WO2022233305A1 - 甲基磺酰脲类化合物及其应用 - Google Patents
甲基磺酰脲类化合物及其应用 Download PDFInfo
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- WO2022233305A1 WO2022233305A1 PCT/CN2022/091012 CN2022091012W WO2022233305A1 WO 2022233305 A1 WO2022233305 A1 WO 2022233305A1 CN 2022091012 W CN2022091012 W CN 2022091012W WO 2022233305 A1 WO2022233305 A1 WO 2022233305A1
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- DXPIZCZNFUTPEI-UHFFFAOYSA-O diphenylphosphanium;azide Chemical compound [N-]=[N+]=[N-].C=1C=CC=CC=1[PH2+]C1=CC=CC=C1 DXPIZCZNFUTPEI-UHFFFAOYSA-O 0.000 description 1
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- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- RIVIDPPYRINTTH-UHFFFAOYSA-N n-ethylpropan-2-amine Chemical compound CCNC(C)C RIVIDPPYRINTTH-UHFFFAOYSA-N 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
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- 239000002777 nucleoside Substances 0.000 description 1
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- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
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- 229940049954 penicillin Drugs 0.000 description 1
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- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VSAISIQCTGDGPU-UHFFFAOYSA-N tetraphosphorus hexaoxide Chemical compound O1P(O2)OP3OP1OP2O3 VSAISIQCTGDGPU-UHFFFAOYSA-N 0.000 description 1
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- IHZAEIHJPNTART-UHFFFAOYSA-N tribromofluoromethane Chemical compound FC(Br)(Br)Br IHZAEIHJPNTART-UHFFFAOYSA-N 0.000 description 1
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the present invention relates to a methylsulfonylurea compound. Specifically, it relates to the compound represented by formula (I) and its pharmaceutically acceptable salt.
- Hepatitis B virus belongs to the Hepatoviridae family. It can cause acute and/or progressive chronic disease. Hepatitis B virus can also cause many other clinical manifestations in pathological morphology, especially chronic inflammation of the liver, cirrhosis and carcinogenesis of hepatocytes. In addition, co-infection with hepatitis D can adversely affect the development of the disease.
- Hepatitis B is a worldwide medical problem. At present, there is no specific drug for the treatment of hepatitis B in the world.
- the current first-line drugs for hepatitis B are mainly nucleoside and interferon drugs, but these drugs cannot be completely cured and require long-term medication, and There are many problems such as renal insufficiency and lactic acidosis, so it is imperative to develop a new type of anti-hepatitis B drug that is more effective and safe for patients.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- R 1 are each independently selected from halogen, OH, CN, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, which are each independently optionally substituted with 1, 2 or 3 halogens;
- n is selected from 0, 1, 2, 3 and 4;
- T 1 and T 2 are each independently selected from CH and N;
- R is selected from H, methyl and F
- Ring A is selected from phenyl and C 4-10 cycloalkyl, each independently optionally substituted with 1, 2 or 3 R a ;
- R a are each independently selected from halogen, OH, CN, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are each independently optionally substituted with 1, 2 or 3 halogens;
- L 2 is selected from a single bond and a methylene group.
- R 1 are independently selected from F, Cl, Br, CN, -CH 3 and -OCH 3 , and the -CH 3 and -OCH 3 are independently optionally selected from 1 , 2 or 3 F substitutions, other variables are as defined in the present invention.
- R 1 are independently selected from F, Cl, Br and CN, and other variables are as defined in the present invention.
- R a are independently selected from F, Cl, Br, CH 3 and OCH 3 , and said CH 3 and OCH 3 are each independently optionally substituted with 1, 2 or 3 F, Other variables are as defined in the present invention.
- the above-mentioned ring A is selected from phenyl, cyclobutyl, cyclohexyl, The phenyl, cyclobutyl, cyclohexyl, Each independently is optionally substituted with 1, 2 or 3 R a , other variables are as defined in the present invention.
- the above-mentioned ring A is selected from Other variables are as defined in the present invention.
- the above-mentioned compound, or a pharmaceutically acceptable salt thereof is selected from:
- R 1 , R 2 , L 2 and m are as defined in any one of the present invention.
- the above-mentioned compound, or a pharmaceutically acceptable salt thereof is selected from:
- R 1 , R 2 , L 2 and m are as defined in any one of the present invention.
- the above-mentioned compound, or a pharmaceutically acceptable salt thereof is selected from:
- R 1 , R 2 , L 2 and m are as defined in any one of the present invention.
- the present invention also provides the following compounds or their pharmaceutically acceptable salts selected from:
- the present invention also provides the following compounds or their pharmaceutically acceptable salts selected from:
- the present invention also provides the following compounds or their pharmaceutically acceptable salts selected from:
- the present invention also provides the following compounds or their pharmaceutically acceptable salts selected from:
- the present invention also provides the application of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating hepatitis B virus infection-related diseases.
- the hepatitis B virus infection-related disease is chronic hepatitis B.
- the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- salts refers to salts of the compounds of the present application, prepared from compounds with specific substituents discovered herein and relatively non-toxic acids or bases.
- base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
- acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
- Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
- the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
- the term “isomer” is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers isomer.
- the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
- enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
- cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
- diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
- any one or more sites in the group can be linked to other groups by chemical bonds.
- connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group.
- the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines express.
- a straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in this group;
- the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group; with a straight dashed double bond Indicates that the groups are connected by double bonds, e.g.
- the straight dashed double bond in the cyclohexyl group indicates that the cyclohexyl group is connected to other groups by a double bond.
- tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature.
- a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
- proton tautomers also called prototropic tautomers
- prototropic tautomers include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization.
- Valence tautomers include interconversions by recombination of some bonding electrons.
- keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
- the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
- the enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
- isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
- Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
- a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
- the diastereoisomers were resolved and the pure enantiomers recovered.
- the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization) such as from amines to amino groups formate).
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
- compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
- deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
- C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
- the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
- Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
- C1-3alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom.
- the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like.
- Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
- C 4-10 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 4 to 10 carbon atoms, which includes monocyclic, bicyclic and tricyclic systems, wherein bicyclic and tricyclic systems include Spiro, condensed and bridged rings.
- the C 4-10 cycloalkyl includes C 4-5 , C 5-6 , C 6-7 , C 6-8 , C 6-9 , C 6 , C 7 , C 8 , C 9 or C 10 , etc. ; it can be monovalent, bivalent, or multivalent.
- C 4-10 cycloalkyl examples include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0] Dicyclodecane etc.
- halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
- substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
- oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
- optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
- any variable eg, R
- its definition in each case is independent.
- the group may optionally be substituted with up to two Rs, with independent options for R in each case.
- combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
- a substituent When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A.
- the direction of attachment is arbitrary, for example, The linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
- the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
- SXRD single crystal X-ray diffraction method
- the cultured single crystal is collected by Bruker D8 venture diffractometer
- the light source is CuK ⁇ radiation
- the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
- the solvent used in the present invention is commercially available.
- the present invention adopts the following abbreviations: eq stands for equivalent, equivalent; M stands for mol/L; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOH stands for ethanol; MeOH stands for methanol; CBz Represents benzyloxycarbonyl, which is an amine protecting group; Boc represents tert-butoxycarbonyl, which is an amine protecting group; IPA represents isopropanol, and dppf represents 1,1'-bisdiphenylphosphinoferrocene.
- the compound of the present invention has a significant inhibitory effect on HBV, has no obvious cytotoxicity in various hepatocytes, has high oral bioavailability in mice, and has a high liver-to-blood ratio of the drug. The antiviral effect is remarkable.
- compound 1-a 300g, 2.36mol, 243.90mL, 1eq
- ethylene glycol 292.85g, 4.72mol, 263.83mL, 2eq
- toluene 1.5L
- p-toluenesulfonic acid 40.63 g, 235.92 mmol, 0.1 eq
- the reaction solution was washed with water (300 mL ⁇ 2).
- the aqueous phase was extracted with ethyl acetate (100 mL).
- compound 1-f (20 g, 56.79 mmol, 1 eq) and DMF (200 mL) were added to a three-necked flask, and after stirring and dissolving, sodium hydrogen (2.95 g, 73.82 mmol, 60% purity was added in batches at 0°C) , 1.3eq).
- the reaction mixture was stirred at 0°C for 30 minutes, then iodomethane (24.18 g, 170.37 mmol, 10.61 mL, 3 eq) was added.
- the mixture was stirred at 50°C for 12 hours.
- the filter cake was washed with water (50 mL) and methanol (20 mL ⁇ 2), and dried under reduced pressure. Compound 1-g was obtained.
- 2,2,6,6-Tetramethylpiperidine (498.33mg, 3.53mmol, 598.95 ⁇ L, 1.2eq) was dissolved in tetrahydrofuran (6mL), the system was cooled to -30°C, n-butyllithium (2.5mL) was added dropwise M, 1.4 mL, 1.19 eq), the reaction was stirred at -30 °C for 0.5 h.
- compound 7-c (150.00 mg, 298.95 ⁇ mol, 1 eq), 7-b (466.64 mg, 1.49 mmol, 5 eq), sodium carbonate (158.43 mg, 1.49 mmol, 5 eq), sodium carbonate (158.43 mg, 1.49 mmol, 5 eq), 1, 4-Dioxane (8 mL) and water (1.5 mL), then Pd(PPh 3 ) 4 (34.55 mg, 29.90 ⁇ mol, 0.1 eq) was added. The mixture was stirred at 100°C for 16 hours.
- 2,2,6,6-Tetramethylpiperidine (2.38g, 16.88mmol, 2.87mL, 1.2eq) was dissolved in tetrahydrofuran (24mL), the system was cooled to -30°C, n-butyllithium (2.5M) was added. , 6.70mL, 1.19eq).
- reaction was stirred at -30 °C for 0.5 hours, the reaction was cooled to -78 °C, a solution of compound 1-n (3.77 g, 14.07 mmol, 1 eq) in tetrahydrofuran (24 mL) was added, stirred at -78 °C for 30 minutes, and compound 9-a was added (2 g, 14.07 mmol, 1.87 mL, 1 eq) in tetrahydrofuran (24 mL). The reaction was slowly warmed to 25°C and stirred at 25°C for 12 hours.
- reaction solution was filtered, spin-dried, water (60 mL) was added, extracted with ethyl acetate (60 mL ⁇ 3), the organic phase was washed with saturated brine (60 mL ⁇ 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude product.
- compound 7-c 200 mg, 398.60 ⁇ mol, 1 eq
- compound 10-b (614.29 mg, 1.99 mmol, 5 eq)
- N,N-diisopropylethylamine 154.55 mg, 1.20 mmol, 208.29 ⁇ L, 3eq
- dichlorobis(triphenylphosphine)palladium 27.98mg, 39.86 ⁇ mol, 0.1eq
- 2,2,6,6-Tetramethylpiperidine (2.90g, 20.53mmol, 3.48mL, 1.1eq) was added to tetrahydrofuran (50mL), cooled to -78°C, n-butyllithium (2.5M, 9.70mL, 1.3eq), the reaction was stirred at -78°C for 30 minutes, the temperature was raised to 0°C, a solution of compound 1-n in tetrahydrofuran (15mL) was added dropwise, the reaction was stirred at 0°C for 30 minutes, iodomethane (3.97 g, 27.99 mmol, 1.74 mL, 1.5 eq) in tetrahydrofuran (15 mL).
- the reaction was stirred at 0°C for 10 minutes, warmed to 25°C and stirred for 12 hours.
- the system was cooled to 0°C, saturated ammonium chloride solution (30 mL) was added to the reaction solution, stirred for 20 minutes, and extracted with ethyl acetate (20 mL ⁇ 2).
- the combined organic phases were concentrated under reduced pressure to give the crude product.
- the crude product was purified by column machine (eluent: petroleum ether/ethyl acetate, gradient: 0-10%) to give compound 13-a.
- 2,2,6,6-Tetramethylpiperidine (2.49g, 17.63mmol, 2.99mL, 1.2eq) was dissolved in tetrahydrofuran (30mL), the system was cooled to -30°C, n-butyllithium (2.5mL) was added dropwise M, 6.99 mL, 1.19 eq). The reaction was stirred at -30 °C for 0.5 hours, the reaction was cooled to -78 °C, a solution of compound 13-a (4.14 g, 14.69 mmol, 1 eq) in tetrahydrofuran (30 mL) was added dropwise, and the solution was stirred at -78 °C for 30 minutes, and compound 1 was added dropwise.
- Methyltriphenylphosphonium bromide (23.09g, 64.63mmol, 1.1eq) was dissolved in tetrahydrofuran (160mL), the reaction solution was cooled to -5°C, and butyllithium (2.5°C) was slowly added dropwise under nitrogen atmosphere. M, 25.85mL, 1.1eq), and then the reaction solution was stirred at 0°C for 1 hour, and then compound 1-m (10g, 58.75mmol, 9.35mL, 1eq) was slowly added dropwise, and the reaction solution was stirred at 25°C for 12 Hour.
- reaction solution was cooled to 0° C., and then saturated ammonium chloride solution (100 mL) was slowly added to the reaction solution, stirred for 10 minutes, and then ethyl acetate (200 mL ⁇ 3) was added for extraction, and the organic phase was extracted with saturated brine ( 100 mL ⁇ 3) washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), the combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and rotary evaporated.
- compound 15-a (2g, 5.61mmol, 1eq)
- compound 1-o (8.26g, 28.07mmol, 5eq)
- N,N-diisopropylethylamine (3.63g, 28.07mmol, 4.89mL, 5eq)
- dichlorobis(triphenylphosphine)palladium (394.08mg, 561.46 ⁇ mol, 0.1eq) were dissolved in 1,4-dioxane (20mL) and water (20mL), and the temperature was raised to 80°C Stir for 12 hours.
- compound 15-b 200mg, 450.92 ⁇ mol, 1eq
- compound 18-a 140.69mg, 676.38 ⁇ mol, 1.5eq
- diisopropylethylamine 174.83mg, 1.35mmol
- a thumb bottle 235.62 ⁇ L, 3 eq
- tetrahydrofuran 5 mL
- tri-n-propyl cyclic phosphoric anhydride 573.90 mg, 901.84 ⁇ mol, 536.35 ⁇ L, 50% pure, 2 eq.
- the mixture was stirred at 50°C for 12 hours.
- the combined organic phases were washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
- compound 20-a (800.00 mg, 2.25 mmol, 1 eq), compound 10-b (2.08 g, 6.74 mmol, 3 eq), N,N-diisopropylethylamine (1.45 g, 11.23 mmol, 1.96mL, 5eq) and dichlorobis(triphenylphosphine)palladium (157.63mg, 224.58 ⁇ mol, 0.1eq) were dissolved in 1,4-dioxane (10mL) and water (10mL), and the reaction solution was mixed The temperature was raised to 80°C and the reaction was stirred for 4 hours.
- compound 20-b 75mg, 163.91 ⁇ mol, 1eq
- compound 20-c 40.21mg, 245.87 ⁇ mol, 1.5eq
- diisopropylethylamine 63.55mg, 491.74 ⁇ mol
- tri-n-propyl cyclic phosphoric anhydride 208.61 mg, 327.82 ⁇ mol, concentration: 50%, 2 eq
- the mixture was stirred at 50°C for 12 hours.
- the reaction solution was concentrated under reduced pressure.
- compound 20-b 50 mg, 109.27 ⁇ mol, 1 eq
- compound 25-a 21.07 mg, 163.91 ⁇ mol, 1.5 eq
- dichloromethane 1.5 mL
- pyridine 43.22 mg, 546.37 ⁇ mol, 44.10 ⁇ L, 5 eq
- phosphorus oxychloride 20.11 mg, 131.13 ⁇ mol, 12.19 ⁇ L, 1.2 eq
- compound 20-b 60 mg, 131.13 ⁇ mol, 1 eq), 27-a (24.01 mg, 157.36 ⁇ mol, 1.2 eq), tri-n-propyl cyclophosphoric anhydride (166.89 mg, 262.26 ⁇ mol, purity : 50%, 2eq) and diisopropylethylamine (50.84mg, 393.39 ⁇ mol, 68.52 ⁇ L, 3eq) were added to tetrahydrofuran (6mL), and the reaction solution was stirred at 50°C for 0.5 hours.
- the crude product was purified by preparative high performance liquid chromatography (column type: Phenomenex Gemini-NX C18 75*30mm*3 ⁇ m; mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile %: 40%-70%, 7min) , to obtain compound 35.
- HBV DNA in HepG2.2.15 cells was detected by real time quantitative qPCR assay (real time-qPCR), and the compound's EC 50 value was used as an indicator to evaluate the inhibitory effect of the compound on HBV.
- HepG2.2.15 cell culture medium (DMEM/F12, Invitrogen-11330057; 10% serum, Invitrogen-10099141; 100 units/ml penicillin and 10 ⁇ g/ml streptomycin, Invitrogen-15140122; 1% non-essential amino acids, Invitrogen-11140076; 2mM L-Glutamine, Invitrogen-25030081; 300 ⁇ g/ml Geneticin, Invitrogen-10131027.
- HepG2.2.15 cells (4x104 cells/well) were transferred to a 96-well plate and incubated overnight at 37°C, 5% CO 2 .
- Upstream primer sequence GTGTCTGCGGCGTTTTATCA
- reaction conditions of PCR are: heating at 95°C for 10 minutes; then denaturation at 95°C for 15 seconds, extension at 60°C for 1 minute, a total of 40 cycles.
- %Inh. [1-(DNA copy number in sample-1 ⁇ M DNA copy number in GLS4)/(DNA copy number in DMSO control-1 ⁇ M DNA copy number in GLS4)] ⁇ 100.
- RLU Sample is the signal value of the sample well
- AverageRLU Cellcontrol is the average signal value of the cell control well
- AverageRLU Mediumcontrol is the average signal value of the medium control well.
