NR ' R " ,-S (O)
2NR ' R " ,-NH-S (O)
2R ' or-NH-CO-R ', wherein each R ' and R are " identical or different and represent hydrogen or C
1-6Alkyl.The example of the suitable substituent on the carbocylic radical comprises halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino ,-CO
2R ' ,-CONR ' R " ,-S (O) R ' ,-S (O)
2R ' ,-S (O) NR ' R " ,-NH-S (O)
2R ' or-NH-CO-R ', wherein each R ' and R are " identical or different and represent hydrogen or C
1-6Alkyl.
Preferred substituents on the carbocylic radical comprises halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group and oxo.The example of the preferred substituents on the carbocylic radical comprises halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro and cyano group.Especially preferred substituting group comprises fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl, nitro and oxo.Especially preferred substituent example comprises fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro.Especially preferred substituent further example comprises fluorine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro.
Heterocyclic radical used herein is generally the saturated or unsaturated carbocyclic of non-aromatics with 5-10 carbon atom, and wherein one or more (for example 1-3) carbon atoms are selected from the heteroatoms displacement of N, O and S.Preferred saturated heterocyclyl.Example comprises tetrahydrofuran base, tetrahydro-thienyl, pyrrolidyl, imidazolidyl, pyrazolidyl, dioxolanyl, thiazolidyl, THP trtrahydropyranyl, piperidyl, dioxane base, piperazinyl, morpholinyl, thio-morpholinyl He thioxane base.Further example comprises dithiolane Ji, oxazolidinyl, tetrahydro thiapyran base and dithiane base.Preferred piperazinyl, piperidyl and morpholinyl.
Heterocyclic radical used herein comprises that heterocyclic radical and phenyl condensed condense ring system.Preferred such fused rings is that wherein 5-to 6-unit's heterocyclic radical and phenyl condensed condense ring system.The example that condenses ring system like this is for wherein 1H-tetrahydroglyoxaline-2 (3H)-ketone group or imidazolidin-2-one base and phenyl ring condense the group that forms 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group.Yet most preferably heterocyclic radical is the monocyclic heterocycles base.
Heterocyclic radical can not be substituted or is substituted in any position.It has 0-2 substituting group usually.
Suitable substituent on the heterocyclic radical comprises halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, oxo ,-CO
2R ' ,-CONR ' R " ,-S (O) R ' ,-S (O)
2R ' ,-S (O) NR ' R " ,-S (O)
2NR ' R " ,-NH-S (O)
2R ' or-NH-CO-R ', wherein each R ' and R are " identical or different and represent hydrogen or C
1-6Alkyl.The example of the suitable substituent on the heterocyclic radical comprises halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino ,-CO
2R ' ,-CONR ' R " ,-S (O) R ' ,-S (O)
2R ' ,-S (O) NR ' R " ,-NH-S (O)
2R ' or-NH-CO-R ', wherein each R ' and R are " identical or different and represent hydrogen or C
1-6Alkyl.
Preferred substituents on the heterocyclic radical comprises halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group and oxo.The example of the preferred substituents on the heterocyclic radical comprises halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro and cyano group.Especially preferred substituting group comprises fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl, nitro and oxo.Especially preferred substituent example comprises fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro.Especially preferred substituent further example comprises fluorine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro.Most preferably heterocyclic radical is not substituted or by 1-2 C
1-2Alkyl replaces.
Halogen used herein is generally chlorine, fluorine, bromine or iodine.Preferred chlorine, fluorine or bromine.More preferably chlorine or fluorine.
Alkoxyl group used herein is generally the described alkyl that connects Sauerstoffatom.Alkylthio is generally the described alkyl that connects sulfenyl.Haloalkyl or halogenated alkoxy are generally described alkyl or the alkoxyl group that is replaced by one or more described halogen atoms.It is replaced by 1-3 described halogen atom usually.Preferred haloalkyl and halogenated alkoxy comprise whole haloalkyl and perhalogeno alkoxyl group, for example-and CX
3With-OCX
3, wherein X is described halogen atom, for example chlorine or fluorine.Especially preferred haloalkyl is-CF
3With-CCl
3Especially preferred halogenated alkoxy is-OCF
3With-OCCl
3
Heteroaryl used herein is generally 5-to 10-unit aromatic ring, and for example 5-or 6-unit encircles, and it comprises at least one heteroatoms that is selected from O, S and N (for example 1-3 heteroatoms).Example comprises pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, furyl, thienyl, pyrazolidyl, pyrryl, oxadiazole base, isoxazolyl, thiadiazolyl group, thiazolyl, imidazolyl and pyrazolyl.Further example Bao Kuo oxazolyl and isothiazolyl.Preferred heteroaryl is pyridyl, thienyl, oxazolyl, isoxazolyl, furyl and pyrazolyl.The example of preferred heteroaryl is pyridyl, thienyl, isoxazolyl and furyl.Heteroaryl used herein comprises that heteroaryl and phenyl condensed condense ring system.Preferred such fused rings is 5-to 6-unit's heteroaryl and phenyl condensed ring system.The example that condenses ring system like this is benzofuryl, benzothienyl, indyl, benzimidazolyl-, benzoxazolyl, quinolyl, quinazolyl and isoquinolyl.Yet most preferably heterocyclic radical is the monocyclic heterocycles base.
Heteroaryl can not be substituted or is substituted in any position.It has a common 0-3 substituting group.
Suitable substituent on the heteroaryl comprises halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino ,-CO
2R ' ,-CONR ' R " ,-S (O) R ' ,-S (O)
2R ' ,-S (O) NR ' R " ,-S (O)
2NR ' R " ,-NH-S (O)
2R ' or-NH-CO-R ', wherein each R ' and R are " identical or different and represent hydrogen or C
1-6Alkyl.The example of the suitable substituent on the heteroaryl comprises halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino ,-CO
2R ' ,-CONR ' R " ,-S (O) R " ,-S (O)
2R ' ,-S (O) NR ' R " ,-NH-S (O)
2R ' or-NH-CO-R ', wherein each R ' and R are " identical or different and represent hydrogen or C
1-6Alkyl.
Preferred substituents on the heteroaryl comprises halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro and cyano group.Especially preferred substituting group comprises fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro.Further preferred substituted comprises fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Haloalkyl and two (C
1-2Alkyl) amino.
Heteroaryl used herein comprises heteroaryl and monocyclic described aryl, carbocylic radical or heterocyclic radical condenses or with other heteroaryl-condensed ring system that condenses.Preferred such ring system is heteroaryl and aryl (for example phenyl) condensed ring system.This example that condenses ring system is that thienyl and phenyl ring condense the group that forms benzothienyl.This further example that condenses ring system is that furyl and phenyl ring condense the group that forms benzofuryl.
Work as R
1During for aryl or heteroaryl, R
1Usually be not substituted or be selected from following substituting group and replace: halogen, C by 1-3
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl or C
1-6Halogenated alkoxy.Preferred R
1Be not substituted or be selected from following substituting group and replace: fluorine, chlorine, bromine, C by 1-2
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl or C
1-4Halogenated alkoxy.More preferably R
1Be not substituted or by a fluorine, chlorine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl or C
1-2Halo-alkoxy substituent replaces.
R
1Be generally C
1-6Alkyl or aryl.Preferred R
1Be C
1-2Alkyl or aryl.More preferably R
1Be C
1-2Alkyl or phenyl.More preferably R
1Be phenyl.
R
2Be generally hydrogen or C
1-4Alkyl.Preferred R
2Be hydrogen.
R
3Be generally halogen, hydroxyl, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, C
1-4Halogenated alkoxy, amino, (a C
1-4Alkyl) amino or two (C
1-4Alkyl) amino.Preferred R
3Be fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl, C
1-2Halogenated alkoxy, amino, (a C
1-2Alkyl)-amino or two (C
1-2Alkyl) amino.More preferably R
3Be methyl, trifluoromethyl, fluorine, chlorine or bromine.R most preferably
3Be methyl or chlorine.Most preferred example is R
3Be chlorine.
N is generally 0,1 or 2.Preferred n is 0 or 1.
R
4Be generally hydrogen or C
1-4Alkyl.Preferred R
4Be hydrogen or C
1-2Alkyl.More preferably R
4Be hydrogen or methyl.R most preferably
4Be hydrogen.
Work as R
5During for heterocyclic radical, it connects by carbon atom usually.R
5Be generally C
1-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1-4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-, aryl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-or-XR
6Typical case R
5Example be: R
5Be C
1-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1-4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-or-XR
6
Preferred R
5Be C
1-4Alkyl; Aryl, for example phenyl and dihydro benzo furyl; Heteroaryl, for example thienyl, furyl, isoxazolyl, pyridyl and benzothienyl; Carbocylic radical, for example cyclopentyl and cyclohexyl; Heterocyclic radical, for example piperidyl, morpholinyl and piperazinyl; Phenyl-(C
1-2Alkyl)-, benzyl for example; Heteroaryl-(C
1-2Alkyl)-, phenyl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-or-XR
6Preferred R
5Example be: R
5Be C
1-4Alkyl; Aryl, for example phenyl and dihydro benzo furyl; Heteroaryl, for example thienyl, furyl, isoxazolyl, pyridyl and benzothienyl; Carbocylic radical, for example cyclopentyl and cyclohexyl; Heterocyclic radical, for example piperidyl, morpholinyl and piperazinyl; Phenyl-(C
1-2Alkyl)-, benzyl for example; Heteroaryl-(C
1-2Alkyl)-or-XR
6
More preferably R
5Be C
1-4Alkyl, phenyl, thienyl, furyl, isoxazolyl, pyridyl, cyclopentyl, cyclohexyl, benzothienyl, dihydro benzo furyl, phenyl-CH
2-, furyl-CH
2-, phenyl-C (O)-C (O)-, thienyl-C (O)-C (O)-or-XR
6More preferably R
5Example be: R
5Be C
1-4Alkyl, phenyl, thienyl, furyl, isoxazolyl, pyridyl, cyclopentyl, cyclohexyl, benzothienyl, dihydro benzo furyl, phenyl-CH
2-, furyl-CH
2-or-XR
6
R most preferably
5Be phenyl-CH
2-, furyl-CH
2-,-C (O)-C (O)-thienyl or-XR
6R most preferably
5Example be: R
5Be phenyl-CH
2-, furyl-CH
2-or-XR
6
X is generally-CO-,-S (O)-or-S (O)
2-.Preferred X is-CO-or-S (O)
2-.
Work as R
6When comprising aryl, heteroaryl, carbocylic radical or heterocyclic radical for-NR ' R " and R ' or R ", R
6Usually be not substituted or be selected from following substituting group and replace: halogen, C by 1-3
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro and cyano group.Preferred aryl groups, heteroaryl, carbocylic radical or heterocyclic radical are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, C
1-4Halogenated alkoxy and nitro.Preferred aryl groups, heteroaryl, carbocylic radical or heterocyclic radical part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro.More preferably aryl, heteroaryl, carbocylic radical or heterocyclic radical part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl and nitro.More preferably aryl, heteroaryl, carbocylic radical or heterocyclic radical part are not substituted or are replaced by a fluorine, chlorine, methyl, methoxyl group or nitro substituent." when being heteroaryl or heterocyclic radical, it connects by carbon atom as R ' or R.
R ' and R " not all are hydrogen usually.Usually, each R ' and R are " identical or different and represent hydrogen, C
1-4Alkyl, aryl, heteroaryl, carbocylic radical, aryl-(C
1-4Alkyl)-or heteroaryl-(C
1-4Alkyl)-.Typical case R ' and R " example be: each R ' and R " are identical or different and represent hydrogen; C
1-4Alkyl; Phenyl; Heteroaryl, for example thienyl; Carbocylic radical, for example cyclohexyl or cyclopentyl; Or phenyl-(C
1-4Alkyl)-.Typical case R ' and R " further example be: each R ' and R " are identical or different and represent hydrogen, C
1-4Alkyl, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl-(CH
2)-.Preferred each R ' and R are " identical or different and represent hydrogen, C
1-4Alkyl, phenyl, phenyl-CH
2-, cyclohexyl or cyclopentyl.More preferably R ' and R " one of represent hydrogen.Most preferably R ' and R " one of another is C for hydrogen
1-4Alkyl, phenyl, phenyl-CH
2-, cyclohexyl or cyclopentyl.In addition, preferred R ' and R " one of another is C for hydrogen
1-4Alkyl, phenyl, thienyl or phenyl-CH
2-.
R
6Be generally C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1-4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-, aryl-(C
1-4Hydroxyalkyl)-, heteroaryl-(C
1-4Hydroxyalkyl)-, carbocylic radical-(C
1-4Hydroxyalkyl)-, heterocyclic radical-(C
1-4Hydroxyalkyl)-, aryl-(C
1-4Alkyl)-O-, heteroaryl-(C
1-4Alkyl)-O-, carbocylic radical-(C
1-4Alkyl)-O-, heterocyclic radical-(C
1-4Alkyl)-O-or-definition of NR ' R ", wherein R ' and R " is the same.Typical case R
6Example be: R
6Be C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1-4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-or the definition of NR ' R ", wherein R ' and R " is the same.
Preferred R
6Be C
1-6Alkyl; C
1-6Alkoxyl group; C
1-6Alkylthio; Aryl, for example phenyl, naphthyl, dihydro benzo furyl, benzo dioxine base, 9H-fluorenes-9-ketone group and indyl; Heteroaryl, for example thienyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl and benzofuryl; Carbocylic radical, for example cyclopentyl and cyclohexyl; Heterocyclic radical, for example piperazinyl, piperidyl, morpholinyl and 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group; Phenyl-(C
1-2Alkyl)-, phenyl-(C
1-2Alkyl)-O-, phenyl-(C
1-2Hydroxyalkyl)-, heteroaryl-(C
1-2Hydroxyalkyl)-, heteroaryl-(C
1-2Alkyl)-or-definition of NR ' R ", wherein R ' and R " is the same.Preferred R
6Example be: R
6Be C
1-4Alkyl; Aryl, for example phenyl and dihydro benzo furyl; Heteroaryl, for example thienyl, furyl, isoxazolyl, pyridyl and benzothienyl; Carbocylic radical, for example cyclopentyl and cyclohexyl; Heterocyclic radical, for example N-heterocyclic radical; Phenyl-(C
1-2Alkyl)-, benzyl for example; Heteroaryl-(C
1-2Alkyl)-or-definition of NR ' R ", wherein R ' and R " is the same.
More preferably R
6Be C
1-4Alkyl, C
1-4Alkoxyl group, phenyl, naphthyl, dihydro benzo furyl, benzo dioxine base, 9H-fluorenes-9-ketone group, indyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl, benzofuryl, cyclopentyl, cyclohexyl, piperazinyl, piperidyl, morpholinyl, phenyl-(C
1-2Alkyl)-, phenyl-CH
2-CH (OH)-, phenyl-CH (OH)-CH
2-, phenyl-(C
1-2Alkyl)-O-, 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group or-definition of NR ' R ", wherein R ' and R " is the same.R most preferably
6Example be: R
6Be C
1-4Alkyl; Phenyl; Thienyl; Furyl; Pyridyl; Cyclopentyl; Cyclohexyl; Benzothienyl; Dihydro benzo furyl; Isoxazolyl; Piperidyl, for example N-piperidyl; Morpholinyl, for example N-morpholinyl; Piperazinyl, N-piperazinyl for example, or-definition of NR ' R ", wherein R ' and R " is the same.
Preferred The compounds of this invention is these compounds, wherein:
-R
1Be C
1-6Alkyl or aryl;
-R
2Be hydrogen or C
1-4Alkyl;
-R
3Be halogen, hydroxyl, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, C
1-4Halogenated alkoxy, amino, (a C
1-4Alkyl) amino or two (C
1-4Alkyl) amino, perhaps preferred R
3Be fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl, C
1-2Halogenated alkoxy, amino, (a C
1-2Alkyl) amino or two (C
1-2Alkyl) amino;
-n is 0,1 or 2;
-R
4Be hydrogen or C
1-4Alkyl;
R
5Be C
1-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1-4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-, aryl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-or-XR
6
-X is-CO-,-S (O)-or-S (O)
2-; And
-R
6Be C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1-4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-, aryl-(C
1-4Hydroxyalkyl)-, heteroaryl-(C
1-4Hydroxyalkyl)-, carbocylic radical-(C
1-4Hydroxyalkyl)-, heterocyclic radical-(C
1-4Hydroxyalkyl)-, aryl-(C
1-4Alkyl)-O-, heteroaryl-(C
1-4Alkyl)-O-, carbocylic radical-(C
1-4Alkyl)-O-, heterocyclic radical-(C
1-4Alkyl)-O-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-4Alkyl, aryl, heteroaryl, carbocylic radical, aryl-(C
1-4Alkyl)-or heteroaryl-(C
1-4Alkyl)-,
R
1Aryl moiety in the group is not substituted or is selected from following substituting group by 1-3 and replaces: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl or C
1-6Halogenated alkoxy;
R
5And R
6Aryl in the group and heteroaryl moieties are not substituted or are selected from following substituting group by 1-3 and replace: halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino ,-CO
2R ' ,-CONR ' R " ,-S (O) R ' ,-S (O)
2R ' ,-S (O) NR ' R " ,-S (O)
2NR ' R " ,-NH-S (O)
2R ' or-NH-CO-R ', wherein each R ' and R are " identical or different and represent hydrogen or C
1-6Alkyl;
R
5And R
6Carbocylic radical in the group and heterocyclic radical part are not substituted or are selected from following substituting group by 1-3 and replace: halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, oxo ,-CO
2R ' ,-CONR ' R " ,-S (O) R ' ,-S (O)
2R ' ,-S (O) NR ' R " ,-S (O)
2NR ' R " ,-NH-S (O)
2R ' or-NH-CO-R ', wherein each R ' and R are " identical or different and represent hydrogen or C
1-6Alkyl; And
R
6Aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1-4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-moieties is not substituted or is replaced by 1-2 hydroxyl substituent.
In these preferred compounds of the present invention, " aryl in the group, heteroaryl and carbocylic radical part are not substituted or are selected from following substituting group by 1-3 and replace: halogen, C for preferred R ' and R
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro and cyano group.
The example of preferred compound of the present invention is these compounds: R wherein
1, R
2, R
3, R
4It is identical with the definition of n with the definition of preferred compound of the present invention,
-R
5Be C
1-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1-4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-or-XR
6
-X is-CO-,-S (O)-or-S (O)
2-; And
-R
6Be C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1-4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-4Alkyl, aryl, heteroaryl, carbocylic radical, aryl-(C
1-4Alkyl)-or heteroaryl-(C
1-4Alkyl)-,
R
5And R
6Aryl in the group, heteroaryl, carbocylic radical and heterocyclic radical part are not substituted or are selected from following substituting group by 1-3 and replace: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro and cyano group.
Further preferred The compounds of this invention is these compounds, wherein:
-R
1Be C
1-2Alkyl or phenyl;
-R
2Be hydrogen or C
1-4Alkyl;
-R
3Be methyl, trifluoromethyl, fluorine, chlorine or bromine;
-n is 0 or 1;
-R
4Be hydrogen or C
1-2Alkyl;
-R
5Be C
1-4Alkyl; Aryl, for example phenyl and dihydro benzo furyl; Heteroaryl, for example thienyl, furyl, isoxazolyl, pyridyl and benzothienyl; Carbocylic radical, for example cyclopentyl and cyclohexyl; Heterocyclic radical, for example piperidyl, morpholinyl and piperazinyl; Phenyl-(C
1-2Alkyl)-, benzyl for example; Heteroaryl-(C
1-2Alkyl)-, phenyl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-or-XR
6, precondition is to work as R
5During for heterocyclic radical, it connects by carbon atom;
-X is-CO-,-S (O)-or-S (O)
2-; And
-R
6Be C
1-6Alkyl; C
1-6Alkoxyl group; C
1-6Alkylthio; Aryl, for example phenyl, naphthyl, dihydro benzo furyl, benzo dioxine base, 9H-fluorenes-9-ketone group and indyl; Heteroaryl, for example thienyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl and benzofuryl; Carbocylic radical, for example cyclopentyl and cyclohexyl; Heterocyclic radical, for example piperazinyl, piperidyl, morpholinyl and 1H-benzo [d] tetrahydroglyoxaline-2-(3H)-ketone group; Phenyl-(C
1-2Alkyl)-, phenyl-(C
1-2Alkyl)-O-, phenyl-(C
1-2Hydroxyalkyl)-, heteroaryl-(C
1-2Hydroxyalkyl)-, heteroaryl-(C
1-2Alkyl)-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen; C
1-4Alkyl; Phenyl; Heteroaryl, for example thienyl; Carbocylic radical, for example cyclohexyl or cyclopentyl; Or phenyl-(C
1-4Alkyl)-,
R
1Phenyl moiety in the group is not substituted or is selected from following substituting group by 1-2 and replaces: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl or C
1-4Halogenated alkoxy;
R
5And R
6Aryl moiety in the group is not substituted or is selected from following substituting group by 1-3 and replaces: halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group ,-CO
2R ' ,-S (O) R ' ,-S (O)
2R ' and-S (O)
2NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen or C
1-4Alkyl;
R
5And R
6Heteroaryl moieties in the group is not substituted or is selected from following substituting group by 1-3 and replaces: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro and cyano group; And
R
5And R
6Carbocylic radical in the group and heterocyclic radical part are not substituted or are selected from following substituting group by 1-3 and replace: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group and oxo; And
R
6Phenyl-(C
1-2Alkyl)-and heteroaryl-(C
1-2Alkyl)-moieties is not substituted or is replaced by a hydroxyl substituent.
In these further preferred The compounds of this invention, " phenyl in the group, heteroaryl and carbocylic radical part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C for preferred R ' and R
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, C
1-4Halogenated alkoxy and nitro.
