WO2014180305A1 - 苯酚衍生物及其制备方法和在医药上的应用 - Google Patents
苯酚衍生物及其制备方法和在医药上的应用 Download PDFInfo
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- WO2014180305A1 WO2014180305A1 PCT/CN2014/076907 CN2014076907W WO2014180305A1 WO 2014180305 A1 WO2014180305 A1 WO 2014180305A1 CN 2014076907 W CN2014076907 W CN 2014076907W WO 2014180305 A1 WO2014180305 A1 WO 2014180305A1
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- CAAULPUQFIIOTL-UHFFFAOYSA-N methyl dihydrogen phosphate Chemical compound COP(O)(O)=O CAAULPUQFIIOTL-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
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- HHQJWDKIRXRTLS-UHFFFAOYSA-N n'-bromobutanediamide Chemical compound NC(=O)CCC(=O)NBr HHQJWDKIRXRTLS-UHFFFAOYSA-N 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- DYMRYCZRMAHYKE-UHFFFAOYSA-N n-diazonitramide Chemical compound [O-][N+](=O)N=[N+]=[N-] DYMRYCZRMAHYKE-UHFFFAOYSA-N 0.000 description 1
- HKNFUJIVKFTWJB-UHFFFAOYSA-N n-methoxy-n-methylcyclobutanecarboxamide Chemical compound CON(C)C(=O)C1CCC1 HKNFUJIVKFTWJB-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
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- IXQGCWUGDFDQMF-UHFFFAOYSA-N o-Hydroxyethylbenzene Natural products CCC1=CC=CC=C1O IXQGCWUGDFDQMF-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
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- 229910052763 palladium Inorganic materials 0.000 description 1
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- LQJARUQXWJSDFL-UHFFFAOYSA-N phenamine Chemical compound CCOC1=CC=C(NC(=O)CN)C=C1 LQJARUQXWJSDFL-UHFFFAOYSA-N 0.000 description 1
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- 229920001184 polypeptide Polymers 0.000 description 1
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- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000006085 pyrrolopyridyl group Chemical group 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
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- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
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- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
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- ZXUCBXRTRRIBSO-UHFFFAOYSA-L tetrabutylazanium;sulfate Chemical compound [O-]S([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC ZXUCBXRTRRIBSO-UHFFFAOYSA-L 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- WBHHLPDFFGXVQS-UHFFFAOYSA-N triethylsilylhydrazine Chemical compound CC[Si](CC)(CC)NN WBHHLPDFFGXVQS-UHFFFAOYSA-N 0.000 description 1
- QNLQKURWPIJSJS-UHFFFAOYSA-N trimethylsilylphosphane Chemical compound C[Si](C)(C)P QNLQKURWPIJSJS-UHFFFAOYSA-N 0.000 description 1
- HUYHHHVTBNJNFM-UHFFFAOYSA-N trimethylsilylsilicon Chemical compound C[Si](C)(C)[Si] HUYHHHVTBNJNFM-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Classifications
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2404—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
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Definitions
- Phenol derivative preparation method thereof and application in medicine
- the present invention relates to a phenol derivative represented by the formula (A), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, a process for the preparation thereof, and a pharmaceutical composition
- a phenol derivative represented by the formula (A) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, a process for the preparation thereof, and a pharmaceutical composition
- the GABA A receptor is the major inhibitory neurotransmitter receptor in the central nervous system.
- the GABA A receptor consists of a pentamer of transmembrane polypeptide subunits, and 19 different subunits make up a variety of different GABA A receptor subtypes.
- GABA A receptors are involved in the pathogenesis and diagnosis of various diseases such as anesthesia, depression, anxiety, epilepsy, memory disorders, and drug dependence. Therefore, the GABA A receptor is a pharmacological and clinically important drug target. Propofol and its derivatives are an important class of compounds targeting GABA A.
- Propofol activates a variety of GABA A receptor subtypes and is a clinically mature intravenous anesthetic widely used for the induction and maintenance of general anesthesia.
- Clinical dose-related propofol directly activates the GABA A receptor-chloride channel complex in mammalian neurons, increases chloride conduction, reduces neural network excitability, and causes general anesthesia (Manami Hara et al. (1993) .Anesthesiology, 79, 781-788).
- the remarkable pharmacokinetic and pharmacodynamic properties of propofol are fast onset, short duration and fast reversible.
- propofol After intravenous administration, propofol rapidly enters the high perfusion area such as heart, lung and liver from the blood. The high fat solubility makes propofol easily cross the blood-brain barrier and enter the brain to exert general anesthesia.
- propofol also has obvious limitations and disadvantages. According to reports, about 70% of patients have a certain degree of pain or discomfort when taking propofol (Pascale Picard (2000). Anesthesia & Analgesia, 90, 963-969), reported to be a C in the aqueous phase of the lipid emulsion.
- Pain-induced injection pain (Klement W et al., 1991, Br J Anaesth 67, 281), several studies have reported that when the aqueous phase concentration of propofol is reduced compared to the propofol content in the aqueous phase of DIPRIVAN Injection pain was significantly reduced (Doenicke AW et al, 1996, Anesth Analg 82, 472; Ueki R et al, 2007, J Anesth 21, 325). Although it has been reported that pretreatment or combination therapy with other drugs can reduce the incidence and severity of propofol injection pain (CH Tan et al. (1998). Anaesthesia, 53, 302-305), this pain is still difficult to avoid. .
- Propofol has been shown to reduce systolic blood pressure, diastolic blood pressure and mean arterial blood pressure, thus causing hypotension in the clinic.
- respiratory depression is also a risk that cannot be ignored when using propofol.
- Sodium propofol is a water-soluble prodrug of propofol that is rapidly hydrolyzed by alkaline phosphatase to release propofol, phosphate and formaldehyde.
- sodium fospropofol relieves the pain of intravenous injection of propofol, it is still propofol
- the form of the drug works, so there is still a risk of respiratory depression and poor hemodynamic effects (Cohen LB (2008). Aliment Pharmacol Ther, 27, 597), while sodium propofol can also cause paresthesia and itching.
- the object of the present invention is to introduce a novel class of propofol derivatives which have a faster onset time, a similar maintenance time, a higher therapeutic index, and a lower fat-soluble property, thereby reducing the incidence of injection pain.
- the possibility A Doenicke et al. (1996). Anesth Analg, 82, 472-474).
- WO2009140275 describes propofol analogs or pharmaceutically acceptable salts thereof, which may be used as an anesthetic, wherein X may be a hydrogen source as follows:
- EP1206934 describes phenol derivatives useful in local anesthesia, antiarrhythmia, anticonvulsant, or pharmaceutically acceptable salts or prodrugs thereof, wherein RR 3 , R 4 , R 5 and R 6 are a hydrogen atom, a halogen atom or D- 7 fluorenyl; 1 2 is d- 7 fluorenyl or hydroxy; alternatively, R 1 and R 2 may optionally form a five-membered or six-membered ring, and the invention differs greatly from the structure of the compound of the present invention. Its general compounds are as follows:
- WO2008008492 describes pharmaceutically fluoro alkyl with hydroxyalkyl substituted phenol compounds and their pharmaceutically acceptable salts for the anesthetic agent or prodrug thereof, wherein, R 1 is a substituted or unsubstituted branched C 3 - 6 alkyl with, R 2 is hydrogen atom, a substituted or unsubstituted alkyl with C r3, the embankment 13 is d- fluoro group 3; in the specification definition, embankment group, refers to a saturated aliphatic groups, including straight-chain alkyl, branched chain alkyl group And a fluorenyl group, the substituted fluorenyl group means a hydrogen substituent of one or more carbon atoms of the fluorenyl moiety Substituted, the substituent includes fluorine, chlorine, bromine, iodine, hydroxy, decyloxy, cyano, amino, decyl, nitro, azide.
- R 1 is
- WO2006106906 describes the preparation of a cyclopropylphenol derivative of the formula wherein RR 2 , R 3 and R 4 each independently may be a hydrogen atom, F, Cl, Br, I, a substitutable d- 6 fluorenyl group, etc.; A hydrogen atom, a substitutable d- 6 fluorenyl group, etc., Y 1 , ⁇ 2 and ⁇ 3 are hydrogen atoms.
- the object of the present invention is to provide a GABA A receptor agonist which is novel in structure, better in efficacy, can reduce injection pain, and is safer, or all stereoisomers, solvates, metabolites thereof, and pharmaceutically acceptable Salt, eutectic or prodrug, preparation method, pharmaceutical composition and its use in the field of central nervous system, in order to induce or maintain anesthesia in animals or humans, promote sedative hypnosis, treat and prevent anxiety, nausea, vomiting, migraine , convulsions, epilepsy, neurodegenerative diseases, and central nervous system-related diseases provide more and better drug selection pathways.
- the present invention relates to a compound of the formula (A), or all stereoisomers, solvates, prodrug metabolites, pharmaceutically acceptable salts or co-crystals thereof:
- R is selected from F, Cl, Br, I, -OR 7 or More preferably F or ;
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxy, d- 8 fluorenyl, d- 8 decyloxy, 3 to 8 membered carbocyclyl or 3 to 8 membered heterocyclic
- the thiol, decyloxy, carbocyclic or heterocyclic group is optionally further Substituted to 5 substituents selected from the group consisting of F, Cl, Br, I, hydroxy, d- 8 fluorenyl, d- 8 methoxy, 3 to 8 membered carbocyclyl or 3 to 8 membered heterocyclyl, said
- the heterocyclic group contains 1 to 2 hetero atoms selected from N, 0 or S, and RR 2 and R 3 are not H at the same time;
- R 1 and R 2 , R 2 and R 3 or any group of R 1 and R 3 may form a 3- to 8-membered ring, and the 3- to 8-membered ring may contain 0 to 2 selected from N, 0. Or a hetero atom of S, and the formed 3 to 8 membered ring may be optionally further substituted with 0 to 4 R 8 ;
- R 4 , R 5 , R 9 , R 1Q , R 11 and R 12 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, cyano, d- 8 fluorenyl, decyloxy, 3 to 8 a carbocyclic group or a 3 to 8 membered heterocyclic group, the fluorenyl group, the decyloxy group, the carbocyclic group or the heterocyclic group optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d Substituted by a substituent of a 8 fluorenyl group, a d- 8 methoxy group, a 3 to 8 membered carbocyclic group or a 3 to 8 membered heterocyclic group, the heterocyclic group having 1 to 2 selected from N, 0 or a hetero atom of S, and R 4 and R 5 are not H at all, preferably, R 9 , R 1Q , R
- R 4 and R 5 , R 9 and R 1Q or any of R 11 and R 12 may form a 3 to 8 membered ring, and the 3 to 8 membered ring may contain 0 to 2 selected from N, 0. Or a hetero atom of S, and the formed 3 to 8 membered ring may be optionally further substituted with 0 to 4 R 8 ;
- R 6 is selected from H, F, Cl, Br, I, hydroxy or d- 8 methoxy, preferably H, F, Cl, hydroxy or d- 8 methoxy, more preferably H, hydroxy or d- 8 oxime Further, H or a hydroxyl group is further preferred;
- R 7 is selected from H, d- 8 fluorenyl, 3 to 8 membered carbocyclic or 3 to 8 membered heterocyclic, and the fluorenyl, carbocyclic or heterocyclic group is optionally further selected from 0 to 5 Substituted from a substituent of F, Cl, Br, I, hydroxy, d- 8 fluorenyl, d- 8 methoxy, 3 to 8 membered carbocyclyl or 3 to 8 membered heterocyclic group, said heterocyclic group containing 1 to 2 hetero atoms selected from N, 0 or S;
- R 8 is selected from the group consisting of F, Cl, Br, I, hydroxy, carboxy, amino, carboxylate, amide, d- 8 fluorenyl, d- 8 decyloxy, 3 to 8 membered carbocyclic or 3 to 8 a heterocyclic group, the heterocyclic group having 1 to 2 hetero atoms selected from N, 0 or S;
- X is selected from H, F or a carboxyl group, preferably H or F, more preferably H ;
- Y is selected from H 13 , PEG, COOR 13 , CONR 13 R 14 , COSR 13 , OR 16 , R 15
- CONR 13 R 14 V m ° ⁇ QR16 or NH 2 , more preferably H, PEG or ⁇ m ° ° r1S , further preferably H;
- R 13 and R 14 are each independently selected from H, d- 6 fluorenyl, 3 to 8 membered carbocyclic or heterocyclic, and the fluorenyl, carbocyclic or heterocyclic group may be further optionally Substituted to 5 substituents selected from the group consisting of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 fluorenyloxy, 3 to 8 membered carbocyclic or 3 to 8 membered heterocyclic group, Said heterocyclic group contains 1 to 2 heteroatoms selected from N, 0 or S;
- R 15 and R 16 are each independently selected from H, an alkali metal ion, an alkaline earth metal ion, a protonated amine or a protonated amino acid, and the alkali metal ion is selected from the group consisting of Na + , K + or Li + , the alkaline earth metal ion Selected from Be 2+ , Mg 2+ or Ca 2+ , the amine is selected from the group consisting of tromethamine, triethanolamine, ethanolamine, triethylamine or N-methylglucamine, said ammonia being selected as R, 15 and R 16 may form a 3 to 8 membered ring, and the 3 to 8 membered ring may contain 0 to 2 hetero atoms selected as g, 0 or S, and the formed 3 to 8 membered ring may optionally be further 0 to 4 R 8 substitutions;
- R 17 is an amino acid side chain group selected from the group consisting of lysine, arginine, histidine, proline, 2,3-diaminopropionic acid, 2,4-diaminopropionic acid, and alanine. Acid, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine , aspartic acid, aspartic acid or glutamic acid;
- Wi, W 2 and W 3 are each independently selected from NR y8 , 0 or S;
- W 4 is selected from CR y9 R ylQ, NR y8, 0, S or not present;
- R yl is independently selected from H, d- 6 embankment group, C 3 - 8 carbon ring group or 4 to 8-membered heterocyclic group, said group embankment, carbocyclyl or heterocyclyl may be optionally further substituted by 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxy, amino, cyano, carboxy, C embankment base, d- 6 embankment group, C 3 - 8 carbon ring group or 4-to 8-membered heterocyclic group Substituted by a substituent, the heterocyclic group containing 1 to 2 heteroatoms selected from N, 0 or S;
- R y3 is selected from H, amino, d 6 fluorenyl, C 3 -8 carbocyclyl or 4 to 8 membered heterocyclic, -(CR ya R yb ) ml -NR y yd or -
- Ry 6 and R y7 are each independently selected from H, F, Cl, Br, I, hydroxy, amino, cyano, carboxy, d- 6 fluorenyl or
- R y6 and R y7 may form a 5- to 8-membered ring together with the atoms to which they are attached, said 5 to 8 or
- the ring may contain from 0 to 4 heteroatoms selected from N, 0 or S, and the 5 to 8 membered ring may optionally be further from 0 to 4
- R y8 are each independently selected from H or d- 6 fluorenyl
- R yio Ry9 each independently selected from the group gH, Cl _ 6 alkyl with, C 3 _
- R ya , Ryb , R ye and R yd are each independently selected from H or Cl -6 fluorenyl;
- q is selected from 1 to 200;
- Ml is selected from 0, 1, 2 or 3;
- p is selected from 0, 1 or 2.