- the cytotoxic CC 50 value of the compounds of the present invention in primary hepatocytes is relatively high.
- RLU Sample is the signal value of the sample well
- AverageRLU Cellcontrol is the average signal value of the cell control well
- AverageRLU Mediumcontrol is the average signal value of the medium control well.
- RLU Sample is the signal value of the sample well
- AverageRLU Cellcontrol is the average signal value of the cell control well
- AverageRLU Mediumcontrol is the average signal value of the medium control well.
- Test compound 11 was mixed with 10% polyethylene glycol-15 hydroxystearate/20% polyethylene glycol 400/70% aqueous solution, vortexed and sonicated to prepare a 0.2 mg/mL clear solution, microporous membrane Use after filtering. Balb/c female mice aged 7 to 10 weeks were selected, and the candidate compound solution was administered intravenously at a dose of 1 mg/kg.
- Test compound 30 was mixed with 10% dimethyl sulfoxide/10% polyethylene glycol-15 hydroxystearate/80% aqueous solution, vortexed and sonicated to prepare a 0.2 mg/mL clear solution, microporous membrane Use after filtering. Balb/c female mice aged 7 to 10 weeks were selected, and the candidate compound solution was administered intravenously at a dose of 1 mg/kg.
- Test compound 36 was mixed with 10% dimethyl sulfoxide/10% polyethylene glycol-15 hydroxystearate/80% aqueous solution, vortexed and sonicated to prepare a 0.2 mg/mL clear solution, microporous membrane Use after filtering. Balb/c female mice aged 7 to 10 weeks were selected, and the candidate compound solution was administered intravenously at a dose of 1 mg/kg.
- Test compounds 11, 30 and 36 were respectively mixed with 10% polyethylene glycol-15 hydroxystearate aqueous solution, vortexed and sonicated to prepare a 1 mg/mL homogeneous suspension for later use.
- Balb/c female mice of 7 to 10 weeks of age were selected, and the candidate compound solution was orally administered at a dose of 10 mg/kg.
- the compounds of the present invention have high oral bioavailability.
- OBJECTIVE To test the anti-HBV effect of the compound in mice by HDI/HBV mouse model.
- the solvent is 10% polyethylene glycol-15 hydroxystearate; a certain amount of test compounds 11, 30 and 36 are respectively dissolved in 10% polyethylene glycol-15 hydroxystearate aqueous solution, Vortex and sonicate to prepare a homogeneous suspension and store at 4°C until use.
- High pressure injection of HBV plasmid DNA solution into the tail vein of mice the day of plasmid injection was set as day 0, the day after injection was set as day 1, and so on. On day 0, all animals were injected with a volume of 8% of their body weight in saline solution containing 10 ⁇ g of plasmid DNA through the tail vein, and the injection was completed within 5 seconds.
- ⁇ Log10 copies represents the difference between the viral load in the administration group and the viral load in the vehicle group
- the compound of the present invention has a significant effect on reducing HBV DNA in HDI model.
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Abstract
公开一种甲基磺酰脲类化合物。具体公开了式(I)所示化合物及其药学上可接受的盐。
Description
本申请主张如下优先权:
CN2021104946968,申请日:2021年5月7日。
本发明涉及一种甲基磺酰脲类化合物。具体涉及式(I)所示化合物及其药学上可接受的盐。
乙型肝炎病毒属于肝病毒科。它可引起急性的和/或持续渐进的慢性病。乙型肝炎病毒还可引起病理形态中的许多其他的临床表征,尤其是肝脏的慢性炎症、肝硬化和肝细胞的癌变。另外,与丁型肝炎的共同感染在疾病的发展过程中会产生不利影响。
乙肝是世界性医学难题,目前全世界范围内还没有治疗乙肝的特效药,乙肝目前的一线药物主要是核苷类和干扰素类药物,但这些药物均无法彻底治愈,都需要长期服药,且存在着肾功能不全,乳酸中毒等诸多问题,因此开发出一种为患者提供更为有效和安全的新型抗乙肝药物势在必行。
发明内容
本发明提供了式(I)所示化合物或其药学上可接受的盐,
其中,
R
1分别独立地选自卤素、OH、CN、NH
2、C
1-3烷基和C
1-3烷氧基,所述C
1-3烷基和C
1-3烷氧基分别独立地任选被1、2或3个卤素取代;
m选自0、1、2、3和4;
T
1和T
2各自独立地选自CH和N;
R
2选自H、甲基和F;
环A选自苯基和C
4-10环烷基,所述苯基和C
4-10环烷基分别独立地任选被1、2或3个R
a取代;
R
a分别独立地选自卤素、OH、CN、NH
2、C
1-3烷基和C
1-3烷氧基,所述C
1-3烷基和C
1-3烷氧基分别独立地任选被1、2或3个卤素取代;
L
1选自单键、-C≡C-和-CR
2=;
L
2选自单键和亚甲基。
在本发明的一些方案中,上述R
1分别独立地选自F、Cl、Br、CN、-CH
3和-OCH
3,所述-CH
3和-OCH
3分别独立地任选被个、2或3个F取代,其他变量如本发明所定义。
在本发明的一些方案中,上述R
1分别独立地选自F、Cl、Br和CN,其他变量如本发明所定义。
在本发明的一些方案中,上述L
1选自-C≡C-、-CH=、-C(F)=和-C(CH
3)=,其他变量如本发明所定义。
在本发明的一些方案中,上述R
a分别独立地选自F、Cl、Br、CH
3和OCH
3,所述CH
3和OCH
3分别独立地任选被1、2或3个F取代,其他变量如本发明所定义。
在本发明的一些方案中,上述化合物或其药学上可接受的盐,其选自:
其中,R
1、R
2、L
2和m如本发明任意一项所定义。
在本发明的一些方案中,上述化合物或其药学上可接受的盐,其选自:
其中,R
1、R
2、L
2和m如本发明任意一项所定义。
在本发明的一些方案中,上述化合物或其药学上可接受的盐,其选自:
其中,R
1、R
2、L
2和m如本发明任意一项所定义。
本发明还有一些方案是由上述各变量任意组合而来。
本发明还提供下述化合物或其药学上可接受的盐,其选自:
本发明还提供下述化合物或其药学上可接受的盐,其选自:
本发明还提供下述化合物或其药学上可接受的盐,其选自:
本发明还提供下述化合物或其药学上可接受的盐,其选自:
在本发明还提供了上述的化合物或其药学上可接受的盐在制备治疗乙肝病毒感染相关疾病的药物上的应用。
本发明的一些方案中,所述乙肝病毒感染相关疾病是慢性乙型肝炎。
定义和说明
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其他问题或并发症,与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本申请化合物的盐,由本申请发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本申请的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。本发明的 某些特定的化合物含有碱性和酸性的官能团,从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
除非另有说明,术语“异构体”意在包括几何异构体、顺反异构体、立体异构体、对映异构体、旋光异构体、非对映异构体和互变异构体。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物,包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体,及其外消旋混合物和其他混合物,例如对映异构体或非对映体富集的混合物,所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物,均包括在本发明的范围之内。
除非另有说明,术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明,术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明,术语“非对映异构体”是指分子具有两个或多个手性中心,并且分子间为非镜像的关系的立体异构体。
除非另有说明,“(+)”表示右旋,“(-)”表示左旋,“(±)”表示外消旋。
除非另有规定,当某一基团具有一个或多个可连接位点时,该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的,且可连接位点存在H原子时,则连接化学键时,该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
直形虚线键
或波浪线
表示。例如-OCH3中的直形实线键表示通过该基团中的氧原子与其他基团相连;
中的直形虚线键表示通过该基团中的氮原子的 两端与其他基团相连;用直形虚线双键
表示基团间通过双键连接,例如
中的直形虚线双键表示环己基以双键与其他基团连接。
本发明的化合物可以存在特定的。除非另有说明,术语“互变异构体”或“互变异构体形式”是指在室温下,不同官能团异构体处于动态平衡,并能很快的相互转化。若互变异构体是可能的(如在溶液中),则可以达到互变异构体的化学平衡。例如,质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化,如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明,术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100%,并且,该异构体或对映体的含量大于等于60%,或者大于等于70%,或者大于等于80%,或者大于等于90%,或者大于等于95%,或者大于等于96%,或者大于等于97%,或者大于等于98%,或者大于等于99%,或者大于等于99.5%,或者大于等于99.6%,或者大于等于99.7%,或者大于等于99.8%,或者大于等于99.9%。
除非另有说明,术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如,其中一种异构体或对映体的含量为90%,另一种异构体或对映体的含量为10%,则异构体或对映体过量(ee值)为80%。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体,可以通过不对称合成或者具有手性助剂的衍生作用来制备,其中将所得非对映体混合物分离,并且辅助基团裂开以提供纯的所需对映异构体。或者,当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时,与适当的光学活性的酸或碱形成非对映异构体的盐,然后通过本领域所公知的常规方法进行非对映异构体拆分,然后回收得到纯的对映体。此外,对映异构体和非对映异构体的分离通常是通过使用色谱法完成的,所述色谱法采用手性固定相,并任选地与化学衍生法相结合)例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氚(
3H),碘-125(
125I)或C-14(
14C)。又例如,可用重氢取代氢形成氘代药物,氘与碳构成的键比普通氢与碳构成的键更坚固,相比于未氘化药物,氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
除非另有规定,术语“C
1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C
1-3烷基包括C
1-2和C
2-3烷基等;其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C
1-3烷基的 实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定,术语“C
1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C
1-3烷氧基包括C
1-2、C
2-3、C
3和C
2烷氧基等。C
1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定,“C
4-10环烷基”表示由4至10个碳原子组成的饱和环状碳氢基团,其包括单环、双环和三环体系,其中双环和三环体系包括螺环、并环和桥环。所述C
4-10环烷基包括C
4-5、C
5-6、C
6-7、C
6-8、C
6-9、C
6、C
7、C
8、C
9或C
10等;其可以是一价、二价或者多价。C
4-10环烷基的实例包括,但不限于,环丁基、环戊基、环己基、环庚基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定,术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的,并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代,取代基可以包括重氢和氢的变体,只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即=O)时,意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代,也可以不被取代,除非另有规定,取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被0-2个R所取代,则所述基团可以任选地至多被两个R所取代,并且每种情况下的R都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时,比如-(CRR)
0-,表示该连接基团为单键。
当其中一个变量选自单键时,表示其连接的两个基团直接相连,比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时,表示该取代基是不存在的,比如A-X中X为空缺时表示该结构实际上是A。当所列举的连接基团没有指明其连接方向,其连接方向是任意的,例如,
中连接基团L为-M-W-,此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构,如果本发明涉及化合物的绝对构型,则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD),把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据,光源为CuKα辐射,扫描方式:
扫描,收集相关数据后,进一步采用直接法(Shelxs97)解析晶体结构,便可以确证绝对构型。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词:eq代表当量、等量;M代表mol/L;DMF代表N,N-二甲基甲酰胺;DMSO代表二甲亚砜;EtOH代表乙醇;MeOH代表甲醇;CBz代表苄氧羰基,是一种胺的保护基团;Boc代表叔丁氧羰基是一种胺保护基团;IPA代表异丙醇,dppf代表1,1′-双二苯基膦二茂铁。
作为新类型的抗乙肝药物,本发明化合物对HBV的抑制作用显著,在多种肝细胞中无明显细胞毒性,小鼠体内口服生物利用度高,药物的肝血比高,在HDI药效模型中的抗病毒效果显著。
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例方式,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
合成路线:
步骤1:化合物1-b的合成
氮气保护下,向圆底烧瓶中加入化合物1-a(300g,2.36mol,243.90mL,1eq),乙二醇(292.85g,4.72mol,263.83mL,2eq)和甲苯(1.5L),然后加入对甲苯磺酸(40.63g,235.92mmol,0.1eq),在120℃下回流12小时,同时用分水器分水。反应液用水(300mL×2)洗涤。水相用乙酸乙酯(100mL)萃取。合并的有机相用饱和食盐水(300mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩液通过硅胶柱层析法(石油醚∶乙酸乙酯=100∶0~50∶50)分离,得到化合物1-b。
1H NMR(400MHz,CDCl
3)δppm7.72(d,J=3.1Hz,1H),7.30-7.08(m,1H),4.11-4.02(m,2H),3.99-3.92(m,2H),1.77(s,3H).
步骤2:化合物1-c的合成
将化合物1-b(20g,116.81mmol,1eq)溶于四氢呋喃(360mL)中,降温至-78℃,缓慢滴加丁基锂(2.5M,51.40mL,1.1eq)。反应液在-78℃搅拌1小时,然后缓慢滴加四溴化碳(42.61g,128.49mmol,1.1eq)的四氢呋喃(40mL)溶液,反应液在-78℃下搅拌0.5小时,再升温至0℃搅拌0.5小时。向反应液中滴加饱和氯化铵溶液(300mL),用乙酸乙酯(300mL×3)萃取。合并的有机相用饱和食盐水(300mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至10/1)纯化,得到化合物1-c。
MS m/z(ESI):249.8[M+1]
+.
1H NMR(400MHz,CDCl
3)δppm 7.65(s,1H),4.12-4.07(m,2H),4.03-3.98(m,2H),1.79(s,3H).
步骤3:化合物1-d的合成
在三口瓶中加入化合物1-c(49.1g,196.31mmol,1eq)和丙酮(280mL),在0℃下加入盐酸水溶液(6M,196.31mL,6eq),于25℃下搅拌反应2小时。向反应液中加入水(200mL),用乙酸乙酯(200mL×3)萃取,合并的有机相用饱和食盐水(200mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到化合物1-d。
1H NMR(400MHz,CDCl
3)δppm 7.87(s,1H),2.65(d,J=0.8Hz,3H).
步骤4:化合物1-e的合成
在三口瓶中加入化合物1-d(22g,106.76mmol,1eq)和甲醇(300mL),然后在0℃下缓慢加入甲醇钠的甲醇溶液(5M,42.71mL,2eq)和草酸二甲酯(18.91g,160.15mmol,1.5eq)。混合物在70℃下搅拌1小时。反应液降至0℃,加入水(300mL),然后用2mol/L稀盐酸调pH=2~3,在0℃搅拌30分钟后过滤。滤饼用甲醇(30mL×3)洗涤后减压干燥。得到化合物1-e。MS m/z(ESI):291.9[M+1]
+.
1H NMR(400MHz,DMSO-d
6)δppm 7.92(s,1H),6.55(s,1H),3.69(s,3H).
步骤5:化合物1-f的合成
在圆底烧瓶中加入化合物1-e(65g,222.52mmol,1eq),磺酰胺(32.08g,333.78mmol,19.93mL,1.5eq)和盐酸/甲醇溶液(4M,500mL,8.99eq)。混合物在70℃下搅拌2小时。将反应液降至0℃,搅拌1小时后过滤。向滤饼中加入水(300mL),搅拌30分钟后过滤。向滤饼中加入叔丁基甲醚(200mL),搅拌30分钟后过滤。滤饼减压干燥得到化合物1-f。MS m/z(ESI):351.9[M+1]
+.
1H NMR(400MHz,DMSO-d
6)δppm 8.05(s,1H),6.84(s,1H),3.81(s,3H).
步骤6:化合物1-g的合成
氮气保护下,在三口瓶中加入化合物1-f(20g,56.79mmol,1eq)和DMF(200mL),搅拌溶解后,在0℃下分批加入钠氢(2.95g,73.82mmol,60%纯度,1.3eq)。反应混合物在0℃在搅拌30分钟,然后加入碘甲烷(24.18g,170.37mmo1,10.61mL,3eq)。混合物在50℃下搅拌12小时。将反应液缓慢倒入冰水(200mL)中,用1M稀盐酸调pH=2~3,搅拌15分钟后过滤。滤饼用水(50mL)和甲醇(20mL×2)冲洗后,减压干燥。得到化合物1-g。
MS m/z(ESI):365.7[M+1]
+.
1H NMR(400MHz,DMSO-d
6)δppm 8.35(s,1H),7.37(s,1H),3.95(s,3H),3.60(s,3H).
步骤7:化合物1-h的合成
将化合物1-g(50g,136.53mmol,1eq)和三乙胺(69.08g,682.67mmol,95.02mL,5eq)加到乙腈(250mL)和水(250mL)中,混合物在50℃下搅拌1小时。向反应液中加入水(200mL),用乙酸乙酯(200mL×2)萃取。合并的有机相依次用水(100mL)和饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。得到化合物1-h。
MS m/z(ESI):351.8[M+1]
+.
步骤8:化合物1-j的合成
将化合物1-i(15g,77.51mmol,1eq)溶于甲醇(450mL)和醋酸(18mL)中,再分批加入还原铁粉(15.00g,268.60mmol,3.47eq),将反应液升温至65℃搅拌反应2小时。将反应液冷却至25℃后过滤,滤液减压浓缩得到粗品。向粗品中加入乙酸乙酯(300mL),再依次用1N的氢氧化钠水溶液(300mL×2)和饱和食盐水(300mL×2)洗涤,合并有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到化合物1-j。
1H NMR(400MHz,CDCl
3)δ=6.47-6.41(m,1H),6.41-6.33(m,1H),3.71(br s,2H).
步骤9:化合物1-k的合成
在0℃下将化合物1-h(15g,42.59mmol,1eq),化合物1-j(6.97g,42.59mmol,1eq),N,N-二异丙基乙胺(16.51g,127.77mmol,22.26mL,3eq)和三正丙基环磷酸酐50%乙酸乙酯溶液(40.66g,63.89mmol,38.00mL,1.5eq)溶于二氯甲烷(450mL)中,将反应体系用氮气置换三次后,再升温至25℃搅拌反应12小时。向反应液中加入水(500mL),用二氯甲烷(500mL×2)萃取,合并有机相,用饱和食盐水(500mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至10/3)纯化,得到化合物1-k。
MS m/z(ESI):498.7[M+1]
+.
