WO2023006087A1 - Macrocyclic pyridone compound and application thereof - Google Patents

Macrocyclic pyridone compound and application thereof Download PDF

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Publication number
WO2023006087A1
WO2023006087A1 PCT/CN2022/109064 CN2022109064W WO2023006087A1 WO 2023006087 A1 WO2023006087 A1 WO 2023006087A1 CN 2022109064 W CN2022109064 W CN 2022109064W WO 2023006087 A1 WO2023006087 A1 WO 2023006087A1
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Prior art keywords
compound
add
crude product
reduced pressure
under reduced
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PCT/CN2022/109064
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French (fr)
Chinese (zh)
Inventor
贺海鹰
冯嘉杰
李鹏
胡国平
黎健
陈曙辉
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南京明德新药研发有限公司
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Priority to CN202280052980.2A priority Critical patent/CN117751118A/en
Publication of WO2023006087A1 publication Critical patent/WO2023006087A1/en

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    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • the present invention relates to the technical field of medicinal chemistry, in particular to a class of macrocyclic pyridone compounds and applications thereof, in particular to compounds represented by formula (I) or pharmaceutically acceptable salts thereof.
  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • HIV belongs to the genus lentivirus of the family Retroviridae.
  • HIV-1 and HIV-2 Both have similar viral structures and transmission routes.
  • HIV-2 is mainly distributed in West Africa and has also been detected in some infected people in Europe and the Americas. Its virulence and transmissibility are lower than that of HIV-1, and the course of AIDS caused by it is slower and milder. HIV-1 is widely distributed all over the world and is the pathogen that causes the prevalence of AIDS all over the world. The research on HIV is also based on HIV-1.
  • Integrase strand transfer inhibitors have recently been shown to be effective antiviral mechanisms, which inhibit the viral replication process by blocking the strand transfer reaction catalyzed by HIV viral integrase. interest.
  • the present invention provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof, which is selected from:
  • R 1 is selected from F, Cl, Br, CN, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 F replacements;
  • n is selected from 1, 2 and 3;
  • R 2 is selected from C 1-3 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl;
  • R is selected from H
  • R 2 and R 3 and the atoms connected to them form a 5-8 membered heterocycloalkyl group, and the 5-8 membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 R a ;
  • R a is independently selected from C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 F ;
  • L 1 is selected from -(CH 2 ) n -, wherein each CH 2 in 1, 2 or 3 CH 2 is optionally independently replaced by 1 R b , and each remaining CH 2 is optionally independently replaced by 1 or 2 Rc substitutions;
  • R c is selected from F, OH, C 1-3 alkoxy, -N(CH 3 ) 2 and -C 1-3 alkyl-OH;
  • n is selected from 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15;
  • L3 is selected from CH2 , NH, O and S ;
  • Ring A is selected from phenyl and 5-6 membered heteroaryl
  • T1 is selected from CH and N ;
  • hetero of the "4-6 membered heterocycloalkyl", "5-8 membered heterocycloalkyl” and “5-6 membered heteroaryl” each independently contain 1, 2 or 3 members independently selected from Heteroatoms or atomic groups of O, S, N and NH.
  • R 1 is selected from F, and other variables are as defined in the present invention.
  • Rc is selected from OH, methoxy, -CH 2 OH, -N(CH 3 ) 2 and Other variables are as defined herein.
  • n is selected from 5, 6, 7, 8, 9, 10 and 11, and other variables are as defined in the present invention.
  • the above-mentioned L 1 is selected from -(CH 2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -(CH 2 ) 9 -, -(CH 2 ) 10 - and -(CH 2 ) 11 -, wherein each of 1, 2 or 3 CH 2s is optionally independently replaced by 1 R b , and each of the remaining CH 2s is optionally are independently substituted by 1 or 2 Rc , other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from phenyl, pyridyl, pyrimidinyl and pyrrolyl, and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from phenyl, and other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the structures shown in (I-1) and (I-2),
  • R 1 , R 2 , R 3 , L 1 , L 2 and m are as defined in the present invention.
  • R 11 is selected from H and F
  • R 2 is selected from C 1-3 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl;
  • R is selected from H
  • R 2 and R 3 and their connected atoms form a 5-6 membered heterocycloalkyl group
  • L 1 is selected from -(CH 2 ) n -, wherein each of 1, 2 or 3 CH 2s is independently optionally replaced by 1 R b ;
  • n is selected from 5, 6, 7, 8, 9 and 10;
  • the present invention provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof, which is selected from:
  • R 1 is selected from F, Cl, Br, CN, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 F replacements;
  • n is selected from 1, 2 and 3;
  • R 2 is selected from C 1-3 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl;
  • R is selected from H
  • R 2 and R 3 and the atoms connected to them form a 5-8 membered heterocycloalkyl group, and the 5-8 membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 R a ;
  • R a is independently selected from C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 F ;
  • L 1 is selected from -(CH 2 ) n -, wherein each CH 2 is optionally substituted by 1 or 2 R b , and each CH 2 is optionally independently substituted by 1 or 2 Rc;
  • Rc is selected from F, OH, C 1-3 alkoxy, -N(CH 3 ) 2 and -C 1-3 alkyl-OH;
  • n is selected from the natural numbers of 4-15;
  • L3 is selected from CH2 , NH, O and S ;
  • Ring A is selected from phenyl and 5-6 membered heteroaryl
  • T1 is selected from CH and N ;
  • 4-6 membered heterocycloalkyl contains 1, 2 or 3 independently selected from O, S, N and NH heteroatoms or groups of atoms.
  • R 1 is selected from F, and other variables are as defined in the present invention.
  • Rc is selected from OH, methoxy, -N(CH 3 ) 2 and Other variables are as defined herein.
  • n is selected from 5, 6, 7, 8, 9, 10 and 11, and other variables are as defined in the present invention.
  • the above-mentioned L 1 is selected from -(CH 2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -(CH 2 ) 9 -, -(CH 2 ) 10 - and -(CH 2 ) 11 -, wherein each CH 2 is optionally replaced by 1 or 2 R b , said -(CH 2 ) n - is optionally replaced by 1 or 2 R c is substituted, and other variables are as defined herein.
  • the above-mentioned ring A is selected from phenyl, pyridyl, pyrimidinyl and pyrrolyl, and other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the structures shown in (I-1) and (I-2),
  • R 1 , R 2 , R 3 , L 1 , L 2 and m are as defined in the present invention.
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof:
  • the above-mentioned compound is selected from,
  • the above-mentioned compound is selected from,
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective dose of a compound of the present invention or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present application further includes pharmaceutically acceptable excipients, adjuvants or carriers.
  • the present application also provides the application of the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a medicament for preventing and/or treating HIV infection.
  • the present invention also provides following synthetic method:
  • the compound of the present invention has significant inhibitory effect on HIV integrase activity, and simultaneously exhibits positive effects in the test of inhibiting HIV pseudovirus gene replication at the cell level and the test of inhibiting HIV live virus replication.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
  • Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
  • 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 both.
  • therapeutically effective dose refers to that amount of a compound of formula sufficient to be therapeutically effective when administered to a mammal in need of such treatment.
  • a therapeutically effective amount will vary depending on the particular activity of the therapeutic agent employed, the age, physiological condition, presence of other disease states and nutritional status of the patient.
  • other drug treatments that the patient may be receiving will affect the determination of a therapeutically effective amount of the therapeutic agent to be administered.
  • treatment means any treatment of a disease in a mammal, including: (i) preventing the disease, that is, causing the clinical symptoms of the disease to not develop; (ii) inhibiting the disease, that is, preventing the development of clinical symptoms; and/or (iii) ) to alleviate the disease, that is, to cause the regression of clinical symptoms.
  • pharmaceutically acceptable excipients, adjuvants or carriers includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.
  • dispersion media includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agents are incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • the compounds of the invention may exist in particular 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 their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
  • diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter.
  • the terms “enriched in an isomer”, “enriched in an isomer”, “enriched in an enantiomer” or “enantiomerically enriched” refer to one of the isomers or enantiomers
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer 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%.
  • tautomer or “tautomeric form” means that isomers with different functional groups are in dynamic equilibrium at room temperature and are rapidly interconvertible. If tautomerism is possible (eg, in solution), then chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • proton tautomers include interconversions via migration of a proton, such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers (valence tautomers) involve interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in an isomer”, “enriched in an isomer”, “enriched in an enantiomer” or “enantiomerically enriched” refer to one of the isomers or enantiomers
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer 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%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. 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 compounds.
  • compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • 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 changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • 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 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 realizable basis.
  • substituted means that a specified atom or group can be replaced by another atom or group as specified.
  • any variable eg, R
  • its definition is independent at each occurrence.
  • said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
  • substituents and/or variations 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 can be bonded to any atom on a ring when the bond of a substituent can cross-link two or more atoms on the ring, e.g., structural unit It means that the substituent R can be substituted at any position on cyclohexyl or cyclohexadiene. When the enumerated substituent does not indicate which atom it is connected to the substituted group, this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring. The carbon atom is attached to the group being substituted.
  • linking group listed does not indicate its linking direction
  • its linking direction is arbitrary, for example,
  • the connecting 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 to form It can also be formed by connecting loop A and loop B in the opposite direction to the reading order from left to right
  • any one or more sites of the group can be linked to other groups through chemical bonds.
  • connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group.
  • the chemical bonds that the site connects with other groups can use straight solid line bonds Straight dotted key or tilde express.
  • the straight-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted line bond indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups;
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” means a “ring” with 5-7 atoms arranged around it.
  • 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 , C 1-3 and C 2-3 alkyl groups, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-3 alkoxy denotes those alkyl groups containing 1 to 3 carbon atoms attached to the rest 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 groups and the like.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, and the C 3-6 cycloalkyl includes C 3-4 , C 4-5 and C 5-6 cycloalkyl, etc.; it may be monovalent, divalent or multivalent.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • the term "5-8 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 5 to 8 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms is a heteroatom or heteroatom group independently selected from O, S, N, and NH, and the remainder is carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S( O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings.
  • a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 5-8-membered heterocycloalkyl group includes 5-6-membered, 6-7-membered, 7-8-membered, 5-membered, 6-membered, 7-membered and 8-membered heterocycloalkyl groups and the like.
  • Examples of 5-8 membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) , tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl,
  • 5-6 membered ring means a cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl ring consisting of 5 to 6 ring atoms base or heteroaryl.
  • the ring includes a single ring, and also includes a double ring system such as a spiro ring, a parallel ring, and a bridged ring.
  • the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • the 5-6 membered ring includes 5-membered, 6-membered rings and the like.
  • 5-6-membered ring includes, for example, phenyl, pyridyl, piperidyl and the like; on the other hand, the term “5-6-membered heterocycloalkyl” includes piperidyl and the like, but does not include phenyl.
  • ring also includes ring systems comprising at least one ring, wherein each "ring” is independently defined above.
  • 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 listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
  • the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • the solvent used in the present invention is commercially available.
  • HOBt stands for 1-hydroxybenzotriazole
  • EDCI stands for 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride
  • DBU stands for 1,8-diazacyclo[5,4 ,0] Undecene-7
  • OBn benzyloxy
  • DCE represents dichloroethane
  • DCC represents dicyclohexylcarbodiimide
  • DMAP represents 2.4-dimethylaminopyridine
  • ACN represents acetonitrile
  • Boc represents tert-butoxy Carbonyl
  • Jane's Catalyst-1B represents dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][[5-[(dimethylamino)sulfonyl ]-2-(1-methylethoxy-O)phenyl]methylene
  • Ruhenium (II) its CAS number is 918870-76
  • Dissolve compound 1h (0.6g, 1.18mmol) in toluene (10mL), cool to 0°C in an ice-water bath, add diisopropylethylamine (612.38mg, 4.74mmol, 825.30 ⁇ L), and then add 7-octenoyl chloride , and then heated to 100°C and stirred for 12 hours.
  • the temperature of the reaction solution was cooled, and the conical flask was taken, and 50 mL of water was added, poured into the reaction solution, and 50 mL of ethyl acetate was added for extraction.
  • the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue.
  • the crude product was purified by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80 ⁇ 30mm ⁇ 3 ⁇ m; mobile phase: [H 2 O(0.04%HCl)-ACN]; ACN%: 30%-60%, 8min), and purified to obtain Compound 6A.
  • Dissolve 7a (0.5g, 792.71 ⁇ mol) in anhydrous dichloromethane (500mL), add Hoveyda-Grubbs second-generation catalyst (58.17mg, 79.27 ⁇ mol) and p-benzoquinone (17.14mg, 158.54 ⁇ mol, 35.70 ⁇ L), Stir at 40°C for 12 hours.
  • the reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a residue.
  • the crude product was purified by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80 ⁇ 30mm ⁇ 3 ⁇ m; mobile phase: [H 2 O (0.04% hydrochloric acid)-ACN]; ACN%: 40%-70%, 8min), and purified to obtain Compound 10A.
  • the pure compound 15b (400mg) was separated by SFC (separation condition: REGIS (S, S) WHELK-O1 (250mm*25mm, 10 ⁇ m); mobile phase: [Neu-EtOH]%: 60%-60%, 7min) , purified to obtain pure products 15ca and 15cb.
  • SFC separation condition: REGIS (S, S) WHELK-O1 (250mm*25mm, 10 ⁇ m); mobile phase: [Neu-EtOH]%: 60%-60%, 7min) , purified to obtain pure products 15ca and 15cb.
  • 17a (0.6g, 930.62 ⁇ mol) was dissolved in dichloromethane (700mL), and Jane's catalyst-1B (68.28mg, 93.06 ⁇ mol) and benzoquinone (20.12mg, 186.12 ⁇ mol, 41.91 ⁇ L) were added, and the oil bath was heated to Stir at 40°C for 12h.
  • the reaction solution was filtered through celite, and concentrated under reduced pressure to obtain a crude product.
  • the pure compound 17b (200mg) was separated by SFC (separation condition: REGIS (S, S) WHELK-O1 (250mm*25mm, 10 ⁇ m); mobile phase: [Neu-IPA]%: 60%-60%, 8min) , purified to obtain pure products 17ca and 17cb.
  • SFC separation condition: REGIS (S, S) WHELK-O1 (250mm*25mm, 10 ⁇ m); mobile phase: [Neu-IPA]%: 60%-60%, 8min) , purified to obtain pure products 17ca and 17cb.
  • the pure product 11b (250mg) was separated by SFC (separation condition: DAICEL CHIRALPAK AD (250mm*30mm, 10 ⁇ m); mobile phase [Neu-EtOH]%: 46%-46%, 15min), and purified to obtain the pure product 19aa and 19ab.
  • the aqueous phase was extracted once more with ethyl acetate (20 mL); the combined organic phases were washed with saturated brine (40 mL), and the organic phases were dried over anhydrous sodium sulfate.
  • the crude product was obtained by filtration and concentration under reduced pressure.
  • 24b was subjected to SFC resolution (separation conditions: DAICEL CHIRALCEL OD 250mm*30mm*10 ⁇ m; mobile phase: [Neu-EtOH]%: 47%-47%, 10min), and the fractions were concentrated under reduced pressure to obtain 24ca and 24cb (analysis method : Column type: Chiralcel OD-3 50mm*4.6mm*3 ⁇ m; mobile phase: [A: CO 2 ; B: EtOH (0.1% IPAm, v/v)]; B%: 5%, 0.2min; 5%- 50%, 1min; 50%, 1min; 50%-5%, 0.4min; 5%, 0.4min; retention time: 1.534min (24ca), 1.608min (24cb)).
  • 25b was subjected to SFC resolution (separation conditions: DAICEL CHIRALPAKAD 250mm*30mm*10 ⁇ m; mobile phase: [Neu-EtOH]%: 46%-46%, 10min), and the fractions were concentrated under reduced pressure to obtain 25ca and 25cb (analysis method: Column type: Chiralpak AD-3 50mm*4.6mm*3 ⁇ m; Mobile phase: [A:CO 2 ; B:EtOH(0.1%IPAm,v/v)]; B%:5%,0.2min; 5%-50 %, 1min; 50%, 1min; 50%-5%, 0.4min; 5%, 0.4min; retention time: 1.831min (25ca), 2.044min (25cb)).
  • 26a (0.5g, 829.61 ⁇ mol) was dissolved in anhydrous dichloromethane (1700mL), and Jane's catalyst-1B (206.97mg, 282.07 ⁇ mol) and p-benzoquinone (60.98mg, 564.13 ⁇ mol) were added, and the oil bath was heated to Stir at 40°C for 12 hours.
  • the reaction solution was cooled and filtered directly, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • 26b (0.6g, 1.04mmol) was separated by SFC (separation condition: DAICEL CHIRALPAK AD 250mm*30mm*10 ⁇ m; mobile phase: [A:CO 2 -B:0.1%NH 3 H 2 O/EtOH]; B%:50 %-50%, 6min), two isomers 26ca and 26cb were obtained (analysis method: column type: Chiralpak AD-3 50mm*4.6mm*3 ⁇ m; mobile phase: [A: CO 2 ; B: EtOH (0.1% IPAm, v/v)]; B%: 5%, 0.2min; 5%-50%, 1min; 50%, 1min; 50%-5%, 0.4min; 5%, 0.4min; retention time: 1.611min (26ca), 1.782min (26cb)).
  • 26ca (0.2g, 348.04 ⁇ mol) was dissolved in anhydrous dichloromethane (5mL), anhydrous magnesium chloride (497.06mg, 5.22mmol) was added, and stirred at 28°C for 12 hours.
  • the reaction solution was directly concentrated under reduced pressure to obtain the crude product, which was subjected to reverse preparative liquid chromatography (separation conditions: Phenomenex Luna 80*30mm*3 ⁇ m; mobile phase: [H 2 O(HCl)-ACN]%: 25%-45%, 8min ) was isolated to give 26A.
  • 26b (0.3g, 522.06 ⁇ mol) was dissolved in ethyl acetate (10mL), palladium on carbon (0.3g, palladium content 10%) was added, and stirred under a hydrogen atmosphere (15psi, 28°C) for 12 hours.
  • the reaction solution was directly filtered through celite, and the filtrate was directly concentrated under reduced pressure to obtain a residue.
  • the crude product was separated by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80*30mm*3 ⁇ m; mobile phase: [H 2 O(HCl)-ACN]%: 30%-60%, 8min) to obtain 27A.
  • the hydrochloride salt of 28e (10.2g) was dissolved in acetonitrile (100mL), paraformaldehyde (625.85mg, 20.84mmol) and potassium carbonate (12.80g, 92.64mmol) were added, and the oil bath was heated to 50°C and stirred for 12 hours.
  • the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue.
  • the crude product was then slurried with ethyl acetate (50 mL) and filtered to give 28f.
  • 29c was separated by SFC (separation conditions: (S, S)-WHELK-O1 250mm*30mm*5 ⁇ m; mobile phase: [Neu-EtOH]%: 60%-60%, 6min), and the fractions were concentrated under reduced pressure to obtain compound 29A and 29B (analysis method: column type: (S,S)-WHELK-O1 50mm*4.6mm*3 ⁇ m; mobile phase: [A:CO 2 ; B:EtOH (0.1%IPAm,v/v)]; B%: 5%, 0.2min; 5%-50%, 1min; 50%, 1min; 50%-5%, 0.4min; 5%, 0.4min; retention time: 2.090min (29A), 2.407min (29B)).
  • 29A (0.2 g, 375.54 ⁇ mol) was dissolved in N,N-dimethylformamide (2 mL), 7-bromo-1-heptene (199.51 mg, 1.13 mmol) and cesium carbonate (244.72 mg, 751.09 ⁇ mol) were added ), stirred at 28°C for 12 hours. Take an Erlenmeyer flask, add 30 mL of water, pour into the reaction solution, add 30 mL of ethyl acetate for extraction, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 30a.
  • Dissolve 30a (0.34g, 540.77 ⁇ mol) in dichloromethane (340mL), add Jane's catalyst-1B (39.68mg, 54.08 ⁇ mol) and p-benzoquinone (11.69mg, 108.15 ⁇ mol), nitrogen replacement 3 times, oil
  • the bath was warmed to 40°C and stirred for 12 hours.
  • the reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a residue.
  • Dissolve 30ca (0.04 g, 66.59 ⁇ mol) in dichloromethane (1 mL), add magnesium chloride (95.10 mg, 998.87 ⁇ mol), and stir at 28° C. for 12 hours. Take the Erlenmeyer flask, add 20 mL of dichloromethane for extraction, dry the organic phase with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a residue. The crude product was slurried with methyl tert-butyl ether and filtered to obtain compound 30A.
  • 33h (0.18g, 266.45 ⁇ mol) was dissolved in N,N-dimethylformamide (10mL), cesium carbonate (130.22mg, 399.68 ⁇ mol) was added, and stirred at 25°C for 12 hours.
  • cesium carbonate 130.22mg, 399.68 ⁇ mol
  • take an Erlenmeyer flask add 50 mL of water, pour into the reaction solution, add 50 mL of ethyl acetate to extract three times, separate the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product.
  • Cyclopropylamine (3.75g, 63.44mmol) and solvent dichloromethane (5mL) were added to a pre-dried 50mL single-necked bottle, followed by dropwise addition of AlMe 3 (30mL, 59.94mmol, 2.0M), and stirring at room temperature for 1.5 h Standby; add 1e (5.95g, 9.99mmol) and dichloromethane (20mL) to a 250mL single-necked bottle, replace with nitrogen twice, and then inject the activated cyclopropylamine mixture into the dichloromethane solution of 1e with nitrogen pressure , stirred at room temperature for 3.0h.
  • Cyclopropylamine (2.43g, 42.56mmol) and solvent dichloromethane (4.0mL) were added to a pre-dried 50mL single-necked bottle, followed by the dropwise addition of AlMe 3 (21.5mL, 43.00mmol, 2.0M), and after the addition, room temperature Stir for 1.5h and set aside; add 1e (4.27g, 7.17mmol) and dichloromethane (14.0ml) to a 250mL single-necked bottle, replace with nitrogen twice, and then inject the activated cyclopropylamine mixture into 1e's dichloromethane with nitrogen pressure. Chloromethane solution, stirred at room temperature for 3.0h.
  • Test Example 1 Using the HIV pseudovirus (PsV) system to evaluate the antiviral activity of the test compound in vitro
  • HIV pseudovirus reporter gene assay is widely used in early screening, instead of HIV virus assay to evaluate the anti-HIV virus activity of compounds.
  • 293T cells were inoculated into 96-well test plates at a density of 55,000 cells per well and 100 ⁇ L per well, and cultured overnight in a 5% CO 2 , 37° C. incubator.
  • the compound after doubling dilution (8 concentration points, duplicate wells) was added, 50 ⁇ L per well.
  • the diluted virus was added to the cells at 100 TCID50 per well, 50 ⁇ L per well.
  • Set up cell control (cells, no compound treatment or virus infection), virus control (cells infected with virus, no compound treatment) and culture medium control (only culture medium).
  • the final volume of the experimental culture solution was 200 ⁇ L, and the final concentration of DMSO in the culture solution was 0.5%.
  • the cells were cultured in a 5% CO 2 , 37°C incubator for 3 days.
  • luciferase reporter gene detection reagent Britelite plus kit PerkinElmer
  • PerkinElmer luciferase reporter gene detection reagent Britelite plus kit
  • the cell viability of each well was detected with a BioTek microplate reader using the cell viability detection reagent CellTiter Glo, and the data were used for sample cytotoxicity analysis.
  • the EC 50 value was analyzed using GraphPad Prism (version 5) software to perform nonlinear fitting analysis on the inhibitory activity of the antibody and the cell viability, and the fitting method was "log(inhibitor) vs. response--Variable slope".
  • Table 1 The inhibitory activity of compound of the present invention to HIV pseudovirus (PsV)
  • the compound of the present invention shows a positive effect in the test of inhibiting HIV pseudovirus gene replication at the cell level.
  • Test Example 2 Evaluation of Anti-HIV-1 Activity of Test Compounds in Vitro by Cytopathic Pathology (CPE) Assay
  • HIV-1 human immunodeficiency virus type 1
  • test compound and the reference compound will be diluted with DMSO and then added to the cell culture plate.
  • HIV-1 and MT-4 cells were co-cultured in a 37°C, 5% CO2 incubator for 1 hour. Infected cells were then seeded in cell culture plates at a density of 10,000 cells per well. The final concentration of DMSO in the cell culture medium was 0.5%. Cells were cultured in a 37°C, 5% CO 2 incubator for 5-6 days.
  • Cell viability was determined by CellTiter-Glo (Promega). The raw data were used to calculate the anti-HIV-1 activity of the compounds.
  • Antiviral activity (test well reading value-virus control average value)/(cell control average value-virus control average value) ⁇ 100
  • Table 2 The compound of the present invention is to the inhibitory activity of HIV-1 virus
  • the compound of the present invention shows a positive effect in the experiment of inhibiting HIV-1 virus at the cell level.

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Abstract

Provided are a macrocyclic pyridone compound and an application thereof in preparation of drugs for treating related diseases. Specifically, provided are a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.

Description

大环吡啶酮类化合物及其应用Macrocyclic pyridone compounds and their applications
本发明主张如下优先权：The present invention claims the following priority:
CN202110873493.X，申请日：2021年7月30日。CN202110873493.X, filing date: July 30, 2021.
技术领域technical field
本发明涉及医药化学技术领域，特别是涉及一类大环吡啶酮类化合物及其应用，具体涉及式(I)所示化合物或其药学上可接受的盐。The present invention relates to the technical field of medicinal chemistry, in particular to a class of macrocyclic pyridone compounds and applications thereof, in particular to compounds represented by formula (I) or pharmaceutically acceptable salts thereof.
背景技术Background technique
在病毒中，已知人免疫缺陷病毒(HIV)，一种逆转录病毒，由HIV感染而引起的疾病称为艾滋病，全称为获得性免疫缺陷综合征(acquired immunodeficiency syndrome，AIDS)，该病患者的免疫功能部份或完全丧失，CD4+细胞数目减少，继而发生机会性感染、肿瘤等，临床表现多种多样。该病传播速度快、病死率高，且现无法治愈，引起了各国政府和社会的关注。Among the viruses, known human immunodeficiency virus (HIV), a retrovirus, the disease caused by HIV infection is called AIDS, and the full name is acquired immunodeficiency syndrome (AIDS). Partial or complete loss of immune function, reduction in the number of CD4+ cells, followed by opportunistic infections, tumors, etc., with various clinical manifestations. The disease spreads quickly, has a high fatality rate, and is currently incurable, which has attracted the attention of governments and societies in various countries.
HIV在病毒分类学上属逆转录病毒科(Retroviridae)慢病毒属(lentivirus)，截止2020年已发现两种HIV，分别为HIV-1和HIV-2。两者具有相似的病毒结构和传播途径。HIV-2主要分布于非洲西部，在欧洲和美洲的一些感染者中也被检测到。其毒力和传播力都低于HIV-1，引起的艾滋病病程较慢且较缓和。HIV-1广泛分布于世界各地，是引起全世界AIDS流行的病原，HIV的研究也是以HIV-1为主进行的。In terms of virus taxonomy, HIV belongs to the genus lentivirus of the family Retroviridae. As of 2020, two types of HIV have been discovered, namely HIV-1 and HIV-2. Both have similar viral structures and transmission routes. HIV-2 is mainly distributed in West Africa and has also been detected in some infected people in Europe and the Americas. Its virulence and transmissibility are lower than that of HIV-1, and the course of AIDS caused by it is slower and milder. HIV-1 is widely distributed all over the world and is the pathogen that causes the prevalence of AIDS all over the world. The research on HIV is also based on HIV-1.
HIV的流行呈世界性分布，非洲为HIV的发源地和重灾区，欧洲和美洲也为主要流行区，近年HIV在亚洲的流行呈高速增长的趋势。我国自1985年首次发现HIV感染者，已有60～80万人发生了感染，专家估计，如果不迅速采取有效的预防措施，按现年平均30％的增长速度，到2010年，我国的HIV感染者将超过1000万。在非洲的有些国家，HIV的感染率达总人口30％以上。因此，预防和治疗艾滋病，已不仅仅是挽救个人生命的问题，而是关系到民族存亡的大事。The prevalence of HIV is distributed worldwide. Africa is the birthplace and hardest hit area of HIV, and Europe and America are also the main epidemic areas. In recent years, the prevalence of HIV in Asia has shown a trend of rapid growth. Since the first discovery of HIV infection in my country in 1985, 600,000 to 800,000 people have been infected. Experts estimate that if effective preventive measures are not taken quickly, according to the current average growth rate of 30%, by 2010, my country's HIV infection will exceed 10 million. In some countries in Africa, the HIV infection rate reaches more than 30% of the total population. Therefore, the prevention and treatment of AIDS is not only a matter of saving individual lives, but a major event related to the survival of the nation.
目前用于AIDS的治疗剂主要选自一组逆转录酶抑制剂(如，AZT、3TC)和蛋白酶抑制剂(如，茚地那韦)，但它们被证实伴有副作用如肾病和出现抗药性病毒。因此，渴望开发具有其它作用机制的抗HIV药物。Current therapeutic agents for AIDS are mainly selected from a group of reverse transcriptase inhibitors (eg, AZT, 3TC) and protease inhibitors (eg, indinavir), but they have been shown to be associated with side effects such as kidney disease and drug resistance Virus. Therefore, the development of anti-HIV drugs having other mechanisms of action is desired.
整合酶链转移抑制剂(INSTI)最近被证明是有效的抗病毒机制，它通过阻断HIV病毒整合酶催化的链转移反应从而抑制病毒的复制过程，目前此类抑制剂的开发引起了广泛的兴趣。Integrase strand transfer inhibitors (INSTIs) have recently been shown to be effective antiviral mechanisms, which inhibit the viral replication process by blocking the strand transfer reaction catalyzed by HIV viral integrase. interest.
发明内容Contents of the invention
本发明提供了下式所示化合物或其药学上可接受的盐，其选自：The present invention provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof, which is selected from:
Figure PCTCN2022109064-appb-000001
Figure PCTCN2022109064-appb-000001
R 1选自F、Cl、Br、CN、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个F取代； R 1 is selected from F, Cl, Br, CN, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 F replacements;
m选自1、2和3；m is selected from 1, 2 and 3;
R 2选自C 1-3烷基、C 3-6环烷基和4-6元杂环烷基； R 2 is selected from C 1-3 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl;
R 3选自H； R is selected from H;
或者，R 2与R 3以及它们相连的原子成5-8元杂环烷基，所述5-8元杂环烷基任选被1、2或3个R a取代； Alternatively, R 2 and R 3 and the atoms connected to them form a 5-8 membered heterocycloalkyl group, and the 5-8 membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 R a ;
R a取各自独立地选自C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个F取代； R a is independently selected from C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 F ;
L 1选自-(CH 2) n-，其中，1、2或3个CH 2中的每一个CH 2任选独立地被1个R b置换，其余各CH 2任选独立地被1或2个Rc取代； L 1 is selected from -(CH 2 ) n -, wherein each CH 2 in 1, 2 or 3 CH 2 is optionally independently replaced by 1 R b , and each remaining CH 2 is optionally independently replaced by 1 or 2 Rc substitutions;
R b各自独立地选自O、NH、-CH＝CH-和-C(O)NH-； R b are each independently selected from O, NH, -CH=CH- and -C(O)NH-;
R c选自F、OH、C 1-3烷氧基、-N(CH 3) 2和-C 1-3烷基-OH； R c is selected from F, OH, C 1-3 alkoxy, -N(CH 3 ) 2 and -C 1-3 alkyl-OH;
n选自4、5、6、7、8、9、10、11、12、13、14和15；n is selected from 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15;
L 2选自CH 2和-C(＝O)-； L 2 is selected from CH 2 and -C(=O)-;
L 3选自CH 2、NH、O和S； L3 is selected from CH2 , NH, O and S ;
环A选自苯基和5-6元杂芳基；Ring A is selected from phenyl and 5-6 membered heteroaryl;
T 1选自CH和N； T1 is selected from CH and N ;
所述“4-6元杂环烷基”、“5-8元杂环烷基”和“5-6元杂芳基”的“杂”各自独立地包含1、2或3个独立选自O、S、N和NH的杂原子或原子团。The "hetero" of the "4-6 membered heterocycloalkyl", "5-8 membered heterocycloalkyl" and "5-6 membered heteroaryl" each independently contain 1, 2 or 3 members independently selected from Heteroatoms or atomic groups of O, S, N and NH.
本发明的一些方案中，上述R 1选自F，其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned R 1 is selected from F, and other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2022109064-appb-000002
选自
Figure PCTCN2022109064-appb-000003
Figure PCTCN2022109064-appb-000004
其他变量如本发明所定义。 In some solutions of the present invention, the above structural units
Figure PCTCN2022109064-appb-000002
selected from
Figure PCTCN2022109064-appb-000003
Figure PCTCN2022109064-appb-000004
Other variables are as defined herein.
本发明的一些方案中，上述Rc选自OH、甲氧基、-CH 2OH、-N(CH 3) 2和
Figure PCTCN2022109064-appb-000005
其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned Rc is selected from OH, methoxy, -CH 2 OH, -N(CH 3 ) 2 and
Figure PCTCN2022109064-appb-000005
Other variables are as defined herein.
本发明的一些方案中，上述n选自5、6、7、8、9、10和11，其他变量如本发明所定义。In some solutions of the present invention, the above n is selected from 5, 6, 7, 8, 9, 10 and 11, and other variables are as defined in the present invention.
本发明的一些方案中，上述L 1选自-(CH 2) 5-、-(CH 2) 6-、-(CH 2) 7-、-(CH 2) 8-、-(CH 2) 9-、-(CH 2) 10-和-(CH 2) 11-，其中，1、2或3个CH 2中的每一个CH 2任选独立地被1个R b置换，其余各CH 2任选独立地被1或2个R c取代，其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned L 1 is selected from -(CH 2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -(CH 2 ) 9 -, -(CH 2 ) 10 - and -(CH 2 ) 11 -, wherein each of 1, 2 or 3 CH 2s is optionally independently replaced by 1 R b , and each of the remaining CH 2s is optionally are independently substituted by 1 or 2 Rc , other variables are as defined in the present invention.
本发明的一些方案中，上述L 1选自-(CH 2) 5-、-(CH 2) 6-、-(CH 2) 7-、-(CH 2) 8-、-(CH 2) 9-、-(CH 2) 10-、-(CH 2) 11-、-(CH 2) 2-CH＝CH-(CH 2) 2-、-(CH 2) 2-CH＝CH-(CH 2) 3-、-(CH 2) 2-CH＝CH-(CH 2) 4-、-(CH 2) 2-CH＝CH-(CH 2) 5-、-(CH 2) 2-CH＝CH-(CH 2) 6-、-(CH 2) 2-CH＝CH-(CH 2) 7-、-(CH 2) 4-CH(OH).-(CH 2) 4-、-(CH 2) 4-CH(OH).-(CH 2) 5-、-(CH 2) 4-CH(CH 2OH).-(CH 2) 4-、-(CH 2) 4-CH(OCH 3)-(CH 2) 4-、
Figure PCTCN2022109064-appb-000006
-(CH 2) 4-NH-(CH 2) 4-、-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-、-(CH 2) 3-O-(CH 2) 2-O(CH 2) 2-、-(CH 2) 3-O-(CH 2) 2-O(CH 2) 3-、-CH 2C(O)NH(CH 2) 6-和-(CH 2) 2-O-(CH 2) 2-O-CH 2-，其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned L 1 is selected from -(CH 2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -(CH 2 ) 9 -, -(CH 2 ) 10 -, -(CH 2 ) 11 -, -(CH 2 ) 2 -CH=CH-(CH 2 ) 2 -, -(CH 2 ) 2 -CH=CH-(CH 2 ) 3 -, -(CH 2 ) 2 -CH=CH-(CH 2 ) 4 -, -(CH 2 ) 2 -CH=CH-(CH 2 ) 5 -, -(CH 2 ) 2 -CH=CH -(CH 2 ) 6 -, -(CH 2 ) 2 -CH=CH-(CH 2 ) 7 -, -(CH 2 ) 4 -CH(OH).-(CH 2 ) 4 -, -(CH 2 ) 4 -CH(OH).-(CH 2 ) 5 -, -(CH 2 ) 4 -CH(CH 2 OH).-(CH 2 ) 4 -, -(CH 2 ) 4 -CH(OCH 3 ) -(CH 2 ) 4 -,
Figure PCTCN2022109064-appb-000006
-(CH 2 ) 4 -NH-(CH 2 ) 4 -, -(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -, -(CH 2 ) 3 -O-( CH 2 ) 2 -O(CH 2 ) 2 -, -(CH 2 ) 3 -O-(CH 2 ) 2 -O(CH 2 ) 3 -, -CH 2 C(O)NH(CH 2 ) 6 - and -(CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 2 -, other variables are as defined herein.
本发明的一些方案中，上述环A选自苯基、吡啶基、嘧啶基和吡咯基，其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned ring A is selected from phenyl, pyridyl, pyrimidinyl and pyrrolyl, and other variables are as defined in the present invention.
发明的一些方案中，上述环A选自苯基，其他变量如本发明所定义。In some schemes of the invention, the above-mentioned ring A is selected from phenyl, and other variables are as defined in the present invention.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其化合物选自(I-1)和(I-2)所示的结构，In some schemes of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the structures shown in (I-1) and (I-2),
Figure PCTCN2022109064-appb-000007
Figure PCTCN2022109064-appb-000007
其中，R 1、R 2、R 3、L 1、L 2和m如本发明所定义。 Wherein, R 1 , R 2 , R 3 , L 1 , L 2 and m are as defined in the present invention.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其化合物选自式(II-1)所示的结构，In some schemes of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the structures shown in formula (II-1),
Figure PCTCN2022109064-appb-000008
Figure PCTCN2022109064-appb-000008
其中，in,
R 11选自H和F； R 11 is selected from H and F;
R 2选自C 1-3烷基、C 3-6环烷基和4-6元杂环烷基； R 2 is selected from C 1-3 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl;
R 3选自H； R is selected from H;
或者，R 2与R 3以及它们相连的原子成5-6元杂环烷基； Alternatively, R 2 and R 3 and their connected atoms form a 5-6 membered heterocycloalkyl group;
L 1选自-(CH 2) n-，其中，1、2或3个CH 2中的每一个CH 2各自独立地任选被1个R b置换； L 1 is selected from -(CH 2 ) n -, wherein each of 1, 2 or 3 CH 2s is independently optionally replaced by 1 R b ;
R b各自独立地选自O、NH、-CH＝CH-和-C(O)NH-； R b are each independently selected from O, NH, -CH=CH- and -C(O)NH-;
n选自5、6、7、8、9和10；n is selected from 5, 6, 7, 8, 9 and 10;
L 2选自CH 2和-C(＝O)-。 L2 is selected from CH2 and -C (=O)-.
本发明提供了下式所示化合物或其药学上可接受的盐，其选自：The present invention provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof, which is selected from:
Figure PCTCN2022109064-appb-000009
Figure PCTCN2022109064-appb-000009
R 1选自F、Cl、Br、CN、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个F取代； R 1 is selected from F, Cl, Br, CN, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 F replacements;
m选自1、2和3；m is selected from 1, 2 and 3;
R 2选自C 1-3烷基、C 3-6环烷基和4-6元杂环烷基； R 2 is selected from C 1-3 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl;
R 3选自H； R is selected from H;
或者，R 2与R 3以及它们相连的原子成5-8元杂环烷基，所述5-8元杂环烷基任选被1、2或3个R a取代； Alternatively, R 2 and R 3 and the atoms connected to them form a 5-8 membered heterocycloalkyl group, and the 5-8 membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 R a ;
R a取各自独立地选自C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个F取代； R a is independently selected from C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 F ;
L 1选自-(CH 2) n-，其中，各CH 2任选被1或2个R b置换，所述各CH 2任选独立地被1或2个Rc取代； L 1 is selected from -(CH 2 ) n -, wherein each CH 2 is optionally substituted by 1 or 2 R b , and each CH 2 is optionally independently substituted by 1 or 2 Rc;
R b各自独立地选自O、NH和-CH＝CH-； R b are each independently selected from O, NH and -CH=CH-;
Rc选自F、OH、C 1-3烷氧基、-N(CH 3) 2和-C 1-3烷基-OH； Rc is selected from F, OH, C 1-3 alkoxy, -N(CH 3 ) 2 and -C 1-3 alkyl-OH;
n选自4-15的自然数；n is selected from the natural numbers of 4-15;
L 2选自CH 2和-C(＝O)-； L 2 is selected from CH 2 and -C(=O)-;
L 3选自CH 2、NH、O和S； L3 is selected from CH2 , NH, O and S ;
环A选自苯基和5-6元杂芳基；Ring A is selected from phenyl and 5-6 membered heteroaryl;
T 1选自CH和N； T1 is selected from CH and N ;
所述“4-6元杂环烷基”、“5-8元杂环烷基”和“5-6元杂芳基”包含1、2或3个独立选自O、S、N和NH的杂原子或原子团。The "4-6 membered heterocycloalkyl", "5-8 membered heterocycloalkyl" and "5-6 membered heteroaryl" contain 1, 2 or 3 independently selected from O, S, N and NH heteroatoms or groups of atoms.
本发明的一些方案中，上述R 1选自F，其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned R 1 is selected from F, and other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2022109064-appb-000010
选自
Figure PCTCN2022109064-appb-000011
Figure PCTCN2022109064-appb-000012
其他变量如本发明所定义。 In some solutions of the present invention, the above structural units
Figure PCTCN2022109064-appb-000010
selected from
Figure PCTCN2022109064-appb-000011
Figure PCTCN2022109064-appb-000012
Other variables are as defined herein.
本发明的一些方案中，上述Rc选自OH、甲氧基、-N(CH 3) 2和
Figure PCTCN2022109064-appb-000013
其他变量如本发明所定义。 In some schemes of the present invention, the above-mentioned Rc is selected from OH, methoxy, -N(CH 3 ) 2 and
Figure PCTCN2022109064-appb-000013
Other variables are as defined herein.
本发明的一些方案中，上述n选自5、6、7、8、9、10和11，其他变量如本发明所定义。In some solutions of the present invention, the above n is selected from 5, 6, 7, 8, 9, 10 and 11, and other variables are as defined in the present invention.
本发明的一些方案中，上述L 1选自-(CH 2) 5-、-(CH 2) 6-、-(CH 2) 7-、-(CH 2) 8-、-(CH 2) 9-、-(CH 2) 10-和-(CH 2) 11-，其中各CH 2任选被1或2个R b置换，所述-(CH 2) n-任选被1或2个R c取代，其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned L 1 is selected from -(CH 2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -(CH 2 ) 9 -, -(CH 2 ) 10 - and -(CH 2 ) 11 -, wherein each CH 2 is optionally replaced by 1 or 2 R b , said -(CH 2 ) n - is optionally replaced by 1 or 2 R c is substituted, and other variables are as defined herein.
