WO2023083191A1 - 苯二氮卓类化合物及其制备方法和在医药上的用途 - Google Patents
苯二氮卓类化合物及其制备方法和在医药上的用途 Download PDFInfo
- Publication number
- WO2023083191A1 WO2023083191A1 PCT/CN2022/130695 CN2022130695W WO2023083191A1 WO 2023083191 A1 WO2023083191 A1 WO 2023083191A1 CN 2022130695 W CN2022130695 W CN 2022130695W WO 2023083191 A1 WO2023083191 A1 WO 2023083191A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- substituted
- alkylene
- alkyl
- halogen
- alkoxy
- Prior art date
Links
- -1 Benzodiazepine compound Chemical class 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 229940049706 benzodiazepine Drugs 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 134
- 239000000203 mixture Substances 0.000 claims abstract description 39
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 239000012453 solvate Substances 0.000 claims abstract description 35
- 206010002091 Anaesthesia Diseases 0.000 claims abstract description 32
- 230000037005 anaesthesia Effects 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 16
- 239000000932 sedative agent Substances 0.000 claims abstract description 16
- 230000001624 sedative effect Effects 0.000 claims abstract description 14
- 229940079593 drug Drugs 0.000 claims abstract description 12
- 238000001990 intravenous administration Methods 0.000 claims abstract description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 270
- 229910052736 halogen Inorganic materials 0.000 claims description 251
- 150000002367 halogens Chemical class 0.000 claims description 231
- 125000000217 alkyl group Chemical group 0.000 claims description 227
- 229910052760 oxygen Inorganic materials 0.000 claims description 189
- 125000003545 alkoxy group Chemical group 0.000 claims description 184
- 125000000623 heterocyclic group Chemical group 0.000 claims description 181
- 229910052799 carbon Inorganic materials 0.000 claims description 168
- 229910052717 sulfur Inorganic materials 0.000 claims description 162
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 162
- 125000001424 substituent group Chemical group 0.000 claims description 128
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 98
- 238000006467 substitution reaction Methods 0.000 claims description 93
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 80
- 229910052739 hydrogen Inorganic materials 0.000 claims description 76
- 239000001257 hydrogen Substances 0.000 claims description 76
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 66
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 65
- 150000002431 hydrogen Chemical group 0.000 claims description 58
- 125000005842 heteroatom Chemical group 0.000 claims description 51
- 229910052757 nitrogen Inorganic materials 0.000 claims description 51
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 43
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 42
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 42
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 36
- 125000004432 carbon atom Chemical group C* 0.000 claims description 32
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 18
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 17
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 17
- 125000004434 sulfur atom Chemical group 0.000 claims description 17
- 230000003444 anaesthetic effect Effects 0.000 claims description 12
- 206010039897 Sedation Diseases 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 230000036280 sedation Effects 0.000 claims description 8
- 239000003193 general anesthetic agent Substances 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 229940035674 anesthetics Drugs 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229940125723 sedative agent Drugs 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 20
- CYHWMBVXXDIZNZ-KRWDZBQOSA-N methyl 3-[(4s)-8-bromo-1-methyl-6-pyridin-2-yl-4h-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate Chemical compound N([C@H](C1=NC=C(C)N1C1=CC=C(Br)C=C11)CCC(=O)OC)=C1C1=CC=CC=N1 CYHWMBVXXDIZNZ-KRWDZBQOSA-N 0.000 abstract description 19
- 229950004245 remimazolam Drugs 0.000 abstract description 18
- 238000011084 recovery Methods 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 12
- 230000006698 induction Effects 0.000 abstract description 5
- 238000012423 maintenance Methods 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 3
- 230000009471 action Effects 0.000 abstract description 2
- 238000001356 surgical procedure Methods 0.000 abstract description 2
- 230000005496 eutectics Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 76
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 238000005481 NMR spectroscopy Methods 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 29
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 17
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000005457 ice water Substances 0.000 description 12
- 239000002994 raw material Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 7
- 230000028527 righting reflex Effects 0.000 description 7
- 239000002253 acid Substances 0.000 description 6
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 235000019260 propionic acid Nutrition 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 3
- 229960003793 midazolam Drugs 0.000 description 3
- SVDDJQGVOFZBNX-UHFFFAOYSA-N 2-chloroethyl carbonochloridate Chemical compound ClCCOC(Cl)=O SVDDJQGVOFZBNX-UHFFFAOYSA-N 0.000 description 2
- IHBVNSPHKMCPST-UHFFFAOYSA-N 3-bromopropanoyl chloride Chemical compound ClC(=O)CCBr IHBVNSPHKMCPST-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 238000002695 general anesthesia Methods 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 2
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 2
- 229960004134 propofol Drugs 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- IIASCQBFNHWZBE-UHFFFAOYSA-N 1-bromoethyl acetate Chemical compound CC(Br)OC(C)=O IIASCQBFNHWZBE-UHFFFAOYSA-N 0.000 description 1
- XYHKNCXZYYTLRG-UHFFFAOYSA-N 1h-imidazole-2-carbaldehyde Chemical compound O=CC1=NC=CN1 XYHKNCXZYYTLRG-UHFFFAOYSA-N 0.000 description 1
- YOCIJWAHRAJQFT-UHFFFAOYSA-N 2-bromo-2-methylpropanoyl bromide Chemical compound CC(C)(Br)C(Br)=O YOCIJWAHRAJQFT-UHFFFAOYSA-N 0.000 description 1
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 1
- RGHQKFQZGLKBCF-UHFFFAOYSA-N 2-bromoethyl acetate Chemical compound CC(=O)OCCBr RGHQKFQZGLKBCF-UHFFFAOYSA-N 0.000 description 1
- ILLHORFDXDLILE-UHFFFAOYSA-N 2-bromopropanoyl bromide Chemical compound CC(Br)C(Br)=O ILLHORFDXDLILE-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M 3-Methylbutanoic acid Natural products CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZYDBQNPLBHTJFF-UHFFFAOYSA-N C(CC)Br.C(C)(=O)O Chemical compound C(CC)Br.C(C)(=O)O ZYDBQNPLBHTJFF-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010065929 Cardiovascular insufficiency Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102000005915 GABA Receptors Human genes 0.000 description 1
- 108010005551 GABA Receptors Proteins 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 206010062237 Renal impairment Diseases 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 description 1
- 229940127085 adjuvant medication Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N beta-methyl-butyric acid Natural products CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- NHYXMAKLBXBVEO-UHFFFAOYSA-N bromomethyl acetate Chemical compound CC(=O)OCBr NHYXMAKLBXBVEO-UHFFFAOYSA-N 0.000 description 1
- 238000013276 bronchoscopy Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 238000013194 cardioversion Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- JYWJULGYGOLCGW-UHFFFAOYSA-N chloromethyl chloroformate Chemical compound ClCOC(Cl)=O JYWJULGYGOLCGW-UHFFFAOYSA-N 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000001839 endoscopy Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000005977 kidney dysfunction Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000005976 liver dysfunction Effects 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000002829 nitrogen Chemical group 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- QQKDTTWZXHEGAQ-UHFFFAOYSA-N propyl carbonochloridate Chemical compound CCCOC(Cl)=O QQKDTTWZXHEGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 238000002693 spinal anesthesia Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the invention belongs to the field of chemical medicine, and in particular relates to a benzodiazepine compound, a preparation method thereof and a medical application thereof.
- Midazolam is the most commonly used benzodiazepine drug, which is relatively safe and acts mainly by binding to central ⁇ -aminobutyric acid (GABAA) receptors.
- GABAA central ⁇ -aminobutyric acid
- the onset is relatively rapid, and it has the effect of reducing intracranial pressure and brain metabolism. It is often used in pre-anesthesia administration, induction and maintenance of general anesthesia, adjuvant medication in spinal anesthesia and local anesthesia, diagnostic or therapeutic operations such as cardiovascular angiography, Sedation of ICU patients during cardioversion, bronchoscopy, gastrointestinal endoscopy, etc.
- Remimazolam is an ultra-short-acting intravenous benzodiazepine sedative/anesthetic that acts on GABA receptors, especially GABA- ⁇ .
- the drug combines the safety of midazolam with the effectiveness of propofol (propofol).
- Remimazolam is rapidly metabolized by tissue esterases into inactive metabolites and is not affected by cytochrome-dependent hepatic pathways. Metabolism is an ultra-short-acting benzodiazepine drug.
- As an intravenous general anesthesia drug it has the characteristics of fast onset, short duration, fast recovery and good tolerance.
- Remimazolam is used for anesthesia induction, maintenance of anesthesia and day surgery anesthesia. Compared with other products, it has certain advantages when applied to patients with cardiovascular disease, respiratory system disease, liver disease and elderly patients.
- remimazolam has a lower potency than other sedative drugs, and it is necessary to increase the dosage in clinical application to increase the potential toxicity; meanwhile, the free base structure of remimazolam is unstable, and the by-products are quite toxic, and It will further affect the activity of drug-metabolizing enzymes in the body, resulting in problems such as high blood drug concentration and drug accumulation during continuous medication. Therefore, it is expected to develop new ultra-short-acting sedative and anesthetic drugs with better safety and higher potency.
- the object of the present invention is to provide a kind of benzodiazepine compound and its preparation method and the application in medicine.
- Each R is independently selected from hydrogen, a short-chain hydrocarbon group, a C3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the short-chain hydrocarbon group, cycloalkyl group or heterocyclic group is selected from 0 to 4 Substituents from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heterocycles selected from N, O, or S Atom, preferably R 1 is a short-chain hydrocarbon group or hydrogen;
- Each R is independently selected from hydrogen, short-chain hydrocarbon group, C 3-10 cycloalkyl group or 3-10 membered heterocyclic group, and the short-chain hydrocarbon group, cycloalkyl group or heterocyclic group is selected from 0-4 Substituents from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heterocycles selected from N, O, or S Atom, preferably R 2 is hydrogen or a short-chain hydrocarbon group;
- R 1 and R 2 on the same carbon atom respectively form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the cycloalkyl group or heterocyclic group is replaced by 0 to 4 members selected from halogen, trifluoro Substituted by methyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heteroatoms selected from N, O, or S;
- n is an integer selected from 0 to 6;
- M is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M2 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy A substituent is substituted, and the NH is substituted by a short-chain hydrocarbon group;
- R 3 is selected from hydrogen, short-chain hydrocarbon group, C 1-8 alkoxy, -C(O)-M 4 -R 5 , C 3-10 cycloalkyl, 6-10 membered aryl or 5-10 membered hetero Aryl, the heteroaryl includes 1 to 3 heteroatoms selected from N, O, or S;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R is selected from short-chain hydrocarbon groups or C 1-8 alkoxy groups
- a is an integer selected from 0 to 6;
- R 4 is selected from pyridine rings with nitrogen at 2, 3, and 4 positions, preferably R 4 is pyridine with nitrogen at 2 positions;
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is an integer selected from 1 to 4.
- M 1 When M 1 is none, a is 1, M 2 is O, M 3 is O or S or NH or C 1-5 alkylene, m is 1, R 3 is -C(O)-M 4 -R 5 , when M 4 is O, R 5 is not selected from short-chain hydrocarbon groups;
- M 1 When M 1 is none, a is 1, M 2 is O, M 3 is O or S or NH or C 1-5 alkylene, m is 1, R 3 is -C(O)-M 4 -R 5 , M 4 is none, R 5 is not selected from C 1-8 alkoxy;
- M 1 When M 1 is none, a is 1, M 2 is O, M 3 is none, m is 1-5, R 3 is -C(O)-M 4 -R 5 , M 4 is O, R 5 is not selected from short chain hydrocarbon groups;
- M 1 is nothing
- a is 1
- M 2 is O
- M 3 is nothing
- m is 1-5
- R 3 is -C(O)-M 4 -R 5
- M 4 is nothing
- R 5 is not selected from C 1-8 alkoxy.
- Each R 1 or R 2 is independently selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocycle or R 1 and R 2 on the same carbon atom respectively constitute a substituted or unsubstituted C 3-10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group; the substituted alkyl, substituted
- the number of substituents of the cycloalkyl or substituted heterocyclic group is 1, 2, 3 or 4, and the substituents of the substituted alkyl, substituted cycloalkyl or substituted heterocyclic group are selected from halogen, trifluoro Methyl, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy; the heteroatoms of the heterocyclic group are selected from N, O, S, and the number of the heteroatoms is 1, 2 or
- n is selected from 0, 1, 2, 3, 4, 5, 6;
- M is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M2 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy A substituent is substituted, and the NH is substituted by C 1-8 alkyl;
- R 3 is selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, -C(O)-M 4 -R 5 , C 3-10 cycloalkyl, 6-10 membered aryl or 5- 10-membered heteroaryl, which includes 1 to 3 heteroatoms selected from N, O, or S;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R is selected from C 1-8 alkyl or C 1-8 alkoxy
- a is selected from 0, 1, 2, 3, 4, 5, 6;
- R 4 is selected from pyridine rings with nitrogen at the 2, 3, and 4 positions;
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is selected from 1, 2, 3, 4;
- M 1 When M 1 is none, a is 1, M 2 is O, M 3 is O or S or NH or C 1-5 alkylene, m is 1, R 3 is -C(O)-M 4 -R 5 , M 4 is O, R 5 is not selected from C 1-8 alkyl;
- M 1 When M 1 is none, a is 1, M 2 is O, M 3 is O or S or NH or C 1-5 alkylene, m is 1, R 3 is -C(O)-M 4 -R 5 , M 4 is none, R 5 is not selected from C 1-8 alkoxy;
- M 1 When M 1 is none, a is 1, M 2 is O, M 3 is none, m is 1-5, R 3 is -C(O)-M 4 -R 5 , M 4 is O, R 5 is not Selected from C 1 ⁇ 8 alkyl groups;
- M 1 is nothing
- a is 1
- M 2 is O
- M 3 is nothing
- m is 1-5
- R 3 is -C(O)-M 4 -R 5
- M 4 is nothing
- R 5 is not selected from C 1-8 alkoxy.
- Each R 1 or R 2 is independently selected from hydrogen, C 1-4 alkyl
- n is selected from 0, 1, 2, 3, 4, 5, 6;
- M is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M2 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy A substituent is substituted, and the NH is substituted by C 1-4 alkyl;
- R 3 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, -C(O)-M 4 -R 5 , C 3-6 cycloalkyl, phenyl, thienyl, pyridyl, imidazolyl;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R is selected from C 1-4 alkyl or C 1-4 alkoxy
- a is selected from 0, 1, 2, 3, 4, 5, 6;
- R 4 is selected from pyridine rings with nitrogen at the 2-position
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is selected from 1;
- M 1 When M 1 is none, a is 1, M 2 is O, M 3 is O or S or NH or C 1-5 alkylene, m is 1, R 3 is -C(O)-M 4 -R 5 , M 4 is O, R 5 is not selected from C 1-4 alkyl;
- M 1 When M 1 is none, a is 1, M 2 is O, M 3 is O or S or NH or C 1-5 alkylene, m is 1, R 3 is -C(O)-M 4 -R 5 , M 4 is none, R 5 is not selected from C 1-4 alkoxy;
- M 1 When M 1 is none, a is 1, M 2 is O, M 3 is none, m is 1-5, R 3 is -C(O)-M 4 -R 5 , M 4 is O, R 5 is not selected from C 1-4 alkyl;
- M 1 is nothing, a is 1, M 2 is O, M 3 is nothing, m is 1-5, R 3 is -C(O)-M 4 -R 5 , M 4 is nothing, R 5 is not selected from C 1-4 alkoxy;
- X is independently selected from -F, -Cl, -Br, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 .