Further the example of preferred The compounds of this invention is these compounds: R wherein
1, R
2, R
3, R
4It is identical with the definition of n with the definition of further preferred The compounds of this invention,
-R
5Be C
1-4Alkyl; Aryl, for example phenyl and dihydro benzo furyl; Heteroaryl, for example thienyl, furyl, isoxazolyl, pyridyl and benzothienyl; Carbocylic radical, for example cyclopentyl and cyclohexyl; Heterocyclic radical, for example piperidyl, morpholinyl and piperazinyl; Phenyl-(C
1-2Alkyl)-, benzyl for example; Heteroaryl-(C
1-2Alkyl)-or-XR
6, precondition is to work as R
5During for heterocyclic radical, it connects by carbon atom;
-X is-CO-,-S (O)-or-S (O)
2-; And
-R
6Be C
1-4Alkyl; Aryl, for example phenyl and dihydro benzo furyl; Heteroaryl, for example thienyl, furyl, isoxazolyl, pyridyl and benzothienyl; Carbocylic radical, for example cyclopentyl and cyclohexyl; Heterocyclic radical, for example N-heterocyclic radical; Phenyl-(C
1-2Alkyl)-, benzyl for example; Heteroaryl-(C
1-2Alkyl)-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-4Alkyl, cyclohexyl, cyclopentyl, phenyl or phenyl-CH
2-,
R
5And R
6Aryl in the group, heteroaryl, carbocylic radical and heterocyclic radical part are not substituted or are selected from following substituting group by 1-2 and replace: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro and cyano group.
In these further preferred The compounds of this invention, " cyclohexyl in the group, cyclopentyl and phenyl moiety are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C for further preferred R ' and R
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro.
Especially preferred The compounds of this invention is an acceptable salt on structural formula (Ia) compound and its pharmacology,
Wherein:
-R
1Be phenyl or methyl;
-R
3Be methyl or chlorine;
-n is 0 or 1;
-R
4Be hydrogen or methyl;
-R
5Be phenyl-CH
2-, furyl-CH
2-, thienyl-C (O)-C (O)-or-XR
6
-X is-CO-or-S (O)
2-; And
-R
6Be C
1-4Alkyl, C
1-4Alkoxyl group, phenyl, naphthyl, dihydro benzo furyl, benzo dioxine base, 9H-fluorenes-9-ketone group, indyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl, benzofuryl, cyclopentyl, cyclohexyl, piperazinyl, piperidyl, morpholinyl, phenyl-(C
1-2Alkyl)-, phenyl-CH
2-CH (OH)-, phenyl-CH (OH)-CH
2-, phenyl-(C
1-2Alkyl)-O-, 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-4Alkyl, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl-(CH
2)-,
R
1Phenyl moiety in the group is not substituted or by a fluorine, chlorine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl or C
1-2Halo-alkoxy substituent replaces;
R
5And R
6Aryl moiety in the group is not substituted or is selected from following substituting group by 1-3 and replaces: fluorine, chlorine, bromine, iodine, C
1-4Alkyl, C
2-4Acyl group, hydroxyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, C
1-4Halogenated alkoxy, amino, (a C
1-4Alkyl) amino, two (C
1-4Alkyl) amino, nitro ,-CO
2R ' ,-S (O)
2R ' and-S (O)
2NH
2, wherein R ' represents C
1-2Alkyl;
R
5And R
6Heteroaryl moieties in the group is not substituted or is selected from following substituting group by 1-2 and replaces: fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Haloalkyl and two (C
1-2Alkyl) amino; And
R
6Heterocyclic radical in the group and carbocylic radical part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro.
Especially preferred structural formula (Ia) examples for compounds is an acceptable salt on structural formula (Ia ') compound and its pharmacology,
Wherein:
-R
1Be phenyl or methyl;
-R
3Be chlorine;
-n is 0 or 1;
-R
5Be phenyl-CH
2-, furyl-CH
2-or-XR
6
-X is-CO-or-S (O)
2-; And
-R
6Be C
1-4Alkyl; Phenyl; Thienyl; Furyl; Pyridyl; Cyclopentyl; Cyclohexyl; Benzothienyl; Dihydro benzo furyl; Isoxazolyl; Piperidyl, for example N-piperidyl; Morpholinyl, for example N-morpholinyl; Piperazinyl, N-piperazinyl for example, or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-4Alkyl, cyclohexyl, cyclopentyl, phenyl or phenyl-CH
2-,
R
5And R
6Phenyl in the group, thienyl, furyl, pyridyl, cyclopentyl, cyclohexyl, benzothienyl, dihydro benzo furyl, isoxazolyl, piperidyl, morpholinyl and piperazinyl part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro.
In these especially preferred The compounds of this invention, " cyclohexyl in the group, cyclopentyl and phenyl moiety are not substituted or are replaced by a fluorine, chlorine, methyl, methoxyl group or nitro substituent for preferred R ' and R.
Comprise structural formula (I) compound of one or more chiral centres can enantiomer or the diastereisomericallypure pure form use, perhaps use with the mixture of isomers form.For fear of ambiguity, all steric isomers of compound shown in chemical structure described herein comprises comprise racemize and non-racemic mixture and pure enantiomer and/or pure diastereomer.
Preferred The compounds of this invention is an optically active isomer.Therefore, for example, comprise the preferred compound of the structural formula of a chiral centre (I) only and comprise the R enantiomer of pure form substantially, the S enantiomer of pure form and the enantiomeric mixture that comprises excessive R enantiomer or excessive S enantiomer substantially.For fear of ambiguity, if desired, structural formula (I) compound can solvate forms use.
On the pharmacology used herein acceptable salt be with pharmacology on the salt that forms of acceptable acid or alkali.Acceptable acid comprises mineral acid for example hydrochloric acid, sulfuric acid, phosphoric acid, tetra-sodium, Hydrogen bromide or nitric acid on the pharmacology, and organic acid for example citric acid, fumaric acid, toxilic acid, oxysuccinic acid, xitix, succsinic acid, tartrate, phenylformic acid, acetate, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid or tosic acid.Acceptable alkali comprises basic metal (for example sodium or potassium) and alkaline-earth metal (for example calcium or magnesium) oxyhydroxide and organic bases for example alkylamine, aralkylamine or heterocyclic amine on the pharmacology.
Especially preferred The compounds of this invention comprises:
1) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-ethanamide;
2) 1,1-diethyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
3) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-propionic acid amide;
4) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-butyramide;
5) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-isobutyramide;
6) 2,2-dimethyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-propionic acid amide;
7) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-cyclopentane formamide;
8) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-cyclohexane carboxamide;
9) 3-methoxyl group N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
10) 4-methoxyl group N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
11) 2-methoxyl group N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
12) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3-trifluoromethyl-benzamide;
13) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
14) thiophene-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepine-3-yl)-3-acid amides;
15) furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
16) piperidines-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
17) morpholine-4-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
18) 4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
19) 3-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
20) 4-methyl-piperazine-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
21) 3,4-two chloro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
22) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-2-trifluoromethyl-benzamide;
23) 4-bromo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
24) 2-methyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
25) 2-chloro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
26) 2-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
27) 2-methoxyl group-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
28) (S)-2-methoxyl group-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
29) benzo [b] thiophene-3-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
30) 2,3-dihydro-cumarone-5-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
31) isoxazole-5-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
32) benzo [b] thiophene-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
33) thiophene-3-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
34) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-Isonicotinamide;
35) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-niacinamide;
36) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-Toluidrin;
37) propane-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-sulphonamide;
38) butane-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-sulphonamide;
39) 2-bromo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzsulfamide;
40) 3-bromo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzsulfamide;
41) 4-bromo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzsulfamide;
42) 2-fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzsulfamide;
43) 3-(2-nitro-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone;
44) 3-(3-nitro-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone;
45) 3-(4-nitro-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone;
46) 3-(2-methoxyl group-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone;
47) 3-(3-methoxyl group-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone;
48) 5-phenyl-3-(2-trifluoromethyl-benzylamino)-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone;
49) 5-phenyl-3-(3-trifluoromethyl-benzylamino)-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone;
50) 5-phenyl-3-(4-trifluoromethyl-benzylamino)-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone;
51) 3-[(furans-2-ylmethyl)-amino]-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone;
52) N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-ethanamide;
53) N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-isobutyramide;
54) N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-Toluidrin;
55) furans-2-N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
56) thiophene-2-N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
57) N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-cyclohexane carboxamide;
58) N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-2-methoxyl group-benzamide;
59) N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-4-methoxyl group-benzamide;
60) N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-2-nitro-benzamide;
61) 2-(2-methoxyl group-phenyl) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-ethanamide;
62) 2-(3-methoxyl group-phenyl) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-ethanamide;
63) 2-(4-methoxyl group-phenyl) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-ethanamide;
64) 2-(4-nitro-phenyl) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-ethanamide;
65) 2-(3-nitro-phenyl) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-ethanamide;
66) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-2-(2-trifluoromethyl-phenyl)-ethanamide;
67) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-2-(3-trifluoromethyl-phenyl)-ethanamide;
68) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-2-(4-trifluoromethyl-phenyl)-ethanamide;
69) 1-(2-methoxyl group-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
70) 1-(2-nitro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
71) 1-(2-chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
72) 1-(4-chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
73) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3-right-tolyl-urea;
74) 1-(2-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
75) 1-(4-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
76) (S)-1-(2-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
77) 4-methylsulfonyl-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
78) (S)-4-methylsulfonyl-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
79) 5-ethanoyl-2-oxyethyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
80) (S)-5-ethanoyl-2-oxyethyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
81) 6-fluoro-4H-benzo [1,3] dioxine-8-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
82) (S)-6-fluoro-4H-benzo [1,3] dioxine-8-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
83) (S)-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-4-trifluoromethyl-benzamide;
84) 2,4,5-three fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
85) (S)-2,4,5-three fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
86) 2-hydroxy-n-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
87) (S)-2-hydroxy-n-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
88) 1H-indoles-7-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
89) (S)-1H-indoles-7-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
90) 3-methoxyl group-naphthalene-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
91) (S)-3-methoxyl group-naphthalene-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
92) N-[7-chloro-5-(2-fluoro-phenyl)-2-oxo-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-4-methoxyl group-benzamide;
93) 1-(2-fluoro-benzyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
94) 1-(4-methoxyl group-benzyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
95) 1-(3-methyl-benzyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
96) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3-(4-trifluoromethyl-phenyl)-urea;
97) 4-chloro-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
98) 4-methoxyl group-3-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl) benzamide;
99) 3-methoxyl group-2-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
100) 5-chloro-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl) benzamide;
101) 5-fluoro-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
102) 2-methoxyl group-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
103) 5-methoxyl group-2-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
104) 3-methoxyl group-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
105) 3-(2-methoxyl group-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl) propionic acid amide;
106) 3-(3-methoxyl group-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-propionic acid amide;
107) 3-(4-methoxyl group-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-propionic acid amide;
108) N-[5-(3-chloro-phenyl)-2-oxo-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-2-methoxyl group-benzamide;
109) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-4-methoxyl group-benzamide;
110) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-2-nitro-benzamide;
111) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-4-nitro-benzamide;
112) 4-methoxyl group-N-[2-oxo-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-benzamide;
113) 2-methoxyl group-N-[2-oxo-5-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-benzamide;
114) 4-methoxyl group-N-[2-oxo-5-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-benzamide;
115) 2-oxyethyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
116) 2,4-dimethoxy-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
117) 2-bromo-5-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
118) 2-methoxyl group-N-[5-(3-methoxyl group-phenyl)-2-oxo-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-benzamide
119) N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-4-nitro-benzamide;
120) 2-methoxyl group-N-(8-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
121) 2-chloro-4-methylsulfonyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
122) 2-dimethylamino-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
123) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzyl carbamate;
124) 1-(3,5-dimethyl-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
125) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3-(4-trifluoromethoxy-phenyl)-urea;
126) 1-(4-bromo-2-trifluoromethyl-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
127) 1-(4-bromo-benzyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
128) 1-(2,3-two chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
129) 1-(2,6-dimethyl-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
130) 1-(2-chloro-6-methyl-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
131) 1-(4-nitro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
132) 1-(2-methylthio group-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
133) 1-(2,6-two chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
134) the 5-tertiary butyl-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
135) 2,5-dimethoxy-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
136) 1-(2,6-two fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
137) 1-(3-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
138) 1-(3-methoxyl group-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
139) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3-(3-trifluoromethyl-phenyl)-urea;
140) 1-(3-chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
141) 2-methoxyl group-4-methylthio group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
142) 4-methylsulfonyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
143) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-to benzoyl amino acid methyl esters;
144) 2-fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
145) 2,6-two fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
146) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-2-propoxy--benzamide;
147) 2-iodo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
148) 3-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-to benzoyl amino acid methyl esters;
149) 4-amino-5-chloro-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-benzamide;
150) between 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3--tolyl-urea;
151) 2-methylthio group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-base-)-benzamide;
152) 2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-5-sulfamyl-benzamide;
153) 2-hydroxy-n-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3-phenyl-propionic acid amide;
154) 3-hydroxy-n-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3-phenyl-propionic acid amide;
155) 3-(2-fluoro-phenyl)-1-methyl isophthalic acid-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
156) 2-methoxyl group-N-methyl-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide;
157) the 1-tertiary butyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
158) 1-cyclohexyl (Cycloheyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
159) 1-ethyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
160) 1-butyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea;
161) 4,5-dimethyl-furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
162) piperidines-1-N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
163) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl] ethanamide;
164) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-isobutyramide;
165) furans-2-N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-methane amide;
166) thiophene-2-N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-methane amide;
167) N-[5-(3 chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-cyclohexane carboxamide;
168) piperidines-1-N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-methane amide;
169) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl] Isonicotinamide;
170) 5-methyl-furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
171) pyrazine-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
172) N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-isobutyramide;
173) thiophene-2-N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-methane amide;
174) N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-cyclohexane carboxamide;
175) piperidines-1-N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-methane amide;
176) piperidines-4-N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-methane amide;
177) N-(8-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-cyclohexane carboxamide;
178) thiophene-2-N-(8-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
179) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3-thiophene-2-base-urea;
180) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3-thiene-3-yl--urea;
181) pyridine-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
182) 1H-pyrazoles-4-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
183) 6-dimethylamino-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-niacinamide;
184) 2-oxyethyl group-naphthalene-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
185) 9-oxo-9H-fluorenes-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
186) 2-oxo-2,3-dihydro-benzoglyoxaline-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
187) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl) t-butyl carbamate;
188) (S)-4,5-two bromo-furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
189) (S)-cumarone-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide;
190) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-Urethylane;
191) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urethanum;
192) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-isobutyl carbamate; With
193) 2-oxo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-2-thiophene-2-base-ethanamide.
And acceptable salt on their pharmacology.
Structural formula (I) compound can be prepared as follows: pass through oxoethanoic acid (HCO-CO under the Dean-Stark condition
2H), benzotriazole and suitable benzyl carbamate in back flow reaction, obtain following important shielded structural formula (II) amino acid in toluene,
Then can be with structural formula (II) amino acid of therefore acquisition and suitable chlorizating agent (for example acyl chlorides) reaction, the 2-aminobenzophenone with following structural formula (III) reacts again,
What obtain is following intermediate structure formula (IV) acid amides,
It need not to characterize.
Structural formula (IV) compound is separated through ammonia then, then encircles closure in containing the acetate of ammonium acetate, obtains the benzodiazepine of following structure formula V protection,
The available then acetate that contains hydrogen bromide of structure formula V compound goes protection, and what obtain following structural formula (VI) removes to protect amine.
Structural formula (I) compound (R wherein
5Be XR
6And X is-CO-) can be by structural formula defined above (VI) compound and acid anhydrides prepared in reaction in appropriate solvent, this reacts preferred pyridine and carries out in ambient temperature; Perhaps have the alkali preparation with chloride of acid in appropriate solvent, this reaction preferably exists triethylamine to carry out in ambient temperature in THF.Perhaps, this compound can exist alkali and coupling agent prepared in reaction by structural formula (VI) compound and acid in appropriate solvent, this reaction preferably in THF, in ambient temperature, have triethylamine and O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU) carries out.
If the chloride of acid that uses is the amino-carbon acyl chlorides, then structural formula (I) compound is uncle's urea.
Work as R
6Be NH-R ' time, such compound can pass through structural formula (VI) compound and isocyanate reaction preparation.Reaction is preferably carried out in ambient temperature in THF.In addition, isocyanic ester can be reflected at alkali (being generally triethylamine) existence and carry out in THF down with corresponding amine and carbonyl chloride in-situ preparing.
Structural formula (I) compound (R wherein
5For-XR
6And X is-S (O)
2-) can pass through structural formula (VI) compound and suitable SULPHURYL CHLORIDE prepared in reaction.Similarly, structural formula (I) compound (R wherein
5Be XR
6And X is-S (O)-) can pass through structural formula (VI) compound and suitable sulphinyl chlorine prepared in reaction.
Structural formula (I) compound (R wherein
5Be not XR
6) can prepare by currently known methods.For example, structural formula (VI) compound can with formula R
5-L compound (wherein L is a leavings group, for example chlorine atom, methylsulfonic acid ester group or trifluoromethanesulfonic acid ester group) reaction.Work as R
5During for aryl or heteroaryl, L can be-B (OH)
2And this reaction can be carried out in the presence of neutralized verdigris.Those skilled in the art are familiar with this class boric acid coupled reaction certainly.R wherein
5For the compound of aryl or heteroaryl also can pass through the Buchwald prepared in reaction, perhaps by structural formula (VI) compound and suitable fluoro aryl or fluorine heteroaryl compound prepared in reaction.R wherein
5For the compound of heteroaryl also can pass through structural formula (VI) compound and suitable chlorine heteroaryl or bromine heteroaryl compound prepared in reaction.R wherein
5For the compound of carbocylic radical also can prepare by currently known methods, R wherein for example
5For the compound of cyclohexyl can pass through structural formula (VI) compound and pimelinketone prepared in reaction, there is reductive agent in reaction.
Structural formula (I) compound (R wherein
5Be aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-) also can pass through the preparation of structural formula (VI) compound and aldehyde reaction, there is reductive agent in reaction.Preferred being reflected between structural formula (VI) compound and the aldehyde of this class carried out, and is reflected in the mixture of methylene dichloride and acetate to exist (triacetyl oxygen base) sodium borohydride to carry out under ambient temperature.
In preparation benzodiazepine skeleton, can use under the situation about needing and be purchased structural formula (III) compound aminobenzophenone.The structural formula that can not be purchased (III) compound can prepare by currently known methods, for example Weinreb type acid amides and the R by following structural formula (VII)
1-Li group or Grignard reagent (R for example
1-MgBr) prepared in reaction.
Preferred this is reflected among the THF and carries out in-100 ℃.
Structural formula (VII) compound is known compound or can prepares by similar currently known methods.For example, the isatoic anhydride and the N of their available following structural formulas (VIII), the O-dimethyl hydroxylamine is prepared in reaction under the standard reaction condition.
Structural formula (II), (III), (VII) and starting raw material (VIII) are known compound, perhaps can be according to similar currently known methods preparation.
Can be by further synthetic structural formula (I) compound that so obtains of handling of ordinary method, so that obtain other structural formula (I) compound.The benzodiazepine of structural formula (I) can be with suitable acid or alkaline purification salify.
Although the approach to claimed compound introduction provides suitable synthetic method for bench scale preparation, also to determine to have the alternative route of production approach potentiality.Two kinds of methods are all used identical starting raw material (2-amino-benzophenone) (1), yet in alternative route, by bromoacetyl bromide (or equal reagent) starting reaction, encircle the closed benzodiazepine ring system that forms with ammoniacal liquor then.These are reflected at, and (for example methylene dichloride) carries out in suitable temperature (scope can be-20 ℃ to 150 ℃) in the appropriate solvent.In order to protect the NH functional group, in this stage, with unsubstituting phenenyl and diaza and alkali and alkylating agent reaction.For example sodium hydride is dissolved in DMF, adds 4-methoxyl group-benzyl chloride then, obtain the intermediate (2) that shows down.This material and alkali (for example potassium tert.-butoxide) is (for example THF or DMF) further reaction in appropriate solvent, use Isopentyl nitrite (or alternate similar reagents) cancellation then, obtain oxime intermediate (3), can be converted into the racemize primary amine with methods such as hydrogen and suitable catalyzer.With this amine process Dynamic Kinetic Resolution (DKR) step, the reaction of racemic amines exists suitable opticity acid and suitable aldehyde then, with high yield and unusual high required (S)-amine salt (4) precipitation of the excessive acquisition of enantiomerism.The suitable acid that is used for this conversion can be for example camphorsulfonic acid, Boc-phenylalanine etc., and suitable aldehyde can be phenyl aldehyde (for example 3,5-dichloro-salicylaldehyde).
Then, the optical amine that so forms is converted to required derivative (for example acid amides or urea).Acid amides forms and can use suitable carboxylic acid and coupling agent, perhaps carbonyl chloride or other suitable reagent, and the preparation urea is with suitable isocyanic ester, or selection and carbonyl chloride react then and suitable amine prepared in reaction.
Then, these derivatives that so form are removed protecting group.Reaction can exist under the Lewis acid (for example aluminum chloride, boron trifluoride, titanium tetrachloride etc.) to be finished.These are reflected in the suitable inert solvent (for example methylene dichloride) and carry out.Temperature of reaction can be-20 ℃ to 150 ℃, but carries out in room temperature or when being lower than room temperature usually.
As mentioned above, The compounds of this invention is effective anti-RSV compound.Therefore the present invention provides a kind of methods of treatment to the patient who suffers from or easily suffer from rsv infection, and this method comprises and gives acceptable salt on structural formula (I) compound of significant quantity or its pharmacology to described patient.