本发明的一些方案中，上述L 1选自-(CH 2) 5-、-(CH 2) 6-、-(CH 2) 7-、-(CH 2) 8-、-(CH 2) 9-、-(CH 2) 10-、-(CH 2) 11-、-(CH 2) 2-CH＝CH-(CH 2) 2-、-(CH 2) 2-CH＝CH-(CH 2) 3-、-(CH 2) 2-CH＝CH-(CH 2) 4-、-(CH 2) 2-CH＝CH-(CH 2) 5-、-(CH 2) 2-CH＝CH-(CH 2) 6-、-(CH 2) 2-CH＝CH-(CH 2) 7-、-(CH 2) 4-CH(OH).-(CH 2) 4-、-(CH 2) 4-CH(OH).-(CH 2) 5-、-(CH 2) 4-CH(CH 2OH).-(CH 2) 4-、-(CH 2) 4-CH(OCH 3)-(CH 2) 4-、
Figure PCTCN2022109064-appb-000014
-(CH 2) 4-NH-(CH 2) 4-、-(CH 2) 3-O-(CH 2) 2-O(CH 2) 2-和-(CH 2) 3-O-(CH 2) 2-O(CH 2) 3-，其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned L 1 is selected from -(CH 2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -(CH 2 ) 9 -, -(CH 2 ) 10 -, -(CH 2 ) 11 -, -(CH 2 ) 2 -CH=CH-(CH 2 ) 2 -, -(CH 2 ) 2 -CH=CH-(CH 2 ) 3 -, -(CH 2 ) 2 -CH=CH-(CH 2 ) 4 -, -(CH 2 ) 2 -CH=CH-(CH 2 ) 5 -, -(CH 2 ) 2 -CH=CH -(CH 2 ) 6 -, -(CH 2 ) 2 -CH=CH-(CH 2 ) 7 -, -(CH 2 ) 4 -CH(OH).-(CH 2 ) 4 -, -(CH 2 ) 4 -CH(OH).-(CH 2 ) 5 -, -(CH 2 ) 4 -CH(CH 2 OH).-(CH 2 ) 4 -, -(CH 2 ) 4 -CH(OCH 3 ) -(CH 2 ) 4 -,
Figure PCTCN2022109064-appb-000014
-(CH 2 ) 4 -NH-(CH 2 ) 4 -, -(CH 2 ) 3 -O-(CH 2 ) 2 -O(CH 2 ) 2 - and -(CH 2 ) 3 -O-(CH 2 ) 2 -O(CH 2 ) 3 -, other variables are as defined in the present invention.
本发明的一些方案中，上述环A选自苯基、吡啶基、嘧啶基和吡咯基，其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned ring A is selected from phenyl, pyridyl, pyrimidinyl and pyrrolyl, and other variables are as defined in the present invention.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其化合物选自(I-1)和(I-2)所示的结构，In some schemes of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the structures shown in (I-1) and (I-2),
Figure PCTCN2022109064-appb-000015
Figure PCTCN2022109064-appb-000015
其中，R 1、R 2、R 3、L 1、L 2和m如本发明所定义。 Wherein, R 1 , R 2 , R 3 , L 1 , L 2 and m are as defined in the present invention.
本发明还有一些方案是由上述各变量任意组合而来。Some schemes of the present invention are formed by any combination of the above-mentioned variables.
本发明还提供下述化合物或其药学上可接受的盐：The present invention also provides the following compounds or pharmaceutically acceptable salts thereof:
Figure PCTCN2022109064-appb-000016
Figure PCTCN2022109064-appb-000016
Figure PCTCN2022109064-appb-000017
Figure PCTCN2022109064-appb-000017
Figure PCTCN2022109064-appb-000018
Figure PCTCN2022109064-appb-000018
本发明一些方案中，上述化合物选自，In some schemes of the present invention, the above-mentioned compound is selected from,
Figure PCTCN2022109064-appb-000019
Figure PCTCN2022109064-appb-000019
Figure PCTCN2022109064-appb-000020
Figure PCTCN2022109064-appb-000020
Figure PCTCN2022109064-appb-000021
Figure PCTCN2022109064-appb-000021
本发明一些方案中，上述化合物选自，In some schemes of the present invention, the above-mentioned compound is selected from,
Figure PCTCN2022109064-appb-000022
Figure PCTCN2022109064-appb-000022
Figure PCTCN2022109064-appb-000023
Figure PCTCN2022109064-appb-000023
本发明提供了一种药物组合物，其包含有效治疗剂量的本发明化合物或其药学上可接受的盐。The present invention provides a pharmaceutical composition comprising a therapeutically effective dose of a compound of the present invention or a pharmaceutically acceptable salt thereof.
在一些实施方案中，本申请的药物组合物还包括药学上可接受的辅料、辅助剂或载体。In some embodiments, the pharmaceutical composition of the present application further includes pharmaceutically acceptable excipients, adjuvants or carriers.
另一方面，本申请还提供了上述的化合物、其立体异构体或其药学上可接受的盐、或其药物组合物，在制备用于预防和/或治疗HIV感染的药物上的应用。On the other hand, the present application also provides the application of the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a medicament for preventing and/or treating HIV infection.
本发明还提供了下列合成方法：The present invention also provides following synthetic method:
路线1Route 1
Figure PCTCN2022109064-appb-000024
Figure PCTCN2022109064-appb-000024
路线2route 2
Figure PCTCN2022109064-appb-000025
Figure PCTCN2022109064-appb-000025
路线3Route 3
Figure PCTCN2022109064-appb-000026
Figure PCTCN2022109064-appb-000026
路线4Route 4
Figure PCTCN2022109064-appb-000027
Figure PCTCN2022109064-appb-000027
技术效果technical effect
本发明化合物对HIV整合酶活性有着显著的抑制作用，同时在细胞水平抑制HIV假病毒基因复制试验以及抑制HIV活病毒复制试验中均展示出积极效应。The compound of the present invention has significant inhibitory effect on HIV integrase activity, and simultaneously exhibits positive effects in the test of inhibiting HIV pseudovirus gene replication at the cell level and the test of inhibiting HIV live virus replication.
定义和说明Definition and Description
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。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
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、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明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。当本发明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的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。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的中性形式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。The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent. Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.
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。The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods. In general, 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 both.
术语“有效治疗剂量”指的是在给予需要这样的治疗的哺乳动物时，足以有效治疗的通式化合物的量。治疗有效量将依赖于所用的治疗药剂的特定活性、患者的年龄、生理状况、其它疾病状态的存在和营养状况而变化。此外，患者可能正接受的其它药物治疗将影响要给予的治疗药剂的治疗有效量的确定。The term "therapeutically effective dose" refers to that amount of a compound of formula sufficient to be therapeutically effective when administered to a mammal in need of such treatment. A therapeutically effective amount will vary depending on the particular activity of the therapeutic agent employed, the age, physiological condition, presence of other disease states and nutritional status of the patient. In addition, other drug treatments that the patient may be receiving will affect the determination of a therapeutically effective amount of the therapeutic agent to be administered.
术语“治疗”意味着对于哺乳动物体内疾病的任何治疗，包括：(i)防止疾病，即造成疾病的临床症状不发展；(ii)抑制疾病，即阻止临床症状的发展；和/或(iii)减轻疾病，即造成临床症状的消退。The term "treatment" means any treatment of a disease in a mammal, including: (i) preventing the disease, that is, causing the clinical symptoms of the disease to not develop; (ii) inhibiting the disease, that is, preventing the development of clinical symptoms; and/or (iii) ) to alleviate the disease, that is, to cause the regression of clinical symptoms.
术语“药学上可接受的辅料、辅助剂或载体”包括任何和全部的溶剂、分散介质、包衣、抗细菌和抗真菌药剂、等渗和吸收延迟剂等。这样的介质和药剂用于药学活性物质在本领域是众所周知的。除非任何常规介质或药剂与活性成分不相容，其在治疗组合物中的应用是可预期的。补充的活性成分也可以并入组合物中。The term "pharmaceutically acceptable excipients, adjuvants or carriers" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agents are incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
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Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereoisomers and interconversions isomer
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。The compounds of the invention may exist in particular 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 their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
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。Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.
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。Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
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。Unless otherwise indicated, the term "diastereoisomer" refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise specified, "(+)" means dextrorotation, "(-)" means levorotation, and "(±)" means racemization.
除非另有规定，
Figure PCTCN2022109064-appb-000028
表示该化合物为顺式(Z式)和反式(E式)的混合物。 Unless otherwise specified,
Figure PCTCN2022109064-appb-000028
Indicates that the compound is a mixture of cis (Z) and trans (E).
除非另有说明，用楔形实线键
Figure PCTCN2022109064-appb-000029
和楔形虚线键
Figure PCTCN2022109064-appb-000030
表示一个立体中心的绝对构型。 Unless otherwise noted, keys with wedge-shaped solid lines
Figure PCTCN2022109064-appb-000029
and dotted wedge keys
Figure PCTCN2022109064-appb-000030
Indicates the absolute configuration of a stereocenter.
，用直形实线键
Figure PCTCN2022109064-appb-000031
和直形虚线键
Figure PCTCN2022109064-appb-000032
表示立体中心的相对构型，用波浪线
Figure PCTCN2022109064-appb-000033
表示楔形实线键
Figure PCTCN2022109064-appb-000034
或楔形虚线键
Figure PCTCN2022109064-appb-000035
或用波浪线
Figure PCTCN2022109064-appb-000036
表示直形实线键
Figure PCTCN2022109064-appb-000037
和直形虚线键
Figure PCTCN2022109064-appb-000038
, use the straight solid line key
Figure PCTCN2022109064-appb-000031
and straight dashed keys
Figure PCTCN2022109064-appb-000032
Indicates the relative configuration of the stereocenter, with a wavy line
Figure PCTCN2022109064-appb-000033
Indicates wedge-shaped solid-line bond
Figure PCTCN2022109064-appb-000034
or dotted wedge key
Figure PCTCN2022109064-appb-000035
or with tilde
Figure PCTCN2022109064-appb-000036
Indicates a straight solid line key
Figure PCTCN2022109064-appb-000037
and straight dashed keys
Figure PCTCN2022109064-appb-000038
除非另有说明，用直形实线键
Figure PCTCN2022109064-appb-000039
或直形虚线键
Figure PCTCN2022109064-appb-000040
与“*”组合表示手性中心为绝对构型但不确定，以(R)或(S)单一对映形式或富含一种对映体形式存在。例如用
Figure PCTCN2022109064-appb-000041
表示
Figure PCTCN2022109064-appb-000042
用
Figure PCTCN2022109064-appb-000043
表示
Figure PCTCN2022109064-appb-000044
Unless otherwise noted, use straight solid-line keys
Figure PCTCN2022109064-appb-000039
or straight dotted key
Figure PCTCN2022109064-appb-000040
Combination with "*" indicates that the chiral center has an absolute configuration but is indeterminate, exists as (R) or (S) single enantiomer or is enriched in one enantiomer. For example with
Figure PCTCN2022109064-appb-000041
express
Figure PCTCN2022109064-appb-000042
use
Figure PCTCN2022109064-appb-000043
express
Figure PCTCN2022109064-appb-000044
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％。Unless otherwise stated, the terms "enriched in an isomer", "enriched in an isomer", "enriched in an enantiomer" or "enantiomerically enriched" refer to one of the isomers or enantiomers The content of the enantiomer is less than 100%, and the content of the isomer or enantiomer 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%.
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。Compounds of the invention may exist specific. Unless otherwise stated, the term "tautomer" or "tautomeric form" means that isomers with different functional groups are in dynamic equilibrium at room temperature and are rapidly interconvertible. If tautomerism is possible (eg, in solution), then chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via migration of a proton, such as keto-enol isomerization and imine-ene Amine isomerization. Valence isomers (valence tautomers) involve interconversions by recombination of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
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％。Unless otherwise stated, the terms "enriched in an isomer", "enriched in an isomer", "enriched in an enantiomer" or "enantiomerically enriched" refer to one of the isomers or enantiomers The content of the enantiomer is less than 100%, and the content of the isomer or enantiomer 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%.
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％。Unless otherwise stated, the terms "isomer excess" or "enantiomeric excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 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)。Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
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。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). For another example, heavy hydrogen can be used to replace hydrogen to form deuterated drugs. The bond formed by deuterium and carbon is stronger than the bond 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 changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
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。The term "optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where said event or circumstance does not occur .
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。所述“各某一基团任选被取代时”，表示前述结构中的任一该基团任选被取代；例如，当“L 1选自-(CH 2) n-，所述各CH 2任选被1或2个R c取代”，指L 1的可选基团中的任一CH 2任选被1或2个R c取代。 The term "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. When a substituent is oxygen (ie =0), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "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 realizable basis. The "when each certain group is optionally substituted" means that any such group in the aforementioned structure is optionally substituted; for example, when "L 1 is selected from -(CH 2 ) n -, each CH 2 is optionally substituted by 1 or 2 Rc ", means that any CH2 in the optional group of L1 is optionally substituted by 1 or 2 Rc .
术语“被置换”指特定的原子或基团可以被替换为指定的其他原子或基团。例如-(CH 2) n-中的各CH 2任选可被O、-CH＝CH-或NH置换得到-O-、-CH＝CH-或-NH-。 The term "substituted" means that a specified atom or group can be replaced by another atom or group as specified. For example, each CH2 in -( CH2 ) n- can optionally be replaced by O, -CH=CH- or NH to give -O-, -CH=CH- or -NH-.
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。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 0-2 R, said group may optionally be substituted with up to two R, with independent options for each occurrence of R. Also, combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
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。 When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
当一个取代基数量为0时，表示该取代基是不存在的，比如-A-(R) 0表示该结构实际上是-A。 When the number of a substituent is 0, it means that the substituent does not exist, such as -A-(R) 0 means that the structure is actually -A.
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。When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A.
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。When one of the variables is selected from a single bond, it means that the two groups connected are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
当一个取代基的键可以交叉连接到一个环上的两个以上原子时，这种取代基可以与这个环上的任意原 子相键合，例如，结构单元
Figure PCTCN2022109064-appb-000045
表示其取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。 A substituent can be bonded to any atom on a ring when the bond of a substituent can cross-link two or more atoms on the ring, e.g., structural unit
Figure PCTCN2022109064-appb-000045
It means that the substituent R can be substituted at any position on cyclohexyl or cyclohexadiene. When the enumerated substituent does not indicate which atom it is connected to the substituted group, this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring. The carbon atom is attached to the group being substituted.
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，
Figure PCTCN2022109064-appb-000046
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
Figure PCTCN2022109064-appb-000047
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
Figure PCTCN2022109064-appb-000048
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。 When the linking group listed does not indicate its linking direction, its linking direction is arbitrary, for example,
Figure PCTCN2022109064-appb-000046
The connecting 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 to form
Figure PCTCN2022109064-appb-000047
It can also be formed by connecting loop A and loop B in the opposite direction to the reading order from left to right
Figure PCTCN2022109064-appb-000048
Combinations of the described linking groups, substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
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
Figure PCTCN2022109064-appb-000049
直形虚线键
Figure PCTCN2022109064-appb-000050
或波浪线
Figure PCTCN2022109064-appb-000051
表示。例如-OCH 3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；
Figure PCTCN2022109064-appb-000052
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；
Figure PCTCN2022109064-appb-000053
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；
Figure PCTCN2022109064-appb-000054
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括
Figure PCTCN2022109064-appb-000055
Figure PCTCN2022109064-appb-000056
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2022109064-appb-000057
仍包括
Figure PCTCN2022109064-appb-000058
这种连接方式的基团，只是在连接1个化学键时，该位点的H会对应减少1个变成相应的一价哌啶基。 Unless otherwise specified, when a group has one or more linkable sites, any one or more sites of the group can be linked to other groups through chemical bonds. When the connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group. The chemical bonds that the site connects with other groups can use straight solid line bonds
Figure PCTCN2022109064-appb-000049
Straight dotted key
Figure PCTCN2022109064-appb-000050
or tilde
Figure PCTCN2022109064-appb-000051
express. For example, the straight-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
Figure PCTCN2022109064-appb-000052
The straight dotted line bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
Figure PCTCN2022109064-appb-000053
The wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups;
Figure PCTCN2022109064-appb-000054
Indicates that any connectable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least
Figure PCTCN2022109064-appb-000055
Figure PCTCN2022109064-appb-000056
These 4 connection methods, even if the H atom is drawn on -N-, but
Figure PCTCN2022109064-appb-000057
still include
Figure PCTCN2022109064-appb-000058
For groups with this connection method, only when a chemical bond is connected, the H at this site will be reduced by one to become the corresponding monovalent piperidinyl group.
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。Unless otherwise specified, the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring" means a "ring" with 5-7 atoms arranged around it.
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、C 1-3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。 Unless otherwise specified, the term "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 , C 1-3 and C 2-3 alkyl groups, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or multivalent ( such as methine). Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
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。 Unless otherwise specified, the term "C 1-3 alkoxy" denotes those alkyl groups containing 1 to 3 carbon atoms attached to the rest 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 groups and the like. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
除非另有规定，“C 3-6环烷基”表示由3至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C 3-6环烷基包括C 3-4、C 4-5和C 5-6环烷基等；其可以是一价、二价或者多价。C 3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。 Unless otherwise specified, "C 3-6 cycloalkyl" means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, and the C 3-6 cycloalkyl includes C 3-4 , C 4-5 and C 5-6 cycloalkyl, etc.; it may be monovalent, divalent or multivalent. Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
除非另有规定，术语“5-8元杂环烷基”本身或者与其他术语联合分别表示由5至8个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S、N和NH的杂原子或杂原子团，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“5-8元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述5-8元杂环烷基包括5-6元、6-7元、7-8元、5元、6元、7元和8元杂环烷基等。5-8元杂环烷基的实例包括但不限于吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。 Unless otherwise specified, the term "5-8 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 5 to 8 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms is a heteroatom or heteroatom group independently selected from O, S, N, and NH, and the remainder is carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S( O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings. In addition, with respect to the "5-8 membered heterocycloalkyl", a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule. The 5-8-membered heterocycloalkyl group includes 5-6-membered, 6-7-membered, 7-8-membered, 5-membered, 6-membered, 7-membered and 8-membered heterocycloalkyl groups and the like. Examples of 5-8 membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) , tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.
除非另有规定，“5-6元环”表示由5至6个环原子组成的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所述的环包括单环，也包括螺环、并环和桥环等双环体系。除非另有规定，该环任选地包含1、2或3个独立选自O、S和N的杂原子。所述5-6元环包括5元、6元环等。“5-6元环”包括例如苯基、吡啶基和哌啶基等；另一方面，术语“5-6元杂环烷基”包括哌啶基等，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。Unless otherwise specified, "5-6 membered ring" means a cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl ring consisting of 5 to 6 ring atoms base or heteroaryl. The ring includes a single ring, and also includes a double ring system such as a spiro ring, a parallel ring, and a bridged ring. Unless otherwise specified, the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N. The 5-6 membered ring includes 5-membered, 6-membered rings and the like. "5-6-membered ring" includes, for example, phenyl, pyridyl, piperidyl and the like; on the other hand, the term "5-6-membered heterocycloalkyl" includes piperidyl and the like, but does not include phenyl. The term "ring" also includes ring systems comprising at least one ring, wherein each "ring" is independently defined above.
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。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 listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
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。The structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
本发明所使用的溶剂可经市售获得。The solvent used in the present invention is commercially available.
本发明使用以下缩略词：This document uses the following acronyms:
HOBt代表1-羟基苯并三唑；EDCI代表1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐；DBU代表1,8- 二氮杂环[5,4,0]十一烯-7；OBn代表苄氧基；DCE代表二氯乙烷；DCC代表二环己基碳二亚胺；DMAP代表2.4-二甲氨基吡啶；ACN代表乙腈；Boc代表叔丁氧羰基；詹氏催化剂-1B代表二氯[1,3-双(2,4,6-三甲基苯基)-2-咪唑烷亚基][[5-[(二甲基氨基)磺酰基]-2-(1-甲基乙氧基-O)苯基]亚甲基C]钌(II)，其CAS号为918870-76-5；eq代表当量；M代表摩尔每升。HOBt stands for 1-hydroxybenzotriazole; EDCI stands for 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride; DBU stands for 1,8-diazacyclo[5,4 ,0] Undecene-7; OBn represents benzyloxy; DCE represents dichloroethane; DCC represents dicyclohexylcarbodiimide; DMAP represents 2.4-dimethylaminopyridine; ACN represents acetonitrile; Boc represents tert-butoxy Carbonyl; Jane's Catalyst-1B represents dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][[5-[(dimethylamino)sulfonyl ]-2-(1-methylethoxy-O)phenyl]methylene C]ruthenium (II), its CAS number is 918870-76-5; eq stands for equivalent; M stands for moles per liter.
化合物依据本领域常规命名原则或者使用
Figure PCTCN2022109064-appb-000059
软件命名，市售化合物采用供应商目录名称。 Compounds are named according to the conventional naming principles in this field or using
Figure PCTCN2022109064-appb-000059
The software is named, and the commercially available compounds adopt the supplier catalog name.
具体实施方式Detailed ways
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。The present invention will be described in detail through examples below, but it does not imply any unfavorable limitation to the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. will be obvious.
实施例1Example 1
Figure PCTCN2022109064-appb-000060
Figure PCTCN2022109064-appb-000060
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000061
Figure PCTCN2022109064-appb-000061
步骤1：化合物1a的合成Step 1: Synthesis of Compound 1a
在干燥的三口瓶中加入4-氟-2-羟基苯腈(25g,182.33mmol)和N,N-二甲基甲酰胺(250mL)，加入4-溴-1-丁烯(73.85g,547.00mmol,55.52mL)和碳酸钾(75.60g,547.00mmol)，氮气置换3次，将反应置于60℃搅拌12个小时。向反应液，加入500mL水，倒入反应液，加入乙酸乙酯(500mL×3)萃取，合并有机相，用1000mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物1a。Add 4-fluoro-2-hydroxybenzonitrile (25g, 182.33mmol) and N,N-dimethylformamide (250mL) into a dry three-necked flask, add 4-bromo-1-butene (73.85g, 547.00 mmol, 55.52 mL) and potassium carbonate (75.60 g, 547.00 mmol), replaced with nitrogen three times, and the reaction was stirred at 60° C. for 12 hours. Add 500 mL of water to the reaction solution, pour into the reaction solution, add ethyl acetate (500 mL×3) for extraction, combine the organic phases, wash with 1000 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 1a.
1H NMR(400MHz,CDCl 3)δ(ppm)＝7.56-7.46(m,1H),6.72-6.60(m,2H),5.88(tdd,J＝6.8,10.2,17.2Hz,1H),5.22-5.05(m,2H),4.09-4.04(m,2H),2.58(q,J＝6.7Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 7.56-7.46 (m, 1H), 6.72-6.60 (m, 2H), 5.88 (tdd, J = 6.8, 10.2, 17.2Hz, 1H), 5.22- 5.05(m,2H),4.09-4.04(m,2H),2.58(q,J=6.7Hz,2H).
步骤2：化合物1b的合成Step 2: Synthesis of Compound 1b
在预先干燥过的三口烧瓶中加入1a(11g,57.53mmol)，加入溶剂四氢呋喃(120mL)中，氮气抽换气三次，冰水浴降温到0℃，加入四氢锂铝(2.18g,57.53mmol)，升温到25℃搅拌12个小时。向反应液中加入50mL水，加入50mL氢氧化钠溶液，加入100mL水，然后过滤，滤饼用200mL四氢呋喃冲洗三次，滤液直接减压浓缩得到残余物。粗品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-50:50)分离，馏分减压浓缩得到1b。Add 1a (11g, 57.53mmol) to a pre-dried three-necked flask, add the solvent tetrahydrofuran (120mL), pump nitrogen for three times, cool down to 0°C in an ice-water bath, add lithium aluminum tetrahydrogen (2.18g, 57.53mmol) , heated to 25°C and stirred for 12 hours. Add 50 mL of water to the reaction solution, add 50 mL of sodium hydroxide solution, add 100 mL of water, then filter, wash the filter cake with 200 mL of tetrahydrofuran three times, and directly concentrate the filtrate under reduced pressure to obtain a residue. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether=100:0-50:50), and the fractions were concentrated under reduced pressure to obtain 1b.
1H NMR(400MHz,CDCl 3)δ(ppm)＝7.13-7.00(m,1H),6.59-6.41(m,2H),5.81(tdd,J＝6.8,10.3,17.1Hz,1H),5.19-5.00(m,2H),3.93(t,J＝6.3Hz,2H),3.68(s,2H),2.55-2.43(m,2H),1.53(br s,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 7.13-7.00 (m, 1H), 6.59-6.41 (m, 2H), 5.81 (tdd, J = 6.8, 10.3, 17.1Hz, 1H), 5.19- 5.00(m,2H),3.93(t,J＝6.3Hz,2H),3.68(s,2H),2.55-2.43(m,2H),1.53(br s,2H).
步骤3：化合物1c的合成Step 3: Synthesis of Compound 1c
在干燥的三口瓶中加入4-氧代-3-苄氧基-4H-吡喃-2,5-二甲酸二甲酯(116g,364.46mmol)和甲苯(500mL)，开启搅拌，随后加入乙酸(8.75g,145.78mmol,8.34mL)，氮气置换3次，外温升温至85℃(内温65℃)，缓慢向体系加入肼基甲酸叔丁酯(52.98g,400.91mmol)和甲苯(500mL)的混合溶液，伴随滴加有固体析出，将反应置于内温65℃搅拌16小时。向反应液加入饱和碳酸氢钠水溶液淬灭反应，通过布氏漏斗过滤得到固体，滤饼用乙酸乙酯500mL洗涤。加入1V(1mL/g)乙酸乙酯溶解，搅拌下缓慢加入石油醚(1mL/g)，室温打浆1小时，过滤得到1c。Add 4-oxo-3-benzyloxy-4H-pyran-2,5-dicarboxylate (116g, 364.46mmol) and toluene (500mL) into a dry three-necked flask, start stirring, and then add acetic acid (8.75g, 145.78mmol, 8.34mL), nitrogen replacement 3 times, the external temperature was raised to 85°C (internal temperature was 65°C), and tert-butyl carbazate (52.98g, 400.91mmol) and toluene (500mL ) mixed solution, with the dropwise addition of solids precipitated, the reaction was placed at an internal temperature of 65°C and stirred for 16 hours. Add saturated aqueous sodium bicarbonate solution to the reaction solution to quench the reaction, filter through a Buchner funnel to obtain a solid, and wash the filter cake with 500 mL of ethyl acetate. Add 1V (1 mL/g) ethyl acetate to dissolve, slowly add petroleum ether (1 mL/g) under stirring, beat at room temperature for 1 hour, and filter to obtain 1c.
1H NMR(400MHz,CDCl 3)δ(ppm)＝8.30(br s,1H),8.23(s,1H),7.45-7.29(m,5H),5.26(s,2H),3.87(s,3H),3.77(s,3H),1.42-1.41(m,1H),1.46(s,8H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 8.30 (br s, 1H), 8.23 (s, 1H), 7.45-7.29 (m, 5H), 5.26 (s, 2H), 3.87 (s, 3H ),3.77(s,3H),1.42-1.41(m,1H),1.46(s,8H).
步骤4：化合物1d的合成Step 4: Synthesis of Compound 1d
在预先干燥过的三口烧瓶中，将1c(50g,115.63mmol)溶于甲醇(400mL)和四氢呋喃(200mL)的溶液中，加入1M的氢氧化锂水溶液(254.38mL)，25℃搅拌12小时。搅拌下缓慢加入2M盐酸调节pH＝4，析出固体，过滤，滤饼用水淋洗，油泵减压旋蒸，得到1d，无需提纯直接用于下一步。In a pre-dried three-necked flask, 1c (50 g, 115.63 mmol) was dissolved in a solution of methanol (400 mL) and tetrahydrofuran (200 mL), and 1M lithium hydroxide aqueous solution (254.38 mL) was added, and stirred at 25°C for 12 hours. With stirring, 2M hydrochloric acid was slowly added to adjust the pH to 4, the solid was precipitated, filtered, the filter cake was rinsed with water, and the oil pump was rotary evaporated under reduced pressure to obtain 1d, which was directly used in the next step without purification.
1H NMR(400MHz,DMSO-d6)δ(ppm)＝8.32(s,1H),7.42-7.30(m,5H),5.10(s,2H),3.75(d,J＝1.0Hz,6H),1.40(br s,9H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 8.32 (s, 1H), 7.42-7.30 (m, 5H), 5.10 (s, 2H), 3.75 (d, J = 1.0Hz, 6H), 1.40(br s,9H).
步骤5：化合物1e的合成Step 5: Synthesis of compound 1e
在干燥的三口瓶中加入1d(13g,31.07mmol)和N,N-二甲基甲酰胺(130mL)开启搅拌，随后加入HOBt(5.46g,40.39mmol)，EDCI(11.91g,62.14mmol)，搅拌90min，然后降温到0℃，加入1b(6.07g,31.07mmol)的N,N-二甲基甲酰胺(130mL)溶液，加毕，升温到25℃搅拌12个小时。向500mL水中倒入反应液，加入乙酸乙酯(500mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝100:1-50:50)分离，得到1e。Add 1d (13g, 31.07mmol) and N,N-dimethylformamide (130mL) to a dry three-necked flask to start stirring, then add HOBt (5.46g, 40.39mmol), EDCI (11.91g, 62.14mmol), Stir for 90min, then cool down to 0°C, add 1b (6.07g, 31.07mmol) in N,N-dimethylformamide (130mL) solution, after the addition is complete, raise the temperature to 25°C and stir for 12 hours. Pour the reaction solution into 500 mL of water, add ethyl acetate (500 mL×3) for extraction, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=100:1-50:50) to obtain 1e.
1H NMR(400MHz,CDCl 3)δ(ppm)＝10.27(br t,J＝5.8Hz,1H),8.50-8.40(m,1H),8.26(br s,1H),7.44-7.35(m,4H),7.33-7.27(m,2H),6.67-6.53(m,2H),6.01-5.86(m,1H),5.30-5.09(m,4H),4.59(d,J＝5.9Hz,2H),4.07(t,J＝6.7Hz,2H),3.80(s,3H),2.74-2.63(m,2H),1.47(s,9H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 10.27 (br t, J = 5.8Hz, 1H), 8.50-8.40 (m, 1H), 8.26 (br s, 1H), 7.44-7.35 (m, 4H),7.33-7.27(m,2H),6.67-6.53(m,2H),6.01-5.86(m,1H),5.30-5.09(m,4H),4.59(d,J＝5.9Hz,2H) ,4.07(t,J=6.7Hz,2H),3.80(s,3H),2.74-2.63(m,2H),1.47(s,9H).
步骤6：化合物1f的合成Step 6: Synthesis of Compound 1f
在预先干燥过的500mL单口瓶中加入1e(22g,36.94mmol)和溶剂四氢呋喃(250mL)，随后加入试剂DBU(1.69g,11.08mmol,1.67mL)，随后加入甲胺乙醇溶液(38.42g,408.15mmol,33％浓度)，反应在60℃下反应12个小时。反应液降温，向反应液中加入500mL二氯甲烷，并用100mL浓度为1N的柠檬酸水溶液洗涤两次，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用5V(1mL/g)的乙酸乙酯打浆，过滤， 得到化合物1f。Add 1e (22g, 36.94mmol) and solvent tetrahydrofuran (250mL) to a pre-dried 500mL one-necked flask, then add reagent DBU (1.69g, 11.08mmol, 1.67mL), then add methylamine ethanol solution (38.42g, 408.15 mmol, 33% concentration), the reaction was reacted at 60°C for 12 hours. The temperature of the reaction solution was cooled, and 500 mL of dichloromethane was added to the reaction solution, washed twice with 100 mL of 1N citric acid aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was slurried with 5V (1 mL/g) ethyl acetate and filtered to obtain compound 1f.
1H NMR(400MHz,CDCl 3)δ(ppm)＝10.21(br t,J＝5.6Hz,1H),8.69(br s,1H),8.48(s,1H),7.39-7.29(m,5H),6.65-6.49(m,3H),5.96(tdd,J＝6.8,10.3,17.0Hz,1H),5.29-5.08(m,4H),4.58(d,J＝6.0Hz,2H),4.05(t,J＝6.7Hz,2H),3.80-3.71(m,2H),2.71(d,J＝5.1Hz,3H),2.67(q,J＝6.6Hz,2H),1.86(td,J＝3.3,6.6Hz,2H),1.42(s,9H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 10.21 (br t, J = 5.6Hz, 1H), 8.69 (br s, 1H), 8.48 (s, 1H), 7.39-7.29 (m, 5H) ,6.65-6.49(m,3H),5.96(tdd,J=6.8,10.3,17.0Hz,1H),5.29-5.08(m,4H),4.58(d,J=6.0Hz,2H),4.05(t ,J=6.7Hz,2H),3.80-3.71(m,2H),2.71(d,J=5.1Hz,3H),2.67(q,J=6.6Hz,2H),1.86(td,J=3.3, 6.6Hz, 2H), 1.42(s, 9H).
步骤7：化合物1g的合成Step 7: Synthesis of Compound 1g
在干燥的三口瓶中，将1f(50g,84.09mmol)溶于乙酸乙酯(250mL)和甲醇(250mL)中，加入4N盐酸/乙酸乙酯(84.09mmol)，搅拌12小时。反应液直接减压浓缩。粗品用5V乙酸乙酯室温打浆，得到1g。In a dry three-necked flask, 1f (50 g, 84.09 mmol) was dissolved in ethyl acetate (250 mL) and methanol (250 mL), and 4N hydrochloric acid/ethyl acetate (84.09 mmol) was added, and stirred for 12 hours. The reaction solution was directly concentrated under reduced pressure. The crude product was slurried with 5V ethyl acetate at room temperature to obtain 1 g.
1H NMR(400MHz,DMSO-d6)δ(ppm)＝10.53(t,J＝5.8Hz,1H),8.75(br d,J＝4.6Hz,1H),8.44(s,1H),7.45-7.31(m,5H),7.23(dd,J＝7.1,8.2Hz,1H),6.94(dd,J＝2.4,11.3Hz,1H),6.73(dt,J＝2.4,8.5Hz,1H),5.96(tdd,J＝6.7,10.3,17.1Hz,1H),5.19(qd,J＝1.6,17.3Hz,1H),5.09-5.03(m,3H),4.43(d,J＝5.8Hz,2H),4.10(t,J＝6.5Hz,2H),2.73(d,J＝4.6Hz,3H),2.58(q,J＝6.5Hz,2H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 10.53 (t, J = 5.8Hz, 1H), 8.75 (br d, J = 4.6Hz, 1H), 8.44 (s, 1H), 7.45-7.31 (m,5H),7.23(dd,J=7.1,8.2Hz,1H),6.94(dd,J=2.4,11.3Hz,1H),6.73(dt,J=2.4,8.5Hz,1H),5.96( tdd, J=6.7, 10.3, 17.1Hz, 1H), 5.19(qd, J=1.6, 17.3Hz, 1H), 5.09-5.03(m, 3H), 4.43(d, J=5.8Hz, 2H), 4.10 (t, J=6.5Hz, 2H), 2.73(d, J=4.6Hz, 3H), 2.58(q, J=6.5Hz, 2H).
步骤8：化合物1h的合成Step 8: Synthesis of Compound 1h
在预先干燥过的250mL单口瓶中加入原料1g(10g,18.83mmol,盐酸)和溶剂乙腈(150mL)，随后加入碳酸钾(15.62g,113.00mmol)和甲醛(622.12mg,20.72mmol,570.75μL)，反应在50℃下反应12小时。LCMS显示原料信号消失，产物信号生成反应液直接过滤，滤液用50mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到1h，无需纯化直接投入下一步。Add raw material 1g (10g, 18.83mmol, hydrochloric acid) and solvent acetonitrile (150mL) to a pre-dried 250mL single-necked bottle, then add potassium carbonate (15.62g, 113.00mmol) and formaldehyde (622.12mg, 20.72mmol, 570.75μL) , and the reaction was carried out at 50° C. for 12 hours. LCMS showed that the raw material signal disappeared, and the product signal generated reaction solution was filtered directly, the filtrate was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to obtain 1h, and directly used in the next step without purification.
1H NMR(400MHz,DMSO-d6)δ(ppm)＝10.40(br t,J＝5.7Hz,1H),8.28(s,1H),7.67-7.28(m,6H),7.23(t,J＝7.6Hz,1H),6.94(dd,J＝2.0,11.2Hz,1H),6.74-6.66(m,1H),5.96(tdd,J＝6.8,10.4,17.1Hz,1H),5.24-5.02(m,4H),4.63(br d,J＝7.7Hz,2H),4.43(br d,J＝5.7Hz,2H),4.09(t,J＝6.5Hz,2H),3.00(s,3H),2.59(q,J＝6.6Hz,2H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 10.40 (br t, J = 5.7Hz, 1H), 8.28 (s, 1H), 7.67-7.28 (m, 6H), 7.23 (t, J = 7.6Hz, 1H), 6.94(dd, J＝2.0, 11.2Hz, 1H), 6.74-6.66(m, 1H), 5.96(tdd, J＝6.8, 10.4, 17.1Hz, 1H), 5.24-5.02(m ,4H),4.63(br d,J=7.7Hz,2H),4.43(br d,J=5.7Hz,2H),4.09(t,J=6.5Hz,2H),3.00(s,3H),2.59 (q,J=6.6Hz,2H).
步骤9：化合物1i的合成Step 9: Synthesis of Compound 1i
将1h(0.8g,1.58mmol)溶于甲苯(10mL)中，加入二异丙基乙基胺(816.48mg,6.32mmol,1.10mL)，然后降温到0℃，加入5-己烯酰氯(837.63mg,6.32mmol)，升到25℃搅拌12小时。加入100mL水，倒入反应液，加入乙酸乙酯(100mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩。粗品经硅胶柱层析(乙酸乙酯：石油醚＝100:0-50:50)分离，得到1i。Dissolve 1h (0.8g, 1.58mmol) in toluene (10mL), add diisopropylethylamine (816.48mg, 6.32mmol, 1.10mL), then cool down to 0°C, add 5-hexenoyl chloride (837.63 mg, 6.32mmol), raised to 25°C and stirred for 12 hours. Add 100 mL of water, pour into the reaction solution, add ethyl acetate (100 mL×3) for extraction, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (ethyl acetate:petroleum ether=100:0-50:50) to obtain 1i.
1H NMR(400MHz,DMSO-d6)δ(ppm)＝10.27-10.22(m,1H),7.56(d,J＝6.8Hz,2H),7.41-7.29(m,3H),7.27-7.20(m,1H),6.97-6.90(m,1H),6.75-6.69(m,1H),6.04-5.91(m,1H),5.85-5.74(m,1H),5.65-5.54(m,1H),5.34-5.24(m,1H),5.21-5.13(m,2H),5.10-4.95(m,4H),4.45(br d,J＝5.9Hz,2H),4.14-4.04(m,2H),3.08-3.03(m,3H),2.68-2.58(m,3H),2.11-2.01(m,2H),1.75-1.59(m,2H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 10.27-10.22 (m, 1H), 7.56 (d, J = 6.8Hz, 2H), 7.41-7.29 (m, 3H), 7.27-7.20 (m ,1H),6.97-6.90(m,1H),6.75-6.69(m,1H),6.04-5.91(m,1H),5.85-5.74(m,1H),5.65-5.54(m,1H),5.34 -5.24(m,1H),5.21-5.13(m,2H),5.10-4.95(m,4H),4.45(br d,J=5.9Hz,2H),4.14-4.04(m,2H),3.08- 3.03(m,3H),2.68-2.58(m,3H),2.11-2.01(m,2H),1.75-1.59(m,2H).
步骤10：化合物1j的合成Step 10: Synthesis of Compound 1j
在预先干燥过的三口烧瓶中加入1i(358.34mg,594.61μmol)和溶剂DCE(350mL)，在15℃，加入Hoveyda-Grubbs二代催化剂(37.26mg,59.46μmol)。加毕，氮气抽换气三次，混合物在80℃继续搅拌16小时。粗品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-0:100)分离，得到1j。1i (358.34 mg, 594.61 μmol) and solvent DCE (350 mL) were added to a pre-dried three-necked flask, and Hoveyda-Grubbs second-generation catalyst (37.26 mg, 59.46 μmol) was added at 15°C. After the addition was complete, nitrogen was purged three times, and the mixture was stirred at 80°C for 16 hours. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether=100:0-0:100) to obtain 1j.
1H NMR(400MHz,CDCl 3)δ(ppm)＝9.68-9.56(m,1H),8.66-8.57(m,1H),7.55-7.47(m,2H),7.36-7.28(m,3H),7.25-7.16(m,1H),6.68-6.53(m,2H),5.58-5.44(m,2H),5.39-5.26(m,4H),4.71-4.61(m,1H),3.95-3.75(m,3H),3.11(s,3H),2.77-2.62(m,1H),2.54-2.28(m,2H),2.22-2.08(m,1H),1.81-1.62(m,2H),1.62-1.47(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 9.68-9.56 (m, 1H), 8.66-8.57 (m, 1H), 7.55-7.47 (m, 2H), 7.36-7.28 (m, 3H), 7.25-7.16(m,1H),6.68-6.53(m,2H),5.58-5.44(m,2H),5.39-5.26(m,4H),4.71-4.61(m,1H),3.95-3.75(m ,3H),3.11(s,3H),2.77-2.62(m,1H),2.54-2.28(m,2H),2.22-2.08(m,1H),1.81-1.62(m,2H),1.62-1.47 (m,2H).
步骤11：化合物1A的合成Step 11: Synthesis of Compound 1A
在干燥的氢化瓶中加入1j(246.01mg,428.13μmol)和乙酸乙酯(5mL)，在氩气保护下加入Pd/C(0.1g,428.13μmol,5％纯度)，随后置换氢气，反应在15psi、20℃搅拌12小时。反应液通过硅藻土过滤，N,N-二甲基甲酰胺溶解通过有机相针头式滤器过滤，得到粗品。粗品经制备反向液相色谱(分离条件:Phenomenex Luna 80×30mm×3μm；流动相:[H 2O(0.04％HCl)-ACN]；ACN％:30％-60％,8min)，分离纯化，得到化合物1A。 Add 1j (246.01mg, 428.13μmol) and ethyl acetate (5mL) to a dry hydrogenation bottle, add Pd/C (0.1g, 428.13μmol, 5% purity) under the protection of argon, then replace the hydrogen, and react in Stir at 15 psi, 20°C for 12 hours. The reaction solution was filtered through celite, and N,N-dimethylformamide dissolved was filtered through a syringe filter of the organic phase to obtain a crude product. The crude product was separated and purified by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80×30mm×3μm; mobile phase: [H 2 O(0.04%HCl)-ACN]; ACN%: 30%-60%, 8min). , to obtain compound 1A.
MS(ESI,m/z):487.2[M+1] +. MS(ESI,m/z):487.2[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝11.62-11.47(m,1H),9.57-9.48(m,1H),8.82(s,1H),7.43-7.33(m,1H),6.88(dd,J＝2.3,11.4Hz,1H),6.81-6.69(m,1H),5.63(d,J＝12.9Hz,1H),5.15(dd,J＝9.2,13.3Hz,1H),5.04(d,J＝12.5Hz,1H),3.97-3.77(m,3H),3.01(s,3H),2.29-2.20(m,2H),1.59-1.03(m,11H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 11.62-11.47 (m, 1H), 9.57-9.48 (m, 1H), 8.82 (s, 1H), 7.43-7.33 (m, 1H), 6.88 (dd, J=2.3,11.4Hz,1H),6.81-6.69(m,1H),5.63(d,J=12.9Hz,1H),5.15(dd,J=9.2,13.3Hz,1H),5.04( d,J＝12.5Hz,1H),3.97-3.77(m,3H),3.01(s,3H),2.29-2.20(m,2H),1.59-1.03(m,11H).