步骤10:化合物1-l的合成
将化合物1-k(6.87g,13.80mmol,1eq)溶于乙醇(100mL)中,将反应液降温到0℃后再缓慢分批加入硼氢化钠(1.04g,27.61mmol,2eq),然后搅拌反应2小时。向反应液中缓慢加入1M的盐酸水溶液调节pH=1~2,再加入水(100mL),搅拌5分钟后过滤。向滤饼中加入甲醇(20mL)打浆30分钟,过滤,滤饼真空干燥得到化合物1-l。
MS m/z(ESI):502.8[M+1]
+.
步骤11:化合物1-o的合成
将2,2,6,6-四甲基哌啶(498.33mg,3.53mmol,598.95μL,1.2eq)溶于四氢呋喃(6mL)中,体系降温至-30℃,滴加正丁基锂(2.5M,1.4mL,1.19eq),反应在-30℃搅拌0.5小时。然后将反应降温至-78℃,滴加化合物1-n(787.81mg,2.94mmol,1eq)的四氢呋喃(6mL)溶液,在-78℃搅拌30min,然后滴加化合物1-m(0.5g,2.94mmol,467.29μL,1eq)的四氢呋喃(6mL)。反应缓慢升温至25℃,在25℃搅拌12小时。反应体系降温至0℃,滴加饱和氯化铵溶液(5mL),反应液在0℃搅拌1小时,反应液过滤后将滤液减压浓缩,加入水(20mL)和乙酸乙酯(20mL)萃取,有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到粗品。粗品用快速柱层析法(洗脱剂:乙酸乙酯/石油醚,梯度:0-20%)纯化。得到化合物1-o。
1H NMR(400MHz,CDCl
3)δ=5.08(s,1H),4.13(q,J=7.1Hz,2H),3.18-3.09(m,1H),2.49(tt,J=3.7,10.9Hz,1H),2.40-2.33(m,1H),2.20(dt,J=3.9,12.6Hz,1H),2.12-1.99(m,3H),1.72-1.58(m,2H),1.30-1.23(m, 15H).
步骤12:化合物1-p的合成
氮气保护下,将化合物1-l(100mg,199.30μmol,1eq),1-o(87.95mg,298.95μmol,1.5eq),碳酸钠(63.37mg,597.90μmol,3eq),二氧六环(3mL)和水(0.5mL)加到拇指瓶中,再加入四(三苯基膦)钯(23.03mg,19.93μmol,0.1eq)。反应在90℃搅拌3小时。反应液中加入水(10mL)和乙酸乙酯(10mL)萃取,有机相减压浓缩得到粗品。粗品用过柱机(洗脱剂:乙酸乙酯/石油醚:0-50%)纯化。得到化合物1-p。
MS m/z(ESI):589.0[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.71-7.61(m,2H),7.57(s,1H),6.37(s,1H),5.04-4.98(m,1H),4.48(dd,J=3.3,11.8Hz,1H),4.18-4.12(m,2H),2.99-2.92(m,1H),2.75(s,3H),2.60-2.20(m,6H),2.07(td,J=3.6,12.5Hz,2H),1.67-1.56(m,2H),1.27-1.24(m,3H).
步骤13:化合物1的合成
将化合物1-p(50mg,84.88μmol,1eq)溶于甲醇(1mL)中,加入氢氧化钠(10.18mg,254.64μmol,3eq)的水(1mL)溶液。反应在25℃搅拌1小时。反应液中加入2M稀盐酸调节pH=1~3,加入乙酸乙酯(20mL)萃取,有机相减压浓缩得到粗品。粗品经制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:40%-70%,7min)纯化,得到化合物1。
MS m/z(ESI):561.2[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.72-7.61(m,2H),7.59-7.56(m,1H),7.58(s,1H),6.38(s,1H),5.02(br dd,J=3.2,11.7Hz,1H),4.48(dd,J=3.1,11.8Hz,1H),2.97(br d,J=13.9Hz,1H),2.76(s,3H),2.64-2.55(m,1H),2.52-2.45(m,1H),2.43-2.29(m,3H),2.28-2.18(m,1H),2.14-2.06(m,2H),1.72-1.54(m,2H).
步骤14:化合物2,3,4和5的合成
将化合物1(90mg,160.42μmol,1eq)进行SFC(柱型:DAICEL CHIRALPAK AD(250mm*30mm,10μm);流动相:[0.1%NH
3H
2O IPA]:50%-50%)拆分得到化合物3和4的混合物、化合物2和化合物5。化合物3和4的混合物进行第二次SFC(柱型:DAICEL CHIRALPAK IG(250mm*30mm,10μm);流动相:[0.1%NH
3H
2O IPA]:60%-60%)分离得到化合物3和化合物4。
化合物2:MS m/z(ESI):560.9[M+1]
+.SFC分析方法(柱型:Chiralpak IG-3 50*4.6mmI.D.,3μm;流动相:异丙醇(0.05%二乙胺);流速:4mL/min),SFC保留时间:0.513分钟,ee%=100%。
1H NMR(400MHz,CD
3OD)δ=7.59-7.50(m,2H),7.46(s,1H),6.26(s,1H),4.90(br dd,J=3.3,11.7Hz,1H),4.35(dd,J=3.3,11.8Hz,1H),2.85(br d,J=14.0Hz,1H),2.64(s,3H),2.46(br t,J=10.6Hz,1H),2.36(br d,J=13.4Hz,1H),2.31-2.17(m,3H),2.14-2.05(m,1H),2.01-1.93(m,2H),1.60-1.47(m,2H).
化合物3:MS m/z(ESI):560.9[M+1]
+.SFC保留时间:0.861分钟,ee%=100%。
1H NMR(400MHz,CD
3OD)δ=7.59-7.50(m,2H),7.46(s,1H),6.26(s,1H),4.90(dd,J=3.3,11.7Hz,1H),4.36(dd,J=3.3,11.8Hz,1H),2.85(br d,J=13.9Hz,1H),2.64(s,3H),2.50-2.42(m,1H),2.40-2.32(m,1H),2.29-2.16(m,3H),2.14-2.05(m,1H),2.02-1.94(m,2H),1.59-1.46(m,2H).
化合物4:MS m/z(ESI):561.0[M+1]
+.SFC保留时间:2.802分钟,ee%=100%。
1H NMR(400MHz,CD
3OD)δ=7.59-7.51(m,2H),7.46(s,1H),6.25(s,1H),4.90(dd,J=3.3,11.8Hz,1H),4.36(dd,J=3.1,11.7Hz,1H),2.86(br d,J=14.1Hz,1H),2.64(s,3H),2.47-2.41(m,1H),2.40-2.33(m,1H),2.29-2.17(m,3H),2.13-2.03(m,1H),2.00-1.93(m,2H),1.61-1.43(m,2H).
化合物5:MS m/z(ESI):560.9[M+1]
+.SFC保留时间:3.495分钟,ee%=100%。
1H NMR(400MHz,CD
3OD)δ=7.71-7.62(m,2H),7.58(s,1H),6.38(s,1H),5.02(dd,J=3.4,11.8Hz,1H),4.47(dd,J=3.2,11.7Hz,1H),2.97(br d,J=13.8Hz,1H),2.76(s,3H),2.62-2.54(m,1H),2.48(br d,J=13.5Hz,1H),2.43-2.29(m,3H),2.25-2.15(m,1H),2.13-2.05(m,2H),1.71-1.58(m,2H).
实施例2
合成路线:
步骤1:化合物6-b的合成
在氮气保护下将化合物1-l(50mg,99.65μmol,1eq)溶于N,N-二甲基甲酰胺(1.4mL)和三乙胺(1.4mL)中,再加入化合物6-a(86.79mg,498.25μmol,5eq)和二氯双(三苯基膦)钯(3.50mg,4.98μmol,0.05eq)和碘化亚铜(3.80mg,19.93μmol,0.2eq),将反应液升温至80℃搅拌反应12小时。向反应液中加入水(10mL)和乙酸乙酯(10mL×3)萃取,有机相依次用1M的稀盐酸(10mL×2)和饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至2/1)纯化,得到化合物6-b。
MS m/z(ESI):594.9[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=8.05(d,J=8.5Hz,2H),7.98(s,1H),7.70-7.62(m,4H),5.05(dd,J=3.1,11.9Hz,1H),4.48(dd,J=3.0,12.1Hz,1H),4.39(d,J=7.1Hz,2H),2.75(s,3H),2.45(td,J=3.2,14.3Hz,1H),2.36-2.27(m,1H),1.42-1.38(m,3H).
步骤2:化合物6的合成
将化合物6-b(40mg,67.22μmol,1eq)溶于甲醇(1mL)和水(1mL)中,再加入氢氧化钠(13.44mg,336.11μmol,5eq),于25℃搅拌反应2小时。向反应液中加入水(10mL),用1M稀盐酸调pH=1-2,再用乙酸乙酯(10mL×3)萃取。合并有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75×30mm×3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:45%-75%,7min)纯化,得到化合物6。
MS m/z(ESI):567.1[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=8.04(d,J=8.5Hz,2H),7.97(s,1H),7.70-7.60(m,4H),5.04(dd,J=3.0,12.0Hz,1H),4.48(dd,J=3.0,12.0Hz,1H),2.74(s,3H),2.48-2.24(m,2H).
实施例3
合成路线:
步骤1:化合物7-c的合成:
化合物1-l(9.3g,18.54mmol,1eq)通过SFC(柱型:REGIS(s,s)WHELK-O1(250mm*50mm,10μm);流动相:[0.1%NH
3H
2O,EtOH]%:25%-25%)分离,收集第二峰得到化合物7-c。
MS m/z(ESI):500.8[M+1]
+.SFC分析方法(柱型:(S,S)-Whelk-O1 100*4.6mm I.D.,3μm;流动相:乙醇(0.05%二乙胺);流速:2.8mL/min);保留时间:2.990分钟;ee%=100%。
步骤2:化合物7-a的合成
向反应瓶中加入化合物1-m(2g,11.75mmol,1.87mL,1eq),三溴氟甲烷(3.82g,14.10mmol,1.2eq),三苯基膦(3.70g,14.10mmol,1.2eq)和四氢呋喃(60mL)。在20℃下滴加二乙基锌(1M,14.10mL,1.2eq)。该反应液在20℃搅拌1小时。向反应液中加入甲醇(50mL),搅拌20分钟后减压浓缩。残余物通过自动过柱机COMBI-FLASH分离(洗脱液:石油醚∶乙酸乙酯=100∶0至10∶1),得到化合物7-a。
1H NMR(400MHz,CDCl
3)δ=4.08-4.02(m,2H),2.72-2.68(m,1H),2.39-2.34(m,2H),1.95-1.81(m,4H),1.52-1.49(m,2H),1.21-1.18(m,3H).
步骤3:化合物7-b的合成
将化合物7-a(2.3g,8.68mmol,1eq)溶于1,4-二氧六环(30mL)中,然后加入频哪醇硼酸酯(4.41g,17.35mmol,2eq),乙酸钾(2.55g,26.03mmol,3eq)和Pd(dppf)Cl
2·CH
2Cl
2(708.46mg,867.54μmol,0.1eq)。氮气置换三次后加热至90℃搅拌16小时。向反应液中加入水(50mL),用乙酸乙酯(30mL×2)萃取,合并有机相用饱和氯化钠水溶液(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩。残余物通过自动过柱机COMBI-FLASH分离(洗脱剂:石油醚∶乙酸乙酯=100∶0至10∶1),得到化合物7-b。
1H NMR(400MHz,CDCl
3)δ=4.08-4.02(m,2H),2.92-2.88(m,2H),2.43-2.37(m,1H),1.97-1.92(m,2H),1.97-1.92(m,2H),1.52-1.49(m,2H),1.21-1.18(m,15H).
步骤4:化合物7-d的合成
氮气保护下,在拇指瓶中加入化合物7-c(150.00mg,298.95μmol,1eq),7-b(466.64mg,1.49mmol,5eq),碳酸钠(158.43mg,1.49mmol,5eq),1,4-二氧六环(8mL)和水(1.5mL),然后加入Pd(PPh
3)
4(34.55mg,29.90μmol,0.1eq)。混合物在100℃下搅拌16小时。待反应降至25℃左右,向反应液中加入水(10mL),用1M稀盐酸调pH=1~2,用乙酸乙酯(15mL×3)萃取。合并的有机相用饱和食盐水(30mL)洗涤,减压浓缩。残余物通过自动过柱机COMBI-FLASH(梯度淋洗:石油醚∶乙酸乙酯=100∶0至70∶30)分离,得到化合物7-d。
MS m/z(ESI):607.0[M+1]
+.
1H NMR(400MHz,DMSO-d
6)δ=7.97-7.90(m,2H),7.73(q,J=5.5Hz,2H),4.97(br t,J=9.8Hz,1H),4.43(dd,J=2.5,12.0Hz,1H),4.10-4.06(m,2H),2.78(br d,J=14.1Hz,1H),2.63(s,3H),2.57(td,J=3.8,10.4Hz,1H),2.42-2.35(m,1H),2.24-2.14(m,2H),2.13-2.05(m,1H),1.87-1.77(m,1H),1.76-1.66(m,1H),1.64-1.57(m,1H),1.56-1.43(m,3H),1.39-1.27(m,1H),1.21-1.18(m,3H).
步骤5:化合物7的合成
在拇指瓶中加入化合物7-d(100mg,164.73μmol,1eq)和四氢呋喃(0.5mL),然后加入氢氧化钠水溶液(2M,0.5mL,6.07eq)。混合物在25℃下搅拌1小时。向反应液中加入水(5mL),用1M稀盐酸调pH=1~2,用乙酸乙酯(15mL×3)萃取。合并的有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。 残余物通过制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:40%-70%,7min)分离,得到化合物7。
MS m/z(ESI):579.0[M+1]
+.
1H NMR(400MHz,DMSO-d
6)δ=7.99-7.88(m,2H),7.78-7.68(m,2H),4.98(br t,J=9.6Hz,1H),4.43(dd,J=2.5,12.0Hz,1H),2.77(br d,J=13.8Hz,1H),2.63(s,3H),2.55(br s,1H),2.49-2.45(m,1H),2.43-2.35(m,1H),2.24-2.11(m,2H),2.08-2.04(m,1H),1.98(br dd,J=4.1,8.1Hz,2H),1.49(q,J=11.6Hz,2H).
实施例4
合成路线:
步骤1:化合物8-c的合成
将化合物8-a(500mg,2.97mmol,1eq)溶于四氢呋喃(15mL)中,将反应液降温到-78℃后,再缓慢地滴加LiHMDS(1M,2.97mL,1eq),反应在-78℃下搅拌反应0.5小时后再向反应液中缓慢地滴加化合物8-b(1.06g,2.97mmol,1eq)的四氢呋喃(15mL)溶液,反应在-78℃下搅拌反应0.5小时后再升温至25℃搅拌反应1小时。向反应液中缓慢加入水(20mL),再加入乙酸乙酯(20mL×3)萃取,合并有机相用饱和食盐水(10mL×3)洗涤后,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至10/1)纯化,得到化合物8-c。
1H NMR(400MHz,CDCl
3)δ=5.62-5.39(m,1H),3.71(d,J=3.5Hz,3H),3.16-3.02(m,1H),2.92(d,J=16.6Hz,2H),2.62-2.50(m,2H),2.48-2.38(m,2H).
步骤2:化合物8-d的合成
在氮气保护下将化合物8-c(400mg,1.33mmol,1eq),双联频哪醇硼酸酯(405.96mg,1.60mmol,1.2eq),醋酸钾(392.24mg,4.00mmol,3eq)和1,1-双(二苯基膦)二茂铁氯化钯(97.48mg,133.22μmol,0.1eq)溶于1,4-二氧六环(7mL)中,反应体系用氮气置换三次后再升温至90℃搅拌反应3小时。将反应液直接减压浓缩,粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至10/1)纯化,得到化合物8-d。
1H NMR(400MHz,CDCl
3)δ=7.12-6.70(m,1H),3.68(s,3H),3.10-2.99(m,1H),2.68-2.53(m,2H),2.53-2.32(m,4H),1.27(s,12H).
步骤3:化合物8-e的合成
在氮气保护下,将化合物7-c(100mg,199.30μmol,1eq),化合物8-d(166.31mg,597.90μmol,3eq),磷酸钾(126.91mg,597.90μmol,3eq)和1,1-双(二苯基膦)二茂铁氯化钯(14.58mg,19.93μmol,0.1eq)溶于1,4-二氧六环(1.4mL)和水(0.4mL)中,将反应体系用氮气置换三次后再升温至80℃搅拌反应3小时。将反应液直接减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至2/1)纯化,得到化合物8-e。
MS m/z(ESI):573.2[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.70-7.60(m,5H),6.43-6.22(m,1H),5.01-4.97(m,1H),4.47-4.44(m,1H),3.68(s,3H),2.79(s,1H),2.73(s,3H),2.49-2.44(m,3H),2.42-2.36(m,2H),2.28(br d,J=14.3Hz,2H).
步骤4:化合物8-f的合成
将化合物8-e(50.00mg,87.26μmol,1eq)溶于甲醇(3mL)中,将反应体系用氮气置换三次后,加入湿钯碳(92.86mg,87.26μmol,10%纯度,1eq),再用氢气置换三次后,反应液在25℃,氢气氛围下(15Psi)搅拌反应3小时。将反应液用硅藻土过滤,减压浓缩得到化合物8-f。
MS m/z(ESI):575.2[M+1]
+.