- Each R is independently selected from hydrogen, a short-chain hydrocarbon group, a C3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the short-chain hydrocarbon group, cycloalkyl group or heterocyclic group is selected from 0 to 4 Substituents from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heterocycles selected from N, O, or S Atom, preferably R 1 is a short-chain hydrocarbon group or hydrogen;
- Each R is independently selected from hydrogen, short-chain hydrocarbon group, C 3-10 cycloalkyl group or 3-10 membered heterocyclic group, and the short-chain hydrocarbon group, cycloalkyl group or heterocyclic group is selected from 0-4 Substituents from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heterocycles selected from N, O, or S Atom, preferably R 2 is hydrogen or a short-chain hydrocarbon group;
- R 1 and R 2 on the same carbon atom respectively form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the cycloalkyl group or heterocyclic group is replaced by 0 to 4 members selected from halogen, trifluoro Substituted by methyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heteroatoms selected from N, O, or S;
- n is an integer selected from 1 to 5;
- M2 is selected from O, S, NH or C 1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C 1-6 alkoxy;
- M3 is selected from O, S, NH or C 1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C 1-6 alkoxy;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R is selected from short-chain hydrocarbon groups
- a is an integer selected from 0 to 6;
- R 4 is selected from pyridine rings with nitrogen at 2, 3, and 4 positions, preferably R 4 is pyridine with nitrogen at 2 positions;
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is an integer selected from 1 to 4.
- M 2 is O
- M 3 is O or S or NH or C 1-5 alkylene
- m is 1
- M 4 is not O;
- M2 is O
- M3 is none
- m is 1-5
- M4 is not O.
- Each R 1 or R 2 is independently selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocycle or R 1 and R 2 on the same carbon atom respectively constitute a substituted or unsubstituted C 3-10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group; the substituted alkyl, substituted
- the number of substituents of the cycloalkyl or substituted heterocyclic group is 1, 2, 3 or 4, and the substituents of the substituted alkyl, substituted cycloalkyl or substituted heterocyclic group are selected from halogen, trifluoro Methyl, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy; the heteroatoms of the heterocyclic group are selected from N, O, S, and the number of the heteroatoms is 1, 2 or
- n is selected from 1, 2, 3, 4, 5;
- M2 is selected from O, S, NH or C 1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C 1-6 alkoxy;
- M3 is selected from O, S, NH or C 1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C 1-6 alkoxy;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-8 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6;
- R 4 is selected from pyridine rings with nitrogen at the 2, 3, and 4 positions;
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is selected from 1,2,3,4.
- Each R 1 or R 2 is independently selected from hydrogen, C 1-4 alkyl
- n is selected from 1, 2, 3, 4, 5;
- M2 is selected from O, S, NH or C 1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C 1-6 alkoxy;
- M3 is selected from O, S, NH or C 1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C 1-6 alkoxy;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-4 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6;
- R 4 is selected from pyridine rings with nitrogen at the 2-position
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is selected from 1;
- X is independently selected from -F, -Cl, -Br, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 .
- Each R 1 or R 2 is independently selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocycle or R 1 and R 2 on the same carbon atom respectively constitute a substituted or unsubstituted C 3-10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group; the substituted alkyl, substituted
- the number of substituents of the cycloalkyl or substituted heterocyclic group is 1, 2, 3 or 4, and the substituents of the substituted alkyl, substituted cycloalkyl or substituted heterocyclic group are selected from halogen, trifluoro Methyl, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy; the heteroatoms of the heterocyclic group are selected from N, O, S, and the number of the heteroatoms is 1, 2 or
- n is selected from 1, 2, 3, 4, 5;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-8 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6;
- R 4 is selected from pyridine rings with nitrogen at the 2, 3, and 4 positions;
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is selected from 1, 2, 3, 4;
- M 4 is not O.
- Each R 1 or R 2 is independently selected from hydrogen, C 1-4 alkyl
- n is selected from 1, 2, 3, 4, 5;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-4 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6;
- R 4 is selected from pyridine rings with nitrogen at the 2-position
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is selected from 1;
- X is independently selected from -F, -Cl, -Br, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 .
- n1 is selected from 0, 1, 2, 3, 4;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-8 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6;
- R 4 is selected from pyridine rings with nitrogen at the 2, 3, and 4 positions;
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is selected from 1, 2, 3, 4;
- M 4 is not O.
- n1 is selected from 0, 1, 2, 3, 4;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-4 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6;
- R 4 is selected from pyridine rings with nitrogen at the 2-position
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is selected from 1;
- X is independently selected from -F, -Cl, -Br, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 .
- n1 is selected from 0, 1, 2, 3, 4;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-8 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6;
- M 4 is not O.
- n1 is selected from 0, 1, 2, 3, 4;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-4 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6.
- Each R is independently selected from hydrogen, a short-chain hydrocarbon group, a C3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the short-chain hydrocarbon group, cycloalkyl group or heterocyclic group is selected from 0 to 4 Substituents from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heterocycles selected from N, O, or S Atom, preferably R 1 is a short-chain hydrocarbon group or hydrogen;
- Each R is independently selected from hydrogen, short-chain hydrocarbon group, C 3-10 cycloalkyl group or 3-10 membered heterocyclic group, and the short-chain hydrocarbon group, cycloalkyl group or heterocyclic group is selected from 0-4 Substituents from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heterocycles selected from N, O, or S Atom, preferably R 2 is hydrogen or a short-chain hydrocarbon group;
- R 1 and R 2 on the same carbon atom respectively form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the cycloalkyl group or heterocyclic group is replaced by 0 to 4 members selected from halogen, trifluoro Substituted by methyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heteroatoms selected from N, O, or S;
- n is an integer selected from 0 to 6;
- M1 is selected from O, S, NH or C 1-5 alkylene, said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, C 1-6 alkoxy;
- M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R is selected from short-chain hydrocarbon groups
- a is an integer selected from 0 to 6;
- R 4 is selected from pyridine rings with nitrogen at 2, 3, and 4 positions, preferably R 4 is pyridine with nitrogen at 2 positions;
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is an integer selected from 1-4.
- Each R 1 or R 2 is independently selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocycle or R 1 and R 2 on the same carbon atom respectively constitute a substituted or unsubstituted C 3-10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group; the substituted alkyl, substituted
- the number of substituents of the cycloalkyl or substituted heterocyclic group is 1, 2, 3 or 4, and the substituents of the substituted alkyl, substituted cycloalkyl or substituted heterocyclic group are selected from halogen, trifluoro Methyl, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy; the heteroatoms of the heterocyclic group are selected from N, O, S, and the number of the heteroatoms is 1, 2 or
- n is selected from 0, 1, 2, 3, 4, 5, 6;
- M1 is selected from O, S, NH or C 1-5 alkylene, said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, C 1-6 alkoxy;
- M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-8 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6;
- R 4 is selected from pyridine rings with nitrogen at the 2, 3, and 4 positions;
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is selected from 1,2,3,4.
- Each R 1 or R 2 is independently selected from hydrogen, C 1-4 alkyl
- n is selected from 0, 1, 2, 3, 4, 5, 6;
- M1 is selected from O, S, NH or C 1-5 alkylene, said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, C 1-6 alkoxy;
- M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-4 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6;
- R 4 is selected from pyridine rings with nitrogen at the 2-position
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is selected from 1;
- X is independently selected from -F, -Cl, -Br, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 .
- Each R 1 or R 2 is independently selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocycle or R 1 and R 2 on the same carbon atom respectively constitute a substituted or unsubstituted C 3-10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group; the substituted alkyl, substituted
- the number of substituents of the cycloalkyl or substituted heterocyclic group is 1, 2, 3 or 4, and the substituents of the substituted alkyl, substituted cycloalkyl or substituted heterocyclic group are selected from halogen, trifluoro Methyl, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy; the heteroatoms of the heterocyclic group are selected from N, O, S, and the number of the heteroatoms is 1, 2 or
- n is selected from 0, 1, 2, 3, 4, 5, 6;
- M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-8 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6;
- R 4 is selected from pyridine rings with nitrogen at the 2, 3, and 4 positions;
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is selected from 1,2,3,4.
- Each R 1 or R 2 is independently selected from hydrogen, C 1-4 alkyl
- n is selected from 0, 1, 2, 3, 4, 5, 6;
- M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-4 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6;
- R 4 is selected from pyridine rings with nitrogen at the 2-position
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is selected from 1;
- X is independently selected from -F, -Cl, -Br, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 .
- Each R 1 or R 2 is independently selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocycle or R 1 and R 2 on the same carbon atom respectively constitute a substituted or unsubstituted C 3-10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group; the substituted alkyl, substituted
- the number of substituents of the cycloalkyl or substituted heterocyclic group is 1, 2, 3 or 4, and the substituents of the substituted alkyl, substituted cycloalkyl or substituted heterocyclic group are selected from halogen, trifluoro Methyl, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy; the heteroatoms of the heterocyclic group are selected from N, O, S, and the number of the heteroatoms is 1, 2 or
- n is selected from 0, 1, 2, 3, 4, 5, 6;
- M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-8 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6.
- Each R 1 or R 2 is independently selected from hydrogen, C 1-4 alkyl
- n is selected from 0, 1, 2, 3, 4, 5, 6;
- M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-4 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6.
- Each R is independently selected from hydrogen, a short-chain hydrocarbon group, a C3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the short-chain hydrocarbon group, cycloalkyl group or heterocyclic group is selected from 0 to 4 Substituents from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heterocycles selected from N, O, or S Atom, preferably R 1 is a short-chain hydrocarbon group or hydrogen;
- Each R is independently selected from hydrogen, short-chain hydrocarbon group, C 3-10 cycloalkyl group or 3-10 membered heterocyclic group, and the short-chain hydrocarbon group, cycloalkyl group or heterocyclic group is selected from 0-4 Substituents from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heterocycles selected from N, O, or S Atom, preferably R 2 is hydrogen or a short-chain hydrocarbon group;
- R 1 and R 2 on the same carbon atom respectively form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the cycloalkyl group or heterocyclic group is replaced by 0 to 4 members selected from halogen, trifluoro Substituted by methyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heteroatoms selected from N, O, or S;
- n is an integer selected from 0 to 6;
- M1 is selected from O, S, NH or C 1-5 alkylene, said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, C 1-6 alkoxy;
- M2 is selected from O, S, NH or C 1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C 1-6 alkoxy;
- M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R is selected from short-chain hydrocarbon groups
- a is an integer selected from 0 to 6;
- R 4 is selected from pyridine rings with nitrogen at 2, 3, and 4 positions, preferably R 4 is pyridine with nitrogen at 2 positions;
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is an integer selected from 1-4.
- Each R 1 or R 2 is independently selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocycle or R 1 and R 2 on the same carbon atom respectively constitute a substituted or unsubstituted C 3-10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group; the substituted alkyl, substituted
- the number of substituents of the cycloalkyl or substituted heterocyclic group is 1, 2, 3 or 4, and the substituents of the substituted alkyl, substituted cycloalkyl or substituted heterocyclic group are selected from halogen, trifluoro Methyl, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy; the heteroatoms of the heterocyclic group are selected from N, O, S, and the number of the heteroatoms is 1, 2 or
- n is selected from 0, 1, 2, 3, 4, 5, 6;
- M1 is selected from O, S, NH or C 1-5 alkylene, said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, C 1-6 alkoxy;
- M2 is selected from O, S, NH or C 1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C 1-6 alkoxy;
- M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-8 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6;
- R 4 is selected from pyridine rings with nitrogen at the 2, 3, and 4 positions;
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is selected from 1,2,3,4.
- Each R 1 or R 2 is independently selected from hydrogen, C 1-4 alkyl
- n is selected from 0, 1, 2, 3, 4, 5, 6;
- M1 is selected from O, S, NH or C 1-5 alkylene, said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, C 1-6 alkoxy;
- M2 is selected from O, S, NH or C 1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C 1-6 alkoxy;
- M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-4 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6;
- R 4 is selected from pyridine rings with nitrogen at the 2-position
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is selected from 1;
- X is independently selected from -F, -Cl, -Br, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 .
- Each R 1 or R 2 is independently selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocycle or R 1 and R 2 on the same carbon atom respectively constitute a substituted or unsubstituted C 3-10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group; the substituted alkyl, substituted
- the number of substituents of the cycloalkyl or substituted heterocyclic group is 1, 2, 3 or 4, and the substituents of the substituted alkyl, substituted cycloalkyl or substituted heterocyclic group are selected from halogen, trifluoro Methyl, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy; the heteroatoms of the heterocyclic group are selected from N, O, S, and the number of the heteroatoms is 1, 2 or
- n is selected from 0, 1, 2, 3, 4, 5, 6;
- M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-8 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6;
- R 4 is selected from pyridine rings with nitrogen at the 2, 3, and 4 positions;
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is selected from 1,2,3,4.
- Each R 1 or R 2 is independently selected from hydrogen, C 1-4 alkyl
- n is selected from 0, 1, 2, 3, 4, 5, 6;
- M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-4 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6;
- R 4 is selected from pyridine rings with nitrogen at the 2-position
- X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;
- n is selected from 1;
- X is independently selected from -F, -Cl, -Br, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 .
- Each R 1 or R 2 is independently selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocycle or R 1 and R 2 on the same carbon atom respectively constitute a substituted or unsubstituted C 3-10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group; the substituted alkyl, substituted
- the number of substituents of the cycloalkyl or substituted heterocyclic group is 1, 2, 3 or 4, and the substituents of the substituted alkyl, substituted cycloalkyl or substituted heterocyclic group are selected from halogen, trifluoro Methyl, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy; the heteroatoms of the heterocyclic group are selected from N, O, S, and the number of the heteroatoms is 1, 2 or
- n is selected from 0, 1, 2, 3, 4, 5, 6;
- M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-8 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6.
- Each R 1 or R 2 is independently selected from hydrogen, C 1-4 alkyl
- n is selected from 0, 1, 2, 3, 4, 5, 6;
- M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;
- R 5 is selected from C 1-4 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6.
- R 3 is selected from C 1-8 alkyl
- a is selected from 0, 1, 2, 3, 4, 5, 6.
- R 3 is selected from C 1-8 alkyl, C 3-6 cycloalkyl, phenyl, thienyl, pyridyl, imidazolyl; a is selected from 0, 1, 2, 3, 4, 5, 6.
- the compound is one of the following compounds:
- the present invention also provides the use of the aforementioned compound, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition in the preparation of sedatives and/or anesthetics;
- the sedative and/or anesthetic is a sedative and/or anesthetic for intravenous sedation and/or anesthesia.
- the present invention also provides a medicine, which uses the aforementioned compound, or its salt, or its stereoisomer, or its solvate, or its co-crystal, or its composition as an active ingredient, plus pharmaceutically Preparations prepared from acceptable excipients or auxiliary ingredients;
- the drug is a sedative and/or anesthetic
- the sedative and/or anesthetic is a sedative and/or anesthetic for intravenous sedation and/or anesthesia.
- the room temperature is 25 ⁇ 5°C, and overnight is 12 ⁇ 2h.
- substitution in the present invention means that the hydrogen atoms in the molecule are replaced by other different atoms or molecules.
- C a ⁇ b alkyl means any alkyl group containing "a" to "b" carbon atoms.
- C 1-10 alkyl refers to straight chain or branched chain alkyl containing 1-10 carbon atoms
- C 1-10 alkoxy refers to alkoxy containing 1-10 carbon atoms.
- the short-chain hydrocarbon group in the present invention is a straight-chain or branched-chain alkyl group containing 1 to 10 carbon atoms.
- C 3-10 cycloalkyl refers to a saturated cycloalkyl group consisting of 3-10 carbon atoms.
- the 3-10 membered heterocyclic group refers to a saturated heterocyclic group, the heterocyclic group is composed of 3-10 atoms, at least one of which is selected from O, S or substituted nitrogen atom, silicon atom .