实施例2Example 2
Figure PCTCN2022109064-appb-000062
Figure PCTCN2022109064-appb-000062
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000063
Figure PCTCN2022109064-appb-000063
步骤1：化合物2A和2B的合成Step 1: Synthesis of Compounds 2A and 2B
在干燥的三口瓶中加入1j(0.16g,278.46μmol)和二氯甲烷(3mL)，开启搅拌，随后加入无水氯化镁(530.24mg,5.57mmol)，氮气置换3次，将反应置于18℃搅拌16小时。减压浓缩得到粗产品。粗品经制备反向液相色谱(分离条件:Phenomenex Luna C18 150×30mm×5μm；流动相:[H 2O(0.1％TFA)-ACN]；ACN％: 20％-50％,8min)，纯化得到产物2A和2B。 Add 1j (0.16g, 278.46μmol) and dichloromethane (3mL) into a dry three-necked flask, start stirring, then add anhydrous magnesium chloride (530.24mg, 5.57mmol), nitrogen replacement 3 times, and place the reaction at 18°C Stir for 16 hours. Concentration under reduced pressure gave crude product. The crude product was purified by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna C18 150×30mm×5μm; mobile phase: [H 2 O(0.1%TFA)-ACN]; ACN%: 20%-50%, 8min) Products 2A and 2B were obtained.
2A:2A:
1H NMR(400MHz,DMSO-d6)δ(ppm)＝11.76-11.57(m,1H),9.63(d,J＝8.8Hz,1H),8.78(s,1H),7.40(dd,J＝7.2,8.1Hz,1H),6.92(dd,J＝2.4,11.2Hz,1H),6.76(dt,J＝2.5,8.4Hz,1H),5.62(d,J＝12.7Hz,1H),5.38-5.27(m,1H),5.25-5.12(m,2H),5.04-4.98(m,1H),5.02(d,J＝12.5Hz,1H),3.98-3.80(m,3H),3.00(s,3H),2.48-2.35(m,2H),2.30-2.21(m,1H),2.06-1.95(m,1H),1.82-1.65(m,2H),1.48-1.32(m,2H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 11.76-11.57 (m, 1H), 9.63 (d, J = 8.8Hz, 1H), 8.78 (s, 1H), 7.40 (dd, J = 7.2 ,8.1Hz,1H),6.92(dd,J=2.4,11.2Hz,1H),6.76(dt,J=2.5,8.4Hz,1H),5.62(d,J=12.7Hz,1H),5.38-5.27 (m,1H),5.25-5.12(m,2H),5.04-4.98(m,1H),5.02(d,J＝12.5Hz,1H),3.98-3.80(m,3H),3.00(s,3H ),2.48-2.35(m,2H),2.30-2.21(m,1H),2.06-1.95(m,1H),1.82-1.65(m,2H),1.48-1.32(m,2H).
2B:2B:
1H NMR(400MHz,DMSO-d6)δ(ppm)＝11.65(s,1H),9.56(d,J＝9.4Hz,1H),8.82(s,1H),7.40-7.31(m,1H),6.92-6.85(m,1H),6.89(s,1H),6.77-6.70(m,1H),6.79-6.69(m,1H),5.70-5.59(m,1H),5.63(d,J＝12.5Hz,1H),5.42-5.17(m,1H),5.45-5.13(m,2H),5.01(d,J＝12.7Hz,1H),3.96-3.78(m,3H),3.00(s,3H),2.48-2.35(m,2H),2.29-2.14(m,1H),2.05-1.92(m,2H),2.10-1.91(m,1H),1.89-1.73(m,1H),1.65-1.34(m,2H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 11.65 (s, 1H), 9.56 (d, J = 9.4Hz, 1H), 8.82 (s, 1H), 7.40-7.31 (m, 1H), 6.92-6.85(m,1H),6.89(s,1H),6.77-6.70(m,1H),6.79-6.69(m,1H),5.70-5.59(m,1H),5.63(d,J=12.5 Hz,1H),5.42-5.17(m,1H),5.45-5.13(m,2H),5.01(d,J＝12.7Hz,1H),3.96-3.78(m,3H),3.00(s,3H) ,2.48-2.35(m,2H),2.29-2.14(m,1H),2.05-1.92(m,2H),2.10-1.91(m,1H),1.89-1.73(m,1H),1.65-1.34( m,2H).
实施例3Example 3
Figure PCTCN2022109064-appb-000064
Figure PCTCN2022109064-appb-000064
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000065
Figure PCTCN2022109064-appb-000065
步骤1：化合物3a的合成Step 1: Synthesis of compound 3a
将化合物1h(1.15g,7.70mmol)溶于N,N-二甲基甲酰胺(15mL)中，加入氢氧化钾(287.99mg,5.13mmol)和5-溴-1-戊烯(1.3g,2.57mmol)，28℃搅拌12小时。取锥形瓶，加入20mL水，倒入反应液，加入20mL乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到残余物。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:1)分离，得到化合物3a。Compound 1h (1.15g, 7.70mmol) was dissolved in N,N-dimethylformamide (15mL), potassium hydroxide (287.99mg, 5.13mmol) and 5-bromo-1-pentene (1.3g, 2.57 mmol), stirred at 28°C for 12 hours. Take an Erlenmeyer flask, add 20 mL of water, pour into the reaction solution, add 20 mL of ethyl acetate to extract three times, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to obtain compound 3a.
1H NMR(400MHz,CDCl 3)δ(ppm)＝10.34(s,1H),8.32-8.31(m,1H),8.31(s,1H),7.56(d,J＝6.9Hz,2H),7.39-7.30(m,3H),7.26-7.20(m,1H),6.93(dd,J＝2.4,11.4Hz,1H),6.72(dt,J＝2.4,8.5Hz,1H),5.96(br dd,J＝10.4,17.1Hz,1H),5.85-5.75(m,1H),5.26-4.94(m,7H),4.43(br d,J＝5.9Hz,2H),4.09(t,J＝6.5Hz,2H),3.05(s,3H),3.00(br s,1H),2.59(q,J＝6.6Hz,2H),2.11(br d,J＝6.9Hz,2H),1.62-1.52(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 10.34 (s, 1H), 8.32-8.31 (m, 1H), 8.31 (s, 1H), 7.56 (d, J = 6.9Hz, 2H), 7.39 -7.30(m,3H),7.26-7.20(m,1H),6.93(dd,J＝2.4,11.4Hz,1H),6.72(dt,J＝2.4,8.5Hz,1H),5.96(br dd, J=10.4,17.1Hz,1H),5.85-5.75(m,1H),5.26-4.94(m,7H),4.43(br d,J=5.9Hz,2H),4.09(t,J=6.5Hz, 2H),3.05(s,3H),3.00(br s,1H),2.59(q,J=6.6Hz,2H),2.11(br d,J=6.9Hz,2H),1.62-1.52(m,2H ).
步骤2：化合物3b的合成Step 2: Synthesis of compound 3b
将化合物3a(0.3g,522.06μmol)溶于二氯甲烷(500mL)中，氮气置换三次，然后加入Hoveyda-Grubbs二代催化剂(88.64mg,104.41μmol)，升温到40℃搅拌12小时。反应液直接过滤，滤液直接减压浓缩得到残余物。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:1)分离，得到化合物3b。Compound 3a (0.3g, 522.06μmol) was dissolved in dichloromethane (500mL), replaced with nitrogen three times, then Hoveyda-Grubbs second-generation catalyst (88.64mg, 104.41μmol) was added, heated to 40°C and stirred for 12 hours. The reaction solution was directly filtered, and the filtrate was directly concentrated under reduced pressure to obtain a residue. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to obtain compound 3b.
1H NMR(400MHz,CDCl 3)δ(ppm)＝9.39(br s,1H),8.61-8.50(m,1H),7.50-7.42(m,2H),7.26-7.11(m,4H),6.55-6.42(m,2H),5.57-5.47(m,1H),5.46-5.34(m,1H),5.25-5.21(m,2H),4.45-3.63(m,4H),3.03(s,3H),2.90-2.80(m,1H),2.58-1.97(m,3H),1.73-1.00(m,5H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 9.39 (br s, 1H), 8.61-8.50 (m, 1H), 7.50-7.42 (m, 2H), 7.26-7.11 (m, 4H), 6.55 -6.42(m,2H),5.57-5.47(m,1H),5.46-5.34(m,1H),5.25-5.21(m,2H),4.45-3.63(m,4H),3.03(s,3H) ,2.90-2.80(m,1H),2.58-1.97(m,3H),1.73-1.00(m,5H).
步骤3：化合物3A的合成Step 3: Synthesis of Compound 3A
将化合物3b(0.12g,219.54μmol)溶于二氯甲烷(2mL)中，加入无水氯化镁(418.06mg,4.39mmol)，28℃搅拌12个小时。反应液直接减压浓缩得到残余物。甲醇溶解通过有机相针头式滤器过滤，得到粗品。粗品经制备反向液相色谱(分离条件:Phenomenex Luna 80×30mm×3μm；流动相:[H 2O(0.04％HCl)-ACN]；ACN％:20％-50％,8min)，分离纯化，得到化合物3A。 Compound 3b (0.12g, 219.54μmol) was dissolved in dichloromethane (2mL), anhydrous magnesium chloride (418.06mg, 4.39mmol) was added, and stirred at 28°C for 12 hours. The reaction solution was directly concentrated under reduced pressure to obtain a residue. Dissolved in methanol and filtered through a syringe filter of the organic phase to obtain the crude product. The crude product was separated and purified by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80×30mm×3μm; mobile phase: [H 2 O(0.04%HCl)-ACN]; ACN%: 20%-50%, 8min). , to obtain compound 3A.
1H NMR(400MHz,DMSO-d6)δ(ppm)＝11.87(s,1H),9.54-9.45(m,1H),8.45-8.37(m,1H),7.31(br d,J＝5.7Hz,1H),6.87-6.65(m,2H),5.57-5.44(m,2H),5.32-5.04(m,2H),4.75-4.61(m,1H),4.12-3.97(m,1H),3.84-3.59(m,1H),3.07(br t,J＝4.9Hz,2H),3.04(s,3H),2.42-2.38(m,1H),2.31-2.20(m,1H),2.08-1.88(m,1H),1.48-1.01(m,4H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 11.87 (s, 1H), 9.54-9.45 (m, 1H), 8.45-8.37 (m, 1H), 7.31 (br d, J = 5.7Hz, 1H),6.87-6.65(m,2H),5.57-5.44(m,2H),5.32-5.04(m,2H),4.75-4.61(m,1H),4.12-3.97(m,1H),3.84- 3.59(m,1H),3.07(br t,J＝4.9Hz,2H),3.04(s,3H),2.42-2.38(m,1H),2.31-2.20(m,1H),2.08-1.88(m ,1H),1.48-1.01(m,4H).
实施例4Example 4
Figure PCTCN2022109064-appb-000066
Figure PCTCN2022109064-appb-000066
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000067
Figure PCTCN2022109064-appb-000067
步骤1：化合物4A的合成Step 1: Synthesis of Compound 4A
准备干燥的氢化瓶，在氩气保护下加入湿Pd/C(0.1g)，随后加入3b(0.12g,219.54μmol)和乙酸乙酯(2mL)，随后置换氢气，反应在15psi、20℃搅拌12小时。反应液通过硅藻土过滤，减压浓缩，N,N-二甲基甲酰胺溶解通过有机相针头式滤器过滤得到粗品。粗品经制备反向液相色谱(分离条件:Phenomenex Luna 80×30mm×3μm；流动相:[H 2O(0.04％HCl)-ACN]；ACN％:25％-55％,8min)，纯化得到化合物4A。 Prepare a dry hydrogenation bottle, add wet Pd/C (0.1 g) under argon protection, then add 3b (0.12 g, 219.54 μmol) and ethyl acetate (2 mL), then replace the hydrogen, and the reaction is stirred at 15 psi, 20 °C 12 hours. The reaction solution was filtered through celite, concentrated under reduced pressure, dissolved in N,N-dimethylformamide and filtered through a syringe filter of the organic phase to obtain a crude product. The crude product was purified by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80×30mm×3μm; mobile phase: [H 2 O(0.04%HCl)-ACN]; ACN%: 25%-55%, 8min), and purified to obtain Compound 4A.
MS(ESI,m/z):459.2[M+1] +. MS(ESI,m/z):459.2[M+1] + .
实施例5Example 5
Figure PCTCN2022109064-appb-000068
Figure PCTCN2022109064-appb-000068
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000069
Figure PCTCN2022109064-appb-000069
步骤1：化合物5a的合成Step 1: Synthesis of Compound 5a
将化合物1h(0.6g,1.18mmol)溶于甲苯(10mL)中，冰水浴降温到0℃，加入二异丙基乙胺(612.38mg,4.74mmol,825.30μL)，然后加入7-辛烯酰氯，然后升温到100℃搅拌12个小时。反应液降温，取锥形瓶，加入50mL水，倒入反应液，加入50mL乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩得到残余物。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:1)分离，得到化合物5a。Dissolve compound 1h (0.6g, 1.18mmol) in toluene (10mL), cool to 0°C in an ice-water bath, add diisopropylethylamine (612.38mg, 4.74mmol, 825.30μL), and then add 7-octenoyl chloride , and then heated to 100°C and stirred for 12 hours. The temperature of the reaction solution was cooled, and the conical flask was taken, and 50 mL of water was added, poured into the reaction solution, and 50 mL of ethyl acetate was added for extraction. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to obtain compound 5a.
1H NMR(400MHz,CDCl 3)δ(ppm)＝10.17(br t,J＝5.9Hz,1H),8.41(s,1H),7.49(dd,J＝1.3,7.7Hz,2H),7.31-7.18(m,6H),6.59-6.50(m,2H),5.90(d,J＝6.8Hz,1H),5.69(br dd,J＝10.3,17.0Hz,1H),5.43-5.32(m,2H),5.24-5.02(m,3H),4.97-4.82(m,2H),4.52(br d,J＝6.0Hz,2H),3.04(s,3H),2.63(q,J＝6.7Hz,2H),2.28(s,1H),2.01-1.91(m,3H),1.34-1.16(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 10.17 (br t, J = 5.9Hz, 1H), 8.41 (s, 1H), 7.49 (dd, J = 1.3, 7.7Hz, 2H), 7.31- 7.18(m,6H),6.59-6.50(m,2H),5.90(d,J=6.8Hz,1H),5.69(br dd,J=10.3,17.0Hz,1H),5.43-5.32(m,2H ),5.24-5.02(m,3H),4.97-4.82(m,2H),4.52(br d,J=6.0Hz,2H),3.04(s,3H),2.63(q,J=6.7Hz,2H ),2.28(s,1H),2.01-1.91(m,3H),1.34-1.16(m,6H).
步骤2：化合物5b的合成Step 2: Synthesis of compound 5b
将5a(0.2g,317.11μmol)溶于二氯甲烷(200mL)中，加入对苯醌(53.84mg,63.42μmol)和Hoveyda-Grubbs二代催化剂(53.84mg,63.42μmol)，升到40℃搅拌12个小时。反应液直接减压浓缩得到残余物。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:1)分离，得到化合物5b。Dissolve 5a (0.2g, 317.11μmol) in dichloromethane (200mL), add p-benzoquinone (53.84mg, 63.42μmol) and Hoveyda-Grubbs second-generation catalyst (53.84mg, 63.42μmol), and stir at 40°C 12 hours. The reaction solution was directly concentrated under reduced pressure to obtain a residue. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to obtain compound 5b.
1H NMR(400MHz,CDCl 3)δ(ppm)＝9.60(br d,J＝4.1Hz,1H),8.53(s,1H),7.44(br d,J＝6.4Hz,2H),7.29-7.12(m,5H),6.66-6.50(m,2H),5.48-5.18(m,5H),4.98(dd,J＝6.6,13.7Hz,1H),4.50(d,J＝12.8Hz,1H),4.08-3.85(m,3H),3.03(s,3H),2.46-2.11(m,4H),1.75-1.55(m,2H),1.30-1.09(m,4H),1.04-0.91(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 9.60 (br d, J = 4.1Hz, 1H), 8.53 (s, 1H), 7.44 (br d, J = 6.4Hz, 2H), 7.29-7.12 (m,5H),6.66-6.50(m,2H),5.48-5.18(m,5H),4.98(dd,J=6.6,13.7Hz,1H),4.50(d,J=12.8Hz,1H), 4.08-3.85(m,3H),3.03(s,3H),2.46-2.11(m,4H),1.75-1.55(m,2H),1.30-1.09(m,4H),1.04-0.91(m,1H ).
步骤3：化合物5A的合成Step 3: Synthesis of Compound 5A
将化合物5b(0.1g,165.93μmol)溶于无水二氯甲烷(1mL)中，加入无水氯化镁(315.97mg,3.32mmol)，28℃搅拌12个小时。反应液减压浓缩得到残余物。甲醇溶解通过有机相针头式滤器过滤，得到粗品。粗品经制备反向液相色谱(分离条件:Phenomenex Luna 80×30mm×3μm；流动相:[H 2O(0.04％HCl)-ACN]；ACN％:30％-60％,8min)分离，得到化合物5A。 Compound 5b (0.1 g, 165.93 μmol) was dissolved in anhydrous dichloromethane (1 mL), anhydrous magnesium chloride (315.97 mg, 3.32 mmol) was added, and stirred at 28° C. for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a residue. Dissolved in methanol and filtered through a syringe filter of the organic phase to obtain the crude product. The crude product was separated by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80×30mm×3μm; mobile phase: [H 2 O(0.04%HCl)-ACN]; ACN%: 30%-60%, 8min) to obtain Compound 5A.
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.37(br s,1H),9.63(br s,1H),8.58(s,1H),6.70-6.53(m,2H),5.70(d,J＝12.5Hz,1H),5.46(t,J＝3.3Hz,2H),4.98(dd,J＝5.9,13.6Hz,1H),4.79(d,J＝12.5Hz,1H),4.12-3.88(m,3H),3.17(s,3H),2.59-2.37(m,2H),2.31-2.09(m,2H),1.82-1.68(m,2H),1.42-0.80(m,7H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.37 (br s, 1H), 9.63 (br s, 1H), 8.58 (s, 1H), 6.70-6.53 (m, 2H), 5.70 (d, J=12.5Hz, 1H), 5.46(t, J=3.3Hz, 2H), 4.98(dd, J=5.9, 13.6Hz, 1H), 4.79(d, J=12.5Hz, 1H), 4.12-3.88( m,3H),3.17(s,3H),2.59-2.37(m,2H),2.31-2.09(m,2H),1.82-1.68(m,2H),1.42-0.80(m,7H).
实施例6Example 6
Figure PCTCN2022109064-appb-000070
Figure PCTCN2022109064-appb-000070
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000071
Figure PCTCN2022109064-appb-000071
步骤1：化合物6A的合成Step 1: Synthesis of Compound 6A
准备干燥的氢化瓶，在氩气保护下加入湿Pd/C(17mg,10％纯度)，随后加入5b(0.1g,165.93μmol)和乙酸乙酯(3mL)，随后置换氢气，反应在15psi、28℃搅拌12小时。反应液通过硅藻土过滤，减压浓缩，甲醇溶解通过有机相针头式滤器过滤得到粗品。粗品经制备反向液相色谱(分离条件:Phenomenex Luna 80×30mm×3μm；流动相:[H 2O(0.04％HCl)-ACN]；ACN％:30％-60％,8min)，纯化得到化合物6A。 Prepare a dry hydrogenation bottle, add wet Pd/C (17mg, 10% purity) under the protection of argon, then add 5b (0.1g, 165.93μmol) and ethyl acetate (3mL), then replace hydrogen, react at 15psi, Stir at 28°C for 12 hours. The reaction solution was filtered through celite, concentrated under reduced pressure, dissolved in methanol and filtered through an organic phase syringe filter to obtain a crude product. The crude product was purified by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80×30mm×3μm; mobile phase: [H 2 O(0.04%HCl)-ACN]; ACN%: 30%-60%, 8min), and purified to obtain Compound 6A.
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.31(br s,1H),9.54(br s,1H),8.50(s,1H),6.63-6.50(m,2H),5.63(d,J＝12.5Hz,1H),4.86(dd,J＝5.6,13.6Hz,1H),4.71(d,J＝12.5Hz,1H),4.03(dd,J＝3.2,13.6Hz,1H),3.97-3.82(m,2H),3.09(s,3H),2.27-2.15(m,1H),2.06-1.97(m,1H),1.72-1.57(m,2H),1.41-0.89(m,12H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.31 (br s, 1H), 9.54 (br s, 1H), 8.50 (s, 1H), 6.63-6.50 (m, 2H), 5.63 (d, J=12.5Hz, 1H), 4.86(dd, J=5.6, 13.6Hz, 1H), 4.71(d, J=12.5Hz, 1H), 4.03(dd, J=3.2, 13.6Hz, 1H), 3.97- 3.82(m,2H),3.09(s,3H),2.27-2.15(m,1H),2.06-1.97(m,1H),1.72-1.57(m,2H),1.41-0.89(m,12H).
实施例7Example 7
Figure PCTCN2022109064-appb-000072
Figure PCTCN2022109064-appb-000072
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000073
Figure PCTCN2022109064-appb-000073
步骤1：化合物7a的合成Step 1: Synthesis of compound 7a
将化合物1h(1g,1.97mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入9-溴-1-壬烯和氢氧化钾(221.55mg,3.95mmol)，25℃搅拌12小时。取锥形瓶，加入20mL水，倒入反应液，加入20mL乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩得到残余物。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:1)分离，得到化合物7a。Dissolve compound 1h (1g, 1.97mmol) in N,N-dimethylformamide (10mL), add 9-bromo-1-nonene and potassium hydroxide (221.55mg, 3.95mmol), stir at 25°C for 12 Hour. Take an Erlenmeyer flask, add 20 mL of water, pour into the reaction solution, add 20 mL of ethyl acetate for extraction, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to obtain compound 7a.
1H NMR(400MHz,CDCl 3)δ(ppm)＝10.33(br t,J＝5.9Hz,1H),8.40(s,1H),7.57-7.48(m,2H),7.31-7.15(m,5H),6.57-6.47(m,2H),5.89(tdd,J＝6.8,10.3,17.1Hz,1H),5.80-5.66(m,1H),5.35-4.82(m,6H),4.51(d,J＝6.0Hz,2H),3.98(t,J＝6.7Hz,2H),3.05(s,3H),2.95-2.87(m,2H),2.60(q,J＝6.7Hz,2H),1.97(q,J＝7.0Hz,2H),1.46-1.17(m,11H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 10.33 (br t, J = 5.9Hz, 1H), 8.40 (s, 1H), 7.57-7.48 (m, 2H), 7.31-7.15 (m, 5H ),6.57-6.47(m,2H),5.89(tdd,J＝6.8,10.3,17.1Hz,1H),5.80-5.66(m,1H),5.35-4.82(m,6H),4.51(d,J =6.0Hz, 2H), 3.98(t, J=6.7Hz, 2H), 3.05(s, 3H), 2.95-2.87(m, 2H), 2.60(q, J=6.7Hz, 2H), 1.97(q ,J＝7.0Hz,2H),1.46-1.17(m,11H).
步骤2：化合物7b的合成Step 2: Synthesis of compound 7b
将7a(0.5g,792.71μmol)溶于无水二氯甲烷(500mL)中，加入Hoveyda-Grubbs二代催化剂(58.17mg,79.27μmol)和对苯醌(17.14mg,158.54μmol,35.70μL)，40℃搅拌12小时。反应液直接过滤，滤液减压浓缩得到残余物。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:1)分离，得到化合物7b。Dissolve 7a (0.5g, 792.71μmol) in anhydrous dichloromethane (500mL), add Hoveyda-Grubbs second-generation catalyst (58.17mg, 79.27μmol) and p-benzoquinone (17.14mg, 158.54μmol, 35.70μL), Stir at 40°C for 12 hours. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to obtain compound 7b.
1H NMR(400MHz,CDCl 3)δ(ppm)＝9.82(br t,J＝4.5Hz,1H),8.47-8.35(m,1H),7.56-7.42(m,2H),7.29-7.13(m,6H),6.60-6.46(m,2H),5.58-5.48(m,1H),5.42-5.30(m,1H),4.09-3.79(m,3H),3.03(s,3H),2.35(q,J＝5.8Hz,2H),1.38(br d,J＝2.1Hz,2H),1.26-1.07(m,8H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 9.82 (br t, J = 4.5Hz, 1H), 8.47-8.35 (m, 1H), 7.56-7.42 (m, 2H), 7.29-7.13 (m ,6H),6.60-6.46(m,2H),5.58-5.48(m,1H),5.42-5.30(m,1H),4.09-3.79(m,3H),3.03(s,3H),2.35(q ,J=5.8Hz,2H),1.38(br d,J=2.1Hz,2H),1.26-1.07(m,8H).
步骤3：化合物7A的合成Step 3: Synthesis of Compound 7A
将化合物7b(0.13g,215.70μmol)溶于无水二氯甲烷(2mL)中，加入无水氯化镁(410.74mg,4.31mmol)，28℃搅拌12个小时。反应液直接减压浓缩得到残余物。甲醇溶解通过有机相针头式滤器过滤，得到粗品。粗品经制备反向液相色谱(分离条件:Phenomenex Luna 80×30mm×3μm；流动相:[H 2O(0.04％HCl)-ACN]；ACN％:35％-65％,8min)分离，得到化合物7A。 Compound 7b (0.13g, 215.70μmol) was dissolved in anhydrous dichloromethane (2mL), anhydrous magnesium chloride (410.74mg, 4.31mmol) was added, and stirred at 28°C for 12 hours. The reaction solution was directly concentrated under reduced pressure to obtain a residue. Dissolved in methanol and filtered through a syringe filter of the organic phase to obtain the crude product. The crude product was separated by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80×30mm×3μm; mobile phase: [H 2 O(0.04%HCl)-ACN]; ACN%: 35%-65%, 8min) to obtain Compound 7A.
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.42(br dd,J＝2.3,3.7Hz,1H),9.89-9.53(m,1H),8.41-8.37(m,1H),7.21-7.12(m,2H),6.55-6.47(m,2H),5.56-5.43(m,1H),5.42-5.22(m,1H),4.87-4.29(m,3H),3.94-3.79(m,2H),3.08(s,3H),2.96(br s,1H),2.34(q,J＝5.8Hz,2H),2.00-1.85(m,2H),1.43-1.41(m,1H),1.42-1.00(m,10H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.42 (br dd, J = 2.3, 3.7Hz, 1H), 9.89-9.53 (m, 1H), 8.41-8.37 (m, 1H), 7.21-7.12 (m,2H),6.55-6.47(m,2H),5.56-5.43(m,1H),5.42-5.22(m,1H),4.87-4.29(m,3H),3.94-3.79(m,2H) ,3.08(s,3H),2.96(br s,1H),2.34(q,J=5.8Hz,2H),2.00-1.85(m,2H),1.43-1.41(m,1H),1.42-1.00( m,10H).
实施例8Example 8
Figure PCTCN2022109064-appb-000074
Figure PCTCN2022109064-appb-000074
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000075
Figure PCTCN2022109064-appb-000075
步骤1：化合物8A的合成Step 1: Synthesis of Compound 8A
将7b(0.18g,298.66μmol)溶于乙酸乙酯(6mL)中，加入湿Pd/C(0.02g,10％纯度)，随后置换氢气，反应在15psi，28℃搅拌12小时。反应液用硅藻土过滤，滤液减压浓缩得到残余物。甲醇溶解通过有机相针头式滤器过滤，得到粗品。粗品经制备反向液相色谱(分离条件:Phenomenex Luna 80×30mm×3μm；流动相:[H 2O(0.04％HCl)-ACN]；ACN％:40％-70％,8min)分离，得到化合物8A。 7b (0.18g, 298.66μmol) was dissolved in ethyl acetate (6mL), wet Pd/C (0.02g, 10% purity) was added followed by hydrogen replacement, and the reaction was stirred at 15psi, 28°C for 12 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a residue. Dissolved in methanol and filtered through a syringe filter of the organic phase to obtain the crude product. The crude product was separated by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80×30mm×3μm; mobile phase: [H 2 O(0.04%HCl)-ACN]; ACN%: 40%-70%, 8min) to obtain Compound 8A.
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.54-11.30(m,1H),9.76(br t,J＝4.2Hz,1H),8.39(s,1H),7.16(d,J＝7.7Hz,1H),6.55-6.46(m,2H),4.75-4.33(m,3H),3.87(t,J＝5.8Hz,2H),3.08(s,3H),2.97(br t,J＝6.4Hz,2H),1.70-1.61(m,2H),1.41(br dd,J＝7.2,14.8Hz,5H),1.31-1.10(m,13H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.54-11.30 (m, 1H), 9.76 (br t, J = 4.2Hz, 1H), 8.39 (s, 1H), 7.16 (d, J = 7.7 Hz,1H),6.55-6.46(m,2H),4.75-4.33(m,3H),3.87(t,J=5.8Hz,2H),3.08(s,3H),2.97(br t,J=6.4 Hz,2H),1.70-1.61(m,2H),1.41(br dd,J=7.2,14.8Hz,5H),1.31-1.10(m,13H).
实施例9Example 9
Figure PCTCN2022109064-appb-000076
Figure PCTCN2022109064-appb-000076
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000077
Figure PCTCN2022109064-appb-000077
步骤1：化合物9a的合成Step 1: Synthesis of compound 9a
在干燥的单口瓶中加入1h(0.9g,1.78mmol)和二氯甲烷(2mL)，开启搅拌，随后加入DCC(549.92mg,2.67mmol)，DMAP(32.56mg,266.52μmol)，三乙胺(269.69mg,2.67mmol,370.97μL)，搅拌20min。最后加入4-戊烯酸(266.83mg,2.67mmol,272.83μL)。加毕，氮气置换3次，将反应置于20℃搅拌12小时。加入水(10mL)淬灭反应，水相用乙酸乙酯(10mL×3)萃取，合并有机相用饱和食盐水(10mL×2)洗涤，有机相用无水硫酸钠干燥。过滤减压浓缩得到粗产品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:0-1:1)分离，纯化得到化合物9a。Add 1h (0.9g, 1.78mmol) and dichloromethane (2mL) to a dry single-necked bottle, start stirring, then add DCC (549.92mg, 2.67mmol), DMAP (32.56mg, 266.52μmol), triethylamine ( 269.69mg, 2.67mmol, 370.97μL), stirred for 20min. Finally 4-pentenoic acid (266.83 mg, 2.67 mmol, 272.83 μL) was added. After the addition was complete, nitrogen was replaced three times, and the reaction was placed at 20° C. and stirred for 12 hours. Water (10 mL) was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (10 mL×3), the combined organic phases were washed with saturated brine (10 mL×2), and the organic phase was dried over anhydrous sodium sulfate. The crude product was obtained by filtration and concentration under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:0-1:1) to obtain compound 9a.
MS(ESI,m/z):589.3[M+1] +. MS(ESI,m/z):589.3[M+1] + .
步骤2：化合物9b的合成Step 2: Synthesis of compound 9b
准备干燥过的三口烧瓶，加入9a(0.2g,339.78μmol)加入溶剂1,2-二氯乙烷(25mL)氮气抽换气三次，随后加入Grubbs二代催化剂(57.69mg,67.96μmol)。加毕，混合物在80℃继续搅拌16小时。减压浓缩得到粗产品根据TLC(二氯甲烷:甲醇＝20:1,Rf＝0.43)，粗品经硅胶柱层析分离(石油醚/乙酸乙酯＝1:0-0:1)，纯化得到化合物9b。Prepare a dried three-necked flask, add 9a (0.2g, 339.78μmol) and solvent 1,2-dichloroethane (25mL) and nitrogen gas three times, then add Grubbs second-generation catalyst (57.69mg, 67.96μmol). After the addition was complete, the mixture was stirred at 80°C for a further 16 hours. Concentrate under reduced pressure to obtain the crude product. According to TLC (dichloromethane:methanol=20:1, Rf=0.43), the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:0-0:1), and purified to obtain Compound 9b.
1H NMR(400MHz,CDCl 3)δ(ppm)＝9.37(br d,J＝9.0Hz,1H),8.77-8.64(m,1H),7.54-7.42(m,2H),7.35-7.24(m,4H),6.68-6.50(m,2H),5.82-5.68(m,1H),5.61-5.44(m,3H),5.39-5.26(m,2H),4.75-4.55(m,1H),4.16-4.03(m,1H),3.89-3.72(m,2H),3.12(s,3H),2.63-2.45(m,1H),2.40-2.08(m,4H),2.00-1.86(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 9.37 (br d, J = 9.0Hz, 1H), 8.77-8.64 (m, 1H), 7.54-7.42 (m, 2H), 7.35-7.24 (m ,4H),6.68-6.50(m,2H),5.82-5.68(m,1H),5.61-5.44(m,3H),5.39-5.26(m,2H),4.75-4.55(m,1H),4.16 -4.03(m,1H),3.89-3.72(m,2H),3.12(s,3H),2.63-2.45(m,1H),2.40-2.08(m,4H),2.00-1.86(m,1H) .
步骤3：化合物9A的合成Step 3: Synthesis of Compound 9A
在干燥的三口瓶中加入9b(20mg,35.68μmol)和二氯甲烷(1mL)，开启搅拌；随后加无水氯化镁(67.94mg,713.56μmol)，氮气置换3次，将反应置于20℃搅拌12小时。减压浓缩，甲醇溶解通过有机相针头式滤器过滤，得到粗品，经制备反向液相色谱(分离条件:Phenomenex Luna 80×30mm×3μm；流动相:[H 2O(0.04％盐酸)-ACN]；ACN％:40％-70％,8min)，分离纯化，得到化合物9A。 Add 9b (20 mg, 35.68 μmol) and dichloromethane (1 mL) into a dry three-necked flask, start stirring; then add anhydrous magnesium chloride (67.94 mg, 713.56 μmol), replace with nitrogen 3 times, and stir the reaction at 20°C 12 hours. Concentrate under reduced pressure, dissolve in methanol and filter through an organic phase syringe filter to obtain the crude product, which is subjected to preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80×30mm×3 μm; mobile phase: [H 2 O (0.04% hydrochloric acid)-ACN ]; ACN%: 40%-70%, 8min), separated and purified to obtain compound 9A.
MS(ESI,m/z):471.1[M+1] +. MS(ESI,m/z):471.1[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝11.80-11.67(m,1H),9.39(d,J＝9.0Hz,1H),8.87(s,1H),7.47-7.35(m,1H),6.86(dd,J＝2.1,11.6Hz,1H),6.79-6.72(m,1H),5.64(d,J＝12.6Hz,1H),5.61-5.56(m,2H),5.26-5.15(m,1H),5.08-5.00(m,1H),4.16-4.07(m,1H),3.84(d,J＝13.3Hz,1H),3.77-3.67(m,1H),3.01(s,3H),2.42-2.35(m,1H),2.31-2.15(m,3H),2.01-1.88(m,2H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 11.80-11.67 (m, 1H), 9.39 (d, J = 9.0Hz, 1H), 8.87 (s, 1H), 7.47-7.35 (m, 1H ),6.86(dd,J=2.1,11.6Hz,1H),6.79-6.72(m,1H),5.64(d,J=12.6Hz,1H),5.61-5.56(m,2H),5.26-5.15( m,1H),5.08-5.00(m,1H),4.16-4.07(m,1H),3.84(d,J＝13.3Hz,1H),3.77-3.67(m,1H),3.01(s,3H) ,2.42-2.35(m,1H),2.31-2.15(m,3H),2.01-1.88(m,2H).
实施例10Example 10
Figure PCTCN2022109064-appb-000078
Figure PCTCN2022109064-appb-000078
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000079
Figure PCTCN2022109064-appb-000079
步骤1：化合物10A的合成Step 1: Synthesis of Compound 10A
准备干燥的氢化瓶，在氩气保护下加入湿Pd/C(10mg,10％纯度)，随后加入9b(48mg,85.63μmol)和乙酸乙酯(5mL)，随后置换氢气，反应在15psi、18℃搅拌12小时。反应液通过硅藻土过滤，减压浓缩，N,N-二甲基甲酰胺溶解通过有机相针头式滤器过滤得到粗品。粗品经制备反向液相色谱(分离条件:Phenomenex Luna 80×30mm×3μm；流动相:[H 2O(0.04％盐酸)-ACN]；ACN％:40％-70％,8min)，纯化得到化 合物10A。 Prepare a dry hydrogenation bottle, add wet Pd/C (10mg, 10% purity) under the protection of argon, then add 9b (48mg, 85.63μmol) and ethyl acetate (5mL), then replace hydrogen, react at 15psi, 18 °C and stirred for 12 hours. The reaction solution was filtered through celite, concentrated under reduced pressure, dissolved in N,N-dimethylformamide and filtered through a syringe filter of the organic phase to obtain a crude product. The crude product was purified by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80×30mm×3μm; mobile phase: [H 2 O (0.04% hydrochloric acid)-ACN]; ACN%: 40%-70%, 8min), and purified to obtain Compound 10A.
MS(ESI,m/z):473.2[M+1] +. MS(ESI,m/z):473.2[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝11.63(br s,1H),9.45-9.35(m,1H),8.69(d,J＝2.4Hz,1H),7.40(td,J＝3.3,6.8Hz,1H),6.91-6.81(m,1H),6.79-6.66(m,1H),5.70-5.57(m,1H),5.24-5.10(m,1H),5.09-4.97(m,1H),4.07(br dd,J＝2.6,9.0Hz,1H),3.86-3.80(m,1H),3.68-3.63(m,1H),3.01(br s,3H),2.03-1.94(m,2H),1.70-1.53(m,3H),1.47-1.21(m,5H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 11.63 (br s, 1H), 9.45-9.35 (m, 1H), 8.69 (d, J = 2.4Hz, 1H), 7.40 (td, J = 3.3,6.8Hz,1H),6.91-6.81(m,1H),6.79-6.66(m,1H),5.70-5.57(m,1H),5.24-5.10(m,1H),5.09-4.97(m, 1H),4.07(br dd,J＝2.6,9.0Hz,1H),3.86-3.80(m,1H),3.68-3.63(m,1H),3.01(br s,3H),2.03-1.94(m, 2H),1.70-1.53(m,3H),1.47-1.21(m,5H).
实施例11Example 11
Figure PCTCN2022109064-appb-000080
Figure PCTCN2022109064-appb-000080
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000081
Figure PCTCN2022109064-appb-000081
步骤1：化合物11a的合成Step 1: Synthesis of Compound 11a
准备在干燥的单口瓶，将1h(1g,1.97mmol)溶于甲苯(10mL)中，加入二异丙基乙基胺(1.02g,7.90mmol,1.38mL)，然后降温到0℃，加入6-庚烯酰氯(1.16g,7.90mmol)，加毕，氮气置换3次，将反应置于100℃搅拌12个小时。加入水(10mL)淬灭反应，水相用乙酸乙酯(10mL×3)萃取，合并有机相用饱和食盐水(10mL×2)洗涤，有机相用无水硫酸钠干燥。过滤减压浓缩得到粗产品。经硅胶柱层析(石油醚/乙酸乙酯＝1:0-1:1)分离，纯化得到化合物11a。Prepare a dry single-necked bottle, dissolve 1h (1g, 1.97mmol) in toluene (10mL), add diisopropylethylamine (1.02g, 7.90mmol, 1.38mL), then cool down to 0°C, add 6 -Heptenoyl chloride (1.16g, 7.90mmol), after the addition was complete, nitrogen was replaced 3 times, and the reaction was stirred at 100°C for 12 hours. Water (10 mL) was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (10 mL×3), the combined organic phases were washed with saturated brine (10 mL×2), and the organic phase was dried over anhydrous sodium sulfate. The crude product was obtained by filtration and concentration under reduced pressure. Compound 11a was obtained by separation and purification by silica gel column chromatography (petroleum ether/ethyl acetate=1:0-1:1).
MS(ESI,m/z):617.4[M+1] +. MS(ESI,m/z):617.4[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝10.24(t,J＝5.9Hz,1H),8.45-8.35(m,1H),7.56(d,J＝6.8Hz,2H),7.42-7.30(m,3H),7.28-7.20(m,1H),6.94(dd,J＝2.4,11.3Hz,1H),6.72(dt,J＝2.4,8.5Hz,1H),6.03-5.74(m, 2H),5.66-5.51(m,1H),5.36-5.25(m,1H),5.24-4.90(m,6H),4.44(br d,J＝5.9Hz,2H),4.10(t,J＝6.5Hz,2H),3.05(s,3H),2.70-2.55(m,4H),2.11-1.97(m,2H),1.64-1.51(m,2H),1.39(quin,J＝7.2Hz,2H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 10.24 (t, J = 5.9Hz, 1H), 8.45-8.35 (m, 1H), 7.56 (d, J = 6.8Hz, 2H), 7.42- 7.30(m,3H),7.28-7.20(m,1H),6.94(dd,J＝2.4,11.3Hz,1H),6.72(dt,J＝2.4,8.5Hz,1H),6.03-5.74(m, 2H),5.66-5.51(m,1H),5.36-5.25(m,1H),5.24-4.90(m,6H),4.44(br d,J=5.9Hz,2H),4.10(t,J=6.5 Hz,2H),3.05(s,3H),2.70-2.55(m,4H),2.11-1.97(m,2H),1.64-1.51(m,2H),1.39(quin,J＝7.2Hz,2H) .
步骤2：化合物11b的合成Step 2: Synthesis of compound 11b
15-20℃，在预先干燥过的三口烧瓶中加入原料1h(0.2g,324.32μmol)加入溶剂1,2-二氯乙烷(200mL)氮气抽换气三次。随后加入Hoveyda-Grubbs二代催化剂(40.64mg,64.86μmol)，加毕，混合物在80℃继续搅拌16小时。减压浓缩得到粗产品，粗产品通过硅胶柱层析分离(石油醚/乙酸乙酯＝1:0-0:1)，纯化得到化合物11b。15-20°C, add the raw materials to a pre-dried three-neck flask for 1h (0.2g, 324.32μmol) and add the solvent 1,2-dichloroethane (200mL) and pump nitrogen three times. Then Hoveyda-Grubbs second-generation catalyst (40.64 mg, 64.86 μmol) was added, and the addition was completed, and the mixture was stirred at 80° C. for 16 hours. Concentrate under reduced pressure to obtain a crude product, which is separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:0-0:1), and purified to obtain compound 11b.
1H NMR(400MHz,DMSO-d6)δ(ppm)＝9.65(br d,J＝8.2Hz,1H),8.96-8.89(m,1H),7.54-7.24(m,6H),6.97-6.86(m,1H),6.81-6.70(m,1H),5.54(br d,J＝13.0Hz,1H),5.47-4.97(m,7H),4.12-3.74(m,4H),3.01(d,J＝1.6Hz,3H),2.35-2.23(m,3H),1.85-1.75(m,1H),1.59-1.44(m,2H),1.25(br s,2H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 9.65 (br d, J = 8.2Hz, 1H), 8.96-8.89 (m, 1H), 7.54-7.24 (m, 6H), 6.97-6.86 ( m,1H),6.81-6.70(m,1H),5.54(br d,J＝13.0Hz,1H),5.47-4.97(m,7H),4.12-3.74(m,4H),3.01(d,J ＝1.6Hz, 3H), 2.35-2.23(m, 3H), 1.85-1.75(m, 1H), 1.59-1.44(m, 2H), 1.25(br s, 2H).