- n 1 or 2;
- n is selected from 1, 2 or 3, preferably 1 or 2, more preferably 1.
- Preferred embodiments of the invention include a compound of the formula (A), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof:
- R is selected from F OR, preferably F, Br or More preferably F or , ;
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxy, d- 7 fluorenyl, d- 7 methoxy, 3 to 6 carbocyclyl or 3 to 6 membered heterocyclyl.
- the fluorenyl group, the decyloxy group, the carbocyclic group or the heterocyclic group is further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d- 7 fluorenyl, d- 7 methoxy, 3 Substituted to a 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms selected from N, 0 or S, and RR 2 When it is different from R 3 , it is H;
- R 1 and R 2 , R 2 and R 3 or any group of R 1 and R 3 may form a 3 to 6 membered ring, and the 3 to 6 membered ring may have 0 to 2 selected from N, 0. Or a hetero atom of S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 8 ;
- R 4 , R 5 , R 9 , R 1Q , R 11 and R 12 are each independently selected from H, F, Cl, Br, I, hydroxy, 7 fluorenyl, decyloxy, 3 to 6 membered carbocyclic or 3
- the fluorenyl, decyloxy, carbocyclic or heterocyclic group is further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, 7 fluorenyl, 7 ⁇ .
- R 9 , R 1Q , R 11 and R 12 are each independently selected from H or F ;
- R 4 and R 5 , R 9 and R 1Q or any of R 11 and R 12 may form a 3 to 6 membered ring, and the 3 to 6 membered ring may contain 0 to 2 selected from N, 0. Or a hetero atom of S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 8 ;
- R 6 is selected from H, F, Cl, Br, I, a hydroxyl group or a 7- methoxy group, preferably H, F, Cl, a hydroxyl group or a 7- methoxy group, more preferably H, a hydroxyl group or a 7- methoxy group, further preferably H or hydroxyl;
- R 7 is selected from H, 7 fluorenyl, 3 to 6 membered carbocyclic or 3 to 6 membered heterocyclic, and the fluorenyl, carbocyclic or heterocyclic group is further optionally 0 to 5 selected from F Substituted with a substituent of a Cl, Br, I, a hydroxyl group, a decyl group, a decyloxy group, a 3 to 6 membered carbocyclic group or a 3 to 6 membered heterocyclic group, the heterocyclic group having 1 to 2 selected from a hetero atom of N, 0 or S;
- R 8 is selected from the group consisting of F, Cl, Br, I, hydroxy, 7 fluorenyl, carboxy, amino, carboxylate, amide, 7 methoxy, 3 to 6 membered carbocyclyl or 3 to 6 membered heterocyclic
- the heterocyclic group contains 1 to 2 hetero atoms selected from N, 0 or S;
- Y is selected from H COR 13 , PEG, COOR 13 , CONR 13 R 14 , COSR 13 , OR 16 , R 15
- R 13 and R 14 are each independently selected from H or d- 6 fluorenyl
- R 15 and R 16 are each independently selected from H or an alkali metal ion, and the alkali metal ion is selected from Na + , K + or Li + ;
- R 17 is an L-amino acid side chain group, and the L-amino acid is selected from the group consisting of lysine, arginine, histidine, 2,3-diaminopropionic acid, 2,4-diaminopropionic acid, and C.
- X is selected from H, F or a carboxyl group, preferably H or F, more preferably H ;
- n 1 or 2;
- n is selected from 1, 2 or 3, preferably 1 or 2, more preferably 1.
- Preferred embodiments of the invention include a compound of the formula (A), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof:
- R is selected from F, Cl, Br, I, -OR 7 or More preferably F or ;
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group.
- the fluorenyl, decyloxy, carbocyclic or heterocyclic group is further optionally from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 fluorenyloxy Substituted with a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group containing 1 to 2 heteroatoms selected from N, 0 or S, and RR 2 and R 3 Not at the same time;
- R 1 and R 2 , R 2 and R 3 or any group of R 1 and R 3 may form a 3 to 5 membered ring,
- the 3- to 5-membered ring may contain 0 to 2 heteroatoms selected from N, 0 or S, and the formed 3- to 5-membered ring may be optionally further substituted with 0 to 4 R 8 ;
- R 4 , R 5 , R 9 , R 1Q , R 11 and R 12 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 a carbocyclic group or a 3 to 5 membered heterocyclic group, which is further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d_ Substituted by a substituent of a 6 fluorenyl group, a d 6 methoxy group, a 3 to 5 membered carbocyclic group or a 3 to 5 membered heterocyclic group, the heterocyclic group having 1 to 2 selected from N, 0 or S miscellaneous Atom, and R 4 and R 5 are not H at all, preferably, R 9 , R 1Q , R 11 and R 12 are each independently selected from H or F ;
- R 4 and R 5 , R 9 and R 1Q or any of R 11 and R 12 may form a 3 to 5 membered ring, and the 3 to 5 membered ring may contain 0 to 2 selected from N. a hetero atom of 0 or S, and the formed 3 to 5 membered ring may be optionally further substituted with 0 to 4 R 8 ;
- R 6 is selected from H, hydroxy or d- 6 methoxy, preferably H or hydroxy;
- R 7 is selected from H, d- 6 fluorenyl, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic, and the fluorenyl, carbocyclic or heterocyclic group is optionally further selected from 0 to 5 Substituted from a substituent of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group, said heterocyclic ring
- the base contains 1 to 2 heteroatoms selected from N, 0 or S;
- R 8 is selected from the group consisting of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, carboxy, amino, carboxylate, amide, d- 6 methoxy, 3 to 5 valent carbocyclyl or 3 to 5 a heterocyclic group, the heterocyclic group having 1 to 2 hetero atoms selected from N, 0 or S;
- X is selected from H or F, preferably H;
- the alkyl group is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, hydroxy, amino, cyano, carboxy, d- 6 alkyl, d- 6 alkoxy, C 3 — substituted by an 8- carbon ring group or a 4- to 8-membered heterocyclic group, the heterocyclic group having 1 to 2 hetero atoms selected from N, 0 or S; Y is preferably H, PEG.
- P( 0)(W 2 R y4 )(W 3 R y5 ), more preferably H, PEG or m ° ° r1S ;
- n is selected from 1, 2 or 3, preferably 1 or 2, more preferably 1.
- Preferred embodiments of the invention include a compound of the formula (A), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof:
- R is selected from F, Cl, Br, I, -OR 7 or , preferably F, Br or, more preferably F or ;
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group.
- the fluorenyl, decyloxy, carbocyclic or heterocyclic group is further optionally from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 fluorenyloxy Substituted with a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group containing 1 to 2 heteroatoms selected from N, 0 or S, and RR 2 and R 3 Not at the same time;
- R 1 and R 2 , R 2 and R 3 or any of R 1 and R 3 may form a 3- to 5-membered ring, and the 3- to 5-membered ring may contain 0 to 2 selected from N, 0. Or a hetero atom of S, and the formed 3 to 5 membered ring may be optionally further substituted with 0 to 4 R 8 ;
- R 4 , R 5 , R 9 , R 1Q , R 11 and R 12 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 a carbocyclic group or a 3 to 5 membered heterocyclic group, which is further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d_ Substituted by a substituent of a 6 fluorenyl group, a d 6 methoxy group, a 3 to 5 membered carbocyclic group or a 3 to 5 membered heterocyclic group, the heterocyclic group having 1 to 2 selected from N, 0 or S a hetero atom, and R 4 and R 5 are not simultaneously H; preferably, R 9 , R 1Q , R 11 and R 12 are each independently selected from H, F, Cl, Br, I, hydroxy or d- 6 fluorenyl;
- R 4 and R 5 , R 9 and R 1Q or any of R 11 and R 12 may form a 3- to 5-membered ring, and the 3- to 5-membered ring may contain 0 to 2 selected from N, 0. Or a hetero atom of S, and the formed 3- to 5-membered ring may be optionally further substituted by 0 to 4 R 8 ; preferably, R 9 and R 1Q or any of R 11 and R 12 may form a 3 to 5 Metacarbon ring group;
- R 6 is selected from H or a hydroxyl group
- R 7 is selected from H, d- 6 fluorenyl, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic, and the fluorenyl, carbocyclic or heterocyclic group is optionally further selected from 0 to 5 Substituted from a substituent of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group, said heterocyclic group containing 1 to 2 hetero atoms selected from N, 0 or S;
- R 8 is selected from the group consisting of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, carboxy, amino, carboxylate, amide, d- 6 methoxy, 3 to 5 valent carbocyclyl or 3 to 5 a heterocyclic group, the heterocyclic group having 1 to 2 hetero atoms selected from N, 0 or S;
- X is selected from H or F
- Y is selected from H
- n is selected from 1, 2 or 3, preferably 1 or 2, more preferably 1.
- a preferred embodiment of the invention a compound of the formula (A), or a stereoisomer, solvate, metabolism thereof a product, prodrug, pharmaceutically acceptable salt or eutectic: wherein:
- R is selected from F, Cl, Br, I, -OR 7 or ⁇ 3 , preferably F, Br or More preferably F or , further preferred;
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group.
- the fluorenyl group, the decyloxy group, the carbocyclic group or the heterocyclic group is further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 Substituted to a 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group containing 1 to 2 hetero atoms selected from N, 0 or S, and wherein RR 2 and R 3 are different Is H;
- R 1 and R 2 , R 2 and R 3 or R 1 and RR 2 3 each form a 3 to 5 membered ring, and the 3 to 5 membered ring contains 0 to 2 selected from N, 0. Or a hetero atom of S, and the formed 3 to 5 membered ring is optionally further substituted with 0 to 4 R 8 ;
- R 4 and R 5 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, cyano, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group.
- the fluorenyl, decyloxy, carbocyclic or heterocyclic group is further optionally from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 fluorenyloxy Substituted by a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group having 1 to 2 hetero atoms selected from N, 0 or S, and R 4 and R 5 Not at the same time;
- R 4 and R 5 may form a 3 to 5 membered ring, and the 3 to 5 membered ring may have 0 to 2 hetero atoms selected from N, 0 or S, and form a 3 to 5 membered ring. It may optionally be further substituted with 0 to 4 R 8 ;
- R 6 is selected from H, hydroxy or d- 6 methoxy, preferably H or hydroxy;
- R 7 is selected from H, d - 4 fluorenyl or a 3 to 5 membered carbocyclic group, and the fluorenyl or carbocyclic group is optionally further 0 to
- R 8 is selected from the group consisting of F, Cl, Br, hydroxy, d 4 fluorenyl, d 4 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group, and said heterocyclic group contains 1 to 2 a hetero atom selected from N, 0 or S;
- R 9 , R 1Q , R 11 and R 12 are each independently selected from H, F, Cl, Br, I, hydroxy, d 6 fluorenyl or d 6 oxo
- X is selected from H, F or a carboxyl group, preferably H;
- the thiol group is further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, hydroxy, amino, cyano, carboxy, d- 6 fluorenyl, d- 6 methoxy, C 3 — substituted by a substituent of an 8- carbon ring group or a 4- to 8-membered heterocyclic group, the heterocyclic group having 1
- R 13 and R 14 are each independently selected from H, d- 6 fluorenyl, 3 to 8 membered carbocyclic or heterocyclic, and the fluorenyl, carbocyclic or heterocyclic group may be further optionally Substituted to 5 substituents selected from the group consisting of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 fluorenyloxy, 3 to 8 membered carbocyclic or 3 to 8 membered heterocyclic group, Said heterocyclic group contains 1 to 2 heteroatoms selected from N, 0 or S;
- R 15 and R 16 are each independently selected from H, an alkali metal ion, an alkaline earth metal ion, a protonated amine or a protonated amino acid, and the alkali metal ion is selected from the group consisting of Na + , K + or Li + , the alkaline earth metal ion Selected from Be 2+ , Mg 2+ or Ca 2+ , the amine is selected from the group consisting of tromethamine, triethanolamine, ethanolamine, triethylamine or N-methylglucamine, and the amino acid is selected from the group consisting of arginine Acid or lysine;
- R 15 and R 16 may form a 3 to 8 membered ring, and the 3 to 8 membered ring may have 0 to 2 hetero atoms selected from N, 0 or S, and the formed 3 to 8 membered ring may be Optionally further substituted by 0 to 4 R 8 ;
- R 17 is an amino acid side chain group selected from the group consisting of lysine, arginine, histidine, proline, 2,3-diaminopropionic acid, 2,4-diaminopropionic acid, and alanine. Acid, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine , aspartic acid, aspartic acid or glutamic acid;
- Wi, W 2 and W 3 are each independently selected from NR y8 , 0 or S;
- W 4 is selected from CR y9 R ylQ, NR y8, 0, S or not present;
- R yl is independently selected from H, d- 6 embankment group, C 3 - 8 carbon ring group or 4 to 8-membered heterocyclic group, said group embankment, carbocyclyl or heterocyclyl may be optionally further substituted by 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxy, amino, cyano, carboxy, C embankment base, d- 6 embankment group, C 3 - 8 carbon ring group or 4-to 8-membered heterocyclic group Substituted by a substituent, the heterocyclic group containing 1 to 2 heteroatoms selected from N, 0 or S;
- R y3 is selected from H, amino, d 6 fluorenyl, C 3 -8 carbocyclyl or 4 to 8 membered heterocyclic, -(CR ya R yb ) ml -NR y yd or -
- R y6 and R y7 are each independently selected from g H , F , Cl, Br, I, hydroxy, amino, cyano, carboxy, d- 6 fluorenyl or d- 6 methoxy;
- R y6 and R y7 may form a 5- to 8-membered ring together with the atoms to which they are attached, said 5 to 8 or
- the ring may contain from 0 to 4 heteroatoms selected from N, 0 or S, and the 5 to 8 membered ring may optionally be further from 0 to 4
- R y8 are each independently selected from H or d- 6 fluorenyl
- R yio Ry9 each independently selected from the group gH, Cl _ 6 alkyl with, C 3 _
- R ya , Ryb , R ye and R yd are each independently selected from H or Cl -6 fluorenyl;
- n is selected from 1, 2 or 3;
- n 1 or 2;
- q is selected from 1 to 200;
- Ml is selected from 0, 1, 2 or 3;
- p is selected from 0, 1 or 2.