RSV is popular in below two years old among the infant.Especially the infant below two years old who suffers from chronic lung disease in serious threat.Therefore, described medicine is generally used for treating the ill children below two years old.Described children suffer from chronic lung disease usually.
In addition 32 weeks of gestation or the recommended for infants that are less than 32 week births are carried out anti-RSV prevention, till they have half years old.Therefore, described medicine is generally used for preventing 32 weeks of gestation or is less than the children's below 6 years old of 32 weeks birth rsv infection.
Have been found that rsv infection with inflammatory reaction (Noah et al, ClinicalImmunology 2000, Vol 97,43-49).The invention still further relates to the combination medicine of acceptable salt and anti-inflammatory compound on structural formula (I) compound or its pharmacology, and use this combination medicine treatment RSV.Described anti-inflammatory compound is generally steroide, for example budesonide or fluticasone; Non-steroids, for example leukotriene antagonist, phosphodiesterase 4 inhibitors or TNF alpha inhibitor or interleukin 8 or interleukin 9 inhibitor.
Therefore, in one embodiment, acceptable salt associating steroid anti-inflammatory compound, for example budesonide or fluticasone on structural formula (I) compound or its pharmacology.In a preferred embodiment, steroide is given with low dosage and is minimized immunosuppressive action.In a further embodiment, acceptable salt associating non-steroidal anti-inflammatory compounds on structural formula (I) compound or its pharmacology, for example Singulair (Merck) or Accolate (Astra Zeneca) of leukotriene antagonist for example, phosphodiesterase 4 inhibitors is roflumilast (Altana) for example, the TNF alpha inhibitor is Enbrel (Amgen), Remicade (Centocor), Humira (Abbott) or CDP870 (Celltech) for example, or NSAIDS.In further embodiment, structural formula (I) compound associating interleukin 8 or interleukin 9 inhibitor.Therefore the present invention also relates to the product that comprises acceptable salt and anti-inflammatory compound on structural formula (I) compound or its pharmacology, its simultaneously, the independent or sequential RSV that is used for the treatment of.
The invention still further relates to the combination medicine of acceptable salt and anti influenza compound on structural formula (I) compound or its pharmacology, use RSV and influenza infection that this combination medicine treatment occurs together.Therefore the present invention also relates to the product that comprises acceptable salt and anti influenza compound on structural formula (I) compound or its pharmacology, its simultaneously, independent or sequential RSV and the influenza infection that occurs together that be used for the treatment of.
Further wonderful discovery is, The compounds of this invention can effectively anti-people's parapneumonia after virus, measles, parainfluenza virus and parotitis.Therefore the present invention provides acceptable salt purposes on virus, measles, parainfluenza virus and the parotitis medicine after preparation is used for the treatment of people's parapneumonia on structural formula (I) compound or its pharmacology.Wonderful in addition discovery is, The compounds of this invention can effectively anti-yellow fever virus (B5 virus strain), singapore hemorrhagic fever 2 C-type virus Cs and west Nile virus.Therefore the present invention provides acceptable salt on structural formula (I) compound or its pharmacology to be used for the treatment of purposes on yellow fever virus (B5 virus strain), singapore hemorrhagic fever 2 C-type virus Cs and the west Nile virus medicine in preparation.
The compounds of this invention can give by different dosage form.Therefore, their Orally-administrables, but for example tablet, dragee, lozenge, water suspension or oil suspension dispersion powder or granule.But The compounds of this invention is administered parenterally also, no matter be in subcutaneous, intravenously, intramuscular, the breastbone, transdermal or infusion administration.Described compound also can the suppository administration.
In a preferred embodiment, The compounds of this invention interior or interior administration of segmental bronchus by nose.The present invention also provides sucker or the atomizer that comprises following composition medicine: (a) acceptable salt and (b) acceptable carrier or thinner on the pharmacology on the benzodiazepine derivative of structural formula defined above (I) or its pharmacology.
The present invention also provides a kind of medicinal compositions, and it comprises on described benzodiazepine derivative or its pharmacology acceptable carrier or thinner on the acceptable salt and pharmacology.
Described medicinal compositions preferably comprises the The compounds of this invention of 85wt% at the most.More preferably comprise the The compounds of this invention of 50wt% at the most.Preferred medicinal compositions is aseptic and does not contain pyrogeneous substance.In addition, medicinal compositions provided by the invention comprises the The compounds of this invention that is substantially pure optical isomer usually.
The compounds of this invention usually with pharmacology on acceptable carrier or thinner prepare and give.For example, the Peroral solid dosage form type can comprise the thinner with active compound, for example lactose, glucose, sucrose, Mierocrystalline cellulose, W-Gum or yam starch; Lubricant, for example silicon-dioxide, talcum powder, stearic acid, Magnesium Stearate or calcium and/or polyoxyethylene glycol; Tackiness agent, for example starch, Sudan Gum-arabic, gelatin, methylcellulose gum, carboxymethyl cellulose or polyvinylpyrrolidone; Disintegrating agent, for example starch, Lalgine, alginate or sodium starch glycolate; Foaming mixtures; Dyestuff; Sweeting agent; Wetting agent, for example Yelkin TTS, polysorbate, lauryl sulfate; And normally used nontoxic and pharmacology inactive substance in the medicine preparation.Such pharmaceutical preparation can be used currently known methods production, for example, and by mixing, granulation, compressing tablet, sweet tablet or coating method preparation.
Oral liquid dispersant can be syrup, emulsion and suspensoid.Syrup can comprise carrier, for example, and sucrose or sucrose and glycerol and/or mannitol and/or sorbyl alcohol.
Suspensoid and emulsion can comprise carrier, for example natural gum, agar, sodiun alginate, pectin, methylcellulose gum, carboxymethyl cellulose or polyvinyl alcohol.The suspensoid of intramuscularly or solution can comprise acceptable carrier on the pharmacology of active compound, for example the Xylotox (if necessary) of sterilized water, sweet oil, ethyl oleate, di-alcohols (as propylene glycol) and appropriate amount.
The solution of injection or infusion can comprise carrier, and for example, sterilized water perhaps is preferably the sterile isotonic salt brine solution.
The patient is treated the The compounds of this invention of significant quantity.According to the frequency and the approach of the activity of specific compound, the type that will treat patient's age, body weight and individual state, disease and severity and administration, typical doses is about 0.001-50mg/kg (body weight).Preferably every day, dosage level was 5mg-2g.
The benzodiazepine derivative of some structural formula (I) is essentially novel cpd.The present invention includes acceptable salt on these novel cpds and its pharmacology.Therefore the present invention also provides acceptable salt on following structural formula (Ib) compound and its pharmacology,
Wherein:
-R
1Represent C
1-6Alkyl, aryl or heteroaryl;
-R
2Represent hydrogen, C
1-6Alkyl;
-each R
3Identical or different and represent halogen, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group ,-CO
2R ' ,-CONR ' R " ,-NH-CO-R ' ,-S (O) R ' ,-S (O)
2R ' ,-NH-S (O)
2R ' ,-S (O) NR ' R " or-S (O)
2NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen or C
1-6Alkyl;
-n is 0-3;
-R
4Represent hydrogen or C
1-6Alkyl;
-R
5 'Represent C
3-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-, carbocylic radical-C (O)-C (O)-, heterocyclic radical-C (O)-C (O)-or-X ', precondition is to work as R
5 'During for heteroaryl, it is not the quinaldine based or 6-chloro-pyrazinyl of 2-, works as R
5 'Be heteroaryl-(C
1-6Alkyl)-time, it is not 2-indyl methyl, 2-(3-indyl) ethyl or 2-furyl methyl, works as R
5 'During for aryl, it is not unsubstituted phenyl, and works as R
5 'Be aryl-(C
1-6Alkyl)-time, it is not unsubstituted phenyl-(C
1-2Alkyl)-or 4-chloro-phenyl--(C
2-3Alkyl)-;
-X ' representative-CO-R
6 ',-S (O)-R
6 "Or-S (O)
2-R
6
-R
6Represent C
1Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-, precondition is (a) to work as R
6 'During for aryl, it is not unsubstituted naphthyl, unsubstituted phenyl, phenyl-monohalide base, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 4-hydroxy phenyl, 4-trifluoromethyl, 4-nitrophenyl, 4-cyano-phenyl, 4-n-propyl phenyl, 4-tert-butyl-phenyl, 4-n-pentyl phenyl, 4-dimethylaminophenyl, 4-methylthio group phenyl, 3-trifluoromethylthio phenyl, 3,4-Dimethoxyphenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3,4,5,6-pentafluorophenyl group, 4-chloro-2-aminophenyl or 4-1,1-dimethyl ethyl phenyl (b) is worked as R
6 'During for heteroaryl, it is not that 2-pyrryl, 2-pyrazinyl, 2-are quinaldine based, 2-quinoxalinyl, 1-methyl indone base (1-methylindonly), 2-methyl-indyl, 2-benzofuryl, 2-benzothienyl, 3-thienyl, 3-indyl, unsubstituted 2-indyl, 5-fluoro indole-2-base, 5-chloro-indole-2-base, 5-bromo indole-2-base, 5-oxyindole-2-base or 5-methoxyl group indoles-2-base, (c) works as R
6 'Be aryl-(C
1-6Alkyl)-time, it is not 4-benzo-thiophene-(CH
2)-, unsubstituted phenyl-(CH
2)-, 4-trifluoromethyl-(CH
2)-, unsubstituted phenyl-(CH
2)
3-, single trifluoromethyl-(CH
2)
2-, 3-p-methoxy-phenyl-(CH
2)
2-, 4-chloro-2-aminophenyl-(CH
2)
2-, 2,4 dichloro benzene base-(CH
2)
2-, mono chloro benzene base-(CH
2)
2-, 2,4-trifluoromethyl-(CH
2)
2-, 4-cyano-phenyl-(CH
2)
2-or 3-cyano-phenyl-(CH
2)
2-, (d) work as R
6 'Be heteroaryl-(C
1-6Alkyl)-time, it is not indyl-(CH of 1-3 for x
2)
x-, unsubstituted furyl-(CH
2)
2-, unsubstituted thienyl-(CH
2)
3-, (e) work as R
6 'During for carbocylic radical, it is not a cyclohexyl, (f) works as R
6 'Be carbocylic radical-(C
1-6Alkyl)-time, it is not unsubstituted cyclohexyl-(CH
2)
1-3-, (g) work as R
6 'During for heterocyclic radical, it is not N-pyrrolidyl or 2-dihydro benzo furyl, (h) works as R
6 'Be aryl-(C
1-6Alkyl)-during O-, it is not unsubstituted phenyl-(CH
2)-O-, and (i) when R ' is hydrogen, R " is not unsubstituted phenyl, 4-halogenophenyl, 3-halogenophenyl, p-methoxy-phenyl, nitrophenyl, 2-chloro-phenyl-, 4-aminomethyl phenyl, dichlorophenyl, 3; 5-3,5-dimethylphenyl, 3-aminomethyl phenyl, 3-cyano-phenyl, 3-aminophenyl, 3-aminocarbonyl-phenyl, 3-phenylformic acid, 3-ethyl benzoate, 6-amino-3-pyridyl, 5-(2-chlorine) pyridyl, 5-(2-methoxyl group) pyridyl, 5-indanyl, unsubstituted cyclohexyl, 1,1-dimethyl ethyl, unsubstituted phenyl-CH
2-, unsubstituted naphthyl or benzotriazole-3-base, when R ' was methyl, R " was not a cyclopropyl-phenyl;
-R
6 "Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-; And
-R
6 Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-, precondition is to work as R
6 During for aryl, it is not the 4-aminomethyl phenyl, and precondition is that structural formula (Ib) compound is not N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-ethanamide.
In structural formula (Ib), preferred
-each R
3Identical or different and represent halogen, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group ,-CO
2R ' ,-CONR ' R " ,-NH-CO-R ' ,-S (O) R ' ,-S (O)
2R ' ,-NH-S (O)
2R ' or-S (O) NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen or C
1-6Alkyl;
-R
5 'Represent C
2-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-X ', precondition is to work as R
5 'During for heteroaryl, it is not the quinaldine based or 6-chloro-pyrazinyl of 2-, and works as R
5 'Be heteroaryl-(C
1-6Alkyl)-time, it is not 2-indyl methyl or 2-(3-indyl) ethyl;
-X ' representative-CO-R
6 ',-S (O)-R
6 "Or-S (O)
2-R
6
-R
6 'Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-or heteroaryl-(C
1-6Alkyl)-, precondition is that (a) works as R
6 'During for aryl, it is not unsubstituted naphthyl, unsubstituted phenyl, phenyl-monohalide base, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 4-hydroxy phenyl, 4-trifluoromethyl, 4-nitrophenyl, 4-cyano-phenyl, 4-n-propyl phenyl, 4-tert-butyl-phenyl, 4-n-pentyl phenyl, 4-dimethylaminophenyl, 4-methylthio group phenyl, 3-trifluoromethylthio phenyl, 3,4-Dimethoxyphenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl or 2,3,4,5, the 6-pentafluorophenyl group (b) is worked as R
6 'During for heteroaryl, it is not that 2-pyrryl, 2-pyrazinyl, 2-are quinaldine based, 2-methyl-indyl, 2-benzofuryl, 2-benzothienyl, 3-thienyl, 3-indyl, unsubstituted 2-indyl, 5-fluoro indole-2-base, 5-chloro-indole-2-base, 5-bromo indole-2-base, 5-oxyindole-2-base or 5-methoxyl group indoles-2-base, (c) works as R
6 'Be aryl-(C
1-6Alkyl)-time, it is not 4-benzo-thiophene-(CH
2)-, (d) works as R
6 'Be heteroaryl-(C
1-6Alkyl)-time, it is not-indyl-(CH
2)
x-, wherein x is 1-3, (e) when R ' is hydrogen, R " be not 4-halogenophenyl, 3-aminomethyl phenyl, 3-cyano-phenyl, 3-aminophenyl, 3-aminocarbonyl-phenyl, 3-phenylformic acid, 3-ethyl benzoate, 6-amino-3-pyridyl, 5-(2-chlorine) pyridyl, 5-(2-methoxyl group) pyridyl, 5-indanyl or benzotriazole-3-base;
-R
6 "Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-or heteroaryl-(C
1-6Alkyl)-; And
-R
6 Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-or heteroaryl-(C
1-6Alkyl)-, precondition is to work as R
6 During for aryl, it is not the 4-aminomethyl phenyl.
R in the preferred structure formula (Ib)
1, R
2, R
3And R
4Group comprises R in the said structure formula (I)
1, R
2, R
3And R
4Preferred group.Preferred structure formula (Ib) compound comprises especially preferred structural formula listed above (I) compound.
In structural formula (Ib), R
2Be generally hydrogen.
Preferred structure formula (Ib) compound is these compounds, wherein:
-R
5 'Represent C
3-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl) ,-aryl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-, carbocylic radical-C (O)-C (O)-, heterocyclic radical-C (O)-C (O)-or-X ', precondition is to work as R
5 'During for heteroaryl, it is not quinaldine based or pyrazinyl, works as R
5 'Be heteroaryl-(C
1-6Alkyl)-time, it is not indyl-(CH
2)
x-, wherein x is 1 or 2, perhaps furyl methyl is worked as R
5 'During for aryl, it is not a phenyl, and works as R
5 'Be aryl-(C
1-6Alkyl)-time, it is not phenyl-(C
1-3Alkyl)-;
-X ' representative-CO-R
6 ',-S (O)-R
6 "Or-S (O)
2-R
6
-R
6 'Represent C
1Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-, precondition is that (a) works as R
6 'During for aryl, it is not a phenyl or naphthyl, (b) works as R
6 'During for heteroaryl, it is not thienyl, pyrryl, pyrazinyl, quinaldine based, quinoline oxazolidinyl, indyl, benzofuryl or benzothienyl,
(c) work as R
6 'Be aryl-(C
1-6Alkyl)-time, it is not benzo-thiophene-(CH
2)-or phenyl-(CH
2)
1-3-,
(d) work as R
6 'Be heteroaryl-(C
1-6Alkyl)-time, it is not indyl-(CH
2)
x-(wherein x is 1-3), thienyl-(CH
2)
3-or furyl-(CH
2)
2-, (e) work as R
6 'During for carbocylic radical, it is not a cyclohexyl ,-, (f) work as R
6 'During for heterocyclic radical, it is not pyrrolidyl or dihydro benzo furyl, (g) works as R
6 'Be carbocylic radical-(C
1-6Alkyl)-time, it is not cyclohexyl-(C
1-3Alkyl)-, (h) work as R
6 'Be aryl-(C
1-6Alkyl)-during O-, it is not phenyl-(CH
2)-O-and (i) when R ' is hydrogen, R " is not phenyl, pyridyl, indanyl, C
4Alkyl, cyclohexyl (cyclohenyl), naphthyl, phenyl-CH
2-, the benzotriazole base, and when R ' was methyl, R " was not a cyclopropyl-phenyl;
-R
6 "Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-; And
-R
6 Represent C
1-18Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or NR ' R ", wherein each R ' and R " are identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-, precondition is to work as R
6 During for aryl, it is not an aminomethyl phenyl.
Preferred structure formula (Ib) examples for compounds is and above-mentioned preferred structure formula (Ib) compound defines identical compound, wherein:
-R
5 'Represent C
2-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-X ', precondition is to work as R
5 'During for heteroaryl, it is not quinaldine based or pyrazinyl, and works as R
5 'Be heteroaryl-(C
1-6Alkyl)-time, it is not indyl-(CH
2)
x-, wherein x is 1 or 2;
-R
6 'Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-or heteroaryl-(C
1-6Alkyl)-, precondition is that (a) works as R
6 'During for aryl, it is not a phenyl or naphthyl, (b) works as R
6 'During for heteroaryl, it is not thienyl, pyrryl, pyrazinyl, quinaldine based, indyl, benzofuryl or benzothienyl, (c) works as R
6 'Be aryl-(C
1-6Alkyl)-time, it is not benzo-thiophene-(CH
2)-, (d) works as R
6 'Be heteroaryl-(C
1-6Alkyl)-time, it is not indyl-(CH
2)
x-, wherein x is 1-3, (e) when R ' is hydrogen, R " is not phenyl, pyridyl, indanyl or benzotriazole base;
-R
6 "Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-or heteroaryl-(C
1-6Alkyl)-; And
-R
6 Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-or heteroaryl-(C
1-6Alkyl)-, precondition is to work as R
6 During for aryl, it is not an aminomethyl phenyl.
Further the compound of preferred structure formula (Ib) is these compounds, wherein:
-R
5 'Be C
3-6Alkyl, C
3-6Cycloalkyl, heterocyclic radical, C
3-6Cycloalkyl-(C
1-6Alkyl), aryl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-, carbocylic radical-C (O)-C (O)-, heterocyclic radical-C (O)-C (O)-or-X ';
-X ' is-CO-R
6 ',-S (O)-R
6 "Or-S (O)
2-R
6
-R
6 'Be C
1Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, C
3-6Cycloalkyl, heterocyclic radical, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-;
-R
6 "Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-3Alkyl, heterocyclic radical, heteroaryl, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-; And
-R
6 Be C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkyl, heterocyclic radical, C
3-6Cycloalkyl-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl), carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-.
Further preferred structure formula (Ib) examples for compounds is and the identical compound of further preferred structure formula (Ib) compound definition, wherein:
-R
5 'Be C
2-6Alkyl, C
3-6Cycloalkyl, heterocyclic radical, C
3-6Cycloalkyl-(C
1-6Alkyl), heterocyclic radical-(C
1-6Alkyl) or-X ';
-X ' is-CO-R
6 ',-S (O)-R
6 "Or-S (O)
2-R
6
-R
6 'Be C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkyl, heterocyclic radical, C
3-6Cycloalkyl-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, C
3-6Cycloalkyl or heterocyclic radical;
-R
6 "Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR ' R " wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-or heteroaryl-(C
1-6Alkyl)-; And
-R
6 Be C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkyl, heterocyclic radical, C
3-6Cycloalkyl-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-or heteroaryl-(C
1-6Alkyl)-.
In described further preferred construction formula (Ib) compound, preferred R
5 ', R
6 ', R
6 "And R
6 Cycloalkyl in the group, heterocyclic radical and carbocylic radical part are not substituted or are selected from following substituting group by 1-3 and replace: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro and cyano group,
In described further preferred construction formula (Ib) compound, more preferably " cycloalkyl in the group, heterocyclic radical, carbocylic radical, aryl and heteroaryl moieties are not substituted or are selected from following substituting group by 1-3 and replace: halogen, C for R ' and R
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro and cyano group.
In described further preferred construction formula (Ib) compound, preferred R
5 ', R
6 ', R
6 "And R
6 Cycloalkyl in the group, heterocyclic radical and carbocylic radical part are not substituted or are selected from following substituting group by 1-3 and replace: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro and cyano group,
In described further preferred construction formula (Ib) compound, more preferably " cycloalkyl in the group, heterocyclic radical, carbocylic radical, aryl and heteroaryl moieties are not substituted or are selected from following substituting group by 1-3 and replace: halogen, C for R ' and R
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro and cyano group.