步骤3：化合物11A的合成Step 3: Synthesis of Compound 11A
准备干燥的三口瓶中加入11b(60mg,101.93μmol)和二氯甲烷(1mL)，开启搅拌；随后加入无水氯化镁(194.10mg,2.04mmol)，氮气置换3次，将反应置于18℃搅拌16小时。减压浓缩得到粗产品，甲醇溶解通过有机相针头式滤器过滤，得到粗品。粗产品通过制备反向液相色谱分离(分离条件:Phenomenex Luna 80×30mm×3μm；流动相:[H 2O(0.04％盐酸)-ACN]；ACN％:30％-60％,8min)，纯化得到化合物11A。 Add 11b (60mg, 101.93μmol) and dichloromethane (1mL) to the three-necked flask prepared for drying, and start stirring; then add anhydrous magnesium chloride (194.10mg, 2.04mmol), nitrogen replacement 3 times, and stir the reaction at 18°C 16 hours. Concentrate under reduced pressure to obtain a crude product, dissolve in methanol and filter the organic phase through a syringe filter to obtain a crude product. The crude product was separated by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80×30mm×3μm; mobile phase: [H 2 O (0.04% hydrochloric acid)-ACN]; ACN%: 30%-60%, 8min), Purification afforded compound 11A.
MS(ESI,m/z):499.2[M+1] +. MS(ESI,m/z):499.2[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝11.67-11.46(m,1H),9.66-9.51(m,1H),8.90-8.72(m,1H),7.41(td,J＝7.7,19.6Hz,1H),6.90(dd,J＝2.0,11.3Hz,1H),6.81-6.69(m,1H),5.64(dd,J＝3.8,12.8Hz,1H),5.47-4.99(m,4H),4.13-3.72(m,3H),3.01(s,3H),2.43-2.21(m,4H),2.19-1.98(m,1H),1.94-1.71(m,2H),1.63-1.41(m,2H),1.39-1.14(m,3H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 11.67-11.46 (m, 1H), 9.66-9.51 (m, 1H), 8.90-8.72 (m, 1H), 7.41 (td, J = 7.7, 19.6Hz, 1H), 6.90(dd, J＝2.0, 11.3Hz, 1H), 6.81-6.69(m, 1H), 5.64(dd, J＝3.8, 12.8Hz, 1H), 5.47-4.99(m, 4H ),4.13-3.72(m,3H),3.01(s,3H),2.43-2.21(m,4H),2.19-1.98(m,1H),1.94-1.71(m,2H),1.63-1.41(m ,2H),1.39-1.14(m,3H).
实施例12Example 12
Figure PCTCN2022109064-appb-000082
Figure PCTCN2022109064-appb-000082
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000083
Figure PCTCN2022109064-appb-000083
步骤1：化合物12A的合成Step 1: Synthesis of compound 12A
准备干燥的氢化瓶，在氩气保护下加入湿Pd/C(10mg,10％纯度)，随后加入11b(60mg,101.93μmol)和甲醇(5mL)，随后置换氢气，反应在15psi、18℃搅拌12小时。反应液通过硅藻土过滤，减压浓缩，N,N-二甲基甲酰胺溶解通过有机相针头式滤器过滤得到粗品。粗品经制备反向液相色谱(分离条件:Phenomenex Luna 80×30mm×3μm；流动相:[H 2O(0.04％盐酸)-ACN]；ACN％:40％-70％,8min)，纯化得到化合物12A。 Prepare a dry hydrogenation bottle and add wet Pd/C (10 mg, 10% purity) under argon, followed by 11b (60 mg, 101.93 μmol) and methanol (5 mL), followed by hydrogen replacement, and the reaction is stirred at 15 psi, 18 °C 12 hours. The reaction solution was filtered through celite, concentrated under reduced pressure, dissolved in N,N-dimethylformamide and filtered through a syringe filter of the organic phase to obtain a crude product. The crude product was purified by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80×30mm×3μm; mobile phase: [H 2 O (0.04% hydrochloric acid)-ACN]; ACN%: 40%-70%, 8min), and purified to obtain Compound 12A.
MS(ESI,m/z):501.2[M+1] +. MS(ESI,m/z):501.2[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝11.53-11.43(m,1H),9.61(br d,J＝7.0Hz,1H),8.80(s,1H),7.41(t,J＝7.6Hz,1H),6.90(dd,J＝2.4,11.4Hz,1H),6.78-6.70(m,1H),5.63(d,J＝12.8Hz,1H),5.08-4.98(m,1H),4.92(br dd,J＝7.3,13.7Hz,1H),4.10-3.80(m,3H),3.01(s,3H),2.18-2.10(m,1H),1.62-1.50(m,3H),1.34-1.11(m,8H),1.01-0.91(m,2H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 11.53-11.43 (m, 1H), 9.61 (br d, J = 7.0Hz, 1H), 8.80 (s, 1H), 7.41 (t, J = 7.6Hz, 1H), 6.90(dd, J＝2.4, 11.4Hz, 1H), 6.78-6.70(m, 1H), 5.63(d, J＝12.8Hz, 1H), 5.08-4.98(m, 1H), 4.92(br dd,J=7.3,13.7Hz,1H),4.10-3.80(m,3H),3.01(s,3H),2.18-2.10(m,1H),1.62-1.50(m,3H),1.34 -1.11(m,8H),1.01-0.91(m,2H).
实施例13Example 13
Figure PCTCN2022109064-appb-000084
Figure PCTCN2022109064-appb-000084
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000085
Figure PCTCN2022109064-appb-000085
步骤1：化合物13a的合成Step 1: Synthesis of compound 13a
在干燥的单口瓶中加入1h(1.5g,2.96mmol)和N,N-二甲基甲酰胺(15mL)，随后加入氢氧化钾(249.22mg,4.44mmol)，最后加入6-溴-1-己烯(1.45g,8.88mmol,1.19mL)，加毕，氮气置换3次，将反应置于20℃搅拌12小时。加入水(20mL)淬灭反应，水相用乙酸乙酯(20mL×3)萃取，合并有机相用饱和食盐水(20mL×2)洗涤，有机相用无水硫酸钠干燥。过滤减压浓缩得到粗产品。粗产品通过硅胶柱层析分离(石油醚/乙酸乙酯＝1:0-0:1)，纯化得到产物化合物13a。Add 1h (1.5g, 2.96mmol) and N,N-dimethylformamide (15mL) to a dry one-necked flask, followed by potassium hydroxide (249.22mg, 4.44mmol), and finally 6-bromo-1- After the addition of hexene (1.45g, 8.88mmol, 1.19mL), the nitrogen was replaced three times, and the reaction was stirred at 20°C for 12 hours. Water (20 mL) was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (20 mL×3), the combined organic phases were washed with saturated brine (20 mL×2), and the organic phase was dried over anhydrous sodium sulfate. The crude product was obtained by filtration and concentration under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:0-0:1), and purified to obtain the product compound 13a.
1H NMR(400MHz,DMSO-d6)δ(ppm)＝10.33(t,J＝5.9Hz,1H),8.29(s,1H),7.63-7.51(m,2H),7.42-7.31(m,3H),7.23(dd,J＝7.0,8.2Hz,1H),6.93(dd,J＝2.4,11.4Hz,1H),6.72(dt,J＝2.4,8.5Hz,1H),5.96(tdd,J＝6.7,10.4,17.1Hz,1H),5.79(tdd,J＝6.7,10.3,17.0Hz,1H),5.19(qd,J＝1.7,17.2Hz,1H),5.12(br s,2H),5.08-5.04(m,1H),5.03-4.93(m,2H),4.43(d,J＝5.9Hz,2H),4.10(t,J＝6.5Hz,2H),3.05(s,3H),3.03-2.97(m,2H),2.63-2.55(m,2H),2.09-2.01(m,2H),1.51-1.37(m,4H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 10.33 (t, J = 5.9Hz, 1H), 8.29 (s, 1H), 7.63-7.51 (m, 2H), 7.42-7.31 (m, 3H ), 7.23(dd, J=7.0, 8.2Hz, 1H), 6.93(dd, J=2.4, 11.4Hz, 1H), 6.72(dt, J=2.4, 8.5Hz, 1H), 5.96(tdd, J= 6.7,10.4,17.1Hz,1H),5.79(tdd,J=6.7,10.3,17.0Hz,1H),5.19(qd,J=1.7,17.2Hz,1H),5.12(br s,2H),5.08- 5.04(m,1H),5.03-4.93(m,2H),4.43(d,J=5.9Hz,2H),4.10(t,J=6.5Hz,2H),3.05(s,3H),3.03-2.97 (m,2H),2.63-2.55(m,2H),2.09-2.01(m,2H),1.51-1.37(m,4H).
步骤2：化合物13b的合成Step 2: Synthesis of compound 13b
在预先干燥过的三口烧瓶中加入原料13a(300mg,509.63μmol)，加入溶剂1,2-二氯乙烷(300mL)氮气抽换气三次，在15℃加入Hoveyda-Grubbs二代催化剂(63.87mg,101.93μmol)，加毕，混合物在80℃继续搅拌16小时。减压浓缩得到粗产品。粗产品通过硅胶柱层析分离(石油醚/乙酸乙酯＝1:0-0:1)，纯化得到化合物13b。Add raw material 13a (300mg, 509.63μmol) to a pre-dried three-necked flask, add solvent 1,2-dichloroethane (300mL) and pump nitrogen three times, add Hoveyda-Grubbs second-generation catalyst (63.87mg , 101.93μmol), the addition was completed, and the mixture was stirred at 80°C for 16 hours. Concentration under reduced pressure gave crude product. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:0-0:1), and purified to obtain compound 13b.
1H NMR(400MHz,DMSO-d6)δ(ppm)＝9.77(t,J＝5.4Hz,1H),8.42-8.30(m,1H),7.55-7.23(m,2H),7.35-7.23(m,3H),6.99-6.58(m,2H),5.75(s,2H),5.59-5.24(m,2H),5.08(s,2H),4.96-4.53(m,2H),3.98-3.81(m,2H),3.10-2.90(m,5H),2.53-2.51(m,2H),2.44-2.36(m,1H),2.12(br d,J＝18.3Hz,1H),1.87-1.71(m,1H),1.28(br s,3H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 9.77 (t, J = 5.4Hz, 1H), 8.42-8.30 (m, 1H), 7.55-7.23 (m, 2H), 7.35-7.23 (m ,3H),6.99-6.58(m,2H),5.75(s,2H),5.59-5.24(m,2H),5.08(s,2H),4.96-4.53(m,2H),3.98-3.81(m ,2H),3.10-2.90(m,5H),2.53-2.51(m,2H),2.44-2.36(m,1H),2.12(br d,J＝18.3Hz,1H),1.87-1.71(m, 1H), 1.28(br s, 3H).
步骤3：化合物13A和13B的合成Step 3: Synthesis of Compounds 13A and 13B
在干燥的三口瓶中加入13b(140mg,249.73μmol)和二氯甲烷(3mL)，开启搅拌，随后加入无水氯化镁 (475.53mg,4.99mmol)，氮气置换3次，将反应置于18℃搅拌16小时。减压浓缩得到粗产品。粗品经制备反向液相色谱(分离条件:Phenomenex Luna 80×30mm×3μm；流动相:[H 2O(0.04％HCl)-ACN]；ACN％:25％-55％,8min)，纯化得到产物13A和13B。 Add 13b (140mg, 249.73μmol) and dichloromethane (3mL) into a dry three-necked flask, start stirring, then add anhydrous magnesium chloride (475.53mg, 4.99mmol), nitrogen replacement 3 times, and stir the reaction at 18°C 16 hours. Concentration under reduced pressure gave crude product. The crude product was purified by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80×30mm×3μm; mobile phase: [H 2 O(0.04%HCl)-ACN]; ACN%: 25%-55%, 8min), and purified to obtain Products 13A and 13B.
13A:MS(ESI,m/z):471.2[M+1] +. 13A:MS(ESI,m/z):471.2[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝11.83(br s,1H),9.55(t,J＝5.5Hz,1H),8.25(s,1H),7.35(dd,J＝7.2,8.2Hz,1H),6.90(dd,J＝2.4,11.2Hz,1H),6.73(dt,J＝2.4,8.4Hz,1H),5.43-5.28(m,2H),5.16-4.58(m,2H),3.86(br d,J＝4.9Hz,2H),3.10-2.96(m,5H),2.52(br s,2H),2.23(td,J＝3.3,8.5Hz,2H),2.01-1.91(m,2H),1.53-0.98(m,4H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 11.83 (br s, 1H), 9.55 (t, J = 5.5Hz, 1H), 8.25 (s, 1H), 7.35 (dd, J = 7.2, 8.2Hz, 1H), 6.90(dd, J＝2.4, 11.2Hz, 1H), 6.73(dt, J＝2.4, 8.4Hz, 1H), 5.43-5.28(m, 2H), 5.16-4.58(m, 2H ),3.86(br d,J=4.9Hz,2H),3.10-2.96(m,5H),2.52(br s,2H),2.23(td,J=3.3,8.5Hz,2H),2.01-1.91( m,2H),1.53-0.98(m,4H).
13B:MS(ESI,m/z):471.2[M+1] +. 13B:MS(ESI,m/z):471.2[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝11.87(s,1H),9.72(t,J＝5.1Hz,1H),8.28(s,1H),7.46-7.36(m,1H),6.91(dd,J＝2.4,11.2Hz,1H),6.77(dt,J＝2.5,8.4Hz,1H),5.44-5.20(m,2H),5.05-4.70(m,2H),3.97-3.81(m,2H),3.04(s,5H),2.52(br s,2H),2.36(br dd,J＝2.7,7.2Hz,2H),1.85-1.71(m,2H),1.44-1.29(m,2H),1.27-1.02(m,2H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 11.87 (s, 1H), 9.72 (t, J = 5.1Hz, 1H), 8.28 (s, 1H), 7.46-7.36 (m, 1H), 6.91(dd, J=2.4,11.2Hz,1H),6.77(dt,J=2.5,8.4Hz,1H),5.44-5.20(m,2H),5.05-4.70(m,2H),3.97-3.81( m,2H),3.04(s,5H),2.52(br s,2H),2.36(br dd,J＝2.7,7.2Hz,2H),1.85-1.71(m,2H),1.44-1.29(m, 2H),1.27-1.02(m,2H).
实施例14Example 14
Figure PCTCN2022109064-appb-000086
Figure PCTCN2022109064-appb-000086
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000087
Figure PCTCN2022109064-appb-000087
步骤1：化合物14A的合成Step 1: Synthesis of Compound 14A
准备干燥的氢化瓶，在氩气保护下加入湿Pd/C(10mg,10％纯度)，随后加入13b(170mg,303.24μmol)和乙酸乙酯(5mL)，随后置换氢气，反应在15psi、18℃搅拌12小时。反应液通过硅藻土过滤，减压浓缩，N,N-二甲基甲酰胺溶解通过有机相针头式滤器过滤得到粗品。粗品经制备反向液相色谱(分离条件:Phenomenex Luna 80×30mm×3μm；流动相:[H 2O(0.04％HCl)-ACN]；ACN％:25％-55％,8min)，纯化得到化合物14A。 Prepare a dry hydrogenation bottle, add wet Pd/C (10mg, 10% purity) under the protection of argon, then add 13b (170mg, 303.24μmol) and ethyl acetate (5mL), then replace hydrogen, react at 15psi, 18 °C and stirred for 12 hours. The reaction solution was filtered through celite, concentrated under reduced pressure, dissolved in N,N-dimethylformamide and filtered through a syringe filter of the organic phase to obtain a crude product. The crude product was purified by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80×30mm×3μm; mobile phase: [H 2 O(0.04%HCl)-ACN]; ACN%: 25%-55%, 8min), and purified to obtain Compound 14A.
MS(ESI,m/z):473.2[M+1] +. MS(ESI,m/z):473.2[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.73-11.30(m,1H),9.64-9.55(m,1H),8.63(d,J＝9.5Hz,1H),7.22(dd,J＝6.8,14.8Hz,1H),6.68-6.50(m,2H),5.71(dd,J＝6.6,12.5Hz,1H),5.57-5.13(m,3H),4.81(dd,J＝2.6,12.6Hz,1H),4.09-3.72(m,3H),3.23-3.14(m,3H),2.61-1.61(m,9H),1.47-1.28(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.73-11.30 (m, 1H), 9.64-9.55 (m, 1H), 8.63 (d, J = 9.5Hz, 1H), 7.22 (dd, J = 6.8,14.8Hz,1H),6.68-6.50(m,2H),5.71(dd,J＝6.6,12.5Hz,1H),5.57-5.13(m,3H),4.81(dd,J＝2.6,12.6Hz ,1H),4.09-3.72(m,3H),3.23-3.14(m,3H),2.61-1.61(m,9H),1.47-1.28(m,2H).
实施例15Example 15
Figure PCTCN2022109064-appb-000088
Figure PCTCN2022109064-appb-000088
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000089
Figure PCTCN2022109064-appb-000089
步骤1：化合物15a的合成Step 1: Synthesis of compound 15a
在干燥的单口瓶中加入1h(1g,1.97mmol)溶于N,N-二甲基甲酰胺(10mL)中，随后加入8-溴-1-辛烯(1.13g,5.92mmol,992.88μL)和碳酸铯(1.29g,3.95mmol)，加毕，氮气置换3次，28℃搅拌12小时。加入水(20mL)淬灭反应，水相用乙酸乙酯(20mL×3)萃取，合并有机相用饱和食盐水(20mL×2)洗涤，有机相用无水硫酸钠干燥。过滤减压浓缩得到粗产品。粗产品通过硅胶柱层析分离(石油醚/乙酸乙酯＝1:0-0:1)，纯化得到产物化合物15a。Add 1h (1g, 1.97mmol) dissolved in N,N-dimethylformamide (10mL) to a dry one-necked flask, followed by 8-bromo-1-octene (1.13g, 5.92mmol, 992.88μL) and cesium carbonate (1.29g, 3.95mmol), after the addition was completed, the nitrogen gas was replaced 3 times, and stirred at 28°C for 12 hours. Water (20 mL) was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (20 mL×3), the combined organic phases were washed with saturated brine (20 mL×2), and the organic phase was dried over anhydrous sodium sulfate. The crude product was obtained by filtration and concentration under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:0-0:1), and purified to obtain the product compound 15a.
1H NMR(400MHz,CDCl 3)δ(ppm)＝8.46(s,1H),7.59-7.55(m,2H),7.35-7.26(m,4H),6.60-6.55(m,2H),6.00-5.90(m,1H),5.84-5.71(m,1H),5.33-5.27(m,1H),5.21-5.15(m,1H),5.09(dd,J＝1.2,10.3Hz,1H),5.01-4.91(m,2H),4.76(br s,3H),4.56(d,J＝6.0Hz,2H),4.04(t,J＝6.7Hz,2H),3.12-3.09(m,3H),2.70-2.63(m,2H),2.19-2.10(m,6H),1.41-1.29(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 8.46 (s, 1H), 7.59-7.55 (m, 2H), 7.35-7.26 (m, 4H), 6.60-6.55 (m, 2H), 6.00- 5.90(m,1H),5.84-5.71(m,1H),5.33-5.27(m,1H),5.21-5.15(m,1H),5.09(dd,J=1.2,10.3Hz,1H),5.01- 4.91(m,2H),4.76(br s,3H),4.56(d,J=6.0Hz,2H),4.04(t,J=6.7Hz,2H),3.12-3.09(m,3H),2.70- 2.63(m,2H),2.19-2.10(m,6H),1.41-1.29(m,6H).
步骤2：化合物15b的合成Step 2: Synthesis of Compound 15b
将15a(0.4g,648.59μmol)溶于二氯甲烷(1200mL)中，氮气置换三次，加入詹氏催化剂-1B(47.59mg,64.86μmol)和对苯醌(14.02mg,129.72μmol,29.21μL)，油浴升温到40℃搅拌12h。反应液用硅藻土过滤，滤液减压浓缩得到残余物。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:1)分离，得到化合物15b。15a (0.4g, 648.59μmol) was dissolved in dichloromethane (1200mL), replaced with nitrogen three times, and added Jane's catalyst-1B (47.59mg, 64.86μmol) and p-benzoquinone (14.02mg, 129.72μmol, 29.21μL) , the oil bath was heated to 40°C and stirred for 12h. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a residue. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to obtain compound 15b.
步骤3：化合物15ca和15cb的合成Step 3: Synthesis of Compounds 15ca and 15cb
将化合物15b纯品(400mg)通过SFC分离(分离条件:REGIS(S,S)WHELK-O1(250mm*25mm,10μm)；流动相:[Neu-EtOH]％:60％-60％,7min)，纯化得到产物纯品15ca和15cb。The pure compound 15b (400mg) was separated by SFC (separation condition: REGIS (S, S) WHELK-O1 (250mm*25mm, 10μm); mobile phase: [Neu-EtOH]%: 60%-60%, 7min) , purified to obtain pure products 15ca and 15cb.
SFC分析：柱型：(S,S)-WHELK-O1 50mm*4.6mm*3μm；流动相:[A:CO 2；B:EtOH(0.1％IPAm,v/v)]；B％:40％,3min；保留时间：1.940min(15ca)，2.186min(15cb)。 SFC analysis: column type: (S,S)-WHELK-O1 50mm*4.6mm*3μm; mobile phase: [A:CO 2 ; B:EtOH(0.1%IPAm,v/v)]; B%:40% ,3min; retention time: 1.940min (15ca), 2.186min (15cb).
15ca:MS(ESI,m/z):589.4[M+1] +. 15ca:MS(ESI,m/z):589.4[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝9.87-9.61(m,1H),8.44(s,1H),7.47(br d,J＝6.8Hz,2H),7.30-7.18(m,5H),6.60-6.47(m,2H),5.62-5.43(m,2H),5.25-5.20(m,3H),4.05(d,J＝7.2Hz,1H),3.90(br d,J＝4.4Hz,2H),3.03(s,3H),2.90(br d,J＝6.8Hz,1H),2.38(br d,J＝1.5Hz,2H),1.97(s,1H),1.81(br s,2H),1.57-1.49(m,1H),1.37(br s,2H),1.28-1.13(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 9.87-9.61 (m, 1H), 8.44 (s, 1H), 7.47 (br d, J = 6.8Hz, 2H), 7.30-7.18 (m, 5H ),6.60-6.47(m,2H),5.62-5.43(m,2H),5.25-5.20(m,3H),4.05(d,J＝7.2Hz,1H),3.90(br d,J＝4.4Hz ,2H),3.03(s,3H),2.90(br d,J=6.8Hz,1H),2.38(br d,J=1.5Hz,2H),1.97(s,1H),1.81(br s,2H ),1.57-1.49(m,1H),1.37(br s,2H),1.28-1.13(m,6H).
15cb:MS(ESI,m/z):589.4[M+1] +. 15cb:MS(ESI,m/z):589.4[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝9.71(br s,1H),8.44(s,1H),7.46(br d,J＝6.7Hz,2H),7.29-7.12(m,5H),6.57-6.48(m,2H),5.46-5.37(m,1H),5.32-5.27(m,1H),5.22(br s,2H),3.85(br t,J＝7.2Hz,2H),3.03(s,3H),2.91(br s,1H),2.40(br s,1H),1.90(br d,J＝6.0Hz,2H),1.70-1.49(m,2H),1.42(br s,2H),1.27-1.15(m,8H).步骤4：化合物15A的合成 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 9.71 (br s, 1H), 8.44 (s, 1H), 7.46 (br d, J = 6.7Hz, 2H), 7.29-7.12 (m, 5H) ,6.57-6.48(m,2H),5.46-5.37(m,1H),5.32-5.27(m,1H),5.22(br s,2H),3.85(br t,J＝7.2Hz,2H),3.03 (s,3H),2.91(br s,1H),2.40(br s,1H),1.90(br d,J＝6.0Hz,2H),1.70-1.49(m,2H),1.42(br s,2H ), 1.27-1.15(m,8H). Step 4: Synthesis of Compound 15A
把15ca(110.00mg,186.86μmol)溶于二氯甲烷(2mL)中，加入无水氯化镁(266.87mg,2.80mmol)，在28℃搅拌12小时。反应液直接减压浓缩得到粗品，粗品经制备反向液相色谱(分离条件:Phenomenex Luna 80*30mm*3μm；流动相:[H 2O(0.04％HCl)-ACN]；ACN％:30％-60％,8min)分离，得到化合物15A。 Dissolve 15ca (110.00 mg, 186.86 μmol) in dichloromethane (2 mL), add anhydrous magnesium chloride (266.87 mg, 2.80 mmol), and stir at 28° C. for 12 hours. The reaction solution was directly concentrated under reduced pressure to obtain the crude product, which was subjected to preparative reverse liquid chromatography (separation condition: Phenomenex Luna 80*30mm*3μm; mobile phase: [H 2 O(0.04%HCl)-ACN]; ACN%: 30% -60%, 8 min) to obtain compound 15A.
15A:MS(ESI,m/z):499.3[M+1] +. 15A:MS(ESI,m/z):499.3[M+1] + .
1HNMR(400MHz,CDCl 3)δ(ppm)＝11.75-11.37(m,1H),9.80(br t,J＝5.0Hz,1H),8.48(s,1H),7.31-7.28(m,1H),6.67-6.55(m,2H),5.67-5.44(m,2H),5.32-4.21(m,2H),3.97(br t,J＝5.2Hz,2H),3.16(s,3H),3.09-2.91(m,2H),2.51-2.33(m,2H),1.96-1.79(m,2H),1.48-1.21(m,9H). 1 HNMR (400MHz, CDCl 3 ) δ (ppm) = 11.75-11.37 (m, 1H), 9.80 (br t, J = 5.0Hz, 1H), 8.48 (s, 1H), 7.31-7.28 (m, 1H) ,6.67-6.55(m,2H),5.67-5.44(m,2H),5.32-4.21(m,2H),3.97(br t,J=5.2Hz,2H),3.16(s,3H),3.09- 2.91(m,2H),2.51-2.33(m,2H),1.96-1.79(m,2H),1.48-1.21(m,9H).
实施例16Example 16
Figure PCTCN2022109064-appb-000090
Figure PCTCN2022109064-appb-000090
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000091
Figure PCTCN2022109064-appb-000091
准备干燥的氢化瓶，在氩气保护下加入湿Pd/C(10mg,10wt％)，随后加入15b(0.13g,220.84μmol)和乙酸乙酯(5mL)，随后置换氢气，反应在15psi、18℃下搅拌12小时。反应液通过硅藻土过滤，减压浓缩，用N,N-二甲基甲酰胺溶解后通过有机相针头式滤器过滤得到粗品。粗品经制备反向液相色谱(分离条件:Phenomenex Luna 80×30mm×3μm；流动相:[H 2O(0.04％HCl)-ACN]；ACN％:30％-60％,8min)，纯化得到化合物16A。MS(ESI,m/z):501.2[M+1] +. Prepare a dry hydrogenation bottle, add wet Pd/C (10mg, 10wt%) under the protection of argon, then add 15b (0.13g, 220.84μmol) and ethyl acetate (5mL), then replace the hydrogen, react at 15psi, 18 Stir at °C for 12 hours. The reaction solution was filtered through celite, concentrated under reduced pressure, dissolved in N,N-dimethylformamide and filtered through an organic phase syringe filter to obtain a crude product. The crude product was purified by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80×30mm×3μm; mobile phase: [H 2 O(0.04%HCl)-ACN]; ACN%: 30%-60%, 8min), and purified to obtain Compound 16A. MS(ESI,m/z):501.2[M+1] + .
实施例17Example 17
Figure PCTCN2022109064-appb-000092
Figure PCTCN2022109064-appb-000092
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000093
Figure PCTCN2022109064-appb-000093
步骤1：化合物17a的合成Step 1: Synthesis of compound 17a
将1h(1g,1.97mmol)溶于甲苯(10mL)中，加入N,N-二异丙基乙基胺(1.02g,7.90mmol,1.38mL)，冰水浴降温到0℃，加入8-壬烯酰氯(1.27g,7.90mmol)，将反应升温至100℃搅拌12小时。取锥形瓶，加入水(50mL)，倒入反应液，水相用乙酸乙酯(50mL×3)萃取，合并有机相用饱和食盐水(20mL×2)洗涤，有机相用无水硫酸钠干燥，过滤后减压浓缩得到粗产品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:1)分离，得到化合物17a。Dissolve 1h (1g, 1.97mmol) in toluene (10mL), add N,N-diisopropylethylamine (1.02g, 7.90mmol, 1.38mL), cool to 0°C in an ice-water bath, add 8-nonyl Dienoyl chloride (1.27g, 7.90mmol), the reaction was heated to 100°C and stirred for 12 hours. Take an Erlenmeyer flask, add water (50mL), pour into the reaction solution, extract the aqueous phase with ethyl acetate (50mL×3), combine the organic phases and wash with saturated brine (20mL×2), and wash the organic phase with anhydrous sodium sulfate Dry, filter and concentrate under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to obtain compound 17a.
1H NMR(400MHz,CDCl 3)δ(ppm)＝10.17(br t,J＝5.9Hz,1H),8.41(s,1H),7.49(dd,J＝1.5,7.8Hz,2H),7.29-7.21(m,4H),6.56-6.51(m,2H),5.96-5.83(m,1H),5.71(dd,J＝10.3,17.0Hz,1H),5.36(br s,1H),5.23(s,1H),5.18-5.11(m,1H),5.07-5.03(m,1H),4.94-4.84(m,2H),4.52(br d,J＝5.7Hz,2H),4.00(t,J＝6.7Hz,2H),3.04(s,3H),2.67-2.58(m,2H),2.35-2.24(m,1H),1.99-1.90(m,2H),1.60-1.43(m,3H),1.33-1.13(m,7H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 10.17 (br t, J = 5.9Hz, 1H), 8.41 (s, 1H), 7.49 (dd, J = 1.5, 7.8Hz, 2H), 7.29- 7.21(m,4H),6.56-6.51(m,2H),5.96-5.83(m,1H),5.71(dd,J=10.3,17.0Hz,1H),5.36(br s,1H),5.23(s ,1H),5.18-5.11(m,1H),5.07-5.03(m,1H),4.94-4.84(m,2H),4.52(br d,J=5.7Hz,2H),4.00(t,J= 6.7Hz, 2H), 3.04(s, 3H), 2.67-2.58(m, 2H), 2.35-2.24(m, 1H), 1.99-1.90(m, 2H), 1.60-1.43(m, 3H), 1.33 -1.13(m,7H).
步骤2：化合物17b的合成Step 2: Synthesis of Compound 17b
将17a(0.6g,930.62μmol)溶于二氯甲烷(700mL)中，加入詹氏催化剂-1B(68.28mg,93.06μmol)和苯醌(20.12mg,186.12μmol,41.91μL)，油浴升温到40℃搅拌12h。反应液通过硅藻土过滤，减压浓缩得到粗产品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:1)分离，得到化合物17b。17a (0.6g, 930.62μmol) was dissolved in dichloromethane (700mL), and Jane's catalyst-1B (68.28mg, 93.06μmol) and benzoquinone (20.12mg, 186.12μmol, 41.91μL) were added, and the oil bath was heated to Stir at 40°C for 12h. The reaction solution was filtered through celite, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to obtain compound 17b.
步骤3：化合物17ca和17cb的合成Step 3: Synthesis of Compounds 17ca and 17cb
将化合物17b纯品(200mg)通过SFC分离(分离条件：REGIS(S,S)WHELK-O1(250mm*25mm,10μm)；流动相:[Neu-IPA]％:60％-60％,8min)，纯化得到产物纯品17ca和17cb。The pure compound 17b (200mg) was separated by SFC (separation condition: REGIS (S, S) WHELK-O1 (250mm*25mm, 10μm); mobile phase: [Neu-IPA]%: 60%-60%, 8min) , purified to obtain pure products 17ca and 17cb.
分析方法：柱型：(S,S)-WHELK-O1 50mm*4.6mm*3μm；流动相:[A:CO 2；B:IPA(0.1％IPAm,v/v)]；B％:40％,3min；保留时间：1.942min(17ca)，2.340min(17cb)。 Analysis method: column type: (S,S)-WHELK-O1 50mm*4.6mm*3μm; mobile phase: [A:CO 2 ; B:IPA(0.1%IPAm,v/v)]; B%:40% , 3min; retention time: 1.942min (17ca), 2.340min (17cb).
17ca:MS(ESI,m/z):617.4[M+1] +. 17ca:MS(ESI,m/z):617.4[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝9.96-9.76(m,1H),8.51(s,1H),7.51-7.40(m,2H),7.28-7.21(m,3H),6.63-6.47(m,2H),5.47-5.20(m,6H),4.73(br dd,J＝4.9,13.9Hz,1H),4.49(br d,J＝12.7Hz,1H),4.10-3.88(m,4H),3.03(s,3H),2.53-2.42(m,1H),2.39-2.28(m,1H),2.16(br t,J＝8.0Hz,2H),1.83(q,J＝6.7Hz,2H),1.21-1.17(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 9.96-9.76 (m, 1H), 8.51 (s, 1H), 7.51-7.40 (m, 2H), 7.28-7.21 (m, 3H), 6.63- 6.47(m,2H),5.47-5.20(m,6H),4.73(br dd,J＝4.9,13.9Hz,1H),4.49(br d,J＝12.7Hz,1H),4.10-3.88(m, 4H),3.03(s,3H),2.53-2.42(m,1H),2.39-2.28(m,1H),2.16(br t,J=8.0Hz,2H),1.83(q,J=6.7Hz, 2H),1.21-1.17(m,2H).
17cb:MS(ESI,m/z):617.4[M+1] +. 17cb:MS(ESI,m/z):617.4[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝9.71(br s,1H),8.49(s,1H),7.47-7.41(m,2H),7.28-7.15(m,5H),6.60-6.50(m,2H),5.47-5.23(m,5H),4.84(br dd,J＝5.8,13.8Hz,1H),4.50(br d,J＝12.8Hz,1H),4.13-4.04(m,1H),3.96(br t,J＝6.5Hz,1H),3.90-3.80(m,1H),3.02(s,3H),2.55-2.44(m,1H),2.38-2.24(m,1H),2.17-2.03(m,2H),2.00-1.78(m,2H),1.35(br dd,J＝5.0,10.9Hz,1H),1.22-1.08(m,6H),1.03-0.76(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 9.71 (br s, 1H), 8.49 (s, 1H), 7.47-7.41 (m, 2H), 7.28-7.15 (m, 5H), 6.60-6.50 (m,2H),5.47-5.23(m,5H),4.84(br dd,J=5.8,13.8Hz,1H),4.50(br d,J=12.8Hz,1H),4.13-4.04(m,1H ),3.96(br t,J＝6.5Hz,1H),3.90-3.80(m,1H),3.02(s,3H),2.55-2.44(m,1H),2.38-2.24(m,1H),2.17 -2.03(m,2H),2.00-1.78(m,2H),1.35(brdd,J＝5.0,10.9Hz,1H),1.22-1.08(m,6H),1.03-0.76(m,3H).
步骤3：化合物17A的合成Step 3: Synthesis of Compound 17A
将17ca(0.11g,208.90μmol,)溶于二氯甲烷(2mL)中，加入无水氯化镁(440.02mg,4.62mmol)，在28℃下搅拌12小时。反应液直接减压浓缩得到残余物，甲醇溶解后通过有机相针头式滤器过滤，得到粗品。粗品经制备反向液相色谱(分离条件:Phenomenex Luna 80*30mm*3μm；流动相:[H 2O(0.04％HCl)-ACN]；ACN％:30％-60％,8min)分离，得到化合物17A。 17ca (0.11g, 208.90μmol,) was dissolved in dichloromethane (2mL), anhydrous magnesium chloride (440.02mg, 4.62mmol) was added, and stirred at 28°C for 12 hours. The reaction solution was directly concentrated under reduced pressure to obtain a residue, which was dissolved in methanol and filtered through an organic phase syringe filter to obtain a crude product. The crude product was separated by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80*30mm*3μm; mobile phase: [H 2 O(0.04%HCl)-ACN]; ACN%: 30%-60%, 8min) to obtain Compound 17A.
17A:MS(ESI,m/z):527.3[M+1] +. 17A:MS(ESI,m/z):527.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.56-11.35(m,1H),10.04-9.91(m,1H),8.58(s,1H),7.27-7.24(m,1H),7.28-7.23(m,1H),6.65-6.60(m,2H),5.55-5.39(m,2H),4.84-4.70(m,2H),4.41(dd,J＝5.2,14.2Hz,1H),4.15-4.08(m,1H),3.99(br dd,J＝4.0,8.3Hz,1H),3.19(s,3H),2.63-2.37(m,2H),2.28-2.09(m,2H),1.92(quin,J＝6.4Hz,2H),1.54-1.42(m,2H),1.32-1.16(m,5H),1.10-1.00(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.56-11.35 (m, 1H), 10.04-9.91 (m, 1H), 8.58 (s, 1H), 7.27-7.24 (m, 1H), 7.28- 7.23(m,1H),6.65-6.60(m,2H),5.55-5.39(m,2H),4.84-4.70(m,2H),4.41(dd,J=5.2,14.2Hz,1H),4.15- 4.08(m,1H),3.99(br dd,J＝4.0,8.3Hz,1H),3.19(s,3H),2.63-2.37(m,2H),2.28-2.09(m,2H),1.92(quin ,J＝6.4Hz,2H),1.54-1.42(m,2H),1.32-1.16(m,5H),1.10-1.00(m,2H).
步骤4：化合物17B的合成Step 4: Synthesis of Compound 17B
将17cb(20mg,32.43μmol)溶于二氯甲烷(1mL)中，加入无水氯化镁(46.32mg,486.48μmol)，28℃搅拌12h。反应液直接浓缩得到残余物，甲醇溶解后通过有机相针头式滤器过滤，得到粗品。粗品经制备反向液相色谱(分离条件:Phenomenex Luna 80*30mm*3μm；流动相:[H 2O(0.04％HCl)-ACN]；ACN％:30％-60％,8min)分离，得到化合物17B。 17cb (20mg, 32.43μmol) was dissolved in dichloromethane (1mL), anhydrous magnesium chloride (46.32mg, 486.48μmol) was added, and stirred at 28°C for 12h. The reaction solution was directly concentrated to obtain a residue, which was dissolved in methanol and filtered through a syringe filter of the organic phase to obtain a crude product. The crude product was separated by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80*30mm*3μm; mobile phase: [H 2 O(0.04%HCl)-ACN]; ACN%: 30%-60%, 8min) to obtain Compound 17B.
17B:MS(ESI,m/z):527.3[M+1] +. 17B:MS(ESI,m/z):527.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.47-11.25(m,1H),9.72(br s,1H),8.48(s,1H),7.18-7.15(m,1H),6.67-6.47(m,2H),5.41-5.27(m,2H),4.77-4.70(m,2H),4.16(dd,J＝4.3,13.7Hz,1H),4.02-3.94(m,1H),3.88-3.75(m,1H),3.09(s,3H),2.62-2.47(m,1H),2.34-2.24(m,1H),2.19-2.08(m,1H),2.05-1.95(m,2H),1.93-1.81(m,1H),1.44-1.33(m,2H),1.23-1.08(m,5H),1.02-0.84(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.47-11.25 (m, 1H), 9.72 (br s, 1H), 8.48 (s, 1H), 7.18-7.15 (m, 1H), 6.67-6.47 (m,2H),5.41-5.27(m,2H),4.77-4.70(m,2H),4.16(dd,J＝4.3,13.7Hz,1H),4.02-3.94(m,1H),3.88-3.75 (m,1H),3.09(s,3H),2.62-2.47(m,1H),2.34-2.24(m,1H),2.19-2.08(m,1H),2.05-1.95(m,2H),1.93 -1.81(m,1H),1.44-1.33(m,2H),1.23-1.08(m,5H),1.02-0.84(m,2H).
实施例18Example 18
Figure PCTCN2022109064-appb-000094
Figure PCTCN2022109064-appb-000094
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000095
Figure PCTCN2022109064-appb-000095
准备干燥的氢化瓶，在氩气保护下加入湿Pd/C(10mg,10wt％)，随后加入17b(0.1g,162.16μmol)和乙酸乙酯(3mL)，随后置换氢气，反应在15psi、18℃下搅拌12小时。反应液通过硅藻土过滤后减压浓缩，N,N-二甲基甲酰胺溶解后通过有机相针头式滤器过滤得到粗品。粗品经制备反向液相色谱(分离条件：Phenomenex Luna 80×30mm×3μm；流动相:[H 2O(0.04％HCl)-ACN]；ACN％:30％-60％,8min)，纯化得到化合物18A。 Prepare a dry hydrogenation bottle, add wet Pd/C (10mg, 10wt%) under the protection of argon, then add 17b (0.1g, 162.16μmol) and ethyl acetate (3mL), then replace the hydrogen, react at 15psi, 18 Stir at °C for 12 hours. The reaction solution was filtered through diatomaceous earth and then concentrated under reduced pressure. N,N-dimethylformamide was dissolved and then filtered through an organic phase syringe filter to obtain a crude product. The crude product was purified by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80×30mm×3μm; mobile phase: [H 2 O(0.04%HCl)-ACN]; ACN%: 30%-60%, 8min), and purified to obtain Compound 18A.
18A:MS(ESI,m/z):529.3[M+1] +. 18A:MS(ESI,m/z):529.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.51-11.31(m,1H),9.89(br s,1H),8.57(s,1H),6.66-6.60(m,2H),5.70(d,J＝12.5Hz,1H),4.86-4.71(m,2H),4.37(dd,J＝5.1,13.9Hz,1H),4.12-3.95(m,2H),3.18(s,3H),2.29(dt,J＝5.6,10.2Hz,1H),2.15(ddd,J＝5.4,10.5,15.5Hz,1H),1.89-1.73(m,2H),1.53-1.37(m,3H),1.29-1.04(m,11H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.51-11.31 (m, 1H), 9.89 (br s, 1H), 8.57 (s, 1H), 6.66-6.60 (m, 2H), 5.70 (d ,J=12.5Hz,1H),4.86-4.71(m,2H),4.37(dd,J=5.1,13.9Hz,1H),4.12-3.95(m,2H),3.18(s,3H),2.29( dt,J=5.6,10.2Hz,1H), 2.15(ddd,J=5.4,10.5,15.5Hz,1H),1.89-1.73(m,2H),1.53-1.37(m,3H),1.29-1.04( m,11H).
实施例19Example 19
Figure PCTCN2022109064-appb-000096
Figure PCTCN2022109064-appb-000096
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000097
Figure PCTCN2022109064-appb-000097
步骤1：化合物19aa和19ab的合成Step 1: Synthesis of Compounds 19aa and 19ab
原料11b纯品(250mg)通过SFC分离(分离条件：DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相[Neu-EtOH]％:46％-46％,15min)，纯化得到产物纯品19aa和19ab。The pure product 11b (250mg) was separated by SFC (separation condition: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase [Neu-EtOH]%: 46%-46%, 15min), and purified to obtain the pure product 19aa and 19ab.
分析方法：柱型：Chiralpak AD-3 50mm*4.6mm*3μm；流动相:[A:CO 2；B:EtOH(0.1％IPAm,v/v)]；B％:40％,3min；保留时间：1.208min(19aa)，1.689min(19ab)。 Analysis method: column type: Chiralpak AD-3 50mm*4.6mm*3μm; mobile phase: [A:CO 2 ; B:EtOH(0.1%IPAm,v/v)]; B%:40%,3min; retention time : 1.208min (19aa), 1.689min (19ab).