- Preferred embodiments of the invention include a compound of the formula (A), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or co-crystals thereof:
- R is selected from F OR Preferably F, Br or more preferably F or , ;
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxy, d- 7 fluorenyl, d- 7 methoxy, 3 to 6 carbocyclyl or 3 to 6 membered heterocyclyl.
- the fluorenyl group, the decyloxy group, the carbocyclic group or the heterocyclic group is further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d- 7 fluorenyl, d- 7 methoxy, 3 Substituted to a 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms selected from N, 0 or S, and RR 2 When it is different from R 3 , it is H;
- R 1 and R 2 , R 2 and R 3 or any group of R 1 and R 3 may form a 3 to 6 membered ring, and the 3 to 6 membered ring may have 0 to 2 selected from N, 0. Or a hetero atom of S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 8 ;
- R 4 , R 5 , R 9 , R 1Q , R 11 and R 12 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, d- 7 fluorenyl, d- 7 methoxy, 3 to 6 a carbocyclic group or a 3- to 6-membered heterocyclic group, the fluorenyl, decyloxy, carbocyclic or heterocyclic group optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d Substituted by a substituent of a 7- mercapto group, a d-- 7 -methoxy group, a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, the heterocyclic group having 1 to 2 selected from N, 0 or a hetero atom of S, and R 4 and R 5 are not H at all, preferably, R 9 , R 1Q , R 11 and R 12 are
- R 4 and R 5 , R 9 and R 1Q or any of R 11 and R 12 may form a 3 to 6 membered ring, and the 3 to 6 membered ring may contain 0 to 2 selected from N, 0. Or a hetero atom of S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 8 ;
- R 6 is selected from H, F, Cl, Br, I, hydroxy or d- 7 methoxy, preferably H, F, Cl, hydroxy or d- 7 methoxy, more preferably H, hydroxy or — 7 ⁇ Further, H or a hydroxyl group is further preferred;
- R 7 is selected from H, d- 7 alkyl, 3 to 6 membered carbocyclic or 3 to 6 membered heterocyclic, and the fluorenyl, carbocyclic or heterocyclic group is optionally further selected from 0 to 5 Substituted from a substituent of F, Cl, Br, I, hydroxy, d- 7 decyl, d- 7 methoxy, 3 to 6 membered carbocyclyl or 3 to 6 membered heterocyclic group, said heterocyclic group containing 1 to 2 hetero atoms selected from N, 0 or S;
- R 8 is selected from the group consisting of F, Cl, Br, I, hydroxy, d- 7 fluorenyl, carboxy, amino, carboxylate, amide, d- 7 methoxy, 3 to 6 membered carbocyclyl or 3 to 6 a heterocyclic group, the heterocyclic group having 1 to 2 hetero atoms selected from N, 0 or S;
- Y is selected from H, PEG, COR 13 , CONR 13 R 14 ,
- R 13 and R 14 are each independently selected from H or d- 6 fluorenyl
- R 15 and R 16 are each independently selected from H or an alkali metal ion, and the alkali metal ion is selected from Na + , K + or
- R 17 is an L-amino acid side chain group, and the L-amino acid is selected from the group consisting of lysine, arginine, histidine, 2,3-diaminopropionic acid, 2,4-diaminopropionic acid, and C.
- X is selected from H, F or a carboxyl group, preferably H or F, more preferably H;
- n 1 or 2;
- n is selected from 1, 2 or 3, preferably 1 or 2, more preferably 1.
- Preferred embodiments of the invention include a compound of the formula (A), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or co-crystals thereof:
- R is selected from F, Cl, Br, I, -OR 7 or , preferably F, Br, more preferably F or , further preferred;
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group.
- the fluorenyl, decyloxy, carbocyclic or heterocyclic group is further optionally from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 fluorenyloxy Substituted with a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group containing 1 to 2 heteroatoms selected from N, 0 or S, and RR 2 and R 3 Not at the same time;
- R 1 and R 2 , R 2 and R 3 or any of R 1 and R 3 may form a 3- to 5-membered ring, and the 3- to 5-membered ring may contain 0 to 2 selected from N, 0. Or a hetero atom of S, and the formed 3 to 5 membered ring may be optionally further substituted with 0 to 4 R 8 ;
- R 4 , R 5 , R 9 , R 1Q , R 11 and R 12 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 a carbocyclic group or a 3 to 5 membered heterocyclic group, the fluorenyl, decyloxy, carbocyclic or heterocyclic group optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d Substituted by a substituent of 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group, said heterocyclic group having 1 to 2 selected from N, 0 or a hetero atom of S, and R 4 and R 5 are not H at all, preferably, R 9 , R 1Q , R 11 and R 12 are each independently selected from H or F ;
- R 4 and R 5 , R 9 and R 1Q or any of R 11 and R 12 may form a 3- to 5-membered ring, and the 3- to 5-membered ring may contain 0 to 2 selected from N, 0. Or a hetero atom of S, and the formed 3 to 5 membered ring may be optionally further substituted with 0 to 4 R 8 ;
- R 6 is selected from H, hydroxy or d- 6 methoxy, preferably H or hydroxy;
- R 7 is selected from H, d- 6 fluorenyl, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic, and the fluorenyl, carbocyclic or heterocyclic group is optionally further selected from 0 to 5 Substituted from a substituent of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group, said heterocyclic ring
- the base contains 1 to 2 heteroatoms selected from N, 0 or S;
- R 8 is selected from the group consisting of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, carboxy, amino, carboxylate, amide, d- 6 ox a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group having 1 to 2 hetero atoms selected from N, 0 or S;
- X is selected from H or F, preferably H;
- Y is selected from H
- n is selected from 1, 2 or 3, preferably 1 or 2, more preferably 1.
- Preferred embodiments of the invention include a compound of the formula (A), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or co-crystals thereof:
- R is selected from F, Cl, Br I, , preferably F, Br, more preferably F or , further preferred;
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group.
- the fluorenyl, decyloxy, carbocyclic or heterocyclic group is further optionally from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 fluorenyloxy Substituted with a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group containing 1 to 2 heteroatoms selected from N, 0 or S, and RR 2 and R 3 Not at the same time;
- R 1 and R 2 , R 2 and R 3 or any of R 1 and R 3 may form a 3- to 5-membered ring, and the 3- to 5-membered ring may contain 0 to 2 selected from N, 0. Or a hetero atom of S, and the formed 3 to 5 membered ring may be optionally further substituted with 0 to 4 R 8 ;
- R 4 , R 5 , R 9 , R 1Q , R 11 and R 12 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 a carbocyclic group or a 3 to 5 membered heterocyclic group, which is further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d_ Substituted by a substituent of a 6 fluorenyl group, a d 6 methoxy group, a 3 to 5 membered carbocyclic group or a 3 to 5 membered heterocyclic group, the heterocyclic group having 1 to 2 selected from N, 0 or S a hetero atom, and R 4 and R 5 are not simultaneously H; preferably, R 9 , R 1Q , R 11 and R 12 are each independently selected from H, F, Cl, Br, I, hydroxy or d 6 fluorenyl; Pre
- R 4 and R 5 , R 9 and R 1Q or any of R 11 and R 12 may form a 3- to 5-membered ring, and the 3- to 5-membered ring may contain 0 to 2 selected from N, 0. Or a hetero atom of S, and the formed 3- to 5-membered ring may be optionally further substituted by 0 to 4 R 8 ; preferably, R 9 and R 1Q or any of R 11 and R 12 may form a 3 to 5 Metacarbon ring group;
- R 6 is selected from H or a hydroxyl group
- R 7 is selected from H, d- 6 fluorenyl, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic, said fluorenyl, carbocyclyl or
- the heterocyclic group is optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group.
- R 8 is selected from the group consisting of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, carboxy, amino, carboxylate, amide, d- 6 methoxy, 3 to 5 valent carbocyclyl or 3 to 5 a heterocyclic group, the heterocyclic group having 1 to 2 hetero atoms selected from N, 0 or S;
- X is selected from H or F
- Y is selected from H
- n is selected from 1, 2 or 3, preferably 1 or 2, more preferably 1.
- a preferred embodiment of the invention a compound of the formula (I), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or eutectics thereof:
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group.
- the fluorenyl, decyloxy, carbocyclic or heterocyclic group optionally further being 0 to 5 Substituted with a substituent selected from the group consisting of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclyl, said
- the heterocyclic group contains 1 to 2 hetero atoms selected from N, 0 or S, and RR 2 and R 3 are not H at the same
- R 1 and R 2 , R 2 and R 3 or any group of R 1 and R 3 may form a 3- to 5-membered ring, and the 3- to 5-membered ring may contain 0 to 2 selected from N, a hetero atom of 0 or S, and the formed 3 to 5 membered ring may be optionally further substituted with 0 to 4 R 8 ;
- R 4 and R 5 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic, Preferred is H, F, Cl, Br, hydroxy, d- 4 fluorenyl or d- 4 methoxy, more preferably H, F, hydroxy, d-4-indenyl or d-4 decyloxy, still more preferably H, F or d- 3 ⁇ , the ⁇
- the group, the methoxy group, the carbocyclic group or the heterocyclic group is further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 Substituted by a carbocyclic group or a substituent of a 3- to 5-membered heterocyclic group, the heterocyclic group having
- R 4 and R 5 may form a 3 to 5 membered ring, and the 3 to 5 membered ring may have 0 to 2 hetero atoms selected from N, 0 or S, and form a 3 to 5 membered ring. Further optionally substituted by 0 to 4 R 8 ; R 6 is selected from H, hydroxy or d- 6 methoxy, preferably H or hydroxy, more preferably H;
- R 7 is selected from H, d- 6 fluorenyl, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic, and the fluorenyl, carbocyclic or heterocyclic group is optionally further selected from 0 to 5 Substituted from a substituent of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group, said heterocyclic ring
- the base contains 1 to 2 heteroatoms selected from N, 0 or S;
- R 8 is selected from the group consisting of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, carboxy, amino, carboxylate, amide, d- 6 methoxy, 3 to 5 valent carbocyclyl or 3 to 5 a heterocyclic group, the heterocyclic group having 1 to 2 hetero atoms selected from N, 0 or S;
- n is selected from 1, 2 or 3, preferably 1 or 2, more preferably 1.
- Preferred embodiments of the invention include a compound of the formula (I), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or co-crystals thereof:
- R is selected from F, Cl, Br, I, -OR 7 or More preferably F, Br or ;
- RR 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic, preferably H, F , hydroxy, d- 4 fluorenyl, d- 4- methoxy or 3 to 5 membered carbocyclic group, more preferably H, F, hydroxy, d- 3 fluorenyl, d- 3 methoxy or 3 to 5 carbon a cyclo group, further preferably H, d_ 3 fluorenyl or a 3 to 4 membered carbocyclic group, the fluorenyl, decyloxy, carbocyclic or heterocyclic group optionally further selected from 0 to 5 selected from F, Cl Substituted with a substituent of Br, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5
- R 1 and R 2 , R 2 and R 3 or any group of R 1 and R 3 may form a 3- to 5-membered ring, and the 3- to 5-membered ring may contain 0 to 2 selected from N, a hetero atom of 0 or S, and the formed 3 to 5 membered ring may be optionally further substituted with 0 to 4 R 8 ;
- R 4 and R 5 are each independently selected from the group consisting of H, F, Cl, Br, hydroxy, d- 5 fluorenyl, d- 5 decyloxy, 3 to 5 membered carbocyclic group Or a 3 to 5 membered heterocyclic group, preferably H, F, Cl, Br, hydroxy, d- 4 fluorenyl or d- 4 methoxy, more preferably H, F, hydroxy, d-4 fluorenyl or d-4
- the oxime group is further preferably H, F or d- 3 fluorenyl
- the fluorenyl group, the decyloxy group, the carbocyclic group or the heterocyclic group is further further selected from 0 to 5 selected from F, Cl, Br, Substituted by a substituent of a hydroxy group, a d- 5 fluorenyl group, a d- 5 methoxy group, a 3 to 5 membered carbocyclic group or a 3 to
- R 4 and R 5 may form a 3 to 5 membered ring, and the 3 to 5 membered ring may have 0 to 2 hetero atoms selected from N, 0 or S, and form a 3 to 5 membered ring.
- R 6 is selected from H or hydroxy, preferably H;
- R 7 is selected from H, d - 5 fluorenyl, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic, and the fluorenyl, carbocyclic or heterocyclic group is optionally further selected from 0 to 5 From F, Cl, Br, I, hydroxy, d- 5 fluorenyl, d- 5 decyloxy or a 3 to 5 membered carbocyclic group;
- R 8 is selected from the group consisting of F, Cl, Br, hydroxy, d- 5 fluorenyl, d- 5 methoxy, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic, said heterocyclic group having 1 to 2 a hetero atom selected from N, 0 or S;
- n is selected from 1, 2 or 3, preferably 1 or 2, more preferably 1.
- Preferred embodiments of the invention include a compound of the formula (I), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or co-crystals thereof:
- R is selected from, further preferred ;
- RR 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic, preferably H, F , hydroxy, d- 4 fluorenyl, d- 4- methoxy or 3 to 5 membered carbocyclic group, more preferably H, F, hydroxy, d- 3 fluorenyl, d- 3 methoxy or 3 to 5 carbon a cyclo group, further preferably H, d_ 3 fluorenyl or a 3 to 4 membered carbocyclic group, the fluorenyl, decyloxy, carbocyclic or heterocyclic group optionally further selected from 0 to 5 selected from F, Cl Substituted with a substituent of Br, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5
- R 1 and R 2 , R 2 and R 3 or any group of R 1 and R 3 may form a 3- to 5-membered ring, and the 3- to 5-membered ring may contain 0 to 2 selected from N, a hetero atom of 0 or S, and the formed 3 to 5 membered ring may be optionally further substituted with 0 to 4 R 8 ;
- R 4 and R 5 are each independently selected from the group consisting of H, F, Cl, Br, hydroxy, d- 4 fluorenyl, d- 4- decyloxy, 3 to 5 membered carbocyclic group Or a 3 to 5 membered heterocyclic group, preferably H, F, Cl, Br, hydroxy, d- 4 fluorenyl or d- 4 methoxy, more preferably H, F, hydroxy, d-4 fluorenyl or d-4
- the oxime group is further preferably H, F or d- 3 fluorenyl
- the fluorenyl group, the decyloxy group, the carbocyclic group or the heterocyclic group is further further selected from 0 to 5 selected from F, Cl, Br, Substituted by a substituent of a hydroxy group, a d- 4 fluorenyl group, a d- 4 methoxy group, a 3 to 5 membered carbocyclic group or a 3 to
- R 4 and R 5 may form a 3 to 5 membered ring, and the 3 to 5 membered ring may have 0 to 2 hetero atoms selected from N, 0 or S, and form a 3 to 5 membered ring.