Especially preferred novel cpd of the present invention is an acceptable salt on following structural formula (Ic) compound and its pharmacology,
Wherein:
-R
1Be phenyl or methyl;
-R
3Be methyl or chlorine;
-n is 0 or 1;
-R
4Be hydrogen or methyl;
-R
5 'Be phenyl-CH
2-thienyl-C (O)-C (O)-or-X ';
-X ' is-CO-R
6 ',-CONR ' R " ,-S (O)
2R
6 Or-S (O)
2-NR ' R "; And
-R
6 'Be C
1Alkyl, C
1-4Alkoxyl group, benzo dioxine base, 9H-fluorenes-9-ketone group, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, cyclopentyl, piperazinyl, piperidyl, morpholinyl, phenyl-CH
2-CH (OH)-, phenyl-CH (OH)-CH
2-, phenyl-(C
2Alkyl)-O-or 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group;
-R
6 Be C
1-4Alkyl, C
1-4Alkoxyl group, phenyl, naphthyl, dihydro benzo furyl, benzo dioxine base, 9H-fluorenes-9-ketone group, indyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl, benzofuryl, cyclopentyl, cyclohexyl, piperazinyl, piperidyl, morpholinyl, phenyl-(C
1-2Alkyl)-, phenyl-CH
2-CH (OH)-, phenyl-CH (OH)-CH
2-, phenyl-(C
1-2Alkyl)-O-or 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group;
-each R ' and R is " identical or different and represent hydrogen, C
1-4Alkyl, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl-(CH
2)-; And
-each R ' and R is " identical or different and represent hydrogen, C
1-4Alkyl, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl-(CH
2)-, be wherein:
R
1Be not substituted in the phenyl moiety in the group or replaced: fluorine, chlorine, C by a following substituting group
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl or C
1-2Halogenated alkoxy
R
5 ', R
6 'And R
6 Aryl moiety in the group is not substituted or is selected from following substituting group by 1-3 and replaces: fluorine, chlorine, bromine, iodine, C
1-4Alkyl, C
2-4Acyl group, hydroxyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-6Haloalkyl, C
1-4Halogenated alkoxy, amino, (a C
1-4Alkyl) amino, two (C
1-4Alkyl) amino, nitro ,-CO
2R ' ,-S (O) R ' and-S (O)
2NH
2, wherein R ' represents C
1-2Alkyl;
R
5 ', R
6 'And R
6 Heteroaryl moieties in the group is not substituted or is selected from following substituting group by 1-2 and replaces: fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Haloalkyl and two (C
1-2Alkyl) amino;
R
6 Heterocyclic radical in the group and carbocylic radical part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro;
R ' and R " in aryl, heteroaryl and the carbocylic radical part is not substituted or be selected from following substituting group by 1-2 replaces: fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl and nitro; And
R ' and R " in aryl, heteroaryl and the carbocylic radical part is not substituted or be selected from following substituting group by 1-2 replaces: fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl and nitro, precondition are that structural formula (Ic) compound is not N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-ethanamide.
The example of especially preferred novel cpd of the present invention is an acceptable salt on following structural formula (Ic ') compound and its pharmacology,
Wherein:
-R
1Be phenyl or methyl;
-R
3Be chlorine;
-n is 0 or 1;
-R
5 'Be phenyl-CH
2-, furyl-CH
2-or-X ';
-X ' is-CO-R
6 ',-CO-NR ' R " ,-S (O)
2-R
6 Or-S (O)
2-NR ' R ";
-R
6 'Be C
1-4Alkyl; The 2-thienyl; Furyl; Pyridyl; Cyclopentyl; Cyclohexyl; The 3-benzothienyl; Dihydro benzo furyl; Isoxazolyl; Piperidyl, for example N-piperidyl; Morpholinyl, for example N-morpholinyl; Piperazinyl, for example N-piperazinyl;
-R
6 Be C
1-4Alkyl; Phenyl; Thienyl; Furyl; Pyridyl; Cyclopentyl; Cyclohexyl; Benzothienyl; Dihydro benzo furyl; Isoxazolyl; Piperidyl, for example N-piperidyl; Morpholinyl, for example N-morpholinyl; Or piperazinyl, for example N-piperazinyl;
-each R ' and R ' are identical or different and represent hydrogen, C
1-4Alkyl, cyclohexyl, cyclopentyl, phenyl or phenyl-CH
2-, and
-each R ' and R is " identical or different and represent hydrogen, C
1-4Alkyl, cyclohexyl, cyclopentyl, phenyl or phenyl-CH
2-,
R
5And R
6 'Phenyl in the group, thienyl, furyl, pyridyl, cyclopentyl, cyclohexyl, benzothienyl, dihydro benzo furyl, isoxazolyl, piperidyl, morpholinyl and piperazinyl part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro,
R
6 Thienyl in the group, furyl, pyridyl, cyclopentyl, cyclohexyl, benzothienyl, dihydro benzo furyl, isoxazolyl, piperidyl, morpholinyl and piperazinyl part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro,
R
6 Phenyl moiety in the group is not substituted or is selected from following substituting group by 1-2 and replaces: fluorine, chlorine, bromine, C
2-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro,
R ' and R " cyclohexyl in the group and cyclopentyl part are not substituted or are replaced by a fluorine, chlorine, methyl, methoxyl group or nitro substituent,
R ' and R " phenyl moiety in the group is not substituted or is replaced by a methoxyl group or nitro substituent, and
" phenyl in the group, cyclohexyl and cyclopentyl part are not substituted or are replaced by a fluorine, chlorine, methyl, methoxyl group or nitro substituent for R ' and R.
Further preferred novel cpd of the present invention is an acceptable salt on structural formula (Ic) compound and its pharmacology, wherein:
-R
5 'For-X ';
-X ' is-CO-R
6 ',-CO-NR ' R " ,-S (O)
2-R
6 Or-S (O)
2-NR ' R ";
-R
6 'Be C
1-4Alkyl; Pyridyl; Cyclopentyl; Cyclohexyl; Dihydro benzo furyl; Isoxazolyl; Piperidyl, for example N-piperidyl; Morpholinyl, for example N-morpholinyl; Piperazinyl, for example N-piperazinyl;
-R
6 Be C
1-4Alkyl; Pyridyl; Cyclopentyl; Cyclohexyl; Dihydro benzo furyl; Isoxazolyl; Piperidyl, for example N-piperidyl; Morpholinyl, for example N-morpholinyl; Piperazinyl, for example N-piperazinyl;
-each R ' and R is " identical or different and represent hydrogen, C
1-4Alkyl, cyclohexyl or cyclopentyl; And
-each R ' and R is " identical or different and represent hydrogen, C
1-4Alkyl, cyclohexyl, cyclopentyl, phenyl or phenyl-CH
2-,
R
6 'And R
6 Pyridyl in the group, cyclopentyl, cyclohexyl, dihydro benzo furyl, isoxazolyl, piperidyl, morpholinyl, piperazinyl part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro, and
Phenyl in R ', R ", R ' and the R " group, cyclohexyl and cyclopentyl part are not substituted or are replaced by a fluorine, chlorine, methyl, methoxyl group or nitro substituent.
Further preferred novel cpd of the present invention is an acceptable salt on following structural formula (Id) compound and its pharmacology,
R wherein
6*Be aryl, it is not substituted or is selected from following substituting group by 1-3 and replaces: halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino ,-CO
2R ' ,-CONR ' R " ,-S (O) R ' ,-S (O)
2R ' ,-S (O) NR ' R " ,-S (O)
2NR ' R " NH-S (O)
2R ' or-NH-CO-R ', wherein each R ' and R are " identical or different and represent hydrogen or C
1-6Alkyl, precondition are R
6*It is not the 4-chloro-phenyl-.
In structural formula (Id) compound, R
6*Be generally phenyl, it is not substituted or is selected from following substituting group by 1-3 and replaces: halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group ,-CO
2R ' ,-S (O) R ' ,-S (O)
2R ' and-S (O)
2NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen or C
1-4Alkyl, precondition are R
6*It is not the 4-halogenophenyl.
In structural formula (Id) compound, preferred R
6*Be phenyl, it is not substituted or is selected from following substituting group by 1-3 and replaces: fluorine, chlorine, bromine, iodine, C
1-4Alkyl, C
2-4Acyl group, hydroxyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, C
1-4Halogenated alkoxy, amino, (a C
1-4Alkyl) amino, two (C
1-4Alkyl) amino, nitro ,-CO
2R ' ,-S (O)
2R ' and-S (O)
2NH
2, wherein R ' represents C
1-2Alkyl, precondition are R
6*It is not the phenyl-monohalide base.
In structural formula (Id) compound, more preferably R
6*Be phenyl, it is not substituted or is selected from following substituting group by 1-2 and replaces: C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl, C
1-2Halogenated alkoxy and nitro.
Acceptable salt on compound that further preferred novel cpd of the present invention is a following structural formula (Ie) and the pharmacology thereof,
R wherein
' *Be aryl, it is not substituted or is selected from following substituting group by 1-2 and replaces: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, C
1-4Halogenated alkoxy and nitro.
In structural formula (Ie) compound, preferred
R ' *Be phenyl, it is not substituted or is selected from following substituting group by 1-2 and replaces: fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl and nitro.
In structural formula (Ie) compound, more preferably
R ' *Unsubstituted phenyl or the phenyl that is replaced by a fluorine, chlorine or bromine substituting group.
The invention still further relates to that acceptable salt is used for the treatment of in the method for human or animal body on novel cpd defined above or its pharmacology.The invention still further relates to the medicinal compositions that comprises acceptable diluent on novel cpd defined above and the pharmacology or carrier.Preferred medicinal compositions comprises acceptable salt on the pharmacology of novel cpd defined above.The definition of acceptable salt is the same on the pharmacology.Novel cpd of the present invention gives in mode defined above usually, and described compound is prepared at administering mode defined above usually.
Preferred medicinal compositions comprises the optically active isomer of novel cpd of the present invention.Therefore, for example, the novel cpd of the present invention that preferably only contains a chiral centre comprises the R enantiomer of pure form substantially, the S enantiomer of pure form and the enantiomeric mixture that comprises excessive R enantiomer or excessive S enantiomer substantially.Especially preferably the medicinal compositions that comprises the The compounds of this invention that is substantially pure optically active isomer.For fear of ambiguity, if desired, novel cpd of the present invention can solvate forms use.
The following example illustrates the present invention.Yet they do not limit the present invention in any way.In this, importantly understand the fc-specific test FC that embodiment partly uses and only be used to show anti-RSV activity, many tests can be used to measure the anti-RSV activity of given compound, thereby the negative findings in any one concrete mensuration is not conclusive.
Embodiment
In this section, all temperature are with a ℃ expression.Flash column chromatography carries out with Merck 9385 silicon-dioxide.Solid-Phase Extraction (SPE) chromatography is carried out with gradient elution progressively under the 15mmHg vacuum with Jones chromatography (Si) post.Tlc (TLC) is carried out on plastic plate.
The LC-MS condition
Sample moves on MicroMass ZMD with detecting sun-anionic electron spray(ES) simultaneously.
Post: YMC-PACK FL-ODS AQ, 50 * 4.6mm I.D S-5 μ m.
Gradient: 95: 5-5: 95v/v H
2O/CH
3CN+0.05% formic acid (4.0 minutes) continues 3 minutes, gets back to 95: 5v/v H
2O/CH
3CN+0.05% formic acid (0.2 minute) keeps 95: 5v/vH
2O/CH
3CN+0.05% formic acid (3 minutes).
Detect and survey: PDA250-340mm.
Flow velocity: 1.5ml/ minute
Preparation intermediate 1
Benzotriazole-1-base-benzyloxycarbonyl amino-acetate
The mixture of oxoethanoic acid monohydrate (4.60g), benzotriazole (5.95g) and benzyl carbamate (7.55g) was refluxed 18 hours in being heated in toluene (100ml) under the Dean-Stark condition.Then mixture is cooled to room temperature, filters and collect the gained throw out.Use diethyl ether recrystallization gained throw out then, obtain Off-white solid (11.66g)
1H?NMR(d6?DMSO，δ)5.07(q+s，3H)7.25(d，1H)7.3-7.63(m，6H)7.92-8.10(m，2H)9.32(d，1H)
LC/MS measured value ES-=325RT=4.68 minute
Preparation intermediate 2
(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzyl carbamate
Cooling (0 ℃) solution that intermediate 1 (11.6g) is dissolved in dry THF (100ml) stirs under nitrogen atmosphere, splashes into the solution-treated that oxalyl chloride (4.4g) is dissolved in dry methylene chloride (50ml) then, then handles with dry dimethyl formamide (2ml).Stir the gained mixture 2 hours, and used 2-(amino-phenyl)-phenyl-ketone (6.1g) and N-methylmorpholine (7.07g) to be dissolved in the solution-treated 30 minutes of dry THF (50ml) then.Reaction mixture is warming up to room temperature, removes by filter inorganic salt.Mother liquor is handled and lasting the stirring 18 hours with the methanol solution (100ml) of 7M ammonia.Evaporating solvent, resistates distributes between ethyl acetate and 1M sodium hydroxide.The extract of evaporation drying is dissolved in raw oil the acetate (200ml) that comprises ammonium acetate (13.4g).Mixture was in stirring at room 18 hours.Evaporating solvent is suspended in ethyl acetate with resistates: diethyl ether (1: 3) (200ml) in.Add 1M sodium hydroxide until pH=8, mixture is cooled to 0-5 ℃ then, filter and collect the solid (6.94g) that produces.
1H?NMR(d6?DMSO，δ)5.05(s，1H)5.09(m，2H)7.25-7.69(m，14H)8.38(d，1H)10.85(s，1H)
LC/MS measured value ES+=386RT=5.46 minute
Preparation intermediate 3
3-amino-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone
Intermediate 2 (1.07g) is dissolved in 48% hydrobromic acetate (30ml) post-heating to 70 ℃ 30 minutes.Cooling mixture is with diethyl ether (30ml) dilution.Filter and collect the yellow solid that forms.Then this material is distributed between ethyl acetate and 1M solution of potassium carbonate.Evaporate behind the dry extract, the oil that obtains is ground with diethyl ether, obtain Off-white solid (0.35g).
1H?NMR(d6?DMSO，δ)4.25(s，1H)7.17-7.66(m，9H)10.65(brs，1H)
LC/MS RT=3.23 minute, but do not have associating molion.
Preparation intermediate 4
[benzotriazole-1-base (2-benzoyl-4-chloro-phenyl amino formyl radical)-methyl]-benzyl carbamate
By the chloride of acid of the method for introducing previously with 5g intermediate 1 preparation intermediate 1.The chloride of acid that makes is dissolved in the stirred solution of THF (40ml) in 0 ℃ of adding (2-amino-5-chloro-phenyl)-phenyl-ketone (3.48g) and N-methylmorpholine (3.1g).Then mixture is warming up to room temperature, stirred 1 hour.Remove by filter throw out, obtain the gumminess solid behind the evaporating solvent, directly use to need not to purify or characterize.
Preparation intermediate 5
(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzyl carbamate
The methanol solution (100ml) that intermediate 4 is dissolved in 7M ammonia was in stirring at room 5 hours.Evaporating solvent, resistates distributes between ethyl acetate and 1M sodium hydroxide.The organic layer of evaporation drying is dissolved in resistates the acetate (200ml) that comprises ammonium acetate (5.8g).The gained mixture is in stirring at room 18 hours, evaporating solvent then.Water-soluble and the ethyl acetate with resistates, with sodium hydroxide with pH regulator to about 8.The organic extract of evaporation drying is used the diethyl ether grinding residues, obtains beige solid (3.27g).
LC/MS measured value ES+=420,422 (C
23H
13ClN
3O
3=419.5)
Preparation intermediate 6
3-amino-7-chloro-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone
The solution that intermediate 5 (3.25g) is dissolved in the acetate (85ml) of 45% hydrogen bromide be heated to 70 ℃ 2 hours.Cooling mixture dilutes with diethyl ether then.Filter the hydrobromide salt that obtains title compound, dry back obtains bright yellow solid (2.7g)
NMR(δ，d6?DMSO)5.18(d，1H)7.32(d，1H)7.40(d，1H)?7.47-7.53(m，5H)7.77(dd，1H)9.07(brs，2H)11.41(s，1H)
Preparation intermediate 7
[(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-base formamyl)-phenyl-methyl]-t-butyl carbamate.
With intermediate 3 (34.9g), (S)-2-t-butoxycarbonyl amino-3-phenyl-propionic acid (55.3g), triethylamine (100ml) and O-benzotriazole-1-base-N, N, N ', the solution that N '-tetramethyl-urea hexafluorophosphate (116g) is dissolved in methylene dichloride (1000ml) stirred 18 hours under room temperature and nitrogen atmosphere.Evaporating solvent then, resistates distributes between 10% citric acid solution and ethyl acetate.Organic phase is further washed after drying (MgSO with 2M sodium hydroxide, water and salt solution
4).The evaporation organic phase obtains oily matter, need not to purify to be used for following step.
LC/MS RT=5.98 minute, measured value ES
+=498
1H?NMR(DMSO，δ)1.29(s，9H)2.72-2.84(m，1H)，3.05-3.18(m，1H)，4.32-4.44(m，1H)，5.20-5.25(m，1H)，6.97-7.05(m，1H)，7.16-7.68(m，14H)，9.17-9.21(d，1H)，10.90(s，1H)。
Preparation intermediate 8
2-amino-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-2-phenyl-ethanamide.
Ethyl acetate (1L) cooling (10 ℃) solution with the disposable adding HCl of intermediate 7 (81.94g) (34g).Reactant stirred 1 hour in this temperature, be warming up to 20 ℃ after restir 2 hours.Cool off reactant to 0 ℃ then, add entry (300mL) with the speed that keeps temperature to be lower than 10 ℃.(2 * 150mL) washing water layers return water layer to reaction flask to use ethyl acetate then.Reactant is cooled to 0 ℃ once more, adds strong aqua until pH=9.0 with the speed that keeps temperature to be lower than 5 ℃.(5 * 150mL) washing reaction things, the organic extract with salt solution (100mL) washing merges with evaporating solvent after the dried over mgso, produces yellow oil with ethyl acetate.The ethyl acetate solution of yellow oil and 5% methyl alcohol is stirred fast up to forming the heavy-gravity white depositions.Filtering precipitate, the revaporization mother liquor.The natural gum of remnants and the ethyl acetate of 5% methyl alcohol are stirred once more up to forming the thickness throw out.This program is repeated several times.By TLC (SiO
2, DCM: EtOH: NH
3, 200: 8: 1) and excessive to throw out analysis each time with the evaluation diastereomer.Every kind of diastereomer that each batch is pure or pure is substantially placed on one side, mixture at first is dissolved in the dichloromethane mixture of 5% methyl alcohol, returns the settling step of evaporation stage then.Each batch comprised pure or pure substantially required diastereomer (R
f=0.25, higher spot) merges and in the ethyl acetate of 5% methyl alcohol, stir and made slurries in 10 minutes, filter then, produce required diastereomer (＞99%d.e.) white powder pure sample product (26.1g).
LC/MS RT=3.83 minute measured value ES
+=399
1H?NMR(CDCl
3，δ)1.36(bs，2H)，2.72(dd，1H，)，3.24(dd，1H，)，3.63(dd，1H，)，5.46(d，1H，)，7.44-7.03(m，14H)，8.43(s，1H)，8.79(d，1H，)。
Preparation intermediate 9
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-2-phenyl-2-(3-phenyl-thioureido)-ethanamide
The solution that intermediate 8 (26.1g) is dissolved in methylene dichloride (500ml) is handled with isocyanide sulfenyl-benzene (14.7g), and mixture was in stirring at room 18 hours.Evaporation removes and desolvates and excess reagent, and resistates is dissolved in methylene dichloride, collects with gasoline dilution after-filtration, obtains colorless solid (36.1g)
LC/MS measured value ES-=532RT=5.47 minute
1H?NMR(CDCl
3，δ)3.83-5.0(m，2H)，5.58-6.87(m，2H)，6.68(d，1H)，6.89-7.40(m，19H)，7.56(d，1H)，8.20(bs，1H)，9.52(bs，1H)。
Preparation intermediate 10
(S)-and 3-amino-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone
(24g) is heated to 50C with intermediate 9, uses trifluoroacetic acid (64ml) to handle then.Stirred the mixture fast 40 minutes, and be evaporated to driedly then, obtain yellow oil.This material is purified through silica gel chromatography.Use methylene dichloride: methyl alcohol: acetate: water; 90: 10: 1: 1 wash-out obtained the acetate (13.1g) of the described amine of light yellow spumescence.
LC/MS RT=3.64 minute measured value ES
+=252
1H?NMR(CDCl
3，δ)2.17(s，3H)4.68(brs，1H)6.98-7.47(m，9H)9.56(brs，1H)10.68(brs，1H)
The free alkali of this material can followingly be emanated.This material of 0.5g is dissolved in methylene dichloride (1ml) back adding 0.880 ammoniacal liquor (1ml) makes its alkalization, filter and collect after drying, obtain colourless throw out (380mg)
Embodiment 1
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-ethanamide
The solution that intermediate 3 (300mg) is dissolved in pyridine (5ml) is handled with diacetyl oxide (183mg).Mixture evaporates after 1.5 hours in stirring at room.Resistates distributes between water and methylene dichloride.Use the sherwood oil grinding residues behind the extract of evaporation drying, obtain colorless solid title compound (231mg)
LC/MS RT=3.82 minute measured value ES-=292
NMR(δ，d6?DMSO)1.99(s，3H)5.25(d，1H)7.21-7.66(m，9H)9.06(s，1H)10.81(s，1H)
Embodiment 2
1,1-diethyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
(100mg) is dissolved in the methylene dichloride that comprises diisopropylethylamine (62mg) with intermediate 3: dimethyl formamide (9: 1; Solution 2ml) is handled with diethylamino formyl chloride (0.05ml).The gained mixture was stirred 18 hours under room temperature and nitrogen atmosphere, between water and methylene dichloride, distribute then.The evaporation organic extract, resistates is purified through silica gel SPE post.With the eluent ethyl acetate that contains 10% methyl alcohol, obtain colorless solid title compound (34mg).