19aa:MS(ESI,m/z):589.3[M+1] +. 19aa:MS(ESI,m/z):589.3[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝9.65(br d,J＝6.8Hz,1H),8.94-8.88(m,1H),7.52(d,J＝6.9Hz,2H),7.49-7.43(m,1H),7.38-7.29(m,3H),6.91(dd,J＝2.4,11.4Hz,1H),6.78(dt,J＝2.3,8.4Hz,1H),5.55(d,J＝13.0Hz,1H),5.49-5.28(m,2H),5.15-4.99(m,4H),4.08(td,J＝4.3,9.1Hz,1H),3.96(br d,J＝12.4Hz,1H),3.87(dt,J＝2.8,9.4Hz,1H),3.01(s,3H),2.34-2.21(m,4H),1.81(br dd,J＝6.1,13.6Hz,1H),1.52(td,J＝6.9,13.8Hz,2H),1.26(br s,3H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 9.65 (br d, J = 6.8Hz, 1H), 8.94-8.88 (m, 1H), 7.52 (d, J = 6.9Hz, 2H), 7.49 -7.43(m,1H),7.38-7.29(m,3H),6.91(dd,J＝2.4,11.4Hz,1H),6.78(dt,J＝2.3,8.4Hz,1H),5.55(d,J =13.0Hz,1H),5.49-5.28(m,2H),5.15-4.99(m,4H),4.08(td,J=4.3,9.1Hz,1H),3.96(br d,J=12.4Hz,1H ), 3.87(dt, J＝2.8, 9.4Hz, 1H), 3.01(s, 3H), 2.34-2.21(m, 4H), 1.81(brdd, J＝6.1, 13.6Hz, 1H), 1.52(td ,J＝6.9,13.8Hz,2H),1.26(br s,3H).
19ab:MS(ESI,m/z):589.3[M+1] +. 19ab:MS(ESI,m/z):589.3[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝9.71-9.61(m,1H),8.94(s,1H),7.55-7.46(m,2H),7.44-7.21(m,4H),6.91(dd,J＝2.5,11.4Hz,1H),6.74(dt,J＝2.4,8.4Hz,1H),5.54(d,J＝13.1Hz,1H),5.43-5.25(m,2H),5.19(br dd,J＝8.8,13.8Hz,1H),5.13-5.00(m,3H),4.06-3.92(m,1H),3.91-3.72(m,2H),3.00(s,3H),2.14(dq,J＝5.3,10.8Hz,2H),1.95-1.77(m,2H),1.64-1.15(m,6H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 9.71-9.61 (m, 1H), 8.94 (s, 1H), 7.55-7.46 (m, 2H), 7.44-7.21 (m, 4H), 6.91 (dd, J=2.5,11.4Hz,1H),6.74(dt,J=2.4,8.4Hz,1H),5.54(d,J=13.1Hz,1H),5.43-5.25(m,2H),5.19( br dd,J＝8.8,13.8Hz,1H),5.13-5.00(m,3H),4.06-3.92(m,1H),3.91-3.72(m,2H),3.00(s,3H),2.14(dq ,J＝5.3,10.8Hz,2H),1.95-1.77(m,2H),1.64-1.15(m,6H).
步骤2：化合物19A和19B的合成Step 2: Synthesis of Compounds 19A and 19B
在干燥的三口瓶中加入19aa或19ab(30mg,60.18μmol)和二氯甲烷(1mL)，开启搅拌，随后加入无水氯化镁(114.60mg,1.20mmol)，氮气置换3次，将反应置于18℃下搅拌16小时。减压浓缩得到粗产品，粗品经加入甲叔醚(2mL)打浆30min后过滤，往滤饼加入1％HCl水溶液(1mL)室温打浆30min后过滤，真空干燥。分别得到产物19A和19B。Add 19aa or 19ab (30 mg, 60.18 μmol) and dichloromethane (1 mL) into a dry three-necked flask, start stirring, then add anhydrous magnesium chloride (114.60 mg, 1.20 mmol), nitrogen replacement 3 times, and place the reaction at 18 Stir at °C for 16 hours. Concentrate under reduced pressure to obtain a crude product, which was filtered by adding tert-methyl ether (2 mL) and beating for 30 min, then adding 1% HCl aqueous solution (1 mL) to the filter cake and beating for 30 min at room temperature, then filtering and drying in vacuo. Products 19A and 19B were obtained, respectively.
19A:MS(ESI,m/z):499.2[M+1] +. 19A:MS(ESI,m/z):499.2[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.59-11.35(m,1H),9.69-9.53(m,1H),8.62(s,1H),7.25(s,1H),6.74-6.50(m,2H),5.71(d,J＝12.5Hz,1H),5.55-5.45(m,1H),5.34(td,J＝7.2,14.7Hz,1H),5.23(dd,J＝7.5,13.7Hz, 1H),4.80(d,J＝12.5Hz,1H),4.05(td,J＝4.3,8.7Hz,1H),3.97(dd,J＝1.8,13.7Hz,1H),3.89-3.82(m,1H),3.17(s,3H),2.62-2.28(m,2H),2.27-2.04(m,2H),1.89(qd,J＝7.0,14.0Hz,1H),1.71-1.60(m,3H),1.39-1.31(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.59-11.35 (m, 1H), 9.69-9.53 (m, 1H), 8.62 (s, 1H), 7.25 (s, 1H), 6.74-6.50 ( m,2H),5.71(d,J=12.5Hz,1H),5.55-5.45(m,1H),5.34(td,J=7.2,14.7Hz,1H),5.23(dd,J=7.5,13.7Hz , 1H), 4.80(d, J=12.5Hz, 1H), 4.05(td, J=4.3, 8.7Hz, 1H), 3.97(dd, J=1.8, 13.7Hz, 1H), 3.89-3.82(m, 1H),3.17(s,3H),2.62-2.28(m,2H),2.27-2.04(m,2H),1.89(qd,J＝7.0,14.0Hz,1H),1.71-1.60(m,3H) ,1.39-1.31(m,2H).
19B:MS(ESI,m/z):499.2[M+1] +. 19B:MS(ESI,m/z):499.2[M+1] + .
实施例20Example 20
Figure PCTCN2022109064-appb-000098
Figure PCTCN2022109064-appb-000098
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000099
Figure PCTCN2022109064-appb-000099
步骤1：化合物20a的合成Step 1: Synthesis of compound 20a
在干燥的三口瓶中加入1e(3g,5.04mmol)和四氢呋喃(45mL)，开启搅拌；随后加入1,8-二氮杂二环[5,4,0]十一烷-7-烯(7.67mg,50.40μmol,7.59μL)和2-(2,2-双甲氧基乙氧基)-1-乙胺(2.64g,17.64mmol)，氮气置换3次，将反应置于65℃搅拌16小时。降温至20-30℃，搅拌下缓慢加入醋酸将体系调至弱酸性(pH＝4-5)。减压浓缩除去四氢呋喃，然后加入乙酸乙酯(20mL)和水(20mL)搅拌混合后分液，水相用乙酸乙酯(20mL)再萃取一次；合并有机相并用饱和食盐水(40mL)洗涤后，用无水硫酸钠干燥。过滤减压浓缩得到粗产品20a。Add 1e (3g, 5.04mmol) and tetrahydrofuran (45mL) into a dry three-necked flask, and start stirring; then add 1,8-diazabicyclo[5,4,0]undec-7-ene (7.67 mg, 50.40μmol, 7.59μL) and 2-(2,2-bismethoxyethoxy)-1-ethylamine (2.64g, 17.64mmol), nitrogen replacement 3 times, the reaction was placed at 65 ° C and stirred for 16 Hour. Cool down to 20-30°C, slowly add acetic acid under stirring to adjust the system to weak acidity (pH=4-5). Concentrate under reduced pressure to remove tetrahydrofuran, then add ethyl acetate (20mL) and water (20mL) to stir and mix, then separate the liquids, and extract the aqueous phase with ethyl acetate (20mL) again; combine the organic phases and wash with saturated brine (40mL) , dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure afforded crude product 20a.
MS(ESI,m/z):713.4[M+1] +. MS(ESI,m/z):713.4[M+1] + .
步骤2：化合物20b的合成Step 2: Synthesis of compound 20b
在干燥的三口瓶中加入20a(1g,1.40mmol)，水(3mL)和乙腈(14mL)，开启搅拌；氮气置换3次升温至60℃。温度在60℃缓慢滴加甲烷磺酸(404.51mg,4.21mmol,299.63μL)和水(3mL)的混合溶液。将反应置于60℃搅拌6小时。反应液降温至20-30℃，搅拌下缓慢加入10％的氢氧化钠水溶液，将体系调至碱性 (pH＝9-10)；减压浓缩除去乙腈，然后加入乙酸乙酯(20mL)和水(20mL)搅拌混合后分液，水相用乙酸乙酯(20mL)再萃取一次；合并有机相用饱和食盐水(40mL)洗涤，有机相用无水硫酸钠干燥。过滤减压浓缩得到粗产品。粗产品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-0:100)分离，馏分减压浓缩得到20b。Add 20a (1g, 1.40mmol), water (3mL) and acetonitrile (14mL) into a dry three-necked flask, start stirring; replace with nitrogen for 3 times and raise the temperature to 60°C. A mixed solution of methanesulfonic acid (404.51 mg, 4.21 mmol, 299.63 μL) and water (3 mL) was slowly added dropwise at a temperature of 60°C. The reaction was stirred at 60°C for 6 hours. The temperature of the reaction solution was lowered to 20-30°C, and 10% aqueous sodium hydroxide solution was slowly added under stirring to adjust the system to alkaline (pH=9-10); concentrated under reduced pressure to remove acetonitrile, then added ethyl acetate (20 mL) and Water (20 mL) was stirred and mixed, and the liquids were separated. The aqueous phase was extracted once more with ethyl acetate (20 mL); the combined organic phases were washed with saturated brine (40 mL), and the organic phases were dried over anhydrous sodium sulfate. The crude product was obtained by filtration and concentration under reduced pressure. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether=100:0-0:100), and the fraction was concentrated under reduced pressure to obtain 20b.
MS(ESI,m/z):549.3[M+1] +. MS(ESI,m/z):549.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝10.36(t,J＝5.9Hz,1H),8.38(s,1H),7.62-7.53(m,2H),7.41-7.33(m, 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 10.36 (t, J = 5.9 Hz, 1H), 8.38 (s, 1H), 7.62-7.53 (m, 2H), 7.41-7.33 (m,
3H),7.27(s,2H),6.65-6.55(m,2H),5.99(tdd,J＝6.8,10.3,17.1Hz,1H),5.90(d,J＝13.0Hz,1H),5.28(d,J＝9.5Hz,1H),5.26-5.11(m,2H),5.01(d,J＝9.5Hz,1H),4.57(d,J＝6.0Hz,2H),4.53-4.43(m,1H),4.06(t,J＝6.7Hz,2H),3.91(dd,J＝2.3,13.9Hz,1H),3.86-3.77(m,2H),3.39(dt,J＝2.7,12.0Hz,1H),2.92-2.76(m,2H),2.71(q,J＝6.7Hz,2H).3H), 7.27(s, 2H), 6.65-6.55(m, 2H), 5.99(tdd, J=6.8, 10.3, 17.1Hz, 1H), 5.90(d, J=13.0Hz, 1H), 5.28(d ,J=9.5Hz,1H),5.26-5.11(m,2H),5.01(d,J=9.5Hz,1H),4.57(d,J=6.0Hz,2H),4.53-4.43(m,1H) ,4.06(t,J=6.7Hz,2H),3.91(dd,J=2.3,13.9Hz,1H),3.86-3.77(m,2H),3.39(dt,J=2.7,12.0Hz,1H), 2.92-2.76(m,2H),2.71(q,J＝6.7Hz,2H).
步骤3：化合物20c的合成Step 3: Synthesis of compound 20c
在干燥的三口瓶中加入20b(0.5g,911.48μmol)和N,N-二甲基甲酰胺(5mL)，开启搅拌；随后加入碳酸铯(890.93mg,2.73mmol)和7-溴-1-庚烯(322.81mg,1.82mmol)，氮气置换3次，反应升温至40℃搅拌24小时。向反应液中加入水(10mL)，用二氯甲烷(10mL*3)萃取三次，合并有机相后用饱和食盐水(30mL)洗涤，无水硫酸钠干燥后过滤。粗产品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-30:70)分离，馏分减压浓缩得到20c。Add 20b (0.5g, 911.48μmol) and N,N-dimethylformamide (5mL) into a dry three-necked flask, start stirring; then add cesium carbonate (890.93mg, 2.73mmol) and 7-bromo-1- Heptene (322.81mg, 1.82mmol) was replaced with nitrogen three times, and the reaction temperature was raised to 40°C and stirred for 24 hours. Water (10 mL) was added to the reaction liquid, extracted three times with dichloromethane (10 mL*3), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether=100:0-30:70), and the fraction was concentrated under reduced pressure to obtain 20c.
MS(ESI,m/z):645.3[M+1] +. MS(ESI,m/z):645.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝10.27(s,1H),8.35(s,1H),7.48(dd,J＝1.6,7.6Hz,2H),7.31-7.22(m, 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 10.27 (s, 1H), 8.35 (s, 1H), 7.48 (dd, J = 1.6, 7.6Hz, 2H), 7.31-7.22 (m,
4H),6.60-6.50(m,2H),5.99-5.85(m,1H),5.71(br dd,J＝10.3,17.0Hz,1H),5.38-5.29(m,2H),5.15(qd,J＝1.6,17.2Hz,1H),5.09-5.03(m,1H),4.97-4.87(m,2H),4.53(d,J＝6.0Hz,3H),4.34-4.17(m,1H),4.01(t,J＝6.7Hz,2H),3.92(br dd,J＝4.1,11.7Hz,1H),3.80-3.74(m,1H),3.57-3.31(m,2H),3.26-3.13(m,1H),2.96(br d,J＝7.6Hz,2H),2.63(d,J＝6.8Hz,2H),1.99-1.94(m,2H),1.40-1.23(m,6H).4H),6.60-6.50(m,2H),5.99-5.85(m,1H),5.71(br dd,J＝10.3,17.0Hz,1H),5.38-5.29(m,2H),5.15(qd,J =1.6,17.2Hz,1H),5.09-5.03(m,1H),4.97-4.87(m,2H),4.53(d,J=6.0Hz,3H),4.34-4.17(m,1H),4.01( t,J=6.7Hz,2H),3.92(br dd,J=4.1,11.7Hz,1H),3.80-3.74(m,1H),3.57-3.31(m,2H),3.26-3.13(m,1H ),2.96(br d,J=7.6Hz,2H),2.63(d,J=6.8Hz,2H),1.99-1.94(m,2H),1.40-1.23(m,6H).
步骤4：化合物20d的合成Step 4: Synthesis of compound 20d
干燥的三口瓶中依次加入20c(0.260g,403.27μmol)、二氯甲烷(2.60mL)和对苯醌(8.72mg,80.65μmol)，搅拌下加入詹氏催化剂-1B(29.59mg,40.33μmol,)，置于40℃下反应24小时。反应液减压浓缩得到粗产品。粗产品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-0:100)分离，馏分减压浓缩得到20d。Add 20c (0.260g, 403.27μmol), dichloromethane (2.60mL) and p-benzoquinone (8.72mg, 80.65μmol) to the dry three-necked flask successively, and add Jane's catalyst-1B (29.59mg, 40.33μmol, ), placed at 40°C for 24 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether=100:0-0:100), and the fraction was concentrated under reduced pressure to obtain 20d.
MS(ESI,m/z):617.3[M+1] +. MS(ESI,m/z):617.3[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝9.74-9.59(m,1H),9.73-9.56(m,1H),8.35(s,1H),8.45-8.25(m,1H),7.53-7.43(m,3H),7.35-7.27(m,3H),6.91-6.84(m,1H),6.79-6.70(m,1H),5.50-5.26(m,2H),5.14-5.02(m,3H),3.97-3.76(m,5H),3.67-3.54(m,1H),3.26-3.10(m,2H),2.40-2.18(m,3H),1.89(br d,J＝4.9Hz,1H),1.76-1.58(m,1H),1.33-1.22(m,6H),1.43-1.19(m,1H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 9.74-9.59 (m, 1H), 9.73-9.56 (m, 1H), 8.35 (s, 1H), 8.45-8.25 (m, 1H), 7.53 -7.43(m,3H),7.35-7.27(m,3H),6.91-6.84(m,1H),6.79-6.70(m,1H),5.50-5.26(m,2H),5.14-5.02(m, 3H),3.97-3.76(m,5H),3.67-3.54(m,1H),3.26-3.10(m,2H),2.40-2.18(m,3H),1.89(br d,J＝4.9Hz,1H ),1.76-1.58(m,1H),1.33-1.22(m,6H),1.43-1.19(m,1H).
步骤5：化合物20A的合成Step 5: Synthesis of Compound 20A
加入20d(164.00mg,265.94μmol)溶于二氯甲烷(5mL)，加入氯化镁(759.62mg,7.98mmol)，25℃下搅拌12小时。反应液减压浓缩后加入2-3mL甲基叔丁基醚打浆1小时，过滤后滤液减压浓缩得到粗产品。粗产品通过反向制备液相色谱(分离条件：Phenomenex Luna 80*30mm*3μm；流动相:[H 2O(HCl)-ACN]；ACN％:40％-60％,8min)纯化得到20A。 Add 20d (164.00 mg, 265.94 μmol) and dissolve in dichloromethane (5 mL), add magnesium chloride (759.62 mg, 7.98 mmol), and stir at 25° C. for 12 hours. After the reaction solution was concentrated under reduced pressure, 2-3 mL of methyl tert-butyl ether was added to make a slurry for 1 hour. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse preparative liquid chromatography (separation conditions: Phenomenex Luna 80*30mm*3μm; mobile phase: [H 2 O(HCl)-ACN]; ACN%: 40%-60%, 8min) to obtain 20A.
MS(ESI,m/z):527.3[M+1] +. MS(ESI,m/z):527.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.93-11.51(m,1H),9.64(br s,1H),8.51-8.45(m,1H),7.26-7.17(m,1H),6.70-6.47(m,2H),5.57-5.28(m,2H),4.82-4.36(m,2H),4.22-3.70(m,4H),3.51(br t,J＝10.0Hz,2H),3.32-3.11(m,2H),3.08-2.92(m,1H),2.58-2.21(m,2H),2.06-1.67(m,2H),1.51-1.04(m,7H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.93-11.51 (m, 1H), 9.64 (br s, 1H), 8.51-8.45 (m, 1H), 7.26-7.17 (m, 1H), 6.70 -6.47(m,2H),5.57-5.28(m,2H),4.82-4.36(m,2H),4.22-3.70(m,4H),3.51(br t,J＝10.0Hz,2H),3.32- 3.11(m,2H),3.08-2.92(m,1H),2.58-2.21(m,2H),2.06-1.67(m,2H),1.51-1.04(m,7H).
实施例21Example 21
Figure PCTCN2022109064-appb-000100
Figure PCTCN2022109064-appb-000100
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000101
Figure PCTCN2022109064-appb-000101
Figure PCTCN2022109064-appb-000102
Figure PCTCN2022109064-appb-000102
步骤1：化合物21A和21B的合成Step 1: Synthesis of Compounds 21A and 21B
将20b进行SFC拆分(分离条件：DAICEL CHIRALPAK AD 250mm*30mm*10μm；流动相:[Neu-IPA]％:50％-50％,6min)，拆分后的馏分分别减压浓缩得到21A和21B。20b was subjected to SFC resolution (separation conditions: DAICEL CHIRALPAK AD 250mm*30mm*10μm; mobile phase: [Neu-IPA]%: 50%-50%, 6min), and the split fractions were concentrated under reduced pressure to obtain 21A and 21B.
分析方法：柱型：Chiralpak AD-3 50mm*4.6mm*3μm；流动相:[A:CO 2；B:IPA(0.1％IPAm,v/v)]；B％:5％,0.2min；5％-50％,1min；50％,1min；50％-5％,0.4min；5％,0.4min；保留时间：1.485min(21A)，1.702min(21B)。 Analysis method: column type: Chiralpak AD-3 50mm*4.6mm*3μm; mobile phase: [A:CO 2 ; B:IPA(0.1%IPAm,v/v)]; B%:5%,0.2min;5 %-50%, 1 min; 50%, 1 min; 50%-5%, 0.4 min; 5%, 0.4 min; retention time: 1.485 min (21A), 1.702 min (21B).
21A:MS(ESI,m/z):549.2[M+1] +. 21A:MS(ESI,m/z):549.2[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝10.33(t,J＝5.9Hz,1H),8.26(s,1H),7.68-7.53(m,3H),7.40-7.31(m,3H),7.27-7.20(m,1H),6.94(dd,J＝2.3,11.3Hz,1H),6.72(dt,J＝2.4,8.5Hz,1H),5.96(tdd,J＝6.7,10.3,17.1Hz,1H),5.19(dd,J＝1.8,17.1Hz,1H),5.12-5.04(m,3H),4.89(ddd,J＝4.6,9.9,12.4Hz,1H),4.43(br d,J＝5.9Hz,2H),4.34(d,J＝4.1Hz,1H),4.10(t,J＝6.4Hz,2H),4.07-3.99(m,2H),3.46(dt,J＝2.8,11.9Hz,1H),3.18(t,J＝10.7Hz,1H),3.06-2.90(m,1H),2.59(q,J＝6.5Hz,2H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 10.33 (t, J = 5.9Hz, 1H), 8.26 (s, 1H), 7.68-7.53 (m, 3H), 7.40-7.31 (m, 3H ),7.27-7.20(m,1H),6.94(dd,J=2.3,11.3Hz,1H),6.72(dt,J=2.4,8.5Hz,1H),5.96(tdd,J=6.7,10.3,17.1 Hz,1H),5.19(dd,J＝1.8,17.1Hz,1H),5.12-5.04(m,3H),4.89(ddd,J＝4.6,9.9,12.4Hz,1H),4.43(br d,J =5.9Hz, 2H), 4.34(d, J=4.1Hz, 1H), 4.10(t, J=6.4Hz, 2H), 4.07-3.99(m, 2H), 3.46(dt, J=2.8, 11.9Hz ,1H),3.18(t,J=10.7Hz,1H),3.06-2.90(m,1H),2.59(q,J=6.5Hz,2H).
21B:MS(ESI,m/z):549.2[M+1] +. 21B:MS(ESI,m/z):549.2[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝10.33(t,J＝5.9Hz,1H),8.26(s,1H),7.63-7.53(m,3H),7.43-7.19(m,4H),6.94(dd,J＝2.4,11.3Hz,1H),6.72(dt,J＝2.4,8.5Hz,1H),5.96(tdd,J＝6.7,10.3,17.1Hz,1H),5.23-5.00(m,4H),4.89(ddd,J＝4.6,9.8,12.4Hz,1H),4.43(d,J＝5.9Hz,2H),4.21-3.98(m,6H),3.52-3.41(m,1H),3.24-3.12(m,1H),3.03-2.93(m,1H),2.62-2.56(m,2H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 10.33 (t, J = 5.9Hz, 1H), 8.26 (s, 1H), 7.63-7.53 (m, 3H), 7.43-7.19 (m, 4H ), 6.94(dd, J=2.4, 11.3Hz, 1H), 6.72(dt, J=2.4, 8.5Hz, 1H), 5.96(tdd, J=6.7, 10.3, 17.1Hz, 1H), 5.23-5.00( m,4H),4.89(ddd,J=4.6,9.8,12.4Hz,1H),4.43(d,J=5.9Hz,2H),4.21-3.98(m,6H),3.52-3.41(m,1H) ,3.24-3.12(m,1H),3.03-2.93(m,1H),2.62-2.56(m,2H).
步骤2：化合物22a的合成Step 2: Synthesis of compound 22a
在干燥的三口瓶中加入21A(0.150g,273.44μmol)和N,N-二甲基甲酰胺(2mL)，开启搅拌；随后加入碳酸铯(267.28mg,820.33μmol)和8-溴-1-辛烯(104.51mg,546.89μmol,91.68μL)，氮气置换3次，将反应置于40℃搅拌24小时。向反应液中加入水(10mL)，用二氯甲烷(10mL*3)萃取三次，合并有机相后用饱和食盐水(30mL)洗涤，无水硫酸钠干燥后过滤，减压浓缩得到粗品。粗产品经硅胶柱层析(乙酸乙酯/石油醚 ＝100:0-50:50)分离，馏分减压浓缩得到22a。Add 21A (0.150g, 273.44μmol) and N,N-dimethylformamide (2mL) into a dry three-necked flask, start stirring; then add cesium carbonate (267.28mg, 820.33μmol) and 8-bromo-1- Octene (104.51 mg, 546.89 μmol, 91.68 μL) was replaced with nitrogen three times, and the reaction was stirred at 40° C. for 24 hours. Water (10 mL) was added to the reaction solution, extracted three times with dichloromethane (10 mL*3), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether = 100:0-50:50), and the fractions were concentrated under reduced pressure to obtain 22a.
MS(ESI,m/z):659.3[M+1] +. MS(ESI,m/z):659.3[M+1] + .
步骤3：化合物22b的合成Step 3: Synthesis of compound 22b
干燥的三口瓶中依次加入22a(0.226g,343.07μmol)、二氯甲烷(2.50mL)和对苯醌(7.42mg,68.61μmol)，搅拌下加入詹氏催化剂-1B(25.17mg,34.31μmol)，置于40℃下反应24小时。反应液减压浓缩得到粗产品。粗产品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-0:100)分离，馏分减压浓缩得到异构体混合物后进行SFC拆分(分离条件：DAICEL CHIRALPAK AD 250mm*30mm*10μm；流动相:[Neu-EtOH]％:60％-60％,20min)，拆分后的馏分减压浓缩得到22b(分析方法：柱型：Chiralpak AD-3 50mm*4.6mm*3μm；流动相:[A:CO 2；B:EtOH(0.1％IPAm,v/v)]；B％:40％,5min；保留时间：3.748min)。 Add 22a (0.226g, 343.07μmol), dichloromethane (2.50mL) and p-benzoquinone (7.42mg, 68.61μmol) to the dry three-necked flask in sequence, and add Jane's Catalyst-1B (25.17mg, 34.31μmol) under stirring , placed at 40°C for 24 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether=100:0-0:100), and the fraction was concentrated under reduced pressure to obtain a mixture of isomers, which was then resolved by SFC (separation condition: DAICEL CHIRALPAK AD 250mm*30mm* 10 μm; mobile phase: [Neu-EtOH]%: 60%-60%, 20min), the split fractions were concentrated under reduced pressure to obtain 22b (analysis method: column type: Chiralpak AD-3 50mm*4.6mm*3μm; flow Phase: [A: CO 2 ; B: EtOH (0.1% IPAm, v/v)]; B%: 40%, 5 min; retention time: 3.748 min).
MS(ESI,m/z):631.3[M+1] +. MS(ESI,m/z):631.3[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝9.78(br t,J＝4.8Hz,1H),8.32(s,1H),7.56-7.24(m,7H),6.95-6.70(m,2H),5.66-5.42(m,2H),5.09(q,J＝10.6Hz,4H),4.10-3.89(m,5H),3.80(br d,J＝11.0Hz,1H),3.69-3.52(m,2H),2.99-2.85(m,1H),1.93-1.70(m,3H),1.44-1.14(m,11H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 9.78 (br t, J = 4.8Hz, 1H), 8.32 (s, 1H), 7.56-7.24 (m, 7H), 6.95-6.70 (m, 2H), 5.66-5.42(m, 2H), 5.09(q, J=10.6Hz, 4H), 4.10-3.89(m, 5H), 3.80(br d, J=11.0Hz, 1H), 3.69-3.52( m,2H),2.99-2.85(m,1H),1.93-1.70(m,3H),1.44-1.14(m,11H).
步骤4：化合物22A的合成Step 4: Synthesis of compound 22A
在干燥的三口瓶中加入22b(0.1g,158.55μmol)和二氯甲烷(1mL)，开启搅拌。随后加入氯化镁(603.84mg,6.34mmol)，氮气置换3次，将反应置于25℃搅拌12小时。减压浓缩反应液，浓缩后的反应液用甲醇溶解后用针头式滤器过滤，得到粗品。粗产品通过反向制备液相色谱分离(分离条件:Phenomenex Luna80*30mm*3μm；流动相:[H 2O(HCl)-MeOH]；MeOH％:35％-65％,8min)，馏分减压浓缩得到22A。 Add 22b (0.1 g, 158.55 μmol) and dichloromethane (1 mL) into a dry three-necked flask, and start stirring. Then magnesium chloride (603.84mg, 6.34mmol) was added, nitrogen was replaced 3 times, and the reaction was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the concentrated reaction solution was dissolved in methanol and filtered with a syringe filter to obtain a crude product. The crude product was separated by reverse preparative liquid chromatography (separation condition: Phenomenex Luna80*30mm*3μm; mobile phase: [H 2 O(HCl)-MeOH]; MeOH%: 35%-65%, 8min), and the fraction was decompressed Concentration afforded 22A.
MS(ESI,m/z):541.3[M+1] +. MS(ESI,m/z):541.3[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝11.93-11.70(m,1H),9.70(t,J＝4.9Hz,1H),8.23(s,1H),7.52-7.35(m,1H),6.90(dd,J＝2.4,11.4Hz,1H),6.77(dt,J＝2.4,8.4Hz,1H),5.62-5.41(m,2H),5.15-5.05(m,1H),4.72-4.13(m,3H),4.04-3.91(m,3H),3.83(br d,J＝9.4Hz,1H),3.64(br t,J＝10.6Hz,1H),3.56-3.44(m,2H),3.13-2.97(m,1H),2.42-2.32(m,2H),1.87-1.73(m,2H),1.43-1.11(m,9H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 11.93-11.70 (m, 1H), 9.70 (t, J = 4.9Hz, 1H), 8.23 (s, 1H), 7.52-7.35 (m, 1H ),6.90(dd,J=2.4,11.4Hz,1H),6.77(dt,J=2.4,8.4Hz,1H),5.62-5.41(m,2H),5.15-5.05(m,1H),4.72- 4.13(m,3H),4.04-3.91(m,3H),3.83(br d,J=9.4Hz,1H),3.64(br t,J=10.6Hz,1H),3.56-3.44(m,2H) ,3.13-2.97(m,1H),2.42-2.32(m,2H),1.87-1.73(m,2H),1.43-1.11(m,9H).
步骤5：化合物23a的合成Step 5: Synthesis of compound 23a
在干燥的三口瓶中加入21B(0.23g,419.28μmol)和N,N-二甲基甲酰胺(2mL)，开启搅拌；随后加入碳酸铯(409.83mg,1.26mmol)和8-溴-1-辛烯(160.26mg,838.56μmol,140.57μL)，氮气置换3次，将反应置于40℃搅拌24小时。向反应液中加入水(10mL)，用二氯甲烷(10mL*3)萃取三次，合并有机相后用饱和食盐水(30mL)洗涤，无水硫酸钠干燥后过滤，减压浓缩得到粗品。粗产品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-50:50)分离，馏分减压浓缩得到23a。Add 21B (0.23g, 419.28μmol) and N,N-dimethylformamide (2mL) into a dry three-necked flask, start stirring; then add cesium carbonate (409.83mg, 1.26mmol) and 8-bromo-1- Octene (160.26 mg, 838.56 μmol, 140.57 μL) was replaced with nitrogen three times, and the reaction was stirred at 40° C. for 24 hours. Water (10 mL) was added to the reaction solution, extracted three times with dichloromethane (10 mL*3), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether=100:0-50:50), and the fraction was concentrated under reduced pressure to obtain 23a.
MS(ESI,m/z):659.3[M+1] +. MS(ESI,m/z):659.3[M+1] + .
步骤6：化合物23b的合成Step 6: Synthesis of compound 23b
干燥的三口瓶中依次加入23a(0.251g,381.02μmol)、二氯甲烷(2.50mL)和对苯醌(8.24mg,76.20μmol,17.16μL)，搅拌下加入詹氏催化剂-1B(27.96mg,38.10μmol)，置于40℃下反应24小时。反应液减压浓缩得到粗产品。粗产品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-0:100)分离，馏分减压浓缩得到异构体混合物后进行SFC拆分(分离条件：REGIS(S,S)WHELK-O1 250mm*25mm,10μm；流动相:[Neu-EtOH]％:60％-60％,25min)，拆分后的馏分减压浓缩得到23b(分析方法：柱型：(S,S)-WHELK-O1 50mm*4.6mm*3μm；流动相:[A:CO 2；B:EtOH(0.1％IPAm,v/v)]；B％:50％,3min；保留时间：1.515min)。 Add 23a (0.251g, 381.02μmol), dichloromethane (2.50mL) and p-benzoquinone (8.24mg, 76.20μmol, 17.16μL) to the dry three-necked flask successively, and add Jane's Catalyst-1B (27.96mg, 38.10 μmol), placed at 40°C for 24 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether=100:0-0:100), and the fraction was concentrated under reduced pressure to obtain a mixture of isomers, which was then resolved by SFC (separation condition: REGIS(S,S)WHELK -O1 250mm*25mm, 10μm; mobile phase: [Neu-EtOH]%: 60%-60%, 25min), the split fractions were concentrated under reduced pressure to obtain 23b (analysis method: column type: (S, S)- WHELK-O1 50mm*4.6mm*3μm; mobile phase: [A: CO 2 ; B: EtOH (0.1% IPAm, v/v)]; B%: 50%, 3min; retention time: 1.515min).
MS(ESI,m/z):631.3[M+1] +. MS(ESI,m/z):631.3[M+1] + .
步骤7：化合物23A的合成Step 7: Synthesis of Compound 23A
在干燥的三口瓶中加入23b(0.1g,158.55μmol)和溶剂二氯甲烷(1mL)，开启搅拌；随后加入氯化镁(603.84mg,6.34mmol)，氮气置换3次，将反应置于25℃搅拌12小时。减压浓缩反应液，浓缩后的反应液用甲醇溶解后用针头式滤器过滤，得到粗品。粗产品通过反向制备液相色谱分离(分离条件:Phenomenex Luna 80*30mm*3μm；流动相:[H 2O(HCl)-MeOH]％:35％-65％,8min)，馏分减压浓缩得到23A。 Add 23b (0.1g, 158.55μmol) and solvent dichloromethane (1mL) into a dry three-necked flask, start stirring; then add magnesium chloride (603.84mg, 6.34mmol), nitrogen replacement 3 times, and stir the reaction at 25°C 12 hours. The reaction solution was concentrated under reduced pressure, and the concentrated reaction solution was dissolved in methanol and filtered with a syringe filter to obtain a crude product. The crude product was separated by reverse preparative liquid chromatography (separation conditions: Phenomenex Luna 80*30mm*3μm; mobile phase: [H 2 O(HCl)-MeOH]%: 35%-65%, 8min), and the fractions were concentrated under reduced pressure Get 23A.
MS(ESI,m/z):541.3[M+1] +. MS(ESI,m/z):541.3[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝11.93-11.70(m,1H),9.70(t,J＝4.9Hz,1H),8.23(s,1H),7.52-7.35(m,1H),6.90(dd,J＝2.4,11.4Hz,1H),6.77(dt,J＝2.4,8.4Hz,1H),5.62-5.41(m,2H),5.15-5.05(m,1H),4.72-4.13(m,3H),4.04-3.91(m,3H),3.83(br d,J＝9.4Hz,1H),3.64(br t,J＝10.6Hz,1H),3.56-3.44(m,2H),3.13-2.97(m,1H),2.42-2.32(m,2H),1.87-1.73(m,2H),1.43-1.11(m,9H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 11.93-11.70 (m, 1H), 9.70 (t, J = 4.9Hz, 1H), 8.23 (s, 1H), 7.52-7.35 (m, 1H ),6.90(dd,J=2.4,11.4Hz,1H),6.77(dt,J=2.4,8.4Hz,1H),5.62-5.41(m,2H),5.15-5.05(m,1H),4.72- 4.13(m,3H),4.04-3.91(m,3H),3.83(br d,J=9.4Hz,1H),3.64(br t,J=10.6Hz,1H),3.56-3.44(m,2H) ,3.13-2.97(m,1H),2.42-2.32(m,2H),1.87-1.73(m,2H),1.43-1.11(m,9H).
实施例22Example 22
Figure PCTCN2022109064-appb-000103
Figure PCTCN2022109064-appb-000103
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000104
Figure PCTCN2022109064-appb-000104
步骤1：化合物24a的合成Step 1: Synthesis of compound 24a
在干燥的三口瓶中加入21B(740mg,1.35mmol)和N,N-二甲基甲酰胺(8mL)，25℃下开启搅拌。随后加入碳酸铯(1.32g,4.05mmol)和7-溴-1-庚烯(477.76mg,2.70mmol)，氮气置换3次，反应升温至40℃搅拌24小时。向反应液中加入水(10mL)和二氯甲烷(10mL)萃取，萃取三次，合并有机相后用饱和食盐水(30mL)洗涤，无水硫酸钠干燥后过滤。粗产品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-30:70)分离，馏分减压浓缩得到24a。Add 21B (740mg, 1.35mmol) and N,N-dimethylformamide (8mL) into a dry three-necked flask, and start stirring at 25°C. Then cesium carbonate (1.32g, 4.05mmol) and 7-bromo-1-heptene (477.76mg, 2.70mmol) were added, replaced with nitrogen three times, and the reaction was heated to 40°C and stirred for 24 hours. Water (10 mL) and dichloromethane (10 mL) were added to the reaction solution for extraction, extracted three times, the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether=100:0-30:70), and the fraction was concentrated under reduced pressure to obtain 24a.
MS(ESI,m/z):645.3[M+1] +. MS(ESI,m/z):645.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝10.39-10.27(m,1H),8.02(s,1H),7.58-7.51(m,2H),7.38-7.28(m,4H),6.68-6.54(m,2H),5.97(tdd,J＝6.8,10.3,17.1Hz,1H),5.80-5.70(m,1H),5.44-5.33(m,2H),5.23-5.09(m,2H),5.05-4.92(m,3H),4.58(br d,J＝5.9Hz,2H),4.06(t,J＝6.7Hz,2H),3.97(br dd,J＝3.8,11.2Hz,1H),3.86-3.77(m,1H),3.64(t,J＝6.7Hz,1H),3.44-3.37(m,1H),2.68(br d,J＝6.7Hz,2H),2.11-1.98(m,3H),1.91-1.51(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 10.39-10.27 (m, 1H), 8.02 (s, 1H), 7.58-7.51 (m, 2H), 7.38-7.28 (m, 4H), 6.68- 6.54(m,2H),5.97(tdd,J＝6.8,10.3,17.1Hz,1H),5.80-5.70(m,1H),5.44-5.33(m,2H),5.23-5.09(m,2H), 5.05-4.92(m,3H),4.58(br d,J=5.9Hz,2H),4.06(t,J=6.7Hz,2H),3.97(br dd,J=3.8,11.2Hz,1H),3.86 -3.77(m,1H),3.64(t,J=6.7Hz,1H),3.44-3.37(m,1H),2.68(br d,J=6.7Hz,2H),2.11-1.98(m,3H) ,1.91-1.51(m,4H).
步骤2：化合物24b的合成Step 2: Synthesis of compound 24b
干燥的三口瓶中依次加入24a(730.00mg,1.13mmol)、二氯甲烷(7.3mL)和对苯醌(24.48mg,226.45μmol)，搅拌下加入詹氏催化剂-1B(91.39mg,124.55μmol)，置于40℃下反应16小时。反应液减压浓缩得到粗产品。粗产品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-0:100)分离，馏分减压浓缩得到异构体混合物24b。MS(ESI,m/z):617.3[M+1] +. Add 24a (730.00mg, 1.13mmol), dichloromethane (7.3mL) and p-benzoquinone (24.48mg, 226.45μmol) to the dry three-necked flask in sequence, and add Jane's Catalyst-1B (91.39mg, 124.55μmol) under stirring , placed at 40°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether=100:0-0:100), and the fraction was concentrated under reduced pressure to obtain the isomer mixture 24b. MS(ESI,m/z):617.3[M+1] + .
步骤3：化合物24ca和24cb的合成Step 3: Synthesis of Compounds 24ca and 24cb
将24b进行SFC拆分(分离条件：DAICEL CHIRALCEL OD 250mm*30mm*10μm；流动相:[Neu-EtOH]％:47％-47％,10min)，馏分分别减压浓缩得到24ca和24cb(分析方法：柱型：Chiralcel OD-3 50mm*4.6mm*3μm；流动相:[A:CO 2；B:EtOH(0.1％IPAm,v/v)]；B％:5％,0.2min；5％-50％,1min；50％,1min；50％-5％,0.4min； 5％,0.4min；保留时间：1.534min(24ca)，1.608min(24cb))。 24b was subjected to SFC resolution (separation conditions: DAICEL CHIRALCEL OD 250mm*30mm*10μm; mobile phase: [Neu-EtOH]%: 47%-47%, 10min), and the fractions were concentrated under reduced pressure to obtain 24ca and 24cb (analysis method : Column type: Chiralcel OD-3 50mm*4.6mm*3μm; mobile phase: [A: CO 2 ; B: EtOH (0.1% IPAm, v/v)]; B%: 5%, 0.2min; 5%- 50%, 1min; 50%, 1min; 50%-5%, 0.4min; 5%, 0.4min; retention time: 1.534min (24ca), 1.608min (24cb)).
24ca: 1H NMR(400MHz,DMSO-d6)δ(ppm)＝9.75(br s,1H),8.42(s,1H),7.57(d,J＝6.8Hz,2H),7.50(t,J＝7.6Hz,1H),7.44-7.33(m,3H),6.94(dd,J＝2.3,11.4Hz,1H),6.83(dt,J＝2.3,8.4Hz,1H),5.60-5.36(m,2H),5.14(q,J＝10.5Hz,3H),4.28-4.12(m,1H),4.10-3.83(m,4H),3.77-3.62(m,1H),3.34-3.16(m,3H),3.10-2.91(m,1H),2.58(d,J＝1.9Hz,2H),2.45-2.32(m,2H),1.88-1.61(m,2H),1.42-1.28(m,6H)； 24ca: 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 9.75 (br s, 1H), 8.42 (s, 1H), 7.57 (d, J = 6.8Hz, 2H), 7.50 (t, J = 7.6Hz, 1H), 7.44-7.33(m, 3H), 6.94(dd, J＝2.3, 11.4Hz, 1H), 6.83(dt, J＝2.3, 8.4Hz, 1H), 5.60-5.36(m, 2H ),5.14(q,J＝10.5Hz,3H),4.28-4.12(m,1H),4.10-3.83(m,4H),3.77-3.62(m,1H),3.34-3.16(m,3H), 3.10-2.91(m,1H),2.58(d,J=1.9Hz,2H),2.45-2.32(m,2H),1.88-1.61(m,2H),1.42-1.28(m,6H);
24cb: 1H NMR(400MHz,DMSO-d6)δ(ppm)＝9.74-9.56(m,1H),8.34(s,1H),7.48(br d,J＝6.5Hz,2H),7.43-7.37(m,1H),7.36-7.28(m,3H),6.89(dd,J＝2.3,11.3Hz,1H),6.74(dt,J＝2.3,8.4Hz,1H),5.51-5.21(m,2H),5.21-4.99(m,3H),4.08-3.91(m,2H),3.90-3.75(m,3H),3.71-3.56(m,1H),3.28-3.09(m,3H),3.04-2.80(m,1H),2.52(br s,2H),2.35-2.21(m,2H),1.90(br d,J＝1.5Hz,2H),1.47-1.17(m,6H). 24cb: 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 9.74-9.56 (m, 1H), 8.34 (s, 1H), 7.48 (br d, J = 6.5Hz, 2H), 7.43-7.37 ( m,1H),7.36-7.28(m,3H),6.89(dd,J=2.3,11.3Hz,1H),6.74(dt,J=2.3,8.4Hz,1H),5.51-5.21(m,2H) ,5.21-4.99(m,3H),4.08-3.91(m,2H),3.90-3.75(m,3H),3.71-3.56(m,1H),3.28-3.09(m,3H),3.04-2.80( m,1H),2.52(br s,2H),2.35-2.21(m,2H),1.90(br d,J=1.5Hz,2H),1.47-1.17(m,6H).