- aryl refers to a group containing aromatic unsaturation without ring heteroatoms and having a single ring or multiple rings (including fused, bridged and spiro ring systems), such as phenyl, anthracenyl, naphthyl.
- Heteroaryl refers to an aromatic unsaturated ring containing at least one heteroatom; including single ring or multiple rings (including fused, bridged and spiro ring systems); wherein heteroatom refers to nitrogen atom, oxygen atom, sulfur atom.
- heteroatom refers to nitrogen atom, oxygen atom, sulfur atom.
- halogen is fluorine, chlorine, bromine or iodine.
- the compound of the present invention has good intravenous sedation and anesthesia effect, and its anesthesia effect is equivalent to that of remimazolam, or even better than that of remimazolam, and is specifically manifested in that the effective dose is significantly reduced, and the duration and recovery time are significantly reduced.
- the compound of the present invention significantly reduces the occurrence of side effects compared with remimazolam, and the quality of recovery is significantly improved.
- the compound of the present invention has quick onset of action, short duration, quick recovery, low toxicity and good tolerance during anesthesia, can be used for anesthesia induction, anesthesia maintenance and daytime operation anesthesia, and has a good application prospect.
- the raw materials and equipment used in the specific embodiment of the present invention are all known products, obtained by purchasing commercially available products.
- reaction solution was filtered, it was poured into 50 mL of water, extracted with 100 mL of dichloromethane, the organic layer was separated, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and 500 mg of light yellow oil was obtained by column chromatography.
- reaction solution was filtered, it was poured into 50 mL of water, extracted with 100 mL of dichloromethane, the organic layer was separated, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and 550 mg of light yellow oil was obtained by column chromatography.
- reaction solution was filtered, it was poured into 50 mL of water, extracted with 100 mL of dichloromethane, the organic layer was separated, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and 530 mg of light green oil was obtained by column chromatography.
- reaction solution was filtered, it was poured into 50 mL of water, extracted with 100 mL of dichloromethane, the organic layer was separated, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and 530 mg of light green oil was obtained by column chromatography.
- the compounds of the present invention are evaluated for their pharmacological activity, efficacy and safety.
- anesthetic drug In clinical application, it is necessary to strictly control the effect of anesthetic drugs, so as to ensure the smooth progress of the operation, diagnosis and other processes, and to terminate the anesthesia as soon as possible after the operation, so that the patient can wake up quickly. If the anesthesia lasts too long, it may cause some adverse effects on the cardiovascular system and respiratory system, such as drowsiness and dizziness. Therefore, an ideal anesthetic drug should have the advantages of quick onset, quick recovery, and high safety.
- each compound was subjected to loss of righting reflex (LORR) experiment in mice, and the anesthesia half effective dose (ED 50 ) of the compound was determined.
- LORR loss of righting reflex
- mice male Kunming mice (25-30g) were randomly selected, the compound was prepared with PEG-400: pure water (3:7), and the administration volume was 0.2mL. According to the preliminary experiment results, between the highest and the lowest dose Set the other three doses according to the geometric sequence. Start administration from the middle dose (the tail vein injection time is about 10s), and observe the disappearance of righting reflex in mice.
- the duration of righting reflex disappearance of the first mouse is more than 30s, it is positive, then the second mouse is given a lower dose; if the first mouse’s righting reflex disappears for less than 30s or the If it disappears, it is negative, and the second mouse is given a higher dose; the experiment is repeated until 8 cycles of positive-negative or negative-positive are crossed to end the experiment.
- the duration of anesthesia is the time from the disappearance of the righting reflex to the recovery of the righting reflex
- the recovery quality is the time from the recovery of the righting reflex to the ability to crawl freely;
- the recovery quality "+” means ⁇ 1 min
- "++" means greater than or equal to Between 1min and less than 3min
- "+++” means greater than or equal to 3min and less than 5min
- "++++” means greater than or equal to 5min to less than 10min
- "++++” means ⁇ 10min .
- the compound of the present invention can reduce the effective dosage, and has the characteristics of quick onset, short recovery time, higher quality of recovery, and as an anesthetic, the effect is obviously better than that of remazolam Zolam.
- the compound of the present invention has good intravenous sedation and anesthesia effects, and its anesthesia effect is comparable to that of remimazolam, or even better than that of remimazolam, specifically manifested in a significant reduction in effective dose, and a significant reduction in duration and recovery time.
- the awakening quality of the compound of the present invention is significantly improved compared with remimazolam.
- the compound of the present invention has quick onset, short duration, quick recovery and good tolerance during anesthesia, can be used for anesthesia induction, anesthesia maintenance and daytime operation anesthesia, and has a good application prospect.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Anesthesiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
提供了苯二氮卓类化合物及其制备方法和在医药上的用途，属于化学医药领域。所述苯二氮卓类化合物是式I所示的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物。所述化合物的静脉镇静麻醉效果佳，其麻醉效果与瑞马唑仑相当，甚至优于瑞马唑仑，具体表现在有效剂量显著降低、持续时间和恢复时间显著减少。同时在大、小鼠尾静脉麻醉模型中，所述化合物相比瑞马唑仑苏醒质量得到显著提高。所述化合物麻醉时起效快、持续时间短、苏醒快、耐受性良好，可用于麻醉诱导、麻醉维持和日间手术麻醉，具有良好的应用前景。
Description
本发明属于化学医药领域，具体涉及苯二氮卓类化合物及其制备方法和在医药上的用途。
咪达唑仑是最常用的苯二氮卓类药，安全性较好，主要是通过结合中枢γ-氨基丁酸(GABAA)受体而发挥作用。起效较为迅速，具有降低颅内压以及脑代谢的作用，常用于麻醉前给药、全麻醉诱导和维持、椎管内麻醉及局部麻醉时辅助用药、诊断或治疗性操作如心血管造影、心律转复、支气管镜检查、消化道内镜检查等时、ICU病人镇静。但由于其代谢依赖于肝脏及肾脏，长时间持续输注会造成药物在体内蓄积，通常出现过度镇静、呼吸循环抑制、药物耐受等不良反应，并且对于肝肾功能障碍患者不能长时间使用。
瑞马唑仑(Remimazolam)的母体结构是咪达唑仑，是一种超短效静脉注射苯二氮卓镇静剂/麻醉剂，作用于GABA受体，特别是GABA-α。该药结合了咪达唑仑的安全性与异丙酚(丙泊酚)的有效性，在人体中，Remimazolam被组织酯酶迅速代谢成无活性代谢物，并且不被细胞色素依赖性肝脏途径代谢，是一种超短效苯二氮卓类药物，其作为静脉全身麻醉药物，具有起效快、持续时间短、苏醒快和耐受性良好的特点。瑞马唑仑用于麻醉诱导、麻醉维持和日间手术麻醉，相比其他产品在应用于伴有心血管疾病、呼吸系统疾病、肝病以及老年患者时具有一定的优势。
但相关报道瑞马唑仑相比其他镇静药物效价较低，临床应用时需提高用药剂量，增加潜在的毒性；同时瑞马唑仑的游离碱结构不稳定，副产物具有相当的毒性，并会进一步影响体内药物代谢酶活性，造成持续用药时血药浓度偏高和药物蓄积等问题。因此期望开发出安全性更好、效价更高的新型超短效镇静麻醉类药物。
发明内容
本发明的目的是提供一种苯二氮卓类化合物及其制备方法和在医药上的用途。
本发明提式I所示的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物：
其中，
每个R
1分别独立选自氢、短链烃基、C
3-10环烷基或3～10元杂环基，所述的短链烃基、环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子，优选R
1为短链烃基或氢；
每个R
2分别独立选自氢、短链烃基、C
3-10环烷基或3～10元杂环基，所述的短链烃基、环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子，优选R
2为氢或短链烃基；
或者同一个碳原子上R
1和R
2分别构成C
3-10环烷基或3～10元杂环基，所述的环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子；
m选自0～6的整数；
M
1选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
2选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
3选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代，所述NH被短链烃基取代；
R
3选自氢、短链烃基、C
1-8烷氧基、-C(O)-M
4-R
5、C
3-10环烷基、6～10元芳基或5～10元杂芳基，所述杂芳基中包括1～3个选自N、O、或S的杂原子；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自短链烃基或C
1-8烷氧基；
a选自0～6的整数；
R
4选自氮在2、3、4位的吡啶环，优选R
4为氮在2位的吡啶；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1～4的整数；
当M
1为无、a为1、M
2为O、M
3为O或S或NH或C
1-5亚烷基、m为1、R
3为-C(O)-M
4-R
5、M
4为O时，R
5不选自短链烃基；
当M
1为无、a为1、M
2为O、M
3为O或S或NH或C
1-5亚烷基、m为1、R
3为-C(O)-M
4-R
5、M
4为无时，R
5不选自C
1-8烷氧基；
当M
1为无、a为1、M
2为O、M
3为无、m为1～5、R
3为-C(O)-M
4-R
5、M
4为O时，R
5不选自短链烃基；
当M
1为无、a为1、M
2为O、M
3为无、m为1～5、R
3为-C(O)-M
4-R
5、M
4为无时，R
5不选自C
1-8烷氧基。
进一步地，
每个R
1或R
2分别独立的选自氢、取代或未取代的C
1-8烷基、取代或未取代的C
3-10环烷基或取代或未取代的3～10元杂环基；或者同一个碳原子上R
1和R
2分别构成取代或未取代的C
3-10环烷基、取代或未取代的3～10元杂环基；所述取代的烷基、取代的环烷基或取代的杂环基的取代基个数为1、2、3或4，所述取代的烷基、取代的环烷基或取代的杂环基的取代基选自卤素、三氟甲基、氰基、硝基、C
1-8烷基、C
1-8烷氧基；所述杂环基的杂原子选自N、O、S，所述杂原子的个数为1、2或3；
m选自0、1、2、3、4、5、6；
M
1选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
2选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
3选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代，所述NH被C
1-8烷基取代；
R
3选自氢、C
1-8烷基、C
1-8烷氧基、-C(O)-M
4-R
5、C
3-10环烷基、6～10元芳基或5～10元杂芳基，所述杂芳基中包括1～3个选自N、O、或S的杂原子；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-8烷基或C
1-8烷氧基；
a选自0、1、2、3、4、5、6；
R
4选自氮在2、3、4位的吡啶环；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1、2、3、4；
当M
1为无、a为1、M
2为O、M
3为O或S或NH或C
1-5亚烷基、m为1、R
3为-C(O)-M
4-R
5、M
4为O时，R
5不选自C
1-8烷基；
当M
1为无、a为1、M
2为O、M
3为O或S或NH或C
1-5亚烷基、m为1、R
3为-C(O)-M
4-R
5、M
4为无时，R
5不选自C
1-8烷氧基；
当M
1为无、a为1、M
2为O、M
3为无、m为1～5、R
3为-C(O)-M
4-R
5、M
4为O时，R
5不选自C
1～8烷基；
当M
1为无、a为1、M
2为O、M
3为无、m为1～5、R
3为-C(O)-M
4-R
5、M
4为无时，R
5不选自C
1-8烷氧基。
进一步地，
每个R