LC/MS RT=4.37 minute measured value ES+=351
1H?NMR(d6?DMSO，δ)1.11(t，6H)2.50(br，4H)5.20(d，1H)6.83(d，1H)7.20-7.66(m，9H)10.78(brs，1H)
Embodiment 3
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-propionic acid amide
This material only is to use propionyl chloride (0.035ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (11mg)
LC/MS RT=4.03 minute measured value ES+=308
1H?NMR(d6?DMSO，δ)1.03(t，3H)2.31(q，2H)5.26(d，1H)7.20-7.67(m，9H)8.94(d，1H)10.80(s，1H)
Embodiment 4
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-butyramide
This material only is to use butyryl chloride (0.041ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (31mg)
LC/MS RT=4.31 minute measured value ES+=320
1H?NMR(d6?DMSO，δ)0.90(brt，3H)1.55(br，2H)2.27(brq，2H)5.26(brd，1H)7.20-7.70(m，9H)8.95(brd，1H)10.80(s，1H)
Embodiment 5
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-isobutyramide
This material only is to use isobutyryl chloride (41ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (35mg)
LC/MS RT=4.30 minute measured value ES+=322
1H NMR (d6 DMSO, δ) 1.03 (d, 6H) 2.72 (septet, 1H) 5.23 (d, 1H) 7.20-7.68 (m, 9H) 8.90 (d, 1H) 10.77 (brs, 1H)
Embodiment 6
2,2-dimethyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-propionic acid amide
This material only is to use 2,2-dimethyl propylene acyl chlorides (0.049ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (22mg)
LC/MS RT=4.74 minute measured value ES+=336
1H?NMR(d6?DMSO，δ)1.20(s，9H)5.23(d，1H)7.20-7.68(m，9H)8.22(d，1H)10.80(br，1H)
Embodiment 7
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-cyclopentane formamide
This material only is to use pentamethylene carbonyl chloride (0.048ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (40mg).
LC/MS RT=4.81 minute measured value ES+=348
1H?NMR(d6?DMSO，δ)1.48-1.90(m，8H)2.89(m，1H)5.24(d，1H)7.20-7.68(m，9H)8.90(d，1H)10.77(brs，1H)
Embodiment 8
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-cyclohexane carboxamide
This material only is to use hexanaphthene carbonyl chloride (0.053ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (57mg).
LC/MS RT=5.54 minute measured value ES+=362
1H?NMR(d6?DMSO，δ)1.10-1.43(5H)1.60-1.82(m，5H)2.44(m，1H)5.22(d，1H)7.20-7.67(m，9H)8.81(d，1H)10.75(s，1H)
Embodiment 9
3-methoxyl group N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material only is to use 3-methoxyl group-Benzoyl chloride (0.056ml) with the method preparation that embodiment 1 introduces.Obtain colorless solid title compound (23mg).
LC/MS RT=5.10 minute measured value ES+=386
1H?NMR(d6?DMSO，δ)3.84(s，3H)5.51(d，1H)7.11-7.71(m，13H)9.51(d，1H)10.87(s，1H)
Embodiment 10
4-methoxyl group N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material only is to use 4-methoxyl group-Benzoyl chloride (68mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (60mg).
LC/MS RT=5.00 minute measured value ES+=386
1H?NMR(d6?DMSO，δ)3.83(s，3H)?5.50(d，1H)7.02(d，2H)7.21-7.79(m，9H)8.02(d，2H)9.28(d，1H)10.85(s，1H)
Embodiment 11
2-methoxyl group N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material only is to use 2-methoxyl group-Benzoyl chloride (0.059ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (69mg).
LC/MS RT=5.12 minute measured value ES+=386
1H?NMR(d6?DMSO，δ)4.05(s，3H)5.44(d，1H)7.11(t，1H)7.24-7.70(m，11H)7.97(dd，1H)9.50(d，1H)10.97(s，1H)
Embodiment 12
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3-trifluoromethyl-benzamide
This material only is to use 3-trifluoromethyl-Benzoyl chloride (0.06ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (88mg).
LC/MS RT=5.27 minute measured value ES+=424
1H?NMR(d6?DMSO，δ)5.41(d，1H)7.22-7.82(m，13H)9.71(d，1H)10.86(brs，1H)
Embodiment 13
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material only is to use Benzoyl chloride (0.046ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (41mg).
LC/MS RT=4.96 minute measured value ES+=356
1H?NMR(d6?DMSO，δ)5.51(d，1H)7.22-7.70(m，12H)8.03(m，2H)9.44(d，1H)10.87(s，1H)
Embodiment 14
Thiophene-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepine-3-yl)-3-acid amides
This material only is to use thiophene-2-carbonyl chloride (0.043ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (81mg).
LC/MS RT=4.87 minute measured value ES+=362
1H?NMR(d6?DMSO，δ)5.46(d，1H)7.19-7.82(m，11H)8.20(m，1H)9.57(d，1H)10.88(s，1H)
Embodiment 15
Furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
This material only is to use furans-2-carbonyl chloride (0.039ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (17mg).
LC/MS RT=4.53 minute measured value ES+=346
1H?NMR(d6?DMSO，δ)5.42(d，1H)6.68(m，1H)7.24-7.70(m，10H)7.90(m，1H)9.02(d，1H)10.95(s，1H)
Embodiment 16
Piperidines-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
This material only is to use piperidines-1-carbonyl chloride (0.049ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (34mg).
LC/MS RT=4.47 minute measured value ES+=363
1H?NMR(d6?DMSO，δ)1.40-1.62(m，6H)3.36-3.42(m，4H)5.21(d，1H)7.20-7.67(m，10H)10.76(s，1H)
Embodiment 17
Morpholine-4-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
This material only is to use morpholine-4-carbonyl chloride (0.046ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (22mg).
LC/MS RT=3.88 minute measured value ES+=365
1H?NMR(d6?DMSO，δ)3.36-3.42(m，4H)3.55-3.62(m，4H)5.21(d，1H)7.22-7.67(m，10H)10.80(s，1H)
Embodiment 18
4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material only is to use 4-nitro-Benzoyl chloride (74mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (90mg).
LC/MS RT=5.25 minute measured value ES+=401
1H?NMR(d6?DMSO，δ)5.50(d，1H)7.23-7.70(m，9H)8.25(d，2H)8.33(d，2H)9.94(d，1H)10.92(s，1H)
Embodiment 19
3-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material only is to use 3-nitro-Benzoyl chloride (74mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (94g).
LC/MS RT=5.25 minute measured value ES+=401
1H?NMR(d6?DMSO，δ)5.51(d，1H)7.22-7.85(m，10H)8.40-8.48(m，2H)8.86(m，1H)10.06(d，1H)10.91(s，1H)
Embodiment 20
4-methyl-piperazine-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
This material only is to use 4-methyl isophthalic acid-piperazine carbonyl chloride (79mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (35mg).
LC/MS RT=3.29 minute measured value ES-=376
1H?NMR(d6?DMSO，δ)2.19(s，3H)2.28(m，4H)3.40(m，4H)5.19(d，1H)7.19-7.65(m，10H)10.75(s，1H)
Embodiment 21
3,4-two chloro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material only is to use 3,4-two chloro-Benzoyl chlorides (83mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (42mg).
LC/MS RT=3.29 minute measured value ES+=424,426
1H?NMR(d6?DMSO，δ)5.48(d，1H)7.22-7.70(m，9H)7.78(d，1H)7.98(dd，1H)8.31(d，1H)9.82(d，1H)10.91(s，1H)
Embodiment 22
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-2-trifluoromethyl-benzamide
This material only is to use 2-trifluoromethyl-Benzoyl chloride (83mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (90mg).
LC/MS RT=5.47 minute measured value ES+=424
1H?NMR(d6?DMSO，δ)5.41(d，1H)7.25-7.83(m，13H)9.81(d，1H)10.93(s，1H)
Embodiment 23
4-bromo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material only is to use 4-bromo-Benzoyl chloride (87mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (159mg).
LC/MS RT=5.76 minute measured value ES+=434,436
1H?NMR(d6?DMSO，δ)5.5(d，1H)7.23-7.68(m，9H)7.72(d，2H)7.98(d，2H)9.7(d，1H)10.94(s，1H)
Embodiment 24
2-methyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material only is to use 2-methyl-Benzoyl chloride (62mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (113mg).
LC/MS RT=5.29 minute measured value ES+=370
1H?NMR(d6?DMSO，δ)2.42(s，3H)5.45(d，1H)7.23-7.55(m，12H)7.65(dt，1H)9.39(d，1H)10.90(s，1H)
Embodiment 25
2-chloro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material only is to use 2-chloro-Benzoyl chloride (70mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (108mg).
LC/MS RT=5.28 minute measured value ES+=390,392
1H?NMR(d6?DMSO，δ)5.43(d，1H)7.26-7.7(m，13H)9.71(d，1H)10.94(s，1H)
Embodiment 26
2-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material only is to use 2-nitro-Benzoyl chloride (74mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (50mg).
LC/MS RT=4.94 minute measured value ES+=401
1H?NMR(d6?DMSO，δ)5.42(d，1H)7.25-7.89(m，12H)8.07(d，1H)10.05(d，1H)10.96(s，1H)
Embodiment 27a
2-methoxyl group-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
With intermediate 3 (40mg), 2-methoxyl group-4-nitro-phenylformic acid (47mg), triethylamine (0.07ml) and O-benzotriazole-1-base-N, N, N ', the N '-mixture of tetramethyl-urea hexafluorophosphate (121mg) in dry tetrahydrofuran (3ml) stirred 18 hours under 20 ℃ and nitrogen atmosphere.Then mixture is distributed between solution of potassium carbonate and methylene dichloride.Organic phase is evaporated after by the Hydrophobic glass strainer.Resistates is purified through silica gel SPE post.Earlier use the methylene dichloride wash-out, use methylene dichloride then: ethanol: 0.880 ammoniacal liquor; Earlier with 400 then with 200: 8: 1 wash-outs, the oil of acquisition grinds with diethyl ether, obtains colorless solid title compound (51mg).
LC/MS RT=5.28 minute measured value ES+=431
1H?NMR(CDCl
3，δ)4.09(s，3H)5.69(d，1H)7.08-7.49(m，9H)7.80-7.86(m，2H)8.27(s，1H)8.31(s，1H)9.52(d，1H)
Embodiment 27b
(S)-2-methoxyl group-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material just replaces intermediate 3 with intermediate 10 with the method preparation that embodiment 27 introduces, and obtains colorless solid title compound (37mg)
1H?NMR(DMSO，δ)4.13(s，3H)5.44(d，1H)7.29-7.70(m，9H)7.97-8.10.(m，3H)9.63(d，1H)11.05(s，1H)
Embodiment 28
Benzo [b] thiophene-3-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
This material only is to use benzo [b] thiophene-3-carbonyl chloride (39mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (60mg).
LC/MS RT=5.85 minute measured value ES+=412
1H?NMR(d6?DMSO，δ)5.57(d，1H)7.27-7.71(m，11H)8.06(m，1H)8.47(m，1H)8.83(s，1H)9.57(d，1H)10.95(s，1H)
Embodiment 29
2,3-dihydro-cumarone-5-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
This material only is to use 2,3-dihydro-cumarone-5-carbonyl chloride (36mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (75mg).
LC/MS RT=5.16 minute measured value ES+=398
1H?NMR(d6?DMSO，δ)3.24(t，2H)4.61(t，2H)5.48(d，1H)6.84(d，1H)7.22-7.95(m，11H)9.25(d，1H)10.89(s，1H)
Embodiment 30
Isoxazole-5-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
This material only is to use isoxazole-5-carbonyl chloride (26mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (22mg).
LC/MS RT=4.58 minute measured value ES+=347
1H?NMR(d6?DMSO，δ)5.44(d，1H)7.23-7.72(m，10H)8.80(d，1H)9.98(d，1H)11.03(s，1H)
Embodiment 31
Benzo [b] thiophene-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
This material only is to use benzo [b] thiophene-2-carbonyl chloride (39mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (33mg).
LC/MS RT=5.90 minute measured value ES+=412
1H?NMR(d6?DMSO，δ)5.49(d，1H)7.25-7.72(m，11H)7.95-8.07(m，2H)8.56(s，1H)9.92(d，1H)10.96(s，1H)
Embodiment 32
Thiophene-3-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
This material only is to use thiophene-3-carbonyl chloride (29mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (30mg).
LC/MS RT=4.96 minute measured value ES+=362
1H?NMR(d6?DMSO，δ)5.47(d，1H)7.23-7.70(m，11H)8.48(m，1H)9.40(d，1H)10.91(s，1H)
Embodiment 33
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-Isonicotinamide
This material only is to use different nicotinoyl chlorine hydrochloride (71mg) and super normal triethylamine with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (22mg).
LC/MS RT=3.98 minute measured value ES+=357
1H?NMR(d6?DMSO，δ)5.50(d，1H)7.24-7.70(m，9H)7.93(d，2H)8.76(d，2H)9.89(d，1H)10.91(s，1H)
Embodiment 34
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-niacinamide
This material only is to use nicotinoyl chlorine hydrochloride and super normal triethylamine with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (16mg).
LC/MS RT=3.90 minute measured value ES+=357
1H?NMR(d6?DMSO，δ)5.51(d，1H)?7.23-7.70(m，10H)8.37(ddd，1H)8.75(dd，1H)9.15(d，1H)9.90(d，1H)10.93(s，1H)
Embodiment 35
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-Toluidrin
This material only is to use methylsulfonyl chloride (0.031ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (40mg).
LC/MS RT=4.20 minute measured value ES+=330
1H?NMR(d6?DMSO，δ)3.13(s，3H)4.81(brd，1H)7.22-7.70(m，9H)8.43(brd，1H)10.95(brs，1H)
Embodiment 36
Propane-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-sulphonamide
This material only is to use propane-1-SULPHURYL CHLORIDE (0.054ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (56mg).
LC/MS RT=4.79 minute measured value ES+=358
1H?NMR(d6?DMSO，δ)1.03(t，3H)1.84(m，2H)3.14(t，2H)4.79(d，1H)7.23-7.69(m，9H)8.49(d，1H)10.94(s，1H)
Embodiment 37
Butane-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-sulphonamide
This material only is to use butane-1-SULPHURYL CHLORIDE (0.062ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (30mg).
LC/MS RT=5.18 minute measured value ES+=372
1H?NMR(d6?DMSO，δ)0.93(t，3H)1.44(m，2H)1.80(m，2H)3.14(t，2H)4.78(brd，1H)7.21-7.68(m，9H)8.47(brd，1H)10.94(brs，1H)
Embodiment 38
2-bromo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzsulfamide
This material only is to use 2-bromo-benzene sulfonyl chloride (122mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (137mg).
LC/MS RT=5.53 minute measured value ES+=470,472
1H?NMR(d6?DMSO，δ)4.95(s，1H)7.03-7.71(m，12H)7.88(m，1H)8.22(m，1H)8.70(br，1H)11.04(s，1H)
Embodiment 39
3-bromo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzsulfamide
This material only is to use 3-bromo-benzene sulfonyl chloride (122mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (90mg).
LC/MS RT=5.63 minute measured value ES+=470,472
1H?NMR(d6?DMSO，δ)4.81(s，1H)6.89(m，2H)7.20-7.70(m，9H)7.82(m，1H)7.94(m，1H)9.3(br，1H)10.97(s，1H)
Embodiment 40
4-bromo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzsulfamide
This material only is to use 4-bromo-benzene sulfonyl chloride (122mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (130mg).
LC/MS RT=5.66 minute measured value ES+=470,472
1H?NMR(d6?DMSO，δ)4.80(brd，1H)6.75(m，2H)7.20-7.70(m，7H)7.78-7.91(m，4H)9.40(brd，1H)10.95s，1H)
Embodiment 41
2-fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzsulfamide
This material only is to use 2-fluoro-benzene sulfonyl chloride (93mg) with the method preparation that embodiment 1 introduces.Obtain colorless solid title compound (140mg).
LC/MS RT=5.26 minute measured value ES+=410
1H?NMR(d6?DMSO，δ)4.94(d，1H)7.07(m，2H)7.23-7.97(m，11H)9.36(d，1H)10.97(s，1H)
Embodiment 42
3-(2-nitro-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone
The solution that intermediate 3 (50mg) and (triacetyl oxygen base) sodium borohydride (106mg) is dissolved in methylene dichloride (6ml) and acetate (1ml) is handled with 2-nitro-phenyl aldehyde (45mg).The gained mixture stirred under nitrogen atmosphere 18 hours.The careful saturated sodium bicarbonate solution that adds is used the dichloromethane extraction mixture.Organic layer evaporates then by the Hydrophobic glass strainer.Resistates is purified through silica gel SPE post.With the gasoline gradient elution of 10-18% ethyl acetate, obtain colorless solid title compound (33mg)
LC/MS RT=4.83 minute measured value ES+=387
1H?NMR(d6?DMSO，δ)3.4(br，1H)4.17(brs，1H)4.31(q，2H)7.15-7.95(m，13H)10.74(s，1H)
Embodiment 43
3-(3-nitro-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone
This material only is to use 3-nitro-phenyl aldehyde (45mg) with the method preparation that embodiment 42 introduces.Obtain colorless solid title compound (32mg).
LC/MS RT=4.95 minute measured value ES+=387
1H?NMR(d6?DMSO，δ)3.45(br，1H)4.16(brs，1H)4.23(brm，2H)7.15-7.63(m，10H)7.85(d，1H)8.08(dd，1H)8.30(s，1H)10.76(s，1H)
Embodiment 44
3-(4-nitro-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone
This material only is to use 4-nitro-phenyl aldehyde (45mg) with the method preparation that embodiment 42 introduces.Obtain colorless solid title compound (33mg).
LC/MS RT=4.88 minute measured value ES+=387
1H?NMR(d6?DMSO，δ)3.42(br，1H)4.11-4.30(brm，3H)7.16-7.63(m，9H)7.70(d，2H)8.20(d，2H)10.77(s，1H)
Embodiment 45
3-(2-methoxyl group-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone
This material only is to use 2-methoxyl group-phenyl aldehyde (41mg) with the method preparation that embodiment 42 introduces.Obtain colorless solid title compound (48mg).
LC/MS RT=4.95 minute measured value ES+=372
1H?NMR(d6?DMSO，δ)3.73(s，3H)3.97(q，2H)4.17(s，1H)6.85-6.96(m，2H)7.15-7.63(m，11H)10.72(s，1H)
Embodiment 46
3-(3-methoxyl group-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone
This material only is to use 3-methoxyl group-phenyl aldehyde (41mg) with the method preparation that embodiment 42 introduces.Obtain colorless solid title compound (43g).
LC/MS RT=5.03 minute measured value ES+=372
1H?NMR(d6?DMSO，δ)3.71(s，3H)3.81-4.18(m，3H)6.74(m，1H)6.80-6.86(m，2H)7.15-7.64(m，10H)10.74(s，1H)
Embodiment 47
5-phenyl-3-(2-trifluoromethyl-benzylamino)-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone
This material only is to use 2-trifluoromethyl-phenyl aldehyde (52mg) with the method preparation that embodiment 42 introduces.Obtain colorless solid title compound (29mg).
LC/MS RT=5.02 minute measured value ES+=410
1H?NMR(d6?DMSO，δ)4.18(s，1H)4.23(brs，2H)7.15-7.70(m，12H)7.91(d，1H)10.76(s，1H)
Embodiment 48
5-phenyl-3-(3-trifluoromethyl-benzylamino)-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone
This material only is to use 3-trifluoromethyl-phenyl aldehyde (52mg) with the method preparation that embodiment 42 introduces.Obtain colorless solid title compound (34mg).
LC/MS RT=5.28 minute measured value ES-=408
1H?NMR(d6?DMSO，δ)4.12(q，2H)4.18(s，1H)?7.15-7.78(m，13H)10.74(s，1H)
Embodiment 49
5-phenyl-3-(4-trifluoromethyl-benzylamino)-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone
This material only is to use 4-trifluoromethyl-phenyl aldehyde (52mg) with the method preparation that embodiment 42 introduces.Obtain colorless solid title compound (25mg).
LC/MS RT=5.27 minute measured value ES-=408
1H?NMR(d6?DMSO，δ)4.13(q，2H)4.20(s，1H)7.15-7.70(m，13H)10.76(s，1H)
Embodiment 50
3-[(furans-2-ylmethyl)-amino]-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza -2-ketone
This material only is to use 2-furfural (29mg) with the method preparation that embodiment 42 introduces.Obtain colorless solid title compound (56mg).
LC/MS RT=4.07 minute measured value ES+=332
1H?NMR(d6?DMSO，δ)3.05(m，1H)3.80-4.13(m，2H)4.18(d，1H)6.19(brs，1H)6.32(brs，1H)7.15-7.65(m，10H)
Embodiment 51
N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-ethanamide
This material only is to use intermediate 6 (57mg) with the method preparation that embodiment 1 introduces.Obtain colorless solid title compound (17mg).
LC/MS RT=4.21 minute measured value ES+=328,330
1H?NMR(d6?DMSO，δ)3.34(s，3H)5.26(d，1H)7.28-7.31(m，2H)7.31-7.58(m，5H)7.71(dd，1H)9.14(d，1H)10.96(s，1H)
Embodiment 52
N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-isobutyramide
This material only is to use intermediate 6 and isobutyl chloride (0.021ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (49mg).
LC/MS RT=4.78 minute measured value ES+=356,358
1H NMR (d6 DMSO, δ) 1.04 (d, 6H) 2.72 (septet, 1H) 5.27 (d, 1H) 7.29-7.55 (m, 7H) 7.71 (dd, 1H) 9.00 (d, 1H) 10.92 (s, 1H)
Embodiment 53
N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-Toluidrin
This material only is to use intermediate 6 and methylsulfonyl chloride (0.015ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (18mg).
LC/MS RT=4.61 minute measured value ES+=364,366
1H?NMR(d6?DMSO，δ)3.13(s，3H)4.85(brd，1H)7.29-7.58(m，7H)7.71(dd，1H)8.46(brd，1H)11.04(brs，1H)
Embodiment 54
Furans-2-N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
This material only is to use intermediate 6 and 2-furans carbonyl chloride (0.020ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (50mg).
LC/MS RT=5.07 minute measured value ES+=380,382
1H?NMR(d6?DMSO，δ)5.45(d，1H)6.68(m，1H)7.28-7.70(m，7H)7.73(dd，1H)7.91(m，1H)9.15(d，1H)11.07(s，1H)
Embodiment 55
Thiophene-2-N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
This material only is to use intermediate 6 and 2 thiophen carbonyl chloride (0.021ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (49mg).