步骤5:化合物8的合成
将化合物8-f(15.00mg,26.08μmol,1eq)溶于甲醇(1mL)和水(1mL)中,再加入氢氧化钠(5.22mg,130.42μmol,5eq),于25℃搅拌反应2小时。向反应液中加入水(10mL),用1M稀盐酸调pH=1-2,再用乙酸乙酯(10mL×3)萃取。合并有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:40%-70%,7min)纯化,得到化合物8。
MS m/z(ESI):561.2[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.70-7.58(m,2H),7.44(s,1H),4.94(br d,J=3.3Hz,1H),4.51-4.39(m,1H),3.02(quin,J=8.3Hz,1H),2.73(s,3H),2.66-2.58(m,1H),2.52-2.09(m,10H).
实施例5
合成路线:
步骤1:化合物9-b的合成
将2,2,6,6-四甲基哌啶(2.38g,16.88mmol,2.87mL,1.2eq)溶于四氢呋喃(24mL)中,体系降温至-30℃,加入正丁基锂(2.5M,6.70mL,1.19eq)。反应在-30℃搅拌0.5小时,反应降温至-78℃,加入化合物1-n(3.77g,14.07mmol,1eq)的四氢呋喃(24mL)溶液,在-78℃搅拌30分钟,加入化合物9-a(2g,14.07mmol,1.87mL,1eq)的四氢呋喃(24mL)。反应缓慢升温至25℃,在25℃搅拌12小时。体系降温至0℃,逐滴加入饱和氯化铵溶液(20mL),反应液在0℃搅拌1小时,反应液过滤后将滤液减压浓缩,加入水(20mL),乙酸乙酯(20mL×2)萃取,有机相用饱和食盐水(20mL)洗涤后减压浓缩。粗品用快速柱层析法(石油醚/乙酸乙酯=100∶0-90∶10)纯化,得到化合物9-b。
1H NMR(400MHz,CDCl
3)δ=5.25-5.15(m,1H),4.27-4.08(m,2H),3.23-3.08(m,4H),3.00-2.93(m,1H),1.30-1.28(m,3H),1.25(d,J=1.5Hz,12H).
步骤2:化合物9-c的合成
氮气保护下,将化合物7-c(100.00mg,199.30μmol,1eq)和化合物9-b(159.13mg,597.90μmol,3eq),碳酸钠(63.37mg,597.90μmol,3eq),1,4-二氧六环(2mL)和水(0.3mL)加到拇指瓶中,再加入四(三苯基膦)钯(23.03mg,19.93μmol,0.1eq)。反应在90℃搅拌12小时。反应液减压浓缩得到粗品。粗品用快速柱层析法(石油醚/乙酸乙酯=100∶0-50∶50)纯化,得到化合物9-c。
MS m/z(ESI):561.0[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.71-7.62(m,2H),7.55(s,1H),6.47(br s,1H),5.01(br d,J=9.3Hz,1H),4.47(dd,J=3.0,11.8Hz,1H),4.19(q,J=7.1Hz,2H),3.33(s,1H),3.22-3.10(m,4H),2.75(s,3H),2.43-2.30(m,2H),1.29(t,J=7.0Hz,3H).
步骤3:化合物9的合成
将化合物9-c(25.00mg,44.56μmol,1eq)溶于甲醇(2mL)中,加入氢氧化钠(5.35mg,133.68μmol,3eq)的水(2mL)溶液。反应在25℃搅拌30分钟。反应液中加入2M稀盐酸调节pH=2~3,加入乙酸乙酯(10mL×3)萃取,有机相减压浓缩得到粗品。粗品经制备型高效液相色谱法(柱型:Welch Xtimate C18 100*40mm*3μm;流动相:[水(0.075%三氟乙酸)-乙腈];乙腈%:45%-75%,8min)纯化,得到化合物9。
MS m/z(ESI):533.1[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.72-7.62(m,2H),7.56(s,1H),6.49(t,J=2.3Hz,1H),5.01(br d,J=9.3Hz,1H),4.47(dd,J=3.4,11.9Hz,1H),3.30(s,1H),3.20(br s,2H),3.14(br d,J=8.5Hz,2H),2.75(s,3H),2.44-2.25(m,2H).
实施例6
合成方法:
步骤1:化合物10-b的合成
在氮气保护下将2,2,6,6-四甲基哌啶(9.20g,65.14mmol,11.06mL,1.2eq)溶于四氢呋喃(120mL)中,反应体系降温至-30℃后缓慢滴加正丁基锂(2.5M,26.05mL,1.2eq),反应液在-30℃搅拌反应0.5小时后再 降温至-78℃,缓慢滴加化合物1-n(14.54g,54.28mmol,1eq)的四氢呋喃(120mL)溶液,反应液在-78℃搅拌反应0.5小时,再加入化合物10-a(10g,54.28mmol,1eq)的四氢呋喃(120mL)的溶液,反应液升温至25℃搅拌反应12小时。反应结束后,将反应液降温至0℃,再慢慢滴加饱和氯化铵溶液(100mL),反应液在0℃搅拌10分钟。将反应液过滤后旋干,加入水(60mL),用乙酸乙酯(60mL×3)萃取,有机相用饱和食盐水(60mL×3)洗涤后,无水硫酸钠干燥,过滤。滤液减压浓缩得到粗品。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至10/1)纯化,得到化合物10-b。
1H NMR(400MHz,CDCl
3)δ=5.05(s,1H),4.18-4.08(m,2H),3.14(br dd,J=1.4,13.4Hz,1H),2.34-2.18(m,4H),2.05-1.95(m,2H),1.91-1.82(m,2H),1.28-1.24(m,15H),1.20-1.09(m,2H).
步骤2:化合物10-d和化合物10-e的合成
在氮气保护下将化合物7-c(200mg,398.60μmol,1eq),化合物10-b(614.29mg,1.99mmol,5eq)和N,N-二异丙基乙胺(154.55mg,1.20mmol,208.29μL,3eq)溶于1,4-二氧六环(1.5mL)和水(1.5mL)中,再加入二氯双(三苯基膦)钯(27.98mg,39.86μmol,0.1eq),反应液升温至100℃搅拌反应12小时。将反应液直接减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至2/1)纯化,得到化合物10-c。再经SFC(柱型:DAICEL CHIRALPAK IG(250mm*30mm,10μm);流动相:[0.1%NH
3H
2O,EtOH]%:60%-60%)纯化,得到化合物10-d和化合物10-e。
化合物10-c:MS m/z(ESI):603.1[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.71-7.59(m,2H),7.54(s,1H),6.33(s,1H),4.99(dd,J=3.5,11.5Hz,1H),4.46(dd,J=3.4,11.7Hz,1H),4.14-4.11(m,2H),2.99(br d,J=13.8Hz,1H),2.74(s,3H),2.44-2.24(m,6H),2.15-2.02(m,2H),1.93(br d,J=12.8Hz,2H),1.25(d,J=1.0Hz,3H),1.17-1.08(m,2H).
SFC分析方法:柱型:Chiralpak IG-3 50*4.6mm I.D.,3μm;流动相:乙醇(0.05%二乙胺);流速:4mL/min。
化合物10-d:MS m/z(ESI):603.1[M+1]
+,SFC保留时间:1.982分钟;ee%=100%。
化合物10-e:MS m/z(ESI):603.1[M+1]
+,SFC保留时间:4.655分钟;ee%=99.5%。
步骤3:化合物10的合成
在茄形瓶内加入化合物10-c(70mg,116.07μmol,1eq),氢氧化钠(2M,290.17μL,5eq)和四氢呋喃(3mL)和水(1mL),然后将反应液在20℃搅拌2小时。向反应液中加入水(10mL),用1M稀盐酸调pH=1-2,再用乙酸乙酯(10mL×3)萃取。合并有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:25%-95%,7min)纯化,得到化合物10。
MS m/z(ESI):575.1[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.78-7.48(m,3H),6.34(br s,1H),5.01(br d,J=9.5Hz,1H),4.47(br d, J=9.0Hz,1H),3.01(br d,J=14.1Hz,1H),2.75(s,3H),2.51-1.84(m,10H),1.42-1.05(m,2H).
步骤4:化合物11的合成
将化合物10-d(260mg,431.11μmol,1eq)溶于甲醇(2mL)和水(2mL)中,再加入氢氧化钠(86.21mg,2.16mmol,5eq),于25℃搅拌反应2小时。向反应液中加入水(10mL),用1M稀盐酸调pH=1-2,再用乙酸乙酯(10mL×3)萃取。合并有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:40%-70%,7min)纯化,得到化合物11。
MS m/z(ESI):575.1[M+1]
+.
SFC分析方法(柱型:ChiralPak AS-3 150×4.6mm I.D.,3μm;流动相:异丙醇(0.05%二乙胺);流速:2.5mL/min);SFC保留时间:5.559分钟;ee%=100%.
1H NMR(400MHz,CD
3OD)δ=7.70-7.60(m,2H),7.54(s,1H),6.33(s,1H),4.99(br dd,J=3.3,11.8Hz,1H),4.46(dd,J=3.3,11.8Hz,1H),3.00(br d,J=13.8Hz,1H),2.74(s,3H),2.46-2.28(m,4H),2.22(d,J=7.0Hz,2H),2.15-2.00(m,2H),1.96(br d,J=12.8Hz,2H),1.24-1.08(m,2H).
步骤5:化合物12的合成
将化合物10-e(210.00mg,348.20μmol,1eq)溶于甲醇(2mL)和水(2mL)中,再加入氢氧化钠(69.64mg,1.74mmol,5eq),于25℃搅拌反应2小时。向反应液中加入水(10mL),用1M稀盐酸调pH=1-2,再用乙酸乙酯(10mL×3)萃取。合并有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:40%-70%,7min)纯化,得到化合物12。
MS m/z(ESI):575.1[M+1]
+,SFC保留时间:5.847分钟;ee%=98.5%.
1H NMR(400MHz,CD
3OD)δ=7.70-7.60(m,2H),7.54(s,1H),6.33(s,1H),4.99(br dd,J=3.3,11.8Hz,1H),4.46(dd,J=3.3,11.8Hz,1H),3.00(br d,J=13.8Hz,1H),2.74(s,3H),2.46-2.28(m,4H),2.22(d,J=7.0Hz,2H),2.15-2.00(m,2H),1.96(br d,J=12.8Hz,2H),1.24-1.08(m,2H).
实施例7
合成路线:
步骤1:化合物13-a的合成
将2,2,6,6-四甲基哌啶(2.90g,20.53mmol,3.48mL,1.1eq)加入四氢呋喃(50mL)中,降温至-78℃,滴加正丁基锂(2.5M,9.70mL,1.3eq),反应在-78℃搅拌30分钟,将温度升至0℃,滴加化合物1-n的四氢呋喃(15mL)溶液,反应在0℃搅拌30分钟,滴加碘甲烷(3.97g,27.99mmol,1.74mL,1.5eq)的四氢呋喃(15mL)溶液。反应在0℃搅拌10分钟,升温至25℃搅拌12小时。体系降温至0℃,向反应液中加入饱和氯化铵溶液(30mL),搅拌20分钟,用乙酸乙酯(20mL×2)萃取。合并的有机相减压浓缩得到粗品。粗品用过柱机(洗脱剂:石油醚/乙酸乙酯,梯度:0-10%)纯化,得到化合物13-a。
1H NMR(400MHz,CDCl
3)δ=1.23(s,24H),1.07(s,3H),0.90-0.84(m,1H).
步骤2:化合物13-b的合成
将2,2,6,6-四甲基哌啶(2.49g,17.63mmol,2.99mL,1.2eq)溶于四氢呋喃(30mL)中,体系降温至-30℃,滴加正丁基锂(2.5M,6.99mL,1.19eq)。反应在-30℃搅拌0.5小时,反应降温至-78℃,滴加化合物13-a(4.14g,14.69mmol,1eq)的四氢呋喃(30mL)溶液,在-78℃搅拌30分钟,滴加化合物1-m(2.5g,14.69mmol,2.34mL,1eq)的四氢呋喃(30mL)。反应缓慢升温至25℃,在25℃搅拌12小时。体系降温至0℃,滴加饱和氯化铵溶液(30mL),反应液在0℃搅拌20分钟,反应液过滤后将滤液减压浓缩。加入水(20mL)和乙酸乙酯(20mL)萃取。合并的有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥后减压浓缩。粗品用过柱机(洗脱剂:石油醚/乙酸乙酯,梯度:0-10%)纯化,得到化合物13-b。
MS m/z(ESI):309.0[M+1]
+.
1H NMR(400MHz,CDCl
3)δ=4.13(q,J=7.1Hz,2H),3.04(br d,J=13.6Hz,1H),2.74(br d,J=13.8Hz,1H),2.56-2.45(m,1H),2.10-1.96(m,3H),1.90-1.81(m,1H),1.70(s,3H),1.62-1.55(m,2H),1.28(s,12H),1.26(br s,3H).
步骤3:化合物13-c的合成
将化合物13-b(100mg,199.30μmol,1eq)和化合物7-c(307.14mg,996.51μmol,5eq)溶于1,4-二氧六环(3mL)中,加入水(0.6mL)和碳酸钠(105.62mg,996.51μ,mol,5eq),氮气置换后加入1,1-双(二苯基膦)二茂铁氯化钯(29.17mg,39.86μmol,0.2eq)。反应在100℃搅拌12小时。反应液减压浓缩得到粗品。粗品用过柱机(洗脱剂:石油醚/乙酸乙酯,梯度:0-40%)纯化,得到化合物13-c。
MS m/z(ESI):603.0[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.73-7.62(m,2H),7.43(s,1H),5.02(dd,J=3.5,11.8Hz,1H),4.48(dd,J=3.3,11.8Hz,1H),4.18-4.11(m,2H),2.86-2.79(m,1H),2.76(s,3H),2.64-2.55(m,2H),2.44-2.28(m,2H),2.16-2.07(m,2H),2.04(s,3H),2.02-1.90(m,2H),1.69-1.60(m,1H),1.56-1.46(m,1H),1.28-1.25(m,3H).
步骤4:化合物13的合成
将化合物13-c(30mg,49.74μmol,1eq)溶于甲醇(2mL)中,加入氢氧化钠(1.99mg,49.74μmol,1eq)的水(2mL)溶液。反应在25℃搅拌0.5小时。反应液中加入2M稀盐酸调节pH=2~3,加入乙酸乙酯(10mL×3)萃取。合并的有机相减压浓缩。粗品经制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:45%-75%,7min)纯化,得到化合物13。
MS m/z(ESI):575.0[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.73-7.60(m,2H),7.43(s,1H),5.02(dd,J=3.4,11.8Hz,1H),4.48(dd,J=3.2,11.8Hz,1H),2.83(br d,J=14.5Hz,1H),2.76(s,3H),2.67-2.51(m,2H),2.44-2.27(m,2H),2.16-2.07(m,2H),2.05(s,3H),1.98(br t,J=11.4Hz,2H),1.68-1.46(m,2H).
实施例8
合成路线:
步骤1:化合物14-a的合成
将甲基三苯基溴化磷(23.09g,64.63mmol,1.1eq)溶于四氢呋喃(160mL)中,将反应液降温至-5℃后,在氮气氛围下缓慢地滴加丁基锂(2.5M,25.85mL,1.1eq),然后反应液在0℃搅拌反应1小时后,再缓慢地滴加化合物1-m(10g,58.75mmol,9.35mL,1eq),反应液在25℃搅拌反应12小时。反应完毕后将反应液降温至0℃,再向反应液中缓慢加入饱和氯化铵溶液(100mL),搅拌10分钟后再加入乙酸乙酯(200mL×3)萃取,有机相用饱和食盐水(100mL×3)洗涤后,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至20/1)纯化,得到化合物14-a。
1H NMR(400MHz,CDCl
3)δ=4.65(s,2H),4.13(q,J=7.1Hz,2H),2.51-2.25(m,3H),2.14-1.94(m,4H),1.65-1.54(m,2H),1.32-1.19(m,3H).
步骤2:化合物14-b的合成
将化合物14-a(3g,17.83mmol,1eq)溶于四氢呋喃(150mL)中,再加入锌-铜(20.69g,160.49mmol,9eq),再缓慢地滴加三氯乙酰氯(16.21g,89.16mmol,9.95mL,5eq),反应液在25℃下搅拌反应12小时。将反应液缓慢倒入到冰水中,再加入乙酸乙酯(200mL×3)萃取,合并有机相用饱和食盐水(100mL×3)洗涤后,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至10/1)纯化,得到化合物14-b。
1H NMR(400MHz,CDCl
3)δ=4.16(dd,J=7.2,13.4Hz,2H),3.04(d,J=14.3Hz,2H),2.57-2.46(m,1H),2.39-2.26(m,1H),2.19-2.07(m,3H),1.92(br d,J=13.3Hz,1H),1.81-1.61(m,3H),1.28(d,J=7.0Hz,3H).步骤3:化合物14-c的合成
将化合物14-b(2.3g,8.24mmol,1eq)溶于冰醋酸(20mL)中,加入锌粉(2.16g,32.96mmol,4eq)。该反应在50℃搅拌2小时。反应液过滤,滤饼用4M稀盐酸淬灭,用饱和氢氧化钠水溶液调pH至中性。滤液倒入到水(50mL)中,用乙酸乙酯(30mL×2)萃取,合并有机相拥饱和氯化钠水溶液(50mL×1)洗涤,无水硫酸钠 干燥,过滤旋蒸。残余物通过自动过柱机COMBI-FLASH分离(洗脱剂:石油醚∶乙酸乙酯=100∶0至10∶1)纯化,得到化合物14-c。
1H NMR(400MHz,CDCl
3)δ=4.16-1.33(m,2H),2.77-2.76(d,J=8.0Hz,,4H),2.37-2.31(m,1H),1.97-1.93(m,2H),1.81-1.77(m,2H),1.65-1.55(m,4H),1.26(t,J=7.2Hz,3H).
