WO2022194278A1 - 双环苯酚类化合物及其应用 - Google Patents

双环苯酚类化合物及其应用 Download PDF

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WO2022194278A1
WO2022194278A1 PCT/CN2022/081686 CN2022081686W WO2022194278A1 WO 2022194278 A1 WO2022194278 A1 WO 2022194278A1 CN 2022081686 W CN2022081686 W CN 2022081686W WO 2022194278 A1 WO2022194278 A1 WO 2022194278A1
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compound
reaction
crude product
ethyl acetate
added
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PCT/CN2022/081686
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English (en)
French (fr)
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张盛彬
于涛
吴成德
刘金鑫
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 CN202280016468.2A priority Critical patent/CN116888103A/zh
Priority to JP2023556885A priority patent/JP2024511015A/ja
Priority to EP22770630.6A priority patent/EP4310077A1/en
Priority to CN202311764201.4A priority patent/CN117624073A/zh
Publication of WO2022194278A1 publication Critical patent/WO2022194278A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a series of bicyclic phenolic compounds and their applications, and specifically discloses the compounds represented by formula (III) and their pharmaceutically acceptable salts.
  • THR ⁇ thyroid hormone receptor
  • THR ⁇ agonists have been developed for the treatment of dyslipidemia, non-alcoholic fatty liver and non-alcoholic steatohepatitis and other metabolic diseases, such as: GC-1, KB141, KB2115 and so on.
  • GC-1 non-alcoholic fatty liver
  • KB2115 non-alcoholic steatohepatitis
  • skeletal and cardiac side effects have hindered its further development, such as KB2115 being stopped in Phase 3 clinical studies due to cartilage damage found in dogs).
  • THR ⁇ is mainly distributed in the brain, heart and skeletal muscle, and it can enhance the activity of osteoclasts, resulting in a decrease in bone density.
  • THR ⁇ agonist MGL-3196 Based on literature (J.Med.Chem.2014,57,3912-3923) reports, the structure of THR ⁇ agonist MGL-3196 is as follows:
  • the present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
  • Ring B is selected from
  • R 1 is independently selected from H, F, Cl, Br, I and C 1-3 alkyl optionally substituted with 1 , 2 or 3 Ra ;
  • R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy is optionally substituted with 1 , 2 or 3 R b ;
  • R 4 is selected from C 1-3 alkyl-phenyl
  • L is selected from -O- and -CH 2 -;
  • Ring A is selected from phenyl, 5-6 membered heteroaryl, The phenyl group, the 5- to 6-membered heteroaryl group, optionally substituted with 1, 2 or 3 R c ;
  • n and m are independently selected from 0, 1 and 2;
  • R a and R b are each independently selected from F, Cl, Br and I;
  • R 1 is independently selected from H, F, Cl, Br, I, and CH 3 , and the CH 3 is optionally substituted by 1, 2 or 3 Ra , and other variables are as defined in the present invention definition.
  • R 1 is independently selected from H, F, Cl, Br, I, CH 3 and CF 3 , and other variables are as defined in the present invention.
  • R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and OCH 3 , and the CH 3 and OCH 3 are optional Substituted with 1, 2 or 3 R b and other variables are as defined in the present invention.
  • R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 F, CHF 2 , CF 3 and OCH 3 , and other variables are as defined in the present invention.
  • Other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from said Optionally substituted with 1, 2 or 3 R c , other variables are as defined herein.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the above R 4 is selected from Other variables are as defined in the present invention.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is independently selected from H, F, Cl, Br, I and C 1-3 alkyl optionally substituted with 1 , 2 or 3 Ra ;
  • R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy is optionally substituted with 1 , 2 or 3 R b ;
  • L is selected from -O- and -CH 2 -;
  • Ring A is selected from phenyl, 5-6 membered heteroaryl, The phenyl group, the 5- to 6-membered heteroaryl group, optionally substituted with 1, 2 or 3 R c ;
  • n and m are independently selected from 0, 1 and 2;
  • R a and R b are each independently selected from F, Cl, Br and I;
  • R is independently selected from F, Cl, Br and I.
  • R 1 is independently selected from H, F, Cl, Br, I, and CH 3 , and the CH 3 is optionally substituted by 1, 2 or 3 Ra , and other variables are as defined in the present invention definition.
  • R 1 is independently selected from H, F, Cl, Br, I, CH 3 and CF 3 , and other variables are as defined in the present invention.
  • R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and OCH 3 , and the CH 3 and OCH 3 are optional Substituted with 1, 2 or 3 R b and other variables are as defined in the present invention.
  • R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 F, CHF 2 , CF 3 and OCH 3 , and other variables are as defined in the present invention.
  • Other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from said Optionally substituted with 1, 2 or 3 R c , other variables are as defined herein.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:
  • R c is F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are optionally 1, 2 or 3 halogen substitutions;
  • R 1 , R 2 , R 3 , L and m are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:
  • R 1 , R 2 , R 3 , L, m and n are as defined in the present invention.
  • the present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating nonalcoholic steatohepatitis.
  • the present invention also provides following synthetic method:
  • -X-Y-Z- is selected from cyclopentenyl, cyclohexenyl, phenyl, thienyl, thiazolyl, furyl and oxazolyl;
  • R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy is optionally substituted with 1 , 2 or 3 R b ;
  • R b is each independently selected from F, Cl, Br and I.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • 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 such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
  • the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2)
  • the following formula (B) indicates that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or exists in two forms of formula (B-1) and formula (B-2) exists as a mixture of isomers.
  • the following formula (C) represents that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of two isomers of formula (C-1) and formula (C-2) exists in the form of a mixture.
  • tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature.
  • a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
  • the enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituents 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. When the listed substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine ring The carbon atom is attached to the substituted group.
  • the direction of attachment is arbitrary, for example,
  • the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
  • Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites in the group can be linked to other groups by chemical bonds.
  • connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group.
  • the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines express.
  • a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
  • the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
  • the wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
  • Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C1-3alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like.
  • Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • the terms “5-6 membered heteroaryl ring” and “5-6 membered heteroaryl” are used interchangeably in the present invention, and the term “5-6 membered heteroaryl” means from 5 to 6 ring atoms It is composed of a monocyclic group with a conjugated ⁇ electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
  • a 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl groups include 5- and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4
  • Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membere
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffractometry (SXRD), using Bruker D8 venture diffractometer to collect the diffraction intensity data of the cultivated single crystal, the light source is CuK ⁇ radiation, scanning mode: ⁇ / ⁇ scanning, after collecting the relevant data, further adopt the direct method (Shelxs97) analysis of the crystal structure, the absolute configuration can be confirmed.
  • SXRD single crystal X-ray diffractometry
  • Bruker D8 venture diffractometer to collect the diffraction intensity data of the cultivated single crystal
  • the light source is CuK ⁇ radiation
  • scanning mode: ⁇ / ⁇ scanning after collecting the relevant data
  • the absolute configuration can be confirmed.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the present invention adopts the following abbreviations: aq represents water; eq represents equivalent, equivalent; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc for ethyl acetate; EtOH for ethanol; MeOH for methanol; CBz for benzyloxycarbonyl, an amine protecting group; BOC for tert-butoxycarbonyl, an amine protecting group; rt for room temperature; O/N for Overnight; THF for tetrahydrofuran; Boc 2 O for di-tert-butyl dicarbonate; TFA for trifluoroacetic acid; DIPEA for diisopropylethylamine; Xantphos for 4,5-bisdiphenylphosphine-9,9- Dimethylxanthene; NBS for N-bromosuccinimide; B
  • the compounds of the present invention have significant THR ⁇ activity and selectivity, and have no drug-drug interactions; the compounds of the present invention have higher exposure and better oral bioavailability, and have excellent pharmacokinetic properties; the compounds of the present invention can Significantly reduced plasma LDL-C levels in rats.
  • Figure 4 The change rate of rat LDL-C after one week of administration relative to the rat LDL-C before administration.
  • the compound of the present invention has good binding with THR ⁇ protein.
  • the compounds of the present invention occupy the binding pocket of THR ⁇ and thyroxine.
  • the binding pocket is a closed, hydrophobic pocket composed of multi-layer ⁇ -helices, and above the pocket is a positive band composed of three arginines (Arg282, Arg316 and Arg320). Electric sub pocket.
  • the 6-azauracil acidic group of the original reference compound MGL-3196 is bound in this sub-pocket, the cyano group forms hydrogen bonds with Arg316, the carbonyl and nitrogen atoms of 6-azauracil form hydrogen bonds with Arg320, and the pyridazine group forms hydrogen bonds with Arg320.
  • the carbonyl oxygen of the ketone forms a hydrogen bond with His435.
  • the benzene ring in the middle, the pyridazinone and the isopropyl group at the end can all form hydrophobic interactions with the surrounding amino acids.
  • the 1,2,4-oxadiazolin-5-one polar head of the compound of the present invention is combined in this sub-pocket, and also forms a hydrogen bond with three arginines, improving the angle of dichlorobenzene through amides, making it easier to Forming a halogen bond with Phe272, the carbonyl or hydroxyl group at the tail can form a hydrogen bond through interaction with His435, and the ring effectively provides hydrophobic interactions. Has better selectivity.
  • reaction solution was poured into water (100 mL) to quench, the aqueous phase (100 mL*3) was extracted with methyl tert-butyl ether, the organic phases were combined, washed with saturated brine (150 mL*3), and the organic phase was collected, Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude product.
  • reaction solution was poured into 20 mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate (20 mL*3), the organic phases were combined, washed with 20 mL of saturated brine, and after separation, the organic phase was washed with anhydrous sulfuric acid. Dry over sodium, filter, and spin the filtrate under reduced pressure to obtain the crude product.
  • reaction solution was poured into 50 mL of saturated aqueous sodium carbonate solution, DCM (50 mL*3) was added for extraction, the organic phases were combined, the organic phase was washed with saturated brine (100 mL), and after separation, the organic phase was washed with anhydrous sulfuric acid Dry over sodium, filter, and spin the filtrate under reduced pressure to obtain the crude product.
  • WX001-7 (2.05 g, 11.30 mmol, 1.90 mL) in THF (40 mL) was added WX001-6 (4 g, 10.27 mmol), cesium carbonate (5.02 g, 15.41 mmol), BINAP (319.87 mg, 513.71 ⁇ mol) , palladium acetate (115.33 mg, 513.71 ⁇ mol), reacted at 65° C. for 12 hours.
  • the crude product was purified by preparative high performance liquid chromatography column (chromatographic column: Waters Xbridge BEH C18 100*30mm*10 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile %: 25%-55%, 10 minutes) Get WX001.
  • reaction solution was poured into ice water (30 mL) to quench, ethyl acetate (20 mL) was added to separate the layers, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (2*20 mL), and the organic phases were combined, Washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product.
  • reaction solution was poured into saturated ammonium chloride solution (20 mL), then ethyl acetate (20 mL) was added to separate the layers, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (20 mL*2), and the organic phases were combined. , washed with saturated brine (20 mL*2) successively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product.
  • reaction solution was poured into 50 mL of saturated aqueous sodium carbonate solution, DCM (50 mL*3) was added for extraction, the organic phases were combined, the organic phase was washed with saturated brine (50 mL), and after separation, the organic phase was washed with anhydrous sulfuric acid Dry over sodium, filter, and spin dry the filtrate under reduced pressure.
  • reaction solution was poured into water (30 mL) to quench, the aqueous phase was extracted with ethyl acetate (30 mL*3), the organic phases were combined, washed with saturated brine (50 mL*2), the organic phase was collected, and anhydrous sulfuric acid was used. Dry over sodium, filter, and concentrate the filtrate under reduced pressure to obtain WX002-8, which is used directly in the next step without purification.
  • Sodium hydride (5.82 g, 145.46 mmol, 60% content, 3 eq) and DMSO (35 mL) were added to the pre-dried reaction flask, nitrogen was replaced three times, and the mixture was stirred at 75° C. for 10 minutes. Then placed at 25°C, a solution of methyltriphenyl iodide (39.20 g, 96.98 mmol, 2eq) in DMSO (25 mL) was slowly added, and the mixture was stirred at 25°C for 20 minutes.
  • reaction solution was poured into saturated ammonium chloride solution (200 mL), then ethyl acetate (200 mL) was added to separate the layers, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (200 mL*2), and the organic phases were combined. , washed successively with saturated brine (600 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • the pH of the reaction solution was adjusted to 6-7 with saturated aqueous sodium bicarbonate solution, water (30 mL) and dichloromethane (30 mL) were added to separate the layers, the organic phase was collected, and the aqueous phase was extracted with dichloromethane (30 mL*2 ), the organic phases were combined, the organic phase was washed with saturated brine (150 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • the reaction solution was cooled to room temperature, water (50 mL) and ethyl acetate (50 mL) were added to separate the layers, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (50 mL*2), the organic phases were combined, and the organic phase was used Washed with saturated brine (300 mL*3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain WX003-7, and the crude product was directly used in the next step.
  • WX003-7 (2.3g, 4.57mmol, 1eq) and THF (25mL) were added to a pre-dried reaction flask, hydrochloric acid (2N, 2.28mL, 1eq) was added, and the mixture was stirred at 25°C for 1 hour.
  • the pH of the reaction solution was adjusted to 6-7 with saturated aqueous sodium bicarbonate solution, water (30 mL) and ethyl acetate (30 mL) were added for separation, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (30 mL*2 ), the organic phases were combined, the organic phase was washed with saturated brine (120 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • Step 8 Synthesis of Compounds WX003-9-1 and WX003-9-2
  • reaction solution was added to water (5mL), ethyl acetate (5mL) was added to extract the liquid separation, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (5mL*2), the organic phases were combined, and the organic phases were sequentially used Wash with saturated brine (20 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain WX003-10-1.
  • reaction solution was added to water (5mL), ethyl acetate (5mL) was added to extract the liquid separation, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (5mL*2), the organic phases were combined, and the organic phases were sequentially used Wash with saturated brine (20 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain WX003-10-2.
  • the crude product was purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10 ⁇ m; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 25%-55%, 8 minutes) to obtain WX003 .
  • the crude product was purified by high performance liquid chromatography (chromatographic column: Waters Xbridge BEH C18 100*30mm*10 ⁇ m; mobile phase: [A: water (ammonium bicarbonate)-B: acetonitrile]; acetonitrile %: 25%-55%, 8min ) to get WX004.
  • the reaction solution was poured into ice water (100 mL), ethyl acetate (100 mL) was added to separate the layers, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (100 mL*2), the organic phases were combined and saturated with Washed with brine (100 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • reaction solution was poured into saturated ammonium chloride solution (50 mL), then ethyl acetate (50 mL) was added to separate the layers, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (50 mL*2), and the organic phases were combined. , washed successively with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • reaction solution was directly filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • reaction solution was added to water (5mL), ethyl acetate (5mL) was added to extract the liquid separation, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (5mL*2), the organic phases were combined, and the organic phases were sequentially used Washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to obtain the crude product of WX006-11, which was directly used in the next step.