LC/MS RT=5.40 minute measured value ES+=396,398
1H?NMR(d6?DMSO，δ)5.49(d，1H)7.22-7.83(m，10H)8.21(dd，1H)9.67(d，1H)11.04(s，1H)
Embodiment 56
N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-cyclohexane carboxamide
This material only is to use intermediate 6 and hexanaphthene carbonyl chloride (0.027) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (52mg).
LC/MS RT=5.61 minute measured value ES+=396,398
1H?NMR(d6?DMSO，δ)1.2-1.33(m，5H)1.60-1.83(m，5H)2.45(m，1H)5.25(d，1H)7.27-7.73(m，8H)8.93(d，1H)10.92(s，1H)
Embodiment 57
N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-2-methoxyl group-benzamide
This material only is to use intermediate 6 and 2-methoxyl group-Benzoyl chloride (0.030ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (55mg).
LC/MS RT=5.58 minute measured value ES+=420,422
1H?NMR(d6?DMSO，δ)4.05(s，3H)5.47(d，1H)7.12(t，1H)7.25-7.61(m，9H)7.72(dd，1H)7.98(dd，1H)9.54(d，1H)11.14(s，1H)
Embodiment 58
N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-4-methoxyl group-benzamide
This material only is to use intermediate 6 and 4-methoxyl group-Benzoyl chloride (0.027ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (61mg).
LC/MS RT=5.48 minute measured value ES+=420,422
1H?NMR(d6?DMSO，δ)3.84(s，3H)5.53(d，1H)7.03(d，2H)7.31-7.59(m，8H)8.04(d，2H)9.39(d，1H)11.01(s，1H)
Embodiment 59
N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-2-nitro-benzamide
This material only is to use intermediate 6 and 2-nitro-Benzoyl chloride (0.027) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (61mg).
LC/MS RT=5.25 minute measured value ES+=435,437
1H?NMR(d6?DMSO，δ)5.45(d，1H)7.36-7.88(m，11H)8.07*d，1H)10.03(d，1H)11.03(s，1H)
Embodiment 60
2-(2-methoxyl group-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-ethanamide
This material only is to use (2-methoxyl group-phenyl)-Acetyl Chloride 98Min. (33mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (13mg).
LC/MS RT=4.98 minute measured value ES+=400
1H?NMR(d6?DMSO，δ)3.63(s，2H)3.79(s，3H)5.25(d，1H)6.89-6.99(m，2H)7.20-7.33(m，5H)7.45-7.68(m，6H)9.01(d，1H)10.87(s，1H)
Embodiment 61
2-(3-methoxyl group-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-ethanamide
This material only is to use (3-methoxyl group-phenyl)-Acetyl Chloride 98Min. (33mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (12mg).
LC/MS RT=4.95 minute measured value ES+=400
1H?NMR(d6?DMSO，δ)3.62(m，2H)3.75(s，3H)5.23(d，1H)6.78-6.96(m，3H)7.19-7.70(m，10H)9.33(d，1H)10.86(s，1H)
Embodiment 62
2-(4-methoxyl group-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-ethanamide
This material only is to use (4-methoxyl group-phenyl)-Acetyl Chloride 98Min. (33mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (20mg).
LC/MS RT=4.86 minute measured value ES+=400
1H?NMR(d6?DMSO，δ)3.58(s，2H)3.73(s，3H)5.22(d，1H)6.87(d，2H)7.23-7.71(m，11H)9.25(d，1H)10.85(s，1H)
Embodiment 63
2-(4-nitro-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-ethanamide
This material only is to use (4-nitro-phenyl)-Acetyl Chloride 98Min. (36mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (18mg).
LC/MS RT=5.03 minute measured value ES+=415
1H?NMR(d6?DMSO，δ)3.86(s，2H)5.24(d，1H)7.24-7.70(m，11H)8.19(d，2H)9.53(d，1H)10.88(s，1H)
Embodiment 64
2-(3-nitro-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-ethanamide
This material only is to use (3-nitro-phenyl)-Acetyl Chloride 98Min. (36mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (25mg).
LC/MS RT=5.02 minute measured value ES+=415
1H?NMR(d6?DMSO，δ)3.86(s，2H)5.24(d，1H)7.24-7.67(m，10H)7.89(d，1H)8.12(dd，1H)8.26(s，1H)9.53(d，1H)10.89(s，1H)
Embodiment 65
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-2-(2-trifluoromethyl-phenyl)-ethanamide
This material only is to use (2-trifluoromethyl-phenyl)-Acetyl Chloride 98Min. (41mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (9mg).
LC/MS RT=5.43 minute measured value ES+=438
1H?NMR(d6?DMSO，δ)3.92(s，2H)5.26(d，1H)7.24-7.70(m，13H)9.41(d，1H)10.87(s，1H)
Embodiment 66
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-2-(3-trifluoromethyl-phenyl)-ethanamide
This material only is to use 3-trifluoromethyl-phenyl with the method preparation that embodiment 2 introduces)-Acetyl Chloride 98Min. (41mg).Obtain colorless solid title compound (20mg).
LC/MS RT=5.56 minute measured value ES+=438
1H?NMR(d6?DMSO，δ)3.80(s，2H)5.24(d，1H)7.24-7.75(m，13H)9.49(d，1H)10.89(s，1H)
Embodiment 67
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-2-(4-trifluoromethyl-phenyl)-ethanamide
This material only is to use (4-trifluoromethyl-phenyl)-Acetyl Chloride 98Min. (41mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (13mg).
LC/MS RT=5.57 minute measured value ES+=438
1H?NMR(d6?DMSO，δ)3.79(s，2H)5.23(d，1H)7.24-7.70(m，13H)9.48(d，1H)10.87(s，1H)
Embodiment 68
1-(2-methoxyl group-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
The solution that 2-methoxyl group-aniline (37mg) is dissolved in dry methylene chloride (3ml) is handled with triethylamine (0.04ml) earlier, uses the toluene (0.08ml) of 20% carbonyl chloride to handle then.Mixture adds intermediate 3 (37mg) then in stirring at room 1 hour, continues to stir 18 hours.Mixture distributes between water and ethyl acetate.Organic layer evaporates after by the Hydrophobic glass strainer, and resistates is purified through silica gel SPE post.With the dichloromethane gradient wash-out of 0-5% methyl alcohol, obtain colorless solid title compound (24mg).
LC/MS RT=5.05 minute measured value ES+=401
1H?NMR(d6?DMSO，δ)3.86(s，3H)5.21(d，1H)6.78-7.02(m，3H)7.23-7.70(m，9H)7.98(m?1H)8.26(d，1H)8.60(s，1H)10.89(s，1H)
Embodiment 69
1-(2-nitro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
This material only is to use 2-nitro-aniline (21mg) with the method preparation that embodiment 68 introduces.Obtain yellow solid title compound (23mg).
LC/MS RT=5.30 minute measured value ES+=416
1H?NMR(d6?DMSO，δ)5.19(d，1H)7.15-7.70(m，11H)8.05(dd，1H)8.17(d，1H)8.82(d，1H)9.68(s，1H)10.95(s，1H)
Embodiment 70
1-(2-chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
This material only is to use 2-chloro-aniline (0.017ml) with the method preparation that embodiment 68 introduces.Obtain colorless solid title compound (21mg).
LC/MS RT=5.34 minute measured value ES+=405
1H?NMR(d6?DMSO，δ)5.21(d，1H)6.94-7.70(m，12H)8.08(m，1H)8.47(d，1H)8.57(s，1H)10.93(s，1H)
Embodiment 71
1-(4-chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Mixture in dry THF (4ml) is handled with triethylamine (0.05ml) with intermediate 3 (30mg) and 4-chloro-1-isocyanato-benzene (0.011ml).Mixture distributes between water and methylene dichloride then in stirring at room 18 hours.Organic layer evaporates after by the Hydrophobic glass strainer.Resistates grinds with sherwood oil, obtains beige solid title compound (34mg).
LC/MS RT=5.45 minute measured value ES+=405
1H?NMR(d6?DMSO，δ)5.17(d，1H)7.25-7.70(m，14H)9.18(s，1H)10.95(s，1H)
Embodiment 72
1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3-is right-tolyl-urea
This material only is to use 1-isocyanato-4-methyl-benzene (0.011ml) with the method preparation that embodiment 71 introduces.Obtain Off-white solid title compound (32mg).
LC/MS RT=5.18 minute measured value ES+=385
1H?NMR(d6?DMSO，δ)2.22(s，3H)5.19(d，1H)7.05(d，2H)7.23-7.70(m，12H)8.92(s，1H)10.92(s，1H)
Embodiment 73a
1-(2-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
This material only is to use 2-fluoro-1-isocyanato-benzene (0.010ml) with the method preparation that embodiment 71 introduces.Obtain beige solid title compound (29mg).
LC/MS RT=5.09 minute measured value ES+=389
1H?NMR(d6?DMSO，δ)5.21(d，1H)6.90-7.70(m，12H)8.07(m，2H)8.93(s，1H)10.94(s，1H)
Embodiment 73b
(S)-1-(2-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
This material only is to use intermediate 10 with the method preparation that embodiment 73 introduces.Obtain colorless solid title compound (33mg).
1H?NMR(DMSO，δ)5.24(d，1H)6.90-7.75(m，12H)8.11-8.17(m，2H)8.95(d，1H)10.95(s，1H)
Embodiment 74
1-(4-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
This material only is to use 4-fluoro-1-isocyanato-benzene (0.010ml) with the method preparation that embodiment 71 introduces.Obtain Off-white solid title compound (26mg).
LC/MS RT=5.02 minute measured value ES+=389
1H?NMR(d6?DMSO，δ)5.18(d，1H)7.08(t，2H)7.25-7.70(m，12H)9.07(s，1H)10.94(s，1H)
Embodiment 75a
4-methylsulfonyl-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide.
This material only is to use 4-methylsulfonyl-2-methoxyl group-phenylformic acid (69mg) with the method preparation that embodiment 27 introduces.Obtain colorless solid title compound (54mg).
1H?NMR(DMSO，δ)3.33(s，3H)4.13(s，3H)5.44(d，1H)7.33-7.71(m，11H)8.10(d，1H)9.61(d，1H)11.06(s，1H)
Embodiment 75b
(S)-4-methylsulfonyl-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material only is to use 4-methylsulfonyl-2-methoxyl group-phenylformic acid (46mg) with the method preparation that embodiment 76b introduces.Obtain colorless solid title compound (55mg)
1H?NMR(DMSO，δ)3.33(s，3H)4.13(s，3H)5.44(d，1H)7.33-7.71(m，11H)8.10(d，1H)9.61(d，1H)11.06(s，1H)
Embodiment 76a
5-ethanoyl-2-oxyethyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material only is to use 5-ethanoyl-2-oxyethyl group-phenylformic acid (41mg) with the method preparation that embodiment 27 introduces.Obtain colorless solid title compound (45mg)
1H?NMR(DMSO，δ)1.59(t，3H)2.59(s，3H)4.42(q，2H)5.44(d，1H)7.30-7.54(m，10H)8.17(ddd，1H)8.58(d，1H)9.71(d，1H)11.07(s，1H)
Embodiment 76b
(S)-5-ethanoyl-2-oxyethyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material only is to use 5-ethanoyl-2-oxyethyl group-phenylformic acid (83mg) with the method preparation that embodiment 76b introduces.Obtain colorless solid title compound (108mg)
1H?NMR(DMSO，δ)1.59(t，3H)2.59(s，3H)4.42(q，2H)5.44(d，1H)7.30-7.54(m，10H)8.17(ddd，1H)8.58(d，1H)9.71(d，1H)11.07(s，1H)
Embodiment 77a
6-fluoro-4H-benzo [1,3] dioxine-8-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material only is to use 6-fluoro-4H-benzo [1,3] dioxine-8-carboxylic acid (36.2mg) with the method preparation that embodiment 27 introduces.Obtain colorless solid title compound (40mg)
1H?NMR(DMSO，δ)5.02(s，2H)5.42(d，1H)5.54(s，2H)7.26-7.70(m，12H)9.37(d，1H)11.06(s，1H)
Embodiment 77b
(S)-6-fluoro-4H-benzo [1,3] dioxine-8-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
This material only is to use 6-fluoro-4H-benzo [1,3] dioxine-8-N-(86mg) with the method preparation that embodiment 76b introduces.Obtain colorless solid title compound (65mg)
1H?NMR(DMSO，δ)5.02(s，2H)5.42(d，1H)5.54(s，2H)7.26-7.70(m，12H)9.37(d，1H)11.06(s，1H)
Embodiment 78
(S)-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-4-trifluoromethyl-benzamide
This material only is to use 2-methoxyl group-4-trifluoromethyl-phenylformic acid (26mg) with the method preparation that embodiment 76b introduces.Obtain colorless solid title compound (32mg).
1H?NMR(DMSO，δ)4.12(s，3H)5.44(d，1H)7.30-7.68(m，11H)8.09(d，1H)9.59(d，1H)11.06(s，1H)
Embodiment 79a
2,4,5-three fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material only is to use 2,4,5-three fluoro-phenylformic acid (39mg) with the method preparation that embodiment 27 introduces.Obtain colorless solid title compound (56mg).
1H?NMR(DMSO，δ)5.42(d，1H)7.29-7.85(m，11H)9.43-9.47(m，1H)11.02(s，1H)
Embodiment 79b
(S)-2,4,5-three fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material only is to use 2,4,5-three fluoro-phenylformic acid (70mg) with the method preparation that embodiment 75b introduces.Obtain colorless solid title compound (74mg).
1H?NMR(DMSO，δ)5.42(d，1H)7.29-7.85(m，11H)9.43-9.47(m，1H)11.02(s，1H)
Embodiment 80a
2-hydroxy-n-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material only is to use 2-hydroxy-benzoic acid (30mg) with the method preparation that embodiment 27 introduces.Obtain colorless solid title compound (40mg).
1H?NMR(DMSO，δ)5.47(d，1H)6.92(t，1H)7.00(d，1H)7.34-7.66(m，10H)8.01(dd，1H)10.07(brs，1H)11.01(s，1H)
Embodiment 80b
(S)-2-hydroxy-n-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
This material only is to use 2-hydroxy-benzoic acid (55mg) with the method preparation that embodiment 75b introduces.Obtain colorless solid title compound (63mg).
1H?NMR(DMSO，δ)5.48(d，1H)6.95(t，1H)7.04(d，1H)7.28-7.70(m，10H)8.06(dd，1H)9.94(d，1H)11.02(s，1H)11.74(brs，1H)
Embodiment 81a
1H-indoles-7-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
This material only is to use 1H-indole-7-carboxylic acid (35mg) with the method preparation that embodiment 27 introduces.Obtain colorless solid title compound (49mg).
1H?NMR(DMSO，δ)5.65(d，1H)6.54(m，1H)7.17-8.10(m，13H)9.56(d，1H)
Embodiment 81b
(S)-1H-indoles-7-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
This material only is to use 1H-indole-7-carboxylic acid (64mg) with the method preparation that embodiment 75b introduces.Obtain colorless solid title compound (69mg).
1H?NMR(DMSO，δ)5.65(d，1H)6.54(m，1H)7.17-8.10(m，13H)9.56(d，1H)
Embodiment 82a
3-methoxyl group-naphthalene-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
This material only is to use 3-methoxyl group-naphthalene-2-carboxylic acid (40mg) with the method preparation that embodiment 27 introduces.Obtain colorless solid title compound (73mg).
1H?NMR(DMSO，δ)4.15(s，3H)5.51(d，1H)7.37-7.63(m，12H)7.95(d，1H)8.03(d，1H)8.58(s，1H)9.69(d，1H)11.05(s，1H)
Embodiment 82b
(S)-3-methoxyl group-naphthalene-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
This material only is to use 3-methoxyl group-naphthalene-2-carboxylic acid (80mg) with the method preparation that embodiment 75b introduces.Obtain colorless solid title compound (113mg).
1H?NMR(DMSO，δ)4.15(s，3H)5.51(d，1H)7.31-7.68(m，12H)7.95(d，1H)8.03(d，1H)8.58(s，1H)9.71(d，1H)11.08(s，1H)
Following compounds is also with similar above-mentioned method preparation:
Embodiment 83) N-[7-chloro-5-(2-fluoro-phenyl)-2-oxo-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-4-methoxyl group-benzamide
Embodiment 84) 1-(2-fluoro-benzyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 85) 1-(4-methoxyl group-benzyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 86) 1-(3-methyl-benzyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 87) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3-(4-trifluoromethyl-phenyl)-urea
Embodiment 88) 4-chloro-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 89) 4-methoxyl group-3-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl) benzamide
Embodiment 90) 3-methoxyl group-2-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 91) 5-chloro-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl) benzamide
Embodiment 92) 5-fluoro-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 93) 2-methoxyl group-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 94) 5-methoxyl group-2-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 95) 3-methoxyl group-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 96) 3-(2-methoxyl group-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl) propionic acid amide
Embodiment 97) 3-(3-methoxyl group-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-propionic acid amide
Embodiment 98) 3-(4-methoxyl group-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-propionic acid amide
Embodiment 99) N-[5-(3-chloro-phenyl)-2-oxo-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-2-methoxyl group-benzamide
Embodiment 100) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-4-methoxyl group-benzamide
Embodiment 101) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-2-nitro-benzamide
Embodiment 102) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-4-nitro-benzamide
Embodiment 103) 4-methoxyl group-N-[2-oxo-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-benzamide
Embodiment 104) 2-methoxyl group-N-[2-oxo-5-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-benzamide
Embodiment 105) 4-methoxyl group-N-[2-oxo-5-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-benzamide
Embodiment 106) 2-oxyethyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 107) 2,4-dimethoxy-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 108) 2-bromo-5-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 109) 2-methoxyl group-N-[5-(3-methoxyl group-phenyl)-2-oxo-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-benzamide
Embodiment 110) N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-4-nitro-benzamide
Embodiment 111) 2-methoxyl group-N-(8-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 112) 2-chloro-4-methylsulfonyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 113) 2-dimethylamino-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 114) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzyl carbamate
Embodiment 115) 1-(3,5-dimethyl-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 116) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3-(4-trifluoromethoxy-phenyl)-urea
Embodiment 117) 1-(4-bromo-2-trifluoromethyl-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 118) 1-(4-bromo-benzyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 119) 1-(2,3-two chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 120) 1-(2,6-dimethyl-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 121) 1-(2-chloro-6-methyl-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 122) 1-(4-nitro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 123) 1-(2-methylthio group-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 124) 1-(2,6-two chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 125) the 5-tertiary butyl-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 126) 2,5-dimethoxy-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 127) 1-(2,6-two fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 128) 1-(3-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 129) 1-(3-methoxyl group-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 130) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3-(3-trifluoromethyl-phenyl)-urea
Embodiment 131) 1-(3-chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 132) 2-methoxyl group-4-methylthio group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 133) 4-methylsulfonyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 134) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-to benzoyl amino acid methyl esters
Embodiment 135) 2-fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 136) 2,6-two fluoro-N (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 137) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-2-propoxy--benzamide
Embodiment 138) 2-iodo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 139) 3-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-to benzoyl amino acid methyl esters
Embodiment 140) 4-amino-5-chloro-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 141) between 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3--tolyl-urea
Embodiment 142) 2-methylthio group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 143) 2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-5-sulfamyl (sylfamoyl)-benzamide
Embodiment 144) 2-hydroxy-n-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3-phenyl-propionic acid amide
Embodiment 145) 3-hydroxy-n-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3-phenyl-propionic acid amide
Embodiment 146) 3-(2-fluoro-phenyl)-1-methyl isophthalic acid-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 147) 2-methoxyl group-N-methyl-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
Embodiment 148) the 1-tertiary butyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 149) 1-cyclohexyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 150) 1-ethyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 151) 1-butyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
Embodiment 152) 4,5-dimethyl-furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
Embodiment 153) piperidines-1-N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
Embodiment 154) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl] ethanamide
Embodiment 155) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-isobutyramide
Embodiment 156) furans-2-N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-methane amide
Embodiment 157) thiophene-2-N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-methane amide
Embodiment 158) N-[5-(3 chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-cyclohexane carboxamide
Embodiment 159) piperidines-1-N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-methane amide
Embodiment 160) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl] Isonicotinamide
Embodiment 161) 5-methyl-furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
Embodiment 162) pyrazine-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
Embodiment 163) N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-isobutyramide
Embodiment 164) thiophene-2-N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-methane amide
Embodiment 165) N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-cyclohexane carboxamide
Embodiment 166) piperidines-1-N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-methane amide
Embodiment 167) piperidines-4-N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-methane amide
Embodiment 168) N-(8-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-cyclohexane carboxamide
Embodiment 169) thiophene-2-N-(8-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
Embodiment 170) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3-thiophene-2-base-urea
Embodiment 171) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-3-thiene-3-yl--urea
Embodiment 172) pyridine-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
Embodiment 173) 1H-pyrazoles-4-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
Embodiment 174) 6-dimethylamino-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-niacinamide
Embodiment 175) 2-oxyethyl group-naphthalene-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
Embodiment 176) 9-oxo-9H-fluorenes-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
Embodiment 177) 2-oxo-2,3-dihydro-benzoglyoxaline-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
Embodiment 178) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl) t-butyl carbamate
Embodiment 179) (S)-4,5-two bromo-furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
Embodiment 180) (S)-cumarone-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
Embodiment 181) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-Urethylane
Embodiment 182) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urethanum
Embodiment 183) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-isobutyl carbamate
Embodiment 184) 2-oxo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-2-thiophene-2-base-ethanamide
Active embodiment 1
With following proposal test implementation example 1-74 and 83-124.