步骤4:化合物14-d的合成
将化合物14-c(300mg,1.43mmol,1eq)溶于四氢呋喃(10mL)中,在-78℃下滴加二(三甲基硅)氨基锂(1.0M,1.57mL,1.1eq)。滴加完毕,在-78℃搅拌0.5小时,然后滴加N-苯基双(三氟甲烷磺酰)亚胺(560.67mg,1.57mmol,1.1eq)和四氢呋喃(10mL)的混合液。该反应在-78℃搅拌0.5小时后升温至-78℃搅拌1小时。向反应液中加入水(10mL),用乙酸乙酯(10mL×2)萃取,合并有机相用饱和氯化钠水溶液(20mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩。残余物通过自动过柱机COMBI-FLASH分离(洗脱剂:石油醚∶乙酸乙酯=100∶0至10∶1)纯化,得到化合物14-d。
1H NMR(400MHz,CDCl
3)δ=5.69(s,0.5H),5.42(s,0.5H),4.09-4.03(m,2H),2.51-2.50(m,,2H),2.26-2.19(m,1H),1.89-1.86(m,2H),1.59-1.51(m,6H),1.18(t,J=6.0Hz,,3H),0.81-0.79((m,1H).
步骤5:化合物14-e的合成
将化合物14-d(400mg,1.17mmol,1eq),双联嚬哪醇硼酸酯(356.06mg,1.40mmol,1.2eq),乙酸钾(344.03mg,3.51mmol,3eq)和[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(95.42mg,116.85μmol,0.1eq)加入到1,4-二氧六环(7mL)中。该混合物用氮气置换三次后升温至-78℃搅拌3小时。向反应液中加入水(10mL),用乙酸乙酯(10mL)萃取,合并有机相用饱和氯化钠水溶液(10mL×1)洗涤,无水硫酸钠干燥,过滤旋蒸。残余物通过自动过柱机COMBI-FLASH分离(洗脱剂:石油醚∶乙酸乙酯=100∶0至10∶1)纯化,得到化合物14-e。
1H NMR(400MHz,CDCl
3)δ=7.15(s,0.5H),6.86(s,0.5H),4.08-4.02(m,2H),2.21(d,J=6.0Hz,,2H),1.82-1.79(m,3H),1.69-1.56(m,2H),1.49-1.39(m,4H),1.23-1.18(m,15H).
步骤6:化合物14-f的合成
将化合物1-l(100mg,199.30μmol,1eq),化合物14-e(191.47mg,597.90μmol,3eq),磷酸钾(126.91mg,597.90μmol,3eq)和[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(16.28mg,19.93μmol,0.1eq)加入到1,4-二氧六环(1.4mL)和水(0.4mL)的混合液中。该反应升温至80℃搅拌3小时。将反应液倒入水(10mL)中,用乙酸乙酯(10mL×3)萃取,合并有机相用饱和氯化钠水溶液(10mL)洗涤,无水硫酸钠干燥过滤旋蒸。残余物通过自动过柱机COMBI-FLASH分离(洗脱剂:石油醚∶乙酸乙酯=100∶0至2∶1)纯化得到化合物14-f。
MS m/z(ESI):615.2[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.64-7.61(m,3H),6.63(s,0.5H),6.33(s,0.5H),5.03(dd,J=3.2Hz,1H),4.49 (dd,J=3.2Hz,1H),4.16-4.11(m,2H),2.75(s,3H),2.53(d,J=3.2Hz,1H),2.39-2.32(m,3H),1.70-1.69(m,2H),1.69-1.49(m,7H),1.29-1.25(m,3H).
步骤7:化合物14-g的合成
将化合物14-f(90mg,146.32μmol,1eq)溶于甲醇(3mL)中,氮气置换三次加入湿钯碳(90mg,146.32μmol,10%纯度,1.00eq)。再用氢气置换三次,该反应在20℃,氢气(15Psi)下搅拌12小时。反应液直接过滤,滤液减压浓缩干燥得到化合物14-g。
MS m/z(ESI):617.2[M+1]
+.
步骤8:化合物14的合成
将化合物14-g(30mg,48.61μmol,1eq)溶于四氢呋喃(2mL)中,加入氢氧化钠(9.72mg,243.06μmol,5eq)和水(1mL)的混合液。该反应在20℃搅拌1小时。反应液直接蒸出有机溶剂,用4N盐酸水溶液调pH=3-4,二氯甲烷(10mL×2)萃取,合并有机相用减压浓缩干燥。粗品通过制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:45%-75%,7min)分离,得到化合物14。
MS m/z(ESI):589.2[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.68-7.63(m,3H),7.62-7.47(m,1H),4.97-4.96(m,1H),4.47(dd,J=3.2Hz,1H),3.79-3.70(m,1H),2.75(s,3H),2.47-2.37(m,1H),2.32-2.29(m,1H),2.25-2.06(m,3H),1.93-1.89(m,4H),1.69-1.51(m,2H),1.49-1.44(m,4H).
实施例9
合成路线:
步骤1:化合物15-a的合成
将化合物1-h(152g,431.59mmol,1eq)加到乙醇(1520mL)中,反应液降温至0℃,缓慢加入硼氢化钠(24.49g,647.39mmol,1.5eq),然后反应液在25℃搅拌0.5小时。反应液缓慢用饱和氯化铵水溶液(500mL)淬灭,用0.5M稀盐酸调至pH为中性。减压浓缩除去大部分乙醇,再加入500mL水,用0.5M稀盐酸调pH=4~6,用乙酸乙酯(1000mL×2)萃取。合并的有机相依次用水(1000mL)和饱和食盐水(1000mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗品用500mL甲基叔丁醚室温打浆1小时,过滤,收集滤饼,减压干燥,得到化合物15-a。
MS m/z(ESI):355.8[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.98-7.54(m,1H),4.99(dd,J=3.0,12.0Hz,1H),4.41(dd,J=2.9,12.4Hz,1H),2.81-2.71(m,3H),2.57-2.44(m,1H),2.27-2.12(m,1H),2.27-2.12(m,1H)。
步骤2:化合物15-b的合成
在氮气保护下,将化合物15-a(2g,5.61mmol,1eq),化合物1-o(8.26g,28.07mmol,5eq),N,N-二异丙基乙胺(3.63g,28.07mmol,4.89mL,5eq)和二氯双(三苯基膦)钯(394.08mg,561.46μmol,0.1eq)溶于1,4-二氧六环(20mL)和水(20mL)中,升温至80℃搅拌12小时。向反应液中加入1M稀盐酸调节pH=1~2,再加入水(50mL),用乙酸乙酯(50mL×3)萃取,合并的有机相用饱和食盐水(50mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品通过快速柱层析法(二氯甲烷/甲醇=1/0至5/1)纯化,得到化合物15-b。
MS m/z(ESI):444.0[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.57(dd,J=3.3,7.5Hz,1H),6.36(s,1H),4.98-4.93(m,1H),4.27(dd,J=2.9,12.4Hz,1H),4.14-4.07(m,1H),2.94(br d,J=14.3Hz,1H),2.75(s,3H),2.60(tt,J=4.0,10.7Hz,1H),2.50-2.41(m,2H),2.31(dt,J=3.9,12.7Hz,2H),2.23-2.14(m,2H),2.10-2.03(m,2H),1.68-1.54(m,2H),1.27-1.23(m,3H).
步骤3:化合物15-d的合成
将化合物15-b(0.1g,225.46μmol,1eq)和化合物15-c(70.34mg,338.19μmol,1.5eq)溶于二氯甲烷(5mL)中,体系降温至0℃,加入三正丙基环磷酸酐(215.21mg,338.19μmol,201.13μL,浓度:50%,1.5eq)和N,N-二异丙基乙胺(87.42mg,676.38μmol,117.81μL,3eq)。反应在25℃搅拌16小时。反应液减压浓缩,粗品用过柱机(洗脱剂:石油醚/乙酸乙酯,梯度:0-50%)纯化。得到化合物15-d。
MS m/z(ESI):632.7[M+1]
+.
步骤4:化合物15的合成
将化合物15-d(50mg,78.92μmol,1eq)溶于甲醇(2mL)中,加入氢氧化钠(9.47mg,236.77μmol,3eq)的水(2mL)溶液,反应在25℃搅拌30分钟。反应液中加入2M稀盐酸调节pH=3~4,加入乙酸乙酯(10mL×3)萃取。合并的有机相减压浓缩。粗品经制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:40%-70%,7min)纯化,得到化合物15。
MS m/z(ESI):605.1[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.78-7.68(m,2H),7.58(s,1H),6.38(s,1H),5.04-4.98(m,1H),4.47(dd,J=3.0,11.8Hz,1H),2.97(br d,J=14.1Hz,1H),2.76(s,3H),2.59(br s,1H),2.51-2.29(m,4H),2.28-2.19(m,1H),2.09(br d,J=12.0Hz,2H),1.71-1.55(m,2H).
实施例10
合成路线:
步骤1:化合物16-b的合成
将化合物15-b(100mg,225.46μmol,1eq),化合物16-a(49.75mg,338.19μmol,1.5eq)溶于二氯甲烷(5mL)中,将反应液降温至0℃后再加入三正丙基环磷酸酐(215.21mg,338.19μmol,201.13μL,浓度:50%,1.5eq)和N,N-二异丙基乙胺(87.42mg,676.38μmol,117.81μL,3eq),反应液升温至25℃搅拌反应12小时。将反应液直接减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至2/1)纯化,得到化合物16-b。
MS m/z(ESI):573.2[M+1]
+.
步骤2:化合物16的合成
将化合物16-b(50mg,87.32μmol,1eq)溶于甲醇(1mL)和水(1mL)中,再加入氢氧化钠(17.46mg,436.59μmol,5eq),反应于25℃搅拌反应2小时。向反应液中加入水(10mL),用1M稀盐酸调pH=1-2,再用乙酸乙酯(10mL×3)萃取。合并的有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75×30mm×3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:35%-65%,7min)纯化得到化合物16。
MS m/z(ESI):544.5[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.60-7.42(m,3H),6.37(s,1H),5.00(br dd,J=3.3,11.8Hz,1H),4.45(br dd,J=3.3,11.8Hz,1H),2.95(br d,J=13.1Hz,1H),2.74(s,3H),2.57(brt,J=10.8Hz,1H),2.46(br d,J=13.3Hz,1H),2.41-2.26(m,3H),2.21(br t,J=11.4Hz,1H),2.07(br d,J=12.3Hz,2H),1.69-1.55(m,2H).
实施例11
合成路线:
步骤1:化合物17-b合成
在圆底瓶中,将化合物17-a(44.25mg,270.55μmol,1.2eq),15-b(100mg,225.46μmol,1eq),三正丙基环磷酸酐(215.21mg,338.19μmol,201.13μL,浓度:50%,1.5eq)和二异丙基乙基胺(87.42mg,676.38μmol,117.81μL,3eq)依次加入到二氯甲烷(5mL)中,反应液在氮气保护下25℃搅拌2小时。向反应液中加入水(50mL),用二氯甲烷(30mL×2)萃取,合并的有机相依次用水(30mL)和饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至10/3)纯化,得到化合物17-b。
MS m/z(ESI):589.1[M+1]
+.
步骤2:化合物17的合成
将化合物17-b(60mg,101.85μmol,1eq)和氢氧化钠(20.37mg,509.27μmol,5eq)加到甲醇(0.5mL)和水(0.5mL)中,反应液在25℃搅拌30分钟。反应液用4M稀盐酸将pH调至pH=4~5,加入水(30mL),乙酸 乙酯(30mL×2)萃取,合并的有机相依次用水(20mL)和饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗品经过制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:35%-65%,7min)纯化,得到化合物17。
MS m/z(ESI):561.1[M+1]
+.
1H NMR(400MHz,DMSO-d
6)δ=12.16(br s,1H),10.38(s,1H),7.91(br d,J=10.0Hz,1H),7.68-7.59(m,1H),7.68-7.59(m,1H),7.41-7.27(m,1H),6.41(s,1H),4.92(br t,J=10.0Hz,1H),4.46(br d,J=10.3Hz,1H),2.83(br d,J=14.1Hz,1H),2.67(s,3H),2.43-2.33(m,3H),2.31-2.21(m,1H),2.17(br d,J=12.8Hz,2H),1.98(br d,J=9.0Hz,2H),1.58-1.36(m,2H).
实施例12
合成路线:
步骤1:化合物18-b的合成
氮气保护下,在拇指瓶中加入化合物15-b(200mg,450.92μmol,1eq),化合物18-a(140.69mg,676.38μmol,1.5eq),二异丙基乙基胺(174.83mg,1.35mmol,235.62μL,3eq)和四氢呋喃(5mL),然后加入三正丙基环磷酸酐(573.90mg,901.84μmol,536.35μL,50%纯度,2eq)。混合物在50℃下搅拌12小时。反应液降至室温25℃,加入水(15mL),用稀盐酸(2M)调pH=1~2,用乙酸乙酯(20mL×3)萃取。合并的有机相用饱和食盐水(20mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩。残余物通过自动过柱机COMBI-FLASH(梯度淋洗:石油醚∶乙酸乙酯=100∶0至80∶20)分离,得到化合物18-b。
MS m/z(ESI):632.8[M+1]
+.
步骤2:化合物18的合成
在拇指瓶中加入化合物18-b(250mg,394.62μmol,1eq),甲醇(5mL),然后加入氢氧化钠(78.92mg,1.97mmol,5eq)的水(1mL)溶液。混合物在25℃下搅拌1小时。向反应液中加入水(5mL),用1M稀盐酸调pH=1~2,用乙酸乙酯(15mL×3)萃取。合并的有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减 压浓缩。残余物通过制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:35%-65%,7min)分离,得到化合物18。
MS m/z(ESI):605.1[M+1]
+.
1H NMR(400MHz,DMSO-d
6)δ=12.16(br s,1H),10.35(s,1H),7.91(br d,J=9.8Hz,1H),7.72-7.61(m,2H),7.34-7.26(m,1H),6.41(s,1H),4.92(brt,J=9.9Hz,1H),4.45(br d,J=10.5Hz,1H),2.83(br d,J=14.1Hz,1H),2.67(s,3H),2.44-2.33(m,3H),2.27(br d,J=11.8Hz,1H),2.22-2.12(m,2H),2.04-1.92(m,2H),1.57-1.37(m,2H).
实施例13
合成路线:
步骤1:化合物19-b的合成
将化合物15-b(100mg,225.46μmol,1eq),化合物19-a(60.88mg,338.19μmol,1.5eq)溶于二氯甲烷(5mL)中,将反应液降温至0℃后再加入三正丙基环磷酸酐(215.21mg,338.19μmol,201.13μL,浓度:50%,1.5eq)和N,N-二异丙基乙胺(87.42mg,676.38μmol,117.81μL,3eq),反应液升温至25℃搅拌反应12小时。将反应液直接减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至2/1)纯化,得到化合物19-b。
MS m/z(ESI):605.1[M+1]
+.
步骤2:化合物19的合成
将化合物19-b(50mg,82.57μmol,1eq)溶于甲醇(1mL)和水(1mL)中,再加入氢氧化钠(16.51mg,412.86μmol,5eq),反应液于25℃搅拌反应2小时。向反应液中加入水(10mL),用1M稀盐酸调pH=1-2,再用乙酸乙酯(10mL×3)萃取。合并有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相色谱法(柱型:PhenomenexGemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:40%-70%,7min)纯化,得到化合物19。
MS m/z(ESI):577.1[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.79(d,J=6.0Hz,2H),7.56(s,1H),6.36(s,1H),5.00(br dd,J=3.4,11.7Hz,1H),4.46(br dd,J=3.1,11.9Hz,1H),2.95(br d,J=14.1Hz,1H),2.74(s,3H),2.57(br t,J=10.8Hz,1H),2.51-2.43(m,1H),2.41-2.27(m,3H),2.20(br t,J=11.4Hz,1H),2.12-2.04(m,2H),1.69-1.55(m,2H).
实施例14
合成路线:
步骤1:化合物20-a的合成
将化合物15-a(10g,28.07mmol,1eq)通过SFC(柱型:DAICEL CHIRALPAKAD(250mm*50mm,10μm);流动相:[0.1%NH
3H
2O,MeOH]%:45%-45%)分离,得到化合物20-a。
MS m/z(ESI):357.7[M+1]
+.SFC分析方法(柱型:Chiralpak AD-3 150*4.6mm I.D.,3μm;流动相:二氧化碳含40%的甲醇(0.05%二乙胺);流速:2.5mL/min);SFC保留时间:3.030分钟;ee%=99.96%.
1H NMR(400MHz,DMSO-d
6)δ=7.84(s,1H),4.76(dd,J=2.6,11.9Hz,1H),3.73(br dd,J=2.3,12.3Hz,1H),3.17(s,1H),2.61(s,3H),2.30(br d,J=14.1Hz,1H),1.95-1.86(m,1H).
步骤2:化合物20-b的合成
在氮气保护下将化合物20-a(800.00mg,2.25mmol,1eq),化合物10-b(2.08g,6.74mmol,3eq),N,N-二异丙基乙胺(1.45g,11.23mmol,1.96mL,5eq)和二氯双(三苯基膦)钯(157.63mg,224.58μmol,0.1eq)溶于1,4-二氧六环(10mL)和水(10mL)中,再将反应液升温至80℃搅拌反应4小时。向反应液中加入1M稀盐酸调节反应液pH=1~2,再加入水(50mL),用乙酸乙酯(50mL×3)萃取。合并的有机相用饱和食盐水(50 mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品通过C18反相柱(水/乙腈=1/0至2/1)纯化,得到化合物20-b。
MS m/z(ESI):458.1[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.54(s,1H),6.33(s,1H),4.97(br dd,J=2.9,11.9Hz,1H),4.39(dd,J=2.8,12.4Hz,1H),4.16-4.10(m,2H),2.99(br d,J=12.0Hz,1H),2.76(s,3H),2.48-2.39(m,2H),2.35-2.20(m,4H),2.15-2.03(m,2H),1.94(br d,J=12.5Hz,2H),1.28-1.24(m,3H),1.21-1.09(m,2H).