1或R
2分别独立的选自氢、C
1-4烷基；
m选自0、1、2、3、4、5、6；
M
1选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
2选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
3选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代，所述NH被C
1-4烷基取代；
R
3选自氢、C
1-4烷基、C
1-4烷氧基、-C(O)-M
4-R
5、C
3-6环烷基、苯基、噻吩基、吡啶基、咪唑基；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-4烷基或C
1-4烷氧基；
a选自0、1、2、3、4、5、6；
R
4选自氮在2位的吡啶环；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1；
当M
1为无、a为1、M
2为O、M
3为O或S或NH或C
1-5亚烷基、m为1、R
3为-C(O)-M
4-R
5、M
4为O时，R
5不选自C
1-4烷基；
当M
1为无、a为1、M
2为O、M
3为O或S或NH或C
1-5亚烷基、m为1、R
3为-C(O)-M
4-R
5、M
4为无时，R
5不选自C
1-4烷氧基；
当M
1为无、a为1、M
2为O、M
3为无、m为1～5、R
3为-C(O)-M
4-R
5、M
4为O时，R
5不选自C
1-4烷基；
当M
1为无、a为1、M
2为O、M
3为无、m为1～5、R
3为-C(O)-M
4-R
5、M
4为无时，R
5不选自C
1-4烷氧基；
优选地，
X分别独立选自-F、-Cl、-Br、-CH
3、-OCH
3、-CF
3、-OCF
3。
进一步地，所述化合物为式II所示：
其中，
每个R
1分别独立选自氢、短链烃基、C
3-10环烷基或3～10元杂环基，所述的短链烃基、环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子，优选R
1为短链烃基或氢；
每个R
2分别独立选自氢、短链烃基、C
3-10环烷基或3～10元杂环基，所述的短链烃基、环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子，优选R
2为氢或短链烃基；
或者同一个碳原子上R
1和R
2分别构成C
3-10环烷基或3～10元杂环基，所述的环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子；
m选自1～5的整数；
M
2选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
3选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自短链烃基；
a选自0～6的整数；
R
4选自氮在2、3、4位的吡啶环，优选R
4为氮在2位的吡啶；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1～4的整数；
当a为1、M
2为O、M
3为O或S或NH或C
1-5亚烷基、m为1时，M
4不为O；
当a为1、M
2为O、M
3为无、m为1～5时，M
4不为O。
进一步地，
每个R
1或R
2分别独立的选自氢、取代或未取代的C
1-8烷基、取代或未取代的C
3-10环烷基或取代或未取代的3～10元杂环基；或者同一个碳原子上R
1和R
2分别构成取代或未取代的C
3-10环烷基、取代或未取代的3～10元杂环基；所述取代的烷基、取代的环烷基或取代的杂环基的取代基个数为1、2、3或4，所述取代的烷基、取代的环烷基或取代的杂环基的取代基选自卤素、三氟甲基、氰基、硝基、C
1-8烷基、C
1-8烷氧基；所述杂环基的杂原子选自N、O、S，所述杂原子的个数为1、2或3；
m选自1、2、3、4、5；
M
2选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
3选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-8烷基；
a选自0、1、2、3、4、5、6；
R
4选自氮在2、3、4位的吡啶环；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1、2、3、4。
进一步地，
每个R
1或R
2分别独立的选自氢、C
1-4烷基；
m选自1、2、3、4、5；
M
2选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
3选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-4烷基；
a选自0、1、2、3、4、5、6；
R
4选自氮在2位的吡啶环；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1；
优选地，
X分别独立选自-F、-Cl、-Br、-CH
3、-OCH
3、-CF
3、-OCF
3。
进一步地，所述化合物为式II-a所示：
其中，
每个R
1或R
2分别独立的选自氢、取代或未取代的C
1-8烷基、取代或未取代的C
3-10环烷基或取代或未取代的3～10元杂环基；或者同一个碳原子上R
1和R
2分别构成取代或未取代的C
3-10环烷基、取代或未取代的3～10元杂环基；所述取代的烷基、取代的环烷基或取代的杂环基的取代基个数为1、2、3或4，所述取代的烷基、取代的环烷基或取代的杂环基的取代基选自卤素、三氟甲基、氰基、硝基、C
1-8烷基、C
1-8烷氧基；所述杂环基的杂原子选自N、O、S，所述杂原子的个数为1、2或3；
m选自1、2、3、4、5；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-8烷基；
a选自0、1、2、3、4、5、6；
R
4选自氮在2、3、4位的吡啶环；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1、2、3、4；
当a为1、m为1时，M
4不为O。
进一步地，
每个R
1或R
2分别独立的选自氢、C
1-4烷基；
m选自1、2、3、4、5；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-4烷基；
a选自0、1、2、3、4、5、6；
R
4选自氮在2位的吡啶环；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1；
优选地，
X分别独立选自-F、-Cl、-Br、-CH
3、-OCH
3、-CF
3、-OCF
3。
进一步地，所述化合物为式II-b所示：
其中，
m1选自0、1、2、3、4；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-8烷基；
a选自0、1、2、3、4、5、6；
R
4选自氮在2、3、4位的吡啶环；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1、2、3、4；
当a为1、m1为0时，M
4不为O。
进一步地，
m1选自0、1、2、3、4；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-4烷基；
a选自0、1、2、3、4、5、6；
R
4选自氮在2位的吡啶环；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1；
优选地，
X分别独立选自-F、-Cl、-Br、-CH
3、-OCH
3、-CF
3、-OCF
3。
进一步地，所述化合物为式II-c所示：
其中，
m1选自0、1、2、3、4；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-8烷基；
a选自0、1、2、3、4、5、6；
当a为1、m1为0时，M
4不为O。
进一步地，
m1选自0、1、2、3、4；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-4烷基；
a选自0、1、2、3、4、5、6。
进一步地，所述化合物为式III所示：
其中，
每个R
1分别独立选自氢、短链烃基、C
3-10环烷基或3～10元杂环基，所述的短链烃基、环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子，优选R
1为短链烃基或氢；
每个R
2分别独立选自氢、短链烃基、C
3-10环烷基或3～10元杂环基，所述的短链烃 基、环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子，优选R
2为氢或短链烃基；
或者同一个碳原子上R
1和R
2分别构成C
3-10环烷基或3～10元杂环基，所述的环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子；
m选自0～6的整数；
M
1选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
3选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自短链烃基；
a选自0～6的整数；
R
4选自氮在2、3、4位的吡啶环，优选R
4为氮在2位的吡啶；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1～4的整数。
进一步地，
每个R
1或R
2分别独立的选自氢、取代或未取代的C
1-8烷基、取代或未取代的C
3-10环烷基或取代或未取代的3～10元杂环基；或者同一个碳原子上R
1和R
2分别构成取代或未取代的C
3-10环烷基、取代或未取代的3～10元杂环基；所述取代的烷基、取代的环烷基或取代的杂环基的取代基个数为1、2、3或4，所述取代的烷基、取代的环烷基或取代的杂环基的取代基选自卤素、三氟甲基、氰基、硝基、C
1-8烷基、C
1-8烷氧基；所述杂环基的杂原子选自N、O、S，所述杂原子的个数为1、2或3；
m选自0、1、2、3、4、5、6；
M
1选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
3选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-8烷基；
a选自0、1、2、3、4、5、6；
R
4选自氮在2、3、4位的吡啶环；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1、2、3、4。
进一步地，
每个R
1或R
2分别独立的选自氢、C
1-4烷基；
m选自0、1、2、3、4、5、6；
M
1选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
3选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-4烷基；
a选自0、1、2、3、4、5、6；
R
4选自氮在2位的吡啶环；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1；
优选地，
X分别独立选自-F、-Cl、-Br、-CH
3、-OCH
3、-CF
3、-OCF
3。
进一步地，所述化合物为式III-a所示：
其中，
每个R
1或R
2分别独立的选自氢、取代或未取代的C
1-8烷基、取代或未取代的C
3-10环烷基或取代或未取代的3～10元杂环基；或者同一个碳原子上R
1和R
2分别构成取代或未取代的C
3-10环烷基、取代或未取代的3～10元杂环基；所述取代的烷基、取代的环烷基或取代的杂环基的取代基个数为1、2、3或4，所述取代的烷基、取代的环烷基或取代的 杂环基的取代基选自卤素、三氟甲基、氰基、硝基、C
1-8烷基、C
1-8烷氧基；所述杂环基的杂原子选自N、O、S，所述杂原子的个数为1、2或3；
m选自0、1、2、3、4、5、6；
M
3选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-8烷基；
a选自0、1、2、3、4、5、6；
R
4选自氮在2、3、4位的吡啶环；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1、2、3、4。
进一步地，
每个R
1或R
2分别独立的选自氢、C
1-4烷基；
m选自0、1、2、3、4、5、6；
M
3选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-4烷基；
a选自0、1、2、3、4、5、6；
R
4选自氮在2位的吡啶环；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1；
优选地，
X分别独立选自-F、-Cl、-Br、-CH
3、-OCH
3、-CF
3、-OCF
3。
进一步地，所述化合物为式III-b所示：
其中，
每个R
1或R
2分别独立的选自氢、取代或未取代的C
1-8烷基、取代或未取代的C
3-10环烷基或取代或未取代的3～10元杂环基；或者同一个碳原子上R
1和R
2分别构成取代或未取代的C
3-10环烷基、取代或未取代的3～10元杂环基；所述取代的烷基、取代的环烷基或取代的杂环基的取代基个数为1、2、3或4，所述取代的烷基、取代的环烷基或取代的杂环基的取代基选自卤素、三氟甲基、氰基、硝基、C
1-8烷基、C
1-8烷氧基；所述杂环基的杂原子选自N、O、S，所述杂原子的个数为1、2或3；
m选自0、1、2、3、4、5、6；
M
3选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-8烷基；
a选自0、1、2、3、4、5、6。
进一步地，
每个R
1或R
2分别独立的选自氢、C
1-4烷基；
m选自0、1、2、3、4、5、6；
M
3选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-4烷基；
a选自0、1、2、3、4、5、6。
进一步地，所述化合物为式IV所示：
其中，
每个R
1分别独立选自氢、短链烃基、C
3-10环烷基或3～10元杂环基，所述的短链烃基、环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子，优选R
1为短链烃基或氢；
每个R
2分别独立选自氢、短链烃基、C
3-10环烷基或3～10元杂环基，所述的短链烃基、环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子，优选R
2为氢或短链烃基；
或者同一个碳原子上R
1和R
2分别构成C
3-10环烷基或3～10元杂环基，所述的环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子；
m选自0～6的整数；
M
1选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
2选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
3选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自短链烃基；
a选自0～6的整数；
R
4选自氮在2、3、4位的吡啶环，优选R
4为氮在2位的吡啶；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1～4的整数。
进一步地，
每个R
1或R
2分别独立的选自氢、取代或未取代的C
1-8烷基、取代或未取代的C
3-10环烷基或取代或未取代的3～10元杂环基；或者同一个碳原子上R
1和R
2分别构成取代或未取代的C
3-10环烷基、取代或未取代的3～10元杂环基；所述取代的烷基、取代的环烷基或取代的杂环基的取代基个数为1、2、3或4，所述取代的烷基、取代的环烷基或取代的杂环基的取代基选自卤素、三氟甲基、氰基、硝基、C
1-8烷基、C
1-8烷氧基；所述杂环基的杂原子选自N、O、S，所述杂原子的个数为1、2或3；
m选自0、1、2、3、4、5、6；
M
1选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
2选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
3选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-8烷基；
a选自0、1、2、3、4、5、6；
R
4选自氮在2、3、4位的吡啶环；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1、2、3、4。
进一步地，
每个R
1或R
2分别独立的选自氢、C
1-4烷基；
m选自0、1、2、3、4、5、6；
M
1选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
2选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
3选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-4烷基；
a选自0、1、2、3、4、5、6；
R
4选自氮在2位的吡啶环；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1；
优选地，
X分别独立选自-F、-Cl、-Br、-CH
3、-OCH
3、-CF
3、-OCF
3。
进一步地，所述化合物为式IV-a所示：
其中，
每个R
1或R
2分别独立的选自氢、取代或未取代的C
1-8烷基、取代或未取代的C
3-10环烷基或取代或未取代的3～10元杂环基；或者同一个碳原子上R
1和R
2分别构成取代或未取代的C
3-10环烷基、取代或未取代的3～10元杂环基；所述取代的烷基、取代的环烷基或取代的杂环基的取代基个数为1、2、3或4，所述取代的烷基、取代的环烷基或取代的杂环基的取代基选自卤素、三氟甲基、氰基、硝基、C
1-8烷基、C
1-8烷氧基；所述杂环基的杂原子选自N、O、S，所述杂原子的个数为1、2或3；
m选自0、1、2、3、4、5、6；
M
3选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-8烷基；
a选自0、1、2、3、4、5、6；
R
4选自氮在2、3、4位的吡啶环；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1、2、3、4。
进一步地，
每个R
1或R
2分别独立的选自氢、C
1-4烷基；
m选自0、1、2、3、4、5、6；
M
3选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-4烷基；
a选自0、1、2、3、4、5、6；
R
4选自氮在2位的吡啶环；
X分别独立选自卤素、取代或未取代的C
1-8烷基、取代或未取代的C
1-8烷氧基；所述烷基或烷氧基的取代基为卤素；
n选自1；
优选地，
X分别独立选自-F、-Cl、-Br、-CH
3、-OCH
3、-CF
3、-OCF
3。
进一步地，所述化合物为式IV-b所示：
其中，
每个R
1或R
2分别独立的选自氢、取代或未取代的C
1-8烷基、取代或未取代的C
3-10环烷基或取代或未取代的3～10元杂环基；或者同一个碳原子上R
1和R
2分别构成取代或未取代的C
3-10环烷基、取代或未取代的3～10元杂环基；所述取代的烷基、取代的环烷基或取代的杂环基的取代基个数为1、2、3或4，所述取代的烷基、取代的环烷基或取代的杂环基的取代基选自卤素、三氟甲基、氰基、硝基、C
1-8烷基、C
1-8烷氧基；所述杂环基的杂原子选自N、O、S，所述杂原子的个数为1、2或3；
m选自0、1、2、3、4、5、6；
M
3选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-8烷基；
a选自0、1、2、3、4、5、6。
进一步地，
每个R
1或R
2分别独立的选自氢、C
1-4烷基；
m选自0、1、2、3、4、5、6；
M
3选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
M
4选自无或选自O、S、NH或C
1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C
1-6烷氧基的取代基取代；
R
5选自C
1-4烷基；
a选自0、1、2、3、4、5、6。
进一步地，所述化合物为式V-a所示：
其中，
R
3选自C
1-8烷基；
a选自0、1、2、3、4、5、6。