The XTT analytical plan
60 holes, inside of 96 hole tissue culturing plates with 100 μ l or 150 μ l substratum with the Vero cell with 3 * 10
4Cells/well (toxicity research be 1 * 10
4Cells/well) add, in 37 ℃ be incubated overnight or up to cell near merging.For preliminary screening, 25 μ l compounds directly are added to every hole 100 μ l substratum, culture plate is duplicate.Prepare the 3rd orifice plate to study toxicity simultaneously.
Be follow-up study, the 70 μ l compounds in duplicate hole directly added substratum with the 3.2x ultimate density, along the formation hole with its 1/2 serial dilution.Preparation double plate is convenient to study simultaneously toxicity.
Obtain m.o.i. ≈ 0.2 with 25 μ l rsv infection cells.100 μ l sterile distilled waters are joined the external holes of plate, then in 33 ℃ of incubations 6 days.0.25 μ l/ml PMS is joined the XTT stock solution, ultimate density 25 μ M PMS.XTT/PMS solution with 25 μ l tepors adds every hole then, then in 37 ℃ of incubations 5 hours.With plate thermal agitation (DynaTechVari-Shaker) 10 minutes, cool off 15 minutes rear encloseds.Measure absorbancy in 450nM, with Microsoft Excel software analysis data.
The maximum value OD of record
450nm(infection, untreated control cells) is equivalent to 100% and suppresses.The minimum value OD of record
450nm(control cells of infection) is equivalent to 0% and suppresses.At OD
450nmDraw logarithm 10 concentration curves, calculate IC from 50% value of graphic representation record or with regression analysis
50Value (table 1).
According to following scheme test implementation example 75-82 and 125-184.
The XTT analytical plan
In order to study compound activity and toxicity, with 100 μ l substratum with the Hep-2 cell with 4 * 10
4Cells/well is inoculated into 60 holes, inside of 96 hole tissue culturing plates, is incubated overnight or up near cytogamy in 37 ℃.
Cell is obtained 80% cell killing with the 25 μ l rsv infections of measuring titre.Add 25 μ M test-compounds to every hole.Final DMSO concentration is 0.5%.200 μ l sterile distilled waters are joined the external holes of plate, in 37 ℃ of incubations 6 days.0.25 μ l/ml PMS is joined the XTT stock solution, ultimate density 25uM PMS.XTT/PMS solution with 25 μ l tepors joined every hole then, in 37 ℃ of incubations 1 hour.
The maximum value OD of record
450nm(infection, untreated control cells) is equivalent to 100% and suppresses.The minimum value OD of record
450nm(control cells of infection) is equivalent to 0% and suppresses.At OD
450nmDraw logarithm 10 concentration curves, calculate IC from 50% value of graphic representation record or with regression analysis
50Value.
The LC-MS data of embodiment 75a-184 also see Table 2.
Table 1
| Embodiment | ??XTT?IC50(uM) | ??TD50(2d) | ??TD50(6d) |
| ??1 | |||
| ??2 | ??4 | ||
| ??3 | ??2.5 | ||
| ??4 | ??5 | ||
| ??5 | ??2.5 | ||
| ??6 | ??6 | ||
| ??7 | ??2 | ||
| ??8 | ??2 | ||
| ??9 | ??2 | ??70 | ??100 |
| ??10 | ??1.5 | ||
| ??11 | ??0.5 | ??100 | |
| ??12 | ??2.5 | ||
| ??13 | ??1.5 | ??100 | |
| ??14 | ??1.5 | ??100 | |
| ??15 | ??1 | ||
| ??16 | ??2 | ||
| ??17 | ??5 | ||
| ??18 | ??2 | ||
| ??19 | ??2 | ??100 | ??100 |
| ??20 | ??25 | ||
| ??21 | ??6 | ??100 | ??100 |
| ??22 | ??4 | ||
| ??23 | ??5 | ||
| ??24 | ??3 | ||
| ??25 | ??2 | ||
| ??26 | ??2 | ||
| ??27a | ??0.3 | ??100 | |
| ??27b | ??＜0.3 | ??＞100 | |
| ??28 | ??5 | ||
| ??29 | ??2 | ||
| ??30 | ??3 | ||
| ??31 | ??5 | ||
| ??32 | ??2 |
| ??33 | ??2.5 | ||
| ??34 | ??3 | ||
| ??35 | ??6 | ||
| ??36 | ??15 | ||
| ??37 | ??15 | ||
| ??38 | ??6 | ??50 | ??40 |
| ??39 | ??10 | ??60 | ??50 |
| ??40 | ??10 | ??50 | ??15 |
| ??41 | ??10 | ??100 | ??100 |
| ??42 | ??20 | ||
| ??43 | ??30 | ||
| ??44 | ??10 | ||
| ??45 | ??20 | ||
| ??46 | ??30 | ||
| ??47 | ??30 | ??100 | ??50 |
| ??48 | ??100 | ??50 | |
| ??49 | ??50 | ??100 | ??100 |
| ??50 | ??50 | ||
| ??51 | ??5 | ||
| ??52 | ??3 | ||
| ??53 | ??5 | ||
| ??54 | ??1.5 | ??30 | |
| ??55 | ??3 | ??30 | |
| ??56 | ??5 | ||
| ??57 | ??0.7 | ||
| ??58 | ??1.2 | ??30 | |
| ??59 | ??5 | ||
| ??60 | ??5 | ||
| ??61 | ??3 | ||
| ??62 | ??1.5 | ||
| ??63 | ??1.7 | ||
| ??64 | ??1 | ||
| ??65 | ??2 | ??100 | |
| ??66 | ??1.5 | ??30 | |
| ??67 | ??1.5 | ??100 | |
| ??68 | ??1 | ||
| ??69 | ??1.5 |
| ??70 | ??1.5 | ??100 | |
| ??71 | ??3 | ??50 | |
| ??72 | ??1.5 | ??100 | |
| ??73a | ??1 | ??100 | |
| ??73b | ??0.7 | ??＞50 | |
| ??74 | ??1.5 | ??100 |
Table 2
| Embodiment number | LC-MS data RT/min ES | ??XTT?IC50(uM) | ??TC50(2d) | ??TC50(6d) | |
| ??75a | ??4.82 | ??ES+464.33 | ??2.4 | ||
| ??75b | ??4.83 | ??ES+464 | ??0.6 | ??＞50 | |
| ??76a | ??5.2 | ??492 | ??3.5 | ??64 | |
| ??76b | ??4.81 | ??ES+442.49 | ??1.2 | ??＞50 | |
| ??77a | ??5.28 | ??ES+432 | ??4.6 | ??＞50 | |
| ??77b | ??4.85 | ??ES+432.46 | ??0.5 | ??33.2 | |
| ??78 | ??5.62 | ??ES+454 | ??2.7 | ??32.5 | |
| ??79a | ??8 | ??65 | |||
| ??79b | ??5.03 | ??ES+410.44 | ??5.8 | ??＞50 | |
| ??80a | ??8.7 | ??33 | |||
| ??80b | ??4.83 | ??ES+372.50 | ??2 | ??＞50 | |
| ??81a | ??5.39 | ??ES+395.46 | ??8.4 | ??63 | |
| ??81b | ??5.01 | ??ES+395.46 | ??1.2 | ??35.6 | |
| ??82a | ??6.7 | ??＞50 | |||
| ??82b | ??5.21 | ??ES+436.49 | ??1.5 | ??＞50 | |
| ??83 | ??5.37 | ??438.44，436.39 | ??6 | ??＞100 | ??32 |
| ??84 | ??4.74 | ??ES+403.54 | ??2 | ??＞100 | ??＞100 |
| ??85 | ??4.6 | ??ES+415.54 | ??4 | ??＞100 | ??＞100 |
| ??86 | ??4.95 | ??ES+399.59 | ??3 | ??＞100 | ??100 |
| ??87 | ??5.68 | ??ES+439.51 | ??4 | ??50 | ??50 |
| ??88 | ??5.64 | ??ES+420，422 | ??0.3 | ??100 | ??40 |
| ??89 | ??5.19 | ??ES+431 | ??0.8 | ??＞100 | ??＞100 |
| ??90 | ??5.11 | ??ES+431 | ??0.5 | ??100 | ??100 |
| ??91 | ??5.65 | ??ES+420，422 | ??0.3 | ??100 | ??100 |
| ??92 | ??5.32 | ??ES+404 | ??＜0.3 | ??100 | ??100 |
| ??93 | ??5.44 | ??ES+431 | ??＜0.3 | ??100 | ??＞100 |
| ??94 | ??4.91 | ??ES+431 | ??1.5 | ??＞100 | ??＞100 |
| ??95 | ??5.51 | ??ES+431 | ??1.5 | ??100 | ??＞100 |
| ??96 | ??5.3 | ??ES+414.54 | ??5 | ??＞100 | ??＞100 |
| ??97 | ??5.14 | ??ES+414.55 | ??5 | ??＞100 | ??＞100 |
| ??98 | ??5.17 | ??ES+414.54 | ??5 | ??＞100 | ??＞100 |
| ??99 | ??5.69 | ??ES+420.49 | ??1 | ??100 | ??＞100 |
| ??100 | ??5.58 | ??ES+420.48 | ??4 | ??＞100 | ??100 |
| ??101 | ??5.36 | ??ES+435.45 | ??2.5 | ??100 | ??100 |
| ??102 | ??5.79 | ??ES+435.46 | ??7 | ??＞100 | ??＞100 |
| ??103 | ??5.69 | ??ES+454.47 | ??7 | ??＞100 | ??30 |
| ??104 | ??5.69 | ??ES+454.48 | ??5 | ??＞100 | ??＞100 |
| ??105 | ??5.6 | ??ES454.49 | ??9 | ??＞100 | ??＞100 |
| ??106 | ??5.7 | ??ES+400 | ??0.7 | ??＞100 | ??＞100 |
| ??107 | ??5.33 | ??ES-414 | ??＜0.3 | ??60 | ??60 |
| ??108 | ??5.32 | ??ES+464，466 | ??2 | ??＞100 | ??＞100 |
| ??109 | ??509 | ??ES+416.54 | ??2 | ??50 | ??100 |
| ??110 | ??5.21 | ??ES+431.53 | ??5 | ??＞100 | ??＞100 |
| ??111 | ??5.29 | ??ES+400.49 | ??3 | ??＞100 | ??＞100 |
| ??112 | ??4.87 | ??ES+468 | ??1.5 | ??＞100 | ??＞100 |
| ??113 | ??4.69 | ??ES+399 | ??1.5 | ??＞100 | ??＞100 |
| ??114 | ??5.37 | ??ES+386 | ??5 | ??＞100 | ??60 |
| ??115 | ??5.32 | ??ES+399.50 | ??1.5 | ??＞100 | ??60 |
| ??116 | ??5.49 | ??ES+455.45 | ??2 | ??20 | ??20 |
| ??117 | ??5.67 | ??ES+517.33，519.33 | ??6 | ??60 | ??100 |
| ??118 | ??5.14 | ??ES+463.41，465.41 | ??2 | ??＞100 | ??100 |
| ??119 | ??5.54 | ??ES+439.40 | ??2 | ??＞100 | ??30 |
| ??120 | ??4.98 | ??ES+399.55 | ??6 | ??＞100 | ??60 |
| ??121 | ??5.02 | ??ES+416.49 | ??4 | ??60 | ??60 |
| ??122 | ??5.2 | ??ES+416.49 | ??0.4 | ??60 | ??20 |
| ??123 | ??5.2 | ??417.48 | ??2 | ??＞100 | ??100 |
| ??124 | ??5.02 | ??ES439.41 | ??5 | ??70 | ??60 |
| ??125 | ??5.84 | ??ES+442.54 | ??6.1 | ??＞50 |
| ??126 | ??4.61 | ??ES+416.44 | ??5.4 | ??＞50 | |
| ??127 | ??4.35 | ??ES+407.44 | ??9.4 | ??＞50 | |
| ??128 | ??4.65 | ??ES+389.46 | ??6.1 | ??＞50 | |
| ??129 | ??4.53 | ??ES+401.47 | ??4.9 | ??＞50 | |
| ??130 | ??4.95 | ??ES-437.35 | ??9.7 | ??39.5 | |
| ??131 | ??4.82 | ??ES+405.44 | ??9.6 | ??＞50 | |
| ??132 | ??5.39 | ??ES+389 | ??6.3 | ??＞50 | |
| ??133 | ??4.26 | ??ES+432 | ??6.2 | ??77.2 | |
| ??134 | ??4.77 | ??ES+414 | ??6.5 | ??77.1 | |
| ??135 | ??5.2 | ??ES+374.42 | ??9.5 | ??＞50 | |
| ??136 | ??5.07 | ??ES+392.42 | ??8.7 | ??＞50 | |
| ??137 | ??5.65 | ??ES+414.46 | ??8.3 | ??＞50 | |
| ??138 | ??5.25 | ??482 | ??8.3 | ??51 | |
| ??139 | ??4.99 | ??ES+400 | ??9.2 | ??98 | |
| ??140 | ??5.03 | ??ES+435.45 | ??2.5 | ??68 | |
| ??141 | ??4.82 | ??ES+412.50 | ??4.3 | ??＞50 | |
| ??142 | ??4.78 | ??ES+402.50 | ??9.4 | ??＞50 | |
| ??143 | ??4.3 | ??ES-463 | ??3.8 | ??＞50 | |
| ??144 | ??4.54 | ??ES+400 | ??5.5 | ??＞50 | |
| ??145 | ??4.39 | ??ES+400 | ??1.9 | ??＞50 | |
| ??146 | ??5.08 | ??ES-401 | ??9.5 | ??＞50 | |
| ??147 | ??5.02 | ??ES+445 | ??15.9 | ??＞50 | |
| ??148 | ??4.56 | ??ES-349.57 | ??5 | ??＞100 | ??＞100 |
| ??149 | ??4.76 | ??ES+377.57 | ??1.5 | ??＞100 | ??＞100 |
| ??150 | ??3.87 | ??ES+345.55 | ??2 | ??＞100 | ??＞100 |
| ??151 | ??4.43 | ??ES+351.58 | ??1.5 | ??＞100 | ??＞100 |
| ??152 | ??5.17 | ??ES+374 | ??0.3 | ??＞100 | ??100 |
| ??153 | ??5.01 | ??ES+397.52 | ??5 | ??＞100 | ??＞100 |
| ??154 | ??4.31 | ??ES+328.49 | ??3 | ??＞100 | ??＞100 |
| ??155 | ??4.95 | ??ES+356.51 | ??6 | ??＞100 | ??＞100 |
| ??156 | ??5.17 | ??ES+380.46 | ??1.5 | ??100 | ??100 |
| ??157 | ??5.51 | ??ES+396.45 | ??5 | ??＞100 | ??100 |
| ??158 | ??5.74 | ??ES+396.53 | ??2 | ??100 | ??＞100 |
| ??159 | ??5.15 | ??ES+397.52 | ??2 | ??＞100 | ??＞100 |
| ??160 | ??4.44 | ??ES+391.48 | ??10 | ??＞100 | ??＞100 |
| ??161 | ??5.52 | ??ES+414 | ??2 | ??100 | ??60 |
| ??162 | ??4.43 | ??ES+358 | ??2 | ??＞100 | ??＞100 |
| ??163 | ??4.67 | ??ES+352.51 | ??5 | ??＞100 | ??＞100 |
| ??164 | ??5 | ??ES+392.56 | ??4 | ??100 | ??100 |
| ??165 | ??5.14 | ??ES+392.56 | ??2 | ??＞100 | ??＞100 |
| ??166 | ??4.77 | ??ES+393.57 | ??5 | ??＞100 | ??＞100 |
| ??167 | ??4.42 | ??387.52 | ??9 | ??＞100 | ??＞100 |
| ??168 | ??5.43 | ??ES+396.53 | ??5 | ??＞100 | ??＞100 |
| ??169 | ??5.18 | ??ES+376.44 | ??5 | ??50 | ??30 |
| ??170 | ??4.42 | ??ES+377.40 | ??3.4 | ??＞50 | |
| ??171 | ??4.43 | ??ES+377.40 | ??4.8 | ??＞50 | |
| ??172 | ??4.61 | ??ES+357 | ??6.4 | ??137.8 | |
| ??173 | ??4.66 | ??ES+346 | ??8.3 | ??95 | |
| ??174 | ??4.06 | ??ES+400.46 | ??6.9 | ??60 | |
| ??175 | ??5.5 | ??ES+450.50 | ??8.2 | ??＞50 | |
| ??176 | ??5.82 | ??ES+458.46 | ??4.3 | ??99 | |
| ??177 | ??5.17 | ??ES+412.50 | ??4.3 | ??＞50 | |
| ??178 | ??4.3 | ??＞50 | |||
| ??179 | ??5.17 | ??ES+504.20 | ??3.9 | ??＞50 | |
| ??180 | ??5.01 | ??ES+396.46 | ??2.6 | ??37.1 | |
| ??181 | ??4.23 | ??ES+310.55 | ??9.6 | ??＞50 | |
| ??182 | ??4.47 | ??ES+324.46 | ??10 | ??＞50 | |
| ??183 | ??4.89 | ??ES+352.48 | ??9.88 | ??＞50 | |
| ??184 | ??5 | ??390 | ??9.5 | ??＞50 |
Claims (45)
1. acceptable salt is used for the treatment of or prevents purposes on the medicine of rsv infection in preparation on the benzodiazepine derivative of following structural formula (I) or its pharmacology,
Wherein:
-R
1Represent C
1-6Alkyl, aryl or heteroaryl;
-R
2Represent hydrogen or C
1-6Alkyl;
-each R
3Identical or different and represent halogen, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group ,-CO
2R ' ,-CONR ' R " ,-NH-CO-R ' ,-S (O) R ' ,-S (O)
2R ' ,-NH-S (O)
2R ' ,-S (O) NR ' R " or-S (O)
2NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen or C
1-6Alkyl;
-n is 0-3;
-R
4Represent hydrogen or C
1-6Alkyl;
-R
5Represent C
1-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, aryl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-, carbocylic radical-C (O)-C (O)-, heterocyclic radical-C (O)-C (O)-or-XR
6
-X representative-CO-,-S (O)-or-S (O)
2-; And
-R
6Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-.
2. the purposes of claim 1, wherein:
-each R
3Identical or different and represent halogen, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group ,-CO
2R ' ,-CONR ' R " ,-NH-CO-R ' ,-S (O) R ' ,-S (O)
2R ' ,-NH-S (O)
2R ' or-S (O) NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen or C
1-6Alkyl;
-R
5Represent C
1-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical (C
1-6Alkyl)-or-XR
6
-X representative-CO-,-S (O)-or-S (O)
2-; And
-R
6Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-or heteroaryl-(C
1-6Alkyl)-.
3. claim 1 or 2 purposes, wherein R
1Be C
1-2Alkyl or aryl.
4. the purposes of each aforementioned claim, wherein R
2Be hydrogen.
5. the purposes of each aforementioned claim, wherein R
3Be halogen, hydroxyl, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, C
1-4Halogenated alkoxy, amino, (a C
1-4Alkyl) amino or two (C
1-4Alkyl) amino.
6. the purposes of claim 5, wherein R
3Be fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl, C
1-2Halogenated alkoxy, amino, (a C
1-2Alkyl) amino or two (C
1-2Alkyl) amino.
7. the purposes of each aforementioned claim, wherein R
4Be hydrogen or C
1-2Alkyl.
8. the purposes of each aforementioned claim, wherein R
5Be C
1-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1-4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-, aryl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-or-XR
6
9. the purposes of claim 8, wherein R
5Be C
1-4Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, phenyl-(C
1-2Alkyl)-, heteroaryl-(C
1-2Alkyl)-, phenyl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-or-XR
6
10. the purposes of claim 9, wherein R
5Be C
1-4Alkyl, phenyl, thienyl, furyl, isoxazolyl, pyridyl, cyclopentyl, cyclohexyl, benzothienyl, dihydro benzo furyl, phenyl-CH
2-, furyl-CH
2-, phenyl-C (O)-C (O)-, thienyl-C (O)-C (O)-or-XR
6
11. the purposes of each aforementioned claim, wherein X be-CO-or-S (O)
2-.
12. the purposes of each aforementioned claim is wherein worked as R
6Identical or different and represent hydrogen, C for-NR ' R " during group, each R ' and R "
1-4Alkyl, aryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-or heteroaryl-(C
1-4Alkyl)-.
13. the purposes of claim 12 is wherein worked as R
6" during group, each R ' and R " is identical or different and represent hydrogen, C to be NR ' R
1-4Alkyl, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl-CH
2-.
14. the purposes of claim 13 is wherein worked as R
6For one of-NR ' R " during group, R ' and R " is a hydrogen.
15. the purposes of each aforementioned claim, wherein R
6Be C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1-4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-, aryl-(C
1-4Hydroxyalkyl)-, heteroaryl-(C
1-4Hydroxyalkyl)-, carbocylic radical-(C
1-4Hydroxyalkyl)-, heterocyclic radical-(C
1-4Hydroxyalkyl)-, aryl-(C
1-4Alkyl)-O-, heteroaryl-(C
1-4Alkyl)-O-, carbocylic radical-(C
1-4Alkyl)-O-, heterocyclic radical-(C
1-4Alkyl)-O-or-NR ' R ".
16. the purposes of claim 15, wherein R
6Be C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, phenyl-(C
1-2Alkyl)-, phenyl-(C
1-2Alkyl)-O-, heteroaryl-(C
1-2Alkyl)-, phenyl-(C
1-2Hydroxyalkyl)-, heteroaryl-(C
1-2Hydroxyalkyl)-or-NR ' R ".
17. the purposes of claim 16, wherein R
6Be C
1-4Alkyl, C
1-4Alkoxyl group, phenyl, naphthyl, dihydro benzo furyl, benzo dioxine base, 9H-fluorenes-9-ketone group, indyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl, benzofuryl, cyclopentyl, cyclohexyl, piperazinyl, piperidyl, morpholinyl, phenyl-(C
1-2Alkyl)-, phenyl-CH
2-CH (OH)-, phenyl-CH (OH)-CH
2-, phenyl-(C
1-2Alkyl)-O-, 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group or-NR ' R ".