- R 8 optionally substituted by 0 to 4 R 8 ;
- R 6 is selected from H or a hydroxyl group, preferably H;
- R 7 is selected from d - 4 fluorenyl or 3 to 5 membered carbocyclic group, and the fluorenyl or carbocyclic group is further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d- 4 Substituted with a substituent of a fluorenyl group, a d- 4 methoxy group or a 3- to 5-membered carbocyclic group;
- R 8 is selected from the group consisting of F, Cl, Br, hydroxy, d-4 fluorenyl, d-4 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group, said heterocyclic group having 1 to 2 heteroatoms selected from N, 0 or S;
- n is selected from 1, 2 or 3, preferably 1 or 2, more preferably 1.
- Preferred embodiments of the invention include a compound of the formula (I), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or co-crystals thereof:
- R choose F, Br, -OR 7 or , preferably F, more preferably F or, ;
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxy, d- 5 fluorenyl, d- 5 decyloxy or a 3 to 5 membered carbocyclic group, preferably H, F, hydroxy, D- 4 fluorenyl, d- 4 methoxy or 3 to 5 membered carbocyclic group, more preferably H, F, hydroxy, d- 3 fluorenyl, d- 3 methoxy or 3 to 5 membered carbocyclic, Further preferred is H, d- 3 fluorenyl or a 3 to 4 membered carbocyclic group, and the fluorenyl, decyloxy or carbocyclic group is optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, hydroxy, d Substituting a substituent of a 5 fluorenyl group, a d- 5 methoxy group or a 3 to 5 membered carbocycl
- R 1 and R 2 , R 2 and R 3 or any of R 1 and R 3 may form a 3 to 5 membered carbocyclic group, preferably a 3 to 4 membered carbocyclic group, and the carbocyclic group may be used.
- R 8 optionally further substituted by 0 to 4 R 8 ;
- R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxy, d- 4 fluorenyl or d- 4 decyloxy, preferably H, F, hydroxy, C M decyl or d- 4 decyloxy More preferably, H, F or d- 3 fluorenyl, the fluorenyl or decyloxy optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, hydroxy, d- 4 fluorenyl or d- 4 ⁇ Substituted by a substituent of an oxy group, and R 4 and R 5 are not simultaneously H;
- R 4 and R 5 may form a 3 to 5 membered carbocyclic group, preferably a 3 to 4 membered carbocyclic group, said carbon
- the cyclic group may be optionally further substituted with from 0 to 4 R 8 ;
- R 6 is selected from H or a hydroxyl group
- R 7 is selected from d - 4 fluorenyl or 3 to 4 - membered carbocyclic group, and the fluorenyl or carbocyclic group may be further substituted by 0 to 5 substituents selected from F, hydroxy or -3 fluorenyl;
- R 8 is selected from the group consisting of F, Cl, Br, hydroxy, d- 4 fluorenyl, C M decyloxy or a 3 to 5 membered carbocyclic group;
- n is selected from 1, 2 or 3, preferably 1 or 2, more preferably 1.
- Preferred embodiments of the invention include a compound of the formula (I), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or co-crystals thereof:
- R is selected from F, Br, -OR 7 or , into
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxy, d- 5 fluorenyl, d- 5 methoxy or 3 to 5 membered carbocyclyl, preferably H, F, hydroxy, d- 4 fluorenyl, d- 4 methoxy or 3 to 5 membered carbocyclic group, more preferably H, F, hydroxy, d- 3 fluorenyl, d- 3 decyloxy or 3 to 5 membered carbocyclic group, further preferably H, d- 3 fluorenyl or 3 to 4 membered carbocyclic group, the fluorenyl, decyloxy or carbocyclic group optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, hydroxy, d- 5 Substituted with a substituent of a fluorenyl group, a d- 5 methoxy group or a 3 to 5 membered carbocyclic group
- R 1 and R 2 , R 2 and R 3 or any of R 1 and R 3 may form a 3 to 5 membered carbocyclic group, preferably a 3 to 4 membered carbocyclic group, and the carbocyclic group may be used.
- R 8 optionally further substituted by 0 to 4 R 8 ;
- R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxy, d- 4 fluorenyl or d- 4 methoxy, preferably H, F, hydroxy, d-4 fluorenyl or -4-oxoxy More preferably H, F or d- 3 fluorenyl, the fluorenyl or decyloxy optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, hydroxy, d- 4 fluorenyl or d- 4 Substituted by a substituent of a methoxy group, and R 4 and R 5 are not H at the same time;
- R 4 and R 5 may form a 3 to 5 membered carbocyclic group, preferably a 3 to 4 membered carbocyclic group, and the carbocyclic group may be optionally further substituted with 0 to 4 R 8 ;
- R 6 is selected from H or a hydroxyl group
- R 7 is selected from d- 4 alkyl with 3-4 yuan or carbocyclyl, said embankment, or carbocyclyl group may be further 0 to 3 substituents selected from F, hydroxy or --3 embankment group substituents;
- R 8 is selected from the group consisting of F, Cl, Br, hydroxy, d- 4 fluorenyl or d- 4 methoxy; n is selected from 1 or 2, preferably 1.
- Preferred embodiments of the invention include a compound of the formula (I), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or co-crystals thereof:
- R is selected from F, Br or , preferably, more preferred
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxy, d 4 fluorenyl, d 4 methoxy or 3 to 5 membered carbocyclic, preferably H, F, hydroxy, d — 4 fluorenyl, d- 4 methoxy or 3 to 5 membered carbocyclic group, more preferably H, F, hydroxy, d- 3 fluorenyl, d- 3 decyloxy or 3 to 5 membered carbocyclic group, further preferably H, d- 3 fluorenyl or 3 to 4 membered carbocyclic group, said fluorenyl, decyloxy or carbocyclic group optionally further from 0 to 3 selected from the group consisting of F, Cl, Br, hydroxy, d- 4 Substituted with a fluorenyl, d- 4 methoxy or 3 to 5-membered carbocyclic group, and RR 2 and R 3 are not H at all;
- R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxy, d- 4 fluorenyl or d- 4 methoxy, preferably H, F, hydroxy, d-4 fluorenyl or -4-oxoxy More preferably H, F or d- 3 fluorenyl, the fluorenyl or decyloxy optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, hydroxy, d- 4 fluorenyl or d- 4 Substituted by a substituent of a methoxy group, and R 4 and R 5 are not H at the same time;
- R 4 and R 5 may form a 3 to 5 membered carbocyclic group, preferably a 3 to 4 membered carbocyclic group, and the carbocyclic group may be optionally further substituted with 0 to 4 R 8 ;
- R 6 is selected from H or a hydroxyl group, preferably H;
- R 8 is selected from the group consisting of F, Cl, Br, hydroxy, d- 4 fluorenyl or d- 4 methoxy, preferably F, hydroxy or d- 3 fluorenyl; n is selected from 1 or 2, preferably 1.
- Preferred embodiments of the invention include a compound of the formula (I), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or co-crystals thereof:
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxy, d 4 fluorenyl, d 4 methoxy or 3 to 5 membered carbocyclic, preferably H, F, hydroxy, d — 4 fluorenyl, d- 4 methoxy or 3 to 5 membered carbocyclic group, more preferably H, F, hydroxy, d- 3 fluorenyl, d- 3 decyloxy or 3 to 5 membered carbocyclic group, further preferably H, d- 3 fluorenyl or 3 to 4 membered carbocyclic group, said fluorenyl, decyloxy or carbocyclic group optionally further from 0 to 3 selected from the group consisting of F, Cl, Br, hydroxy, d- 4 Substituted by a substituent of a fluorenyl group, a d- 4- yloxy group or a 3- to 5-membered carbocyclic group, and
- R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxy, d- 4 fluorenyl or d- 4 methoxy, preferably H, F, hydroxy, d-4 fluorenyl or -4-oxoxy More preferably H, F or d- 3 fluorenyl, the fluorenyl or decyloxy optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, hydroxy, d- 4 fluorenyl or d- 4 Substituted by a substituent of a methoxy group, and R 4 and R 5 are not H at the same time;
- R 4 and R 5 may form a 3 to 5 membered carbocyclic group, preferably a 3 to 4 membered carbocyclic group, and the carbocyclic group may be optionally further substituted with 0 to 4 R 8 ;
- R 6 is selected from H or a hydroxyl group, preferably H;
- R 8 is selected from F, Cl, Br, hydroxy, d- 4 alkyl with or ⁇ --4 embankment group, preferably F, or hydroxy --3 embankment group; n is selected from 1.
- a preferred embodiment of the invention comprises a compound of the formula (I), wherein the compound is selected from the compounds of the formula (II), or all stereoisomers, solvates, metabolites, prodrugs thereof, pharmaceutics Acceptable salt or total
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxy, d 4 fluorenyl, d 4 methoxy or 3 to 5 membered carbocyclic, preferably H, F, hydroxy, d — 4 fluorenyl, d- 4 methoxy or 3 to 5 membered carbocyclic group, more preferably H, F, hydroxy, d- 3 fluorenyl, d- 3 decyloxy or 3 to 5 membered carbocyclic group, further preferably H, d- 3 fluorenyl or 3- to 4-membered carbocyclic group, the fluorenyl, decyloxy or carbocyclic group optionally further from 0 to 3 selected from the group consisting of F, Cl, Br, hydroxy, CM fluorenyl Substituted with a d-4 methoxy group or a 3 to 5 membered carbocyclic group, and RR 2 and R 3 are not simultaneously H; alternatively
- R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxy, d- 4 fluorenyl or d- 4 methoxy, preferably H, F, hydroxy, d- 4 fluorenyl or d- 4 oxo More preferably H, F or d- 3 fluorenyl, the fluorenyl or decyloxy optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, hydroxy, d- 4 fluorenyl or d- 4 Substituted by a substituent of a methoxy group, and R 4 and R 5 are not H at the same time;
- R 4 and R 5 may form a 3 to 5 membered carbocyclic group, preferably a 3 to 4 membered carbocyclic group, and the carbocyclic group may be optionally further substituted with 0 to 4 R 8 ;
- R 6 is selected from H or a hydroxyl group, preferably H;
- R 8 is selected from F, Cl, Br, hydroxy, d- 4 alkyl with or ⁇ --4 embankment group, preferably F, or hydroxy --3 embankment group.
- Preferred embodiments of the invention include a compound of the formula (II), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or eutectic thereof:
- RR 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxy, d- 4 fluorenyl, C M methoxy or 3 to 5 membered carbocyclic, preferably H, F, hydroxy, d - 4 ⁇ a group, d- 4 methoxy or a 3 to 5 membered carbocyclic group, more preferably H, F, hydroxy, d- 3 fluorenyl, d- 3 decyloxy or a 3 to 5 membered carbocyclic group, further preferably H, a d- 3 fluorenyl or a 3- to 4-membered carbocyclic group, optionally further 0 to 3 selected from the group consisting of F, hydroxy, d- 4 fluorenyl or d- 4 Substituted by a substituent of a methoxy group, and RR 2 and R 3 are not simultaneously H;
- R 1 and R 2 , R 2 and R 3 or any of R 1 and R 3 may form a 3 to 5 membered carbocyclic group, preferably a 3 to 4 membered carbocyclic group, and the carbocyclic group may be used.
- R 8 optionally further substituted by 0 to 4 R 8 ;
- R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxy, d- 4 fluorenyl or d- 4 methoxy, preferably H, F, hydroxy, d-4 fluorenyl or -4-oxoxy More preferably, H, F or d- 3 fluorenyl, said fluorenyl or decyloxy optionally further having from 0 to 3 selected from the group consisting of F, hydroxy, d- 4 fluorenyl or -4- oxoxy Substituted by a substituent, and R 4 and R 5 are not H at the same time;
- R 4 and R 5 may form a 3 to 5 membered carbocyclic group, preferably a 3 to 4 membered carbocyclic group, and the carbocyclic group may be optionally further substituted with 0 to 4 R 8 ;
- R 6 is selected from H or a hydroxyl group, preferably H;
- R 8 selected from F, hydroxy, d- 4 alkyl with or --4 embankment group, preferably F, or hydroxy --3 embankment group.
- Preferred embodiments of the invention include a compound of the formula (II), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or co-crystals thereof:
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxy, d- 4 fluorenyl, C M methoxy or a 3 to 5 membered carbocyclic group, preferably H, F, hydroxy, d a 3 fluorenyl, d- 3 methoxy or 3 to 5 membered carbocyclic group, more preferably H, d 3 fluorenyl or a 3 to 4 membered carbocyclic group, said fluorenyl, decyloxy or carbocyclic group Optionally further substituted by 0 to 3 substituents selected from F or hydroxy, and RR 2 and R 3 are not simultaneously H;
- R 1 and R 2 , R 2 and R 3 or any of R 1 and R 3 may form a 3 to 5 membered carbocyclic group, preferably a 3 to 4 membered carbocyclic group, and the carbocyclic group may be used.
- R 1 and R 2 , R 2 and R 3 or any of R 1 and R 3 may form a 3 to 5 membered carbocyclic group, preferably a 3 to 4 membered carbocyclic group, and the carbocyclic group may be used.
- R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxy, d- 4 fluorenyl or d- 4 methoxy, preferably H, F, hydroxy, d-4 fluorenyl or -4-oxoxy More preferably, H, F or d- 3 fluorenyl, said fluorenyl or decyloxy being optionally further substituted by 0 to 3 substituents selected from F or hydroxy, and R 4 and R 5 are different Is H; Alternatively, R 4 and R 5 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group;
- R 6 is selected from H or a hydroxyl group, preferably H.
- Preferred embodiments of the invention include a compound of the formula (II), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or co-crystals thereof:
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxy, d- 4 fluorenyl, C M methoxy or a 3 to 5 membered carbocyclic group, preferably H, F, hydroxy, d a 3 fluorenyl group, a d- 3 methoxy group or a 3 to 5 membered carbocyclic group, more preferably an H, d.3 fluorenyl group or a 3 to 4 membered carbocyclic group, said fluorenyl group, decyloxy group or carbocyclic group
- the base is optionally further substituted with 0 to 3 substituents selected from F or a hydroxyl group, and RR 2 and R 3 are not simultaneously H;
- R 1 and R 2 , R 2 and R 3 or any of R 1 and R 3 may form a 3 to 5 membered carbocyclic group, preferably a 3 to 4 membered carbocyclic group, and the carbocyclic group may be used.
- R 1 and R 2 , R 2 and R 3 or any of R 1 and R 3 may form a 3 to 5 membered carbocyclic group, preferably a 3 to 4 membered carbocyclic group, and the carbocyclic group may be used.