  • reaction solution was quenched with saturated sodium bicarbonate solution, diluted with ethyl acetate (30 mL), water (30 mL) was added to separate the layers, the organic phase was collected, the aqueous phase (30 mL*3) was extracted with ethyl acetate, and the combined The organic phase was washed with saturated brine (30 mL*2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • reaction solution was cooled to room temperature, water (200 mL) was added, the aqueous phase (200 mL*3) was extracted with ethyl acetate, the organic phases were combined, and the organic phase was washed with saturated brine (300 mL*1), anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure to obtain the crude product.
  • reaction solution was quenched by adding water (200 mL), the aqueous phase (500 mL*3) was extracted with dichloromethane, the organic phases were combined, the organic phase was washed with saturated brine (550 mL*2), and dried over anhydrous sodium sulfate. , filtered, and the filtrate was concentrated under reduced pressure to obtain crude product.
  • reaction solution was poured into saturated ammonium chloride solution (5 mL) to quench, then ethyl acetate (5 mL) was added to separate the layers, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (2*5 mL), and the combined The organic phase was washed successively with saturated brine (2*5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • reaction solution was poured into (30 mL) saturated aqueous sodium carbonate solution, DCM (30 mL*3) was added for extraction, the organic phases were combined, the organic phase was washed with saturated brine (30 mL), and after separation, the organic phase was washed with Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product.
  • reaction solution was quenched by adding water (200mL), the aqueous phase (500mL*3) was extracted with dichloromethane, the organic phases were combined, and the organic phases were washed with saturated brine (550mL*2), anhydrous sodium sulfate. Dry, filter, and concentrate the filtrate under reduced pressure to obtain the crude product.
  • reaction solution was added to water (5mL), ethyl acetate (5mL) was added to extract the liquid separation, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (5mL*2), the organic phases were combined, and the organic phases were sequentially used Wash with saturated brine (20 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product.
  • the crude product was purified by high performance liquid chromatography (chromatographic column: Waters Xbridge BEH C18 100*30mm*10 ⁇ m; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile%: 35%-55%, 8min) to obtain organic separation , machine separation and liquid extraction, the organic phase was collected, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain WX007.
  • chromatographic column Waters Xbridge BEH C18 100*30mm*10 ⁇ m; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile%: 35%-55%, 8min
  • the organic phase was washed with saturated brine (500 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure using a water pump at 50°C to obtain a crude product of pale yellow solid.
  • WX008-5 (20g, 78.64mmol, 1eq) and THF (200mL) were added to the pre-dried reaction flask, and sodium hydride (12.58g, 314.56mmol, 60% content, 4eq) was added slowly at 0°C, 0°C Continue stirring for 0.5 hours.
  • WX008-6 (36.80 g, 235.92 mmol, 18.87 mL, 3 eq) was added dropwise at 0°C, and the mixture was stirred at 0°C for 0.5 hours. The temperature was raised to 25°C and stirring was continued for 15 hours.
  • reaction solution was quenched with water (100 mL), the aqueous phase (100 mL*3) was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine (100 mL*3), the organic phase was collected, and dried over anhydrous sodium sulfate. , filtered, and the filtrate was concentrated under reduced pressure to obtain crude product.
  • WX008-8 (6.35g, 33.03mmol, 1eq) and DCM (120mL) were added to the pre-dried reaction flask, hydrogen was replaced three times, and 2,6-lutidine (8.85g, 82.57mmol, 9.62mL) was slowly added dropwise. , 2.5eq), and then dropwise added WX008-9 (20.24g, 66.06mmol, 17.76mL, 2eq), and stirred at 25°C for 16 hours.
  • reaction solution was quenched by adding water (120 mL), the aqueous phase (150 mL*3) was extracted with dichloromethane, the organic phases were combined, washed with saturated brine (100 mL*2), the organic phase was collected, anhydrous sodium sulfate Dry, filter, and concentrate under reduced pressure to obtain crude product.
  • the crude product was purified by (chromatographic column: Phenomenex C18 80*40mm*3 ⁇ m; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile%: 25%-45%, 8 minutes) to obtain WX008-17.
  • WX008-17 (60mg, 101.04 ⁇ mol) was separated by chiral (chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10 ⁇ m); mobile phase: A: carbon dioxide B: [0.1% ammonia water-ethanol]; B%: 35%-35 %, 14 minutes) to obtain WX008 and WX009.
  • chromatographic column: DAICEL CHIRALPAK AD 250mm*30mm, 10 ⁇ m
  • mobile phase A: carbon dioxide
  • B [0.1% ammonia water-ethanol]
  • B% 35%-35 %, 14 minutes
  • the product WX009 was purified by (chromatographic column: Phenomenex C18 75*30mm*3 ⁇ m; mobile phase: [water (ammonia+ammonium bicarbonate)-acetonitrile]; acetonitrile%: 15%-45%, 8 minutes) to obtain WX009.
  • Detection by chiral method shows that the retention time of WX010-2-1 is 2.893 minutes, and the ee% is 100%; the retention time of WX010-2-2 is 3.190 minutes, and the ee% is 91.06%.
  • reaction solution was poured into saturated ammonium chloride solution (20 mL), then ethyl acetate (20 mL) was added to separate the layers, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (20 mL*2), and the organic phases were combined. , washed with saturated brine (20 mL*2) successively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product.
  • reaction solution was diluted with dichloromethane (10 mL), then washed with 2N hydrochloric acid (10 mL), the organic phase was collected, and the organic phase was washed with saturated sodium bicarbonate solution (10 mL) and saturated brine (20 mL). , dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product.
  • WX012-4 500mg, 1.26mmol, 1eq
  • purify by supercritical chromatography chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10 ⁇ m); mobile phase: A: carbon dioxide B: [0.1% ammonia water + isopropanol]; B%: 30%-30%, 10 minutes) to obtain WX012-5-1 and WX012-5-2.
  • the organic phase was successively washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • the reaction solution was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, the pH of the concentrate was adjusted to 7-8 with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (10 mL*3), and the mixture was combined. The organic phase; the organic phase was successively washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • reaction solution was added to water (5mL), ethyl acetate (5mL) was added to extract the liquid separation, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (5mL*2), the organic phases were combined, and the organic phases were sequentially used Wash with saturated brine (20 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product.
  • the crude product was purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10 ⁇ m; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile %: 20%-65%, 10 minutes) to obtain WX012 .
  • reaction solution was added to water (5mL), ethyl acetate (5mL) was added to extract the liquid separation, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (5mL*2), the organic phases were combined, and the organic phases were sequentially used Wash with saturated brine (20 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product.
  • the crude product was purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10 ⁇ m; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile %: 20%-65%, 10 minutes) to obtain WX013 .
  • TR alpha/beta-UAS-bla HEK 293T Cell-based Assay method uses ThermoFisher developed TR alpha/beta-UAS-bla HEK 293T Cell-based Assay method, the principle is that TR alplha-UAS-bla HEK 293T Cell and TR beta-UAS-bla HEK 293T Cell express ⁇ -lactamase, this reporter gene is controlled