步骤4：化合物24A的合成Step 4: Synthesis of Compound 24A
在干燥的三口瓶中加入24ca(158mg,256.21μmol)和二氯甲烷(1mL)，开启搅拌。随后加入氯化镁(487.88mg,5.12mmol)，氮气置换3次，将反应置于25℃搅拌12小时。减压浓缩反应液，浓缩后的反应液用甲醇溶解后用针头式滤器过滤，得到粗品。粗产品通过反向制备液相色谱分离(分离条件：Phenomenex Luna 80*30mm*3μm；流动相:[H 2O(HCl)-MeOH]％:55％-75％,8min)，馏分减压浓缩得到24A。 Add 24ca (158 mg, 256.21 μmol) and dichloromethane (1 mL) into a dry three-necked flask, and start stirring. Then magnesium chloride (487.88mg, 5.12mmol) was added, nitrogen was replaced 3 times, and the reaction was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the concentrated reaction solution was dissolved in methanol and filtered with a syringe filter to obtain a crude product. The crude product was separated by reverse preparative liquid chromatography (separation conditions: Phenomenex Luna 80*30mm*3μm; mobile phase: [H 2 O(HCl)-MeOH]%:55%-75%, 8min), and the fractions were concentrated under reduced pressure Get 24A.
MS(ESI,m/z):527.3[M+1] +. MS(ESI,m/z):527.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.93-11.51(m,1H),9.64(br s,1H),8.46(s,1H),7.24(d,J＝8.0Hz,1H),6.66-6.47(m,2H),5.60-5.25(m,2H),4.84-4.41(m,2H),4.10(br dd,J＝3.0,11.3Hz,1H),4.02-3.78(m,3H),3.51(br t,J＝10.5Hz,2H),3.30-3.10(m,2H),3.07-2.87(m,1H),2.59-2.24(m,2H),1.95-1.53(m,4H),1.48-1.16(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.93-11.51 (m, 1H), 9.64 (br s, 1H), 8.46 (s, 1H), 7.24 (d, J = 8.0Hz, 1H), 6.66-6.47(m,2H),5.60-5.25(m,2H),4.84-4.41(m,2H),4.10(br dd,J＝3.0,11.3Hz,1H),4.02-3.78(m,3H) ,3.51(br t,J＝10.5Hz,2H),3.30-3.10(m,2H),3.07-2.87(m,1H),2.59-2.24(m,2H),1.95-1.53(m,4H), 1.48-1.16(m,6H).
步骤5：化合物24B的合成Step 5: Synthesis of Compound 24B
在干燥的三口瓶中加入24cb(80.00mg,129.73μmol)和二氯甲烷(1mL)，开启搅拌。随后加入氯化镁(247.03mg,2.59mmol)，氮气置换3次，将反应置于25℃搅拌12小时。减压浓缩反应液，浓缩后的反应液用甲醇溶解后用针头式滤器过滤，得到粗品。粗产品通过反向制备液相色谱分离(分离条件:Phenomenex Luna 80*30mm*3μm；流动相:[H 2O(HCl)-ACN]％:30％-60％,8min)，馏分减压浓缩得到24B。 Add 24cb (80.00 mg, 129.73 μmol) and dichloromethane (1 mL) into a dry three-necked flask, and start stirring. Then magnesium chloride (247.03mg, 2.59mmol) was added, nitrogen was replaced 3 times, and the reaction was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the concentrated reaction solution was dissolved in methanol and filtered with a syringe filter to obtain a crude product. The crude product was separated by reverse preparative liquid chromatography (separation conditions: Phenomenex Luna 80*30mm*3μm; mobile phase: [H 2 O(HCl)-ACN]%: 30%-60%, 8min), and the fractions were concentrated under reduced pressure Get 24B.
MS(ESI,m/z):527.3[M+1] +. MS(ESI,m/z):527.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.78(s,1H),9.75-9.56(m,1H),8.50(s,1H),7.20(dd,J＝6.8,8.2Hz,1H),6.63-6.50(m,2H),5.50-5.30(m,2H),4.91-4.32(m,2H),4.17-4.02(m,1H),4.03-3.66(m,4H),3.62-3.39(m,2H),3.35-3.13(m,2H),3.08-2.82(m,1H),2.54-2.26(m,2H),2.09-1.84(m,2H),1.42-1.25(m,7H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.78 (s, 1H), 9.75-9.56 (m, 1H), 8.50 (s, 1H), 7.20 (dd, J = 6.8, 8.2Hz, 1H) ,6.63-6.50(m,2H),5.50-5.30(m,2H),4.91-4.32(m,2H),4.17-4.02(m,1H),4.03-3.66(m,4H),3.62-3.39( m,2H),3.35-3.13(m,2H),3.08-2.82(m,1H),2.54-2.26(m,2H),2.09-1.84(m,2H),1.42-1.25(m,7H).
步骤6：化合物25a的合成Step 6: Synthesis of compound 25a
在干燥的三口瓶中加入21A(656mg,1.20mmol)和N,N-二甲基甲酰胺(7mL)，25℃开启搅拌；随后加入碳酸铯(1.17g,3.59mmol)和7-溴-1-庚烯(423.53mg,2.39mmol)，氮气置换3次，反应升温至40℃搅拌 16小时。向反应液中加入水(10mL)和二氯甲烷(10mL)萃取，萃取三次，合并有机相后用饱和食盐水(30mL)洗涤，无水硫酸钠干燥后过滤。粗产品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-30:70)分离，馏分减压浓缩得到25a。Add 21A (656mg, 1.20mmol) and N,N-dimethylformamide (7mL) to a dry three-necked flask, start stirring at 25°C; then add cesium carbonate (1.17g, 3.59mmol) and 7-bromo-1 -Heptene (423.53mg, 2.39mmol), nitrogen replacement 3 times, the reaction temperature was raised to 40°C and stirred for 16 hours. Water (10 mL) and dichloromethane (10 mL) were added to the reaction solution for extraction, extracted three times, the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether=100:0-30:70), and the fraction was concentrated under reduced pressure to obtain 25a.
MS(ESI,m/z):645.3[M+1] +. MS(ESI,m/z):645.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝10.33(br t,J＝5.8Hz,1H),8.02(s,1H),7.54(dd,J＝1.5,7.7Hz,2H),7.35-7.28(m,4H),6.64-6.57(m,2H),5.97(tdd,J＝6.8,10.3,17.1Hz,1H),5.80-5.69(m,1H),5.44-5.33(m,2H),5.21(dd,J＝1.6,17.1Hz,1H),5.12(d,J＝10.3Hz,1H),5.05-4.91(m,3H),4.59(d,J＝6.0Hz,2H),4.06(t,J＝6.7Hz,2H),3.97(br dd,J＝4.1,11.5Hz,1H),3.87-3.79(m,1H),3.65(t,J＝6.6Hz,1H),3.46-3.38(m,1H),3.30-3.17(m,1H),3.08-3.00(m,1H),2.69(q,J＝6.7Hz,2H),2.10-1.98(m,3H),1.90-1.77(m,1H),1.63-1.55(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 10.33 (br t, J = 5.8Hz, 1H), 8.02 (s, 1H), 7.54 (dd, J = 1.5, 7.7Hz, 2H), 7.35- 7.28(m,4H),6.64-6.57(m,2H),5.97(tdd,J＝6.8,10.3,17.1Hz,1H),5.80-5.69(m,1H),5.44-5.33(m,2H), 5.21(dd, J=1.6, 17.1Hz, 1H), 5.12(d, J=10.3Hz, 1H), 5.05-4.91(m, 3H), 4.59(d, J=6.0Hz, 2H), 4.06(t ,J=6.7Hz,2H),3.97(br dd,J=4.1,11.5Hz,1H),3.87-3.79(m,1H),3.65(t,J=6.6Hz,1H),3.46-3.38(m ,1H),3.30-3.17(m,1H),3.08-3.00(m,1H),2.69(q,J＝6.7Hz,2H),2.10-1.98(m,3H),1.90-1.77(m,1H ),1.63-1.55(m,1H).
步骤7：化合物25b的合成Step 7: Synthesis of compound 25b
干燥的三口瓶中依次加入25a(700mg,1.09mmol)、二氯甲烷(7mL)和对苯醌(23.47mg,217.14μmol)，搅拌下加入詹氏催化剂-1B(87.63mg,119.43μmol)置于40℃下反应16小时。反应液减压浓缩得到粗产品。粗产品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-0:100)分离，馏分减压浓缩得到异构体混合物25b。Add 25a (700mg, 1.09mmol), dichloromethane (7mL) and p-benzoquinone (23.47mg, 217.14μmol) to the dry three-necked flask successively, and add Jane's catalyst-1B (87.63mg, 119.43μmol) under stirring React at 40°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether=100:0-0:100), and the fraction was concentrated under reduced pressure to obtain the isomer mixture 25b.
MS(ESI,m/z):617.3[M+1] +. MS(ESI,m/z):617.3[M+1] + .
步骤8：化合物25ca和25cb的合成Step 8: Synthesis of Compounds 25ca and 25cb
将25b进行SFC拆分(分离条件:DAICEL CHIRALPAKAD 250mm*30mm*10μm；流动相:[Neu-EtOH]％:46％-46％,10min)，馏分分别减压浓缩得到25ca和25cb(分析方法：柱型：Chiralpak AD-3 50mm*4.6mm*3μm；流动相:[A:CO 2；B:EtOH(0.1％IPAm,v/v)]；B％:5％,0.2min；5％-50％,1min；50％,1min；50％-5％,0.4min；5％,0.4min；保留时间：1.831min(25ca)，2.044min(25cb))。 25b was subjected to SFC resolution (separation conditions: DAICEL CHIRALPAKAD 250mm*30mm*10μm; mobile phase: [Neu-EtOH]%: 46%-46%, 10min), and the fractions were concentrated under reduced pressure to obtain 25ca and 25cb (analysis method: Column type: Chiralpak AD-3 50mm*4.6mm*3μm; Mobile phase: [A:CO 2 ; B:EtOH(0.1%IPAm,v/v)]; B%:5%,0.2min; 5%-50 %, 1min; 50%, 1min; 50%-5%, 0.4min; 5%, 0.4min; retention time: 1.831min (25ca), 2.044min (25cb)).
25ca: 1H NMR(400MHz,DMSO-d6)δ(ppm)＝9.74-9.62(m,1H),8.36(s,1H),7.51(d,J＝6.9Hz,2H),7.44(t,J＝7.6Hz,1H),7.38-7.27(m,3H),6.87(dd,J＝2.2,11.4Hz,1H),6.76(dt,J＝2.3,8.3Hz,1H),5.53-5.31(m,2H),5.08(q,J＝10.5Hz,3H),4.23-3.77(m,6H),3.17-3.08(m,2H),3.03-2.90(m,1H),2.32(br d,J＝1.4Hz,2H),1.68(br d,J＝5.0Hz,2H),1.28(s,7H). 25ca: 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 9.74-9.62 (m, 1H), 8.36 (s, 1H), 7.51 (d, J = 6.9Hz, 2H), 7.44 (t, J =7.6Hz, 1H), 7.38-7.27(m, 3H), 6.87(dd, J=2.2, 11.4Hz, 1H), 6.76(dt, J=2.3, 8.3Hz, 1H), 5.53-5.31(m, 2H), 5.08(q, J=10.5Hz, 3H), 4.23-3.77(m, 6H), 3.17-3.08(m, 2H), 3.03-2.90(m, 1H), 2.32(br d, J=1.4 Hz,2H),1.68(br d,J=5.0Hz,2H),1.28(s,7H).
25cb: 1H NMR(400MHz,DMSO-d6)δ(ppm)＝9.72(br s,1H),8.40(s,1H),7.54(br d,J＝6.8Hz,2H),7.45(t,J＝7.6Hz,1H),7.42-7.31(m,3H),6.95(dd,J＝2.3,11.3Hz,1H),6.80(dt,J＝2.3,8.4Hz,1H),5.51-5.31(m,2H),5.26-5.03(m,3H),4.10-3.61(m,6H),3.30-3.16(m,2H),3.12-2.82(m,1H),2.34(q,J＝7.1Hz,2H),1.97(s,2H),1.65-1.19(m,7H). 25cb: 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 9.72 (br s, 1H), 8.40 (s, 1H), 7.54 (br d, J = 6.8Hz, 2H), 7.45 (t, J =7.6Hz,1H),7.42-7.31(m,3H),6.95(dd,J=2.3,11.3Hz,1H),6.80(dt,J=2.3,8.4Hz,1H),5.51-5.31(m, 2H), 5.26-5.03(m, 3H), 4.10-3.61(m, 6H), 3.30-3.16(m, 2H), 3.12-2.82(m, 1H), 2.34(q, J=7.1Hz, 2H) ,1.97(s,2H),1.65-1.19(m,7H).
步骤9：化合物25A的合成Step 9: Synthesis of Compound 25A
在干燥的三口瓶中加入25ca(224.00mg,363.24μmol)和二氯甲烷(2mL)，开启搅拌。随后加入氯化镁(691.68mg,7.26mmol)，氮气置换3次，将反应置于25℃搅拌12小时。减压浓缩反应液，浓缩后的反应液用甲醇溶解后用针头式滤器过滤，得到粗品。粗产品通过反向制备液相色谱分离(分离条件:Phenomenex  Luna 80*30mm*3μm；流动相:[H 2O(HCl)-ACN]％:30％-60％,8min)，馏分减压浓缩得到25A。 Add 25ca (224.00 mg, 363.24 μmol) and dichloromethane (2 mL) into a dry three-necked flask, and start stirring. Then magnesium chloride (691.68mg, 7.26mmol) was added, nitrogen was replaced 3 times, and the reaction was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the concentrated reaction solution was dissolved in methanol and filtered with a syringe filter to obtain a crude product. The crude product was separated by reverse preparative liquid chromatography (separation conditions: Phenomenex Luna 80*30mm*3μm; mobile phase: [H 2 O(HCl)-ACN]%: 30%-60%, 8min), and the fractions were concentrated under reduced pressure Get 25A.
MS(ESI,m/z):527.3[M+1] +. MS(ESI,m/z):527.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.91-11.56(m,1H),9.64(br s,1H),8.46(s,1H),7.25(dd,J＝7.0,8.2Hz,1H),6.65-6.50(m,2H),5.58-5.22(m,2H),4.84-4.43(m,2H),4.10(br dd,J＝3.2,11.2Hz,1H),3.99-3.78(m,3H),3.51(br t,J＝10.3Hz,2H),3.27-3.13(m,2H),3.06-2.94(m,1H),2.58-2.24(m,2H),1.95-1.54(m,4H),1.50-1.18(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.91-11.56 (m, 1H), 9.64 (br s, 1H), 8.46 (s, 1H), 7.25 (dd, J = 7.0, 8.2Hz, 1H ),6.65-6.50(m,2H),5.58-5.22(m,2H),4.84-4.43(m,2H),4.10(br dd,J＝3.2,11.2Hz,1H),3.99-3.78(m, 3H), 3.51(br t, J=10.3Hz, 2H), 3.27-3.13(m, 2H), 3.06-2.94(m, 1H), 2.58-2.24(m, 2H), 1.95-1.54(m, 4H ),1.50-1.18(m,6H).
步骤10：化合物25B的合成Step 10: Synthesis of Compound 25B
在干燥的三口瓶中加入25cb(140.00mg,227.02μmol)和二氯甲烷(1mL)，开启搅拌。随后加入氯化镁(432.30mg,4.54mmol)，氮气置换3次，将反应置于25℃搅拌12小时。减压浓缩反应液，浓缩后的反应液用甲醇溶解后用针头式滤器过滤，得到粗品。粗产品通过反向制备液相色谱分离(分离条件:Phenomenex Luna 80*30mm*3μm；流动相:[H 2O(HCl)-ACN]％:30％-60％,8min)，馏分减压浓缩得到25B。 Add 25cb (140.00 mg, 227.02 μmol) and dichloromethane (1 mL) into a dry three-necked flask, and start stirring. Then magnesium chloride (432.30mg, 4.54mmol) was added, nitrogen was replaced 3 times, and the reaction was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the concentrated reaction solution was dissolved in methanol and filtered with a syringe filter to obtain a crude product. The crude product was separated by reverse preparative liquid chromatography (separation conditions: Phenomenex Luna 80*30mm*3μm; mobile phase: [H 2 O(HCl)-ACN]%: 30%-60%, 8min), and the fractions were concentrated under reduced pressure Get 25B.
MS(ESI,m/z):527.3[M+1] +. MS(ESI,m/z):527.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.95-11.45(m,1H),9.64(br s,1H),8.50(s,1H),7.20(dd,J＝6.8,8.1Hz,1H),6.64-6.45(m,2H),5.49-5.26(m,2H),4.84-4.36(m,2H),4.11(br d,J＝10.0Hz,1H),4.03-3.69(m,4H),3.60-3.40(m,2H),3.37-3.12(m,2H),3.08-2.93(m,1H),2.39(br d,J＝6.6Hz,2H),1.94(br d,J＝5.9Hz,2H),1.50-1.05(m,7H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.95-11.45 (m, 1H), 9.64 (br s, 1H), 8.50 (s, 1H), 7.20 (dd, J = 6.8, 8.1Hz, 1H ),6.64-6.45(m,2H),5.49-5.26(m,2H),4.84-4.36(m,2H),4.11(br d,J＝10.0Hz,1H),4.03-3.69(m,4H) ,3.60-3.40(m,2H),3.37-3.12(m,2H),3.08-2.93(m,1H),2.39(br d,J＝6.6Hz,2H),1.94(br d,J＝5.9Hz ,2H),1.50-1.05(m,7H).
实施例23Example 23
Figure PCTCN2022109064-appb-000105
Figure PCTCN2022109064-appb-000105
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000106
Figure PCTCN2022109064-appb-000106
步骤1：化合物26a的合成Step 1: Synthesis of compound 26a
将1h(1.5g,2.96mmol)溶于N,N-二甲基甲酰胺(15mL)中，加入7-溴-1-庚烯(1.57g,8.88mmol)和碳酸铯(1.93g,5.92mmol)，28℃搅拌12小时。取锥形瓶，加入30mL水，倒入反应液后加入30mL乙酸乙酯萃取，有机相用无水硫酸钠干燥后过滤，减压浓缩得到26a。1h (1.5g, 2.96mmol) was dissolved in N,N-dimethylformamide (15mL), 7-bromo-1-heptene (1.57g, 8.88mmol) and cesium carbonate (1.93g, 5.92mmol) were added ), stirred at 28°C for 12 hours. Take an Erlenmeyer flask, add 30 mL of water, pour into the reaction solution, add 30 mL of ethyl acetate for extraction, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 26a.
MS(ESI,m/z):603.3[M+1] +. MS(ESI,m/z):603.3[M+1] + .
步骤2：化合物26b的合成Step 2: Synthesis of Compound 26b
将26a(0.5g,829.61μmol)溶于无水二氯甲烷(1700mL)中，加入詹氏催化剂-1B(206.97mg,282.07μmol)和对苯醌(60.98mg,564.13μmol)，油浴升温到40℃搅拌12小时。反应液降温，直接过滤，滤液减压浓缩得到粗品。粗品通过硅胶柱层析(石油醚：乙酸乙酯＝1:1)分离纯化，馏分减压浓缩得到26b。26a (0.5g, 829.61μmol) was dissolved in anhydrous dichloromethane (1700mL), and Jane's catalyst-1B (206.97mg, 282.07μmol) and p-benzoquinone (60.98mg, 564.13μmol) were added, and the oil bath was heated to Stir at 40°C for 12 hours. The reaction solution was cooled and filtered directly, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1), and the fractions were concentrated under reduced pressure to obtain 26b.
MS(ESI,m/z):575.3[M+1] +. MS(ESI,m/z):575.3[M+1] + .
步骤3：化合物26ca和26cb的合成Step 3: Synthesis of compounds 26ca and 26cb
26b(0.6g,1.04mmol)经SFC分离(分离条件：DAICEL CHIRALPAK AD 250mm*30mm*10μm；流动相:[A:CO 2-B:0.1％NH 3H 2O/EtOH]；B％:50％-50％,6min)，得到两个异构体26ca和26cb(分析方法：柱型：Chiralpak AD-3 50mm*4.6mm*3μm；流动相:[A:CO 2；B:EtOH(0.1％IPAm,v/v)]；B％:5％,0.2min；5％-50％,1min；50％,1min；50％-5％,0.4min；5％,0.4min；保留时间：1.611min(26ca)，1.782min(26cb))。 26b (0.6g, 1.04mmol) was separated by SFC (separation condition: DAICEL CHIRALPAK AD 250mm*30mm*10μm; mobile phase: [A:CO 2 -B:0.1%NH 3 H 2 O/EtOH]; B%:50 %-50%, 6min), two isomers 26ca and 26cb were obtained (analysis method: column type: Chiralpak AD-3 50mm*4.6mm*3μm; mobile phase: [A: CO 2 ; B: EtOH (0.1% IPAm, v/v)]; B%: 5%, 0.2min; 5%-50%, 1min; 50%, 1min; 50%-5%, 0.4min; 5%, 0.4min; retention time: 1.611min (26ca), 1.782min (26cb)).
26ca: 1H NMR(400MHz,CDCl 3)δ(ppm)＝9.81-9.67(m,1H),8.53(s,1H),7.55-7.49(m,2H),7.34-7.27(m,3H),7.22-7.19(m,1H),7.24-7.19(m,1H),6.62-6.46(m,2H),5.55-5.46(m,1H),5.35-5.23(m,4H),3.92-3.84(m,2H),3.11-3.06(m,3H),2.96-2.87(m,2H),2.41-2.26(m,2H),1.91-1.69(m,1H),1.51-1.39(m,3H),1.37-1.10(m,6H). 26ca: 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 9.81-9.67 (m, 1H), 8.53 (s, 1H), 7.55-7.49 (m, 2H), 7.34-7.27 (m, 3H), 7.22-7.19(m,1H),7.24-7.19(m,1H),6.62-6.46(m,2H),5.55-5.46(m,1H),5.35-5.23(m,4H),3.92-3.84(m ,2H),3.11-3.06(m,3H),2.96-2.87(m,2H),2.41-2.26(m,2H),1.91-1.69(m,1H),1.51-1.39(m,3H),1.37 -1.10(m,6H).
26cb: 1H NMR(400MHz,CDCl 3)δ(ppm)＝9.80-9.69(m,1H),8.52(s,1H),7.49(dd,J＝1.3,7.7Hz,2H),7.32-7.22(m,5H),7.16(dd,J＝6.8,8.1Hz,1H),6.60-6.49(m,2H),5.45-5.36(m,1H),5.32-5.21(m,4H),3.88-3.70 (m,3H),3.09(s,3H),3.02-2.79(m,2H),2.46-2.27(m,2H),2.04-1.91(m,3H),1.73-1.58(m,2H),1.42-1.22(m,5H). 26cb: 1 H NMR (400MHz, CDCl 3 )δ (ppm) = 9.80-9.69 (m, 1H), 8.52 (s, 1H), 7.49 (dd, J = 1.3, 7.7Hz, 2H), 7.32-7.22 ( ( m,3H),3.09(s,3H),3.02-2.79(m,2H),2.46-2.27(m,2H),2.04-1.91(m,3H),1.73-1.58(m,2H),1.42- 1.22(m,5H).
步骤4：化合物26A的合成Step 4: Synthesis of Compound 26A
将26ca(0.2g,348.04μmol)溶于无水二氯甲烷(5mL)中，加入无水氯化镁(497.06mg,5.22mmol)，28℃下搅拌12小时。反应液直接减压浓缩得到粗品，经反向制备液相色谱(分离条件：Phenomenex Luna 80*30mm*3μm；流动相:[H 2O(HCl)-ACN]％:25％-45％,8min)分离得到26A。 26ca (0.2g, 348.04μmol) was dissolved in anhydrous dichloromethane (5mL), anhydrous magnesium chloride (497.06mg, 5.22mmol) was added, and stirred at 28°C for 12 hours. The reaction solution was directly concentrated under reduced pressure to obtain the crude product, which was subjected to reverse preparative liquid chromatography (separation conditions: Phenomenex Luna 80*30mm*3μm; mobile phase: [H 2 O(HCl)-ACN]%: 25%-45%, 8min ) was isolated to give 26A.
MS(ESI,m/z):487.3[M+1] +. MS(ESI,m/z):487.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.67-11.27(m,1H),9.64(br s,1H),8.50-8.38(m,1H),7.18-7.13(m,1H),6.59-6.41(m,2H),5.49-5.36(m,1H),5.28-5.12(m,1H),3.89-3.75(m,2H),3.09(s,3H),2.97-2.87(m,2H),2.30(br s,2H),1.66(br s,6H),1.47-1.14(m,8H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.67-11.27 (m, 1H), 9.64 (br s, 1H), 8.50-8.38 (m, 1H), 7.18-7.13 (m, 1H), 6.59 -6.41(m,2H),5.49-5.36(m,1H),5.28-5.12(m,1H),3.89-3.75(m,2H),3.09(s,3H),2.97-2.87(m,2H) ,2.30(br s,2H),1.66(br s,6H),1.47-1.14(m,8H).
步骤5：化合物26B合成Step 5: Synthesis of Compound 26B
将26cb(0.3g,522.06μmol)溶于无水二氯甲烷(3mL)中，加入无水氯化镁(745.59mg,7.83mmol)，升温到28℃搅拌12小时。反应液直接减压浓缩得到粗品，经反向制备液相色谱(分离条件：Phenomenex Luna 80*30mm*3μm；流动相:[H 2O(HCl)-MeOH]％:45％-75％,8min)分离得到26B。 Dissolve 26cb (0.3g, 522.06μmol) in anhydrous dichloromethane (3mL), add anhydrous magnesium chloride (745.59mg, 7.83mmol), heat up to 28°C and stir for 12 hours. The reaction solution was directly concentrated under reduced pressure to obtain the crude product, which was subjected to reverse preparative liquid chromatography (separation conditions: Phenomenex Luna 80*30mm*3μm; mobile phase: [H 2 O(HCl)-MeOH]%: 45%-75%, 8min ) was isolated to give 26B.
MS(ESI,m/z):485.2[M+1] +. MS(ESI,m/z):485.2[M+1] + .
实施例24Example 24
Figure PCTCN2022109064-appb-000107
Figure PCTCN2022109064-appb-000107
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000108
Figure PCTCN2022109064-appb-000108
步骤1：化合物27A的合成Step 1: Synthesis of compound 27A
将26b(0.3g,522.06μmol)溶于乙酸乙酯(10mL)中，加入钯碳(0.3g,钯含量10％)，在氢气氛围(15psi,28℃)下搅拌12小时。反应液直接用硅藻土过滤，滤液直接减压浓缩得到残余物。粗品经制备反向液相色谱(分离条件：Phenomenex Luna 80*30mm*3μm；流动相:[H 2O(HCl)-ACN]％:30％-60％,8min)分离得到27A。 26b (0.3g, 522.06μmol) was dissolved in ethyl acetate (10mL), palladium on carbon (0.3g, palladium content 10%) was added, and stirred under a hydrogen atmosphere (15psi, 28°C) for 12 hours. The reaction solution was directly filtered through celite, and the filtrate was directly concentrated under reduced pressure to obtain a residue. The crude product was separated by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80*30mm*3μm; mobile phase: [H 2 O(HCl)-ACN]%: 30%-60%, 8min) to obtain 27A.
MS(ESI,m/z):487.2[M+1] +. MS(ESI,m/z):487.2[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.72-11.42(m,1H),9.82-9.63(m,1H),8.51(s,1H),7.23(dd,J＝6.8,8.2Hz,1H),6.64-6.54(m,2H),3.87(br t,J＝6.0Hz,2H),3.18(s,3H),3.09-2.99(m,1H),1.70-1.62(m,2H),1.63-1.62(m,1H),1.47-1.07(m,16H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.72-11.42 (m, 1H), 9.82-9.63 (m, 1H), 8.51 (s, 1H), 7.23 (dd, J = 6.8, 8.2Hz, 1H),6.64-6.54(m,2H),3.87(br t,J＝6.0Hz,2H),3.18(s,3H),3.09-2.99(m,1H),1.70-1.62(m,2H), 1.63-1.62(m,1H),1.47-1.07(m,16H).
实施例25Example 25
Figure PCTCN2022109064-appb-000109
Figure PCTCN2022109064-appb-000109
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000110
Figure PCTCN2022109064-appb-000110
步骤1：化合物28a的合成Step 1: Synthesis of Compound 28a
在干燥的三口瓶中加入4-氟-2-羟基苯甲醛(1g,7.14mmol)，盐酸羟胺(1.49g,21.41mmol)和无水乙醇(10mL)，开启搅拌，随后加入乙酸钠(2.34g,28.55mmol)，氮气置换3次后将反应加热至80℃搅拌2小时。降温至20-30℃，搅拌下缓慢加入醋酸将体系调至弱酸性(pH＝4-5)，减压浓缩除去四氢呋喃，然后加入乙酸乙酯(20mL)和水(20mL)搅拌混合后分液，水相用乙酸乙酯(20mL)再萃取一次。合并有机相后用饱和食盐水(40mL)洗涤，然后用无水硫酸钠干燥。过滤减压浓缩得到28a。Add 4-fluoro-2-hydroxybenzaldehyde (1g, 7.14mmol), hydroxylamine hydrochloride (1.49g, 21.41mmol) and absolute ethanol (10mL) into a dry three-necked flask, start stirring, and then add sodium acetate (2.34g , 28.55 mmol), nitrogen replacement 3 times, the reaction was heated to 80 ° C and stirred for 2 hours. Cool down to 20-30°C, slowly add acetic acid under stirring to adjust the system to weak acidity (pH=4-5), concentrate under reduced pressure to remove tetrahydrofuran, then add ethyl acetate (20mL) and water (20mL), stir and mix, then separate the liquids , and the aqueous phase was extracted once more with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (40 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure afforded 28a.
MS(ESI,m/z):156.2[M+1] +. MS(ESI,m/z):156.2[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝10.89(br s,1H),8.28(br s,2H),7.58-7.20(m,3H),6.83(dd,J＝2.5,10.9Hz,1H),6.64(dt,J＝2.6,8.5Hz,1H),3.88(br s,2H) 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 10.89 (br s, 1H), 8.28 (br s, 2H), 7.58-7.20 (m, 3H), 6.83 (dd, J = 2.5, 10.9Hz ,1H),6.64(dt,J=2.6,8.5Hz,1H),3.88(br s,2H)
步骤2：化合物28b的合成Step 2: Synthesis of Compound 28b
在干燥的氢化瓶中加入28a(1.11g,7.13mmol)和无水乙醇(100mL)，在氩气保护下加入钯碳(0.3g,钯含量10％)，随后加入浓盐酸(12M,3.5mL)，反应在50psi、25℃下搅拌16小时。反应液通过硅藻土过滤，滤饼用乙醇(10mL*3)淋洗，滤液减压浓缩得到粗产品。粗品用乙酸乙酯(50mL)打浆，过滤得到28b。Add 28a (1.11g, 7.13mmol) and absolute ethanol (100mL) into a dry hydrogenation bottle, add palladium carbon (0.3g, palladium content 10%) under the protection of argon, then add concentrated hydrochloric acid (12M, 3.5mL ), the reaction was stirred at 50 psi, 25°C for 16 hours. The reaction solution was filtered through diatomaceous earth, the filter cake was rinsed with ethanol (10 mL*3), and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was slurried with ethyl acetate (50 mL) and filtered to give 28b.
步骤3：化合物28c的合成Step 3: Synthesis of compound 28c
在干燥的单口瓶中加入1d(16.31g,38.98mmol)和N,N-二甲基甲酰胺(200mL)，随后加2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(17.79g,46.78mmol)和4-二甲氨基吡啶(11.91g,97.45mmol)，氮气置换3次，25℃搅拌0.5小时。最后加入28b(9g,50.67mmol,HCl)，将反应置于60℃搅拌12小时。反应完全后，向体系加入水(350mL)，析出白色固体后过滤，滤饼用100mL水淋洗，得到28c。Add 1d (16.31g, 38.98mmol) and N,N-dimethylformamide (200mL) to a dry one-necked flask, followed by 2-(7-azobenzotriazole)-N,N,N , N-tetramethyluronium hexafluorophosphate (17.79g, 46.78mmol) and 4-dimethylaminopyridine (11.91g, 97.45mmol), replaced with nitrogen three times, and stirred at 25°C for 0.5 hours. Finally 28b (9 g, 50.67 mmol, HCl) was added and the reaction was stirred at 60 °C for 12 hours. After the reaction was complete, water (350 mL) was added to the system, a white solid was precipitated and filtered, and the filter cake was rinsed with 100 mL of water to obtain 28c.
MS(ESI,m/z):542.3[M+1] +. MS(ESI,m/z):542.3[M+1] + .
步骤4：化合物28d的合成Step 4: Synthesis of compound 28d
将28c(8g,14.77mmol)溶于无水四氢呋喃(60mL)中。加入甲胺乙醇溶液(15.35g,163.10mmol,33％含量)，然后加入1.8-二氮杂二环[5.4.0]十一烷-7-烯(674.72mg,4.43mmol,668.04μL)，60℃下搅拌12小时。反应液降温后向其中加入500mL二氯甲烷，并用150mL浓度为1N的柠檬酸水溶液洗涤两次，再用50mL饱和食盐水洗涤两次。分离出有机相，无水硫酸钠干燥后过滤，减压浓缩得到28d。28c (8 g, 14.77 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL). Add methylamine ethanol solution (15.35g, 163.10mmol, 33% content), then add 1.8-diazabicyclo[5.4.0]undec-7-ene (674.72mg, 4.43mmol, 668.04μL), 60 Stir at °C for 12 hours. After cooling the reaction solution, 500 mL of dichloromethane was added thereto, and washed twice with 150 mL of 1N citric acid aqueous solution, and then twice with 50 mL of saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 28d.
MS(ESI,m/z):541.3[M+1] +. MS(ESI,m/z):541.3[M+1] + .
步骤5：化合物28e的合成Step 5: Synthesis of Compound 28e
将28d(8g,14.80mmol)溶于乙酸乙酯(40mL)和无水甲醇(40mL)中，加入氯化氢乙酸乙酯溶液(4M,27.90mL)，28℃下搅拌12小时。然后将反应液直接减压浓缩得到28e的盐酸盐。28d (8g, 14.80mmol) was dissolved in ethyl acetate (40mL) and anhydrous methanol (40mL), ethyl hydrogen chloride acetate solution (4M, 27.90mL) was added, and stirred at 28°C for 12 hours. Then the reaction solution was directly concentrated under reduced pressure to obtain the hydrochloride salt of 28e.
步骤6：化合物28f的合成Step 6: Synthesis of compound 28f
将28e的盐酸盐(10.2g)溶于乙腈(100mL)中，加入多聚甲醛(625.85mg,20.84mmol)和碳酸钾(12.80g,92.64mmol)，油浴升温到50℃搅拌12小时。在锥形瓶中加入200mL水，倒入反应液，加入200mL二氯甲烷萃取，分离出有机相。有机相用无水硫酸钠干燥后过滤，减压浓缩得到残余物。然后粗品用乙酸乙酯(50mL)打浆后过滤得到28f。The hydrochloride salt of 28e (10.2g) was dissolved in acetonitrile (100mL), paraformaldehyde (625.85mg, 20.84mmol) and potassium carbonate (12.80g, 92.64mmol) were added, and the oil bath was heated to 50°C and stirred for 12 hours. Add 200mL of water into the Erlenmeyer flask, pour into the reaction solution, add 200mL of dichloromethane for extraction, and separate the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was then slurried with ethyl acetate (50 mL) and filtered to give 28f.
MS(ESI,m/z):453.1[M+1] +. MS(ESI,m/z):453.1[M+1] + .
步骤7：化合物28g的合成Step 7: Synthesis of Compound 28g
将28f(0.3g,663.08μmol)溶于N,N-二甲基甲酰胺(6mL)中，加入1,2-双(2-溴乙氧基)乙烷(201.29mg,729.39μmol)和碳酸铯(648.13mg,1.99mmol)，28℃下搅拌12小时。取锥形瓶，加入20mL水，倒入反应液，加入20mL乙酸乙酯萃取，有机相用20mL饱和食盐水洗涤，无水硫酸钠干燥后过滤，减压浓缩得到粗品， 通过硅胶柱层析(二氯甲烷：甲醇＝10:1)分离，馏分减压浓缩得到28g。Dissolve 28f (0.3 g, 663.08 μmol) in N,N-dimethylformamide (6 mL), add 1,2-bis(2-bromoethoxy)ethane (201.29 mg, 729.39 μmol) and carbonic acid Cesium (648.13mg, 1.99mmol), stirred at 28°C for 12 hours. Take the Erlenmeyer flask, add 20mL of water, pour into the reaction solution, add 20mL of ethyl acetate for extraction, the organic phase is washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which is subjected to silica gel column chromatography ( Dichloromethane:methanol=10:1) was separated, and the fraction was concentrated under reduced pressure to obtain 28g.
MS(ESI,m/z):567.2[M+1] +. MS(ESI,m/z):567.2[M+1] + .
步骤8：化合物28A的合成Step 8: Synthesis of Compound 28A
将28g(0.19g,335.35μmol)溶于无水二氯甲烷中，加入无水氯化镁(478.93mg,5.03mmol)，28℃下搅拌12小时。反应液直接减压浓缩得到残余物。粗品经反向制备液相色谱(分离条件：Phenomenex Luna 80*30mm*3μm；流动相:[H 2O(HCl)-ACN]％:15％-35％,8min)分离得到28A。 Dissolve 28g (0.19g, 335.35μmol) in anhydrous dichloromethane, add anhydrous magnesium chloride (478.93mg, 5.03mmol), and stir at 28°C for 12 hours. The reaction solution was directly concentrated under reduced pressure to obtain a residue. The crude product was separated by reverse preparative liquid chromatography (separation conditions: Phenomenex Luna 80*30mm*3μm; mobile phase: [H 2 O(HCl)-ACN]%:15%-35%, 8min) to obtain 28A.
MS(ESI,m/z):477.1[M+1] +. MS(ESI,m/z):477.1[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝11.90-11.69(m,1H),9.71(t,J＝4.8Hz,1H),8.35(s,1H),7.41-7.35(m,1H),6.94-6.89(m,1H),6.78-6.72(m,1H),5.32-4.58(m,2H),4.06-4.02(m,2H),3.65-3.59(m,3H),3.36-3.32(m,4H),3.31-3.21(m,5H),3.05-3.00(m,3H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 11.90-11.69 (m, 1H), 9.71 (t, J = 4.8Hz, 1H), 8.35 (s, 1H), 7.41-7.35 (m, 1H ),6.94-6.89(m,1H),6.78-6.72(m,1H),5.32-4.58(m,2H),4.06-4.02(m,2H),3.65-3.59(m,3H),3.36-3.32 (m,4H),3.31-3.21(m,5H),3.05-3.00(m,3H).
实施例26Example 26
Figure PCTCN2022109064-appb-000111
Figure PCTCN2022109064-appb-000111
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000112
Figure PCTCN2022109064-appb-000112
Figure PCTCN2022109064-appb-000113
Figure PCTCN2022109064-appb-000113
步骤1：化合物29a的合成Step 1: Synthesis of compound 29a
在干燥的三口瓶中加入1e(5g,5.04mmol)，四氢呋喃(50mL)和甲醇(25mL)，开启搅拌。加入氢氧化钠(5M,5.04mL)，55℃下搅拌12小时。取锥形瓶，加入40mL 2M盐酸调节pH＝4，加入100mL水和100mL乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥后过滤，减压浓缩得到29a。Add 1e (5 g, 5.04 mmol), tetrahydrofuran (50 mL) and methanol (25 mL) into a dry three-necked flask, and start stirring. Sodium hydroxide (5M, 5.04mL) was added and stirred at 55°C for 12 hours. Take a Erlenmeyer flask, add 40mL of 2M hydrochloric acid to adjust the pH=4, add 100mL of water and 100mL of ethyl acetate to extract three times, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 29a.
MS(ESI,m/z):582.3[M+1] +. MS(ESI,m/z):582.3[M+1] + .
步骤2：化合物29b的合成Step 2: Synthesis of compound 29b
将1-羟基苯并三唑(1.45g,10.73mmol)，1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(3.16g,16.51mmol)加入到29a(4.8g,8.25mmol)的N,N-二甲基甲酰胺(50mL)溶液中，搅拌1.5小时，然后降温到0℃，加入4-氨基丁醛二甲基缩醛(1.10g,8.25mmol)的N,N-二甲基甲酰胺(50mL)溶液，升温到25℃搅拌12小时。取锥形瓶，加入100mL水，倒入反应液，加入100mL乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥后过滤，减压浓缩得到残余物。粗产品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-50:50)分离，馏分减压浓缩得到化合物29b。Add 1-hydroxybenzotriazole (1.45g, 10.73mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3.16g, 16.51mmol) , 8.25mmol) in N,N-dimethylformamide (50mL) solution, stirred for 1.5 hours, then cooled to 0°C, added 4-aminobutyraldehyde dimethyl acetal (1.10g, 8.25mmol) in N , N-dimethylformamide (50mL) solution, heated to 25°C and stirred for 12 hours. Take an Erlenmeyer flask, add 100mL of water, pour into the reaction solution, add 100mL of ethyl acetate to extract three times, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether=100:0-50:50), and the fraction was concentrated under reduced pressure to obtain compound 29b.
MS(ESI,m/z):697.3[M+1] +. MS(ESI,m/z):697.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝8.39(s,1H),7.94(s,1H),7.39-7.19(m,6H),6.96(t,J＝5.8Hz,1H),6.60-6.48(m,2H),5.92(tdd,J＝6.8,10.3,17.1Hz,1H),5.18(s,3H),4.01(t,J＝6.7Hz,2H),3.22(s,6H),3.19-3.15(m,2H),2.62(q,J＝6.7Hz,2H),1.56-1.42(m,4H),1.39(s,9H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 8.39 (s, 1H), 7.94 (s, 1H), 7.39-7.19 (m, 6H), 6.96 (t, J = 5.8Hz, 1H), 6.60 -6.48(m,2H),5.92(tdd,J=6.8,10.3,17.1Hz,1H),5.18(s,3H),4.01(t,J=6.7Hz,2H),3.22(s,6H), 3.19-3.15(m,2H),2.62(q,J=6.7Hz,2H),1.56-1.42(m,4H),1.39(s,9H).