- R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxy, d- 4 fluorenyl or d- 4 decyloxy, preferably H, F, hydroxy, C M decyl or d- 4 decyloxy More preferably, H, F or d- 3 fluorenyl, the fluorenyl or decyloxy group is optionally further substituted by 0 to 3 substituents selected from F or hydroxy, and R 4 and R 5 are not simultaneously H;
- R 4 and R 5 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group;
- R 6 is selected from H.
- Preferred embodiments of the invention include a compound of the formula (II), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or co-crystals thereof:
- R 1 , R 2 and R 3 are each independently selected from the group consisting of H, F, Cl, Br, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, hydroxy, methyl, ethyl , n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy a group, a sec-butoxy group, a tert-butoxy group, a cyclopropyl group or a cyclobutyl group, and I 1 , R 2 and R 3 are not simultaneously H; preferably H, F, Br, CH 2 F, a hydroxyl group, a methyl group, Ethyl, methoxy, ethoxy, n-propyl, isopropyl, sec-but
- R 1 and R 2 , R 2 and R 3 or any group of R 1 and R 3 may form a cyclopropyl group
- R 4 and R 5 are each independently selected from the group consisting of H, F, Cl, Br, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CHFCH 3 ,
- R 4 and R 5 may form a cyclopropyl group
- R 6 is selected from H.
- Preferred embodiments of the invention include a compound of the formula (II), or all stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or eutectic thereof, wherein:
- R 1 , R 2 and R 3 are each independently selected from the group consisting of H, F, Br, CH 2 F, CHFCH 2 F, hydroxy, methyl, ethyl, methoxy, ethoxy, n-propyl, isopropyl , sec-butyl, cyclopropyl or cyclobutyl, preferably H, F, CH 2 F, hydroxy, methyl, ethyl or cyclopropyl, and RR 2 and R 3 are not simultaneously H;
- R 1 and R 2 , R 2 and R 3 or any group of R 1 and R 3 may form a cyclopropyl group
- R 4 and R 5 are each independently selected from H, F, hydroxy, methyl, ethyl, methoxy or ethoxy, preferably H, hydroxy, methyl or ethyl, and R 4 and R 5 are not H at the same time. ;
- R 6 is selected from H.
- a preferred embodiment of the invention a compound of the formula (I), or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or eutectic thereof, wherein:
- R is selected from F, Cl, Br, I, -OR 7 ;
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group.
- the fluorenyl, decyloxy, carbocyclic or heterocyclic group is further optionally from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 fluorenyloxy Substituted with a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group containing 1 to 2 heteroatoms selected from N, 0 or S, and RR 2 and R 3 Not at the same time;
- R 1 and R 2 , R 2 and R 3 or any of R 1 and R 3 form a 3 to 5 membered ring, and the 3 to 5 membered ring contains 0 to 2 selected from N, 0 or a hetero atom of S, and the formed 3 to 5 membered ring is optionally further substituted with 0 to 4 R 8 ;
- R 4 and R 5 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, cyano, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group.
- the fluorenyl group, the decyloxy group, the carbocyclic group or the heterocyclic group is further selected from 0 to 5 selected from the group consisting of a hydroxyl group, a d- 6 fluorenyl group, a d- 6 methoxy group, a 3 to 5 membered carbocyclic group.
- R 4 and R 5 may form a 3 to 5 membered ring, and the 3 to 5 membered ring may have 0 to 2 a hetero atom selected from N, O or S, and the formed 3- to 5-membered ring may be optionally further substituted with 0 to 4 R 8 ;
- R 6 is selected from H or a hydroxyl group;
- R 7 is selected from H, d - 4 fluorenyl or a 3 to 5 membered carbocyclic group, and the fluorenyl or carbocyclic group is optionally further 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d Substituted by a substituent of 4 fluorenyl, d- 4 methoxy or 3 to 5 membered carbocyclyl;
- R 8 is selected from the group consisting of F, Cl, Br, hydroxy, d-4 fluorenyl, d-4 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group, said heterocyclic group having 1 to 2 heteroatoms selected from N, 0 or S;
- n is selected from 1, 2 or 3.
- a preferred embodiment of the invention a compound of the formula (I), or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or eutectic thereof, wherein:
- R is selected from F, Br, -OR 7 or ;
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxy, d- 5 fluorenyl, d- 5 methoxy or 3 to 5 membered carbocyclyl, said fluorenyl, decyloxy Or the carbocyclic group is optionally further substituted with 0 to 3 substituents selected from the group consisting of F, Cl, Br, hydroxy, d-4 fluorenyl, d-4 decyloxy or a 3 to 5 membered carbocyclic group, and RR 2 and R 3 are not H at the same time; alternatively, R 1 and R 2 , R 2 and R 3 or any of R 1 and R 3 may form a 3 to 5 membered carbocyclic ring, and the carbon ring may be optionally selected. Further substituted by 0 to 4 R 8 ;
- R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxy, cyano, d 4 fluorenyl or d 4 methoxy or 3 to 5 valent carbocyclyl, fluorenyl, decyloxy Or the carbocyclic group is optionally further substituted with 0 to 3 substituents selected from hydroxy, d- 4 fluorenyl or CM methoxy, and R 4 and R 5 are not H at the same time;
- R 4 and R 5 may form a 3 to 5 membered carbocyclic group, and the carbocyclic group may be optionally further substituted with 0 to 4 R 8 ;
- R 6 is selected from H or a hydroxyl group
- R 7 is selected from d- 4 alkyl with 3-4 yuan or carbocyclyl, said embankment, or carbocyclyl group may be further 0 to 3 substituents selected from F, hydroxy or ⁇ - substituted alkyl with the substituent of group 3 ;
- R 8 is selected from the group consisting of F, Cl, Br, hydroxy, d- 4 fluorenyl or d- 4 methoxy;
- n is selected from 1 or 2.
- a preferred embodiment of the invention a compound of the formula (I), or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or eutectic thereof, wherein:
- R is selected from Br or ;
- RR 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxy, d- 4 fluorenyl, C M methoxy or 3 to 5 Carbocyclyl, said fluorenyl, decyloxy or carbocyclic group optionally further from 0 to 3 selected from the group consisting of F, Cl, Br, hydroxy, d-4 fluorenyl, d-4-methoxy or 3 to Substituted by a 5-membered carbocyclic group, and RR 2 and R 3 are not H at all; alternatively, R 1 and R 2 , R 2 and R 3 or any of R 1 and R 3 may form a 3 to a 5-membered carbocyclic group, which may be optionally further substituted with 0 to 4 R 8 ;
- R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxy, cyano, d- 4 fluorenyl or d- 4 decyloxy or a 3 to 5 membered carbocyclic group, said fluorenyl group, hydrazine
- the oxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from hydroxy, d- 4 fluorenyl or CM methoxy, and R 4 and R 5 are not H at the same time;
- R 4 and R 5 may form a 3 to 5 membered carbocyclic group, and the carbocyclic group may be optionally further substituted with 0 to 4 R 8 ;
- R 6 is selected from H or a hydroxyl group
- R 7 is selected from d- 4 alkyl with 3-4 yuan or carbocyclyl, said embankment, or carbocyclyl group may be further 0 to 3 substituents selected from F, hydroxy or --3 embankment group substituents;
- R 8 is selected from the group consisting of F, Cl, Br, hydroxy, d-4 fluorenyl or -4-methoxy;
- n is selected from 1 or 2.
- a preferred embodiment of the invention a compound of the formula (I), or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the formula Compounds shown in (II):
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxy, d 4 fluorenyl, d 4 methoxy or 3 to 5 membered carbocyclyl, said fluorenyl, decyloxy Or the carbocyclic group is optionally further substituted with 0 to 3 substituents selected from the group consisting of F, Cl, Br, hydroxy, d-4 fluorenyl, d-4 decyloxy or a 3 to 5 membered carbocyclic group, and RR 2 and R 3 are not H at the same time; alternatively, R 1 and R 2 , R 2 and R 3 or any of R 1 and R 3 may form a 3- to 5-membered carbocyclic group, preferably a 3-membered carbocyclic ring.
- the carbocyclic group may be optionally further substituted with 0 to 4 R 8 ;
- R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxy, cyano, d 4 fluorenyl or d 4 methoxy or 3 to 5 valent carbocyclyl, fluorenyl, decyloxy Or the carbocyclic group is optionally further substituted with 0 to 3 substituents selected from the group consisting of hydroxy, d- 4 fluorenyl or -4- methoxy, and R 4 and R 5 are not H at the same time;
- R 4 and R 5 may form a 3 to 5 membered carbocyclic group, and the carbocyclic group may be optionally further substituted with 0 to 4 R 8 ;
- R 6 is selected from H or a hydroxyl group
- R 8 is selected from the group consisting of F, Cl, Br, hydroxy, d- 4 fluorenyl or -4- decyloxy, preferably F or hydroxy;
- n is selected from 1 or 2.
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxy, d- 4 fluorenyl, C M decyloxy or a 3 to 5 membered carbocyclic group, said fluorenyl group, hydrazine group a group or a carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F or a hydroxyl group, and I 1 , R 2 and R 3 are not simultaneously H;
- R 1 and R 2 , R 2 and R 3 or any of R 1 and R 3 may form a 3-membered carbocyclic group, which may optionally be further 0 to 4 selected from F. Or substituted with a substituent of a hydroxyl group;
- R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxy, cyano, d- 4 fluorenyl, d- 4- decyloxy or a 3 to 5 membered carbocyclic group, said fluorenyl group, hydrazine An oxy or carbocyclic group is optionally further substituted with 0 to 3 hydroxy groups, and R 4 and R 5 are not simultaneously H;
- R 6 is selected from H or a hydroxyl group
- n is selected from 1 or 2.
- a preferred embodiment of the invention a compound of the formula (II), or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, wherein:
- RR 2 and R 3 are each independently selected from H, hydroxy, d- 4 fluorenyl or a 3 to 5 membered carbocyclic group, and the fluorenyl or carbocyclic group is optionally further 0 to 3 selected from F or hydroxy. Substituted by a substituent, and RR 2 and R 3 are not H at the same time;
- R 1 and R 2 , R 2 and R 3 or any of R 1 and R 3 may form a 3-membered carbocyclic group, which may optionally be further 0 to 4 selected from F. Or substituted with a substituent of a hydroxyl group;
- R 4 and R 5 are each independently selected from H, hydroxy, cyano, d- 4 fluorenyl or a 3 to 5 membered carbocyclic group, and the fluorenyl or carbocyclic group is optionally further substituted by 0 to 3 hydroxy groups. And R 4 and R 5 are not H at the same time;
- R 6 is selected from H or a hydroxyl group
- n is selected from 1 or 2.
- a preferred embodiment of the invention a compound of the formula (I), or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the formula Compounds shown in (II):
- R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrazine, hydroxy, methyl, ethyl or cyclopropyl, and RR 2 and R 3 are not H at the same time ;
- R 1 and R 2 , R 2 and R 3 or any group of R 1 and R 3 may form a cyclopropyl group
- R 4 and R 5 are each independently selected from H, hydroxy, cyano, methyl, ethyl or cyclopropyl, and R 4 and R 5 are not simultaneously H;
- R 6 is selected from H or a hydroxyl group
- n is selected from 1 or 2.
- the invention relates to a compound selected from, but not limited to:
- a preferred embodiment of the invention a compound of the formula (A) or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, wherein:
- R 9 , R 1Q , R 11 and R 12 are H;
- Y is selected from H, PEG, ⁇ m ° ' ° R16 , d - 2 .
- the thiol group is optionally further selected from 0 to 4 selected from H, F, Cl,
- R 13 and R 14 are each independently selected from H or d- 6 fluorenyl
- R 15 and R 16 are each independently selected from H or an alkali metal ion, and the alkali metal ion is selected from Na + , K + or
- Wi, W 2 and W 3 are each independently selected from NR y8 , O or S;
- W 4 is selected from CR y9 R ylQ, NR y8, 0, S or not present;
- R yl are each independently selected from H, d- 6 fluorenyl, C 3 —
- R y3 is selected from H, amino, d 6 fluorenyl, C 3 -8 carbocyclyl or 4 to 8 membered heterocyclic, -(CR ya R yb ) ml -NR y yd or -
- R y6 and R y7 are each independently selected from g H , F , Cl, Br, I, hydroxy, amino, cyano, carboxy, d- 6 fluorenyl or d- 6 methoxy;
- R y6 and R y7 may form a 5- to 8-membered ring together with the atom to which they are attached, and the 5- to 8-membered ring may contain 0 to 4 heteroatoms selected from N, 0 or S, said 5
- the 8- to 8-membered ring may be optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, I, d- 6 fluorenyl or d- 6 methoxy;
- R y8 are each independently selected from 11 or 6 fluorenyl
- R ylQ R y9 are each independently selected from H, d- 6 embankment group, C 3 - 8 carbon ring group or 4 to 8-membered heterocyclic group, said group embankment Further, the carbocyclic group and the heterocyclic group are further further selected from 0 to 4 selected from the group consisting of H, hydroxy, amino, decyl, carboxy, decyl, carbamoyl, d- 6 fluorenyl, d- 6 methoxy, 3 to Substituted by a substituent of an 8-membered carbocyclic ring or a 3- to 8-membered heterocyclic ring;
- R ya , Ryb , R ye and R yd are each independently selected from H or Cl -6 fluorenyl;
- q is selected from 1 to 200;
- Ml is selected from 0, 1, 2 or 3;
- p is selected from 0, 1 or 2.
- a preferred embodiment of the invention a compound of the formula (A), or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, wherein:
- Y is selected from 1 () fluorenyl, -(CH 2 CH 2 0) q -H, -(CR ya
- the thiol group is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, hydroxy, amino, cyano, carboxy, 6 fluorenyl, d- 6 methoxy, C 3 carbocyclyl.
- q is selected from 1 to 100, preferably 1 to 10, further preferably 1, 2, 3, 4 or 5;
- Ml is selected from 0, 1, 2 or 3, preferably 0, 1 or 2;
- p is selected from 0, 1 or 2, preferably 0 or 1.
- a preferred embodiment of the invention a compound of the formula (A), or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or eutectic thereof, wherein:
- Wi, W 2 and W 3 are each independently selected from NR y8 , 0 or S, preferably NR y8 or 0;
- W 4 is selected from CR y9 R ylQ, NR y8, 0, S or not present, preferably CR y9 R ylQ, NR y8, O or absent;
- R y8 is each independently selected from H or d- 6 fluorenyl, preferably H or d- 4 fluorenyl, further preferably H, methyl or ethyl;
- R yio R y 9 are each independently selected from H, Cl _ 6 alkyl with, C 3 _ 8 carbocyclyl or 4 to 8-membered heterocyclic group, preferably H, d_ 6 embankment group, C 3 - 6 carbocyclyl Or a 4- to 6-membered heterocyclic group, further preferably H, d- 6 fluorenyl or 4 to 6-membered heterocyclic group, more preferably H or d- 4 fluorenyl, still more preferably H, methyl, isopropyl, sec.