  • the receptor binds to the DNA-binding region to form a complete GAL4 dimer, using the GAL4-UAS system to activate the expression of ⁇ -lactamase and decompose the substrate CCF4- AM (coumarin), the product generates fluorescence at 447 nm under excitation at 409 nm.
  • ⁇ -lactamase If ⁇ -lactamase is not expressed, under excitation at 409 nm, it directly generates fluorescence at 520 nm by FRET. By detecting the ratio of the two fluorescence ( 447nm/520nm) to determine the binding of the compound to the protein, so as to calculate the EC 50 of the compound.
  • HEK 293T-TR beta was incubated in a 37°C incubator for 16 hours
  • HEK 293T-TR alpha was incubated for 22 hours
  • LiveBLAzer TM -FRET B/G(CCF4-AM) substrate was added to the cell plate, and incubated at room temperature in the dark for 2 hours.
  • the Flexstation 3 instrument was used to detect the product under excitation at 409nm, and the fluorescence value of 460nm/530nm wavelength was emitted. By detecting the ratio of the two fluorescence (460nm/530nm), the software Graphpad Prism was used to calculate the EC 50 of the compound.
  • the reference compound triiodothyronine (T3) will be used as a positive control in the experiment.
  • the calculation of the Z factor (>0.5) will be used to monitor the stability of each experiment.
  • the compound of the present invention has significant THR ⁇ activity and selectivity.
  • the inhibitory effect of the test compound WX001 on the activity of human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) was determined.
  • test compound control sample was 1:1DMSO:MeOH and 1:9DMSO:MeOH respectively; after pre-incubating in a 37°C water bath for 10min, 20.0 ⁇ L of coenzyme factor (NADPH) solution was added to the reaction plate.
  • NADPH coenzyme factor
  • the CYP3A4 metabolic reaction of the probe substrate the reaction time is 3 minutes; the CYP2C19 reaction using (S)-mephenytoin as the probe substrate and the CYP2D6 reaction using dextromethorphan as the probe substrate, the reaction time is 20 400 ⁇ L of pre-cooled acetonitrile solution (internal standard containing 200 ng/mL Tolbutamide and Labetalol) was added to terminate the reaction; the reaction plate was placed on a shaker, shaken and mixed for 10 min; then at 4°C, Centrifuge at 4000 rpm for 20 min; add 200 ⁇ L of supernatant to 100 ⁇ L of water for sample dilution; finally seal the plate, shake, shake well, and perform LC/MS/MS detection.
  • pre-cooled acetonitrile solution internal standard containing 200 ng/mL Tolbutamide and Labetalol
  • Compound WX001 has no inhibitory effect on CYP1A2, CYP2C19, CYP2D6 and CYP3A4, but has moderate inhibitory effect on CYP2C9.
  • the compound of the present invention has higher exposure and better oral bioavailability.
  • the in vivo efficacy of the compounds to be tested was detected by using a rat model induced by dietary cholesterol cholic acid.
  • the compound of the present invention can significantly reduce the level of plasma LDL-C in rats.

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Abstract

一系列苯酚类化合物及其应用，具体公开了式(III)所示化合物及其药学上可接受的盐。

Description

双环苯酚类化合物及其应用
本申请主张如下优先权
CN202110298570.3，申请日：2021年03月19日；
CN202110443424.5，申请日：2021年04月23日；
CN202210107896.8，申请日：2022年01月28日。
技术领域
本发明涉及一系列双环苯酚类化合物及其应用，具体公开了式(III)所示化合物及其药学上可接受的盐。
背景技术
甲状腺激素受体(THR)有两种亚型：THRα和THRβ。过去数十年，多种THRβ激动剂被开发用于血脂异常，非酒精性脂肪肝和非酒精性脂肪肝炎等代谢类疾病的治疗，例如：GC-1,KB141,KB2115等。然而骨骼和心脏副作用阻碍了其进一步开发，例如KB2115由于在犬中发现软骨损伤而停止了三期临床研究)。THRα主要分布在大脑、心脏和骨骼肌，它能够增强破骨细胞活性，造成骨密度降低。因此，人们认为这些副作用是由于激动THRα亚型导致的，希望通过提高靶点选择性和肝组织选择性来避免。该策略的代表性品种是MGL-3196和VK-2809，安全性和有效性均通过临床得到初步验证。因此，开发肝脏组织分布特异性和甲状腺激素受体亚型选择性高的甲状腺激素类似物具有重大的临床价值。
基于文献(J.Med.Chem.2014,57,3912-3923)报道，THRβ激动剂MGL-3196结构如下：
Figure PCTCN2022081686-appb-000001
发明内容
本发明提供了式(III)所示化合物或其药学上可接受的盐，
Figure PCTCN2022081686-appb-000002
其中，
环B选自
Figure PCTCN2022081686-appb-000003
R 1独立地选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代；
R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、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R b取代；
R 4选自C 1-3烷基-苯基；
L选自-O-和-CH 2-；
环A选自苯基、5～6元杂芳基、
Figure PCTCN2022081686-appb-000004
所述苯基、5～6元杂芳基、
Figure PCTCN2022081686-appb-000005
任选被1、2或3个R c取代；
n和m分别独立地选自0、1和2；
R a和R b分别独立地选自F、Cl、Br和I；
R c独立地选自F、Cl、Br、I、＝O、＝N-C 1-3烷氧基、C 1-3烷基和C 1-3烷氧基，所述＝N-C 1-3烷氧基、C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代。
本发明的一些方案中，上述R 1独立地选自H、F、Cl、Br、I和CH 3，所述CH 3任选被1、2或3个R a取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 1独立地选自H、F、Cl、Br、I、CH 3和CF 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和OCH 3，所述CH 3和OCH 3任选被1、2或3个R b取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2F、CHF 2、CF 3和OCH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R c独立地选自F、Cl、Br、I、＝O、＝N-O-CH 3、＝N-O-CH 2CH 3、CH 3、OCH 3和OCH 2CH 3，所述＝N-O-CH 3、＝N-O-CH 2CH 3、CH 3、OCH 3和OCH 2CH 3任选被1、2或3个卤素取代，其他变量如本发明所定义。
本发明的一些方案中，上述R c独立地选自F、Cl、Br、I、＝O、＝N-O-CH 3、＝N-O-CH 2CH 3、CH 3、OCH 3和OCH 2CH 3，所述＝N-O-CH 3、＝N-O-CH 2CH 3、CH 3、OCH 3和OCH 2CH 3任选被1、2或3个R取代，其他变量如本发明所定义。
本发明的一些方案中，上述R c独立地选自F、Cl、Br、I、＝O、＝N-O-CH 3、＝N-O-CH 2CH 3、CH 3、OCH 3和OCH 2CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述环A选自
Figure PCTCN2022081686-appb-000006
Figure PCTCN2022081686-appb-000007
所述
Figure PCTCN2022081686-appb-000008
Figure PCTCN2022081686-appb-000009
任选被1、2或3个R c取代，其他变量如本发明所定义。
本发明的一些方案中，上述环A选自
Figure PCTCN2022081686-appb-000010
Figure PCTCN2022081686-appb-000011
Figure PCTCN2022081686-appb-000012
其他变量如本发明所定义。本发明的一些方案中，上述R 4选自
Figure PCTCN2022081686-appb-000013
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2022081686-appb-000014
选自
Figure PCTCN2022081686-appb-000015
Figure PCTCN2022081686-appb-000016
Figure PCTCN2022081686-appb-000017
其他变量如本发明所定义。
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2022081686-appb-000018
其中，
R 1独立地选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代；
R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、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R b取代；
L选自-O-和-CH 2-；
环A选自苯基、5～6元杂芳基、
Figure PCTCN2022081686-appb-000019
所述苯基、5～6元杂芳基、
Figure PCTCN2022081686-appb-000020
任选被1、2或3个R c取代；
n和m分别独立地选自0、1和2；
R a和R b分别独立地选自F、Cl、Br和I；
R c独立地选自F、Cl、Br、I、＝O、＝N-C 1-3烷氧基、C 1-3烷基和C 1-3烷氧基，所述＝N-C 1-3烷氧基、C 1-3烷基和C 1-3烷氧基任选被1、2或3个R取代；
R独立地选自F、Cl、Br和I。
本发明的一些方案中，上述R 1独立地选自H、F、Cl、Br、I和CH 3，所述CH 3任选被1、2或3个R a取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 1独立地选自H、F、Cl、Br、I、CH 3和CF 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和OCH 3，所述CH 3和OCH 3任选被1、2或3个R b取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2F、CHF 2、CF 3和OCH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R c独立地选自F、Cl、Br、I、＝O、＝N-O-CH 3、＝N-O-CH 2CH 3、CH 3、OCH 3和OCH 2CH 3，所述＝N-O-CH 3、＝N-O-CH 2CH 3、CH 3、OCH 3和OCH 2CH 3任选被1、2或3个R取代，其他变量如本发明所定义。
本发明的一些方案中，上述R c独立地选自F、Cl、Br、I、＝O、＝N-O-CH 3、＝N-O-CH 2CH 3、CH 3、OCH 3和OCH 2CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述环A选自
Figure PCTCN2022081686-appb-000021
Figure PCTCN2022081686-appb-000022
所述
Figure PCTCN2022081686-appb-000023
Figure PCTCN2022081686-appb-000024
任选被1、2或3个R c取代，其他变量如本发明所定义。
本发明的一些方案中，上述环A选自
Figure PCTCN2022081686-appb-000025
Figure PCTCN2022081686-appb-000026
Figure PCTCN2022081686-appb-000027
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2022081686-appb-000028
选自
Figure PCTCN2022081686-appb-000029
Figure PCTCN2022081686-appb-000030
Figure PCTCN2022081686-appb-000031
Figure PCTCN2022081686-appb-000032
其他变量如本发明所定义。
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自：
Figure PCTCN2022081686-appb-000033
其中，
Figure PCTCN2022081686-appb-000034
为单键时，R c为F、Cl、Br、I、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个卤素取代；
Figure PCTCN2022081686-appb-000035
为双键时，R c为＝O和＝N-C 1-3烷氧基，所述＝N-C 1-3烷氧基任选被1、2或3个卤素取代；
R 1、R 2、R 3、L和m如本发明所定义。
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自：
Figure PCTCN2022081686-appb-000036
其中，R 1、R 2、R 3、L、m和n如本发明所定义。
本发明还有一些方案是由上述各变量任意组合而来。
本发明还提供了下式所示化合物或其药学上可接受的盐，
Figure PCTCN2022081686-appb-000037
Figure PCTCN2022081686-appb-000038
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自：
Figure PCTCN2022081686-appb-000039
Figure PCTCN2022081686-appb-000040
本发明还提供了上述化合物或其药学上可接受的盐在制备治疗非酒精性脂肪肝炎的药物中的应用。
本发明还提供了下述合成方法：
Figure PCTCN2022081686-appb-000041
其中，
-X-Y-Z-选自环戊烯基、环己烯基、苯基、噻吩基、噻唑基、呋喃基和恶唑基；
R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、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R b取代；
R b分别独立地选自F、Cl、Br和I。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，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接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2022081686-appb-000042
和楔形虚线键
Figure PCTCN2022081686-appb-000043
表示一个立体中心的绝对构型，用直形实 线键