进一步地，所述化合物为式V-b所示：
其中，
R
3选自C
1-8烷基、C
3-6环烷基、苯基、噻吩基、吡啶基、咪唑基；a选自0、1、2、3、4、5、6。
进一步地，所述化合物为如下化合物之一：
本发明还提供了前述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物在制备镇静剂和/或麻醉剂中的用途；
优选地，所述镇静剂和/或麻醉剂为静脉镇静和/或麻醉给药的镇静剂和/或麻醉剂。
本发明还提供了一种药物，它是以前述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物为活性成分，加上药学上可接受的辅料或辅助性成分制备而成的制剂；
优选地，所述药物为镇静剂和/或麻醉剂；
更优选地，所述镇静剂和/或麻醉剂为静脉镇静和/或麻醉给药的镇静剂和/或麻醉剂。
本发明中，室温为25±5℃，过夜为12±2h。
本发明中提供的化合物和衍生物根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。
本发明中“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
本发明中，碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，C
a～b烷基 表明任何含“a”至“b”个碳原子的烷基。因此，例如，C
1～10烷基是指包含1～10个碳原子的直链或支链烷基；C
1～10烷氧基是指包含1～10个碳原子的烷氧基。
本发明中短链烃基为包含1～10个碳原子的直链或支链烷基。
本发明中，C
3～10环烷基是指饱和的环烷基，该环烷基由3～10个碳原子构成。
本发明中，3～10元杂环基是指饱的杂环基，该杂环基由3～10个原子构成，所述原子中至少一个选自O、S或取代的氮原子、硅原子。
本发明中，芳基是指含没有环杂原子且具有单个环或多个环(包括稠合、桥连和螺环体系)的含有芳香性不饱和的基团，如苯基、蒽基、萘基。杂芳基是指包含至少一个杂原子的芳香性不饱和环；包括单个环或多个环(包括稠合、桥连和螺环体系)；其中杂原子指氮原子、氧原子、硫原子。如噻吩基、吡啶基、吡嗪基、哒嗪基、吡唑基、咪唑基等。
本发明中，卤素为氟、氯、溴或碘。
本发明化合物的静脉镇静麻醉效果佳，其麻醉效果与瑞马唑仑相当，甚至优于瑞马唑仑，具体表现在有效剂量显著降低、持续时间和恢复时间显著减少。同时在大、小鼠尾静脉麻醉模型中，本发明化合物相比瑞马唑仑明显降低了副作用的发生，苏醒质量得到显著提高。本发明化合物麻醉时起效快、持续时间短、苏醒快、毒性低、耐受性良好，可用于麻醉诱导、麻醉维持和日间手术麻醉，具有良好的应用前景。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
实施例1
将500mg(1.18mmol，1eq)3-((4S)-8-溴-6-(4,5-二氢吡啶-2-基)-1-甲基-4H-苯并[f]咪唑[1,2-a][1,4]二氮杂-4-基)丙酸溶于10mL DMF中，加入367.2mg(1.76mmol，1.5eq)乙酸溴甲酯和325mg(2.36mmol，2eq)碳酸钾，室温搅拌5小时。点板，原料基本反应完全。将反应液过滤后，冲入50mL水中，用100mL二氯甲烷萃取，分出有机层，用无水硫酸钠干燥，过滤得滤液，减压浓缩，经柱层析得浅黄色油状物500mg。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.57(d,J＝5.5Hz,1H), 8.15(d,J＝7.9Hz,1H),7.80(td,J＝7.8,1.7Hz,1H),7.72(dd,J＝8.7,2.3Hz,1H),7.63(d,J＝2.2Hz,1H),7.35(dd,J＝7.5,4.9Hz,1H),7.30(d,J＝8.7Hz,1H),6.88–6.84(m,1H),5.77–5.70(m,2H),4.04(t,J＝6.7Hz,1H),2.83(dt,J＝17.2,6.8Hz,4H),2.33(s,3H),2.06(d,J＝3.2Hz,3H)..MS：m/z：497.32(M+1)
实施例2
将500mg(1.18mmol，1eq)3-((4S)-8-溴-6-(4,5-二氢吡啶-2-基)-1-甲基-4H-苯并[f]咪唑[1,2-a][1,4]二氮杂-4-基)丙酸溶于10mL DMF中，加入367.2mg(1.76mmol，1.5eq)乙酸-2-溴乙酯和325mg(2.36mmol，2eq)碳酸钾，室温搅拌5小时。点板，原料基本反应完全。将反应液过滤后，冲入50mL水中，用100mL二氯甲烷萃取，分出有机层，用无水硫酸钠干燥,过滤得滤液，减压浓缩，经柱层析得浅黄色油状物550mg。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.56(d,J＝4.8Hz,1H),8.16(d,J＝8.0Hz,1H),7.79(t,J＝7.7Hz,1H),7.71(dd,J＝8.7,2.3Hz,1H),7.63(dd,J＝4.2,2.3Hz,1H),7.34(dd,J＝7.5,3.7Hz,1H),7.29(d,J＝8.7Hz,1H),6.84(q,J＝4.9Hz,2H),4.11(q,J＝7.1Hz,1H),2.79(dt,J＝15.6,7.4Hz,4H),2.33(s,3H),2.00(d,J＝2.2Hz,3H),1.43(dd,J＝5.4,3.4Hz,3H)..MS：m/z：511.21(M+1)
实施例3
将500mg(1.18mmol，1eq)3-((4S)-8-溴-6-(4,5-二氢吡啶-2-基)-1-甲基-4H-苯并[f]咪唑[1,2-a][1,4]二氮杂-4-基)丙酸溶于10mL DMF中，加入294.5mg(1.76mmol，1.5eq)乙酸-1-溴乙酯和325mg(2eq)碳酸钾，室温搅拌5小时。点板，原料基本反应完全。将反应液过滤后，冲入50mL水中，用100mL二氯甲烷萃取，分出有机层，用无水硫酸钠干燥,过滤得滤液，减压浓缩，经柱层析得浅绿色油状物530mg。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.55(d,J＝4.0Hz,1H),8.26(d,J＝7.8Hz,0H),8.15(d,J＝8.0Hz,1H),7.80(dd,J＝7.8,1.7Hz,1H),7.70(dd,J＝8.7,2.3Hz,1H),7.62(d,J＝2.3Hz,1H),7.35–7.31(m,1H),7.29(d,J＝8.7Hz,1H),6.85(d,J＝1.0Hz,1H),4.28–4.21(m,4H),2.85–2.75(m,4H),2.33(s,3H),2.02(s,3H)..MS：m/z： 511.21(M+1)
实施例4
将3g(25.86mmol，1eq)化合物1溶于40ml乙腈中，加入5.31g(31.03mmol，1.2eq)苄溴，7.14g(51.72mmol，2eq)碳酸钾，混匀，90℃加热回流过夜，点板(PE/EA＝3:1)，原料基本反应完全后，过滤旋干，用石油醚乙酸乙酯(0％-10％)过柱，得到化合物2 3.6g，产率67.54％。
将3.2g化合物2溶于40ml无水四氢呋喃中，氮气保护下于0℃滴加12.5ml 2.5M四氢铝锂四氢呋喃溶液，常温反应过夜，点板(PE/EA＝3:1)，反应完全后，置于0℃下，按顺序滴加1.2ml水，1.2ml 15％氢氧化钠溶液，3.6ml水，猝灭四氢铝锂，搅拌20min，加入无水硫酸钠干燥，过滤旋干，用石油醚乙酸乙酯(0％-15％)过柱，得到化合物3 1.9g，产率61.29％。
将500mg(2.8mmol，1eq)化合物3溶于15ml二氯甲烷，加入20mg(0.16mmol，0.05eq)DMAP，滴加0.53mL醋酸酐，室温反应5h，点板(PE/EA＝5:1)，原料基本反应完后旋干，用石油醚乙酸乙酯(0％-8％)过柱，得到化合物4 576mg，产率93.35％。
将500mg化合物4溶于20ml乙酸乙酯中，加入50mg10％钯碳，氢气常温反应过夜，点板，原料基本还原完后，过滤，低温浓缩得到化合物5，直接投于下步反应。
将200mg(0.47mmol，1eq)化合物10溶于10ml二氯甲烷中，加入124mg(2eq)化合物5,135mg(1.5eq)DCC,5.6mg(0.1eq)DMAP，混匀，常温反应5h，点板(DCM/MeOH＝15:1)，原料基本反应完全后，过滤旋干，用石油醚乙酸乙酯(10％-70％)过柱，得到化合物170mg。
该化合物的核磁共振氢谱：
1H NMR(400MHz,CDCl3)δ8.56(d,J＝4.2Hz,1H),8.18(d,J＝7.8Hz,1H),7.80(td,J＝7.8,1.6Hz,1H),7.72(dd,J＝8.8,2.4Hz,1H),7.64(d,J＝ 2.2Hz,1H),7.38–7.32(m,1H),7.30(d,J＝8.6Hz,1H),6.86(d,J＝0.8Hz,1H),4.30(s,2H),4.04(dd,J＝8.2,5.0Hz,1H),2.88–2.68(m,4H),2.34(s,3H),2.03(s,3H),0.98–0.82(m,4H)ppm..MS：m/z：537.11(M+1)
实施例5
将500mg(2.8mmol，1eq)化合物3溶于30ml二氯甲烷，加入777μl(2eq)三乙胺，在冰浴下滴加519.7mg(2eq，用DCM先溶解)丙酰氯，室温反应5h，点板，原料基本反应完后水洗1-2次，干燥过滤旋干，用石油醚乙酸乙酯(0％-8％)过柱，得到化合物6，630mg，产率95.7％。
将500mg化合物6溶于20ml乙酸乙酯中，加入50mg10％钯碳，氢气常温反应过夜，点板，原料基本还原完后，过滤，旋干得到化合物7，直接投于下步反应。
将200mg(0.47mmol，1eq)化合物10溶于10ml二氯甲烷中，加入100mg(1.5eq)化合物7,143mg(1.5eq)DCC,6mg(0.1eq)DMAP，混匀，常温反应5h，点板，原料基本反应完全后，过滤旋干，用石油醚乙酸乙酯(10％-70％)过柱，得到化合物160mg。
该化合物的核磁共振氢谱：
1H NMR(400MHz,CDCl3)δ8.60–8.56(m,1H),8.18(d,J＝7.8Hz,1H),7.80(td,J＝7.8,1.6Hz,1H),7.72(dd,J＝8.6,2.4Hz,1H),7.64(d,J＝2.2Hz,1H),7.35(ddd,J＝7.6,4.8,1.2Hz,1H),7.30(d,J＝8.6Hz,1H),6.86(d,J＝1.0Hz,1H),4.30(s,2H),4.04(dd,J＝8.2,5.2Hz,1H),2.86–2.72(m,4H),2.30(dd,J＝15.2,7.6Hz,5H),1.12(t,J＝7.6Hz,3H),0.98–0.82(m,4H)ppm..MS：m/z：551.12(M+1)
实施例6
将1g(1eq)瑞马唑仑溶于20mL四氢呋喃溶液中，在-20℃条件下加入1.6mL 1M/L 的氢化铝锂四氢呋喃溶液(0.7eq)，搅拌反应2小时后再依次加入水(1eq)，15％NaOH(4eq)水溶液淬灭反应，再用层析柱纯化得中间体1-2，再取300mg中间体1-2(1eq)与134mg氯甲酸正丙酯(1.5eq)在吡啶(2eq)和二氯甲烷中反应5h得到该化合物。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Methanol-d
4)δ8.89–8.85(m,1H),8.53(td,J＝7.9,1.6Hz,1H),8.25(d,J＝8.0Hz,1H),8.14(dd,J＝8.8,2.2Hz,1H),8.06(ddd,J＝7.7,5.5,1.1Hz,1H),8.00(d,J＝2.2Hz,1H),7.92(d,J＝8.8Hz,1H),7.54(d,J＝1.1Hz,1H),4.58(dd,J＝10.2,4.3Hz,1H),4.38–4.24(m,2H),4.06(t,J＝6.4Hz,2H),2.68(dtd,J＝15.1,10.0,5.0Hz,1H),2.53(d,J＝1.0Hz,3H),2.49–2.41(m,1H),2.25(ddq,J＝16.4,11.4,5.6Hz,1H),2.01–1.92(m,1H),1.65(h,J＝7.3Hz,2H),0.93(t,J＝7.4Hz,3H).MS：m/z：497.11(M+1)
实施例7
将1g(1eq)瑞马唑仑溶于20mL四氢呋喃溶液中，在-20℃条件下加入1.6mL 1M/L的氢化铝锂四氢呋喃溶液(0.7eq)，搅拌反应2小时后再依次加入水(1eq)，15％NaOH(4eq)水溶液淬灭反应，再用层析柱纯化得中间体1-2，再取300mg中间体1-2(1eq)与134mg氯甲酸异丙酯(1.5eq)在吡啶(2eq)与二氯甲烷中反应5h得到该化合物。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Methanol-d
4)δ8.83–8.81(m,1H),8.63(td,J＝7.7,1.6Hz,1H),8.15(d,J＝8.0Hz,1H),8.03(dd,J＝8.8,2.2Hz,1H),8.00(ddd,J＝7.7,5.5,1.1Hz,1H),7.98(d,J＝2.2Hz,1H),7.95(d,J＝8.8Hz,1H),7.43(d,J＝1.1Hz,1H),5.24(p,J＝6.8Hz,1H),4.63(td,J＝12.2,3.3Hz,1H),4.54(t,J＝6.6Hz,1H),4.45(td,J＝12.2,3.2Hz,1H),2.40(s,3H),1.92(dt,J＝9.8,6.3Hz,2H),1.78(dddq,J＝14.8,9.1,6.2,3.0Hz,1H),1.60(dtq,J＝15.5,9.4,3.2Hz,1H),1.32(d,J＝6.8Hz,3H),1.27(d,J＝6.8Hz,3H).MS：m/z：497.11(M+1)
实施例8
将1g(1eq)瑞马唑仑溶于20mL四氢呋喃溶液中，在-20℃条件下加入1.6mL 1M/L的氢化铝锂四氢呋喃溶液(0.7eq)，搅拌反应2小时后再依次加入水(1eq)，15％NaOH(4eq)水溶液淬灭反应，再用层析柱纯化得中间体1-2，再取300mg中间体1-2(1eq)与150mg氯甲酸异丁酯(1.5eq)在吡啶(2eq)与二氯甲烷中反应5h得到该化合物。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.50(d,J＝4.3Hz,1H),8.12(d,J＝7.9Hz,1H),7.80–7.60(m,3H),7.29(t,J＝9.1Hz,2H),6.94(s,1H),4.22(tt,J＝7.1,3.7Hz,2H),3.85(d,J＝6.7Hz,1H),3.81(dd,J＝6.7,1.0Hz,2H),2.40(s,3H),2.04–1.89(m,2H),1.85–1.72(m,2H),1.59–1.49(m,1H),0.95(dd,J＝25.0,6.8Hz,6H)..MS：m/z：511.12(M+1)
实施例9
取300mg中间体1-2(1eq)与150mg氯甲酸氯乙酯(1.5eq)，加入吡啶(1.5eq)在二氯甲烷中反应5h后，用酸水洗涤干燥后得到中间体1-3，再与乙酸(1eq)，K
2CO
3(3eq)在DMF中反应6h后，往体系中加入冰水，再用乙酸乙酯萃取，再水洗2次，合并有机相，干燥，经柱层析得到该化合物。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.50(ddd,J＝4.8,1.7,0.8Hz,1H),8.13–8.08(m,1H),7.73(td,J＝7.8,1.8Hz,1H),7.65(dd,J＝8.7,2.3Hz,1H),7.58(d,J＝2.3Hz,1H),7.27(ddd,J＝7.5,4.8,1.1Hz,1H),7.21(d,J＝10.2Hz,1H),6.79(q,J＝1.1Hz,1H),5.16(ddd,J＝12.1,10.3,1.8Hz,1H),4.68(td,J＝12.2,2.7Hz,1H),4.64–4.57(m,2H),4.51(dt,J＝12.2,1.6Hz,1H),4.39(td,J＝12.0,4.0Hz,1H),4.28(dt,J＝12.5,1.4Hz,1H),2.40(s,3H),2.02(s,3H),1.92(td,J＝7.4,2.8Hz,2H),1.78(ddq,J＝11.9,9.3,3.0Hz,1H),1.68(ttd,J＝12.2,7.9,4.0Hz,1H)..MS：m/z：541.10(M+1)
实施例10
取300mg中间体1-2(1eq)与氯甲酸氯甲酯(1.5eq)，加入吡啶(1.5eq)在二氯甲烷中反应5h后，用酸水洗涤干燥后得到中间体1-4，再与乙酸(1eq)，K
2CO
3(3eq)在DMF中反应6h后，往体系中加入冰水，再用乙酸乙酯萃取，再水洗2次，合并有机相，干燥，经柱层析得到该化合物。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.61–8.57(m,1H),7.67(td,J＝7.9,1.1Hz,1H),7.64–7.61(m,1H),7.58(dd,J＝7.5,2.0Hz,1H),7.55(ddd,J＝7.9,5.1,1.1Hz,1H),7.53–7.50(m,2H),6.99(s,1H),6.42(d,J＝12.5Hz,1H),6.32(d,J＝12.5Hz,1H),5.19–5.11(m,1H),4.49(dd,J＝10.9,2.3Hz,1H),3.88(tt,J＝12.2,2.9Hz, 1H),2.40(s,3H),2.11(s,3H),1.90–1.73(m,3H),1.56–1.43(m,1H)..MS：m/z：527.10(M+1)
实施例11
取300mg中间体1-2(1eq)与氯甲酸氯乙酯(1.5eq)，加入吡啶(1.5eq)在二氯甲烷中反应5h后，用酸水洗涤干燥后得到中间体1-5，再与乙酸(1eq)，K
2CO
3(3eq)在DMF中反应6h后，往体系中加入冰水，再用乙酸乙酯萃取，再水洗2次，合并有机相，干燥，经柱层析得到该化合物。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.50(d,J＝4.7Hz,1H),8.13–8.07(m,1H),7.73(td,J＝7.8,1.7Hz,1H),7.65(dd,J＝8.7,2.3Hz,1H),7.61–7.56(m,1H),7.27(ddd,J＝7.5,4.8,1.1Hz,1H),7.21(d,J＝11.9Hz,1H),6.79(d,J＝1.0Hz,1H),6.39–6.30(m,1H),4.60(td,J＝12.2,2.9Hz,1H),4.49(dd,J＝11.5,1.1Hz,1H),4.39(td,J＝12.1,3.4Hz,1H),2.40(s,3H),2.08(s,3H),2.02–1.92(m,2H),1.75(d,J＝6.8Hz,3H),1.69(d,J＝12.9Hz,1H),1.57–1.47(m,1H).MS：m/z：541.10(M+1)
实施例12
取300mg中间体1-2(1eq)与58mg醋酸(2eq)，K
2CO
3(3eq)在DMF反应5h后，往体系中加入冰水，再用乙酸乙酯萃取，再水洗2次，合并有机相，干燥，经柱层析得到该化合物。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.51(ddd,J＝4.8,1.6,0.8Hz,1H),8.10(d,J＝7.9Hz,1H),7.73(td,J＝7.8,1.8Hz,1H),7.65(dd,J＝8.7,2.3Hz,1H),7.57(d,J＝2.3Hz,1H),7.28(ddd,J＝7.5,4.8,1.1Hz,1H),7.21(d,J＝10.5Hz,1H),6.82(d,J＝1.1Hz,1H),4.14(t,J＝6.6Hz,2H),3.87(dd,J＝9.0,5.3Hz,1H),2.62–2.39(m,2H),2.27(d,J＝0.9Hz,3H),2.07–2.00(m,1H),1.96(s,3H),1.84(dtd,J＝13.7,6.5,3.8Hz,1H).MS：m/z：453.11(M+1)
实施例13
取300mg中间体1-2(1eq)与63mg环丙基甲酸(2eq)，K
2CO
3(3eq)在DMF常温搅拌反应5h后，往体系中加入冰水，再用乙酸乙酯萃取，再水洗2次，合并有机相，干燥，经柱层析得到该化合物。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.51(ddd,J＝4.8,1.6,0.8Hz,1H),8.11(d,J＝7.9Hz,1H),7.73(td,J＝7.8,1.8Hz,1H),7.65(dd,J＝8.7,2.3Hz,1H),7.57(d,J＝2.2Hz,1H),7.28(ddd,J＝7.5,4.9,1.1Hz,1H),7.22(s,1H),6.82(d,J＝1.0Hz,1H),4.58(dd,J＝11.7,2.0Hz,1H),4.37–4.30(m,1H),4.05(td,J＝12.1,3.3Hz,1H),2.40(s,3H),2.01(ddd,J＝11.4,9.0,2.8Hz,1H),1.78–1.71(m,1H),1.70–1.66(m,1H),1.64(dd,J＝8.8,3.8Hz,2H),1.08(tt,J＝8.4,4.3Hz,2H),0.84(tt,J＝7.2,4.3Hz,2H).MS：m/z：479.10(M+1)