- a preferred embodiment of the invention a compound of the formula (A), or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, wherein:
- R yl is each independently selected from the group consisting of H, d- 6 fluorenyl, C 3 carbocyclyl, C 4 carbocyclyl, ⁇ carbocyclyl, 0>carbocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl or 6
- the heterocyclic group is preferably H, d- 6 fluorenyl, ⁇ carbocyclyl, 0>carbocyclyl, 5-membered heterocyclic or 6-membered heterocyclic group, further preferably 11 or -6 fluorenyl, more preferably 11 Or a 4- mercapto group, still more preferably H, methyl, ethyl or isopropyl; the fluorenyl, carbocyclic or heterocyclic group may be further further selected from 0 to 5 selected from H, F , Cl, Br, I, hydroxy, amino, cyano, carboxy, d- 6 fluorenyl, d- 6 methoxy
- a preferred embodiment of the invention a compound of the formula (A), or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, wherein:
- R y6 and R y7 are each independently selected from H, hydroxy, amino, cyano, carboxy, d- 6 fluorenyl or d- 6 fluorenyloxy, preferably 11, d- 4 fluorenyl or d- 4 decyloxy, Further preferably 11 or ⁇ 4 fluorenyl;
- R y6 and R y7 may form a 5- to 8-membered ring together with the atom to which they are attached, preferably forming a 5- to 6-membered ring, further preferably forming a phenyl group, and the ring may contain 1 to 4 selected from N a hetero atom of 0 or S; said ring may be optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, I, d- 6 fluorenyl or d- 6 fluorenyloxy , preferably substituted by 0 to 4 substituents selected from H, d- 4 fluorenyl or d- 4 fluorenyloxy;
- R y9 and R ylQ Each independently selected from H, d- 6 fluorenyl, C 3 carbocyclyl, C 4 carbocyclyl, ⁇ carbocyclyl, C 6 carbocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6-membered Heterocyclic group, preferably H, d- 6 fluorenyl, 4 membered heterocyclic group, 5-membered heterocyclic group, 6-membered heterocyclic group, further preferably 11 or 4 fluorenyl group, more preferably H, methyl or isopropyl group a thiol group, a sec-butyl group, a 2-methylpropyl group or a benzyl group; the fluorenyl
- R ya , R yb And R ye and R yd are each independently selected from H or -6 fluorenyl, preferably 11 or 4 fluorenyl, further preferably H, methyl, ethyl, propyl or isopropyl.
- a preferred embodiment of the invention a compound of the formula (A), or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, wherein:
- R is selected from F, Cl, Br, I, -OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group.
- the fluorenyl group, the decyloxy group, the carbocyclic group or the heterocyclic group is further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d- 6 fluorenyl, d- 6 methoxy, 3 Substituted to a 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group containing 1 to 2 heteroatoms selected from N, 0 or S, and RR 2 When it is different from R 3 , it is H;
- R 1 and R 2 , R 2 and R 3 or any of R 1 and R 3 form a 3 to 5 membered ring, and the 3 to 5 membered ring contains 0 to 2 selected from N, 0 or a hetero atom of S, and the formed 3 to 5 membered ring is optionally further substituted with 0 to 4 R 8 ;
- R 4 and R 5 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, cyano, d- 6 fluorenyl, d- 6 fluorenyloxy, 3 to 5 membered carbocyclic or 3 to 5 valent a cyclyl group, a decyloxy group, a carbocyclic group or a heterocyclic group, optionally further selected from 0 to 5 selected from the group consisting of a hydroxyl group, a d- 6 fluorenyl group, a d- 6 methoxy group, a 3 to 5 membered carbon Substituted by a substituent of a cyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group having 1 to 2 hetero atoms selected from N, 0 or S, and R 4 and R 5 are not H at the same time;
- R 4 and R 5 may form a 3 to 5 membered ring, and the 3 to 5 membered ring may have 0 to 2 hetero atoms selected from N, 0 or S, and form a 3 to 5 membered ring. It may optionally be further substituted with 0 to 4 R 8 ; R 6 is selected from H or a hydroxyl group;
- R 7 is selected from H, d - 4 fluorenyl or a 3 to 5 membered carbocyclic group, and the fluorenyl or carbocyclic group is optionally further 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d Substituted by a substituent of 4 fluorenyl, d- 4 methoxy or 3 to 5 membered carbocyclyl;
- R 8 is selected from the group consisting of F, Cl, Br, hydroxy, d 4 fluorenyl, d 4 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group, and said heterocyclic group contains 1 to 2 a hetero atom selected from N, 0 or S;
- R 9 , R 1Q , R 11 and R 12 are H;
- X is selected from H, F or a carboxyl group
- Y is selected from H, PEG, m ° , 0R1S , d- 20 thiol , -(CH 2 CH 2 0)qH, -(CR ya R yb ) ml COOR y - cRyaRyb ⁇ Wi c oxw ⁇ y 3 ) or - (cRyaRyb w pp oxwsRy ⁇ WgRy 5 ) or Said optionally further substituted by alkyl with 0-4 selected from H, F, Cl, Br, I, hydroxy, amino, cyano, carboxy, C embankment base, d- 6 embankment group, C 3 - 8 Substituted by a carbocyclic group or a 4- to 8-membered heterocyclic group;
- R 13 and R 14 are each independently selected from H or d 6 fluorenyl
- R 16 are each independently selected from H or an alkali metal ion selected from the group consisting of Na + , K + or Li.
- R 9 , R 1Q , R 11 and R 12 are H; R is selected from Br, OR 7 or 5 R 3 ;
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxy, d- 5 fluorenyl, d- 5 decyloxy or a 3 to 5-membered carbocyclic group, said fluorenyl group, hydrazine
- the oxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from the group consisting of F, Cl, Br, hydroxy, C 4 fluorenyl, d- 4 decyloxy or a 3 to 5 membered carbocyclic group, and RR 2 and R 3 are not simultaneously H; alternatively, R 1 and R 2 , R 2 and R 3 or any of R 1 and R 3 may form a 3 to 5 membered carbocyclic group, said carbocyclic group.
- further R 2 is substituted with from 0 to 4 R 8 ;
- R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxy, cyano, d- 4 fluorenyl or d- 4 decyloxy or a 3 to 5 membered carbocyclic group, said fluorenyl group, hydrazine
- the oxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from the group consisting of hydroxy, d- 4 fluorenyl or -4- oxooxy, and R 4 and R 5 are not simultaneously H;
- R 4 and R 5 may form a 3 to 5 membered carbocyclic group, and the carbocyclic group may be optionally further substituted with 0 to 4 R 8 ;
- R 6 is selected from H or a hydroxyl group
- R 7 is selected from H or d- 4 fluorenyl
- R 8 is selected from the group consisting of F, Cl, Br, hydroxy, d-4 fluorenyl or -4-methoxy;
- X is H
- Y is selected from H, PEG, , d- 20 ⁇ , -(CH 2 CH 2 0)qH, -(CR ya R yb ) ml COOR y
- the thiol group is further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, hydroxy, amino, cyano, carboxy, d- 6 fluorenyl, d- 6 methoxy, C 3 — substituted with an 8- carbon ring group or a 4- to 8-membered heterocyclic group;
- R 13 and R 14 are each independently selected from H or d 6 fluorenyl
- R 15 and R 16 are each independently selected from H or an alkali metal ion, and the alkali metal ion is selected from Na + , K + or Li + ;
- R yl is independently selected from H, d- 6 embankment group, C 3 - 6 carbocyclic group or 4 to 6-membered heterocyclic group, said group embankment, carbocyclyl or heterocyclyl may be optionally further substituted by 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxy, amino, cyano, carboxy, d- 6 alkyl with, d- 6 embankment group, C 3 - 8 carbon ring group or a heteroaromatic 4-8 yuan Substituted by a substituent of a cyclic group, the heterocyclic group containing 1 to 2 hetero atoms selected from N, 0 or S;
- R ylQ RY 9 are each independently selected from H, d- 6 embankment group, C 3 - 6 carbocyclic group or 4 to 6-membered heterocyclic group, said embankment, carbocyclic group and heterocyclic group optionally further From 0 to 4 selected from H, hydroxy, amino, decyl, carboxy, decyl, carbamoyl, d- 6 fluorenyl, d- 6 decyloxy, 3 to 8 membered carbocyclic or 3 to 8 membered heterocyclic ring Substituted by a substituent;
- a preferred embodiment of the invention a compound of the formula (A), or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, wherein:
- R 9 , R 1Q , R 11 and R 12 are H;
- R is selected from Br, OR 7 or
- RR 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxy, d- 4 fluorenyl, C M decyloxy or a 3 to 5 membered carbocyclic group, said fluorenyl, decyloxy or carbon
- the cyclo group is optionally further substituted with 0 to 3 substituents selected from the group consisting of F, Cl, Br, hydroxy, d-4 fluorenyl, d-4 decyloxy or a 3 to 5 membered carbocyclic group, and RR 2 and R 3 is not H at the same time; alternatively, R 1 and R 2 , R 2 and R 3 or any group of R 1 and R 3 may form a 3- to 5-membered carbocyclic group, and the carbocyclic group may be optionally selected. Further substituted by 0 to 4 R 8 ;
- R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxy, cyano, d- 4 fluorenyl or d- 4 decyloxy or a 3 to 5 membered carbocyclic group, said fluorenyl group, hydrazine
- the oxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from the group consisting of hydroxy, d- 4 fluorenyl or -4- oxooxy, and R 4 and R 5 are not simultaneously H;
- R 4 and R 5 may form a 3 to 5 membered carbocyclic group, and the carbocyclic group may be optionally further substituted with 0 to 4 R 8 ;
- R 6 is selected from H or a hydroxyl group
- R 7 is selected from H or d- 4 fluorenyl
- R 8 is selected from the group consisting of F, Cl, Br, hydroxy, d-4 fluorenyl or -4-methoxy;
- X is H
- Y is selected from Cwo fluorenyl, -(CH 2 CH 2 0) q -H, -(CRyaRyb W pC ⁇ OXW y 3 ) or -(CR ya R yb ) ml - (wOp-p ⁇ c ⁇ Ry ⁇ WgRy 5 ) or
- the thiol group is optionally further selected from o to 4
- Wi, W 2 and W 3 are each independently selected from NR y8 , 0 or S;
- W 4 is selected from CR y9 R ylQ, NR y8, 0, S or not present;
- R y3 is selected from H, amino, d- 6 embankment group, C 3 - 6 carbocyclic group or 4 to 6-membered heterocyclyl, - (CR ya R yb) ml -NR y yd or -
- R y6 and RY 7 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, amino, cyano, carboxy, d- 6 fluorenyl or d- 6 methoxy;
- R y6 and R y7 may form a 5- to 8-membered ring together with the atom to which they are attached, and the 5- to 8-membered ring may contain 0 to 4 heteroatoms selected from N, 0 or S, said 5
- the 8- to 8-membered ring may be optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, I, d- 6 fluorenyl or d- 6 methoxy;
- R y8 are each independently selected from H or d- 6 fluorenyl
- R ylQ R y9 are each independently selected from H, d- 6 embankment group, C 3 - 6 carbocyclic group or 4 to 6-membered heterocyclic group, said group embankment
- carbocyclic group and the heterocyclic group are further further selected from 0 to 4 selected from the group consisting of H, hydroxy, amino, decyl, carboxy, decyl, carbamoyl, 6 fluorenyl, d- 6 methoxy, 3 to 8 Substituted by a carbocyclic or 3- to 8-membered heterocyclic substituent;
- R y R yb , R yc and R yd are each independently selected from H or d- 6 fluorenyl;
- n is selected from 1 to 200;
- Ml is selected from 0, 1, 2 or 3;
- p is selected from 0, 1 or 2.
- a preferred embodiment of the invention a compound of the formula (A), or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, wherein:
- R 9 , R 1Q , R 11 and R 12 are H; R is selected from Br, ;
- R 1 , R 2 and R 3 are each independently selected from H, hydroxy, methyl, ethyl or cyclopropyl, and RR 2 and R 3 are not H at the same time ;
- R 1 and R 2 , R 2 and R 3 or any group of R 1 and R 3 may form a cyclopropyl group
- R 4 and R 5 are each independently selected from H, hydroxy, cyano, methyl, ethyl or cyclopropyl, and R 4 and R 5 are not simultaneously
- X is H
- R 7 is selected from H, methyl or ethyl
- embankment group optionally further substituted with from 0 to 4 substituents selected H, F, Cl, Br, I, hydroxy, amino, cyano, carboxy, d- 4 embankment group or C 3 - 6 carbocyclyl substituent Replaced
- Wi, W 2 and W 3 are each independently selected from NR y8 , 0 or S;
- W 4 is selected from CR y9 R ylQ, NR y8, 0, S or not present;
- the amino group embankment, carbocyclyl or heterocyclyl may be optionally further substituted by
- R y 6 and R y 7 are each independently selected from H , d- 4 fluorenyl or d- 4 fluorenyloxy;
- R y6 and R y7 may form a 5- to 6-membered ring together with the atom to which they are attached, and the 5- to 6-membered ring may contain 0 to 4 heteroatoms selected from N, 0, S;
- R y8 are each independently selected from 11 or 4 - 4 fluorenyl
- RY 9 and R ylQ are each independently selected from H, d- 6 fluorenyl or 4 to 6 membered heterocyclic group, and the fluorenyl and heterocyclic groups are optionally further selected from 0 to 4 selected from H, hydroxy, amino. Substituted with a substituent of a fluorenyl group, a carboxy group, a fluorenyl group, a carbamoyl group, a d- 6 fluorenyl group, a d- 6 methoxy group, a 3 to 6 membered carbocyclic ring or a 4 to 6 membered heterocyclic ring;
- R ya , R yb , R yc and R yd are each independently selected from H or d 4 fluorenyl; q is selected from 1 to 10;
- Ml is selected from 0, 1, 2 or 3;
- p is selected from 0, 1 or 2.