Figure PCTCN2022081686-appb-000044
和直形虚线键
Figure PCTCN2022081686-appb-000045
表示立体中心的相对构型，用波浪线
Figure PCTCN2022081686-appb-000046
表示楔形实线键
Figure PCTCN2022081686-appb-000047
或楔形虚线键
Figure PCTCN2022081686-appb-000048
或用波浪线
Figure PCTCN2022081686-appb-000049
表示直形实线键
Figure PCTCN2022081686-appb-000050
和直形虚线键
Figure PCTCN2022081686-appb-000051
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用波浪线
Figure PCTCN2022081686-appb-000052
连接，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。例如下式(A)表示该化合物以式(A-1)或式(A-2)的单一异构体形式存在或以式(A-1)和式(A-2)两种异构体的混合物形式存在；下式(B)表示该化合物以式(B-1)或式(B-2)的单一异构体形式存在或以式(B-1)和式(B-2)两种异构体的混合物形式存在。下式(C)表示该化合物以式(C-1)或式(C-2)的单一异构体形式存在或以式(C-1)和式(C-2)两种异构体的混合物形式存在。
Figure PCTCN2022081686-appb-000053
除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体 过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。
术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的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。
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 PCTCN2022081686-appb-000054
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 PCTCN2022081686-appb-000055
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 PCTCN2022081686-appb-000056
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。
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 PCTCN2022081686-appb-000057
直形虚线键
Figure PCTCN2022081686-appb-000058
或波浪线
Figure PCTCN2022081686-appb-000059
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 PCTCN2022081686-appb-000060
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 PCTCN2022081686-appb-000061
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 PCTCN2022081686-appb-000062
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 PCTCN2022081686-appb-000063
Figure PCTCN2022081686-appb-000064
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2022081686-appb-000065
仍包括
Figure PCTCN2022081686-appb-000066
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。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，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)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：φ/ω扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；eq代表当量、等量；DCM代表二氯甲烷；PE代表石油醚；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；NBS代表N-溴代丁二酰亚胺；BINAP代表2,2-双(二苯膦基)-1,1-联萘；TEA代表三乙胺；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2022081686-appb-000067
软件命名，市售化合物采用供应商目录名称。
技术效果
本发明化合物具有显著的THRβ活性和选择性，无药物-药物相互作用；本发明化合物具有较高的暴露量以及较好的口服生物利用度，具有优异的药代动力学性质；本发明化合物能够显著降低大鼠血浆LDL-C水平。
附图说明
图1：化合物A与MGL-3196结合模式预测；
图2：化合物B与MGL-3196结合模式预测；
图3：化合物C与MGL-3196结合模式预测；
图4：给药一周后大鼠LDL-C相对给药前大鼠LDL-C变化率。
具体实施方式
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。
计算例1
Figure PCTCN2022081686-appb-000068
分子对接过程：通过使用Maestro(
Figure PCTCN2022081686-appb-000069
版本2017-2)中的GlideSP[1]和默认选项进行的。选择MGL-3196作为对接模板。为了制备蛋白质，使用Maestro[2]的蛋白质制备向导模块添加氢原子，并使用OPLS3力场。对于配体的制备，生成了3D结构，并使用LigPrep进行了能量最小化[3]。使用1Q4X晶体结构中的配体质心生成
Figure PCTCN2022081686-appb-000070
对接网格。通过Induced Fit Docking，约束配体中心5A范围内的氨基酸侧链以B factor范围运动，生成复合物模型。然后除去配体，并在分子对接过程中放置实例化合物。分析蛋白质受体与配体的相互作用类型，然后根据计算得到的docking scrore以及globalStrain值选择并保存了合理对接构象。化合物A-C与MGL-3196结合模式见附图1-3。
[1]Glide,
Figure PCTCN2022081686-appb-000071
LLC,New York,NY,2017.
[2]Maestro,
Figure PCTCN2022081686-appb-000072
LLC,New York,NY,2017.
[3]LigPrep,
Figure PCTCN2022081686-appb-000073
LLC,New York,NY,2017.
结论：本发明化合物与THRβ蛋白具有较好的结合。本发明化合物占据THRβ与甲状腺素的结合口袋，结合口袋是一个由多层α螺旋组成的封闭的、疏水的口袋，口袋上方是由三个精氨酸(Arg282,Arg316和 Arg320)组成的带正电的亚口袋。原参考化合物MGL-3196的6-氮杂尿嘧啶酸性基团结合在这个亚口袋中，氰基与Arg316形成氢键，6-氮杂尿嘧啶的羰基和氮原子与Arg320形成氢键，哒嗪酮的羰基氧与His435形成氢键。中间的苯环、末端的哒嗪酮和异丙基均可以和周围的氨基酸形成疏水相互作用。本发明化合物1,2,4-恶二唑啉-5-酮极性头部结合在这个亚口袋中，同样与三个精氨酸形成氢键，通过酰胺改善二氯苯的角度，更容易与Phe272形成卤键，尾部的羰基或羟基可以通过与His435的相互影响形成氢键，并环有效的提供了疏水相互作用。具有较好的选择性。
实施例1
Figure PCTCN2022081686-appb-000074
合成路线：
Figure PCTCN2022081686-appb-000075
步骤1：化合物WX001-2的合成
在预先干燥的反应瓶中加入WX001-1(5g,33.74mmol)和乙腈(50mL)，加入NBS(6.61g,37.11mmol)，置换氮气三次，置于25℃下搅拌16小时。反应完成后，将反应液直接减压浓缩，浓缩物加入甲基叔丁基醚(200mL)打浆，25℃下打浆30分钟，过滤，收集滤液，滤液经饱和食盐水洗涤(200mL*2)，收集有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到WX001-2。 1H NMR(400MHz,氘代氯仿)δ7.29-7.30(d,J＝2.4Hz,1H),6.55-6.57(d,J＝8.4Hz,1H),4.91(s,1H),2.73-2.74(m,2H),2.66-2.68(m,2H),1.81- 1.84(m,4H)。
步骤2：化合物WX001-3的合成
在预先干燥的反应瓶中加入WX001-2(6.2g,27.30mmol)和DMF(140mL)，0℃下分批加入碳酸铯(22.24g,68.25mmol)，置换氮气三次，0℃下缓慢滴入氯甲基甲醚(3.30g,40.95mmol,3.11mL)，置于0℃下继续搅拌2小时，补加氯甲基甲醚(1.76g,21.84mmol,1.66mL,0.8eq)，继续0℃搅拌1小时。反应完成后，将反应液倒入水(100mL)中淬灭，甲基叔丁基醚萃取水相(100mL*3)，合并有机相，饱和食盐水洗涤(150mL*3)，收集有机相，无水硫酸钠干燥，过滤，减压浓缩得粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1)，得到WX001-3。 1H NMR(400MHz,氘代氯仿)δ7.31-7.33(d,J＝8.4Hz,1H),6.78-6.81(d,J＝8.4Hz,1H),5.18(s,2H),3.48(s,3H),2.68-2.74(m,4H),1.76-1.79(m,4H)。
步骤3：化合物WX001-5的合成
在预先干燥的反应瓶中，加WX001-3(6g,22.13mmol)和THF(60mL)，降温至-78℃，加入正丁基锂(2.5M,9.29mL)，保持-78℃搅拌1小时，加入THF(6mL)和WX001-4(4.71g,22.13mmol)的混合溶液，继续在-78℃下搅拌1小时。反应完成后，将反应液倒入20mL的饱和氯化铵水溶液中，加入乙酸乙酯(20mL*3)萃取，合并有机相，用20mL饱和食盐水洗涤，分液后，有机相用无水硫酸钠干燥，过滤，将滤液减压旋干得到粗品。粗品经柱层析(乙酸乙酯：石油醚＝2％转5％)纯化，得到WX001-5。 1H NMR(400MHz,氘代氯仿)δ7.10(s,2H),6.77-6.79(d,J＝8.4Hz,1H),6.67-6.69(d,J＝8.8Hz,1H),6.13-6.14(d,J＝4.8Hz,1H),5.07-5.11(m,2H),3.46(s,3H),2.92-2.97(m,1H),2.71-2.74(m,2H),2.57-2.62(m,1H),2.26(s,6H),1.88-1.89(d,J＝4.4Hz,1H),1.76-1.83(m,4H)。
步骤4：化合物WX001-6的合成
在预先干燥的反应瓶中，加入WX001-5(8.4g,20.72mmol)和DCM(100mL)，降温至0℃，然后加入三乙基硅烷(3.61g,31.09mmol,4.97mL)，TFA(3.54g,31.09mmol,2.30mL)，反应体系在0℃下搅拌1小时。反应完成后，将反应液倒入50mL饱和碳酸钠水溶液中，加入DCM(50mL*3)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，分液后，有机相用无水硫酸钠干燥，过滤，将滤液减压旋干得到粗品。粗品经柱层析(乙酸乙酯：石油醚＝2％转5％转10％)纯化，得到WX001-6。 1H NMR(400MHz,氘代氯仿)δ7.22(s,2H),6.66-6.68(d,J＝8.4Hz,1H),6.20-6.22(d,J＝8.4Hz,1H),5.13(s,2H),3.73(s,2H),3.46(s,3H),2.73-2.78(m,4H),2.15(s,6H),1.80-1.90(m,4H)。
步骤5：化合物WX001-8的合成
向WX001-7(2.05g,11.30mmol,1.90mL)的THF(40mL)溶液中加入WX001-6(4g,10.27mmol)，碳酸铯(5.02g,15.41mmol)，BINAP(319.87mg,513.71μmol)，醋酸钯(115.33mg,513.71μmol)，在65℃下反应12小时。反应完成后，向反应液中加入水(50mL)，加入乙酸乙酯(50mL*3)萃取，合并有机相，有机相用饱和食盐水(50mL)洗涤，分液后，有机相用无水硫酸钠干燥，过滤，将滤液减压旋干，得 到WX001-8。
步骤6：化合物WX001-9的合成
在预先干燥的反应瓶中，加入WX001-8(4.5g,9.19mmol)和HCl(8mL)，THF(40mL)，25℃下搅拌1小时。反应完成后，向反应液中加入50mL饱和碳酸钠水溶液，加入乙酸乙酯(50mL*3)萃取，合并有机相，有机相用饱和食盐水(50mL)洗涤，分液后，有机相用无水硫酸钠干燥，过滤，将滤液减压旋干。粗品经柱层析(乙酸乙酯：石油醚＝5％转10％转20％)纯化，得到WX001-9。 1H NMR(400MHz,氘代氯仿)δ6.66-6.68(d,J＝8.4Hz,1H),6.46(s,2H),6.31-6.34(d,J＝8.4Hz,1H),5.14(s,2H),3.69(s,2H),3.46(s,3H),2.73-2.80(m,4H),2.09(s,6H),1.80-1.87(m,4H)。
步骤7：化合物WX001-11的合成
在干燥的反应瓶中，依次加入WX001-9(450mg,1.38mmol,1eq)，THF(4mL)，加入TEA(419.75mg,4.15mmol,577.37μL,3eq)和WX001-10(308.01mg,2.07mmol,1.5eq)的THF(3mL)溶液，置换氮气，在20℃下，搅拌1小时。反应完全后，加入水(10mL)稀释，加乙酸乙酯(10mL*3)萃取，分液后收集有机相，依次用饱和食盐水溶液(10mL*3)洗涤，无水硫酸钠干燥，减压浓缩得到粗品。粗品通过薄层层析硅胶板(DCM：MeOH＝20:1)纯化。得到WX001-11。 1H NMR(400MHz,氘代氯仿)δ8.51(br s,1H),7.31(s,2H),6.65(d,J＝8.4Hz,1H),6.24(d,J＝8.4Hz,1H),5.17-5.08(m,2H),3.78-3.73(m,2H),3.48-3.43(m,3H),2.79-2.74(m,4H),2.19-2.14(m,6H),1.88(br d,J＝4.5Hz,2H),1.84-1.79(m,2H)。
步骤8：化合物WX001的合成
在干燥的反应瓶中，依次加入WX001-11(400mg,914.31μmol,1eq)，MeOH(4mL)和HCl(0.8mL,37％纯度)，升温至50℃，搅拌2小时。反应完全后，加入水(10mL)稀释，加乙酸乙酯(10mL*3)萃取，分液后收集有机相。有机相依次用饱和碳酸氢钠水溶液(20mL)，饱和食盐水溶液(10mL*3)洗涤，无水硫酸钠干燥，减压浓缩得到粗品。粗品通过制备高效液相色谱柱纯化(色谱柱:Waters Xbridge BEH C18 100*30mm*10μm；流动相:[水(10mM碳酸氢铵)-乙腈]；乙腈％:25％-55％,10分钟)得到WX001。 1H NMR(400MHz,氘代甲醇)δ7.41(s,2H),6.36(d,J＝8.3Hz,1H),6.05(d,J＝8.3Hz,1H),3.77-3.73(m,2H),2.80-2.74(m,2H),2.69-2.64(m,2H),2.15(s,6H),1.88-1.88(m,1H),1.90-1.85(m,2H),1.82-1.78(m,2H)。MS-ESI m/z:392.5[M-H] -。
实施例2
Figure PCTCN2022081686-appb-000076
合成路线：
Figure PCTCN2022081686-appb-000077
步骤1：化合物WX002-2的合成
在预先干燥的反应瓶中加入WX002-1(1g,5.43mmol,1eq)和氯仿(67mL)，加入四丁基三溴化铵(3.14g,6.51mmol,1.2eq)，置换氮气三次，置于25℃下搅拌3小时。反应完成后，将反应液直接减压浓缩，浓缩物加入乙酸乙酯稀释(30mL)，加入水(30mL)，分液，乙酸乙酯萃取水相(30mL*2)，合并有机相，有机相依次用1N盐酸(30mL)和饱和食盐水(30mL)洗涤，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1)得到WX002-2。 1H NMR(400MHz,氘代氯仿)δ7.35-7.29(m,2H),7.27-7.20(m,5H),6.71-6.66(m,1H),4.74(s,1H),3.96(s,2H)。
步骤2：化合物WX002-3的合成
在预先干燥的反应瓶中加入WX002-2(2.46g,9.35mmol,66.63mL,1eq)和DMF(24.6mL)，置换氮气三次，置于0℃下，加入碳酸铯(13.07g,40.11mmol,4.29eq)，然后滴入氯甲基甲醚(2.15g,26.70mmol,2.03mL,2.86eq)，25℃下搅拌2小时。反应完成后，将反应液冷倒入冰水(30mL)中淬灭，加入乙酸乙 酯(20mL)分液，收集有机相，水相用乙酸乙酯萃取(2*20mL)，合并有机相，用饱和食盐水洗涤(20mL*3)，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转10:1转5:1)得到WX002-3。 1H NMR(400MHz,氘代氯仿)δ7.32-7.27(m,3H),7.25-7.17(m,4H),6.97(d,J＝8.7Hz,1H),5.15(s,2H),3.96(s,2H),3.37(s,3H)。
步骤3：化合物WX002-4的合成