步骤3：化合物29A和29B的合成Step 3: Synthesis of Compounds 29A and 29B
在干燥的三口瓶中加入29b(2g,2.87mmol)，水(10mL)和乙腈(20mL)，开启搅拌，氮气置换3次升温至65℃。温度在60℃缓慢滴加甲磺酸(827.59mg,8.61mmol,613.03μL)和乙腈(20mL)的混合溶液，将反应置于60℃搅拌6小时。加入10％氢氧化钠水溶液，将体系调至pH＝9-10。然后加入乙酸乙酯(20mL)和水(20mL)搅拌混合后分液，水相用乙酸乙酯(20mL)再萃取一次。合并有机相用饱和食盐水(40mL)洗涤后用无水硫酸钠干燥，过滤减压浓缩得到粗产品。粗产品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-0:100)分离，馏分减压浓缩得到消旋化合物29c。29c通过SFC分离(分离条件:(S,S)-WHELK-O1 250mm*30mm*5μm；流动相:[Neu-EtOH]％:60％-60％,6min)，馏分减压浓缩得到化合物29A和29B(分析方法：柱型：(S,S)-WHELK-O1 50mm*4.6mm*3μm；流动相:[A:CO 2；B:EtOH(0.1％IPAm,v/v)]；B％:5％,0.2min；5％-50％,1min；50％,1min；50％-5％,0.4min；5％,0.4min；保留时间：2.090min(29A)，2.407min(29B))。 Add 29b (2g, 2.87mmol), water (10mL) and acetonitrile (20mL) into a dry three-necked flask, start stirring, replace with nitrogen three times and raise the temperature to 65°C. A mixed solution of methanesulfonic acid (827.59 mg, 8.61 mmol, 613.03 μL) and acetonitrile (20 mL) was slowly added dropwise at 60°C, and the reaction was stirred at 60°C for 6 hours. Add 10% aqueous sodium hydroxide solution to adjust the system to pH=9-10. Then ethyl acetate (20 mL) and water (20 mL) were added, stirred and mixed, the layers were separated, and the aqueous phase was extracted once more with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether=100:0-0:100), and the fraction was concentrated under reduced pressure to obtain racemic compound 29c. 29c was separated by SFC (separation conditions: (S, S)-WHELK-O1 250mm*30mm*5μm; mobile phase: [Neu-EtOH]%: 60%-60%, 6min), and the fractions were concentrated under reduced pressure to obtain compound 29A and 29B (analysis method: column type: (S,S)-WHELK-O1 50mm*4.6mm*3μm; mobile phase: [A:CO 2 ; B:EtOH (0.1%IPAm,v/v)]; B%: 5%, 0.2min; 5%-50%, 1min; 50%, 1min; 50%-5%, 0.4min; 5%, 0.4min; retention time: 2.090min (29A), 2.407min (29B)).
29A:MS(ESI,m/z):533.3[M+1] +. 29A:MS(ESI,m/z):533.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝10.32(br t,J＝5.8Hz,1H),8.37(s,1H),7.33-7.12(m,5H),6.59-6.46(m,2H),5.89(tdd,J＝6.8,10.3,17.1Hz,1H),5.67(br d,J＝13.0Hz,1H),5.20-4.97(m,4H),4.68-4.39(m,3H),3.97(t,J＝6.7Hz,2H),3.46-3.39(m,2H),2.60(q,J＝6.7Hz,2H),2.25-1.82(m,2H),1.79-1.54(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 10.32 (br t, J = 5.8Hz, 1H), 8.37 (s, 1H), 7.33-7.12 (m, 5H), 6.59-6.46 (m, 2H ),5.89(tdd,J=6.8,10.3,17.1Hz,1H),5.67(br d,J=13.0Hz,1H),5.20-4.97(m,4H),4.68-4.39(m,3H),3.97 (t,J=6.7Hz,2H),3.46-3.39(m,2H),2.60(q,J=6.7Hz,2H),2.25-1.82(m,2H),1.79-1.54(m,2H).
29B:MS(ESI,m/z):533.3[M+1] +. 29B:MS(ESI,m/z):533.3[M+1] + .
步骤4：化合物30a的合成Step 4: Synthesis of compound 30a
将29A(0.2g,375.54μmol)溶于N,N-二甲基甲酰胺(2mL)中，加入7-溴-1-庚烯(199.51mg,1.13mmol)和碳酸铯(244.72mg,751.09μmol)，28℃搅拌12小时。取锥形瓶，加入30mL水，倒入反应液，加入30mL乙酸乙酯萃取，有机相用无水硫酸钠干燥后过滤，减压浓缩得到化合物30a。29A (0.2 g, 375.54 μmol) was dissolved in N,N-dimethylformamide (2 mL), 7-bromo-1-heptene (199.51 mg, 1.13 mmol) and cesium carbonate (244.72 mg, 751.09 μmol) were added ), stirred at 28°C for 12 hours. Take an Erlenmeyer flask, add 30 mL of water, pour into the reaction solution, add 30 mL of ethyl acetate for extraction, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 30a.
MS(ESI,m/z):629.3[M+1] +. MS(ESI,m/z):629.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝8.39(s,1H),7.93(s,2H),7.57-7.15(m,5H),6.52(dt,J＝2.3,5.7Hz,2H),5.96-5.62(m,2H),5.37-4.89(m,6H),4.56-4.43(m,2H),3.98(t,J＝6.7Hz,2H),3.78-3.43(m,2H),3.33(t,J＝6.8Hz,2H),2.63-2.48(m,2H),1.94-1.75(m,4H),1.46-1.18(m,10H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 8.39 (s, 1H), 7.93 (s, 2H), 7.57-7.15 (m, 5H), 6.52 (dt, J = 2.3, 5.7Hz, 2H) ,5.96-5.62(m,2H),5.37-4.89(m,6H),4.56-4.43(m,2H),3.98(t,J＝6.7Hz,2H),3.78-3.43(m,2H),3.33 (t,J=6.8Hz,2H),2.63-2.48(m,2H),1.94-1.75(m,4H),1.46-1.18(m,10H).
步骤5：化合物30ca和30cb的合成Step 5: Synthesis of Compounds 30ca and 30cb
将30a(0.34g,540.77μmol)溶于二氯甲烷(340mL)中，加入詹氏催化剂-1B(39.68mg,54.08μmol)和对苯醌(11.69mg,108.15μmol)，氮气置换3次，油浴升温到40℃搅拌12小时。反应液直接过滤，滤液减压浓缩得到残余物。粗产品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-0:100)分离，馏分减压浓缩得到异构体混合物30b。30b通过SFC拆分(分离条件:DAICEL CHIRALCEL OJ 250mm*30mm*10μm)；流动相:[Neu-IPA]％:42％-42％,12min)，馏分分别减压浓缩得到化合物30ca和30cb(分析方法：柱型：Chiralpak IC-3 50mm*4.6mm*3μm；流动相:[A:CO 2；B:EtOH:ACN＝1:1(0.1％IPAm,v/v)]；B％:40％,5min；保留时间：2.506min(30ca)，3.295min(30cb))。 Dissolve 30a (0.34g, 540.77μmol) in dichloromethane (340mL), add Jane's catalyst-1B (39.68mg, 54.08μmol) and p-benzoquinone (11.69mg, 108.15μmol), nitrogen replacement 3 times, oil The bath was warmed to 40°C and stirred for 12 hours. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether=100:0-0:100), and the fraction was concentrated under reduced pressure to obtain the isomer mixture 30b. 30b was resolved by SFC (separation condition: DAICEL CHIRALCEL OJ 250mm*30mm*10μm); Mobile phase: [Neu-IPA]%: 42%-42%, 12min), fractions were concentrated under reduced pressure to obtain compounds 30ca and 30cb (analysis Method: Column type: Chiralpak IC-3 50mm*4.6mm*3μm; Mobile phase: [A:CO 2 ; B:EtOH:ACN＝1:1(0.1%IPAm,v/v)]; B%:40% ,5min; retention time: 2.506min (30ca), 3.295min (30cb)).
30ca:MS(ESI,m/z):601.3[M+1] +. 30ca:MS(ESI,m/z):601.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝9.70(br d,J＝9.0Hz,1H),8.51(s,1H),7.45(t,J＝7.3Hz,2H),7.27-7.20(m,3H),7.16-7.09(m,1H),6.60-6.41(m,2H),5.48-5.12(m,6H),4.95(td,J＝6.8,16.6Hz,1H),3.98-3.63(m,5H),3.56-3.43(m,1H),2.90-2.68(m,1H),2.57-2.35(m,2H),2.34-2.13(m,2H),2.05-1.78(m,5H),1.41-1.18(m,6H),1.14-1.03(m,1H),0.88-0.71(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 9.70 (br d, J = 9.0Hz, 1H), 8.51 (s, 1H), 7.45 (t, J = 7.3Hz, 2H), 7.27-7.20 ( m,3H),7.16-7.09(m,1H),6.60-6.41(m,2H),5.48-5.12(m,6H),4.95(td,J＝6.8,16.6Hz,1H),3.98-3.63( m,5H),3.56-3.43(m,1H),2.90-2.68(m,1H),2.57-2.35(m,2H),2.34-2.13(m,2H),2.05-1.78(m,5H), 1.41-1.18(m,6H),1.14-1.03(m,1H),0.88-0.71(m,1H).
30cb:MS(ESI,m/z):601.3[M+1] +. 30cb:MS(ESI,m/z):601.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝9.70(br d,J＝9.0Hz,1H),8.51(s,1H),7.48-7.42(m,2H),7.27-7.20(m,3H),7.14-7.08(m,1H),6.59-6.43(m,2H),5.51-5.16(m,5H),4.95(td,J＝6.8,16.6Hz,1H),3.94-3.62(m,4H),3.53-3.42(m,1H),2.90-2.75(m,1H),2.58-2.35(m,2H),2.33-2.13(m,2H),2.03-1.80(m,5H),1.46-1.21(m,6H),1.16-1.04(m,2H),0.86-0.76(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 9.70 (br d, J = 9.0Hz, 1H), 8.51 (s, 1H), 7.48-7.42 (m, 2H), 7.27-7.20 (m, 3H ),7.14-7.08(m,1H),6.59-6.43(m,2H),5.51-5.16(m,5H),4.95(td,J＝6.8,16.6Hz,1H),3.94-3.62(m,4H ),3.53-3.42(m,1H),2.90-2.75(m,1H),2.58-2.35(m,2H),2.33-2.13(m,2H),2.03-1.80(m,5H),1.46-1.21 (m,6H),1.16-1.04(m,2H),0.86-0.76(m,1H).
步骤6：化合物30A的合成Step 6: Synthesis of compound 30A
将30ca(0.04g,66.59μmol)溶于二氯甲烷(1mL)，加入氯化镁(95.10mg,998.87μmol)，28℃搅拌12小时。取锥形瓶，加入20mL二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤减压浓缩得到残余物。粗产品用甲基叔丁基醚打浆，过滤得到化合物30A。Dissolve 30ca (0.04 g, 66.59 μmol) in dichloromethane (1 mL), add magnesium chloride (95.10 mg, 998.87 μmol), and stir at 28° C. for 12 hours. Take the Erlenmeyer flask, add 20 mL of dichloromethane for extraction, dry the organic phase with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a residue. The crude product was slurried with methyl tert-butyl ether and filtered to obtain compound 30A.
MS(ESI,m/z):511.2[M+1] +. MS(ESI,m/z):511.2[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝9.46-9.23(m,1H),8.45-8.29(m,1H),7.52-7.31(m,1H),6.71-6.30(m,2H),5.49-5.00(m,6H),4.08-3.70(m,6H),2.93-2.73(m,1H),2.33-2.05(m,10H),1.54-1.35(m,6H),0.98-0.91(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 9.46-9.23 (m, 1H), 8.45-8.29 (m, 1H), 7.52-7.31 (m, 1H), 6.71-6.30 (m, 2H), 5.49-5.00(m,6H),4.08-3.70(m,6H),2.93-2.73(m,1H),2.33-2.05(m,10H),1.54-1.35(m,6H),0.98-0.91(m ,2H).
步骤7：化合物30B的合成Step 7: Synthesis of compound 30B
将30cb(0.03g,49.94μmol)溶于二氯甲烷(1mL)，加入氯化镁(71.33mg,749.15μmol)，28℃搅拌12小时。取锥形瓶，加入20mL二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤减压浓缩得到残余物。粗产品用甲基叔丁基醚打浆，过滤得到化合物30B。Dissolve 30cb (0.03 g, 49.94 μmol) in dichloromethane (1 mL), add magnesium chloride (71.33 mg, 749.15 μmol), and stir at 28° C. for 12 hours. Take the Erlenmeyer flask, add 20 mL of dichloromethane for extraction, dry the organic phase with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a residue. The crude product was slurried with methyl tert-butyl ether and filtered to obtain compound 30B.
MS(ESI,m/z):511.2[M+1] +. MS(ESI,m/z):511.2[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝9.71-9.57(m,1H),8.51-8.40(m,1H),6.61-6.44(m,3H),5.61-5.34(m,6H),5.13-5.09(m,1H),3.88-3.78(m,4H),3.71(br s,1H),2.88-2.76(m,1H),2.51-2.32(m,5H),2.19(br s,5H),1.24(br s,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 9.71-9.57 (m, 1H), 8.51-8.40 (m, 1H), 6.61-6.44 (m, 3H), 5.61-5.34 (m, 6H), 5.13-5.09(m,1H),3.88-3.78(m,4H),3.71(br s,1H),2.88-2.76(m,1H),2.51-2.32(m,5H),2.19(br s,5H ),1.24(br s,6H).
步骤8：化合物31a的合成Step 8: Synthesis of Compound 31a
将29B(1.3g,2.44mmol)溶于N,N-二甲基甲酰胺(12mL)中，加入7-溴-1-庚烯(1.3g,7.32mmol)和碳酸铯(1.59g,4.88mmol)，28℃搅拌12小时。取锥形瓶，加入30mL水，倒入反应液，加入30mL乙酸乙酯萃取，有机相用无水硫酸钠干燥后过滤，减压浓缩得到化合物31a。29B (1.3 g, 2.44 mmol) was dissolved in N,N-dimethylformamide (12 mL), 7-bromo-1-heptene (1.3 g, 7.32 mmol) and cesium carbonate (1.59 g, 4.88 mmol) were added ), stirred at 28°C for 12 hours. Take an Erlenmeyer flask, add 30 mL of water, pour into the reaction solution, add 30 mL of ethyl acetate for extraction, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 31a.
MS(ESI,m/z):629.3[M+1] +. MS(ESI,m/z):629.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝8.39(s,1H),7.93(s,1H),7.57-7.17(m,5H),6.58-6.45(m,2H),5.97-5.62 (m,3H),5.39-4.89(m,6H),4.51(d,J＝6.0Hz,1H),4.01-3.93(m,2H),3.78-3.42(m,2H),3.33(t,J＝6.9Hz,2H),2.64-2.47(m,2H),1.94-1.74(m,4H),1.53-1.19(m,10H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 8.39 (s, 1H), 7.93 (s, 1H), 7.57-7.17 (m, 5H), 6.58-6.45 (m, 2H), 5.97-5.62 ( m,3H),5.39-4.89(m,6H),4.51(d,J=6.0Hz,1H),4.01-3.93(m,2H),3.78-3.42(m,2H),3.33(t,J= 6.9Hz, 2H), 2.64-2.47(m, 2H), 1.94-1.74(m, 4H), 1.53-1.19(m, 10H).
步骤9：化合物31b的合成Step 9: Synthesis of Compound 31b
将31a(260.00mg,413.53μmol)溶于二氯甲烷(260mL)中，加入詹氏催化剂-1B(30.34mg,41.35μmol)和对苯醌(8.94mg,82.71μmol)，氮气置换3次，油浴升温到40℃搅拌12小时。反应液直接过滤，滤液减压浓缩得到残余物。粗产品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-0:100)分离，馏分减压浓缩得到化合物31b。Dissolve 31a (260.00mg, 413.53μmol) in dichloromethane (260mL), add Jane's catalyst-1B (30.34mg, 41.35μmol) and p-benzoquinone (8.94mg, 82.71μmol), nitrogen replacement 3 times, oil The bath was warmed to 40°C and stirred for 12 hours. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether=100:0-0:100), and the fraction was concentrated under reduced pressure to obtain compound 31b.
MS(ESI,m/z):601.3[M+1] +. MS(ESI,m/z):601.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝9.70(br d,J＝8.4Hz,1H),8.50(s,1H),7.57-7.42(m,3H),7.31-7.20(m,4H),6.58-6.45(m,3H),4.86(br s,8H),3.90-3.64(m,4H),3.53-3.41(m,1H),2.63-2.16(m,5H),1.95-1.79(m,4H),1.48-1.22(m,7H),1.14-1.03(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 9.70 (br d, J = 8.4Hz, 1H), 8.50 (s, 1H), 7.57-7.42 (m, 3H), 7.31-7.20 (m, 4H ),6.58-6.45(m,3H),4.86(br s,8H),3.90-3.64(m,4H),3.53-3.41(m,1H),2.63-2.16(m,5H),1.95-1.79( m,4H),1.48-1.22(m,7H),1.14-1.03(m,1H).
步骤10：化合物31A的合成Step 10: Synthesis of compound 31A
在干燥的单口瓶中加入31b(40.00mg,66.59μmol)和乙酸乙酯(5mL)，在氮气保护下加入湿钯碳(0.15g,钯含量10％)，随后置换三次氢气，25℃搅拌16小时。反应液通过硅藻土过滤，滤饼用乙酸乙酯(10mL)淋洗，减压浓缩滤液得到粗产品。粗品用甲基叔丁基醚打浆，过滤得到化合物31A。Add 31b (40.00 mg, 66.59 μmol) and ethyl acetate (5 mL) into a dry one-necked flask, add wet palladium carbon (0.15 g, palladium content 10%) under nitrogen protection, then replace hydrogen three times, and stir at 25 ° C for 16 Hour. The reaction solution was filtered through celite, the filter cake was rinsed with ethyl acetate (10 mL), and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was slurried with methyl tert-butyl ether and filtered to obtain compound 31A.
MS(ESI,m/z):513.2[M+1] +. MS(ESI,m/z):513.2[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.31-10.86(m,1H),9.60(br d,J＝7.5Hz,1H),8.45(s,1H),7.14(br t,J＝7.4Hz,1H),6.58-6.41(m,2H),5.21(br dd,J＝8.2,13.4Hz,1H),5.14(br t,J＝6.8Hz,1H),3.88-3.60(m,5H),2.85(td,J＝7.7,11.9Hz,1H),2.65-2.53(m,1H),2.38-2.29(m,1H),2.11-1.99(m,2H),1.98-1.90(m,1H),1.51-1.43(m,2H),1.36-1.24(m,4H),1.22-1.08(m,7H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.31-10.86 (m, 1H), 9.60 (br d, J = 7.5Hz, 1H), 8.45 (s, 1H), 7.14 (br t, J = 7.4Hz, 1H), 6.58-6.41(m, 2H), 5.21(br dd, J＝8.2, 13.4Hz, 1H), 5.14(br t, J＝6.8Hz, 1H), 3.88-3.60(m, 5H ),2.85(td,J＝7.7,11.9Hz,1H),2.65-2.53(m,1H),2.38-2.29(m,1H),2.11-1.99(m,2H),1.98-1.90(m,1H ),1.51-1.43(m,2H),1.36-1.24(m,4H),1.22-1.08(m,7H).
实施例27Example 27
Figure PCTCN2022109064-appb-000114
Figure PCTCN2022109064-appb-000114
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000115
Figure PCTCN2022109064-appb-000115
步骤1：化合物32a的合成Step 1: Synthesis of compound 32a
将乙二醇双(丙腈)醚(3g,17.84mmol)溶于浓盐酸(12M,15.00mL)中，油浴升温到70℃搅拌12小时。等到反应冷却到室温，直接将反应液减压浓缩得到粗品，然后粗品通过硅胶柱层析分离(石油醚:乙酸乙酯＝1:1)纯化得到32a。Ethylene glycol bis(propionitrile) ether (3 g, 17.84 mmol) was dissolved in concentrated hydrochloric acid (12M, 15.00 mL), and the oil bath was heated to 70° C. and stirred for 12 hours. After the reaction was cooled to room temperature, the reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 32a.
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.31-9.46(m,1H),3.84-3.72(m,5H),3.66-3.57(m,4H),2.72-2.58(m,4H).步骤2：化合物32b的合成 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.31-9.46 (m, 1H), 3.84-3.72 (m, 5H), 3.66-3.57 (m, 4H), 2.72-2.58 (m, 4H). Step 2: Synthesis of compound 32b
将32a(1.1g,5.33mmol)溶于无水四氢呋喃(20mL)中，冰水浴降温到0℃，分批次加入四氢铝锂(1.21g,32.01mmol)，加料完毕后油浴再升到65℃搅拌12小时。将反应液用冰水浴降温到0℃，然后加入2mL水，4mL1N氢氧化钠溶液，过滤，滤液用20mL乙酸乙酯和10mL水萃取三次，无水硫酸钠干燥后过滤，减压浓缩得到粗品，粗品通过硅胶柱层析分离(石油醚:乙酸乙酯＝1:1)纯化得到32b。Dissolve 32a (1.1g, 5.33mmol) in anhydrous tetrahydrofuran (20mL), cool down to 0°C in an ice-water bath, add lithium aluminum hydride (1.21g, 32.01mmol) in batches, and raise the oil bath to Stir at 65°C for 12 hours. Cool the reaction solution to 0°C with an ice-water bath, then add 2 mL of water and 4 mL of 1N sodium hydroxide solution, filter, and extract the filtrate three times with 20 mL of ethyl acetate and 10 mL of water, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 32b.
1H NMR(400MHz,CDCl 3)δ(ppm)＝3.78-3.70(m,4H),3.63(dt,J＝1.5,5.7Hz,4H),3.57(d,J＝1.5Hz,4H),3.17-2.92(m,2H),1.87-1.70(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 3.78-3.70 (m, 4H), 3.63 (dt, J = 1.5, 5.7Hz, 4H), 3.57 (d, J = 1.5Hz, 4H), 3.17 -2.92(m,2H),1.87-1.70(m,4H).
步骤3：化合物32c的合成Step 3: Synthesis of compound 32c
将N-溴代丁二酰亚胺(898.78mg,5.05mmol)溶解到无水二氯甲烷(10mL)中，干冰丙酮浴降温到-78℃，加入三苯基膦(1.32g,5.05mmol)和32b(0.3g,1.68mmol)，然后升到25℃搅拌12小时。取锥形瓶，加入50mL水，倒入反应液，加入50mL乙酸乙酯萃取三次，饱和食盐水洗涤，无水硫酸钠干燥后过滤，减压浓缩得到粗品。粗品通过硅胶柱层析分离(石油醚:乙酸乙酯＝3:1)纯化得到32c。Dissolve N-bromosuccinimide (898.78mg, 5.05mmol) in anhydrous dichloromethane (10mL), cool down to -78°C in a dry-ice acetone bath, and add triphenylphosphine (1.32g, 5.05mmol) and 32b (0.3g, 1.68mmol), then raised to 25°C and stirred for 12 hours. Take a Erlenmeyer flask, add 50 mL of water, pour into the reaction solution, add 50 mL of ethyl acetate to extract three times, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to obtain 32c.
1H NMR(400MHz,CDCl 3)δ(ppm)＝3.57-3.51(m,8H),3.45(t,J＝6.5Hz,4H),2.09-2.00(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 3.57-3.51 (m, 8H), 3.45 (t, J = 6.5Hz, 4H), 2.09-2.00 (m, 4H).
步骤4：化合物32d的合成Step 4: Synthesis of compound 32d
将28f(0.2g,442.05μmol)溶于N,N-二甲基甲酰胺(20mL)中，加入32c(147.83mg,486.26μmol)和碳酸铯(216.04mg,663.08μmol)，28℃搅拌12小时。取锥形瓶，加入50mL水，倒入反应液后加入50mL乙酸乙酯萃取，有机相用无水硫酸钠干燥后过滤，减压浓缩得到粗品。粗品通过硅胶柱层析分离(石油醚:乙酸乙酯＝1:1)纯化得到32d。Dissolve 28f (0.2g, 442.05μmol) in N,N-dimethylformamide (20mL), add 32c (147.83mg, 486.26μmol) and cesium carbonate (216.04mg, 663.08μmol), and stir at 28°C for 12 hours . Take an Erlenmeyer flask, add 50 mL of water, pour into the reaction solution, add 50 mL of ethyl acetate for extraction, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 32d.
步骤5：化合物32e的合成Step 5: Synthesis of compound 32e
将32d(0.18g,266.45μmol)溶于N,N-二甲基甲酰胺(10mL)中，加入碳酸铯(130.22mg,399.68μmol)， 25℃搅拌12小时。取锥形瓶，加入50mL水后倒入反应液，加入50mL乙酸乙酯萃取三次，分离出有机相，饱和食盐水洗涤，无水硫酸钠干燥后过滤，减压浓缩得到粗品。粗品通过硅胶柱层析分离(石油醚:乙酸乙酯＝1:1)纯化得到32e。32d (0.18 g, 266.45 μmol) was dissolved in N,N-dimethylformamide (10 mL), cesium carbonate (130.22 mg, 399.68 μmol) was added, and stirred at 25° C. for 12 hours. Take an Erlenmeyer flask, add 50 mL of water, pour into the reaction solution, add 50 mL of ethyl acetate for extraction three times, separate the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 32e.
步骤6：化合物32A的合成Step 6: Synthesis of compound 32A
将32e(0.2g,336.34μmol)溶于无水二氯甲烷(2mL)中，加入无水氯化镁(480.35mg,5.05mmol)，25℃搅拌12小时。反应液直接减压浓缩得到粗品。甲醇溶解后通过有机相针头式滤器过滤，经制备反向液相色谱(分离条件：Phenomenex Luna 80*30mm*3μm；流动相:[H 2O(HCl)-ACN]％:15％-40％,8min)分离得到32A。 32e (0.2g, 336.34μmol) was dissolved in anhydrous dichloromethane (2mL), anhydrous magnesium chloride (480.35mg, 5.05mmol) was added, and stirred at 25°C for 12 hours. The reaction solution was directly concentrated under reduced pressure to obtain a crude product. After methanol was dissolved, it was filtered through an organic phase syringe filter, and subjected to preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80*30mm*3μm; mobile phase: [H 2 O(HCl)-ACN]%: 15%-40% ,8min) to isolate 32A.
MS(ESI,m/z):505.2[M+1] +. MS(ESI,m/z):505.2[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.72-11.22(m,1H),9.77-9.52(m,1H),8.52(s,1H),7.13(dd,J＝6.8,8.1Hz,1H),6.52(dt,J＝2.3,8.3Hz,1H),6.44(dd,J＝2.3,10.9Hz,1H),4.78-4.33(m,2H),3.82(t,J＝5.6Hz,2H),3.75-3.38(m,9H),3.16(t,J＝6.3Hz,2H),3.09(s,3H),3.06-3.02(m,1H),1.91-1.79(m,2H),1.73(br d,J＝5.5Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.72-11.22 (m, 1H), 9.77-9.52 (m, 1H), 8.52 (s, 1H), 7.13 (dd, J = 6.8, 8.1Hz, 1H), 6.52(dt, J=2.3, 8.3Hz, 1H), 6.44(dd, J=2.3, 10.9Hz, 1H), 4.78-4.33(m, 2H), 3.82(t, J=5.6Hz, 2H ),3.75-3.38(m,9H),3.16(t,J＝6.3Hz,2H),3.09(s,3H),3.06-3.02(m,1H),1.91-1.79(m,2H),1.73( br d,J=5.5Hz,2H).
实施例28Example 28
Figure PCTCN2022109064-appb-000116
Figure PCTCN2022109064-appb-000116
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000117
Figure PCTCN2022109064-appb-000117
步骤1：化合物33b的合成Step 1: Synthesis of compound 33b
在干燥的三口瓶中加入33a(4.9g,30.99mmol)，盐酸羟胺(6.46g,92.98mmol)和乙醇(50mL)，随后加入乙酸钠(10.17g,123.97mmol)将反应置于80℃搅拌2小时。取锥形瓶，加入200mL水，倒入反应液，加入200mL乙酸乙酯萃取三次，有机相用200mL饱和食盐水洗涤，无水硫酸钠干燥，过滤减压浓缩得到33b。Add 33a (4.9g, 30.99mmol), hydroxylamine hydrochloride (6.46g, 92.98mmol) and ethanol (50mL) in a dry there-necked flask, then add sodium acetate (10.17g, 123.97mmol) and place the reaction at 80°C for 2 Hour. Take an Erlenmeyer flask, add 200 mL of water, pour into the reaction solution, add 200 mL of ethyl acetate to extract three times, wash the organic phase with 200 mL of saturated brine, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain 33b.
步骤2：化合物33c的合成Step 2: Synthesis of compound 33c
在干燥的氢化瓶中加入33b(4.9g,28.30mmol)和乙醇(100mL)，在氩气保护下加入湿钯碳(2.5g,钯含量10％)，随后置换氢气，加入盐酸(12M,13.89mL)，反应在50psi、25℃搅拌16小时。反应液通过硅藻土过滤，滤饼用乙醇(10mL)淋洗三次，减压浓缩滤液得到粗品。粗品用乙酸乙酯(25mL)打浆，25℃搅拌2小时，过滤得到33c。Add 33b (4.9g, 28.30mmol) and ethanol (100mL) into a dry hydrogenation bottle, add wet palladium carbon (2.5g, palladium content 10%) under the protection of argon, then replace the hydrogen, add hydrochloric acid (12M, 13.89 mL), the reaction was stirred at 50 psi, 25°C for 16 hours. The reaction solution was filtered through celite, the filter cake was rinsed three times with ethanol (10 mL), and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was slurried with ethyl acetate (25 mL), stirred at 25 °C for 2 hours, and filtered to give 33c.
步骤3：化合物33d的合成Step 3: Synthesis of compound 33d
在干燥的单口瓶中加入1d(4.71g,11.25mmol)和N,N-二甲基甲酰胺(10mL)随后加入O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(4.67g,12.27mmol)，氮气置换3次，搅拌30分钟；最后加入33c(2g,10.23mmol)和4-(二甲氨基)吡啶(3.12g,25.56mmol)，将反应置于60℃搅拌12小时。取锥形瓶，加入200mL水和200mL乙酸乙酯，萃取三次，分离出有机相，用20mL饱和食盐水洗涤，无水硫酸钠干燥后过滤减压浓缩滤液得到粗品。粗品用乙酸乙酯(25mL)打浆，25℃搅拌2小时，过滤得到33d。In a dry one-necked flask was added 1d (4.71 g, 11.25 mmol) and N,N-dimethylformamide (10 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N ,N',N'-Tetramethyluronium hexafluorophosphate (4.67g, 12.27mmol), replaced with nitrogen 3 times, stirred for 30 minutes; finally added 33c (2g, 10.23mmol) and 4-(dimethylamino)pyridine (3.12g, 25.56mmol), the reaction was stirred at 60°C for 12 hours. Take an Erlenmeyer flask, add 200mL water and 200mL ethyl acetate, extract three times, separate the organic phase, wash with 20mL saturated brine, dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was slurried with ethyl acetate (25 mL), stirred at 25 °C for 2 hours, and filtered to give 33d.
步骤4：化合物33e的合成Step 4: Synthesis of compound 33e
在干燥的单口瓶中加入33d(4g,7.15mmol)和四氢呋喃(50mL)开启搅拌，随后加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(326.51mg,2.14mmol,323.28μL)和甲胺乙醇(29.60g,285.96mmol,30％含量)，氮气置换3次，将反应置于60℃搅拌12小时。取锥形瓶，加入200mL水和200mL乙酸乙酯，萃取三次，分离出有机相，用20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤减压浓缩滤液得到粗品。粗品用乙酸乙酯(20mL)打浆，25℃搅拌2小时，过滤得到33e。Add 33d (4g, 7.15mmol) and tetrahydrofuran (50mL) to a dry one-necked flask to start stirring, then add 1,8-diazabicyclo[5.4.0]undec-7-ene (326.51mg, 2.14mmol , 323.28μL) and methylaminoethanol (29.60g, 285.96mmol, 30% content), replaced with nitrogen three times, and the reaction was stirred at 60°C for 12 hours. Take an Erlenmeyer flask, add 200 mL of water and 200 mL of ethyl acetate, extract three times, separate the organic phase, wash with 20 mL of saturated brine, dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was slurried with ethyl acetate (20 mL), stirred at 25°C for 2 hours, and filtered to afford 33e.
步骤5：化合物33f的合成Step 5: Synthesis of compound 33f
将33e(1g,1.79mmol)溶于乙酸乙酯(10mL)和甲醇(10mL)中，加入盐酸/乙酸乙酯(4M,3.37mL)，28℃下搅拌12小时。反应液经过减压浓缩滤液得到粗品。粗品用乙酸乙酯(5mL)打浆，25℃搅拌2小时，过滤得到33f。Dissolve 33e (1 g, 1.79 mmol) in ethyl acetate (10 mL) and methanol (10 mL), add hydrochloric acid/ethyl acetate (4M, 3.37 mL), and stir at 28°C for 12 hours. The reaction solution was concentrated under reduced pressure and the filtrate was obtained to obtain a crude product. The crude product was slurried with ethyl acetate (5 mL), stirred at 25 °C for 2 hours, and filtered to give 33f.
步骤6：化合物33g的合成Step 6: Synthesis of Compound 33g
将33f(0.8g,1.75mmol)溶于乙腈(20mL)中，加入碳酸钾(964.79mg,6.98mmol)和多聚甲醛(47.17mg,1.57mmol,43.27μL)，油浴升温到50℃，搅拌12小时。在锥形瓶中加入40mL水，倒入反应液，加入40mL二氯甲烷萃取，分离出有机相，有机相用无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用乙酸乙酯(10mL)打浆，25℃搅拌2小时，过滤得到33g。Dissolve 33f (0.8g, 1.75mmol) in acetonitrile (20mL), add potassium carbonate (964.79mg, 6.98mmol) and paraformaldehyde (47.17mg, 1.57mmol, 43.27μL), heat the oil bath to 50°C, stir 12 hours. Add 40 mL of water into the Erlenmeyer flask, pour into the reaction solution, add 40 mL of dichloromethane for extraction, separate the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product was slurried with ethyl acetate (10 mL), stirred at 25°C for 2 hours, and filtered to obtain 33 g.
步骤7：化合物33h的合成Step 7: Synthesis of compound 33h
将33g溶到N,N-二甲基甲酰胺(10mL)中，加入二溴化合物(142.18mg,467.66μmol)和碳酸铯(207.78mg,637.72μmol)，28℃搅拌12小时。取锥形瓶，加入20mL水，倒入反应液，加入20mL乙酸乙酯萃取，分离出有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品通过硅胶柱层析分离(石油醚:乙酸乙酯＝1:1)纯化得到33h。Dissolve 33 g in N,N-dimethylformamide (10 mL), add dibromo compound (142.18 mg, 467.66 μmol) and cesium carbonate (207.78 mg, 637.72 μmol), and stir at 28° C. for 12 hours. Take an Erlenmeyer flask, add 20 mL of water, pour into the reaction solution, add 20 mL of ethyl acetate for extraction, separate the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 33h.
步骤8：化合物33i的合成Step 8: Synthesis of compound 33i
将33h(0.18g,266.45μmol)溶到N,N-二甲基甲酰胺(10mL)中，加入碳酸铯(130.22mg,399.68μmol)，25℃搅拌12小时。取锥形瓶，加入50mL水，倒入反应液，加入50mL乙酸乙酯萃取三次，分离出有机相，饱和食盐水洗涤，无水硫酸钠干燥后过滤，减压浓缩得到粗品。粗品通过硅胶柱层析分离(石油醚:乙酸乙酯＝1:1)纯化得到33i。33h (0.18g, 266.45μmol) was dissolved in N,N-dimethylformamide (10mL), cesium carbonate (130.22mg, 399.68μmol) was added, and stirred at 25°C for 12 hours. Take an Erlenmeyer flask, add 50 mL of water, pour into the reaction solution, add 50 mL of ethyl acetate to extract three times, separate the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 33i.
步骤9：化合物33A的合成Step 9: Synthesis of compound 33A
将33i(0.27g,440.73μmol)溶到无水二氯甲烷(3mL)中，加入无水氯化镁(629.44mg,6.61mmol)，25℃搅拌12小时。反应液直接减压浓缩得到粗品。粗品经制备反向液相色谱(分离条件：Phenomenex Luna 80*30mm*3μm；流动相:[H 2O(HCl)-ACN]％:25％-45％,8min)分离得到33A。 Dissolve 33i (0.27g, 440.73μmol) in anhydrous dichloromethane (3mL), add anhydrous magnesium chloride (629.44mg, 6.61mmol), and stir at 25°C for 12 hours. The reaction solution was directly concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80*30mm*3μm; mobile phase: [H 2 O(HCl)-ACN]%:25%-45%, 8min) to obtain 33A.
MS(ESI,m/z):523.2[M+1] +. MS(ESI,m/z):523.2[M+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)＝11.72-11.14(m,1H),9.74(br d,J＝4.3Hz,1H),8.50(s,1H),6.49-6.24(m,2H),4.70-4.39(m,3H),3.85(t,J＝5.5Hz,2H),3.64-3.43(m,9H),3.14(br t,J＝6.1Hz,2H),3.09(s,3H),1.95-1.83(m,2H),1.71(br d,J＝5.1Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 11.72-11.14 (m, 1H), 9.74 (br d, J = 4.3Hz, 1H), 8.50 (s, 1H), 6.49-6.24 (m, 2H ),4.70-4.39(m,3H),3.85(t,J＝5.5Hz,2H),3.64-3.43(m,9H),3.14(br t,J＝6.1Hz,2H),3.09(s,3H ),1.95-1.83(m,2H),1.71(br d,J＝5.1Hz,2H).
实施例29Example 29
Figure PCTCN2022109064-appb-000118
Figure PCTCN2022109064-appb-000118
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000119
Figure PCTCN2022109064-appb-000119
步骤1：化合物34a的合成Step 1: Synthesis of compound 34a
在干燥的单口瓶中加入溴乙酰溴(387.59mg,5.45mmol)和二氯甲烷(5mL)，随后加入三乙胺(501.32mg,4.95mmol,689.58μL)，降温至-78℃，逐滴加入3-丁烯-1-胺(1g,4.95mmol,431.03μL)的二氯甲烷(1mL)溶液，反应在-78℃下反应10分钟，然后室温反应2小时。取锥形瓶，加入20mL水和20mL二氯甲烷，萃取三次，分离出有机相，用20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤减压浓缩得到化合物34a。Add bromoacetyl bromide (387.59mg, 5.45mmol) and dichloromethane (5mL) to a dry single-necked flask, then add triethylamine (501.32mg, 4.95mmol, 689.58μL), cool to -78°C, and add 3-Buten-1-amine (1 g, 4.95 mmol, 431.03 μL) in dichloromethane (1 mL) was reacted at -78°C for 10 minutes, then at room temperature for 2 hours. Take an Erlenmeyer flask, add 20 mL of water and 20 mL of dichloromethane, extract three times, separate the organic phase, wash with 20 mL of saturated brine, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain compound 34a.
步骤2：化合物34b的合成Step 2: Synthesis of compound 34b
在干燥的单口瓶中加入28f(0.05g,110.51μmol,81.97μL)和N,N-二甲基甲酰胺(5mL)，随后加入34a(23.35mg,121.56μmol)和碳酸铯(108.02mg,331.54μmol)，反应在28℃下反应3小时。取锥形瓶，缓慢滴加1M盐酸，调节pH至7，加入20mL水和20mL二氯甲烷，萃取三次，分离出有机相，用20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤减压浓缩得到粗品。粗品通过硅胶柱层析分离(二氯甲烷:甲醇＝20:1)纯化得到34b。28f (0.05g, 110.51μmol, 81.97μL) and N,N-dimethylformamide (5mL) were added to a dry one-necked flask, followed by 34a (23.35mg, 121.56μmol) and cesium carbonate (108.02mg, 331.54 μmol), the reaction was carried out at 28°C for 3 hours. Take a conical flask, slowly add 1M hydrochloric acid dropwise, adjust the pH to 7, add 20mL water and 20mL dichloromethane, extract three times, separate the organic phase, wash with 20mL saturated saline, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure get crude. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain 34b.
1H NMR(400MHz,CDCl 3)δ(ppm)＝10.37-10.16(m,1H),8.47-8.29(m,1H),7.99-7.85(m,1H),7.52-7.36(m,2H),7.34-7.22(m,3H),6.66-6.31(m,3H),5.81-5.53(m,1H),5.27-4.85(m,4H),4.64-4.08(m,5H),2.96-2.66(m,3H),2.36-2.10(m,2H),1.74-1.58(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 10.37-10.16 (m, 1H), 8.47-8.29 (m, 1H), 7.99-7.85 (m, 1H), 7.52-7.36 (m, 2H), 7.34-7.22(m,3H),6.66-6.31(m,3H),5.81-5.53(m,1H),5.27-4.85(m,4H),4.64-4.08(m,5H),2.96-2.66(m ,3H),2.36-2.10(m,2H),1.74-1.58(m,1H).
步骤3：化合物34c的合成Step 3: Synthesis of compound 34c
在干燥的单口瓶中加入34b(0.05g,88.72μmol,81.97μL)和N,N-二甲基甲酰胺(5mL)，随后加入5-溴-1-戊烯(14.54mg,97.59μmol,45.92μL)和碳酸铯(86.72mg,266.16μmol)，反应在28℃下反应12小时。取锥形瓶，缓慢滴加1M盐酸，调节pH至7，加入20mL水和20mL二氯甲烷，萃取三次，分离出有机相，用20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤减压浓缩得到粗品。粗品通过硅胶柱层析分离(二氯甲烷:甲醇＝20:1)纯化得到34c。34b (0.05 g, 88.72 μmol, 81.97 μL) and N,N-dimethylformamide (5 mL) were added to a dry one-necked flask, followed by 5-bromo-1-pentene (14.54 mg, 97.59 μmol, 45.92 μL) and cesium carbonate (86.72mg, 266.16μmol), the reaction was carried out at 28°C for 12 hours. Take a conical flask, slowly add 1M hydrochloric acid dropwise, adjust the pH to 7, add 20mL water and 20mL dichloromethane, extract three times, separate the organic phase, wash with 20mL saturated saline, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure get crude. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain 34c.
1H NMR(400MHz,DMSO-d6)δ(ppm)＝8.39-8.13(m,2H),7.55(d,J＝6.9Hz,2H),7.41-7.27(m,5H),6.92-6.76 (m,2H),5.87-5.77(m,2H),5.75-5.72(m,1H),5.14-4.95(m,7H),4.65-4.48(m,5H),3.27(q,J＝6.8Hz,2H),3.06-3.00(m,4H),2.26(q,J＝7.0Hz,2H),2.12(q,J＝7.0Hz,2H),1.64-1.53(m,2H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 8.39-8.13 (m, 2H), 7.55 (d, J = 6.9Hz, 2H), 7.41-7.27 (m, 5H), 6.92-6.76 (m ,2H),5.87-5.77(m,2H),5.75-5.72(m,1H),5.14-4.95(m,7H),4.65-4.48(m,5H),3.27(q,J＝6.8Hz,2H ),3.06-3.00(m,4H),2.26(q,J=7.0Hz,2H),2.12(q,J=7.0Hz,2H),1.64-1.53(m,2H).
步骤4：化合物34d的合成Step 4: Synthesis of compound 34d
将化合物34c(0.1g,158.30μmol)溶到二氯甲烷(100mL)中，加入詹氏催化剂-1B(11.62mg,15.83μmol)和对苯醌(3.42mg,31.66μmol,7.13μL)，氮气置换3次，油浴升温到40℃搅拌12小时。反应液直接过滤，滤液减压浓缩得到粗品。粗品通过硅胶柱层析分离(二氯甲烷:甲醇＝20:1)纯化，馏分减压浓缩得到34d。Dissolve compound 34c (0.1g, 158.30μmol) in dichloromethane (100mL), add Jane's catalyst-1B (11.62mg, 15.83μmol) and p-benzoquinone (3.42mg, 31.66μmol, 7.13μL), nitrogen replacement Three times, the temperature of the oil bath was raised to 40°C and stirred for 12 hours. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=20:1), and the fractions were concentrated under reduced pressure to obtain 34d.