- a preferred embodiment of the invention a compound of the formula (A), or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, wherein:
- R 9 , R 1Q , R 11 and R 12 are H;
- R is selected from Br, OR 7 or ;
- R 1 , R 2 and R 3 are each independently selected from H, hydroxy, methyl, ethyl or cyclopropyl, and RR 2 and R 3 are not H at the same time ;
- R 1 and R 2 , R 2 and R 3 or any group of R 1 and R 3 may form a cyclopropyl group
- R 4 and R 5 are each independently selected from H, hydroxy, cyano, methyl, ethyl or cyclopropyl, and R 4 and R 5 are not simultaneously
- X is H
- R 7 is selected from H, methyl or ethyl
- ⁇ is selected from d- 4 thiol, , ?, ⁇ 6
- R y4 and R y5 are each independently selected from the group consisting of H, an alkali metal ion, d 4 thiol, -(CR ya R yb ) ml -5 to 6 membered ring, -
- R y and R y7 are each independently H or d- 4 fluorenyl
- R y6 and R y7 may form a 5- to 6-membered ring together with the atom to which they are attached, and the 5- to 6-membered ring may contain 0 to 4 heteroatoms selected from N, 0, S;
- R y8 is selected from 11 or 4 - 4 fluorenyl
- R y9 is selected from 11 or 4 - 4 fluorenyl
- R ylQ is selected from 11 or 4 - fluorenyl, and the fluorenyl group is further optionally 0 to 4 selected from the group consisting of H, hydroxy, amino, thiol, carboxyl, decyl, carbamoyl, d- 4 fluorenyl, Substituted by a 5- to 6-membered carbocyclic substituent;
- q is selected from 1 to 10;
- Ml is selected from 0, 1, 2 or 3;
- p is selected from 0, 1 or 2.
- a preferred embodiment of the invention a compound of the formula (A), or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, wherein:
- R is selected from Br, OR 7 ;
- R 1 , R 2 and R 3 are each independently selected from H, hydroxy, methyl, ethyl or cyclopropyl, and RR 2 and R 3 are not H at the same time ;
- R 1 and R 2 , R 2 and R 3 or any group of R 1 and R 3 may form a cyclopropyl group
- R 4 and R 5 are each independently selected from H, hydroxy, cyano, methyl, ethyl or cyclopropyl, and R 4 and R 5 are not simultaneously
- X is H; R 7 is selected from H, methyl or ethyl;
- ⁇ is selected from
- Wi, W 2 , W 3 are each independently selected from NH or O;
- W 4 is independently selected from CHR ylQ , 0 or is absent;
- R y and R y7 are each independently H or d- 4 fluorenyl
- R y6 and R y7 may form a 5- to 6-membered ring together with the atom to which they are attached, preferably forming a phenyl group, and the 5- to 6-membered ring may contain 0 to 4 impurities selected from N, 0, and S. atom;
- R y8 is selected from 11 or - 4 fluorenyl
- R y9 is selected from 11 or - 4 fluorenyl
- R ylQ is selected from 11 or 4 - fluorenyl, preferably H, methyl, isopropyl, sec-butyl, 2-methylpropyl or benzyl, optionally further selected from 0 to 4 Substituted from H, d- 4 fluorenyl, 5- to 6-membered carbocyclic substituents;
- R ya , R y , R w and R yd are each independently selected from 11 or ⁇ : 1 - 4 fluorenyl, preferably H, methyl or ethyl;
- q is selected from 1 to 10;
- Ml is selected from 0, 1, 2 or 3;
- p is selected from 0, 1 or 2.
- a preferred embodiment of the invention a compound of the formula (A) or a stereoisomer, solvate, metabolite thereof,
- W 2 and W 3 are each independently selected from NH or O;
- W 4 is selected from CHR ylQ or O;
- R y3 is selected from the group consisting of amino, aminomethylene, isopropyl, t-butyl, (tert-butoxycarbonyl;)amino, (tert-butoxycarbonyl;) aminomethylene, pyrrolidinyl, phenyl or pyridine
- the amino group, pyrrolidinyl group, phenyl group and pyridyl group are optionally further substituted by 0 to 4 substituents selected from the group consisting of t-butoxycarbonyl, acetoxy and benzyloxycarbonyl;
- R ylQ is selected from H, methyl, isopropyl, sec-butyl, 2-methylpropyl or benzyl.
- the invention further relates to pharmaceutically acceptable salts of the compounds of the formula (A) or (I), including but not limited to alkali metal salts, alkaline earth metal salts, ammonium salts, tetradecylammonium salts, ethanolamines Salt, diethanolamine salt, triethanolamine salt, trimethylamine, N-methylglucamine, hydrochloride, sulfate, phosphate, acetate, trifluoroacetate, fumarate, semi-fumaric acid Salt, maleate, malate, citrate, succinate, besylate or p-toluenesulfonate; preferably ammonium, potassium, sodium, calcium, magnesium, hydrochloride, Acetate, trifluoroacetate, fumarate, besylate or p-toluenesulfonate.
- the invention relates to a system comprising:
- the compound of the formula (Ia) is reacted with the compound of the formula (Ib) to give a compound of the formula (I); wherein preferably the compound of the formula (Ia) and the compound of the formula (Ib) are produced at -4 to 35 ° C Reaction, stirring reaction 2
- the compound of the formula (Ia) is reacted with the compound of the formula (Ib) at a temperature of -4 to 35 ° C, and the reaction is stirred for 2 to 20 hours, and the obtained product is further subjected to removal of R' to obtain a compound of the formula (I). ;
- the compound of the formula (Ia) is reacted with the compound of the formula (Ib) at a temperature of -4 to 35 ° C, and the product obtained after stirring for 2 to 20 hours is dehydroxylated under a reducing agent to obtain a formula (I).
- the compound of the formula (Ia) is reacted with the compound of the formula (Ib) at -4 to 35 ° C, and the product obtained after stirring for 2 to 20 hours is stripped of R', and further removed by a reducing agent.
- a hydroxy group to give a compound of the formula (I); wherein R' is selected from the group consisting of H, methyl, ethyl, benzyl, p-methoxybenzyl, trityl, trimethylsilyl or tert-butyldimethyl
- R' is selected from the group consisting of H, methyl, ethyl, benzyl, p-methoxybenzyl, trityl, trimethylsilyl or tert-butyldimethyl
- X is selected from F, Cl, Br or I;
- the compound of the formula (I-c) is reacted with a compound of the formula (I-d) by a Grignard reaction or with an organolithium reagent, and then R" is obtained to obtain a compound of the formula (I);
- the compound of the formula (Ic) is subjected to a Grignard reaction at -4 to 35 ° C, stirred for 2 to 20 hours, or reacted with a compound of the formula (Id) for 30 minutes under the action of an organolithium reagent at -78 to 50 ° C. ⁇ 8 hours, then remove R" to obtain a compound of formula (I);
- the compound of the formula (Ic) is subjected to a Grignard reaction at -4 to 35 ° C, stirred for 2 to 20 hours, or reacted with a compound of the formula (Id) for 30 minutes under the action of an organolithium reagent at -78 to 50 ° C. ⁇ 8 hours, then the product obtained by removing R" is further dehydroxylated under the action of a reducing agent to obtain a compound of the formula (I);
- the compound of the formula (Ic) is subjected to a Grignard reaction at -4 to 35 ° C, stirred for 2 to 20 hours, or reacted with a compound of the formula (Id) for 30 minutes under an action of an organolithium reagent at -78 to -50 ° C. ⁇ 8 hours, the obtained product is further thiolated, and then R" is removed to obtain a compound of the formula (I);
- R is selected from the group consisting of methyl, ethyl, benzyl, p-methoxybenzyl, trityl, trimethylsilyl or tert-butyldimethylsilyl, R, R 4 , R 5 and
- n is consistent with the definition of the compound of formula (I);
- the present invention relates to a process for the preparation of a prodrug compound of the formula (A) according to the invention, which process comprises: among them:
- the compound of the formula (I) is first subjected to a nucleophilic substitution reaction with a compound of the formula (IA) under a base to obtain an intermediate of the compound of the formula (IB), which is then exchanged or reacted with a metal salt by hydrolysis to obtain a formula ( IB) a compound;
- a compound of the formula: and a compound of the formula (IA) are subjected to a nucleophilic substitution reaction under the action of a base to obtain an intermediate of the compound of the formula (IB), which is further reacted with a nucleophile by a base to obtain a formula (IB).
- a nucleophilic substitution reaction under the action of a base to obtain an intermediate of the compound of the formula (IB), which is further reacted with a nucleophile by a base to obtain a formula (IB).
- R 18 or R 19 are each independently selected from the group consisting of F, Cl, Br, I, d- 1Q fluorenyl or d- 1Q methoxy, preferably F, Cl, Br, I, d- 6 fluorenyl or d- 6 ⁇ oxy, further preferably F, Cl, Br, I, d 4 fluorenyl or d 4 fluorenyloxy;
- R 2Q , R 21 and R 22 are each independently selected from H, F, Cl, Br, I Or C 14 .
- Sulfhydryl preferably H, F, Cl, Br,
- I or d- 6 fluorenyl further preferably H, F, Cl, Br, I or d- 4 fluorenyl;
- V is selected from F, Cl, Br, I; n, R, R 4 , R 5 or R 6 are as defined in the formula (I).
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the formula (I) or (A) or all stereoisomers, solvates, metabolites thereof, pharmaceutically acceptable a salt, eutectic or prodrug, and one or more pharmaceutically acceptable carriers and/or excipients.
- the present invention relates to a compound of the formula (I) or (A), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof, in the preparation of the induction And in the maintenance of animal or human anesthesia, promotion of animal or human sedative hypnosis, treatment and / or prevention of anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions or epilepsy drugs, preferably in the preparation of induction and Use in animal or human anesthetics.
- the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopic conditions, and the carbons involved in the groups and compounds of the present invention.
- Hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C and 14 C, and the hydrogen isotopes include strontium (H), hydrazine (D, Also known as heavy hydrogen), ⁇ ( ⁇ , also called super heavy hydrogen), oxygen isotopes include 16 0, 17 0 and 18 0, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 C1 and 37 C1, and bromine isotopes include 79 Br and 81 Br.
- the "mercapto group” means a linear or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably a fluorenyl group of 1 to 8 carbon atoms, more preferably a fluorenyl group of 1 to 6 carbon atoms, further preferably A fluorenyl group of 1 to 4 carbon atoms.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various thereof a branched isomer;
- Alkoxy means -0-fluorenyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropane Oxyl and cyclobutoxy.
- the decyloxy group appearing herein is defined by this definition.
- PEG means a polymer containing ⁇ , wherein n is an integer in the range of from 2 to about 1,000, preferably from 2 to about 500, more preferably from 2 to about 250, still more preferably from 2 to about 125, still more preferably 2 ⁇ An integer in the range of approximately 25.
- Amino means -NH 2 .
- Mercaptoamino means an amino group having one or two mercapto substituents.
- Cyano means ⁇
- ⁇ means f- ⁇ SH.
- Carboxylic acid ester group means -COOR 19a wherein 1 13 ⁇ 4 is d- 6 fluorenyl.
- Amido means -CONR 2Qa R 21a , wherein R 2Q n R 21a are each independently selected from H, fluorenyl or carbocyclyl, and R 2Qa and R 21a may optionally be further selected from 0 to 3 selected from F, Cl.
- Haldroxymethane is a fluorenyl group substituted by 1, 2 or 3 hydroxy groups, and the fluorenyl group is preferably a d- 4 fluorenyl group.
- Non-limiting examples include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxypropyl, 1 ,3-dihydroxypropyl, and 2,3-dihydroxypropyl.
- Alkenyl means a straight or branched unsaturated aliphatic hydrocarbon group having from 1 to 3 carbon-carbon double bonds, consisting of 2 to 20 carbon atoms, preferably an alkenyl group of 2 to 12 carbon atoms, more preferably Alkenyl group of 2 to 8 carbon atoms.
- Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexene-2-yl, Hexene-3,hepten-2-yl,hepten-3-yl,hepten-4-yl,octen-3-yl,nonen-3-yl,nonen-4-yl and eleven Alk-3-yl.
- the alkenyl group may be further optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, decyl, decyloxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, fluorenyl Substituted by a substituent of an amide group, a carbocyclic group or a heterocyclic group.
- Alkynyl means a straight or branched chain unsaturated aliphatic hydrocarbon group having from 1 to 3 carbon-carbon triple bonds, consisting of 2 to 20 carbon atoms, preferably an alkynyl group of 2 to 12 carbon atoms, more preferably An alkynyl group of 2 to 8 carbon atoms.
- Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl Butyrynyl-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyne-4- Base, octyn-3-yl, decyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl.
- the alkynyl group may be further optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, decyl, decyloxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, fluorenyl Substituted by a substituent of an amide group, a carbocyclic group or a heterocyclic group.
- Carbocyclyl means a saturated or unsaturated aromatic or non-aromatic ring.
- the aromatic or non-aromatic ring may be a 3 to 8 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered tricyclic ring system.
- the ring group may be attached to a bridged ring or a spiro ring, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and Cyclodecyl, cyclohexene, ⁇ , , , ⁇ .
- the definition of carbocyclic groups appearing herein is consistent with this definition.
- Heterocyclyl means a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 8 membered monocyclic ring, a 4 to 12 membered bicyclic ring or 10 to 15 a tricyclic ring system, and comprising 1 to 3 hetero atoms selected from N, 0 or S, preferably a 3 to 8 membered heterocyclic group, and optionally substituted N, S in the ring of the heterocyclic group may be oxidized into various Oxidation state.
- the heterocyclic group may be attached to a hetero atom or a carbon atom, and the heterocyclic group may be bonded to a bridged or spiro ring, and non-limiting examples include epoxyethyl, azacyclopropyl, oxetanyl, aza.
- the heterocyclic groups appearing herein are defined in accordance with this definition.
- “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” means that the compound of the invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is passed through with a non-toxic inorganic base or An organic base, a salt obtained by reacting a free base with a non-toxic inorganic or organic acid.
- Non-limiting examples of the inorganic base include Al, Ca, Li, Mg, K, Na, and Zn; non-limiting examples of the organic base include ammonia, isopropylamine, trimethylamine, Diethylamine, triethylamine, tripropylamine, tetramethylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine , procaine, choline, betaine, phenamine penicillin, ethylenediamine, glucosamine, N-methylmethylglucamine, theobromine, triethanolamine, tromethamine, hydrazine, piperazine, Piperidine, N-ethylpiperidine and polyamine resins; non-limiting examples of the inorganic and organic acids include sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid
- “Pharmaceutical composition” means a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof and other chemical components, wherein “other chemical components” means pharmaceutically acceptable Accepted carriers, excipients, and/or one or more additional therapeutic agents.
- Carrier means a material that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound.
- Excipient means an inert substance that is added to a pharmaceutical composition to facilitate administration of the compound.
- Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, bonding Agent and disintegrant.
- Prodrug means a compound of the invention that can be converted to biological activity by metabolism in vivo.
- the prodrugs of the present invention are prepared by modifying the phenolic groups of the compounds of the present invention which can be removed by conventional procedures or in vivo to yield the parent compound.
- a prodrug of the invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group.