在预先干燥的反应瓶中加入WX002-3(2.34g,7.62mmol,1eq)和THF(23.4mL)，置换氮气三次，置于-78℃下，缓慢滴入正丁基锂(2.5M,3.35mL,1.1eq)，-78℃下搅拌1小时，然后在-78℃下滴入WX001-4(1.46g,6.86mmol,0.9eq)和THF(23.4mL)的混合溶液，-78℃下继续搅拌1小时。反应完成后，将反应液倒入饱和氯化铵溶液中(20mL)，然后加入乙酸乙酯(20mL)分液，收集有机相，水相用乙酸乙酯(20mL*2)萃取，合并有机相，依次用饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1转5:1)得到WX002-4。 1H NMR(400MHz,氘代氯仿)δ7.18-7.14(m,2H),7.12-7.05(m,5H),6.99(s,1H),6.93-6.86(m,2H),6.14(d,J＝4.1Hz,1H),5.23(s,1H),5.05(s,2H),3.89(d,J＝5.6Hz,2H),3.26(s,3H),2.15(s,6H)。
步骤4：化合物WX002-5的合成
在预先干燥的反应瓶中加入WX002-4(2.23g,5.05mmol,1eq)和DCM(23mL)，置换氮气三次，置于0℃下，依次缓慢滴入Et 3SiH(881.28mg,7.58mmol,1.21mL,1.5eq)和三氟乙酸(864.15mg,7.58mmol,561.13μL,1.5eq)，0℃下继续搅拌1小时。反应完成后，将反应液倒入50mL饱和碳酸钠水溶液中，加入DCM(50mL*3)萃取，合并有机相，有机相用饱和食盐水(50mL)洗涤，分液后，有机相用无水硫酸钠干燥，过滤，将滤液减压旋干。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1)得到WX002-5。 1H NMR(400MHz,氘代氯仿)δ7.24(d,J＝7.4Hz,2H),7.21-7.12(m,5H),6.93(d,J＝8.4Hz,1H),6.78(d,J＝1.9Hz,1H),6.72(dd,J＝2.0,8.4Hz,1H),5.10(s,2H),3.93(s,2H),3.89(s,2H),3.34(s,3H),2.19(s,6H)。
步骤5：化合物WX002-6的合成
在预先干燥的反应瓶中加入WX002-5(1.8g,4.23mmol,1eq)，WX001-7(843.62mg,4.65mmol,781.13μL,1.1eq)和二氧六环(36mL)，加入碳酸铯(2.07g,6.35mmol,1.5eq)，置换氮气三次，依次加入Xantphos(195.89mg,338.54μmol,0.08eq)和Pd 2(dba) 3(232.51mg,253.90μmol,0.06eq)，再次置换氮气三次，置于100℃下搅拌16小时。反应完成后，将反应液中加入水(200mL)和乙酸乙酯(200mL)，分液，水相用乙酸乙酯萃取(200mL*3)，合并有机相，饱和食盐水洗涤(300mL*2)，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到WX002-6无需纯化，直接用于下一步。
步骤6：化合物WX002-7的合成
在预先干燥的反应瓶中加入WX002-6(2.22g,4.22mmol,1eq)和THF(25mL)，加入2N盐酸(5.78 mL,2.74eq)，置换氮气三次，置于25℃下搅拌1小时。反应完成后，将反应液经饱和碳酸氢钠溶液(100mL)淬灭，乙酸乙酯萃取水相(100mL*3)，合并有机相，饱和食盐水洗涤(150mL*2)，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转10:1转5:1转2:1)得到WX002-7。 1H NMR(400MHz,氘代氯仿)δ7.24(d,J＝7.2Hz,2H),7.17(d,J＝7.5Hz,3H),6.91(d,J＝8.3Hz,1H),6.86(d,J＝1.8Hz,1H),6.76(dd,J＝1.8,8.3Hz,1H),6.43(s,2H),5.09(s,2H),3.94(s,2H),3.85(s,2H),3.50(br s,2H),3.33(s,3H),2.14(s,6H)。
步骤7：化合物WX002-8的合成
在预先干燥的反应瓶中加入WX001-10(474.51mg,3.20mmol,1.50eq)和THF(8mL)，置换氮气三次，滴入WX002-7(770mg,2.13mmol,1eq)和THF(8mL)的混合溶液，加入TEA(646.65mg,6.39mmol,889.48μL,3eq)，置于25℃下搅拌1小时。反应完成后，将反应液倒入水(30mL)中淬灭，乙酸乙酯萃取水相(30mL*3)，合并有机相，饱和食盐水洗涤(50mL*2)，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到WX002-8无需纯化，直接用于下一步。
步骤8：化合物WX002的合成
在预先干燥的反应瓶中加入WX002-8(1.09g,2.30mmol,1eq)和MeOH(22mL)，加入HCl(12M,4.36mL,22.73eq)，置换氮气三次，置于50℃下搅拌3小时。反应完成后，将反应液用饱和碳酸氢钠溶液调pH至7左右，加乙酸乙酯(30mL*3)萃取，分液后收集有机相，合并有机相，有机相用饱和食盐水溶液(40mL*3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经高效液相色谱纯化(色谱柱:Waters Xbridge BEH C18 250*50mm*10μm；流动相:[水(碳酸氢铵)-乙腈]；乙腈％:25％-65％,10min)得到WX002。 1H NMR(400MHz,氘代甲醇)δ7.36(s,2H),7.25-7.08(m,5H),6.67-6.59(m,3H),3.88(s,2H),3.84(s,2H),2.18(s,6H)；MS-ESI m/z:428.2[M-H] -。
实施例3
Figure PCTCN2022081686-appb-000078
合成路线：
Figure PCTCN2022081686-appb-000079
步骤1：化合物WX003-2的合成
在预先干燥的反应瓶中加入氢化钠(5.82g,145.46mmol,60％含量,3eq)和DMSO(35mL)，置换氮气三次，置于75℃下搅拌10分钟。然后置于25℃下，缓慢加入甲基三苯基碘化瞵(39.20g,96.98mmol,2eq)的DMSO(25mL)溶液，25℃下搅拌20分钟。在25℃下滴入WX003-1(10g,48.49mmol,1eq)的DMSO(10mL)溶液，升温至65℃继续搅拌12小时。反应完成后，将反应液倒入冰水(200mL)中，加入甲基叔丁基醚(200mL)分液，收集有机相，水相用甲基叔丁基醚萃取(200mL*2)，合并有机相，用饱和 食盐水洗涤(600mL*3)，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗产品通过自动过柱机分离(石油醚：乙酸乙酯＝1:0至5:1)纯化得到WX003-2。 1H NMR(400MHz,氘代氯仿)δ7.14-7.06(m,1H),6.99(d,J＝8.1Hz,1H),6.81(d,J＝7.5Hz,1H),5.94(d,J＝2.4Hz,1H),5.33-5.27(m,1H),5.23(s,2H),3.52(s,2H),3.56-3.48(m,1H),2.90-2.83(m,1H),2.87(t,J＝6.4Hz,1H),2.56-2.50(m,1H),2.57-2.48(m,1H),1.89(quin,J＝6.4Hz,1H),1.96-1.84(m,1H)。
步骤2：化合物WX003-3的合成
在氮气环境下，在预先干燥的氢化瓶中依次加入乙酸乙酯(300mL)和Pd/C(2.32g,20.56mmol,10％含量,1eq)，加入WX003-2(4.2g,20.56mmol,1eq)，置换氢气三次，置于氢气压力为15psi环境中，25℃搅拌2小时。反应完成后，将反应液直接经硅藻土过滤，滤液减压浓缩得到WX003-3。 1H NMR(400MHz,氘代氯仿)δ7.09-7.02(m,1H),6.90(d,J＝8.1Hz,1H),6.76(d,J＝7.6Hz,1H),5.23(s,2H),3.51(s,2H),3.57(s,1H),3.30-3.16(m,1H),2.88-2.67(m,2H),1.93-1.70(m,3H),1.96-1.64(m,1H),1.25(d,J＝7.0Hz,3H)。
步骤3：化合物WX003-4的合成
在预先干燥的反应瓶中加入WX003-3(4g,19.39mmol,1eq)和THF(40mL)，加入NBS(3.45g,19.39mmol,1eq)，置换氮气三次，置于-78℃下搅拌0.5小时。反应完成后，将反应液中加入水(100mL)和乙酸乙酯(100mL)分液，收集有机相，水相用乙酸乙酯萃取(100mL*2)，合并有机相，用饱和食盐水洗涤(400mL*3)，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗产品通过自动过柱机分离(石油醚：乙酸乙酯＝1:0至10:1)纯化得到WX003-4。 1H NMR(400MHz,氘代氯仿)δ7.36-7.30(m,1H),6.83(d,J＝8.6Hz,1H),5.20(d,J＝0.9Hz,2H),3.55-3.46(m,1H),3.49(s,2H),3.29-3.18(m,1H),2.95-2.83(m,1H),2.62-2.48(m,1H),1.92-1.79(m,2H),1.76-1.67(m,2H),1.23(d,J＝7.0Hz,3H)。
步骤4：化合物WX003-5的合成
在预先干燥的反应瓶里加入WX003-4(4.9g,17.18mmol,1eq)和THF(50mL)，然后置于-78℃缓慢滴入正丁基锂(2.5M,7.56mL,1.1eq)，搅拌1小时，然后缓慢滴入WX001-4(3.29g,15.46mmol,0.9eq)的THF(25mL)溶液，置于-78℃搅拌1小时。反应完成后，将反应液倒入饱和氯化铵溶液中(200mL)，然后加入乙酸乙酯(200mL)分液，收集有机相，水相用乙酸乙酯(200mL*2)萃取，合并有机相，依次用饱和食盐水(600mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗产品通过自动过柱机分离(石油醚:乙酸乙酯＝1:0至10:1至5:1)纯化得到WX003-5。 1H NMR(400MHz,氘代氯仿)δ7.19(d,J＝8.5Hz,2H),6.94(d,J＝8.6Hz,1H),6.86-6.74(m,1H),6.21(dd,J＝4.4,10.0Hz,1H),5.27-5.14(m,2H),3.57-3.43(m,3H),3.34-3.19(m,1H),3.10-3.00(m,1H),2.92-2.72(m,1H),2.47-2.35(m,1H),2.26(d,J＝6.9Hz,6H),1.92-1.84(m,1H),1.79-1.69(m,2H),1.29-1.22(m,3H)。
步骤5：化合物WX003-6的合成
在预先干燥的反应瓶里加入WX003-5(2.45g,5.84mmol,1eq)和DCM(25mL)，置于-10℃然后加入 Et 3SiH(1.02g,8.76mmol,1.40mL,1.5eq)和TFA(999.25mg,8.76mmol,648.86μL,1.5eq)，置于-10℃搅拌1小时。反应完成后，将反应液用饱和碳酸氢钠水溶液调pH至6-7，加入水(30mL)和二氯甲烷(30mL)分液，收集有机相，水相用二氯甲烷萃取(30mL*2)，合并有机相，有机相用饱和食盐水洗涤(150mL*3)，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗产品通过自动过柱机分离(石油醚：乙酸乙酯＝1:0至10:1至5:1)纯化得到WX003-6。 1H NMR(400MHz,氘代氯仿)δ7.23(s,1H),7.25-7.20(m,1H),6.69(d,J＝8.6Hz,1H),6.21(d,J＝8.4Hz,1H),5.16(s,2H),3.82-3.62(m,2H),3.48(s,3H),3.28(td,J＝3.5,6.8Hz,1H),2.93-2.83(m,1H),2.67-2.57(m,1H),2.15(s,6H),1.92(br dd,J＝4.8,10.1Hz,2H),1.78(td,J＝4.5,9.4Hz,2H),1.27(d,J＝7.0Hz,3H)。
步骤6：化合物WX003-7的合成
在预先干燥的反应瓶里加入WX003-6(1.9g,4.71mmol,1eq)和二氧六环(20mL)，然后加入碳酸铯(2.30g,7.07mmol,1.5eq)和WX001-7(939.07mg,5.18mmol,869.51μL,1.1eq)，置换氮气三次，加入Xantphos(218.05mg,376.84μmol,0.08eq)和Pd 2(dba) 3(258.81mg,282.63μmol,0.06eq)，再次置换氮气，置于100℃搅拌12小时。反应完成后，将反应液冷却至室温，加入水(50mL)和乙酸乙酯(50mL)分液，收集有机相，水相用乙酸乙酯萃取(50mL*2)，合并有机相，有机相用饱和食盐水洗涤(300mL*3)，无水硫酸钠干燥，过滤，滤液减压浓缩得到WX003-7，粗品直接用于下一步。
步骤7：化合物WX003-8的合成
在预先干燥的反应瓶里加入WX003-7(2.3g,4.57mmol,1eq)和THF(25mL)，加入盐酸(2N,2.28mL,1eq)，置于25℃搅拌1小时。反应完成后，将反应液用饱和碳酸氢钠水溶液调pH至6-7，加入水(30mL)和乙酸乙酯(30mL)分液，收集有机相，水相用乙酸乙酯萃取(30mL*2)，合并有机相，有机相用饱和食盐水洗涤(120mL*3)，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗产品通过自动过柱机分离(石油醚：乙酸乙酯＝1:0至10:1至5:1至3:1)纯化得到WX003-8。 1H NMR(400MHz,氘代氯仿)δ6.68(d,J＝8.4Hz,1H),6.53(s,2H),6.30(d,J＝8.5Hz,1H),5.15(s,2H),3.81-3.57(m,2H),3.54-3.41(m,3H),3.36-3.21(m,1H),2.96-2.82(m,1H),2.70-2.55(m,1H),2.22-2.02(m,6H),1.99-1.85(m,2H),1.84-1.69(m,2H),1.27(d,J＝7.0Hz,3H)。
步骤8：化合物WX003-9-1和WX003-9-2的合成
将WX003-8(250mg,736.44μmol,1eq)进行手性分离，分离方法：(色谱柱:DAICEL CHIRALCEL OJ(250mm*30mm,10μm)；A:食品级超临界二氧化碳；B:流动相:[0.1％氨水+异丙醇]；B％:35％-35％,10min)得到WX003-9-1和WX003-9-2。WX003-9-1保留时间为3.671分钟，WX003-9-2保留时间为4.112分钟，分析方法(仪器:CAS-TJ-ANA-SFC-C(Waters UPCC with PDA)；色谱柱:Chiralpak OJ-3,150×4.6mm I.D.,3μm；流动相：A:食品级超临界二氧化碳；B:异丙醇(0.1％异丙胺，体积比)；梯度：B含量在3.5分钟内从10％升高到50％并保持1分钟，然后在0.5分钟内从50％升高到10％；流速:2.5mL/min；柱温：35℃；检测波 长：220nm；系统背压:100bar)。WX003-9-1： 1H NMR(400MHz,氘代氯仿)δ6.68(d,J＝8.4Hz,1H),6.47(s,2H),6.32(d,J＝8.5Hz,1H),5.15(s,2H),3.79-3.57(m,2H),3.47(s,3H),3.32-3.23(m,1H),2.93-2.84(m,1H),2.62(ddd,J＝7.3,10.6,17.6Hz,1H),2.09(s,6H),1.95-1.86(m,2H),1.80-1.74(m,2H),1.30-1.25(d,J＝7.0Hz,3H)。WX003-9-2： 1H NMR(400MHz,氘代氯仿)δ6.68(d,J＝8.5Hz,1H),6.47(s,2H),6.32(d,J＝8.5Hz,1H),5.15(s,2H),3.77-3.58(m,2H),3.47(s,3H),3.32-3.23(m,1H),2.94-2.84(m,1H),2.62(ddd,J＝7.4,10.5,17.5Hz,1H),2.09(s,6H),1.96-1.87(m,2H),1.81-1.74(m,2H),1.27(d,J＝7.0Hz,3H)。
步骤9：化合物WX003-10-1和WX003-10-2的合成
在干燥的反应瓶中，加入WX001-10(46.59mg,313.72μmol,1.5eq)的THF(1mL)溶液，将WX003-9-1(71mg,209.15μmol,1eq)用THF(1mL)溶解后加入反应瓶中，加入TEA(63.49mg,627.45μmol,87.33μL,3eq)，置于20℃搅拌1小时。反应完成后，将反应液加入水(5mL)中，加入乙酸乙酯(5mL)萃取分液，收集有机相，水相用乙酸乙酯(5mL*2)萃取，合并有机相，有机相依次用饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到WX003-10-1。
在干燥的反应瓶中，加入WX001-10(46.59mg,313.72μmol,1.5eq)的THF(1mL)溶液，将WX003-9-2(71mg,209.15μmol,1eq)用THF(1mL)溶解后加入反应瓶中，加入TEA(63.49mg,627.45μmol,87.33μL,3eq)，置于20℃搅拌1小时。反应完成后，将反应液加入水(5mL)中，加入乙酸乙酯(5mL)萃取分液，收集有机相，水相用乙酸乙酯(5mL*2)萃取，合并有机相，有机相依次用饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到WX003-10-2。
步骤10：化合物WX003和WX004的合成
在预先干燥的反应瓶里加入WX003-10-1(100.00mg,221.48μmol,1eq)和DMA(1mL)，然后加入HCl(0.2mL,37％纯度)，置换氮气三次，置于50℃搅拌6小时。反应完成后，将反应液加入水(10mL)稀释，用饱和碳酸氢钠溶液调pH至中性，加入乙酸乙酯(10mL*3)萃取，分液后收集有机相，合并有机相，有机相用饱和食盐水(50mL*3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到产物粗品。粗产品通过高效液相色谱纯化(色谱柱:Waters Xbridge BEH C18 100*30mm*10μm；流动相:[水(碳酸氢铵)-乙腈]；B％:25％-55％,8分钟)得到WX003。 1H NMR(400MHz,氘代二甲基亚砜)δ10.34(br s,1H),8.93(s,1H),7.45(s,2H),6.40(d,J＝8.3Hz,1H),5.96(d,J＝8.3Hz,1H),3.70(s,1H),3.62(s,1H),3.10(td,J＝3.5,6.8Hz,1H),2.88-2.79(m,1H),2.58(br s,1H),2.09(s,6H),1.89-1.78(m,2H),1.68(br d,J＝3.1Hz,2H),1.18(d,J＝6.9Hz,3H)；MS-ESI m/z:406.2[M-H] -。