步骤3:化合物20-d的合成
氮气保护下,在拇指瓶中加入化合物20-b(75mg,163.91μmol,1eq),化合物20-c(40.21mg,245.87μmol,1.5eq),二异丙基乙基胺(63.55mg,491.74μmol,85.65μL,3eq)和四氢呋喃(3mL),然后加入三正丙基环磷酸酐(208.61mg,327.82μmol,浓度:50%,2eq)。混合物在50℃下搅拌12小时。反应液减压浓缩。残余物通过自动过柱机COMBI-FLASH(梯度淋洗:石油醚∶乙酸乙酯=100∶0至70∶30)分离,得到化合物20-d。
MS m/z(ESI):603.1[M+1]
+.
步骤4:化合物20的合成
在拇指瓶中加入化合物20-d(80mg,132.65μmol,1eq)和甲醇(1mL),然后加入氢氧化钠(2M,331.62μL,5eq)水溶液。混合物在25℃下搅拌1小时。向反应液中加入水(5mL),用1M稀盐酸调pH=1~2,用乙酸乙酯(15mL×2)萃取。合并的有机相用饱和食盐水(30mL)洗涤后减压浓缩。残余物通过制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:40%-70%,7min)纯化,得到化合物20。
MS m/z(ESI):575.0[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=8.00(t,J=7.8Hz,1H),7.56(s,1H),7.37-7.24(m,1H),6.35(s,1H),5.03(dd,J=3.1,11.9Hz,1H),4.52(dd,J=3.0,12.0Hz,1H),3.08-2.94(m,1H),2.80(s,3H),2.52-2.40(m,2H),2.38-2.28(m,2H),2.24(d,J=7.0Hz,2H),2.18-2.02(m,2H),1.98(br d,J=12.3Hz,2H),1.27-1.08(m,2H).
实施例15
合成路线:
步骤1:化合物21-b的合成
将化合物20-b(75.00mg,163.91μmol,1eq)和化合物21-a(40.21mg,245.87μmol,1.5eq)溶于四氢呋喃(3mL)中,将反应液降温至0℃后再加入三正丙基环磷酸酐(208.61mg,327.82μmol,浓度:50%,2eq)和N,N-二异丙基乙胺(63.55mg,491.74μmol,85.65μL,3eq),将反应液升温至50℃搅拌反应12小时。将反应液直接减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至2/1)纯化,得到化合物21-b。
MS m/z(ESI):603.1[M+1]
+.
步骤2:化合物21的合成
将化合物21-b(50mg,82.90μmol,1eq)溶于甲醇(1mL)和水(1mL)中,再加入氢氧化钠(16.58mg,414.52μmol,5eq),反应液于25℃搅拌反应2小时。向反应液中加入水(10mL),用1M稀盐酸调pH=1-2,再用乙酸乙酯(10mL×3)萃取。合并有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相色谱法(柱型:PhenomenexGemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:40%-70%,7min)纯化,得到化合物21。
MS m/z(ESI):575.1[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.68(dt,J=5.6,8.7Hz,1H),7.55(s,1H),7.15(dt,J=2.0,8.9Hz,1H),6.33(s,1H),5.02(dd,J=3.1,12.2Hz,1H),4.51(dd,J=3.1,11.9Hz,1H),3.00(br d,J=13.8Hz,1H),2.80(s,3H),2.49-2.39(m,2H),2.37-2.26(m,2H),2.22(d,J=7.0Hz,2H),2.16-2.00(m,2H),1.97(br d,J=11.5Hz,2H),1.25-1.09(m,2H).
实施例16
合成路线:
步骤1:化合物22-b的合成
在氮气保护下将化合物20-b(75mg,163.91μmol,1eq)和化合物22-a(40.21mg,245.87μmol,1.5eq)溶于四氢呋喃(3mL)中,将反应液降温至0℃后再加入三正丙基环磷酸酐(208.61mg,327.82μmol,194.97μL,浓度:50%,2eq)和N,N-二异丙基乙胺(63.55mg,491.74μmol,85.65μL,3eq),将反应液升温至50℃搅拌反应12小时。将反应液直接减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至2/1)纯化,得到化合物22-b。
MS m/z(ESI):603.1[M+1]
+.
步骤2:化合物22的合成
将化合物22-b(10mg,16.58μmol,1eq)溶于甲醇(1mL)和水(1mL)中,再加入氢氧化钠(3.32mg,82.90μmol,5eq),于25℃搅拌反应2小时。向反应液中加入水(10mL),用1M稀盐酸调pH=1-2,再用乙酸乙酯(10mL×3)萃取。合并有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈]:乙腈%:40%-70%,7min)纯化,得到化合物22。
MS m/z(ESI):575.1[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.84(dd,J=8.0,11.8Hz,1H),7.58-7.50(m,2H),6.33(s,1H),5.02(dd,J=3.0,12.0Hz,1H),4.52(dd,J=3.3,12.0Hz,1H),3.00(br d,J=14.1Hz,1H),2.82(s,3H),2.54-2.40(m,2H),2.37-2.27(m,2H),2.23(d,J=7.0Hz,2H),2.16-2.00(m,2H),1.97(br d,J=11.8Hz,2H),1.23-1.09(m,2H).
实施例17
合成路线:
步骤1:化合物23-b合成
在一个圆底瓶中,氮气保护,将23-a(500mg,3.12mmol,1eq)和湿钯碳(67.47mg,31.23μmol,5%纯度,0.01eq)加到甲醇(50mL)中,然后置换三次氢气,反应液在H2(25psi)氛围下,40℃搅拌1小时。反应液过滤,减压浓缩,得到化合物23-b。
MS m/z(ESI):130.8[M+1]
+.
1H NMR(400MHz,DMSO-d
6)δ=7.28(t,J=2.6Hz,1H),7.06(ddd,J=2.4,8.6,11.9Hz,1H),5.54(br s,2H).步骤2:化合物23-c合成
将20-b(50mg,109.27μmol,1eq),23-b(17.06mg,131.13μmol,1.2eq),三正丙基环磷酸酐(139.08mg,218.55μmol,浓度:50%,2eq)和二异丙基乙基胺(42.37mg,327.82μmol,57.10μL,3eq)加到四氢呋喃(5mL)中,氮气保护,反应液在50℃搅拌0.5小时。向反应液中加入水(50mL),用乙酸乙酯(30mL×2)萃取。合并的有机相依次用水(30mL)和饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至10/3)纯化,得到化合物23-c。
MS m/z(ESI):570.0[M+1]
+.
步骤3:化合物23的合成
将化合物23-c(40mg,70.22μmol,1eq)和氢氧化钠(28.09mg,702.19μmol,10eq)加入到甲醇(1mL)和水(1mL)中,反应液在25℃搅拌1小时。反应液用4M稀盐酸调pH至pH=4~5,加入水(30mL),乙酸乙酯(30mL×2)萃取。合并的有机相依次用水(20mL)和饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗品经制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈]:乙腈%:35%-55%,7min)纯化,得到化合物23。
MS m/z(ESI):541.9[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=8.29(ddd,J=2.3,8.7,11.2Hz,1H),8.21(t,J=2.0Hz,1H),7.57(s,1H),6.35(s,1H),5.02(br dd,J=3.0,11.8Hz,1H),4.54(dd,J=3.1,11.7Hz,1H),3.09-2.94(m,1H),2.77(s,3H),2.49-2.20(m,6H),2.19-1.92(m,4H),1.29-1.04(m,2H).
实施例18
合成路线:
步骤1:化合物24-b的合成
氮气保护下,在拇指瓶中加入化合物20-b(75mg,163.91μmol,1eq),化合物24-a(31.61mg,245.87μmol,1.5eq),二异丙基乙基胺(63.55mg,491.73μmol,85.65μL,3eq)和四氢呋喃(3mL),然后加入三正丙基环磷酸酐(208.61mg,327.82μmol,194.97μL,浓度:50%,2eq)。混合物在50℃下搅拌12小时。反应液减压浓缩。残余物通过自动过柱机COMBI-FLASH(梯度淋洗:石油醚∶乙酸乙酯=100∶0至50∶50)分离,得到化合物24-b。
MS m/z(ESI):568.0[M+1]
+.
步骤2:化合物24的合成
在拇指瓶中加入化合物24-b(40mg,70.41μmol,1eq)和甲醇(1mL),然后加入氢氧化钠(2M,0.5mL,14.20eq)。混合物在25℃下搅拌1小时。向反应液中加入水(5mL),用1M稀盐酸调pH=5~6,用乙酸乙酯(15mL×3)萃取。合并的有机相用饱和食盐水(30mL)洗涤后减压浓缩。残余物通过制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈]:乙腈%:40%-70%,7min)纯化,得到化合物24。
MS m/z(ESI):540.1[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=8.72(br s,1H),8.41-8.23(m,2H),7.57(s,1H),6.35(s,1H),5.02(br d,J=8.8Hz,1H),4.56(dd,J=3.0,11.8Hz,1H),3.11-2.94(m,1H),2.78(s,3H),2.50-2.38(m,2H),2.37-2.28(m,2H),2.25(d,J=7.0Hz,2H),2.17-1.95(m,4H),1.27-1.06(m,2H).
实施例19
合成路线:
步骤1:化合物25-b的合成
氮气保护下,在拇指瓶中加入化合物20-b(50mg,109.27μmol,1eq),化合物25-a(21.07mg,163.91μmol,1.5eq)和二氯甲烷(1.5mL),然后加入吡啶(43.22mg,546.37μmol,44.10μL,5eq)和三氯氧磷(20.11mg,131.13μmol,12.19μL,1.2eq),混合物在20℃下搅拌1小时。将反应液减压浓缩,得到粗品化合物25-b。
MS m/z(ESI):568.1[M+1]
+.
步骤2:化合物25的合成
在拇指瓶中加入化合物25-b(100mg,176.02μmol,1eq)和甲醇(2mL),然后加入氢氧化钠水溶液(2M,1mL,11.36eq)。混合物在25℃下搅拌1小时。向反应液中加入水(5mL),用1M稀盐酸调pH=1-2,用乙酸乙酯(15mL×3)萃取。合并的有机相用饱和食盐水(30mL)洗涤后减压浓缩。残余物通过制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈]:乙腈%:30%-60%,7min)分离,得到化合物25。
MS m/z(ESI):540.2[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=8.26(d,J=5.5Hz,1H),7.89(d,J=1.8Hz,1H),7.63(dd,J=1.8,5.8Hz,1H),7.57(s,1H),6.35(s,1H),5.01(dd,J=3.8,11.5Hz,1H),4.58(dd,J=3.5,11.5Hz,1H),3.02(br d,J=13.6Hz,1H),2.75(s,3H),2.47-2.29(m,4H),2.25(d,J=6.8Hz,2H),2.17-2.02(m,2H),1.98(br d,J=12.0Hz,2H),1.31-1.02(m,2H).
实施例20
合成路线:
步骤1:化合物26-b的合成
在氮气保护下将化合物20-b(50mg,109.27μmol,1eq),化合物26-a(22.31mg,163.91μmol,1.5eq)溶于四氢呋喃(2mL)中,将反应液降温到0℃后再缓慢加入三正丙基环磷酸酐(139.08mg,218.55μmol,129.98μL,50%纯度,2eq)和N,N-二异丙基乙胺(42.37mg,327.82μmol,57.10μL,3eq),再将反应液升温至50℃搅拌反应12小时。将反应液直接减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至2/1)纯化,得到化合物26-b。
MS m/z(ESI):576.1[M+1]
+.
步骤2:化合物26的合成
将化合物26-b(20mg,34.74μmol,1eq)溶于甲醇(1mL)和水(1mL)中,再加入氢氧化钠(6.95mg,173.71μmol,5eq),反应液于25℃搅拌反应2小时。向反应液中加入水(10mL),用1M稀盐酸调pH=1-2,再用乙酸乙酯(10mL×3)萃取。合并有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈]:乙腈%:35%-65%,7min)分离,得到化合物26。
MS m/z(ESI):548.2[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.89-7.83(m,2H),7.55(s,1H),7.34-7.28(m,1H),6.33(s,1H),5.00(dd,J=3.6,11.7Hz,1H),4.52(dd,J=3.4,11.7Hz,1H),3.00(br d,J=14.6Hz,1H),2.75(s,3H),2.44-2.36(m,2H),2.34-2.25(m,2H),2.22(d,J=7.0Hz,2H),2.15-2.03(m,2H),1.97(br d,J=12.5Hz,2H),1.21-1.10(m,2H).
实施例21
合成路线:
步骤1:化合物27-b合成
在一个圆底瓶中,将化合物20-b(60mg,131.13μmol,1eq),27-a(24.01mg,157.36μmol,1.2eq),三正丙基环磷酸酐(166.89mg,262.26μmol,纯度:50%,2eq)和二异丙基乙基胺(50.84mg,393.39μmol,68.52μL,3eq)加入到四氢呋喃(6mL)中,反应液在50℃搅拌0.5小时。向反应液中加入水(50mL),用乙酸乙酯(30mL×2)萃取,合并有机相,依次用水(30mL)和饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至10/3)纯化,得到化合物27-b。
MS m/z(ESI):591.9[M+1]
+.
步骤2:化合物27的合成
将化合物27-b(40mg,67.55μmol,1eq)和氢氧化钠(27.02mg,675.53μmol,10eq)加入到甲醇(1mL)和水(1mL)中,反应液在25℃搅拌1小时。反应液用4M盐酸调pH=4~5,加入水(30mL),用乙酸乙酯(30mL×2)萃取。合并的有机相依次用水(20mL)和饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗品经制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈]:乙腈%:45%-65%,7min)纯化,得到化合物27。
MS m/z(ESI):564.0[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=8.18-7.87(m,2H),7.69-7.40(m,2H),6.35(s,1H),5.02(dd,J=3.4,11.7Hz,1H),4.54(dd,J=3.4,11.7Hz,1H),3.15-2.90(m,1H),2.77(s,3H),2.55-2.20(m,6H),2.15-1.88(m,4H),1.26-1.06(m,2H).
实施例22
合成路线:
步骤1:化合物28-b的合成
将化合物28-a(500.00mg,2.37mmol,1eq)溶于叔丁醇(10mL)中,再加入叠氮磷酸二苯酯(784.28mg,2.85mmol,617.54μL,1.2eq)和三乙胺(288.37mg,2.85mmol,396.66μL,1.2eq),再将反应液升温至90℃搅拌反应6小时。向反应液中加入水(15mL),用乙酸乙酯(15mL×3)萃取。合并的有机相用饱和食盐水(15mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至2/1)纯化,得到化合物28-b。
1H NMR(400MHz,CDCl
3)δ=8.04(br d,J=11.5Hz,1H),6.73-6.56(m,1H),1.54(s,9H)
步骤2:化合物28-c的合成
将化合物28-b(400.00mg,1.42mmol,1eq)溶于二氯甲烷(2mL)中,再加入三氟乙酸(2mL),反应液在25℃下搅拌反应0.5小时。将反应液减压浓缩得到粗品化合物28-c。
1H NMR(400MHz,CDCl
3)δ=6.54(td,J=7.6,11.2Hz,1H),3.75(br s,2H).
步骤3:化合物28-d的合成
氮气保护下,将化合物20-b(50mg,109.27μmol,1eq),化合物28-c(29.76mg,163.9lμmol,1.5eq)溶于四氢呋喃(2mL)中,将反应液降温到0℃后再缓慢加入三正丙基环磷酸酐(139.08mg,218.54μmol,50%纯度,2eq)和N,N-二异丙基乙胺(42.37mg,327.81μmol,57.10μL,3eq),反应液升温至50℃搅拌12小时。将反应液直接减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至2/1)纯化,得到化合物28-d。
MS m/z(ESI):621.1[M+1]
+.
步骤4:化合物28的合成
将化合物28-d(20.00mg,32.20μmol,1eq)溶于甲醇(1mL)和水(1mL)中,再加入氢氧化钠(6.44mg,161.01μmol,5eq),反应液于25℃搅拌反应2小时。向反应液中加入水(10mL),用1M稀盐酸调pH=1-2,再用乙酸乙酯(10mL×3)萃取。合并的有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,滤液 减压浓缩。粗品经制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈]:乙腈%:40%-70%,7min)分离,得到化合物28。
MS m/z(ESI):593.1[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.92-7.85(m,1H),7.55(s,1H),6.33(s,1H),5.01(br d,J=8.5Hz,1H),4.55-4.50(m,1H),3.00(br d,J=13.3Hz,1H),2.78(s,3H),2.45-2.39(m,2H),2.35-2.26(m,2H),2.22(d,J=7.0Hz,2H),2.15-2.03(m,2H),1.96(br d,J=12.0Hz,2H),1.15(br d,J=12.5Hz,2H).
实施例23
合成路线:
步骤1:化合物29-a的合成
在一个圆底瓶中,将20-b(70mg,152.98μmol,1eq),3-氯-4-氟苯胺(26.72mg,183.58μmol,1.2eq),三正丙基环磷酸酐(194.71mg,305.97μmol,181.97μL,浓度:50%,2eq)和二异丙基乙基胺(79.09mg,611.94μmol,106.59μL,4eq)加到四氢呋喃(5mL)中,反应液在氮气保护下50℃搅拌1小时。向反应液中加入水(50mL),用乙酸乙酯(30mL×2)萃取。合并的有机相依次用水(30mL)和饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至10/3)纯化,得到化合物29-a。
MS m/z(ESI):585.1[M+1]
+.