实施例14
取300mg中间体1-2(1eq)与62mg异丁酸(2eq)，K
2CO
3(3eq)与DMF反应5h后，往体系中加入冰水，再用乙酸乙酯萃取，再水洗2次，合并有机相，干燥，经柱层析得到该化合物。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.50(d,J＝4.3Hz,1H),8.13–8.08(m,1H),7.73(td,J＝7.7,1.4Hz,1H),7.65(dd,J＝8.7,2.3Hz,1H),7.58(d,J＝2.2Hz,1H),7.27(ddd,J＝7.5,4.8,1.0Hz,1H),7.21(d,J＝10.5Hz,1H),6.79(s,1H).2.67(hept,J＝6.8Hz,1H),2.40(s,3H),2.04–1.94(m,1H),1.72(ddd,J＝14.6,12.2,3.1Hz,1H),1.68–1.63(m,1H),1.62–1.55(m,1H),1.26(d,J＝6.8Hz,3H),1.21(d,J＝6.9Hz,3H).MS：m/z：481.11(M+1)
实施例15
取300mg中间体1-2(1eq)与71mg异戊酸(2eq)，K
2CO
3(3eq)在DMF反应5h后，往体系中加入冰水，再用乙酸乙酯萃取，再水洗2次，合并有机相，干燥，经柱层析得到该化合物。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.61–8.56(m,1H),7.80–7.69(m,2H),7.61–7.54(m,2H),7.53–7.48(m,2H),6.99(s,1H),4.53–4.46(m,2H),4.18(td,J＝12.3,1.9Hz,1H),2.44(dd,J＝12.4,7.1Hz,1H),2.40(s,3H),2.30(dd,J＝12.4,7.0Hz,1H),2.13(dp,J＝13.7,6.8Hz,1H),1.96–1.89(m,2H),1.76(dtt,J＝15.5,7.6,3.9Hz,1H),1.50–1.41(m,1H),1.00(d,J＝6.8Hz,3H),0.94(d,J＝6.8Hz,3H).MS：m/z：495.13(M+1)
实施例16
取310mg中间体1-2(1eq)与228mg溴乙酰溴(1.5eq)，吡啶(2eq)在二氯甲烷中反应5h后，用酸水洗涤干燥后得到中间体1-6，再与乙酸(1eq)，K
2CO
3(3eq)在DMF中反应6h后，往体系中加入冰水，再用乙酸乙酯萃取，再水洗2次，合并有机相，干燥，经柱层析得到该化合物。
1H NMR(400MHz,Chloroform-d)δ8.51(dd,J＝4.4,1.3Hz,1H),8.10(d,J＝7.9Hz,1H),7.73(td,J＝7.8,1.8Hz,1H),7.66(dd,J＝8.7,2.3Hz,1H),7.58(d,J＝2.2Hz,1H),7.28(ddd,J＝7.5,4.8,1.2Hz,1H),7.24(d,J＝8.7Hz,1H),6.80(d,J＝1.0Hz,1H).5.21(d,J＝12.5Hz,1H),4.57(d,J＝12.5Hz,1H),4.52(dd,J＝12.2,2.4Hz,1H),4.48–4.42(m,1H),3.82(ddd,J＝12.2,9.3,3.3Hz,1H),2.40(s,3H),2.18(s,3H),1.90–1.82(m,1H),1.78–1.64(m,2H),1.44–1.33(m,1H).MS：m/z：511.11(M+1)
实施例17
取272mg中间体1-2(1eq)与214mg 2-溴丙酰溴(1.5eq)、吡啶(2eq)，在二氯甲烷中反应5h后，用酸水洗涤干燥后得到中间体1-7，再与乙酸(1eq)，K
2CO
3(3eq)在DMF反应6h后，往体系中加入冰水，再用乙酸乙酯萃取，再水洗2次，合并有机相，干燥，经柱层析得到该化合物。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.50(d,J＝4.3Hz,1H),8.14–8.07(m,1H),7.73(td,J＝7.7,1.4Hz,1H),7.65(dd,J＝8.7,2.3Hz,1H),7.58(d,J＝2.2Hz,1H),7.27(ddd,J＝7.5,4.8,1.0Hz,1H),7.21(d,J＝10.5Hz,1H),6.79(q,J＝1.0Hz,1H),4.98(qd,J＝7.1,2.8Hz,1H),4.23(td,J＝6.4,2.0Hz,2H),3.87(dd,J＝9.1,5.1Hz,1H),2.60–2.39(m,2H),2.27(s,3H),2.05(d,J＝1.1Hz,3H),1.81–1.70(m,2H),1.40(dd,J＝7.1,2.4Hz,3H).MS：m/z：525.11(M+1)
实施例18
取300mg中间体1-2(1eq)与252mg 2-溴异丁酰溴(1.5eq)、吡啶(2eq)，在二氯甲烷中反应5h后，用酸水洗涤干燥后得到中间体1-8，再与乙酸(1eq)，K
2CO
3(3eq)在DMF反应6h后，往体系中加入冰水，再用乙酸乙酯萃取，再水洗2次，合并有机相，干燥，经柱层析得到该化合物。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.60-8.54(d,J＝4.3Hz,1H),8.24–8.17(m,1H),7.56(dd,J＝7.3,1.4Hz,1H),7.55(dd,J＝8.3,2.3Hz,1H),7.45(d,J＝2.2Hz,1H),7.30(ddd,J＝7.6,4.3,1.0Hz,1H),7.11(d,J＝10.5Hz,1H),6.83(q,J＝1.0Hz,1H),4.62(dd,J＝11.6,2.0Hz,1H),4.54(td,J＝11.8,2.4Hz,1H),3.84(td,J＝12.2,3.5Hz,1H),2.40(s,3H),2.12(s,3H),2.08(ddd,J＝11.8,9.1,3.0Hz,1H),1.78–1.71(m,1H),1.66(s,3H),1.63(d,J＝3.2Hz,1H),1.61(s,4H).MS：m/z：539.11(M+1)
实施例19
取300mg中间体1-2(1eq)与188mg 3-溴丙丁酰氯(1.5eq)、吡啶(2eq)，在二氯甲烷中反应5h后，用酸水洗涤干燥后得到中间体1-9，再与乙酸(1eq)，K
2CO
3(3eq) 在DMF反应6h后，往体系中加入冰水，再用乙酸乙酯萃取，再水洗2次，合并有机相，干燥，经柱层析得到该化合物。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.73-8.54(d,J＝4.3Hz,1H),8.26–8.19(m,1H),7.73(dd,J＝7.3,1.4Hz,1H),7.65(dd,J＝8.3,2.3Hz,1H),7.55(d,J＝2.2Hz,1H),7.36(ddd,J＝7.6,4.3,1.0Hz,1H),7.23(d,J＝10.5Hz,1H),6.76(q,J＝1.0Hz,1H)5.34–5.26(m,1H),4.59–4.50(m,2H),4.44(dt,J＝12.3,2.4Hz,1H),3.85–3.77(m,1H),2.66(td,J＝12.1,2.4Hz,1H),2.45(ddd,J＝12.2,2.4,1.1Hz,1H),2.39(s,3H),2.06(ddd,J＝11.2,8.5,2.6Hz,1H),2.02(s,3H),1.76(tt,J＝11.3,5.0Hz,1H),1.64–1.50(m,2H).MS：m/z：525.11(M+1)
实施例20
取300mg中间体1-2(1eq)与203mg 3-溴丙丁酰氯(1.5eq)、吡啶(2eq)，在二氯甲烷中反应5h后，用酸水洗涤干燥后得到中间体1-10，再与乙酸(1eq)，K
2CO
3(3eq)在DMF反应6h后，往体系中加入冰水，再用乙酸乙酯萃取，再水洗2次，合并有机相，干燥，经柱层析得到该化合物。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.52–8.49(m,1H),8.10(d,J＝7.9Hz,1H),7.73(td,J＝7.8,1.8Hz,1H),7.66(dd,J＝8.7,2.3Hz,1H),7.58(d,J＝2.3Hz,1H),7.28(ddd,J＝7.5,4.8,1.2Hz,1H),7.24(d,J＝8.7Hz,1H),6.80(d,J＝1.0Hz,1H).4.51–4.43(m,2H),4.23(td,J＝12.6,2.2Hz,1H),4.19–4.09(m,2H),2.54(td,J＝12.8,2.5Hz,1H),2.40(s,3H),2.28(td,J＝12.7,2.6Hz,1H),2.02(s,4H),1.92(ddt,J＝9.1,6.6,2.9Hz,2H),1.79–1.65(m,2H),1.47(tt,J＝12.7,2.5Hz,1H).MS：m/z：539.12(M+1)
实施例21
取330mg中间体1-2(1eq)与105mg丙二酸(2eq)加入DCC(1.5eq)，DMAP(0.1eq)，在二氯甲烷中反应5h后，过滤，干燥后得到经柱层析得到中间体1-11，再与甲醇(1.5eq)DCC(1.5eq)，DMAP(0.1eq)在二氯甲烷中反应6h后，过滤，干燥后得到经柱层析得到该化合物。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.51(ddd,J＝4.8,1.7,0.8Hz,1H),8.10(d,J＝7.9Hz,1H),7.73(td,J＝7.8,1.8Hz,1H),7.66(dd,J＝8.7,2.3Hz,1H),7.58(d,J＝2.2Hz,1H),7.28(ddd,J＝7.5,4.8,1.2Hz,1H),7.24(d,J＝8.7Hz,1H),6.80(d,J＝1.0Hz,1H).4.54(dd,J＝11.6,1.6Hz,1H),4.35(td,J＝12.2,3.2Hz,1H),4.13(td,J＝12.0,3.2Hz,1H),4.03(d,J＝12.3Hz,1H),3.76(d,J＝12.5Hz,1H),3.73(s,3H),2.40(s,3H),2.00–1.90(m,1H),1.78–1.69(m,1H),1.69–1.63(m,1H),1.62–1.53(m,1H).MS：m/z：511.11(M+1)
实施例22
取410mg中间体1-2(1eq)与235.6mg丁二酸(2eq)，加入DCC(1.5eq)，DMAP(0.1eq)，在二氯甲烷中反应5h后，过滤，干燥后得到经柱层析得到中间体1-12，再与甲醇(1.5eq)，DCC(1.5eq)，DMAP(0.1eq)在二氯甲烷中反应6h后，过滤，干燥后得到经柱层析得到该化合物。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.63(ddd,J＝4.8,1.7,0.8Hz,1H),8.21(d,J＝7.8Hz,1H),7.76(dd,J＝7.8,1.8Hz,1H),7.66(dd,J＝8.7,2.3Hz,1H),7.60(d,J＝2.2Hz,1H),7.32(ddd,J＝7.5,4.8,1.2Hz,1H),7.26(d,J＝8.3Hz,1H),6.92(d,J＝1.0Hz,1H).4.62(td,J＝12.2,3.0Hz,1H),4.47(dd,J＝11.6,1.8Hz,1H),3.63(s,4H),3.24–3.12(m,2H),2.64–2.50(m,2H),2.40(s,3H),1.82(qd,J＝12.1,2.4Hz,1H),1.72–1.64(m,1H),1.63–1.53(m,1H),1.39(qt,J＝12.4,2.2Hz,1H).MS：m/z：525.11(M+1)
实施例23
该反应操作同实施例3，将500mg(1.18mmol，1eq)3-((4S)-8-溴-6-(4,5-二氢吡啶-2-基)-1-甲基-4H-苯并[f]咪唑[1,2-a][1,4]二氮杂-4-基)丙酸溶于10mL DMF中，加入320.5mg(1.76mmol，1.5eq)乙酸-1-溴丙酯和325mg(2eq)碳酸钾，室温搅拌5小时。点板，原料基本反应完全。将反应液过滤后，冲入50mL水中，用100mL二氯甲烷萃取，分出有机层，用无水硫酸钠干燥,过滤得滤液，减压浓缩，经柱层析得浅绿色油状物530mg。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Methanol-d
4)δ8.70(d,J＝4.8Hz,1H), 8.26(td,J＝7.8,1.4Hz,1H),8.20(d,J＝7.9Hz,1H),8.08(dd,J＝8.7,2.2Hz,1H),7.90–7.76(m,3H),7.52(s,1H),4.55(dd,J＝9.9,3.9Hz,1H),4.25–4.05(m,3H),2.91–2.60(m,4H),2.52(s,3H),2.05–1.71(m,5H).MS：m/z：525.11(M+1)
实施例24
取300mg中间体1-2(1eq)再加入丙酰氯136.5mg(2eq)再二氯甲烷中冰浴下搅拌，逐滴加入吡啶115mg(2eq)滴加完毕后移至室温反应2h.再用pH为5左右的水洗涤，合并有机相，柱层析得到该产物。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.57(ddd,J＝4.2,1.6,0.8Hz,1H),8.20(d,J＝6.9Hz,1H),7.73(td,J＝6.8,1.8Hz,1H),7.85(dd,J＝8.6,2.3Hz,1H),7.67(d,J＝3.3Hz,1H),7.48(ddd,J＝6.5,4.8,1.1Hz,1H),7.31(d,J＝10.2Hz,1H),6.92(d,J＝1.1Hz,1H),4.24(t,J＝6.6Hz,2H),3.87(dd,J＝9.0,5.3Hz,1H),2.62–2.39(m,2H),2.27(d,J＝0.9Hz,3H),2.07–2.00(m,1H),1.96(s,3H),1.84(dt,J＝13.7,6.5,3.8Hz,1H).1.12(t,J＝8.0Hz,3H).MS：m/z：467.12(M+1)
实施例25
该反应操作同实施例24。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.51(d,J＝5.5Hz,1H),8.10(d,J＝8.0Hz,1H),7.73(td,J＝7.8,1.8Hz,1H),7.65(dd,J＝8.7,2.3Hz,1H),7.58(d,J＝2.3Hz,1H),7.28(ddd,J＝7.5,4.8,1.1Hz,1H),7.21(d,J＝10.4Hz,1H),6.82(d,J＝1.0Hz,1H),4.15(t,J＝6.6Hz,2H),3.88(dd,J＝9.0,5.3Hz,1H),2.56(dtd,J＝14.5,9.6,5.4Hz,1H),2.45(ddd,J＝19.5,10.6,5.7Hz,1H),2.27(s,3H),2.18(t,J＝7.5Hz,2H),2.00(dtd,J＝12.2,9.7,8.4,6.1Hz,1H),1.85(ddd,J＝13.7,10.0,6.4Hz,1H),1.62–1.56(m,2H),0.86(t,J＝7.4Hz,3H).MS：m/z：481.12(M+1)
实施例26
该反应操作同实施例24。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.51(d,J＝5.5Hz,1H),8.10(d,J＝8.0Hz,1H),7.73(td,J＝7.8,1.8Hz,1H),7.65(dd,J＝8.7,2.3Hz,1H),7.58(d,J＝2.3Hz,1H),7.28(ddd,J＝7.5,4.8,1.1Hz,1H),7.21(d,J＝10.4Hz,1H),6.82(d,J＝1.0Hz,1H),4.15(t,J＝6.6Hz,2H),3.88(dd,J＝9.0,5.3Hz,1H),2.40(s,3H),2.07–1.99(m,1H),1.98–1.88(m,3H),1.78–1.69(m,1H),1.68–1.62(m,1H),1.60–1.53(m,1H),1.53–1.45(m,2H),0.85–0.76(m,6H).MS：m/z：509.15(M+1)
实施例27
该反应操作同实施例24。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.50(d,J＝4.8Hz,1H),8.12(d,J＝8.0Hz,1H),7.73(td,J＝7.7,1.6Hz,1H),7.67(d,J＝3.7Hz,1H),7.64(dd,J＝8.7,2.2Hz,1H),7.55(d,J＝2.2Hz,1H),7.44(d,J＝5.0Hz,1H),7.27(dd,J＝7.5,4.9Hz,1H),7.20(d,J＝6.1Hz,1H),7.02–6.97(m,1H),6.80(s,1H),4.45–4.30(m,2H),3.96(dd,J＝8.9,5.5Hz,1H),2.69–2.49(m,2H),2.27(s,3H),2.16–2.00(m,2H).MS：m/z：521.10(M+1)
实施例28
该反应操作同实施例24。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.50(d,J＝4.8Hz,1H),8.12(d,J＝8.0Hz,1H),7.73(td,J＝7.7,1.6Hz,1H),7.67(d,J＝3.7Hz,1H),7.64(dd,J＝8.7,2.2Hz,1H),7.55(d,J＝2.2Hz,1H),7.44(d,J＝5.0Hz,1H),7.27(dd,J＝7.5,4.9Hz, 1H),6.80(s,1H),4.45–4.30(m,2H),3.96(dd,J＝8.9,5.5Hz,1H),2.69–2.49(m,2H),2.27(s,3H),2.16–2.00(m,2H).MS：m/z：505.10(M+1)
实施例29
该反应操作同实施例24。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.50(d,J＝4.8Hz,1H),8.12(d,J＝8.0Hz,1H),δ8.02(dd,J＝7.5,1.9Hz,2H),7.79(tt,J＝7.8,1.9Hz,1H),7.73(td,J＝7.7,1.6Hz,1H),7.67(d,J＝3.7Hz,1H),7.55(d,J＝2.2Hz,1H),7.42(t,J＝7.5Hz,2H),7.27(dd,J＝7.5,4.9Hz,1H),6.80(s,1H),4.45–4.30(m,2H),3.96(dd,J＝8.9,5.5Hz,1H),2.69–2.49(m,2H),2.27(s,3H),2.16–2.00(m,2H).MS：m/z：515.10(M+1)
实施例30
该反应操作同实施例24。
该化合物的核磁共振氢谱：
1H NMR(400MHz,Chloroform-d)δ8.90(d,J＝5.2Hz,2H),δ8.50(d,J＝4.8Hz,1H),8.12(d,J＝8.0Hz,1H),8.00(d,J＝5.2Hz,2H),7.79(tt,J＝7.8,1.9Hz,1H),7.67(d,J＝3.7Hz,1H),7.55(d,J＝2.2Hz,1H),7.27(dd,J＝7.5,4.9Hz,1H),6.80(s,1H),4.45–4.30(m,2H),3.96(dd,J＝8.9,5.5Hz,1H),2.69–2.49(m,2H),2.27(s,3H),2.16–2.00(m,2H).MS：m/z：516.40(M+1)
以下通过具体的试验例证明本发明化合物的有益效果。
对本发明化合物进行药理活性、药效以及安全性评价。
在临床应用中，需要对麻醉药物的作用进行严格把控，从而保证在手术、诊断等过程顺利进行，并且在操作结束后可以尽快终止麻醉，让病人快速苏醒。如果麻醉持续时间过长，可能会造成对心血管系统和呼吸系统一些不良影响，例如嗜睡、头晕等。因此理想的麻醉药物应该具有起效快、恢复快、安全性高等优点。
试验例1、瑞马唑仑衍生物在小鼠体内的药效学研究
1、试验方法
采用序贯法(Dixon-Mood Method)单次尾静脉给药，对各化合物进行小鼠翻正反射消失(Loss of righting reflex，LORR)实验，测定化合物的麻醉半数有效剂量(ED
50)。
ED