18. the purposes of each aforementioned claim, wherein the benzodiazepine derivative of structural formula (I) is the benzodiazepine derivative of following structural formula (Ia):
Wherein:
-R
1Be phenyl or methyl;
-R
3Be methyl or chlorine;
-n is 0 or 1;
-R
4Be hydrogen or methyl;
-R
5Be phenyl-CH
2-, furyl-CH
2-, thienyl-C (O)-C (O)-or-XR
6
-X is-CO-or-S (O)
2-; And
-R
6Be C
1-4Alkyl, C
1-4Alkoxyl group, phenyl, naphthyl, dihydro benzo furyl, benzo dioxine base, 9H-fluorenes-9-ketone group, indyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl, benzofuryl, cyclopentyl, cyclohexyl, piperazinyl, piperidyl, morpholinyl, phenyl-(C
1-2Alkyl)-, phenyl-CH
2-CH (OH)-, phenyl-CH (OH)-CH
2-, phenyl-(C
1-2Alkyl)-O-, 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-4Alkyl, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl-(CH
2)-,
R
1Phenyl moiety in the group is not substituted or by a fluorine, chlorine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl or C
1-2Halo-alkoxy substituent replaces;
R
5And R
6Aryl moiety in the group is not substituted or is selected from following substituting group by 1-3 and replaces: fluorine, chlorine, bromine, iodine, C
1-4Alkyl, C
2-4Acyl group, hydroxyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, C
1-4Halogenated alkoxy, amino, (a C
1-4Alkyl) amino, two (C
1-4Alkyl) amino, nitro ,-CO
2R ' ,-S (O)
2R ' and-S (O)
2NH
2, wherein R ' represents C
1-2Alkyl;
R
5And R
6Heteroaryl moieties in the group is not substituted or is selected from following substituting group by 1-2 and replaces: fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Haloalkyl and two (C
1-2Alkyl) amino; And
R
6Heterocyclic radical in the group and carbocylic radical part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro.
19. the purposes of each aforementioned claim, wherein said medicine is used for the treatment of the child patient below two years old.
20. the purposes of claim 19, wherein said children suffer from chronic lung disease.
21. six years old following childhood infection RSV that each purposes of claim 1-18, wherein said medicine are used to prevent 32 weeks of gestation or are less than the birth of 32 weeks.
22. the purposes of each aforementioned claim, wherein said medicine are suitable in the nose or administration in the segmental bronchus.
23. the purposes of each aforementioned claim, wherein said medicine further comprise anti-inflammatory compound or anti influenza compound.
24. the purposes of claim 23, wherein said anti-inflammatory compound are budesonide or fluticasone.
25. the purposes of claim 23, wherein said anti-inflammatory compound are leukotriene antagonist, phosphodiesterase 4 inhibitors or TNF alpha inhibitor.
26. the purposes of claim 23, wherein said anti-inflammatory compound are interleukin 8 or interleukin 9 inhibitor.
27. each purposes of claim 1-22, the anti-inflammatory compound or the anti influenza compound of wherein said medicine and each definition of claim 24-26 give simultaneously.
28. a treatment suffers from or easily suffer from the patient's of rsv infection method, this method comprises and gives acceptable salt on structural formula (I) the benzodiazepine derivative of each definition of claim 1-19 of significant quantity or its pharmacology to described patient.
29. the method for claim 28, wherein said patient is the patient of each definition of claim 19-21.
30. the method for claim 28 or 329 wherein gives described benzodiazepine derivative or its salt in the nose or in the segmental bronchus.
31. a sucker or an atomizer that comprises medicine, wherein said medicine comprises:
(a) on the structural formula of each definition of claim 1-18 (I) benzodiazepine derivative or its pharmacology acceptable salt and
(b) acceptable carrier or thinner on the pharmacology.
32. a product, it comprises the anti-inflammatory compound or the anti influenza compound of acceptable salt and each definition of claim 24-26 on structural formula (I) compound of each definition of claim 1-18 or its pharmacology.
33. the product of claim 32 is used for the treatment of the purposes on the medicine of simultaneous RSV and influenza infection in preparation.
34. acceptable salt is used for the treatment of the purposes on the medicine of following disease on the structural formula of each definition of claim 1-18 (I) compound or its pharmacology in preparation: virus, measles, parainfluenza virus, parotitis, yellow fever virus (B5 virus strain), singapore hemorrhagic fever 2 C-type virus Cs or west Nile virus after people's parapneumonia.
35. acceptable salt on structural formula below a kind (Ib) benzodiazepine derivative or its pharmacology,
Wherein:
-R
1Represent C
1-6Alkyl, aryl or heteroaryl;
-R
2Represent hydrogen, C
1-6Alkyl;
-each R
3Identical or different and represent halogen, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group ,-CO
2R ' ,-CONR ' R " ,-NH-CO-R ' ,-S (O) R ' ,-S (O)
2R ' ,-NH-S (O)
2R ' ,-S (O) NR ' R " or-S (O)
2NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen or C
1-6Alkyl;
-n is 0-3;
-R
4Represent hydrogen or C
1-6Alkyl;
-R
5' represent C
3-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-, carbocylic radical-C (O)-C (O)-, heterocyclic radical-C (O)-C (O)-or-X ', precondition is to work as R
5' when being heteroaryl, it is not the quinaldine based or 6-chloro-pyrazinyl of 2-, works as R
5' be heteroaryl-(C
1-6Alkyl)-time, it is not 2-indyl methyl, 2-(3-indyl) ethyl or 2-furyl methyl, works as R
5' when being aryl, it is not unsubstituted phenyl, and works as R
5' be aryl-(C
1-6Alkyl)-time, it is not unsubstituted phenyl-(C
1-2Alkyl)-or 4-chloro-phenyl--(C
2-3Alkyl)-;
-X ' representative-CO-R
6' ,-S (O)-R
6" or-S (O)
2-R
6;
-R
6' represent C
1Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-, precondition is that (a) works as R
6' when being aryl, it is not unsubstituted naphthyl, unsubstituted phenyl, the phenyl-monohalide base, the 4-aminomethyl phenyl, the 4-p-methoxy-phenyl, the 4-hydroxy phenyl, the 4-trifluoromethyl, the 4-nitrophenyl, the 4-cyano-phenyl, 4-n-propyl phenyl, the 4-tert-butyl-phenyl, 4-n-pentyl phenyl, the 4-dimethylaminophenyl, 4-methylthio group phenyl, 3-trifluoromethylthio phenyl, 3, the 4-Dimethoxyphenyl, 3, the 4-dichlorophenyl, 3, the 5-dichlorophenyl, 2,3,4,5, the 6-pentafluorophenyl group, 4-chloro-2-aminophenyl or 4-1,1-dimethyl ethyl phenyl (b) is worked as R
6' when being heteroaryl, it is quinaldine based for 2-pyrryl, 2-pyrazinyl, 2-, 2-quinoxalinyl, 1-methyl indone base, 2-methyl-indyl, 2-benzofuryl, 2-benzothienyl, 3-thienyl, 3-indyl, do not replace 2-indyl, 5-fluoro indole-2-base, 5-chloro-indole-2-base, 5-bromo indole-2-base, 5-oxyindole-2-base or 5-methoxyl group indoles-2-base, (c) works as R
6' be aryl-(C
1-6Alkyl)-time, it is not 4-benzo-thiophene-(CH
2)-, unsubstituted phenyl-(CH
2)-, 4-trifluoromethyl-(CH
2)-, unsubstituted phenyl-(CH
2)
3-, single trifluoromethyl-(CH
2)
2-, 3-p-methoxy-phenyl-(CH
2)
2-, 4-chloro-2-aminophenyl-(CH
2)
2-, 2,4 dichloro benzene base-(CH
2)
2-, mono chloro benzene base-(CH
2)
2-, 2,4-trifluoromethyl-(CH
2)
2-, 4-cyano-phenyl-(CH
2)
2-or 3-cyano-phenyl-(CH
2)
2-, (d) work as R
6' be heteroaryl-(C
1-6Alkyl)-time, it is not that wherein x is indyl-(CH of 1-3
2)
x-, unsubstitued furyl-(CH
2)
2-, substituted thiophene base-(CH not
2)
3-, (e) work as R
6' when being carbocylic radical, it is not a cyclohexyl, (f) works as R
6' carbocylic radical-(C
1-6Alkyl)-time, it is not unsubstituted cyclohexyl-(CH
2)
1-3-, (g) work as R
6' when being heterocyclic radical, it is not N-pyrrolidyl or 2-dihydro benzo furyl, (h) works as R
6' be aryl-(C
1-6Alkyl)-during O-, it is not unsubstituted phenyl-(CH
2)-O-, (i) when R ' is hydrogen, R " is not unsubstituted phenyl, 4-halogenophenyl, 3-halogenophenyl, p-methoxy-phenyl, nitrophenyl, 2-chloro-phenyl-, 4-aminomethyl phenyl, dichlorophenyl, 3; 5-3,5-dimethylphenyl, 3-aminomethyl phenyl, 3-cyano-phenyl, 3-aminophenyl, 3-aminocarbonyl-phenyl, 3-phenylformic acid, 3-ethyl benzoate, 6-amino-3-pyridyl, 5-(2-chlorine) pyridyl, 5-(2-methoxyl group) pyridyl, 5-indanyl, unsubstituted ring hexyl, 1,1-dimethyl ethyl, unsubstituted phenyl-CH
2-, unsubstituting naphthyl or benzotriazole-3-base, and when R ' was methyl, R " was not a cyclopropyl-phenyl;
-R
6" represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-; And
-R
6 represents C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-, precondition is to work as R
6When was aryl, it was not the 4-aminomethyl phenyl, and precondition is that structural formula (Ib) compound is not N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-ethanamide.
36. the benzodiazepine derivative of claim 35, wherein:
-R
5' be C
3-6Alkyl, C
3-6Cycloalkyl, heterocyclic radical, C
3-6Cycloalkyl-(C
1-6Alkyl), aryl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-, carbocylic radical-C (O)-C (O)-, heterocyclic radical-C (O)-C (O)-or-X ';
-X ' is-CO-R
6' ,-S (O)-R
6" or-S (O)
2-R
6;
-R
6' be C
1Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, heterocyclic radical-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, C
3-6Cycloalkyl, heterocyclic radical, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-;
-R
6" represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-3Alkyl, heterocyclic radical, heteroaryl, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-; And
-R
6 is C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkyl, heterocyclic radical, C
3-6Cycloalkyl-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR ' R ", wherein each R ' and R " is identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl), carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-.
37. the benzodiazepine derivative of claim 35 or 36, wherein R
2Be hydrogen.
38. acceptable salt on structural formula below a kind (Ic) benzodiazepine derivative or its pharmacology,
Wherein:
-R
1Be phenyl or methyl;
-R
3Be methyl or chlorine;
-n is 0 or 1;
-R
4Be hydrogen or methyl;
-R
5' be phenyl-CH
2-thienyl-C (O)-C (O)-or-X ';
-X ' is-CO-R
6' ,-CONR ' R " ,-S (O)
2R
6 or-S (O)
2-NR ' R "; And
-R
6' be C
1Alkyl, C
1-4Alkoxyl group, benzo dioxine base, 9H-fluorenes-9-ketone group, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, cyclopentyl, piperazinyl, piperidyl, morpholinyl, phenyl-CH
2-CH (OH)-, phenyl-CH (OH)-CH
2-, phenyl-(C
2Alkyl)-O-or 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group;
-R
6 is C
1-4Alkyl, C
1-4Alkoxyl group, phenyl, naphthyl, dihydro benzo furyl, benzo dioxine base, 9H-fluorenes-9-ketone group, indyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl, benzofuryl, cyclopentyl, cyclohexyl, piperazinyl, piperidyl, morpholinyl, phenyl-(C
1-2Alkyl)-, phenyl-CH
2-CH (OH)-, phenyl-CH (OH)-CH
2-, phenyl-(C
1-2Alkyl)-O-or 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group;
-each R ' and R is " identical or different and represent hydrogen, C
1-4Alkyl, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl-(CH
2)-; And
-each R ' and R is " identical or different and represent hydrogen, C
1-4Alkyl, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl-(CH
2)-, be wherein:
R
1Phenyl moiety in the group is not substituted or by a fluorine, chlorine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl or C
1-2Halo-alkoxy substituent replaces;
R
5', R
6' and R
6Aryl moiety in the group is not substituted or is selected from following substituting group by 1-3 and replaces: fluorine, chlorine, bromine, iodine, C
1-4Alkyl, C
2-4Acyl group, hydroxyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-6Haloalkyl, C
1-4Halogenated alkoxy, amino, (a C
1-4Alkyl) amino, two (C
1-4Alkyl) amino, nitro ,-CO
2R ' ,-S (O)
2R ' and-S (O)
2NH
2, wherein R ' represents C
1-2Alkyl;
R
5', R
6' and R
6Heteroaryl moieties in the group is not substituted or is selected from following substituting group by 1-2 and replaces: fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Haloalkyl and two (C
1-2Alkyl) amino;
R
6Heterocyclic radical in the group and carbocylic radical part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro;
R ' and R " in aryl, heteroaryl and the carbocylic radical part is not substituted or be selected from following substituting group by 1-2 replaces: fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl and nitro; And
R ' and R " in aryl, heteroaryl and the carbocylic radical part is not substituted or be selected from following substituting group by 1-2 replaces: fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl and nitro,
Precondition is that structural formula (Ic) compound is not N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-ethanamide.
39. acceptable salt on structural formula below a kind (Id) benzodiazepine derivative or its pharmacology,
R wherein
6*Be aryl, it is not substituted or is selected from following substituting group by 1-3 and replaces: halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino ,-CO
2R ' ,-CONR ' R " ,-S (O) R ' ,-S (O)
2R ' ,-S (O) NR ' R " ,-S (O)
2NR ' R " ,-NH-S (O)
2R ' or-NH-CO-R ', wherein each R ' and R are " identical or different and represent hydrogen or C
1-6Alkyl, precondition are R
6*It is not the 4-chloro-phenyl-.
40. acceptable salt on structural formula below a kind (Ie) benzodiazepine derivative or its pharmacology,
R ' wherein
*Be aryl, it is not substituted or is selected from following substituting group by 1-2 and replaces: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, C
1-4Halogenated alkoxy and nitro.
41.
1) 1,1-diethyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
2) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-propionic acid amide
3) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-butyramide
4) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-isobutyramide
5) 2,2-dimethyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-propionic acid amide
6) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-cyclopentane formamide
7) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-cyclohexane carboxamide
8) piperidines-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
9) morpholine-4-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
10) 4-methyl-piperazine-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
11) benzo [b] thiophene-3-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
12) isoxazole-5-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
13) benzo [b] thiophene-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
14) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-Toluidrin
15) propane-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-sulphonamide
16) butane-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-sulphonamide
17) N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-isobutyramide
18) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-Isonicotinamide
19) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-niacinamide
20) N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-ethanamide
21) (S)-2-methoxyl group-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
22) (S)-1-(2-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
23) 2-chloro-4-methylsulfonyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
24) 1-(4-nitro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
25) 4-methylsulfonyl-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
26) 2-methoxyl group-4-methylthio group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
27) 4-methylsulfonyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
28) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-to benzoyl amino acid methyl esters
29) 5-ethanoyl-2-oxyethyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
30) 3-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-to benzoyl amino acid methyl esters
31) 2-methylthio group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
32) 4-amino-5-chloro-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
33) 4-methylsulfonyl-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
34) (S)-2,4,5-three fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
35) (S)-5-ethanoyl-2-oxyethyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-benzamide
36) 2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-5-sulfamyl-benzamide
37) the 1-tertiary butyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
38) 1-cyclohexyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
39) 1-ethyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
40) 1-butyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urea
41) 4,5-dimethyl-furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
42) piperidines-1-N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
43) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl) ethanamide
44) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-isobutyramide
45) N-[5-(3 chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-cyclohexane carboxamide
46) piperidines-1-N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-methane amide
47) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl] Isonicotinamide
48) N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-isobutyramide
49) N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-cyclohexane carboxamide
50) piperidines-1-N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-methane amide
51) piperidines-4-N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl]-methane amide
52) N-(8-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-cyclohexane carboxamide
53) 6-morpholine-4-base-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-niacinamide
54) pyridine-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
55) 6-fluoro-4H-benzo [1,3] dioxine-8-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
56) 1H-pyrazoles-4-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
57) 6-dimethylamino-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-niacinamide
58) 2-oxyethyl group-naphthalene-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
59) 9-oxo-9H-fluorenes-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
60) 2-oxo-2,3-dihydro-benzoglyoxaline-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
61) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl) t-butyl carbamate
62) (S)-6-fluoro-4H-benzo [1,3] dioxine-8-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
63) (S)-4,5-two bromo-furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
64) (S)-3-methoxyl group-naphthalene-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-methane amide
65) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-Urethylane
66) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-urethanum
67) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-isobutyl carbamate
68) 2-oxo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza -3-yl)-2-thiophene-2-base-ethanamide,
Or acceptable salt on their pharmacology.
42. each benzodiazepine derivative of claim 35-41, it is used for the treatment of in the method for human or animal body.
43. a medicinal compositions, its comprise claim 35-41 each benzodiazepine derivative or its pharmacology on acceptable diluent or carrier on acceptable salt and the pharmacology.
44. the composition of claim 43, it comprises each the optically active isomer of benzodiazepine derivative of claim 35-41.
45. the composition of claim 43 or 44, but it is tablet, dragee, lozenge, water suspension or oil suspension dispersion powder or granule form.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0221923.6 | 2002-09-20 | ||
| GBGB0221923.6A GB0221923D0 (en) | 2002-09-20 | 2002-09-20 | Chemical compounds |
| GB0302078.1 | 2003-01-29 | ||
| GB0302078A GB0302078D0 (en) | 2003-01-29 | 2003-01-29 | Chemical compounds |
| PCT/GB2003/004050 WO2004026843A1 (en) | 2002-09-20 | 2003-09-22 | Benzodiazepine derivatives and pharmaceutical compositions containing them |
Publications (2)
| Publication Number | Publication Date |
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| CN1694874A true CN1694874A (en) | 2005-11-09 |
| CN1694874B CN1694874B (en) | 2010-06-09 |
Family
ID=9944504
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN038251906A Expired - Fee Related CN1694874B (en) | 2002-09-20 | 2003-09-22 | Benzodiazepine derivatives and pharmaceutical compositions containing them |
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| Country | Link |
|---|---|
| CN (1) | CN1694874B (en) |
| GB (1) | GB0221923D0 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114555604A (en) * | 2019-08-20 | 2022-05-27 | 瑞威有限公司 | Pharmaceutical compounds |
| CN114761397A (en) * | 2019-10-22 | 2022-07-15 | 瑞威有限公司 | Benzodiazepine derivatives for the treatment of Respiratory Syncytial Virus (RSV) infection |
| CN116075515A (en) * | 2020-07-07 | 2023-05-05 | 辉瑞大药厂 | Benzodiazepine derivatives useful for the treatment of respiratory syncytial virus infection |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4970207A (en) * | 1988-07-07 | 1990-11-13 | Fujisawa Pharmaceutical Company, Ltd. | Benzodiazepine derivatives |
| GB9015879D0 (en) * | 1990-07-19 | 1990-09-05 | Fujisawa Pharmaceutical Co | Benzodiazepine derivatives |
| GB9203790D0 (en) * | 1992-02-21 | 1992-04-08 | Merck Sharp & Dohme | Therapeutic agents |
| GB2282595A (en) * | 1993-08-25 | 1995-04-12 | Yamanouchi Pharma Co Ltd | Benzodiazepine derivatives |
| US5426185A (en) * | 1993-11-22 | 1995-06-20 | Merck & Co., Inc. | Antiarrhythmic benzodiazepines |
| FR2716195B1 (en) * | 1994-02-14 | 1996-06-21 | Sanofi Sa | Polysubstituted 3-acylamino-5-phenyl-1,4-benzodiazepin-2-one derivatives, process for their preparation and pharmaceutical compositions containing them |
| KR970705395A (en) * | 1994-08-18 | 1997-10-09 | 폴락 도나 엘. | 2,3-Dihydro-1- (2,2,2-trifluoroethyl) -2-oxo-5-phenyl-1H-1,4-benzodiazepine , 2-trifluoroethyl) -2-oxo-5-phenyl-1H-1,4-benzodiazepines) |
| DE60007960T2 (en) * | 1999-04-30 | 2004-10-21 | Univ Michigan Ann Arbor | Therapeutic applications of pro-apoptotic benzodiazepines |
| IL151576A0 (en) * | 2000-04-03 | 2003-04-10 | Bristol Myers Squibb Pharma Co | Cyclic lactams as inhibitors of a-beta protein production |
| GB0012671D0 (en) * | 2000-05-24 | 2000-07-19 | Merck Sharp & Dohme | Therapeutic agents |
-
2002
- 2002-09-20 GB GBGB0221923.6A patent/GB0221923D0/en not_active Ceased
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114555604A (en) * | 2019-08-20 | 2022-05-27 | 瑞威有限公司 | Pharmaceutical compounds |
| CN114761397A (en) * | 2019-10-22 | 2022-07-15 | 瑞威有限公司 | Benzodiazepine derivatives for the treatment of Respiratory Syncytial Virus (RSV) infection |
| CN116075515A (en) * | 2020-07-07 | 2023-05-05 | 辉瑞大药厂 | Benzodiazepine derivatives useful for the treatment of respiratory syncytial virus infection |
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| Publication number | Publication date |
|---|---|
| GB0221923D0 (en) | 2002-10-30 |
| CN1694874B (en) | 2010-06-09 |
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