- Eutectic refers to a crystal in which an active pharmaceutical ingredient (API) and a eutectic former (CCF) are combined by hydrogen bonding or other non-covalent bonds, wherein the pure states of API and CCF are at room temperature. Solid, and there is a fixed stoichiometric ratio between the components. Eutectic is a multi-component crystal that contains both a binary eutectic formed between two neutral solids and a multi-component eutectic formed by a neutral solid with a salt or solvate.
- API active pharmaceutical ingredient
- CCF eutectic former
- Non-limiting examples include alanine, valine, leucine, isoleucine, valine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, Tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, aspartic acid, glutamic acid, pyroglutamic acid, sulfuric acid, phosphoric acid, nitric acid, hydrogen Bromo acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinyl sulfonic acid, formic acid, fumaric acid, Capric acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionate, lactic acid, maleic
- Animal is meant to include mammals such as humans, companion animals, zoo animals and domestic animals, preferably humans, horses or dogs.
- Stepoisomer refers to isomers produced by the different arrangement of atoms in a molecule in space, including cis-isolation Constructs, enantiomers and conformers.
- heterocyclic group optionally substituted by a thiol group means that the fluorenyl group may, but does not necessarily exist, the description including the case where the heterocyclic group is substituted by a thiol group, and wherein the heterocyclic group is not substituted by a thiol group happening.
- ED 50 half effective amount: The dose required to cause 50% of the mice to have a righting reflex loss by testing.
- ED 95 (95% effective amount): The dose required to cause 95% of mice to lose righting reflexes by testing.
- LD 5Q half lethal dose
- LD 5 (5% lethal dose): The dose required to kill 5% of mice by testing.
- Anesthesia induction time and anesthesia maintenance time Start timing after administration, and closely observe the general symptoms of the animal and changes in the administration site and breathing. If a normal animal pushes it down or is lying on its back, it can be turned over immediately. This reflection is judged as a normal reflection. On the contrary, it is regarded as the reversal reflection disappears, the reflection disappearance time is recorded, and when the animal reappears the rectification reflection, the reflection recovery time is recorded. The time from the end of administration to the righting reflex was recorded as the anesthesia onset time, and the time from the disappearance of the righting reflex to the reflex recovery was recorded as the anesthesia maintenance time.
- TI therapeutic index, ie LD 50 / ED 50
- SI safety index, ie LD 5 / ED 95 .
- MTD maximum tolerated dose
- the compound of formula (Ia) reacts with the compound of formula (Ib), and the reaction is stirred 2 ⁇ 20 Obtaining the compound of the formula (I) in an hour; or using tetrahydrofuran, toluene, diethyl ether or methyl tert-butyl ether as a solvent, -4 to 35 ° C, under the protection of nitrogen, the compound of the formula (Ia) and the compound of the formula (Ib)
- the Grignard reaction occurs, the reaction is stirred for 2 to 20 hours, and then the phenolic hydroxyl protecting group (R') is removed to obtain the compound of the formula 1, and the deprotecting agent is selected from the group consisting of Pd/C, palladium hydroxide, Raney nickel, and trifluoro Acetic acid, hydrochloric acid
- the compound of the formula (Ic) reacts with magnesium to form a Grignard reagent under the protection of nitrogen at -4 to 35 ° C, and the obtained Grignard reagent and formula (Id)
- the compound undergoes a Grignard reaction, the reaction is stirred for 2 to 20 hours, and then the phenolic hydroxyl protecting group (IT) is removed to obtain a compound of the formula (I), and the deprotecting agent is as described above;
- the organolithium reagent is selected from n-butyl lithium, t-butyl lithium, phenyl lithium, lithium diisopropylamide or Lithium hexamethyldisilazide, deprotecting reagent as described above;
- the compound of formula (Ic) reacts with the compound of formula (Id), and the reaction is stirred 2 ⁇ 20 Hours, then reacting with a thiolation reagent, and further removing the phenolic hydroxyl protecting group (R") to give a compound of the formula (I), the deprotecting reagent is as described above; or organic at -78 to -50 ° C
- the compound of the formula (Ic) is reacted with the compound of the formula (Id) for 30 minutes under the action of a lithium reagent.
- the product obtained in ⁇ 8 hours is further reacted with a thiolation reagent in the presence of sodium hydride or potassium t-butoxide, and then the phenolic hydroxyl protecting group (R") is removed to obtain a compound of the formula, and the thiolation reagent is selected from the group consisting of iodine.
- a thiolation reagent selected from the group consisting of iodine. Methane, methyl p-toluenesulfonate, dimethyl sulfate, ethyl bromide, ethyl p-toluenesulfonate or diethyl sulfate, organolithium reagent, reducing agent and deprotecting reagent as described above;
- R, R 4 , R 5 and n are in accordance with the definitions of the compounds of the formula (I), R" is as defined above; the invention relates to a preparation of the prodrug compounds of the formula (A) according to the invention Method, the method includes: among them:
- R 18 or R 19 are each independently selected from g F, Cl, Br, I, decyl or decyloxy,
- V is selected from F, Cl, Br, I; n, R, R 4 , R 5 or R 6 are as defined in the formula (I);
- the compound of the formula (I) is first subjected to a nucleophilic substitution reaction with a compound of the formula (IA) under a base to obtain an intermediate of the compound of the formula (IB), which is then exchanged or reacted with a metal salt by hydrolysis to obtain a formula ( IB) a compound;
- (Ib) is a halophosphoryl compound, wherein R 18 or R 19 is selected from the group consisting of F, Cl, Br, I, d- 1 () fluorenyl, 1Q decyloxy, the base is Including inorganic base and organic base, preference is given to triethylamine, diisopropylethylamine or sodium hydride, the selected reaction temperature is -80 ° C -150 ° C, the reaction time is 5 minutes - 2 days;
- the metal salt is a metal organic salt or an inorganic salt, and an alkali metal salt or an alkaline earth metal salt is preferred.
- the base includes an inorganic base and an organic base, and preference is given to triethylamine and diisopropylethylamine. Or sodium hydride, the selected reaction temperature is -80 ° C -150 ° C, the reaction time is 5 minutes - 2 days;
- R 2Q , R 21 and R 22 are each independently selected from H, F, Cl, Br, I or C w . ⁇ ;
- V is selected from F, Cl, Br, I; n, R, R 4 , R 5 or R 6 are as defined in the formula (I);
- a compound of the general formula (ID) is first subjected to a nucleophilic substitution reaction with a general formula (IE) under the action of a base to obtain an intermediate of the compound of the formula (IF), which is then exchanged or reacted with a metal salt by hydrolysis to obtain a formula ( IF) compound;
- a compound of the general formula (ID) and a general formula (IE) undergoing a nucleophilic substitution reaction under the action of a base to obtain an intermediate of the compound of the formula (IF), and further reacting with an electrophile under the action of a base to obtain a general formula (IF) compound;
- (I-C) is preferably a dihalogenated compound
- V is preferably F, Cl, Br or I, preferably a reaction temperature of 0 ° C to 150 ° C, preferably a reaction time of 0.5 to 12 hours;
- (IE) is a phosphoric acid compound, wherein R 21 and R 22 are preferably H, F, Cl, Br, I or C.
- the base is an inorganic base and an organic base, preferably triethylamine, diisopropylethylamine or sodium hydride, the selected reaction temperature is -50 ° C - 150 ° C, reaction time 5 Minute - 2 days;
- the metal salt is a metal organic salt or an inorganic salt, and an alkali metal salt or an alkaline earth metal salt is preferred.
- the base includes an inorganic base and an organic base, and preference is given to triethylamine and diisopropylethylamine. Or sodium hydride, the selected reaction temperature is -80 ° C - 150 ° C, and the reaction time is 5 minutes - 2 days.
- Figure 1 shows the test compound 16 milky injection and propofol intravenously administered to the awake Beagle dog heart rate
- Figure 2 shows the mean arterial pressure of the conscious patient Beagle dogs by intravenous administration of the test compound 16 emulsion injection and propofol.
- Figure 3 shows the results of determination of the API concentration of the aqueous phase of the compound.
- the structure of the compound is determined by nuclear magnetic resonance (NMR) or (; and) mass spectrometry (MS).
- NMR nuclear magnetic resonance
- MS mass spectrometry
- ⁇ is given in units of 10 - 6 (ppm).
- the NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ), deuterated methanol (CD 3 OD). ), the internal standard is tetramethylsilane (TMS);
- HPLC was determined using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 4.6 mm, 3.5 ⁇ M) ;
- the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
- the silica gel plate used for thin layer chromatography (TLC) has a specification of 0.15 mm ⁇ 0.20 mm, and the thin layer chromatography separation and purification product has a specification of 0.4 mm. ⁇ 0.5 mm;
- Column chromatography generally uses Yantai Huanghai silica gel 200 ⁇ 300 mesh silica gel as carrier;
- the starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anike Chemical, Shanghai Demo, Chengdu Kelon Chemical, Suiyuan Chemical Technology, Belling Technology, etc. the company;
- the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume;
- the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume;
- the hydrogenation reaction is usually evacuated, filled with hydrogen, and operated three times;
- reaction is carried out under a nitrogen atmosphere
- the solution means an aqueous solution
- reaction temperature is room temperature
- optimum reaction temperature at room temperature is 20 ° C ⁇ 30 ° C;
- Soluto HS15 polyethylene glycol stearic acid 15;
- the fourth step 2 - (1 -cyclopropyl- ⁇ -ethyl-ethyl)-6-isopropyl-phenol ( 3 ⁇ )
- Step 5 2-(l-Cyclopropylethyl; )-6-isopropylphenol (Compound 3)
- dichloromethane (10 mL) was added to the reaction flask, and diethylzinc (1.21 g, 9.80 mmol) and trifluoroacetic acid (1.12 g, 9.80 mmol) were slowly added dropwise under ice bath, and stirred for 30 minutes.
- Step 5 2-(l-Cyclobutylethyl; )-6-isopropylphenol (Compound 7)
- O-methoxyphenol (8A) 200 g, 1.6 mol, Jinzhi Chemical
- p-toluenesulfonic acid pyridinium salt 40.4 g, 0.16 mol, Kangmanlin
- dichloromethane 1.6 L
- the fourth step 2 - (1 -cyclopropyl- ⁇ -ethyl-ethyl)-6-methoxy-phenol ( 8 ⁇ )
- Step 2 Cyclopropyl-(3-isopropyl-2-tetrahydrofuran-2-phenoxy;)methanone (9C) Cyclopropyl-(3-isopropyl-2-tetrahydropyran-2-yloxy-phenyl)methanone
- Step 4 2 - (1 -cyclopropyl- ⁇ -propyl-propyl) -6 -isopropyl-phenol ( 9 ⁇ )
- Step 5 2-(l-cyclopropylpropyl 6-isopropyl-phenol (Compound 9)
- the organic phase was collected, washed with saturated sodium bicarbonate solution (500 mL X 3 ), and the organic phase was transferred to a reaction flask, and tetrabutyl was added.
- Ammonium fluoride (127.16 g, 487.12 mmol), stirred at room temperature for 12 hours, added with water (300 mL), and allowed to stand for separation.
- the organic phase was washed with water (100 mL ⁇ 3) and brine (100 mL ⁇ 2)
- the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated.
- Compound 13 is a racemate containing two chiral centers. After resolution, only three isomers can be obtained, namely compounds 18, 19 and 20.
- Second step 2-[(lR)-l-cyclopropylethyl]-6-sec-butyl-phenol (Compound 24).
- Trifluoroacetic acid (11.7 g, 0.1 mol) was added dropwise at 30 ° C or lower, and the reaction was carried out at 5 ° C for 3 hours after the completion of the dropwise addition; the reaction was quenched by adding 30 mL of water, and the mixture was allowed to stand for separation. The aqueous phase was extracted with dichloromethane.
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AU2014264103A AU2014264103C1 (en) | 2013-05-09 | 2014-05-06 | Phenol derivative and preparation method and use in medicine thereof |
JP2016512211A JP6254681B2 (ja) | 2013-05-09 | 2014-05-06 | フェノール誘導体及びその製造方法及び医薬的な応用 |
ES14795509T ES2746987T3 (es) | 2013-05-09 | 2014-05-06 | Derivado de fenol y método de preparación y uso en medicina de los mismos |
BR112015028212-1A BR112015028212B1 (pt) | 2013-05-09 | 2014-05-06 | Composto derivado de fenol, métodos de preparação do referido composto, composição farmacêutica compreendendo o referido composto e uso do mesmo |
CN201480000451.3A CN104507899B (zh) | 2013-05-09 | 2014-05-06 | 苯酚衍生物及其制备方法和在医药上的应用 |
KR1020157034856A KR101871732B1 (ko) | 2013-05-09 | 2014-05-06 | 페놀유도체, 이의 제조방법 및 의약에서의 이의 용도 |
MX2015015534A MX364376B (es) | 2013-05-09 | 2014-05-06 | Derivado de fenol y metodo de preparacion y uso en la medicina del mismo. |
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EA201592144A EA029073B1 (ru) | 2013-05-09 | 2014-05-06 | Производное фенола и способ его получения и его применение в медицине |
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HK15107424.4A HK1206712A1 (zh) | 2013-05-09 | 2015-08-03 | 苯酚衍生物及其製備方法和在醫藥上的應用 |
US14/936,310 US9517988B2 (en) | 2013-05-09 | 2015-11-09 | Phenol derivative and preparation method and use in medicine thereof |
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KR101871732B1 (ko) | 2018-06-27 |
KR20160005361A (ko) | 2016-01-14 |
AU2014264103C1 (en) | 2018-08-02 |
HK1206712A1 (zh) | 2016-01-15 |
EP2995604A1 (en) | 2016-03-16 |
CA2911845A1 (en) | 2014-11-13 |
US9517988B2 (en) | 2016-12-13 |
EP2995604B1 (en) | 2019-07-10 |
AU2014264103B2 (en) | 2018-03-22 |
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ES2746987T3 (es) | 2020-03-09 |
JP2016520054A (ja) | 2016-07-11 |
PT2995604T (pt) | 2019-10-11 |
BR112015028212A2 (pt) | 2017-07-25 |
MX364376B (es) | 2019-04-23 |
JP6254681B2 (ja) | 2017-12-27 |
CN104507899B (zh) | 2016-11-30 |
ZA201508948B (en) | 2017-03-29 |
MX2015015534A (es) | 2016-06-17 |
JP6431155B2 (ja) | 2018-11-28 |
EA029073B1 (ru) | 2018-02-28 |
CN104507899A (zh) | 2015-04-08 |
EA201592144A1 (ru) | 2016-07-29 |
CA2911845C (en) | 2019-08-13 |
JP2018012727A (ja) | 2018-01-25 |
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