50测定：随机选取雄性昆明小鼠(25-30g)，化合物用PEG-400：纯水(3：7)进行配制，给药体积为0.2mL，根据预实验结果，在最高和最低剂量之间按照等比数列设置另三个剂量。从中间剂量开始给药(尾静脉推注时间10s左右)，观察小鼠翻正反射消失情况。若第一只小鼠翻正反射消失持续时间在30s以上即为阳性，则第二只小鼠给予低一个剂量；若第一只小鼠翻正反射消失持续时间不到30s或翻正反射未消失即为阴性，则第二只小鼠给予高一个剂量；以此反复实验，直到出现阳性-阴性或阴性-阳性8个循环交叉结束实验。
2、试验结果
试验结果如表1所示
表1.各化合物的药效学研究结果
表1中麻醉持续时间为翻正反射消失到翻正反射恢复的时间，苏醒质量为翻正反射恢复到可自由爬行的时间；苏醒质量“+”表示＜1min，“++”表示大于或等于1min到小于3min之间，“+++”表示大于或等于3min到小于5min之间，“++++”表示大于或等于5min到小于10min之间，“+++++”表示≥10min。
由上述试验结果可知：与瑞马唑仑相比，本发明化合物可以降低有效给药剂量，并且具有起效快、恢复时间短的特点，苏醒质量更高，作为麻醉剂，效果明显优于瑞马唑仑。
综上，本发明化合物的静脉镇静麻醉效果佳，其麻醉效果与瑞马唑仑相当，甚至优于瑞马唑仑，具体表现在有效剂量显著降低、持续时间和恢复时间显著减少。同时在大、小鼠尾静脉麻醉模型中，本发明化合物相比瑞马唑仑苏醒质量得到显著提高。本发明化合物麻醉时起效快、持续时间短、苏醒快、耐受性良好，可用于麻醉诱导、麻醉维持和日间手术麻醉，具有良好的应用前景。
Claims (31)
- 式I所示的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物：
其中，每个R 1分别独立选自氢、短链烃基、C 3-10环烷基或3～10元杂环基，所述的短链烃基、环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子，优选R 1为短链烃基或氢；每个R 2分别独立选自氢、短链烃基、C 3-10环烷基或3～10元杂环基，所述的短链烃基、环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子，优选R 2为氢或短链烃基；或者同一个碳原子上R 1和R 2分别构成C 3-10环烷基或3～10元杂环基，所述的环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子；m选自0～6的整数；M 1选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 2选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 3选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代，所述NH被短链烃基取代；R 3选自氢、短链烃基、C 1-8烷氧基、-C(O)-M 4-R 5、C 3-10环烷基、6～10元芳基或5～10元杂芳基，所述杂芳基中包括1～3个选自N、O、或S的杂原子；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自短链烃基或C 1-8烷氧基；a选自0～6的整数；R 4选自氮在2、3、4位的吡啶环，优选R 4为氮在2位的吡啶；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1～4的整数；当M 1为无、a为1、M 2为O、M 3为O或S或NH或C 1-5亚烷基、m为1、R 3为-C(O)-M 4-R 5、M 4为O时，R 5不选自短链烃基；当M 1为无、a为1、M 2为O、M 3为O或S或NH或C 1-5亚烷基、m为1、R 3为-C(O)-M 4-R 5、M 4为无时，R 5不选自C 1-8烷氧基；当M 1为无、a为1、M 2为O、M 3为无、m为1～5、R 3为-C(O)-M 4-R 5、M 4为O时，R 5不选自短链烃基；当M 1为无、a为1、M 2为O、M 3为无、m为1～5、R 3为-C(O)-M 4-R 5、M 4为无时，R 5不选自C 1-8烷氧基。 - 根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：每个R 1或R 2分别独立的选自氢、取代或未取代的C 1-8烷基、取代或未取代的C 3-10环烷基或取代或未取代的3～10元杂环基；或者同一个碳原子上R 1和R 2分别构成取代或未取代的C 3-10环烷基、取代或未取代的3～10元杂环基；所述取代的烷基、取代的环烷基或取代的杂环基的取代基个数为1、2、3或4，所述取代的烷基、取代的环烷基或取代的杂环基的取代基选自卤素、三氟甲基、氰基、硝基、C 1-8烷基、C 1-8烷氧基；所述杂环基的杂原子选自N、O、S，所述杂原子的个数为1、2或3；m选自0、1、2、3、4、5、6；M 1选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 2选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 3选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代，所述NH被C 1-8烷基取代；R 3选自氢、C 1-8烷基、C 1-8烷氧基、-C(O)-M 4-R 5、C 3-10环烷基、6～10元芳基或5～10元杂芳基，所述杂芳基中包括1～3个选自N、O、或S的杂原子；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-8烷基或C 1-8烷氧基；a选自0、1、2、3、4、5、6；R 4选自氮在2、3、4位的吡啶环；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1、2、3、4；当M 1为无、a为1、M 2为O、M 3为O或S或NH或C 1-5亚烷基、m为1、R 3为-C(O)-M 4-R 5、M 4为O时，R 5不选自C 1-8烷基；当M 1为无、a为1、M 2为O、M 3为O或S或NH或C 1-5亚烷基、m为1、R 3为-C(O)-M 4-R 5、M 4为无时，R 5不选自C 1-8烷氧基；当M 1为无、a为1、M 2为O、M 3为无、m为1～5、R 3为-C(O)-M 4-R 5、M 4为O时，R 5不选自C 1～8烷基；当M 1为无、a为1、M 2为O、M 3为无、m为1～5、R 3为-C(O)-M 4-R 5、M 4为无时，R 5不选自C 1-8烷氧基。
- 根据权利要求2所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：每个R 1或R 2分别独立的选自氢、C 1-4烷基；m选自0、1、2、3、4、5、6；M 1选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 2选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 3选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代，所述NH被C 1-4烷基取代；R 3选自氢、C 1-4烷基、C 1-4烷氧基、-C(O)-M 4-R 5、C 3-6环烷基、苯基、噻吩基、吡啶基、咪唑基；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-4烷基或C 1-4烷氧基；a选自0、1、2、3、4、5、6；R 4选自氮在2位的吡啶环；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1；当M 1为无、a为1、M 2为O、M 3为O或S或NH或C 1-5亚烷基、m为1、R 3为-C(O)-M 4-R 5、M 4为O时，R 5不选自C 1-4烷基；当M 1为无、a为1、M 2为O、M 3为O或S或NH或C 1-5亚烷基、m为1、R 3为-C(O)-M 4-R 5、M 4为无时，R 5不选自C 1-4烷氧基；当M 1为无、a为1、M 2为O、M 3为无、m为1～5、R 3为-C(O)-M 4-R 5、M 4为O时，R 5不选自C 1-4烷基；当M 1为无、a为1、M 2为O、M 3为无、m为1～5、R 3为-C(O)-M 4-R 5、M 4为无时，R 5不选自C 1-4烷氧基；优选地，X分别独立选自-F、-Cl、-Br、-CH 3、-OCH 3、-CF 3、-OCF 3。
- 根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：所述化合物为式II所示：
其中，每个R 1分别独立选自氢、短链烃基、C 3-10环烷基或3～10元杂环基，所述的短链烃基、环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子，优选R 1为短链烃基或氢；每个R 2分别独立选自氢、短链烃基、C 3-10环烷基或3～10元杂环基，所述的短链烃基、环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子，优选R 2为氢或短链烃基；或者同一个碳原子上R 1和R 2分别构成C 3-10环烷基或3～10元杂环基，所述的环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子；m选自1～5的整数；M 2选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 3选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自短链烃基；a选自0～6的整数；R 4选自氮在2、3、4位的吡啶环，优选R 4为氮在2位的吡啶；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1～4的整数；当a为1、M 2为O、M 3为O或S或NH或C 1-5亚烷基、m为1时，M 4不为O；当a为1、M 2为O、M 3为无、m为1～5时，M 4不为O。 - 根据权利要求4所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：每个R 1或R 2分别独立的选自氢、取代或未取代的C 1-8烷基、取代或未取代的C 3-10环烷基或取代或未取代的3～10元杂环基；或者同一个碳原子上R 1和R 2分别构成取代或未取代的C 3-10环烷基、取代或未取代的3～10元杂环基；所述取代的烷基、取代的环烷基或取代的杂环基的取代基个数为1、2、3或4，所述取代的烷基、取代的环烷基或取代的杂环基的取代基选自卤素、三氟甲基、氰基、硝基、C 1-8烷基、C 1-8烷氧基；所述杂环基的杂原子选自N、O、S，所述杂原子的个数为1、2或3；m选自1、2、3、4、5；M 2选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 3选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-8烷基；a选自0、1、2、3、4、5、6；R 4选自氮在2、3、4位的吡啶环；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1、2、3、4。
- 根据权利要求5所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：每个R 1或R 2分别独立的选自氢、C 1-4烷基；m选自1、2、3、4、5；M 2选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 3选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-4烷基；a选自0、1、2、3、4、5、6；R 4选自氮在2位的吡啶环；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1；优选地，X分别独立选自-F、-Cl、-Br、-CH 3、-OCH 3、-CF 3、-OCF 3。
- 根据权利要求4所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：所述化合物为式II-a所示：
其中，每个R 1或R 2分别独立的选自氢、取代或未取代的C 1-8烷基、取代或未取代的C 3-10环烷基或取代或未取代的3～10元杂环基；或者同一个碳原子上R 1和R 2分别构成取代或未取代的C 3-10环烷基、取代或未取代的3～10元杂环基；所述取代的烷基、取代的环烷基或取代的杂环基的取代基个数为1、2、3或4，所述取代的烷基、取代的环烷基或取代的杂环基的取代基选自卤素、三氟甲基、氰基、硝基、C 1-8烷基、C 1-8烷氧基；所述杂环基的杂原子选自N、O、S，所述杂原子的个数为1、2或3；m选自1、2、3、4、5；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-8烷基；a选自0、1、2、3、4、5、6；R 4选自氮在2、3、4位的吡啶环；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1、2、3、4；当a为1、m为1时，M 4不为O。 - 根据权利要求7所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：每个R 1或R 2分别独立的选自氢、C 1-4烷基；m选自1、2、3、4、5；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-4烷基；a选自0、1、2、3、4、5、6；R 4选自氮在2位的吡啶环；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1；优选地，X分别独立选自-F、-Cl、-Br、-CH 3、-OCH 3、-CF 3、-OCF 3。
- 根据权利要求7所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：所述化合物为式II-b所示：
其中，m1选自0、1、2、3、4；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-8烷基；a选自0、1、2、3、4、5、6；R 4选自氮在2、3、4位的吡啶环；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1、2、3、4；当a为1、m1为0时，M 4不为O。 - 根据权利要求9所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：m1选自0、1、2、3、4；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-4烷基；a选自0、1、2、3、4、5、6；R 4选自氮在2位的吡啶环；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1；优选地，X分别独立选自-F、-Cl、-Br、-CH 3、-OCH 3、-CF 3、-OCF 3。
- 根据权利要求9所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：所述化合物为式II-c所示：
其中，m1选自0、1、2、3、4；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-8烷基；a选自0、1、2、3、4、5、6；当a为1、m1为0时，M 4不为O。 - 根据权利要求11所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：m1选自0、1、2、3、4；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-4烷基；a选自0、1、2、3、4、5、6。
- 根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：所述化合物为式III所示：
其中，每个R 1分别独立选自氢、短链烃基、C 3-10环烷基或3～10元杂环基，所述的短链烃基、环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子，优选R 1为短链烃基或氢；每个R 2分别独立选自氢、短链烃基、C 3-10环烷基或3～10元杂环基，所述的短链烃基、环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子，优选R 2为氢或短链烃基；或者同一个碳原子上R 1和R 2分别构成C 3-10环烷基或3～10元杂环基，所述的环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子；m选自0～6的整数；M 1选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 3选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自短链烃基；a选自0～6的整数；R 4选自氮在2、3、4位的吡啶环，优选R 4为氮在2位的吡啶；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1～4的整数。 - 根据权利要求13所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：每个R 1或R 2分别独立的选自氢、取代或未取代的C 1-8烷基、取代或未取代的C 3-10环烷基或取代或未取代的3～10元杂环基；或者同一个碳原子上R 1和R 2分别构成取代或未取代的C 3-10环烷基、取代或未取代的3～10元杂环基；所述取代的烷基、取代的环烷基或取代的杂环基的取代基个数为1、2、3或4，所述取代的烷基、取代的环烷基或取代的杂环基的取代基选自卤素、三氟甲基、氰基、硝基、C 1-8烷基、C 1-8烷氧基；所述杂环基的杂原子选自N、O、S，所述杂原子的个数为1、2或3；m选自0、1、2、3、4、5、6；M 1选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 3选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-8烷基；a选自0、1、2、3、4、5、6；R 4选自氮在2、3、4位的吡啶环；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1、2、3、4。
- 根据权利要求14所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：每个R 1或R 2分别独立的选自氢、C 1-4烷基；m选自0、1、2、3、4、5、6；M 1选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 3选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-4烷基；a选自0、1、2、3、4、5、6；R 4选自氮在2位的吡啶环；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1；优选地，X分别独立选自-F、-Cl、-Br、-CH 3、-OCH 3、-CF 3、-OCF 3。
- 根据权利要求13所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：所述化合物为式III-a所示：
其中，每个R 1或R 2分别独立的选自氢、取代或未取代的C 1-8烷基、取代或未取代的C 3-10环烷基或取代或未取代的3～10元杂环基；或者同一个碳原子上R 1和R 2分别构成取代或未取代的C 3-10环烷基、取代或未取代的3～10元杂环基；所述取代的烷基、取代的环烷基或取代的杂环基的取代基个数为1、2、3或4，所述取代的烷基、取代的环烷基或取代的杂环基的取代基选自卤素、三氟甲基、氰基、硝基、C 1-8烷基、C 1-8烷氧基；所述杂环基的杂原子选自N、O、S，所述杂原子的个数为1、2或3；m选自0、1、2、3、4、5、6；M 3选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-8烷基；a选自0、1、2、3、4、5、6；R 4选自氮在2、3、4位的吡啶环；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1、2、3、4。 - 根据权利要求16所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：每个R 1或R 2分别独立的选自氢、C 1-4烷基；m选自0、1、2、3、4、5、6；M 3选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-4烷基；a选自0、1、2、3、4、5、6；R 4选自氮在2位的吡啶环；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1；优选地，X分别独立选自-F、-Cl、-Br、-CH 3、-OCH 3、-CF 3、-OCF 3。