步骤2:化合物29的合成
将化合物29-a(50mg,85.45μmol,1eq)和氢氧化钠(17.09mg,427.27μmol,5eq)加到甲醇(0.5mL)和水(0.5mL)中,反应液在25℃搅拌60分钟。反应液用4M稀盐酸调pH=4~5,加入水(30mL),乙酸乙酯(30mL×2)萃取。合并的有机相依次用水(20mL)和饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗品经制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈]:乙腈%:40%-70%,7min)纯化,得到化合物29。
MS m/z(ESI):556.8[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.91(dd,J=2.6,6.7Hz,1H),7.58-7.49(m,2H),7.23(t,J=8.9Hz,1H),6.35(s,1H),5.02(dd,J=3.3,11.8Hz,1H),4.44(dd,J=3.3,11.8Hz,1H),3.11-2.91(m,1H),2.77(s,3H),2.51-2.19(m,6H),2.19-1.92(m,4H),1.29-1.01(m,2H).
步骤3:化合物30和31的合成
化合物29(20mg,35.90μmol)通过SFC(柱型:DAICEL CHIRALCEL OJ(250mm*30mm,10μm);流动相:[0.1%NH
3H
2O,MeOH]%:40%-40%)分离,得到化合物30和31。
SFC分析方法:柱型:ChiralCel OJ-H 150×4.6mm I.D.,5μm;流动相:甲醇(0.05%二乙胺);流速:2.5mL/min。
化合物30:MS m/z(ESI):556.9[M+1]
+.SFC保留时间:7.427分钟。
1H NMR(400MHz,CD
3OD)δ=7.91(dd,J=2.6,6.7Hz,1H),7.68-7.44(m,2H),7.24(t,J=8.9Hz,1H),6.35(s,1H),5.02(dd,J=3.4,11.7Hz,1H),4.44(dd,J=3.3,11.8Hz,1H),3.07-2.93(m,1H),2.77(s,3H),2.51-2.26(m,4H),2.22(d,J=7.0Hz,2H),2.16-1.93(m,4H),1.28-1.08(m,2H).
化合物31:MS m/z(ESI):556.9[M+1]
+.SFC保留时间:7.808分钟。
1H NMR(400MHz,CD
3OD)δ=7.91(dd,J=2.6,6.7Hz,1H),7.69-7.47(m,2H),7.24(t,J=9.0Hz,1H),6.35(s,1H),5.10-4.95(m,1H),4.44(dd,J=3.0,11.5Hz,1H),3.02(br d,J=14.1Hz,1H),2.77(s,3H),2.52-2.26(m,4H),2.22(br d,J=6.8Hz,2H),2.17-1.93(m,4H),1.27-1.08(m,2H).
实施例24
合成路线:
步骤1:化合物32-a的合成
在氮气保护下将化合物20-b(50mg,109.27μmol,1eq),化合物15-c(22.73mg,109.27μmol,1eq)溶于四氢呋喃(2mL)中,将反应液降温到0℃后再缓慢加入三正丙基环磷酸酐(139.08mg,218.55μmol,129.98μL,浓度:50%,2eq)和N,N-二异丙基乙胺(42.37mg,327.82μmol,57.10μL,3eq),再将反应液升温至50℃搅拌反应12小时。将反应液直接减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至2/1)纯化,得到化合物32-a。
MS m/z(ESI):647.0[M+1]
+.
步骤2:化合物32的合成
将化合物32-a(40mg,61.77μmol,1eq)溶于甲醇(1mL)和水(1mL)中,再加入氢氧化钠(12.35mg,308.86μmol,5eq),反应液于25℃搅拌反应2小时。向反应液中加入水(10mL),用1M稀盐酸调pH=1-2,再用乙酸乙酯(10mL×3)萃取。合并有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:40%-70%,7min)分离,得到化合物32。
MS m/z(ESI):618.9[M+1]
+.
步骤3:化合物33和34的合成
将化合物32(25mg,40.36μmol,1eq)通过SFC(柱型:DAICEL CHIRALPAK AS(250mm*30mm,10μm);流动相:[0.1%NH
3H
2O,EtOH]%:35%-35%)纯化,得到化合物33和34。
SFC分析方法:柱型:ChiralPak AS-3 150×4.6mm I.D.,3μm;流动相:异丙醇(0.05%二乙胺);流速:2.5mL/min。
化合物33:MS m/z(ESI):619.0[M+1]
+.SFC保留时间:5.872分钟,ee%=92.5%。
1H NMR(400MHz,CD
3OD)δ=7.80-7.66(m,2H),7.55(s,1H),6.33(s,1H),4.99(dd,J=3.4,11.7Hz,1H),4.46(dd,J=3.5,11.8Hz,1H),3.00(br d,J=13.1Hz,1H),2.74(s,3H),2.45-2.27(m,4H),2.26-2.18(m,2H),2.15-2.00(m,2H),1.97(br d,J=11.5Hz,2H),1.22-1.10(m,2H).
化合物34:MS m/z(ESI):619.0[M+1]
+.SFC分析方法(柱型:Chiralpak AD-3 150*4.6mm I.D.,3μm;流动相:异丙醇(0.05%二乙胺);流速:2.5mL/min),保留时间:6.150分钟,ee%=84.8%。
1H NMR(400MHz,CD
3OD)δ=7.79-7.65(m,2H),7.55(s,1H),6.33(s,1H),4.99(dd,J=3.4,11.7Hz,1H),4.46(dd,J=3.5,11.8Hz,1H),3.00(br d,J=13.8Hz,1H),2.74(s,3H),2.45-2.27(m,4H),2.22(d,J=6.8Hz,2H),2.15-2.00(m,2H),1.99-1.93(m,2H),1.21-1.09(m,2H).
实施例25
合成路线:
步骤1:化合物35-a的合成
在氮气保护下将化合物20-b(325mg,710.28μmol,1eq)和化合物17-a(174.25mg,1.07mmol,1.5eq)溶于二氯甲烷(15mL)中,将反应液降温至0℃后再缓慢加入三氯氧磷(163.36mg,1.07mmol,99.01μL,1.5eq)和吡啶(280.92mg,3.55mmol,286.65μL,5eq),反应液在0℃搅拌反应1小时。将反应液直接减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至2/1)纯化,得到化合物35-a。
MS m/z(ESI):603.1[M+1]
+.
步骤2:化合物35-b和35-c的合成
将化合物35-a(220mg,364.78μmol,1eq)通过SFC(柱型:DAICEL CHIRALCEL OJ(250mm*30mm,10μm);流动相:[0.1%NH
3H
2O,EtOH]%=40%-40%)分离,得到化合物35-b和35-c。
化合物35-b:SFC分析方法(柱型:ChiralCel OJ-H 150×4.6mm I.D.,5um;流动相:乙醇醇(0.05%二乙胺);流速:2.5mL/min);MS m/z(ESI):603.1[M+1]
+.SFC保留时间:5.635分钟,ee%=100%。
化合物35-b:MS m/z(ESI):603.1[M+1]
+.SFC保留时间:6.192分钟,ee%=98.8%。
步骤3:化合物35的合成
将化合物35-b(90mg,149.23μmol,1eq)溶于甲醇(3mL)和水(3mL)中,再加入氢氧化钠(29.84mg,746.14μmol,5eq),反应液于25℃搅拌反应2小时。向反应液中加入水(10mL),用1M稀盐酸调pH=1-2,再用乙酸乙酯(10mL×3)萃取。合并的有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品通过制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:40%-70%,7min)纯化,得到化合物35。
SFC分析方法:柱型:ChiralCel OJ-H 150×4.6mm I.D.,5μm;流动相:乙醇(0.05%二乙胺);流速:2.5mL/min.MS m/z(ESI):575.1[M+1]
+.SFC保留时间:5.950分钟,ee%=98.3%。
1H NMR(400MHz,CD
3OD)δ=7.68(dt,J=5.8,8.7Hz,1H),7.55(s,1H),7.15(dt,J=2.3,8.9Hz,1H),6.34(s,1H),5.02(dd,J=3.1,12.2Hz,1H),4.51(dd,J=3.0,12.0Hz,1H),3.00(br d,J=13.6Hz,1H),2.80(s,3H),2.47-2.40(m,2H),2.37-2.27(m,2H),2.22(d,J=7.0Hz,2H),2.16-2.01(m,2H),1.97(br d,J=12.3Hz,2H),1.23-1.09(m,2H).
步骤4:化合物36的合成
在拇指瓶中加入化合物35-c(100mg,165.81μmol,1eq)和甲醇(2mL),然后加入氢氧化钠水溶液(2M,1mL,12.06eq),在25℃下搅拌30分钟。反应液用1M稀盐酸调pH=1~2,用乙酸乙酯(15mL×3)萃取。合并的有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。残余物通过制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:35%-65%,7min)分离。得到化合物36。
MS m/z(ESI):575.1[M+1]
+.SFC保留时间:6.251分钟,ee%=100%。
1H NMR(400MHz,CD
3OD)δ=7.74-7.65(m,1H),7.57(s,1H),7.17(dt,J=2.0,8.9Hz,1H),6.35(s,1H),5.04(dd,J=3.3,12.0Hz,1H),4.53(dd,J=3.0,12.0Hz,1H),3.02(br d,J=14.8Hz,1H),2.82(s,3H),2.51-2.40(m,2H),2.39-2.29(m,2H),2.24(d,J=6.8Hz,2H),2.18-1.94(m,4H),1.28-1.04(m,2H).
实施例26
合成路线:
步骤1:化合物37-a的合成
在氮气保护下将化合物20-b(45mg,98.35μmol,1eq),化合物18-a(30.68mg,147.52μmol,1.5eq)溶于四氢呋喃(2mL)中,将反应液降温至0℃后再加入三正丙基环磷酸酐(125.17mg,196.69μmol,116.98μL,浓度:50%,2eq)和N,N-二异丙基乙胺(38.13mg,295.04μmol,51.39μL,3eq),反应液升温至50℃搅拌反应 12小时。将反应液直接减压浓缩。粗品通过快速柱层析法(石油醚/乙酸乙酯=1/0至2/1)纯化,得到化合物37-a。
MS m/z(ESI):647.1[M+1]
+.
步骤2:化合物37的合成
将化合物37-a(20mg,30.89μmol,1eq)溶于甲醇(1mL)和水(1mL)中,再加入氢氧化钠(6.18mg,154.43μmol,5eq),反应液于25℃搅拌反应2小时。向反应液中加入水(10mL),用1M稀盐酸调pH=1-2,再用乙酸乙酯(10mL×3)萃取。合并的有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:40%-70%,7min)纯化,得到化合物37。
MS m/z(ESI):618.8[M+1]
+.
1H NMR(400MHz,DMSO-d6)δ=7.71-7.60(m,2H),7.37-7.23(m,1H),6.37(s,1H),4.91(br d,J=10.0Hz,1H),4.44(dd,J=2.5,12.0Hz,1H),2.87(br d,J=14.1Hz,1H),2.66(s,3H),2.42-2.33(m,2H),2.26-2.12(m,4H),2.09-1.84(m,4H),1.17-1.05(m,1H).
实施例27
合成路线:
步骤1:化合物38-a的合成
在氮气保护下将化合物20-a(0.3g,842.18μmol,1eq),化合物1-o(371.65mg,1.26mmol,1.5eq),N,N-二异丙基乙胺(544.22mg,4.21mmol,733.45μL,5eq)和二氯双(三苯基膦)钯(59.11mg,84.22μmol,0.1eq)溶于1,4-二氧六环(4mL)和水(4mL)中,升温至80℃搅拌12小时。向反应液中加入水(10mL),用1M稀 盐酸调pH=1-2,再用乙酸乙酯(10mL×3)萃取。合并有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到化合物38-a,粗品直接用于下一步反应。
MS m/z(ESI):444.1[M+1]
+.
步骤2:化合物38-b的合成
将化合物38-a(100mg,225.46μmol,1eq)和化合物17-a(55.31mg,338.19μmol,1.5eq)溶于二氯甲烷(3mL)中,将反应液降温至0℃,缓慢加入三氯氧磷(69.14mg,450.92μmol,41.90μL,2eq)和吡啶(89.17mg,1.13mmol,90.99μL,5eq),在0℃搅拌1小时。将反应液减压浓缩得到粗品化合物38-b。
MS m/z(ESI):589.1[M+1]
+.
步骤3:化合物38的合成
将化合物38-b(30mg,50.93μmol,1eq)溶于甲醇(1mL)和水(1mL)中,再加入氢氧化钠(10.19mg,254.65μmol,5eq),于25℃搅拌反应2小时。向反应液中加入水(10mL),用1M稀盐酸调pH=1-2,再用乙酸乙酯(10mL×3)萃取。合并的有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:40%-70%,7min)分离,得到化合物38。
MS m/z(ESI):561.1[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.68(ddd,J=5.6,8.2,9.2Hz,1H),7.57(s,1H),7.15(dt,J=2.0,8.9Hz,1H),6.37(s,1H),5.02(dd,J=3.0,12.0Hz,1H),4.51(dd,J=3.0,12.0Hz,1H),2.96(br d,J=13.8Hz,1H),2.83-2.76(m,3H),2.63-2.52(m,1H),2.45(td,J=3.4,13.9Hz,2H),2.37-2.17(m,3H),2.12-2.04(m,2H),1.70-1.54(m,2H).
实施例28
合成路线:
步骤1:化合物39-a的合成
氮气保护下,在拇指瓶中加入化合物20-b(50mg,109.27μmol,1eq),16-a(24.11mg,163.91μmol,17.35μL,1.5eq)和二氯甲烷(1.5mL),然后加入吡啶(43.22mg,546.37μmol,44.10μL,5eq)和三氯氧磷(20.11mg,131.13μmol,12.19μL,1.2eq),混合物在0℃下搅拌1小时。反应液减压浓缩得到粗品化合物39-a。
MS m/z(ESI):587.1[M+1]
+.
步骤2:化合物39的合成
在拇指瓶中加入化合物39-a(60mg,102.28μmol,1eq)和甲醇(1mL),然后加入氢氧化钠(2M,0.5mL,9.78eq),然后在25℃下搅拌1小时。反应液用1M稀盐酸调pH=1~2,用乙酸乙酯(15mL×3)萃取。合并的有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。残余物通过制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:35%-65%,7min)分离,得到化合物39.
MS m/z(ESI):559.1[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.56(s,1H),7.54-7.47(m,1H),7.22-7.09(m,1H),6.35(s,1H),5.03(dd,J=3.1,11.9Hz,1H),4.53(dd,J=3.0,12.0Hz,1H),3.02(br d,J=14.1Hz,1H),2.81(s,3H),2.51-2.40(m,2H),2.38-2.28(m,2H),2.24(d,J=7.0Hz,2H),2.17-1.95(m,4H),1.29-1.07(m,2H).
步骤3:化合物40和41的合成
将化合物39(25mg,44.76μmol,1eq)通过手性SFC(柱型:DAICEL CHIRALCEL OJ-H(250mm*30mm,5μm);流动相:[0.1%NH
3H
2O,MeOH]%:40%-40%)分离,得到化合物40和41。
SFC分析方法:柱型:Chiralcel OJ-3 150*4.6mm I.D.,3μm;流动相:甲醇(0.05%二乙胺);流速:2.5mL/min.
化合物40:MS m/z(ESI):558.9[M+1]
+.SFC保留时间:1.864分钟,ee%=96.2%。
1H NMR(400MHz,CD
3OD)δ=7.57(s,1H),7.54-7.47(m,1H),7.21-7.12(m,1H),6.35(s,1H),5.04(dd,J=3.1,11.9Hz,1H),4.53(dd,J=3.0,12.0Hz,1H),3.02(br d,J=13.8Hz,1H),2.81(s,3H),2.49-2.41(m,2H),2.39-2.27(m,2H),2.24(d,J=7.0Hz,2H),2.18-2.03(m,2H),1.99(br d,J=12.8Hz,2H),1.27-1.07(m,2H).
化合物41:MS m/z(ESI):558.9[M+1]
+.SFC保留时间:2.307分钟,ee%=80.5%。
1H NMR(400MHz,CD
3OD)δ=7.56(s,1H),7.55-7.47(m,1H),7.22-7.12(m,1H),6.35(s,1H),5.04(dd,J=3.1,11.9Hz,1H),4.53(dd,J=3.0,12.0Hz,1H),3.02(br d,J=13.3Hz,1H),2.81(s,3H),2.50-2.40(m,2H),2.39-2.27(m,2H),2.22(br d,J=7.0Hz,2H),2.17-2.02(m,2H),1.99(br d,J=11.8Hz,2H),1.24-1.10(m,2H)
实施例29
合成路线:
步骤1:化合物42-a的合成
氮气保护下,在拇指瓶中加入化合20-b(50mg,109.27μmol,1eq),2-氟-3-氯苯胺(23.86mg,163.91μmol,26.02μL,1.5eq)和二氯甲烷(1.5mL),然后加入吡啶(43.22mg,546.37μmol,44.10μL,5eq)和三氯氧磷(20.11mg,131.13μmol,12.19μL,1.2eq),混合物在0℃下搅拌1小时。将反应液减压浓缩,得到化合物42-a。
MS m/z(ESI):585.1[M+1]
+.
步骤2:化合物42的合成
在拇指瓶中加入化合物42-a(60mg,102.54μmol,1eq)和甲醇(1mL),然后加入氢氧化钠(2M,0.5mL,9.75eq),然后在25℃下搅拌1小时。反应液用1M稀盐酸调pH=1~2,用乙酸乙酯(15mL×3)萃取。合并的有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。残余物通过制备型高效液相色谱法(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.225%甲酸)-乙腈];乙腈%:35%-65%,7min)分离,得到化合物42。
MS m/z(ESI):557.0[M+1]
+.