在预先干燥的反应瓶里加入WX003-10-2(100.00mg,221.48μmol,1eq)和DMA(1mL)，然后加入HCl(0.2mL,37％纯度)，置换氮气三次，置于50℃搅拌6小时。反应完成后，将反应液加入水(10mL)稀释，用饱和碳酸氢钠溶液调pH至中性，加入乙酸乙酯(10mL*3)萃取，分液后收集有机相，合并有机相，有机相用饱和食盐水(50mL*3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到产物粗品。粗产品 通过高效液相色谱纯化(色谱柱:Waters Xbridge BEH C18 100*30mm*10μm；流动相:[A:水(碳酸氢铵)-B:乙腈]；乙腈％:25％-55％,8min)得到WX004。 1H NMR(400MHz,氘代二甲基亚砜)δ10.23(s,1H),8.92(s,1H),7.45(s,2H),6.39(d,J＝8.3Hz,1H),5.95(d,J＝8.3Hz,1H),3.69(s,1H),3.60(br s,1H),3.08(td,J＝3.5,6.8Hz,1H),2.87-2.78(m,1H),2.62-2.53(m,1H),2.07(s,6H),1.89-1.77(m,2H),1.66(br d,J＝3.3Hz,2H),1.17(d,J＝6.9Hz,3H)；MS-ESI m/z:406.2[M-H] -。
实施例4
Figure PCTCN2022081686-appb-000080
合成路线：
Figure PCTCN2022081686-appb-000081
步骤1：化合物WX005的合成
在预先干燥的反应瓶中加入WX001(50mg,127.09μmol,1eq)和THF(2.8mL)，加入TEA(0.28mL)，置换氮气三次，置于-78℃下加入一氯化碘(24.76mg,152.50μmol,7.78μL,1.20eq)，-78℃下搅拌2小时。反应完成后，将反应液经2N盐酸调节pH至6～7，饱和硫代硫酸钠溶液洗涤(10mL*2)，收集有机相，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经高效液相色谱纯化(色谱柱:Phenomenex Luna 80*30mm*3μm；流动相:[水(HCl)-乙腈]；乙腈％:60％-80％,8min)得到WX005。 1H NMR(400MHz,氘代甲醇)δ7.44(s,2H),6.51(s,1H),3.76(s,2H),2.81-2.66(m,4H),2.17(s,6H),1.91-1.77(m,4H)；MS-ESI m/z:518.0[M-H] -。
实施例5
Figure PCTCN2022081686-appb-000082
合成路线：
Figure PCTCN2022081686-appb-000083
步骤1：化合物WX006-3的合成
在预先干燥的反应瓶中加入WX006-1(5.5g,38.15mmol,13.75mL,1eq)和异丙醇(250mL)，加入WX006-2(12.14g,41.96mmol,1.1eq)和1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(20.27g,57.22mmol,1.5eq)，置换氮气三次，置于80℃下搅拌12小时。反应完毕后，将反应液直接减压浓缩得到粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转50:1)得到WX006-3。 1H NMR(400MHz,氘代氯仿)δ8.21(d,J＝8.19Hz,1H),7.80(d,J＝8.19Hz,1H),7.46-7.55(m,2H),7.39(dd,J＝5.20,8.99Hz,1H),7.28-7.32(m,1H),5.48(d,J＝4.40Hz,1H)。 19F NMR(377MHz,氘代氯仿)δ-145.48(s,1F)。
步骤2：化合物WX006-4的合成
在预先干燥的反应瓶中加入WX006-3(3.0g,18.50mmol,1eq)和乙醇(100mL)，加入钯碳(1g,18.50mmol,10％含量,1eq)，置换氢气三次，置于氢气(373.70mg,185.00mmol,10eq)50psi环境中，60℃搅拌16小时。反应完毕后，将反应液直接经硅藻土过滤，滤液减压浓缩得到粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0)得到WX006-4。 1H NMR(400MHz,氘代氯仿)δ6.78-6.91(m,1H),6.58(dd,J＝5.38,8.38Hz,1H),5.03(d,J＝5.13Hz,1H),2.71(s,4H),1.75-1.81(m,4H)。 19F NMR(376MHz,氘代氯仿)δ-145.84 (s,1F)。
步骤3：化合物WX006-5的合成
在预先干燥的反应瓶中加入WX006-4(4g,24.07mmol,1eq)和乙腈(80mL)，加入NBS(4.71g,26.48mmol,1.1eq)，置换氮气三次，置于25℃下搅拌2小时。反应完毕后，将反应液中加入水(150mL)和乙酸乙酯(150mL)分液，收集有机相，水相用乙酸乙酯萃取(200mL*2)，合并有机相，用饱和食盐水洗涤(300mL*3)，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转50:1)得到WX006-5。 1H NMR(400MHz,氘代氯仿)δ7.17(d,J＝9.51Hz,1H),5.04(s,1H),2.69(td,J＝5.85,15.82Hz,4H),1.73-1.85(m,1H),1.77(d,J＝5.25Hz,3H)。 19F NMR(377MHz,氘代二甲基亚砜)δ0.00(s,1F)。
步骤4：化合物WX006-6的合成
在预先干燥的反应瓶中加入WX006-5(6g,24.48mmol,1eq)和DMF(120mL)，置换氮气三次，置于0℃下，加入碳酸铯(23.93g,73.44mmol,3eq)，然后滴入氯甲醚(3.94g,48.96mmol,3.72mL,2eq)，25℃下搅拌2小时。反应完毕后，将反应液冷倒入冰水(100mL)中，加入乙酸乙酯(100mL)分液，收集有机相，水相用乙酸乙酯萃取(100mL*2)，合并有机相，用饱和食盐水洗涤(100mL*3)，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗产品经薄层色谱硅胶板纯化(石油醚：乙酸乙酯＝10:1)得到WX006-6。 1H NMR(400MHz,氘代氯仿)δ7.20(d,J＝10.38Hz,1H),5.11(s,2H),3.53-3.65(m,3H),2.78(t,J＝6.07Hz,2H),2.67(t,J＝6.00Hz,2H),1.70-1.82(m,4H)。 19F NMR(376MHz,氘代氯仿)δ-132.23(s,1F)。
步骤5：化合物WX006-7的合成
在预先干燥的反应瓶中加入WX006-6(1g,3.46mmol,1eq)和四氢呋喃(10mL)，置换氮气三次，置于-78℃下，缓慢滴入正丁基锂(2.5M,1.52mL,1.1eq)，-78℃下搅拌1小时，然后在-78℃下滴入WX001-4(663.22mg,3.11mmol,0.9eq)和四氢呋喃(10mL)的混合溶液，-78℃下继续搅拌1小时。反应完毕后，将反应液倒入饱和氯化铵溶液中(50mL)，然后加入乙酸乙酯(50mL)分液，收集有机相，水相用乙酸乙酯(50mL*2)萃取，合并有机相，依次用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转10:1转5:1)得到WX006-7。 1H NMR(400MHz,氘代氯仿)δ7.19(s,2H),6.88(d,J＝12.88Hz,1H),6.17(d,J＝3.50Hz,1H),5.13(s,2H),3.58(s,3H),2.80(d,J＝3.00Hz,2H),2.72-2.76(m,1H),2.58(d,J＝17.64Hz,1H),2.38(s,1H),2.34(s,1H),2.25(s,6H),1.92(d,J＝4.00Hz,1H),1.79(d,J＝5.63Hz,1H)。 19F NMR(376MHz,氘代氯仿)δ-134.26(s,1F)。
步骤6：化合物WX006-8的合成
在预先干燥的反应瓶中加入WX006-7(800mg,1.89mmol,1eq)，WX001-7(376.75mg,2.08mmol,348.84μL,1.1eq)和1,4-二氧六环(16mL)，加入碳酸铯(923.62mg,2.83mmol,1.5eq)，置换氮气三次，依次加入Xantphos(87.48mg,151.19μmol,0.08eq)和Pd 2(dba) 3(103.83mg,113.39μmol,0.06eq)，再次置换 氮气三次，置于100℃下搅拌16小时。反应完毕后，将反应液直接经硅藻土过滤，滤液减压浓缩得到粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1转3:1)得到WX006-8。 1H NMR(400MHz,氘代氯仿)δ7.84-7.92(m,1H),7.87(d,J＝6.90Hz,1H),7.62(d,J＝6.90Hz,2H),7.48-7.54(m,3H),7.32-7.38(m,3H),7.21(d,J＝8.41Hz,2H),6.85(d,J＝13.55Hz,1H),6.11(s,1H),5.13(s,2H),3.59(s,3H),2.79(d,J＝7.28Hz,3H),2.62(s,1H),2.12(s,6H),1.81(dd,J＝3.39,6.27Hz,2H),1.69(d,J＝5.14Hz,1H),1.55(s,1H)。 19F NMR(376MHz,氘代氯仿)δ-133.29(s,1F)。
步骤7：化合物WX006-9的合成
在预先干燥的反应瓶中加入WX006-8(600mg,1.15mmol,1eq)和四氢呋喃(12mL)，加入盐酸(2M,572.92μL,1eq)，置换氮气三次，置于25℃下搅拌1小时。反应完毕后，将反应液经饱和碳酸氢钠溶液调节pH至7左右，乙酸乙酯萃取水相(20mL*3)，合并有机相，饱和食盐水洗涤(20mL*2)，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经薄层色谱硅胶板纯化(石油醚：乙酸乙酯＝1:1)得到WX006-9。 1H NMR(400MHz,氘代氯仿)δ7.05(d,J＝13.13Hz,1H),6.47(s,2H),6.12(s,1H),5.12(s,2H),3.59(s,3H),2.78(d,J＝5.75Hz,2H),2.25-2.32(m,2H),2.23-2.24(m,1H),2.19(s,6H),1.66-1.76(m,4H)。 19F NMR(377MHz,氘代氯仿)δ-134.74(s,1F)。
步骤8：化合物WX006-10的合成
在预先干燥的反应瓶中加入MeOH(30mL)，冰醋酸(25mL)和湿Pd/C(50mg,10％含量)，加入WX006-9(500mg,1.39mmol,1eq)，置换氢气三次，置于氢气压力50psi环境下，25℃搅拌16小时。反应完成后，将反应液使用硅藻土过滤，减压浓缩得到产物粗品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝20：1转10：1)得到WX006-10。 1H NMR(400MHz,氘代氯仿)δ6.47-6.37(m,2H),6.15(d,J＝13.0Hz,1H),5.10-5.06(m,2H),3.67-3.62(m,2H),3.59-3.56(m,3H),2.81(br t,J＝6.1Hz,2H),2.72(br t,J＝6.1Hz,2H),2.08(s,6H),1.90-1.84(m,2H),1.82-1.77(m,2H)。
步骤9：化合物WX006-11的合成
在干燥的反应瓶中，加入WX006-10的THF(2mL)溶液，置换氮气三次，将WX001-10用THF(2mL)溶解后加入反应瓶中，加入TEA(150.27mg,1.49mmol,206.70μL,3eq)，置于20℃搅拌1小时。反应完成后，将反应液加入水(5mL)中，加入乙酸乙酯(5mL)萃取分液，收集有机相，水相用乙酸乙酯(5mL*2)萃取，合并有机相，有机相依次用饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤，减压旋干得到WX006-11粗产品，直接用于下一步。
步骤10：化合物WX006的合成
在预先干燥的反应瓶中加入WX006-11和MeOH(5mL)，加入HCl(12N,60.19μL,1eq)，置换氮气三次，置于50℃下搅拌0.5小时。反应完成后，将反应液经饱和碳酸氢钠溶液淬灭，用乙酸乙酯(30mL)稀释，加入水(30mL)分液，收集有机相，乙酸乙酯萃取水相(30mL*3)，合并有机相，饱和食盐水洗 涤(30mL*2)，收集有机相，无水硫酸钠干燥，过滤，减压浓缩得粗产品。粗产品经HPLC高相液相色谱纯化(色谱柱:Phenomenex luna C18 80*40mm*3μm；流动相:[水(HCl)-乙腈]；乙腈％:49％-69％,7min)，得到WX006。 1H NMR(400MHz,氘代甲醇)δ7.42(s,2H),5.89(d,J＝12.3Hz,1H),3.77(s,2H),2.76-2.67(m,4H),2.17(s,6H),1.90-1.77(m,4H)；MS-ESI m/z:410.1[M-H] -。
实施例6
Figure PCTCN2022081686-appb-000084
合成路线：
Figure PCTCN2022081686-appb-000085
步骤1：化合物WX007-2的合成
在氮气环境下，在预先干燥的两个氢化瓶中分别依次加入EtOH(1000mL)和Pd/C(10g,312.17mmol,10％含量,1eq)，分别加入WX007-1(50g,312.17mmol,1eq)，置换氢气三次，置于氢气压力为50psi的环境中，60℃搅拌4小时。反应完成后，将反应液直接经硅藻土过滤，滤液减压浓缩得到粗产品。粗产品 经柱层析纯化(石油醚：乙酸乙酯＝1:0转10:1转5:1)得到WX007-2。 1H NMR(400MHz,氘代氯仿)δ12.43(s,1H),7.39-7.35(m,1H),6.81-6.80(m,1H),6.73-6.71(m,1H),2.95-2.92(m,2H),2.71-2.69(m,2H),2.15-2.08(m,2H)。
步骤2：化合物WX007-3的合成
在预先干燥的反应瓶中加入WX007-2(10g,61.66mmol,1eq)，甲氧基胺盐酸盐(5.66g,67.82mmol,1.1eq)和EtOH(100mL)，加入碳酸钾(25.56g,184.97mmol,3eq)，置换氮气三次，置于60℃下搅拌12小时。反应完成后，将反应液冷却至室温，加入水(200mL)，乙酸乙酯萃取水相(200mL*3)，合并有机相，有机相经饱和食盐水洗涤(300mL*1)，无水硫酸钠干燥，过滤，滤液减压浓缩得粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1转5:1)得到WX007-3。 1H NMR(400MHz,氘代氯仿)δ11.33(s,1H),7.17-7.13(m,1H),6.82-6.80(d,1H),6.68-6.66(d,1H),4.00(s,3H),2.83-2.76(m,4H),1.90-1.83(m,2H)。
步骤3：化合物WX007-4的合成
在预先干燥的反应瓶中加入WX007-3(11g,57.52mmol,1eq)和DCM(200mL)，加入2，6-二甲基吡啶(24.65g,230.09mmol,26.80mL,4eq)，加入三异丙基硅基(三氟甲基硫酸)酯(52.88g,172.57mmol,46.38mL,3eq)，置换氮气三次，置于25℃下搅拌6小时。反应完成后，将反应液中加入水(200mL)淬灭，二氯甲烷萃取水相(500mL*3)，合并有机相，有机相用饱和食盐水洗涤(550mL*2)，无水硫酸钠干燥，过滤，滤液减压浓缩得粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1转5:1)得到WX007-4。 1H NMR(400MHz,氘代氯仿)δ7.07-7.03(m,1H),6.77-6.72(m,2H),3.97(s,3H),2.76-2.72(m,2H),2.61-2.58(m,2H),1.75-1.70(m,2H),1.35-1.29(m,3H),1.28-1.10(m,18H)。
步骤4：化合物WX007-5的合成
在预先干燥的反应瓶中加入WX007-4(4g,11.51mmol,1eq)和乙腈(40mL)，加入NBS(2.25g,12.66mmol,1.1eq)，置换氮气三次，置于25℃下搅拌2小时。反应完成后，将反应液中加入水(50mL)淬灭，乙酸乙酯萃取水相(60mL*3)，合并有机相，饱和食盐水洗涤(100mL*2)，收集有机相，无水硫酸钠干燥，过滤，减压浓缩得粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1)得到WX007-5。 1H NMR(400MHz,氘代氯仿)δ7.32-7.30(m,1H),6.67-6.65(d,1H),3.97(s,3H),2.75-2.71(m,4H),1.75-1.72(m,2H),1.33-1.25(m,3H),1.11-1.09(m,18H)。
步骤5：化合物WX007-6的合成
在预先干燥的反应瓶中加入WX007-5(0.5g,1.17mmol,1eq)和THF(5mL)，置换氮气三次，置于-78℃下，缓慢滴入正丁基锂(2.5M,515.87μL,1.1eq)，-78℃下搅拌1小时，然后在-78℃下滴入WX001-4(249.81mg,1.17mmol,1eq)和THF(5mL)的混合溶液，-78℃下继续搅拌1小时。反应完成后，将反应液倒入饱和氯化铵溶液中(5mL)淬灭，然后加入乙酸乙酯(5mL)分液，收集有机相，水相用乙酸乙 酯(2*5mL)萃取，合并有机相，有机相依次用饱和食盐水(2*5mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1)得到WX007-6。 1H NMR(400MHz,氘代二甲基亚砜)δ7.18(s,3H),6.95-6.93(m,1H),6.70-6.68(m,1H),6.24-6.23(d,1H),3.97(s,3H),2.74-2.70(m,3H),2.63(m,1H),2.23(s,6H),1.70-1.66(m,2H),1.30-1.26(m,3H),1.24-1.08(m,18H)。
步骤6：化合物WX007-7的合成
在预先干燥的反应瓶中加入WX007-6(470mg,838.33μmol,1eq)和DCM(10mL)，置换氮气三次，置于0℃下，依次缓慢滴入Et 3SiH(146.22mg,1.26mmol,200.85μL,1.5eq)和TFA(143.38mg,1.26mmol,93.10μL,1.5eq)，0℃下继续搅拌1小时。反应完成后，将反应液倒入(30mL)饱和碳酸钠水溶液中，加入DCM(30mL*3)萃取，合并有机相，有机相用饱和食盐水(30mL)洗涤，分液后，有机相用无水硫酸钠干燥，过滤，将滤液减压浓缩得到粗品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1)得到WX007-7。 1H NMR(400MHz,氘代二甲基亚砜)δ11.25(s,1H),7.30(s,2H),6.58-6.56(m,1H),6.23-6.21(m,1H),3.96(s,3H),3.78(s,2H),2.88-2.80(m,4H),2.11(s,6H),1.88-1.85(m,2H)。