- 根据权利要求16所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：所述化合物为式III-b所示：
其中，每个R 1或R 2分别独立的选自氢、取代或未取代的C 1-8烷基、取代或未取代的C 3-10环烷基或取代或未取代的3～10元杂环基；或者同一个碳原子上R 1和R 2分别构成取代或未取代的C 3-10环烷基、取代或未取代的3～10元杂环基；所述取代的烷基、取代的环烷基或取代的杂环基的取代基个数为1、2、3或4，所述取代的烷基、取代的环烷基或取代的杂环基的取代基选自卤素、三氟甲基、氰基、硝基、C 1-8烷基、C 1-8烷氧基；所述杂环基的杂原子选自N、O、S，所述杂原子的个数为1、2或3；m选自0、1、2、3、4、5、6；M 3选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-8烷基；a选自0、1、2、3、4、5、6。 - 根据权利要求18所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：每个R 1或R 2分别独立的选自氢、C 1-4烷基；m选自0、1、2、3、4、5、6；M 3选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-4烷基；a选自0、1、2、3、4、5、6。
- 根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：所述化合物为式IV所示：
其中，每个R 1分别独立选自氢、短链烃基、C 3-10环烷基或3～10元杂环基，所述的短链烃基、环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子，优选R 1为短链烃基或氢；每个R 2分别独立选自氢、短链烃基、C 3-10环烷基或3～10元杂环基，所述的短链烃基、环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取代，且所述的杂环中包括1～3个选自N、O、或S的杂原子，优选R 2为氢或短链烃基；或者同一个碳原子上R 1和R 2分别构成C 3-10环烷基或3～10元杂环基，所述的环烷基或杂环基被0～4个选自卤素、三氟甲基、氰基、硝基、短链烷基、或烷氧基的取代基取 代，且所述的杂环中包括1～3个选自N、O、或S的杂原子；m选自0～6的整数；M 1选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 2选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 3选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自短链烃基；a选自0～6的整数；R 4选自氮在2、3、4位的吡啶环，优选R 4为氮在2位的吡啶；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1～4的整数。 - 根据权利要求20所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：每个R 1或R 2分别独立的选自氢、取代或未取代的C 1-8烷基、取代或未取代的C 3-10环烷基或取代或未取代的3～10元杂环基；或者同一个碳原子上R 1和R 2分别构成取代或未取代的C 3-10环烷基、取代或未取代的3～10元杂环基；所述取代的烷基、取代的环烷基或取代的杂环基的取代基个数为1、2、3或4，所述取代的烷基、取代的环烷基或取代的杂环基的取代基选自卤素、三氟甲基、氰基、硝基、C 1-8烷基、C 1-8烷氧基；所述杂环基的杂原子选自N、O、S，所述杂原子的个数为1、2或3；m选自0、1、2、3、4、5、6；M 1选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 2选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 3选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-8烷基；a选自0、1、2、3、4、5、6；R 4选自氮在2、3、4位的吡啶环；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1、2、3、4。
- 根据权利要求21所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：每个R 1或R 2分别独立的选自氢、C 1-4烷基；m选自0、1、2、3、4、5、6；M 1选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 2选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 3选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-4烷基；a选自0、1、2、3、4、5、6；R 4选自氮在2位的吡啶环；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1；优选地，X分别独立选自-F、-Cl、-Br、-CH 3、-OCH 3、-CF 3、-OCF 3。
- 根据权利要求20所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：所述化合物为式IV-a所示：
其中，每个R 1或R 2分别独立的选自氢、取代或未取代的C 1-8烷基、取代或未取代的C 3-10环烷基或取代或未取代的3～10元杂环基；或者同一个碳原子上R 1和R 2分别构成取代或未取代的C 3-10环烷基、取代或未取代的3～10元杂环基；所述取代的烷基、取代的环烷基或取代的杂环基的取代基个数为1、2、3或4，所述取代的烷基、取代的环烷基或取代的杂环基的取代基选自卤素、三氟甲基、氰基、硝基、C 1-8烷基、C 1-8烷氧基；所述杂环基的杂原子选自N、O、S，所述杂原子的个数为1、2或3；m选自0、1、2、3、4、5、6；M 3选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-8烷基；a选自0、1、2、3、4、5、6；R 4选自氮在2、3、4位的吡啶环；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1、2、3、4。 - 根据权利要求23所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：每个R 1或R 2分别独立的选自氢、C 1-4烷基；m选自0、1、2、3、4、5、6；M 3选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-4烷基；a选自0、1、2、3、4、5、6；R 4选自氮在2位的吡啶环；X分别独立选自卤素、取代或未取代的C 1-8烷基、取代或未取代的C 1-8烷氧基；所述烷基或烷氧基的取代基为卤素；n选自1；优选地，X分别独立选自-F、-Cl、-Br、-CH 3、-OCH 3、-CF 3、-OCF 3。
- 根据权利要求23所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：所述化合物为式IV-b所示：
其中，每个R 1或R 2分别独立的选自氢、取代或未取代的C 1-8烷基、取代或未取代的C 3-10环烷基或取代或未取代的3～10元杂环基；或者同一个碳原子上R 1和R 2分别构成取代或未取代的C 3-10环烷基、取代或未取代的3～10元杂环基；所述取代的烷基、取代的环烷基或取代的杂环基的取代基个数为1、2、3或4，所述取代的烷基、取代的环烷基或取代的杂环基的取代基选自卤素、三氟甲基、氰基、硝基、C 1-8烷基、C 1-8烷氧基；所述杂环基的杂原子选自N、O、S，所述杂原子的个数为1、2或3；m选自0、1、2、3、4、5、6；M 3选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-8烷基；a选自0、1、2、3、4、5、6。 - 根据权利要求25所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：每个R 1或R 2分别独立的选自氢、C 1-4烷基；m选自0、1、2、3、4、5、6；M 3选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；M 4选自无或选自O、S、NH或C 1-5亚烷基，所述的亚烷基被0～4个选自卤素、三氟甲基、C 1-6烷氧基的取代基取代；R 5选自C 1-4烷基；a选自0、1、2、3、4、5、6。
- 根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：所述化合物为式V-a所示：
其中，R 3选自C 1-8烷基；a选自0、1、2、3、4、5、6。 - 根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：所述化合物为式V-b所示：
其中，R 3选自C 1-8烷基、C 3-6环烷基、苯基、噻吩基、吡啶基、咪唑基；a选自0、1、2、3、4、5、6。 - 根据权利要求1～28任一项所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物，其特征在于：所述化合物为如下化合物之一：
- 权利要求1～29任一项所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物在制备镇静剂和/或麻醉剂中的用途；优选地，所述镇静剂和/或麻醉剂为静脉镇静和/或麻醉给药的镇静剂和/或麻醉剂。
- 一种药物，其特征在于：它是以权利要求1～29任一项所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其共晶、或其组合物为活性成分，加上药学上可接受的辅料或辅助性成分制备而成的制剂；优选地，所述药物为镇静剂和/或麻醉剂；更优选地，所述镇静剂和/或麻醉剂为静脉镇静和/或麻醉给药的镇静剂和/或麻醉剂。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111321435.2 | 2021-11-09 | ||
| CN202111321435 | 2021-11-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2023083191A1 true WO2023083191A1 (zh) | 2023-05-19 |
Family
ID=86262074
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2022/130695 WO2023083191A1 (zh) | 2021-11-09 | 2022-11-08 | 苯二氮卓类化合物及其制备方法和在医药上的用途 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN116102557B (zh) |
| WO (1) | WO2023083191A1 (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024251275A1 (zh) * | 2023-06-09 | 2024-12-12 | 成都麻沸散医药科技有限公司 | 一种氮杂*类化合物及其组合物和应用 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000069836A1 (en) * | 1999-05-14 | 2000-11-23 | Glaxo Group Limited | Short-acting benzodiazepines |
| CN106892924A (zh) * | 2015-12-17 | 2017-06-27 | 四川科伦博泰生物医药股份有限公司 | 短效苯并二氮*衍生物、其制备方法及其用途 |
| CN108033964A (zh) * | 2017-12-28 | 2018-05-15 | 杭州奥默医药股份有限公司 | 一种吡啶基咪唑并苯并二氮杂卓丙酸酯化合物及其合成和应用 |
| WO2018148361A1 (en) * | 2017-02-09 | 2018-08-16 | Watson Laboratories Inc. | Process for the preparation of remimazolam and solid state forms of remimazolam salts |
| CN112142746A (zh) * | 2019-06-28 | 2020-12-29 | 四川大学华西医院 | 苯二氮卓类化合物及其制备方法和在医药上的作用 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5670640A (en) * | 1996-02-02 | 1997-09-23 | Hoffmann-La Roche Inc. | Process for the manufacture of imidazodiazepine derivatives |
| WO2007042421A1 (en) * | 2005-10-11 | 2007-04-19 | F. Hoffmann-La Roche Ag | Imidazo benzodiazepine derivatives |
| WO2016011943A1 (zh) * | 2014-07-23 | 2016-01-28 | 李勤耕 | 新的苯并二氮杂䓬类衍生物及其用途 |
| CN110418791B (zh) * | 2017-04-28 | 2022-07-01 | 四川科伦博泰生物医药股份有限公司 | 包含苯并二氮䓬类化合物的注射用组合物及其制备方法 |
| EP3714884A1 (en) * | 2019-03-27 | 2020-09-30 | Paion UK Limited | Medical uses for benzodiazepines with a particular eeg pattern |
| CN112174890B (zh) * | 2020-10-09 | 2022-05-27 | 成都麻沸散医药科技有限公司 | 酮取代杂环化合物及其麻醉作用 |
| JP2022553326A (ja) * | 2019-10-22 | 2022-12-22 | ウェストチャイナホスピタル、スーチョワンユニバーシティ | 置換フェノールヒドロキシ酸エステルのｎ含有誘導体、製造及び使用 |
-
2022
- 2022-11-08 WO PCT/CN2022/130695 patent/WO2023083191A1/zh active Application Filing
- 2022-11-08 CN CN202211392447.9A patent/CN116102557B/zh active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000069836A1 (en) * | 1999-05-14 | 2000-11-23 | Glaxo Group Limited | Short-acting benzodiazepines |
| CN106892924A (zh) * | 2015-12-17 | 2017-06-27 | 四川科伦博泰生物医药股份有限公司 | 短效苯并二氮*衍生物、其制备方法及其用途 |
| WO2018148361A1 (en) * | 2017-02-09 | 2018-08-16 | Watson Laboratories Inc. | Process for the preparation of remimazolam and solid state forms of remimazolam salts |
| CN108033964A (zh) * | 2017-12-28 | 2018-05-15 | 杭州奥默医药股份有限公司 | 一种吡啶基咪唑并苯并二氮杂卓丙酸酯化合物及其合成和应用 |
| CN112142746A (zh) * | 2019-06-28 | 2020-12-29 | 四川大学华西医院 | 苯二氮卓类化合物及其制备方法和在医药上的作用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116102557B (zh) | 2024-04-26 |
| CN116102557A (zh) | 2023-05-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6947644B2 (ja) | 重水素化ケノデオキシコール酸誘導体およびこの化合物を含む薬物組成物 | |
| WO2021121371A1 (zh) | Kras g12c抑制剂及其在医药上的应用 | |
| CN105646389B (zh) | 一种作为吲哚胺-2,3-双加氧酶抑制剂的氨基磺酸脂及其制备方法和用途 | |
| WO2022222994A1 (zh) | 一种核苷类化合物及其在治疗猫传染性腹膜炎中的应用 | |
| CN112142746B (zh) | 苯二氮卓类化合物及其制备方法和在医药上的作用 | |
| CN103739553B (zh) | 含有醚侧链的n-取代咪唑羧酸酯手性化合物、制备方法和用途 | |
| CN103588757B (zh) | 超短效麻醉效应的n-取代咪唑羧酸酯类化合物、制备方法和用途 | |
| CN114765979A (zh) | 一种核苷类化合物及其在治疗猫传染性腹膜炎中的应用 | |
| CN113603677B (zh) | 一种具有高口服生物利用度的jak抑制剂 | |
| CN111662294A (zh) | 一类具有降解Btk活性的化合物 | |
| WO2023016529A1 (zh) | 作为atr抑制剂的萘啶衍生物及其制备方法 | |
| WO2023155866A1 (zh) | 一种吡唑并吡啶衍生物及其在医药上的应用 | |
| WO2023083191A1 (zh) | 苯二氮卓类化合物及其制备方法和在医药上的用途 | |
| WO2018121774A1 (zh) | 一种选择性抑制激酶化合物及其用途 | |
| CN114948953A (zh) | 一种杂原子取代芳香类化合物及其盐的用途 | |
| CN110003188B (zh) | 取代吡咯甲酸酯类衍生物及其用途 | |
| CN116554127B (zh) | 哌嗪取代苯酚类衍生物及其用途 | |
| WO2020135454A1 (zh) | 一类类固醇化合物及其用途 | |
| CN113274390B (zh) | 哌马色林在制备抗肿瘤药物中的应用 | |
| CN103772374B (zh) | 一种杂环类化合物及其应用 | |
| CN111285825B (zh) | 一类苯磺酰胺取代的衍生物，其制法及其用途 | |
| CN100569740C (zh) | N-or酰胺类化合物,其制备方法和其应用 | |
| WO2025067474A1 (zh) | 一种含吡啶的化合物及其制备方法和用途 | |
| WO2024012570A1 (zh) | 一种含氮杂环衍生物及其组合物和药学上的应用 | |
| CN117700376A (zh) | N-苄基苯甲酰胺类化合物及其药物组合物和应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22891985 Country of ref document: EP Kind code of ref document: A1 |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 22891985 Country of ref document: EP Kind code of ref document: A1 |