步骤5：化合物34A的合成Step 5: Synthesis of compound 34A
在干燥的单口瓶中加入34d(0.06g,99.40μmol)和乙酸乙酯(10mL)，在氮气保护下加入湿钯碳(0.1g,含10％钯)，随后置换三次氢气，25℃搅拌16小时。反应液直接过滤，滤液减压浓缩得到粗品。将粗品溶解到25V的甲醇(1.5mL)打浆得到化合物34A。Add 34d (0.06g, 99.40μmol) and ethyl acetate (10mL) into a dry one-necked flask, add wet palladium on carbon (0.1g, containing 10% palladium) under nitrogen protection, then replace hydrogen three times, and stir at 25°C for 16 Hour. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in methanol (1.5 mL) at 25V and slurried to obtain compound 34A.
MS(ESI,m/z):516.2[M+1] +. MS(ESI,m/z):516.2[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝11.93-11.60(m,1H),10.35(br t,J＝6.1Hz,1H),8.65-8.40(m,1H),8.32-8.07(m,1H),7.50(t,J＝7.6Hz,1H),6.99-6.68(m,2H),5.15-4.71(m,2H),4.57-4.40(m,1H),3.32(s,2H),3.04(s,3H),1.69-0.21(m,9H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 11.93-11.60 (m, 1H), 10.35 (br t, J = 6.1Hz, 1H), 8.65-8.40 (m, 1H), 8.32-8.07 ( m,1H),7.50(t,J=7.6Hz,1H),6.99-6.68(m,2H),5.15-4.71(m,2H),4.57-4.40(m,1H),3.32(s,2H) ,3.04(s,3H),1.69-0.21(m,9H).
实施例30Example 30
Figure PCTCN2022109064-appb-000120
Figure PCTCN2022109064-appb-000120
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000121
Figure PCTCN2022109064-appb-000121
步骤1：化合物2的合成Step 1: Synthesis of compound 2
将N-溴代丁二酰亚胺(2.75g,15.45mmol)溶解到无水二氯甲烷(20mL)中，干冰丙酮浴降温到-78℃， 加入三苯基膦(4.05g,15.45mmol)和四缩乙二醇(1g,5.15mmol,884.96μL)，然后升到25℃搅拌12小时。取锥形瓶，加入50mL水，倒入反应液，加入50mL乙酸乙酯萃取三次，饱和食盐水洗涤，无水硫酸钠干燥后过滤，减压浓缩得到粗品，经过硅胶柱层析(乙酸乙酯/石油醚＝3:1)纯化，减压浓缩得到2。Dissolve N-bromosuccinimide (2.75g, 15.45mmol) in anhydrous dichloromethane (20mL), cool down to -78°C in a dry-ice acetone bath, add triphenylphosphine (4.05g, 15.45mmol) and tetraethylene glycol (1g, 5.15mmol, 884.96μL), then raised to 25°C and stirred for 12 hours. Take the Erlenmeyer flask, add 50mL water, pour into the reaction solution, add 50mL ethyl acetate to extract three times, wash with saturated brine, filter after drying over anhydrous sodium sulfate, concentrate under reduced pressure to obtain the crude product, go through silica gel column chromatography (ethyl acetate /petroleum ether=3:1) was purified and concentrated under reduced pressure to obtain 2.
1H NMR(400MHz,CDCl 3)δ(ppm)＝3.86-3.80(m,4H),3.80-3.78(m,1H),3.70(s,8H),3.52-3.46(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) = 3.86-3.80 (m, 4H), 3.80-3.78 (m, 1H), 3.70 (s, 8H), 3.52-3.46 (m, 4H).
步骤2：化合物3的合成Step 2: Synthesis of compound 3
将int-7(0.2g,425.15μmol)溶到N,N二甲基甲酰胺(2mL)中，加入化合物2(204.08mg,637.72μmol)和碳酸铯(207.78mg,637.72μmol)，25℃搅拌12小时。取锥形瓶，加入20mL水，倒入反应液，加入20mL乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，减压浓缩得到粗品。粗品经过硅胶柱层析(乙酸乙酯/石油醚＝1:1)纯化，馏分减压浓缩得到3。Dissolve int-7 (0.2g, 425.15μmol) in N,N dimethylformamide (2mL), add compound 2 (204.08mg, 637.72μmol) and cesium carbonate (207.78mg, 637.72μmol), and stir at 25°C 12 hours. Take an Erlenmeyer flask, add 20 mL of water, pour into the reaction solution, add 20 mL of ethyl acetate for extraction, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:1), and the fractions were concentrated under reduced pressure to obtain 3.
MS(ESI,m/z):629.3[M+1] +. MS(ESI,m/z):629.3[M+1] + .
步骤3：化合物35A的合成Step 3: Synthesis of compound 35A
将3(0.2g,318.16μmol)溶于无水二氯甲烷(3mL)中，加入无水氯化镁(454.38mg,4.77mmol)，25℃搅拌12小时。反应液直接减压浓缩得到粗品，经反向制备液相色谱(分离条件：Phenomenex Luna80*30mm*3μm；流动相:[H 2O(HCl)-ACN]；ACN％:25％-45％,8min)分离得到35A。 3 (0.2g, 318.16μmol) was dissolved in anhydrous dichloromethane (3mL), anhydrous magnesium chloride (454.38mg, 4.77mmol) was added, and stirred at 25°C for 12 hours. The reaction solution was directly concentrated under reduced pressure to obtain the crude product, which was subjected to reverse preparative liquid chromatography (separation condition: Phenomenex Luna80*30mm*3μm; mobile phase: [H 2 O(HCl)-ACN]; ACN%: 25%-45%, 8 min) to isolate 35A.
MS(ESI,m/z):539.2[M+1] +. MS(ESI,m/z):539.2[M+1] + .
1H NMR(400MHz,DMSO-d6)δ(ppm)＝11.80-11.65(m,1H),9.97(t,J＝4.7Hz,1H),8.34(s,1H),7.00-6.86(m,2H),5.05-4.75(m,2H),4.58-4.34(m,2H),4.23-4.16(m,2H),3.78(br s,2H),3.53(br d,J＝5.0Hz,4H),3.41-3.39(m,3H),3.31(br s,3H),3.27(br t,J＝4.3Hz,2H),3.05(s,3H). 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 11.80-11.65 (m, 1H), 9.97 (t, J = 4.7Hz, 1H), 8.34 (s, 1H), 7.00-6.86 (m, 2H ),5.05-4.75(m,2H),4.58-4.34(m,2H),4.23-4.16(m,2H),3.78(br s,2H),3.53(br d,J＝5.0Hz,4H), 3.41-3.39(m,3H),3.31(br s,3H),3.27(br t,J＝4.3Hz,2H),3.05(s,3H).
实施例31Example 31
Figure PCTCN2022109064-appb-000122
Figure PCTCN2022109064-appb-000122
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000123
Figure PCTCN2022109064-appb-000123
步骤1：化合物36f的合成Step 1: Synthesis of Compound 36f
在预先干燥过的50mL单口瓶中加入环丙氨(3.75g,63.44mmol)和溶剂二氯甲烷(5mL)，随后滴加AlMe 3(30mL,59.94mmol,2.0M)，加毕后室温搅拌1.5h备用；向250mL的单口瓶中加入1e(5.95g,9.99mmol)和二氯甲烷(20mL)，氮气置换2次，再将活化的环丙氨混合液用氮气压入1e的二氯甲烷溶液中，室温搅拌3.0h。将反应液缓慢滴入饱和酒石酸钾钠(500mL)和二氯甲烷(400mL)的混合溶液中，分液，有机相用在依次用饱和酒石酸钾钠(250mL)和饱和食盐水(250mL)洗涤一次,水相用二氯甲烷(350mL)萃洗两次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(乙酸乙酯/正庚烷＝1/2)分离，得到化合物36f。MS(ESI,m/z):623[M+1] +. Cyclopropylamine (3.75g, 63.44mmol) and solvent dichloromethane (5mL) were added to a pre-dried 50mL single-necked bottle, followed by dropwise addition of AlMe 3 (30mL, 59.94mmol, 2.0M), and stirring at room temperature for 1.5 h Standby; add 1e (5.95g, 9.99mmol) and dichloromethane (20mL) to a 250mL single-necked bottle, replace with nitrogen twice, and then inject the activated cyclopropylamine mixture into the dichloromethane solution of 1e with nitrogen pressure , stirred at room temperature for 3.0h. The reaction solution was slowly dropped into a mixed solution of saturated potassium sodium tartrate (500mL) and dichloromethane (400mL), separated, and the organic phase was washed once with saturated potassium sodium tartrate (250mL) and saturated brine (250mL). , the aqueous phase was washed twice with dichloromethane (350 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (ethyl acetate/n-heptane=1/2), Compound 36f was obtained. MS(ESI,m/z):623[M+1] + .
步骤2：化合物36g的合成Step 2: Synthesis of compound 36g
向50mL单口瓶中加入36f(4.86g,7.80mmol)和乙酸乙酯(23mL)溶清，再加入浓盐酸(0.94g，9.27mmol,36％)/甲醇(23mL)的混合液，50℃下搅拌过夜。反应液减压浓缩，粗品加入8mL乙酸乙酯打浆，过滤得到36g。Add 36f (4.86g, 7.80mmol) and ethyl acetate (23mL) to a 50mL single-necked bottle to dissolve it, then add a mixture of concentrated hydrochloric acid (0.94g, 9.27mmol, 36%)/methanol (23mL), at 50°C Stir overnight. The reaction solution was concentrated under reduced pressure, the crude product was slurried by adding 8 mL of ethyl acetate, and filtered to obtain 36 g.
MS(ESI,m/z):523[M+1] +. MS(ESI,m/z):523[M+1] + .
步骤3：化合物36h的合成Step 3: Synthesis of compound 36h
向25mL单口瓶中加入36g(1.10g,2.10mmol)、乙腈(17mL)和无水碳酸钾(3.48g,25.26mmol)，氮气置换2次，再加入多聚甲醛(0.0765g,2.55mmol)，反应1h。反应液过滤，取有机相，乙腈(15mL)冲洗滤饼，滤液用20mL饱和食盐水洗涤，分液，水相10mL二氯甲烷萃洗，分液，合并有机相，无水硫酸钠干燥，过滤浓缩得到36h，无需纯化直接投入下一步。MS(ESI,m/z):535[M+1] +. Add 36g (1.10g, 2.10mmol), acetonitrile (17mL) and anhydrous potassium carbonate (3.48g, 25.26mmol) to a 25mL single-necked bottle, replace with nitrogen twice, then add paraformaldehyde (0.0765g, 2.55mmol), Reaction 1h. Filter the reaction solution, take the organic phase, wash the filter cake with acetonitrile (15 mL), wash the filtrate with 20 mL of saturated brine, separate the liquids, wash the aqueous phase with 10 mL of dichloromethane, separate the liquids, combine the organic phases, dry over anhydrous sodium sulfate, and filter Concentration gave 36h, which was directly put into the next step without purification. MS(ESI,m/z):535[M+1] + .
步骤4：化合物36i的合成Step 4: Synthesis of compound 36i
将36h(0.53g,0.99mmol)溶于甲苯(6.5mL)中，加入二异丙基乙基胺(0.73g,5.65mmol)，室温搅拌2h，然后冰水浴降温，加入5-己烯酰氯(0.69g,5.20mmol)，转至室温搅拌过夜。反应液中加入15mL水，10mL乙酸乙酯萃取，分液，水相加入20mL乙酸乙酯萃取一次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩。粗品硅胶柱层析(乙酸乙酯/正庚烷＝1/2-1/1)分离，得到化合物36i。Dissolve 36h (0.53g, 0.99mmol) in toluene (6.5mL), add diisopropylethylamine (0.73g, 5.65mmol), stir at room temperature for 2h, then cool down in an ice-water bath, add 5-hexenoyl chloride ( 0.69g, 5.20mmol), turned to room temperature and stirred overnight. Add 15 mL of water to the reaction solution, extract with 10 mL of ethyl acetate, separate the layers, add 20 mL of ethyl acetate to the aqueous phase for extraction once, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (ethyl acetate/n-heptane=1/2-1/1) to obtain compound 36i.
MS(ESI,m/z):631[M+1] +. MS(ESI,m/z):631[M+1] + .
步骤5：化合物36j的合成Step 5: Synthesis of compound 36j
向三口烧瓶中加入36i(307.1mg,486.90μmol)和溶剂DCE(280mL)，室温下加入詹氏催化剂-1B(35.7mg,48.65μmol)。加毕，氮气抽换气三次，混合物在84℃油浴下继续搅拌16小时。粗品经硅胶柱层析(乙酸乙酯/正庚烷＝1/2)分离，得到36j。Add 36i (307.1mg, 486.90μmol) and solvent DCE (280mL) into the three-necked flask, and add Jane's catalyst-1B (35.7mg, 48.65μmol) at room temperature. After the addition was complete, nitrogen was purged three times, and the mixture was stirred for 16 hours in an oil bath at 84°C. The crude product was separated by silica gel column chromatography (ethyl acetate/n-heptane=1/2) to obtain 36j.
MS(ESI,m/z):603[M+1] +. MS(ESI,m/z):603[M+1] + .
步骤6：化合物36A的合成Step 6: Synthesis of compound 36A
在干燥的反应试管中加入36j(0.2691mg,446.52μmol)和乙酸乙酯(5.5mL)，加入Pd/C(0.7182g,10％纯度)，随后置换氢气，反应在室温下搅拌3h。反应液过滤，减压浓缩得到粗品，粗品经制备反向液相色谱分离纯化，得到化合物36A。36j (0.2691 mg, 446.52 μmol) and ethyl acetate (5.5 mL) were added to a dry reaction tube, Pd/C (0.7182 g, 10% purity) was added, followed by hydrogen replacement, and the reaction was stirred at room temperature for 3 h. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by preparative reverse liquid chromatography to obtain compound 36A.
MS(ESI,m/z):515[M+1] +. MS(ESI,m/z):515[M+1] + .
1H NMR(600MHz,DMSO-d6)δ(ppm)＝11.64(s,1H),9.54(d,J＝8.7Hz,1H),8.83(s,1H),7.39(t,J＝7.5Hz,1H),6.87(d,J＝10.9Hz,1H),6.74(t,J＝7.4Hz,1H),5.70(d,J＝12.9Hz,1H),5.16(dd,J＝13.3,9.1Hz,1H),4.92(d,J＝12.9Hz,1H),4.57(dt,J＝13.5,6.7Hz,1H),3.96–3.76(m,3H),2.23(d,J＝7.7Hz,2H),1.64–0.96(m,16H). 1 H NMR (600MHz, DMSO-d6) δ (ppm) = 11.64 (s, 1H), 9.54 (d, J = 8.7Hz, 1H), 8.83 (s, 1H), 7.39 (t, J = 7.5Hz, 1H), 6.87(d, J=10.9Hz, 1H), 6.74(t, J=7.4Hz, 1H), 5.70(d, J=12.9Hz, 1H), 5.16(dd, J=13.3, 9.1Hz, 1H), 4.92(d, J=12.9Hz, 1H), 4.57(dt, J=13.5, 6.7Hz, 1H), 3.96–3.76(m, 3H), 2.23(d, J=7.7Hz, 2H), 1.64–0.96(m,16H).
实施例32Example 32
Figure PCTCN2022109064-appb-000124
Figure PCTCN2022109064-appb-000124
合成路线：synthetic route:
Figure PCTCN2022109064-appb-000125
Figure PCTCN2022109064-appb-000125
步骤1：化合物37f的合成Step 1: Synthesis of compound 37f
在预先干燥过的50mL单口瓶中加入环丙氨(2.43g,42.56mmol)和溶剂二氯甲烷(4.0mL)，随后滴加AlMe 3(21.5mL,43.00mmol,2.0M)，加毕后室温搅拌1.5h备用；向250mL的单口瓶中加入1e(4.27g,7.17mmol)和二氯甲烷(14.0ml)，氮气置换2次，再将活化的环丙氨混合液用氮气压入1e的二氯甲烷溶液中，室温搅拌3.0h。将反应液缓慢滴入饱和酒石酸钾钠(360mL)和二氯甲烷(280mL)的混合溶液中，分液，水相用二氯甲烷(200mL)萃洗两次，合并有机相，有机相用在依次用饱和酒石酸钾钠(250mL)和饱和食盐水(100mL)洗涤一次,无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(乙酸乙酯/正庚烷＝1/1)分离，得到化合物37f。MS(ESI,m/z):621[M+1] +. Cyclopropylamine (2.43g, 42.56mmol) and solvent dichloromethane (4.0mL) were added to a pre-dried 50mL single-necked bottle, followed by the dropwise addition of AlMe 3 (21.5mL, 43.00mmol, 2.0M), and after the addition, room temperature Stir for 1.5h and set aside; add 1e (4.27g, 7.17mmol) and dichloromethane (14.0ml) to a 250mL single-necked bottle, replace with nitrogen twice, and then inject the activated cyclopropylamine mixture into 1e's dichloromethane with nitrogen pressure. Chloromethane solution, stirred at room temperature for 3.0h. The reaction solution was slowly dropped into a mixed solution of saturated potassium sodium tartrate (360mL) and dichloromethane (280mL), separated, the aqueous phase was extracted and washed twice with dichloromethane (200mL), the organic phases were combined, and the organic phase was used in Washed once with saturated potassium sodium tartrate (250 mL) and saturated brine (100 mL) successively, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column chromatography (ethyl acetate/n-heptane=1/1), Compound 37f is obtained. MS(ESI,m/z):621[M+1] + .
步骤2：化合物37g的合成Step 2: Synthesis of Compound 37g
向50mL单口瓶中加入37f(2.81g,4.53mmol)和乙酸乙酯(13.5mL)溶清，再加入浓盐酸(1.42g，13.58mmol,36％)/甲醇(13.5mL)的混合液，50℃下搅拌过夜。反应液减压浓缩，粗品加入6mL乙酸乙酯打浆，过滤得到37g。Add 37f (2.81g, 4.53mmol) and ethyl acetate (13.5mL) to a 50mL single-necked bottle to dissolve, then add a mixture of concentrated hydrochloric acid (1.42g, 13.58mmol, 36%)/methanol (13.5mL), 50 Stir overnight at °C. The reaction solution was concentrated under reduced pressure, and the crude product was slurried by adding 6 mL of ethyl acetate, and filtered to obtain 37 g.
步骤3：化合物37h的合成Step 3: Synthesis of compound 37h
向50mL三口瓶中加入37g(1.09g,2.09mmol)、乙腈(18mL)和无水碳酸钾(1.76g,12.73mmol)，氮气置换2次，置于50℃下搅拌1.0h，再加入多聚甲醛(0.0584g,1.94mmol)，反应30min。向反应液中加入甲醇(12mL)，过滤，取有机相，无水硫酸钠干燥，过滤浓缩得到37h，无需纯化直接投入下一步。Add 37g (1.09g, 2.09mmol), acetonitrile (18mL) and anhydrous potassium carbonate (1.76g, 12.73mmol) into a 50mL three-necked flask, replace with nitrogen twice, stir at 50°C for 1.0h, then add polymer Formaldehyde (0.0584g, 1.94mmol), reacted for 30min. Methanol (12 mL) was added to the reaction solution, filtered, and the organic phase was taken, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 37h, which was directly put into the next step without purification.
步骤4：化合物37i的合成Step 4: Synthesis of compound 37i
将37h(0.88g,1.65mmol)溶于甲苯(10mL)中，加入二异丙基乙基胺(2.19g,16.94mmol)，室温搅拌1.5h，然后冰水浴降温，加入5-己烯酰氯(2.24g,16.89mmol)，转至室温搅拌4h。反应液中加入15mL水，10mL乙酸乙酯萃取，分液，水相加入20mL乙酸乙酯萃取一次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩。粗品硅胶柱层析(乙酸乙酯/正庚烷＝1/1)分离，得到化合物37i。Dissolve 37h (0.88g, 1.65mmol) in toluene (10mL), add diisopropylethylamine (2.19g, 16.94mmol), stir at room temperature for 1.5h, then cool down in an ice-water bath, add 5-hexenoyl chloride ( 2.24g, 16.89mmol), turned to room temperature and stirred for 4h. Add 15 mL of water to the reaction solution, extract with 10 mL of ethyl acetate, separate the layers, add 20 mL of ethyl acetate to the aqueous phase for extraction once, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (ethyl acetate/n-heptane=1/1) to obtain compound 37i.
MS(ESI,m/z):629[M+1] +. MS(ESI,m/z):629[M+1] + .
步骤5：化合物37j的合成Step 5: Synthesis of compound 37j
向三口烧瓶中加入37i(381.2mg,604.42μmol)和溶剂DCE(356mL)，室温下加入詹氏催化剂-1B(44.4mg,60.44μmol)。加毕，氮气抽换气三次，混合物在84℃油浴下继续搅拌16小时。粗品经硅胶柱层析(乙酸乙酯/正庚烷＝1/1)分离，得到37j。37i (381.2mg, 604.42μmol) and solvent DCE (356mL) were added to the three-necked flask, and Jane's catalyst-1B (44.4mg, 60.44μmol) was added at room temperature. After the addition was complete, nitrogen was purged three times, and the mixture was stirred for 16 hours in an oil bath at 84°C. The crude product was separated by silica gel column chromatography (ethyl acetate/n-heptane=1/1) to obtain 37j.
MS(ESI,m/z):601[M+1] +. MS(ESI,m/z):601[M+1] + .
步骤6：化合物37A的合成Step 6: Synthesis of compound 37A
在干燥的反应试管中加入37j(125.3mg,0.21μmol)和乙酸乙酯(2.5mL)，加入Pd/C(1.25g,10％纯度)，随后置换氢气，反应在室温下搅拌16h。反应液过滤，减压浓缩得到粗品，粗品经制备反向液相色谱分离纯化，得到化合物37A。37j (125.3 mg, 0.21 μmol) and ethyl acetate (2.5 mL) were added to a dry reaction tube, Pd/C (1.25 g, 10% purity) was added, followed by hydrogen replacement, and the reaction was stirred at room temperature for 16 h. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by preparative reverse liquid chromatography to obtain compound 37A.
MS(ESI,m/z):513[M+1] +. MS(ESI,m/z):513[M+1] + .
1H NMR(600MHz,DMSO-d6)δ(ppm)＝11.01(s,1H),9.53(d,J＝8.7Hz,1H),8.79(s,1H),7.39(t,J＝7.5Hz,1H),6.87(d,J＝11.1Hz,1H),6.74(t,J＝8.3Hz,1H),5.44(d,J＝12.6Hz,1H),5.16(dd,J＝13.2,9.0Hz,1H),5.03(d,J＝12.5Hz,1H),4.05–3.76(m,3H),2.74(s,1H),2.22(t,J＝7.6Hz,2H),1.63–0.62(m,14H). 1 H NMR (600MHz, DMSO-d6) δ (ppm) = 11.01 (s, 1H), 9.53 (d, J = 8.7Hz, 1H), 8.79 (s, 1H), 7.39 (t, J = 7.5Hz, 1H), 6.87(d, J=11.1Hz, 1H), 6.74(t, J=8.3Hz, 1H), 5.44(d, J=12.6Hz, 1H), 5.16(dd, J=13.2, 9.0Hz, 1H), 5.03(d, J＝12.5Hz, 1H), 4.05–3.76(m, 3H), 2.74(s, 1H), 2.22(t, J＝7.6Hz, 2H), 1.63–0.62(m, 14H ).
生物测试biological test
试验例1：使用HIV假病毒(PsV)系统评价受试化合物体外抗病毒的活性Test Example 1: Using the HIV pseudovirus (PsV) system to evaluate the antiviral activity of the test compound in vitro
通过测定化合物的半数有效浓度(EC 50)值来评价化合物对HIV假病毒的抗病毒活性。HIV假病毒报告基因实验被广泛用于早期筛选，替代HIV病毒实验来评价化合物的抗HIV病毒活性。 The antiviral activity of the compound against HIV pseudovirus was evaluated by determining the half effective concentration (EC 50 ) value of the compound. HIV pseudovirus reporter gene assay is widely used in early screening, instead of HIV virus assay to evaluate the anti-HIV virus activity of compounds.
HIV假病毒报告基因实验：HIV pseudovirus reporter gene experiment:
第一天，293T细胞以每孔55,000个细胞，每孔100μL的密度接种到96孔测试板中，并于5％CO 2、37℃培养箱中培养过夜。 On the first day, 293T cells were inoculated into 96-well test plates at a density of 55,000 cells per well and 100 μL per well, and cultured overnight in a 5% CO 2 , 37° C. incubator.
第二天，加入倍比稀释后的化合物(8个浓度点、双复孔)，50μL每孔。随后稀释好的病毒以每孔100TCID50加入细胞，50μL每孔。设置细胞对照(细胞，无化合物处理或病毒感染)，病毒对照(细胞感染病毒，无化合物处理)和培养液对照(只有培养液)。该实验培养液终体积为200μL，培养液中DMSO的终浓度分别为0.5％。细胞于5％CO 2、37℃培养箱中培养3天。 On the second day, the compound after doubling dilution (8 concentration points, duplicate wells) was added, 50 μL per well. Then the diluted virus was added to the cells at 100 TCID50 per well, 50 μL per well. Set up cell control (cells, no compound treatment or virus infection), virus control (cells infected with virus, no compound treatment) and culture medium control (only culture medium). The final volume of the experimental culture solution was 200 μL, and the final concentration of DMSO in the culture solution was 0.5%. The cells were cultured in a 5% CO 2 , 37°C incubator for 3 days.
使用荧光素酶报告基因检测试剂Britelite plus kit(PerkinElmer)检测测试板中每孔荧光素酶活性，数 据用于样品抗病毒活性分析。使用细胞活力检测试剂CellTiter Glo，用BioTek酶标仪检测每孔细胞活力，数据用于样品细胞毒性分析。Use the luciferase reporter gene detection reagent Britelite plus kit (PerkinElmer) to detect the luciferase activity in each well of the test plate, and the data are used for sample antiviral activity analysis. The cell viability of each well was detected with a BioTek microplate reader using the cell viability detection reagent CellTiter Glo, and the data were used for sample cytotoxicity analysis.
用GraphPad Prism软件绘制剂量-效应曲线。抗体的抗病毒活性(﹪Inhibition)的计算公式如下：Dose-effect curves were drawn with GraphPad Prism software. The formula for calculating the antiviral activity (﹪Inhibition) of the antibody is as follows:
抗病毒活性(％)＝(EC 50测试孔读值-病毒对照平均值)/(细胞对照平均值-病毒对照平均值)×100 Antiviral activity (%)=( EC50 test well reading value-virus control average value)/(cell control average value-virus control average value)×100
EC 50值使用GraphPad Prism(version 5)软件，对抗体的抑制活性和细胞活率进行非线性拟合分析，拟合方法为"log(inhibitor)vs.response--Variable slope"。 The EC 50 value was analyzed using GraphPad Prism (version 5) software to perform nonlinear fitting analysis on the inhibitory activity of the antibody and the cell viability, and the fitting method was "log(inhibitor) vs. response--Variable slope".
本发明化合物对HIV假病毒的抑制活性见表1。See Table 1 for the inhibitory activity of the compounds of the present invention to HIV pseudoviruses.
表1 本发明化合物对HIV假病毒(PsV)的抑制活性Table 1 The inhibitory activity of compound of the present invention to HIV pseudovirus (PsV)
化合物编号Compound number EC 50(nM) EC50 (nM)
1A1A 2828
2A2A 6161
5A5A 2626
11A11A 1111
12A12A 1919
13B13B 5252
15A15A 1919
16A16A 5353
17A17A 4141
18A18A 8686
19A19A 1313
20A20A 2020
24A24A 1818
24B24B 9191
25A25A 1313
25B25B 4242
26A26A 9.59.5
26B26B 5858
27A27A 2626
30A30A 2929
30B30B 9.79.7
31A31A 3636
32A32A 5.05.0
33A33A 1.91.9
34A34A 7.47.4
35A35A 9.39.3
36A36A 3333
结论：本发明化合物在细胞水平抑制HIV假病毒基因复制试验中展示出积极效应。Conclusion: the compound of the present invention shows a positive effect in the test of inhibiting HIV pseudovirus gene replication at the cell level.
试验例2：应用细胞病变(CPE)实验评价受试化合物的体外抗HIV-1活性Test Example 2: Evaluation of Anti-HIV-1 Activity of Test Compounds in Vitro by Cytopathic Pathology (CPE) Assay
通过测定化合物的半数有效浓度(EC 50)值来评价化合物的体外抗病毒人免疫缺陷病毒1型(HIV-1)活性。 The in vitro antiviral human immunodeficiency virus type 1 (HIV-1) activity of the compound was evaluated by determining the half effective concentration (EC 50 ) value of the compound.
实验方案：Experimental program:
受试化合物和参照化合物(AZT)将用DMSO倍比稀释好后加入细胞培养板中。将HIV-1和MT-4细胞于37℃、5％CO2培养箱中共培养1小时。随后将感染细胞以每孔10,000个细胞的密度接种于细胞培养板中。细胞培养液中DMSO终浓度为0.5％。将细胞置于37℃、5％CO 2培养箱中培养5-6天。 The test compound and the reference compound (AZT) will be diluted with DMSO and then added to the cell culture plate. HIV-1 and MT-4 cells were co-cultured in a 37°C, 5% CO2 incubator for 1 hour. Infected cells were then seeded in cell culture plates at a density of 10,000 cells per well. The final concentration of DMSO in the cell culture medium was 0.5%. Cells were cultured in a 37°C, 5% CO 2 incubator for 5-6 days.
细胞活力由CellTiter-Glo(Promega)测定。原始数据用于化合物抗HIV-1活性计算。Cell viability was determined by CellTiter-Glo (Promega). The raw data were used to calculate the anti-HIV-1 activity of the compounds.
应用GraphPad Prism软件(four parameter logistic equations)计算化合物的EC 50值。抗体的抗病毒活性(﹪Inhibition)的计算公式如下： EC 50 values of compounds were calculated using GraphPad Prism software (four parameter logistic equations). The formula for calculating the antiviral activity (﹪Inhibition) of the antibody is as follows:
抗病毒活性(％)＝(测试孔读值-病毒对照平均值)/(细胞对照平均值-病毒对照平均值)×100Antiviral activity (%)=(test well reading value-virus control average value)/(cell control average value-virus control average value)×100
本发明化合物对HIV-1病毒的抑制活性见表2。See Table 2 for the inhibitory activity of the compounds of the present invention on HIV-1 virus.
表2 本发明化合物对HIV-1病毒的抑制活性Table 2 The compound of the present invention is to the inhibitory activity of HIV-1 virus
化合物编号Compound number EC 50(nM) EC50 (nM)
24A24A 3.33.3
25A25A 6.46.4
26A26A 1515
结论：本发明化合物在细胞水平抑制HIV-1病毒实验中展示出积极效应。Conclusion: the compound of the present invention shows a positive effect in the experiment of inhibiting HIV-1 virus at the cell level.

Claims (16)

  1. 式(I)所示化合物或其药学上可接受的盐，其选自：A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which is selected from:
    Figure PCTCN2022109064-appb-100001
    Figure PCTCN2022109064-appb-100001
    R 1选自F、Cl、Br、CN、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个F取代； R 1 is selected from F, Cl, Br, CN, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 F replacements;
    m选自1、2和3；m is selected from 1, 2 and 3;
    R 2选自C 1-3烷基、C 3-6环烷基和4-6元杂环烷基； R 2 is selected from C 1-3 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl;
    R 3选自H； R is selected from H;
    或者，R 2与R 3以及它们相连的原子成5-8元杂环烷基，所述5-8元杂环烷基任选被1、2或3个R a取代； Alternatively, R 2 and R 3 and the atoms connected to them form a 5-8 membered heterocycloalkyl group, and the 5-8 membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 R a ;
    R a取各自独立地选自C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个F取代； R a is independently selected from C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 F ;
    L 1选自-(CH 2) n-，其中，1、2或3个CH 2中的每一个CH 2各自独立地任选被1个R b置换，其余各CH 2任选独立地被1或2个R c取代； L 1 is selected from -(CH 2 ) n -, wherein each of the 1, 2 or 3 CH 2s is independently optionally replaced by 1 R b , and each of the remaining CH 2 is optionally independently replaced by 1 or 2 R c substitutions;
    R b各自独立地选自O、NH、-CH＝CH-和-C(O)NH-； R b are each independently selected from O, NH, -CH=CH- and -C(O)NH-;
    R c选自F、OH、C 1-3烷氧基、-N(CH 3) 2和-C 1-3烷基-OH； R c is selected from F, OH, C 1-3 alkoxy, -N(CH 3 ) 2 and -C 1-3 alkyl-OH;
    n选自4-15的整数；n is an integer selected from 4-15;
    L 2选自CH 2和-C(＝O)-； L 2 is selected from CH 2 and -C(=O)-;
    L 3选自CH 2、NH、O和S； L3 is selected from CH2 , NH, O and S ;
    T 1选自CH和N； T1 is selected from CH and N ;
    环A选自苯基和5-6元杂芳基；Ring A is selected from phenyl and 5-6 membered heteroaryl;
    所述“4-6元杂环烷基”、“5-8元杂环烷基”和“5-6元杂芳基”的“杂”各自独立地包含1、2或3个独立选自O、S、N和NH的杂原子或原子团。The "hetero" of the "4-6 membered heterocycloalkyl", "5-8 membered heterocycloalkyl" and "5-6 membered heteroaryl" each independently contain 1, 2 or 3 members independently selected from Heteroatoms or atomic groups of O, S, N and NH.
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 1选自F。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is selected from F.
  3. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022109064-appb-100002
    选自
    Figure PCTCN2022109064-appb-100003
    Figure PCTCN2022109064-appb-100004
    The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit
    Figure PCTCN2022109064-appb-100002
    selected from
    Figure PCTCN2022109064-appb-100003
    Figure PCTCN2022109064-appb-100004
  4. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R c选自OH、甲氧基、-CH 2OH、-N(CH 3) 2和
    Figure PCTCN2022109064-appb-100005
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R c is selected from OH, methoxy, -CH 2 OH, -N(CH 3 ) 2 and
    Figure PCTCN2022109064-appb-100005
  5. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，n选自5、6、7、8、9、10和11。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein n is selected from 5, 6, 7, 8, 9, 10 and 11.
  6. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，L 1选自-(CH 2) 5-、-(CH 2) 6-、-(CH 2) 7-、-(CH 2) 8-、-(CH 2) 9-、-(CH 2) 10-和-(CH 2) 11-，其中，1、2或3个CH 2中的每一个CH 2各自独立地任选被1个R b置换，其余各CH 2任选独立地被1或2个R c取代。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from -(CH 2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -(CH 2 ) 9 -, -(CH 2 ) 10 -, and -(CH 2 ) 11 -, wherein each of 1, 2 or 3 CH 2s is independently optionally is replaced by 1 R b , and each of the remaining CH 2 is optionally independently substituted by 1 or 2 R c .
  7. 根据权利要求5所述的化合物或其药学上可接受的盐，其中，L 1选自-(CH 2) 5-、-(CH 2) 6-、-(CH 2) 7-、-(CH 2) 8-、-(CH 2) 9-、-(CH 2) 10-、-(CH 2) 11-、-(CH 2) 2-CH＝CH-(CH 2) 2-、-(CH 2) 2-CH＝CH-(CH 2) 3-、-(CH 2) 2-CH＝CH-(CH 2) 4-、-(CH 2) 2-CH＝CH-(CH 2) 5-、-(CH 2) 2-CH＝CH-(CH 2) 6-、-(CH 2) 2-CH＝CH-(CH 2) 7-、-(CH 2) 4-CH(OH)-(CH 2) 4-、-(CH 2) 4-CH(OH)-(CH 2) 5-、-(CH 2) 4-CH(CH 2OH)-(CH 2) 4-、-(CH 2) 4-CH(OCH 3)-(CH 2) 4-、
    Figure PCTCN2022109064-appb-100006
    Figure PCTCN2022109064-appb-100007
    -(CH 2) 4-NH-(CH 2) 4-、-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-、-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 2-、-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-CH 2C(O)NH(CH 2) 6-、-(CH 2) 2-O-(CH 2) 2-O-CH 2-和-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-CH 2-。     The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from -(CH 2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -(CH 2 ) 9 -, -(CH 2 ) 10 -, -(CH 2 ) 11 -, -(CH 2 ) 2 -CH=CH-(CH 2 ) 2 -, -(CH 2 ) 2 -CH=CH-(CH 2 ) 3 -, -(CH 2 ) 2 -CH=CH-(CH 2 ) 4 -, -(CH 2 ) 2 -CH=CH-(CH 2 ) 5 - , -(CH 2 ) 2 -CH=CH-(CH 2 ) 6 -, -(CH 2 ) 2 -CH=CH-(CH 2 ) 7 -, -(CH 2 ) 4 -CH(OH)-( CH 2 ) 4 -, -(CH 2 ) 4 -CH(OH)-(CH 2 ) 5 -, -(CH 2 ) 4 -CH(CH 2 OH)-(CH 2 ) 4 -, -(CH 2 ) 4 -CH(OCH 3 )-(CH 2 ) 4 -,
    Figure PCTCN2022109064-appb-100006
    Figure PCTCN2022109064-appb-100007
    -(CH 2 ) 4 -NH-(CH 2 ) 4 -, -(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -, -(CH 2 ) 3 -O-( CH 2 ) 2 -O-(CH 2 ) 2 -, -(CH 2 ) 3 -O-(CH 2 ) 2 -O-(CH 2 ) 3 -, -CH 2 C(O)NH(CH 2 ) 6 -, -(CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 2 -and-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 2 -.
  8. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，环A选自苯基、吡啶基、嘧啶基和吡咯基。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl, pyridyl, pyrimidyl and pyrrolyl.
  9. 根据权利要求8所述的化合物或其药学上可接受的盐，其中，环A选自苯基。The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl.
  10. 根据权利要求1-7任意一项所述的化合物或其药学上可接受的盐，其化合物选自式(I-1)和(I-2)所示的结构，The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein the compound is selected from the structures shown in formula (I-1) and (I-2),
    Figure PCTCN2022109064-appb-100008
    Figure PCTCN2022109064-appb-100008
    其中，in,
    R 1、R 2、R 3、L 1、L 2和m如权利要求1-7任意一项所定义。 R 1 , R 2 , R 3 , L 1 , L 2 and m are as defined in any one of claims 1-7.
  11. 根据权利要求1所述的化合物或其药学上可接受的盐，其化合物选自式(II-1)所示的结构，The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the structures shown in formula (II-1),
    Figure PCTCN2022109064-appb-100009
    Figure PCTCN2022109064-appb-100009
    其中，in,
    R 11选自H和F； R 11 is selected from H and F;
    R 2选自C 1-3烷基、C 3-6环烷基和4-6元杂环烷基； R 2 is selected from C 1-3 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl;
    R 3选自H； R is selected from H;
    环B选自5-6元杂环烷基；Ring B is selected from 5-6 membered heterocycloalkyl;
    L 1选自-(CH 2) n-，其中，1、2或3个CH 2中的每一个CH 2各自独立地任选被1个R b置换； L 1 is selected from -(CH 2 ) n -, wherein each of 1, 2 or 3 CH 2s is independently optionally replaced by 1 R b ;
    R b各自独立地选自O、NH、-CH＝CH-和-C(O)NH-； R b are each independently selected from O, NH, -CH=CH- and -C(O)NH-;
    n选自5、6、7、8、9和10；n is selected from 5, 6, 7, 8, 9 and 10;
    L 2选自CH 2和-C(＝O)-。 L2 is selected from CH2 and -C (=O)-.
  12. 下列所示化合物或其药学上可接受的盐，Compounds shown below or pharmaceutically acceptable salts thereof,
    Figure PCTCN2022109064-appb-100010
    Figure PCTCN2022109064-appb-100010
    Figure PCTCN2022109064-appb-100011
    Figure PCTCN2022109064-appb-100011
    Figure PCTCN2022109064-appb-100012
    Figure PCTCN2022109064-appb-100012
    Figure PCTCN2022109064-appb-100013
    Figure PCTCN2022109064-appb-100013
  13. 根据权利要求12所述的化合物或其药学上可接受的盐，其化合物选自，The compound or pharmaceutically acceptable salt thereof according to claim 12, wherein the compound is selected from the group consisting of,
    Figure PCTCN2022109064-appb-100014
    Figure PCTCN2022109064-appb-100014
    Figure PCTCN2022109064-appb-100015
    Figure PCTCN2022109064-appb-100015
    Figure PCTCN2022109064-appb-100016
    Figure PCTCN2022109064-appb-100016
  14. 根据权利要求12所述的化合物或其药学上可接受的盐，其化合物选自，The compound or pharmaceutically acceptable salt thereof according to claim 12, wherein the compound is selected from the group consisting of,
    Figure PCTCN2022109064-appb-100017
    Figure PCTCN2022109064-appb-100017
    Figure PCTCN2022109064-appb-100018
    Figure PCTCN2022109064-appb-100018
  15. 一种药物组合物，其包含有效治疗剂量的权利要求1～14任意一项所述的化合物或其药学上可接受的盐；任选地还包括药学上可接受的辅料、辅助剂或载体。A pharmaceutical composition, which comprises a therapeutically effective dose of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-14; optionally, a pharmaceutically acceptable adjuvant, adjuvant or carrier.
  16. 权利要求1～14任意一项所述的化合物或其药学上可接受的盐，或权利要求15所述的药物组合物在制备用于预防和/或治疗HIV感染的药物上的应用。Use of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15 in the preparation of a medicament for preventing and/or treating HIV infection.
PCT/CN2022/109064 2021-07-30 2022-07-29 Macrocyclic pyridone compound and application thereof WO2023006087A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080161271A1 (en) * 2005-02-21 2008-07-03 Hiroshi Yoshida Bicyclic Carbamoylpyridone Derivative Having Hiv Integrase Inhibitory Activity
CN101346376A (en) * 2005-10-27 2009-01-14 盐野义制药株式会社 Polycyclic carbamoylpyridone derivative having inhibitory activity on HIV integrase
CN104995198A (en) * 2012-12-21 2015-10-21 吉里德科学公司 Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
WO2019160783A1 (en) * 2018-02-15 2019-08-22 Merck Sharp & Dohme Corp. Tricyclic heterocycle compounds useful as hiv integrase inhibitors
CN112513042A (en) * 2018-05-31 2021-03-16 盐野义制药株式会社 Polycyclic carbamoylpyridone derivatives

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080161271A1 (en) * 2005-02-21 2008-07-03 Hiroshi Yoshida Bicyclic Carbamoylpyridone Derivative Having Hiv Integrase Inhibitory Activity
CN101346376A (en) * 2005-10-27 2009-01-14 盐野义制药株式会社 Polycyclic carbamoylpyridone derivative having inhibitory activity on HIV integrase
CN104995198A (en) * 2012-12-21 2015-10-21 吉里德科学公司 Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
WO2019160783A1 (en) * 2018-02-15 2019-08-22 Merck Sharp & Dohme Corp. Tricyclic heterocycle compounds useful as hiv integrase inhibitors
CN112513042A (en) * 2018-05-31 2021-03-16 盐野义制药株式会社 Polycyclic carbamoylpyridone derivatives

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