步骤7：化合物WX007-8的合成
在预先干燥的反应瓶中加入WX007-7(320mg,824.11μmol,1eq)和DCM(6.4mL)，加入2，6-二甲基吡啶(353.21mg,3.30mmol,383.93μL,4eq)，加入三异丙基硅基(三氟甲基硫酸)酯(757.57mg,2.47mmol,664.54μL,3eq)，置换氮气三次，置于25℃下搅拌1小时。反应完成后，将反应液中加入水(200mL)淬灭，二氯甲烷萃取水相(500mL*3)，合并有机相，有机相依次用饱和食盐水洗涤(550mL*2)，无水硫酸钠干燥，过滤，滤液减压浓缩得粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1转5:1)得到WX007-8。 1H NMR(400MHz,氘代二甲基亚砜)δ7.21(s,2H),6.57-6.55(d,1H),6.25-6.23(m,1H),3.97(s,3H),3.80(s,2H),2.78-2.69(m,4H),2.13(s,6H),1.82-1.80(m,2H),1.27-1.21(m,3H),1.08(m,18H)。
步骤8：化合物WX007-9的合成
在预先干燥的反应瓶中加入WX007-8(518mg,951.09μmol,1eq)，WX001-7(189.61mg,1.05mmol,175.56μL,1.1eq)和二氧六环(10mL)，加入碳酸铯(464.83mg,1.43mmol,1.5eq)，置换氮气三次，依次加入Xantphos(44.03mg,76.09μmol,0.08eq)和Pd 2(dba) 3(52.26mg,57.07μmol,0.06eq)，再次置换氮气三次，置于100℃下搅拌6小时。反应完成后，将反应液直接经硅藻土过滤，滤液减压浓缩得到WX007-9。
步骤9：化合物WX007-10的合成
在预先干燥的反应瓶中加入WX007-9(615mg,953.55μmol,1eq)和THF(10mL)，加入HCl(2N,1.91mL,4eq)，置换氮气三次，置于25℃下搅拌1小时。反应完成后，将反应液经饱和碳酸氢钠溶液(100mL)淬灭，乙酸乙酯萃取水相(100mL*3)，合并有机相，饱和食盐水洗涤(150mL*2)，收集有机相，无水硫 酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转10:1转5:1转2:1)得到WX007-10。 1H NMR(400MHz,氘代氯仿)δ6.64-6.62(m,1H),6.47-6.45(m,3H),3.99(s,3H),3.72(s,2H),3.53(s,1H),2.89-2.83(m,4H),2.08(s,6H),1.96-1.95(m,2H)。
步骤10：化合物WX007的合成
在干燥的反应瓶中，加入WX001-10(32.96mg,221.94μmol,0.8eq)的THF(1mL)溶液，将WX007-10(90mg,277.42μmol,1eq)用THF(1mL)溶解后加入反应瓶中，加入TEA(84.22mg,832.27μmol,115.84μL,3eq)，置于20℃搅拌1小时。反应完成后，将反应液加入水(5mL)中，加入乙酸乙酯(5mL)萃取分液，收集有机相，水相用乙酸乙酯(5mL*2)萃取，合并有机相，有机相依次用饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到产物粗品。粗品通过高效液相色谱纯化(色谱柱:Waters Xbridge BEH C18 100*30mm*10μm；流动相:[水(碳酸氢铵)-乙腈]；乙腈％:35％-55％,8min)得到机分液，机分液萃取，收集有机相，有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩得到WX007。 1H NMR(400MHz,氘代甲醇)δ7.41(s,2H),6.51(d,J＝8.5Hz,1H),6.32(d,J＝8.6Hz,1H),3.98(s,3H),3.85(s,2H),2.92-2.85(m,4H),2.16(s,6H),1.97-1.91(m,2H)；MS-ESI m/z:437.2[M+H] +。
实施例7
Figure PCTCN2022081686-appb-000086
合成路线：
Figure PCTCN2022081686-appb-000087
步骤1：化合物WX008-4的合成
在预先干燥的反应瓶中加入WX007-2(113g,696.74mmol,1eq)和DMF(1050mL)，加入WX008-3(214.50g,1.25mol,148.96mL,1.8eq)和碳酸钾(173.33g,1.25mol,1.8eq)，置换氮气三次，25℃下搅拌16小时。反应完成后，在体系中加入水(1000mL)，然后加入甲基叔丁基醚(500mL*3)萃取，分液后合并有机相。用饱和食盐水(500mL*2)洗涤有机相，无水硫酸钠干燥，过滤，50℃下使用水泵减压浓缩得到淡黄色固体的粗品。粗产品通过快速柱层析分离(硅胶目数：100-200目；石油醚:乙酸乙酯＝1:0至100:2)纯化得到WX008-4。
步骤2：化合物WX008-5的合成
在预先干燥的反应瓶中加入WX008-4(90g,356.71mmol,1eq)和MeOH(900mL)，置于0℃下缓慢加入硼氢化钠(16.19g,428.05mmol,1.2eq)，0℃下继续搅拌0.5小时。反应完成后，将反应液经饱和氯化铵溶液(900mL)淬灭，加入乙酸乙酯(900mL)，分液，乙酸乙酯萃取水相(900mL*2)，合并有机相， 饱和食盐水洗涤(900mL*2)，收集有机相，无水硫酸钠干燥，过滤，减压浓缩。粗产品通过快速柱层析分离(石油醚:乙酸乙酯＝1:0至100:1)纯化得到WX008-5。 1H NMR(400MHz,氘代氯仿)δ7.48-7.32(m,5H),7.16(t,J＝8.0Hz,1H),6.80(dd,J＝8.1,10.1Hz,2H),5.20-5.08(m,3H),3.10(s,1H),2.88-2.77(m,1H),2.75-2.63(m,1H),2.10-1.98(m,1H),1.98-1.88(m,2H),1.80-1.70(m,1H)。
步骤3：化合物WX008-7的合成
在预先干燥的反应瓶中加入WX008-5(20g,78.64mmol,1eq)和THF(200mL)，置于0℃下缓慢加入氢化钠(12.58g,314.56mmol,60％含量,4eq)，0℃下继续搅拌0.5小时。0℃下滴入WX008-6(36.80g,235.92mmol,18.87mL,3eq)，0℃下搅拌0.5小时。升温至25℃继续搅拌15小时。反应完成后，将反应液经水(100mL)淬灭，乙酸乙酯萃取水相(100mL*3)，合并有机相，饱和食盐水洗涤(100mL*3)，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1转5:1)得到WX008-7。 1H NMR(400MHz,氘代氯仿)δ7.48-7.39(m,2H),7.33-7.37(m,3H),7.14-7.12(m,1H),6.76-6.72(m,2H),5.14-5.05(m,2H),4.72-4.70(m,1H),3.68-3.64(m,1H),3.52-3.48(m,1H),2.86-2.81(m,1H),2.71-2.68(m,1H),2.24-2.23(m,1H),2.21-2.20(m,1H),1.74-1.73(m,1H),1.54-1.51(m,1H),1.17-1.13(m,3H)。
步骤4：化合物WX008-8的合成
在预先干燥的反应瓶中加入乙酸乙酯(300mL)和Pd/C(2g,10％含量)，加入WX008-7(14.36g,50.85mmol,1eq)，置换氢气三次，置于氢气压力为15psi的环境下，25℃搅拌16小时。反应完成后，将反应液使用硅藻土过滤，减压浓缩得到产物粗品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1)得到WX008-8。 1H NMR(400MHz,氘代氯仿)δ8.33(s,1H),7.11-7.07(m,1H),6.73-6.71(m,1H),6.65-6.63(m,1H),4.91-4.88(m,1H),3.80-3.76(m,1H),3.63-3.59(m,1H),2.79-2.76(m,1H),2.71-2.69(m,1H),2.25(m,1H),1.92-1.91(m,2H),1.86-1.72(m,1H),1.34-1.30(m,3H)。
步骤5：化合物WX008-10的合成
在预先干燥的反应瓶中加入WX008-8(6.35g,33.03mmol,1eq)和DCM(120mL)，置换氢气三次，缓慢滴入2,6-二甲基吡啶(8.85g,82.57mmol,9.62mL,2.5eq)，然后滴入WX008-9(20.24g,66.06mmol,17.76mL,2eq)，25℃搅拌16小时。反应完成后，将反应液中加入水(120mL)淬灭，二氯甲烷萃取水相(150mL*3)，合并有机相，饱和食盐水洗涤(100mL*2)，收集有机相，无水硫酸钠干燥，过滤，减压浓缩得粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1)得到WX008-10。 1H NMR(400MHz,氘代氯仿)δ7.04-7.00(m,1H),6.68-6.63(m,2H),4.78-4.77(m,1H),3.72-3.68(m,1H),3.52-3.48(m,1H),2.84(m,1H),2.70-2.68(m,1H),2.31-2.28(m,1H),2.10(m,1H),1.69(m,1H),1.47(m,1H),1.36-1.34(m,3H),1.21-1.19(m,3H),1.17-1.12(m,18H)。
步骤6：化合物WX008-11的合成
在预先干燥的反应瓶中加入WX008-10(11g,31.56mmol,1eq)和乙腈(220mL)，加入NBS(6.18g,34.71mmol,1.1eq)，置换氮气三次，置于25℃下搅拌2小时。反应完成后，将反应液中加入水(50mL)淬灭，乙酸乙酯萃取水相(60mL*3)，合并有机相，饱和食盐水洗涤(100mL*2)，收集有机相，无水硫酸钠干燥，过滤，减压浓缩得粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1)得到WX008-11。 1H NMR(400MHz,氘代氯仿)δ7.31-7.29(m,1H),6.58-6.56(m,1H),4.77-4.75(m,1H),3.72-3.68(m,1H),3.51-3.47(m,1H),2.90-2.88(m,1H),2.51(m,1H),2.30-2.29(m,1H),2.26(m,1H),1.75(m,1H),1.55(s,1H),1.44-1.32(m,3H),1.21-1.18(m,3H),1.17-1.11(m,18H)。
步骤7：化合物WX008-12的合成
在干燥的反应瓶中加入WX008-11，加入THF(20mL)，置换氮气后，降温至-78℃，滴加n-BuLi(2.5M,2.06mL,1.1eq)，-78℃反应1小时，加入WX001-4的THF(10mL)溶液，-78℃反应1小时。反应完毕后，向反应液中加入20mL饱和氯化铵溶液淬灭，加入30mL乙酸乙酯萃取，分液后收集有机相，水相用乙酸乙酯萃取。合并有机相，依次用饱和食盐水(20mL*3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品通过自动过柱机分离(石油醚:乙酸乙酯＝1:0至5:1)，纯化得到WX008-12。
步骤8：化合物WX008-13的合成
在反应瓶中加入WX008-12(680mg,1.21mmol,1eq)，二氧六环(7mL)，然后加入WX001-7(241.36mg,1.33mmol,223.48μL,1.1eq)，碳酸铯(591.70mg,1.82mmol,1.5eq)，置换氮气后，加入Pd 2(dba) 3(49.89mg,54.48μmol,0.045eq)，Xantphos(31.52mg,54.48μmol,0.045eq)，再置换氮气三次，然后升温至100℃搅拌12小时。反应完毕后，将反应体系冷却至室温，将反应液过滤，滤液减压浓缩即为粗品。粗品通过自动过柱机分离(石油醚:乙酸乙酯＝1:0至5:1)，纯化得到WX008-13。
步骤9：化合物WX008-14的合成
在预先干燥的反应瓶中加入WX008-13(470mg,709.99μmol,1eq)，THF(8mL)，置换氮气三次，降温至0℃，然后加入稀盐酸(2M,354.99μL,1eq)，置于20℃下搅拌0.5小时。反应完毕后，将反应液经饱和碳酸氢钠溶液调节pH至7左右，乙酸乙酯萃取水相(10mL*3)，合并有机相，饱和食盐水洗涤(10mL*2)，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品通过自动过柱机分离(石油醚:乙酸乙酯＝1:0至3:1转2:1)，纯化得到WX008-14。
步骤10：化合物WX008-15的合成
在预先干燥的反应瓶中通入氩气，加入Pd/C(10mg,10％含量)，加入乙酸乙酯(18mL)，冰乙酸(2mL)，加入WX008-14(175mg,351.56μmol,1eq)，置换氢气，置于25℃下15psi搅拌4小时。反应完毕后，将反应液直接经硅藻土过滤，滤液减压浓缩得到粗品。粗品直接用于下一步反应。得到WX008-15。 1H NMR(400MHz,氘代氯仿)δ6.50-6.44(m,3H),6.27(d,J＝8.3Hz,1H),4.81(s,1H),3.77-3.73(m,1H),3.73-3.68(m,1H),3.65(s,1H),3.59(s,1H),3.56-3.51(m,1H),2.92(dd,J＝5.8,17.2Hz,1H),2.58(ddd,J＝ 6.7,11.6,17.7Hz,1H),2.37-2.26(m,1H),2.17-2.09(m,1H),2.07(s,6H),1.89-1.76(m,1H),1.30-1.26(m,3H),1.22(t,J＝7.1Hz,3H),1.11(dd,J＝7.5,11.2Hz,18H)。
步骤11：化合物WX008-16的合成
在干燥的反应瓶中，加入WX008-15(260mg,539.66μmol,1eq)和THF(0.3mL)，加入WX001-10(120.21mg,809.49μmol,1.5eq)的THF(0.3mL)溶液，加入三乙胺(163.82mg,1.62mmol,225.34μL,3eq)，置于20℃搅拌1小时。反应完毕后，向反应液中加入10mL饱和碳酸氢钠溶液淬灭，加入30mL乙酸乙酯萃取，分液后收集有机相，水相用乙酸乙酯(20mL*3)萃取。合并有机相，依次用饱和食盐水(20mL*3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗产品通过自动过柱机分离(石油醚:乙酸乙酯＝1:0至2:1)，纯化得到WX008-16。 1H NMR(400MHz,氘代氯仿)δ8.49(br s,1H),7.23(br s,2H),6.42(br d,J＝8.4Hz,1H),6.16(br d,J＝8.4Hz,1H),4.78(br s,1H),3.77-3.68(m,1H),3.67-3.59(m,1H),3.58-3.47(m,2H),3.27(q,J＝7.4Hz,1H),2.89-2.79(m,1H),2.29(br d,J＝12.9Hz,2H),2.10(br s,1H),2.05(br d,J＝3.1Hz,6H),1.81(br d,J＝1.6Hz,1H),1.26(td,J＝3.8,7.3Hz,3H),1.22-1.18(m,3H),1.06(dd,J＝7.4,11.6Hz,18H)。
步骤12：化合物WX008-17的合成
在干燥的反应瓶中，加入WX008-16(270mg,454.68μmol,1eq)和THF(0.3mL)，加入三乙胺三氢氟酸盐(366.49mg,2.27mmol,370.57μL,5eq)，置换氮气三次，置于50℃搅拌12小时。反应完毕后，将反应体系冷却至室温，向反应液中加入30mL水淬灭，加入20mL乙酸乙酯萃取，分液后收集有机相，水相用乙酸乙酯(20mL*3)萃取。合并有机相，依次用饱和食盐水(20mL*3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品用二氯甲烷和乙酸乙酯倒瓶发现溶解度差，故用一点甲醇溶解，得到的溶液浓缩旋干经检测发现乙氧基变为甲氧基。粗品经(色谱柱:Phenomenex C18 80*40mm*3μm；流动相:[水(碳酸氢铵)-乙腈]；乙腈％:25％-45％,8分钟)纯化得到WX008-17。
步骤13：化合物WX008和WX009的合成
WX008-17(60mg,101.04μmol)经手性分离(色谱柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:A:二氧化碳B:[0.1％氨水-乙醇]；B％:35％-35％,14分钟)，得到WX008和WX009。经手性方法检测(方法：色谱柱Chiralpak AD-3,50×4.6mm I.D.,3μm；流动相:A:二氧化碳B:乙醇(0.1％IPAm,v/v),流速:2.5毫升/分钟；柱温:35℃；压力:2000psi)显示，WX008(ee％＝98.64％，保留时间为3.482分钟)和WX009(ee％＝97.98％，保留时间为3.831分钟)。产物WX009再经(色谱柱:Phenomenex C18 75*30mm*3μm；流动相:[水(氨水+碳酸氢铵)-乙腈]；乙腈％:15％-45％,8分钟)纯化，得到WX009。
WX008： 1H NMR(400MHz,氘代甲醇)δ7.41(s,2H),6.44(d,J＝8.1Hz,1H),6.19(d,J＝8.6Hz,1H),4.67(t,J＝3.2Hz,1H),3.86-3.67(m,2H),3.47(s,3H),2.97-2.87(m,1H),2.67-2.54(m,1H),2.29-2.22(m,1H),2.14(s,6H),2.03-1.94(m,1H),1.91-1.84(m,1H),1.65-1.55(m,1H)。
WX009： 1H NMR(400MHz,氘代甲醇)δ7.42(s,2H),6.45(d,J＝8.3Hz,1H),6.20(d,J＝8.3Hz,1H),4.67(t,J＝2.8Hz,1H),3.86-3.66(m,2H),3.47(s,3H),2.98-2.86(m,1H),2.61(ddd,J＝6.2,11.4,17.6Hz,1H),2.32-2.20(m,1H),2.14(s,6H),2.05-1.96(m,1H),1.92-1.80(m,1H),1.66-1.55(m,1H)。
实施例8
Figure PCTCN2022081686-appb-000088