1H NMR(400MHz,CD
3OD)δ=7.75(ddd,J=1.6,6.8,8.2Hz,1H),7.57(s,1H),7.35(ddd,J=1.5,6.8,8.3Hz,1H),7.19(dt,J=1.6,8.2Hz,1H),6.35(s,1H),5.04(dd,J=3.0,12.0Hz,1H),4.53(dd,J=3.0,12.0Hz,1H),3.02(br d,J=13.6Hz,1H),2.82(s,3H),2.53-2.29(m,4H),2.25(d,J=6.8Hz,2H),2.18-1.96(m,4H),1.27-1.07(m,2H).
步骤3:化合物43和44的合成
化合物42(25mg,44.88μmol,1eq)通过SFC(柱型:DAICEL CHIRALCEL OJ(250mm*30mm,10μm);流动相:[0.1%NH
3H
2O,MeOH]%:40%-40%)分离,得到化合物43和44。
SFC分析方法:柱型:Chiralcel OJ-3 150*4.6mm I.D.,3μm;流动相:甲醇(0.05%二乙胺);流速:2.5mL/min.
化合物43:MS m/z(ESI):556.9[M+1]
+.SFC保留时间:3.996分钟,ee%=98.3%。
1H NMR(400MHz,CD
3OD)δ=7.69-7.60(m,1H),7.45(s,1H),7.23(dt,J=1.5,7.4Hz,1H),7.07(dt,J=1.6,8.2Hz,1H),6.23(s,1H),4.92(dd,J=3.3,12.0Hz,1H),4.41(dd,J=3.0,12.0Hz,1H),2.90(br d,J=13.8Hz,1H),2.82(s,3H),2.38-2.16(m,4H),2.12(d,J=7.0Hz,2H),2.05-1.83(m,4H),1.14-0.92(m,2H).
化合物44:MS m/z(ESI):557.0[M+1]
+.SFC保留时间:5.221分钟,ee%=98.4%.
1H NMR(400MHz,CD
3OD)δ=7.75(t,J=7.4Hz,1H),7.56(s,1H),7.35(dt,J=1.4,7.5Hz,1H),7.19(dt,J=1.5,8.2Hz,1H),6.35(s,1H),5.04(br d,J=9.3Hz,1H),4.53(dd,J=2.8,12.0Hz,1H),3.02(br d,J=14.3Hz,1H),2.82(s,3H),2.51-2.39(m,2H),2.39-2.28(m,2H),2.24(d,J=7.0Hz,2H),2.18-2.08(m,1H),2.05(dt,J=3.5,7.3Hz,1H),1.98(br d,J=12.3Hz,2H),1.26-1.06(m,2H).
生物活性测试
实验例1:HBV体外测试定量qPCR试验
1实验目的:
通过实时定量qPCR试验(real time-qPCR)检测HepG2.2.15细胞内的HBV DNA含量,以化合物的EC
50值为指标,来评价化合物对HBV的抑制作用。
2实验材料:
2.1细胞系:HepG2.2.15细胞
HepG2.2.15细胞培养基(DMEM/F12,Invitrogen-11330057;10%血清,Invitrogen-10099141;100units/ml青霉素和10μg/ml链霉素,Invitrogen-15140122;1%非必需氨基酸,Invitrogen-11140076;2mM左旋谷氨酰胺,Invitrogen-25030081;300μg/ml遗传霉素,Invitrogen-10131027。
2.2试剂:
胰酶(Invitrogen-25300062)
DPBS(Hyclone-SH30028.01B)
DMSO(Sigma-D2650-100ML)
高通量DNA纯化试剂盒(QIAamp 96 DNA Blood Kit,Qiagen-51162)
定量快速启动通用探针试剂(FastStart Universal Probe Master,Roche-04914058001)
2.3耗材与仪器:
96孔细胞培养板(Coming-3599)
CO
2培养箱(HERA-CELL-240)
光学封板膜(ABI-4311971)
定量PCR 96孔板(Applied Biosystems-4306737)
荧光定量PCR仪(Applied Biosystems-7500 real time PCR system)
3.实验步骤和方法:
3.1种HepG2.2.15细胞(4x104细胞/孔)到96孔板,在37℃,5%CO
2培养过夜。
3.2第二天,稀释化合物,共8个浓度,3倍梯度稀释。加不同浓度化合物到培养孔中,双复孔。培养液中DMSO的终浓度为1%。1μM GLS4作为100%抑制对照;1%的DMSO作为0%抑制对照。
3.3第五天,更换含有化合物的新鲜培养液。
3.4第八天收取培养孔中的培养液,使用高通量DNA纯化试剂盒(Qiagen-51162)提取DNA,具体步骤参照该产品说明书。
3.5PCR反应液的配制如表1所示:
表1.PCR反应液的配制
上游引物序列:GTGTCTGCGGCGTTTTATCA
下游引物序列:GACAAACGGGCAACATACCTT
探针序列:5′+FAM+CCTCTKCATCCTGCTGCTATGCCTCATC+TAMRA-3′
3.6在96孔PCR板中每孔加入15μL的反应混合液,然后每孔加入10μL的样品DNA或HBV DNA的标 准品。
3.7 PCR的反应条件为:95℃加热10分钟;然后95℃变性15秒,60℃延伸1分钟,共40个循环。
3.8数据分析:
3.8.1计算抑制百分比:%Inh.=【1-(样品中DNA拷贝数-1μM GLS4中DNA拷贝数)/(DMSO对照中DNA拷贝数-1μM GLS4中DNA拷贝数)】x100。
3.8.2计算EC
50:使用GraphPad Prism软件计算化合物对HBV的50%抑制浓度(EC
50)值。
4实验结果如表2所示:
表2.qPCR实验检测EC
50测试结果
结论:本发明化合物对HBV的抑制作用显著。
实验例2:肝细胞毒性测试实验
2.1:PHH细胞毒性测试实验
1.将化合物用DMSO(二甲基亚砜)以3倍梯度稀释8个点,双复孔,加入96孔板中。化合物浓度为最终测试浓度的200倍。
2.复苏冻存的人原代肝细胞(PHH),用细胞计数仪计数细胞密度,并用培养基将细胞密度调整到所需要的密度。
3.将细胞加入到已经加好化合物的96孔板中,每孔中DMSO的终浓度为0.5%。以含0.5%DMSO的细胞孔为无毒性阴性对照,以细胞培养液孔为100%细胞毒性对照。然后将细胞板放置于37℃、5%CO
2细胞培养箱内培养3天。
4.用细胞活力检测试剂盒CellTiter-Glo,按试剂盒说明书,用多功能酶标仪Synegy2-BioTek检测细胞板中各孔的化学发光信号(RLU,相对化学发光单位)。
5.将原始数据(RLU)代入下面的公式,计算测试各孔的细胞活力(细胞活力%):
细胞活力%=(RLU
Sample-AverageRLU
Mediumcontrol/(AverageRLU
Cellcontrol-AverageRLU
Mediumcontrol)×100%
RLU
Sample为样品孔的信号值;AverageRLU
Cellcontrol为细胞对照孔信号平均值;AverageRLU
Mediumcontrol为培养基对照孔信号平均值。
6.用GraphPad Prism软件,将细胞活力数据非线性拟合绘制剂量效应曲线,并得出化合物的半数细胞毒性浓度(CC
50)值,结果如表3。
表3.半数细胞毒性浓度(CC
50)值测试结果
化合物 | CC 50(μM) |
化合物11 | >100 |
结论:本发明化合物在原代肝细胞中的细胞毒性CC
50值比较高。
2.2:Huh7细胞毒性测试实验
1.将化合物用DMSO(二甲基亚砜)以3倍梯度稀释8个点,双复孔,加入96孔板中。化合物浓度为最终测试浓度的200倍。
2.将细胞用PBS(磷酸盐缓冲液)润洗一遍,加入0.25%的胰酶在37℃、5%CO
2培养箱中消化约2-5分钟后,用细胞培养基终止消化,并用枪吹打将细胞分散成单细胞。
3.用细胞计数仪计数细胞密度,并用培养基将细胞密度调整到所需要的密度。
4.将细胞加入到已经加好化合物的96孔板中,每孔中DMSO的终浓度为0.5%。以含0.5%DMSO的细胞孔为无毒性阴性对照,以细胞培养液孔为100%细胞毒性对照。然后将细胞板放置于37℃、5%CO
2细胞培养箱内培养3天。
5.用细胞活力检测试剂盒CellTiter-Glo,按试剂盒说明书,用多功能酶标仪Synegy2-BioTek检测细胞板中各孔的化学发光信号(RLU,相对化学发光单位)。
6.将原始数据(RLU)代入下面的公式,计算测试各孔的细胞活力(细胞活力%):
细胞活力%=(RLU
Sample-AverageRLU
Mediumcontrol/(AverageRLU
Cellcontrol-AverageRLU
Mediumcontrol)×100%
RLU
Sample为样品孔的信号值;AverageRLU
Cellcontrol为细胞对照孔信号平均值;AverageRLU
Mediumcontrol为培养基对照孔信号平均值。
7.用GraphPad Prism软件,将细胞活力数据非线性拟合绘制剂量效应曲线,并得出化合物的半数细胞毒性浓度(CC
50)值,结果如表4。
表4.半数细胞毒性浓度(CC
50)值测试结果
化合物 | CC 50(μM) |
化合物11 | 86.71 |
结论:本发明化合物在肝癌细胞Huh7中的细胞毒性CC
50值比较高。
2.3:HepG2细胞毒性测试实验
1.将化合物用DMSO(二甲基亚砜)以3倍梯度稀释8个点,双复孔,加入96孔板中。化合物浓度为最终测试浓度的200倍。
2.将细胞用PBS(磷酸盐缓冲液)润洗一遍,加入0.25%的胰酶在37℃、5%CO
2培养箱中消化约2-5分钟后,用细胞培养基终止消化,并用枪吹打将细胞分散成单细胞。
3.用细胞计数仪计数细胞密度,并用培养基将细胞密度调整到所需要的密度。
4.将细胞加入到已经加好化合物的96孔板中,每孔中DMSO的终浓度为0.5%。以含0.5%DMSO的细胞孔为无毒性阴性对照,以细胞培养液孔为100%细胞毒性对照。然后将细胞板放置于37℃、5%CO
2细胞培养箱内培养3天。
5.用细胞活力检测试剂盒CellTiter-Glo,按试剂盒说明书,用多功能酶标仪Synegy2-BioTek检测细胞板中各孔的化学发光信号(RLU,相对化学发光单位)。
6.将原始数据(RLU)代入下面的公式,计算测试各孔的细胞活力(细胞活力%):
细胞活力%=(RLU
Sample-AverageRLU
Mediumcontrol/(AverageRLU
Cellcontrol-AverageRLU
Mediumcontrol)×100%
RLU
Sample为样品孔的信号值;AverageRLU
Cellcontrol为细胞对照孔信号平均值;AverageRLU
Mediumcontrol为培养基对照孔信号平均值。
7.用GraphPad Prism软件,将细胞活力数据非线性拟合绘制剂量效应曲线,并得出化合物的半数细胞毒性浓度(CC
50)值,结果如表5。
表5.半数细胞毒性浓度(CC
50)值测试结果
化合物 | CC 50(μM) |
化合物11 | 79.35 |
结论:本发明化合物在肝癌细胞HepG2中的细胞毒性CC
50值比较高。
实验例3:药代动力学研究
Balb/c小鼠口服及静脉注射受试化合物的药代动力学研究:
受试化合物11与10%聚乙二醇-15羟基硬脂酸酯/20%聚乙二醇400/70%水溶液混合,涡旋并超声,制备得到0.2mg/mL澄清溶液,微孔滤膜过滤后备用。选取7至10周龄的Balb/c雌性小鼠,静脉注射给予候选化合物溶液,剂量为1mg/kg。
受试化合物30与10%二甲基亚砜/10%聚乙二醇-15羟基硬脂酸酯/80%水溶液混合,涡旋并超声,制备得到0.2mg/mL澄清溶液,微孔滤膜过滤后备用。选取7至10周龄的Balb/c雌性小鼠,静脉注射给予候选化合物溶液,剂量为1mg/kg。
受试化合物36与10%二甲基亚砜/10%聚乙二醇-15羟基硬脂酸酯/80%水溶液混合,涡旋并超声,制备得到0.2mg/mL澄清溶液,微孔滤膜过滤后备用。选取7至10周龄的Balb/c雌性小鼠,静脉注射给予候选化合物溶液,剂量为1mg/kg。
受试化合物11,30和36分别与10%聚乙二醇-15羟基硬脂酸酯水溶液混合,涡旋并超声,制备得到1mg/mL均匀混悬液备用。选取7至10周龄的Balb/c雌性小鼠,口服给予候选化合物溶液,剂量为10mg/kg。
收集一定时间的全血,制备得到血浆,以LC-MS/MS方法分析药物浓度,并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数,结果如表6所示。
表6.受试化合物的药代动力学结果
结论:本发明化合物口服生物利用度高。
实验例4:小鼠体内肝血比研究
Balb/c小鼠口服受试化合物的肝血比研究
化合物与10%聚乙二醇-15羟基硬脂酸酯水溶液混合,涡旋并超声,制备得到1mg/mL均匀混悬液备用。选取7至10周龄的Balb/c雌性小鼠,口服给予候选化合物溶液,剂量为10mg/kg。
收集一定时间的全血,制备得到血浆,收集相应时间的肝脏组织,制备得组织均浆液,以LC-MS/MS方法分析药物浓度,并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数。结果如表7所示。
表7受试化合物的肝血比结果
结论:本发明化合物在肝脏和血浆中的比值比较高。
实验例5:体内药效研究
HDI/HBV模型
实验目的:通过HDI/HBV小鼠模型检测化合物在小鼠体内抗乙型肝炎病毒效果。
化合物配制:溶剂为10%的聚乙二醇-15羟基硬脂酸酯;将一定量的受试化合物11,30和36分别溶解于10%聚乙二醇-15羟基硬脂酸酯水溶液,涡旋并超声,制备得到均一的混悬液,保存在4℃备用。
小鼠尾静脉高压注射HBV质粒DNA溶液:将注射质粒当天定为第0天,注射后1天为第1天,依此类推。在第0天所有动物按体重8%的体积通过尾静脉注射含有10μg质粒DNA的生理盐水溶液,5秒内完成注射。
给药:第1-6天所有动物每天灌胃给药两次(间隔时间8/16小时),第7天给药一次,所有动物在第7天下午安乐死。每天监控小鼠体重,整个实验过程中小鼠体重保持平稳。
样品收集:所有动物在第5天早上第一次给药后四小时颌下静脉采血收集血浆,所有血样收集于K
2-EDTA抗凝管中,4℃,7000g离心10分钟,以制备约40μL血浆。第7天所有动物在早上给药后四小时经CO
2安乐死,心脏采血,血浆制备方法同上。收集两份肝脏组织,每份70-100mg,液氮速冻。样品全部收集后保存在-80℃冰箱直至干冰条件下送到药明康德生物部体外实验室进行HBV DNA含量的检测。
样品分析:所有的血浆样品和肝脏样品用qPCR法检测HBV DNA。
实验结果:实验结果如表8。
表8 HDI药效实验结果
注:ΔLog10 copies表示给药组病毒载量与vehicle组病毒载量的差值
结论:本发明化合物在HDI模型中降低HBV DNA效果显著。
Claims (19)
- 式(I)所示化合物或其药学上可接受的盐,其中,R 1分别独立地选自卤素、OH、CN、NH 2、C 1-3烷基和C 1-3烷氧基,所述C 1-3烷基和C 1-3烷氧基分别独立地任选被1、2或3个卤素取代;m选自0、1、2、3和4;T 1和T 2各自独立地选自CH和N;环A选自苯基、C 4-10环烷基,所述苯基和C 4-10环烷基分别独立地任选被1、2或3个R a取代;R a分别独立地选自卤素、OH、CN、NH 2、C 1-3烷基和C 1-3烷氧基,所述C 1-3烷基和C 1-3烷氧基分别独立地任选被1、2或3个卤素取代;L 1选自单键、-C≡C-和-CR 2=;R 2选自H、甲基和F;L 2选自单键和亚甲基。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R 1分别独立地选自F、Cl、Br、CN、-CH 3和-OCH 3,所述-CH 3和-OCH 3分别独立地任选被1、2或3个F取代。
- 根据权利要求2所述化合物或其药学上可接受的盐,其中,R 1分别独立地选自F、Cl、Br和CN。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,L 1选自-C≡C-、-CH=、-C(F)=和-C(CH 3)=。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R a分别独立地选自F、Cl、Br、CH 3和OCH 3,所述CH 3和OCH 3分别独立地任选被1、2或3个F取代。
- 根据权利要求1-17任意一项所述的化合物或其药学上可接受的盐在制备治疗乙肝病毒感染相关疾病的药物上的应用。
- 根据权利要求18所述的应用,所述乙肝病毒感染相关疾病是慢性乙型肝炎。
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WO2019206072A1 (zh) * | 2018-04-24 | 2019-10-31 | 浙江海正药业股份有限公司 | 磺酰胺芳基甲酰胺衍生物及其制备方法和用途 |
CN110621672A (zh) * | 2017-03-02 | 2019-12-27 | 组装生物科学股份有限公司 | 环状磺酰胺化合物及其使用方法 |
WO2020051319A1 (en) * | 2018-09-05 | 2020-03-12 | Assembly Biosciences, Inc. | Cyclic sulfamide compounds for treatment of hbv |
WO2020051320A1 (en) * | 2018-09-05 | 2020-03-12 | Assembly Biosciences, Inc. | Cyclic sulfamide compounds for treatment of hbv |
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WO2019206072A1 (zh) * | 2018-04-24 | 2019-10-31 | 浙江海正药业股份有限公司 | 磺酰胺芳基甲酰胺衍生物及其制备方法和用途 |
WO2020051319A1 (en) * | 2018-09-05 | 2020-03-12 | Assembly Biosciences, Inc. | Cyclic sulfamide compounds for treatment of hbv |
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