合成路线：
Figure PCTCN2022081686-appb-000089
步骤1：化合物WX010-1的合成
在预先干燥的反应瓶中依次加入WX008-16(200mg,336.80μmol,1eq)，THF(5mL)和四丁基氟化铵(1M,404.16μL,1.2eq)，置换氮气三次，置于20℃搅拌1小时。反应完成后，将反应液直接减压浓缩得到粗产品。粗产品通过pre-TLC(二氯甲烷：甲醇＝10:1)纯化得到WX010-1。
步骤2：化合物WX010-2-1和WX010-2-2的合成
在预先干燥的反应瓶中加入WX010-1(70mg,160.00μmol,1eq)和吡啶(2mL)，加入醋酸酐(245.02mg,2.40mmol,224.79μL,15eq)，置于25℃下搅拌1小时。反应完成后，将反应液用0.5N盐酸调节pH至4-5，用二氯甲烷(5mL)萃取，收集有机相，水相用二氯甲烷(5mL*2)萃取，合并有机相，有机相依次通过0.5M盐酸(10mL*2)洗涤，饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。然后通过超临界色谱分离(色谱柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:A:二氧化碳B:[0.1％氨水-乙醇]；B％:25％-25％,11分钟)纯化得到WX010-2-1和WX010-2-2。经手性方法检测(方法：色谱柱Chiralpak AD-3,150×4.6mm I.D.,3μm；流动相:A:二氧化碳B:甲醇(0.1％IPAm,v/v),流速:2.5毫升/分钟；柱温:35℃；压力:2000psi)显示，WX010-2-1保留时间为2.893分钟，ee％为100％；WX010-2-2保留时间为3.190分钟，ee％为91.06％。
步骤3：化合物WX010和WX011的合成
在预先干燥的反应瓶中依次加入WX010-2-1(16mg,33.37μmol,1eq)和MeOH(4mL)，加入碳酸钾(9.22mg,66.73μmol,2eq)，置换氮气三次，置于20℃搅拌4小时。反应完成后，将反应液过滤，减压浓缩得到产物粗品。粗产品通过高效液相色谱纯化(色谱柱:Phenomenex C18 75*30mm*3μm；流动相:[水(碳酸氢铵)-乙腈]；乙腈％:25％-55％,8min)得到WX010。 1H NMR(400MHz,氘代甲醇)δ7.42(s,2H),6.44(d,J＝8.3Hz,1H),6.19(d,J＝8.1Hz,1H),4.78(t,J＝2.9Hz,1H),3.85-3.75(m,2H),3.75-3.67(m,2H),2.98-2.88(m,1H),2.68-2.56(m,1H),2.26-2.18(m,1H),2.16-2.12(m,6H),2.08-1.99(m,1H),1.92-1.83(m,1H),1.68-1.58(m,1H),1.21(t,J＝7.0Hz,3H)；MS-ESI m/z:436.2[M-H] +。
在预先干燥的反应瓶中依次加入WX010-2-2(10.00mg,20.85μmol,1eq)和MeOH(2.5mL)，加入碳酸钾(5.76mg,41.71μmol,2eq)，置换氮气三次，置于20℃搅拌4小时。反应完成后，将反应液过滤，减压浓缩得到产物粗品。粗产品通过高效液相色谱纯化(色谱柱:Phenomenex C18 75*30mm*3μm；流动相:[水(碳酸氢铵)-乙腈]；乙腈％:25％-55％,8分钟)得到WX011。 1H NMR(400MHz,氘代甲醇)δ7.42(s,2H),6.44(d,J＝8.4Hz,1H),6.19(d,J＝8.4Hz,1H),4.78(t,J＝3.1Hz,1H),3.84-3.76(m,2H),3.74-3.68(m,2H),3.00-2.87(m,1H),2.69-2.55(m,1H),2.25-2.19(m,1H),2.14(s,6H),2.07-2.00(m,1H),1.93-1.82(m,1H),1.67-1.59(m,1H),1.21(t,J＝7.1Hz,3H)；MS-ESI m/z:436.1[M-H] -。
实施例9
Figure PCTCN2022081686-appb-000090
合成路线：
Figure PCTCN2022081686-appb-000091
步骤1：化合物WX012-1的合成
在预先干燥的反应瓶中加入WX008-11(5g,11.70mmol,1eq)和THF(100mL)，置换氮气三次，置于-78℃下，缓慢滴入DMF(3.42g,46.78mmol,3.60mL,4eq)，-78℃下搅拌0.5小时，然后在-78℃下滴入正丁基锂(2.5M,5.15mL,1.1eq)，-78℃下继续搅拌1小时。反应完成后，将反应液倒入饱和氯化铵溶液中(20mL)，然后加入乙酸乙酯(20mL)分液，收集有机相，水相用乙酸乙酯(20mL*2)萃取，合并有机相，依次用饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1转5:1)得到WX012-1。 1H NMR(400MHz,氘代氯仿)δ10.107(s,1H),7.66-7.63(m,1H),6.80-6.78(m,1H),4.79(s,1H),3.74-3.71(m,1H),3.54-3.48(m,1H),2.94(m,1H),2.34(m,1H),2.05(m,1H),1.80(m,1H),1.55(s,1H),1.45-1.39(m,3H),1.37-1.35(m,3H),1.22-1.19(m,18H)。
步骤2：化合物WX012-2的合成
在预先干燥的反应瓶中加入WX012-1(1g,2.66mmol,1eq)和DCM(10mL)，加入间氯过氧苯甲酸 (1.13g,6.55mmol,2.47eq)，置换氮气三次，25℃下继续搅拌16小时。反应完成后，将反应液中加入饱和碳酸氢钠溶液溶液淬灭(20mL)，搅拌30min，然后加入二氯甲烷(20mL)分液，收集有机相，水相用二氯甲烷(20mL*2)萃取，合并有机相，用饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到中间体，将中间体(1g,2.66mmol,1eq)，DCM(5mL)和MeOH(5mL)加入在预先干燥的反应瓶中，加入TEA(1.42g,14.07mmol,1.96mL,5.3eq)，置换氮气三次，25℃下继续搅拌40分钟。反应完成后，将反应液用二氯甲烷(10mL)稀释，然后用2N盐酸洗涤(10mL)，收集有机相，有机相用饱和碳酸氢钠溶液(10mL)洗涤，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1转5:1)得到WX012-2。 1H NMR(400MHz,氘代氯仿)δ6.56-6.55(m,2H),4.76-4.75(s,1H),4.34(s,1H),3.73-3.69(m,1H),3.53-3.49(m,1H),2.77(m,1H),2.46-2.44(m,1H),2.29-2.26(m,1H),2.06(m,1H),1.75(m,1H),1.55(s,1H),1.42-1.31(m,3H),1.22-1.20(m,3H),1.18-1.11(m,18H)。
步骤3：化合物WX012-4的合成
在预先干燥的反应瓶中加入WX012-2(690mg,1.89mmol,1eq)和DMF(14mL)，加入碳酸钾(392.34mg,2.84mmol,1.5eq)，置换氮气三次，25℃下搅拌0.5小时，缓慢加入WX012-3(516.63mg,2.46mmol,1.3eq)，置换氮气三次，置于100℃下搅拌15.5小时。反应完成后，经水(30mL)淬灭，分液，用乙酸乙酯萃取水相(50mL*3)，合并有机相，饱和食盐水洗涤(100mL*3)，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转10:1转5:1)得到WX012-4。 1H NMR(400MHz,氘代氯仿)δ8.31(m,1H),8.28(m,2H),6.03-6.01(m,1H),5.97-5.95(m,1H),4.90(s,1H),3.85-3.81(m,1H),3.73-3.69(m,1H),3.23-3.18(m,1H),2.72-2.71(m,1H),2.37-2.33(m,1H),2.15(m,1H),1.95-1.94(m,1H),1.70-1.68(m,1H),1.29-1.26(m,3H)。
步骤4：化合物WX012-5-1和WX012-5-2的合成
取WX012-4(500mg,1.26mmol,1eq)通过超临界色谱纯化(色谱柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:A:二氧化碳B:[0.1％氨水+异丙醇]；B％:30％-30％,10分钟)，得到WX012-5-1与WX012-5-2。经手性方法检测(仪器:CAS-TJ-ANA-SFC-H(Waters UPCC with SQ Detector 2)；色谱柱:Chiralpak AD-3,50×4.6mm I.D.,3μm；流动相：A:食品级超临界二氧化碳；B:异丙醇(0.1％异丙胺，体积比)；梯度：B含量在1.2分钟内从5％升高到50％并保持1分钟，然后在0.4分钟内从50％升高到5％；流速:3.4mL/min；柱温：35℃；检测波长：220nm；系统背压:100ba。)WX012-5-1的保留时间为1.197，ee％为100％；WX012-5-2的保留时间为1.295，ee％为98.56％。WX012-5-1： 1H NMR(400MHz,氘代二甲基亚砜)δ8.52(s,2H),8.50-8.48(m,1H),6.29-6.21(m,1H),6.19-6.14(m,1H),4.80(s,1H),3.82-3.68(m,1H),3.65-3.52(m,1H),3.06(br dd,J＝3.1,17.8Hz,1H),2.74-2.64(m,1H),2.33(td,J＝1.8,3.6Hz,1H),2.29-2.18(m,1H),1.99-1.79(m,1H),1.69-1.54(m,1H),1.14(t,J＝7.0Hz,3H)。WX012-5-2： 1H NMR (400MHz,氘代二甲基亚砜)δ8.51(s,2H),8.51-8.47(m,1H),6.29-6.21(m,1H),6.20-6.11(m,1H),4.80(s,1H),3.83-3.69(m,1H),3.60(dd,J＝7.1,8.9Hz,1H),3.06(br dd,J＝3.4,17.9Hz,1H),2.72-2.59(m,1H),2.35-2.21(m,1H),1.97-1.80(m,2H),1.67-1.56(m,1H),1.14(t,J＝6.9Hz,3H)。
步骤5：化合物WX012-6-1和WX012-6-2的合成
在预先干燥的反应瓶中加入WX012-5-1和冰醋酸(1mL)，异丙醇(2mL)，水(1mL)，置于50℃下，分批次缓慢加入铁粉(98.17mg,1.76mmol,7eq)，置换氮气三次，置于90℃下搅拌2小时。反应完成后，将反应液降温至室温，经硅藻土过滤，滤液减压浓缩，浓缩物经饱和碳酸氢钠溶液调节pH至7～8，乙酸乙酯萃取水相(10mL*3)，合并有机相；有机相依次经饱和食盐水洗涤(20mL*2)，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经pre-TLC纯化(石油醚：乙酸乙酯＝1:1)纯化得到WX012-6-1。 1H NMR(400MHz,氘代二甲基亚砜)δ6.67(s,2H),6.15-6.07(m,1H),6.05-5.96(m,1H),5.58(s,2H),4.76(br s,1H),3.78-3.66(m,1H),3.65-3.55(m,1H),3.00(br dd,J＝4.3,18.0Hz,1H),2.70-2.57(m,1H),2.24-2.11(m,1H),1.93-1.72(m,2H),1.59-1.46(m,1H),1.12(t,J＝7.0Hz,3H)。
在预先干燥的反应瓶中加入WX012-5-2(150mg,376.66μmol,1eq)和冰醋酸(1.5mL)，异丙醇(3mL)，水(1.5mL)，置于50℃下，分批次缓慢加入铁粉(147.26mg,2.64mmol,7eq)，置换氮气三次，置于90℃下搅拌2小时。反应完成后，将反应液降温至室温，经硅藻土过滤，滤液减压浓缩，浓缩物经饱和碳酸氢钠溶液调节pH至7～8，乙酸乙酯萃取水相(10mL*3)，合并有机相；有机相依次经饱和食盐水洗涤(20mL*2)，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经pre-TLC纯化(石油醚：乙酸乙酯＝1:1)纯化得到WX012-6-2。 1H NMR(400MHz,氘代二甲基亚砜)δ6.67(s,2H),6.19-6.07(m,1H),6.05-5.96(m,1H),5.58(s,2H),4.76(br s,1H),3.79-3.52(m,2H),3.00(br dd,J＝3.9,17.8Hz,1H),2.69-2.53(m,1H),2.18(br d,J＝12.8Hz,1H),1.95-1.73(m,2H),1.61-1.47(m,1H),1.17-1.05(m,3H)。
步骤6：化合物WX012和WX013的合成
在干燥的反应瓶中，加入WX001-10(48.39mg,325.86μmol,1.5eq)的THF(1.6mL)溶液，将WX012-6-1(80mg,217.24μmol,1eq)用THF(1mL)溶解后加入反应瓶中，加入TEA(65.95mg,651.72μmol,90.71μL,3eq)，置于20℃搅拌1小时。反应完成后，将反应液加入水(5mL)中，加入乙酸乙酯(5mL)萃取分液，收集有机相，水相用乙酸乙酯(5mL*2)萃取，合并有机相，有机相依次用饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到产物粗品。粗产品通过高效液相色谱纯化(色谱柱:Waters Xbridge BEH C18 100*30mm*10μm；流动相:[水(碳酸氢铵)-乙腈]；乙腈％:20％-65％,10分钟)得到WX012。 1H NMR(400MHz,氘代甲醇)δ7.94(br s,2H),6.21-6.14(m,1H),6.13-6.06(m,1H),5.00(br s,1H),3.92-3.78(m,2H),3.22(br dd,J＝5.0,17.9Hz,1H),2.73(ddd,J＝6.0,11.9,18.2Hz,1H),2.40-2.31(m,1H),2.13-1.91(m,2H),1.76-1.63(m,1H),1.31-1.22(m,3H)。
在干燥的反应瓶中，加入WX001-10(66.54mg,448.06μmol,1.5eq)的THF(2mL)溶液，将WX012- 6-2(110mg,298.71μmol,1eq)用THF(1mL)溶解后加入反应瓶中，加入TEA(90.68mg,896.12μmol,124.73μL,3eq)，置于20℃搅拌1小时。反应完成后，将反应液加入水(5mL)中，加入乙酸乙酯(5mL)萃取分液，收集有机相，水相用乙酸乙酯(5mL*2)萃取，合并有机相，有机相依次用饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到产物粗品。粗产品通过高效液相色谱纯化(色谱柱:Waters Xbridge BEH C18 100*30mm*10μm；流动相:[水(碳酸氢铵)-乙腈]；乙腈％:20％-65％,10分钟)得到WX013。 1H NMR(400MHz,氘代甲醇)δ7.94(br s,2H),6.22-6.15(m,1H),6.12-6.12(m,1H),6.15-6.09(m,1H),5.00(br s,1H),3.92-3.77(m,2H),3.22(br dd,J＝4.5,18.1Hz,1H),2.73(ddd,J＝6.3,11.9,18.0Hz,1H),2.43-2.29(m,1H),2.14-1.91(m,2H),1.77-1.63(m,1H),1.31-1.24(m,3H)。
生物测试
实验一：本发明化合物对甲状腺激素受体在细胞水平激活活性测试
实验原理：
本实验采用ThermoFisher开发的
Figure PCTCN2022081686-appb-000092
TR alpha/beta-UAS-bla HEK 293T Cell-based Assay方法，其原理是TR alplha-UAS-bla HEK 293T Cell和TR beta-UAS-bla HEK 293T Cell表达β-内酰胺酶，这个报告基因受控于上游的UAS序列，当化合物进入细胞与THR结合时，受体与DNA结合区域结合形成一个完整的GAL4二聚体，利用GAL4-UAS系统，激活β-内酰胺酶表达，分解底物CCF4-AM(香豆素)，产物在409nm激发作用下，产生447nm波长的荧光，如果没有表达β-内酰胺酶，在409nm激发作用下，直接通过FRET产生520nm波长的荧光，通过检测两荧光比值(447nm/520nm)来判定化合物与蛋白的结合情况，从而计算化合物的EC 50。
实验方法：
采用ECHO液体工作站将化合物转移到384孔板，每个化合物10个梯度浓度，3倍稀释，双复孔。铺1.5×10 4个细胞(TR beta-UAS-bla HEK 293T Cell)或1.0×10 4个细胞(TR alpha-UAS-bla HEK 293T Cell)于384孔板中。HEK 293T-TR beta在37℃培养箱中孵育16小时，HEK 293T-TR alpha孵育22小时，LiveBLAzer TM-FRET B/G(CCF4-AM)底物加入细胞板中，避光常温孵育2小时，Flexstation 3仪器用于检测产物在409nm激发作用下，发射460nm/530nm波长的荧光值，通过检测两荧光比值(460nm/530nm)，用软件Graphpad Prism来计算化合物的EC 50。在每次实验中，参考化合物三碘甲状腺原氨酸(T3)将作为阳性对照品用于实验。Z因子的计算(>0.5)将用于监控每次实验的稳定性。
表1各实施例的THRα例和THRβ例活性
化合物 THRαEC 50(nM)，最大激动能力 THRβEC 50(nM)，最大激动能力
T3 0.057，100％ 0.2，100％
WX001 121.9，24％ 39.42，103％
WX002 999.6，101％ 85.55，99％
WX003 149.1，88％ 27.62，93％
WX004 76.24，96％ 9.073，94％
WX005 155.1，85％ 57.84，96％
WX006 435，86％ 104.9，90％
WX008 402.6，79％ 118.6，94％
WX009 772.9，83％ 154.2，93％
WX010 93.05，90％ 9.95，94％
WX011 65.53，73％ 13，97％
实验结论：本发明化合物具有显著的THRβ活性和选择性。
实验二：细胞色素P450同工酶抑制性研究
实验目的：
测定受试化合物WX001对人肝微粒体细胞色素P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)活性的抑制作用。
实验操作：
首先将受试化合物(10.0mM)进行稀释，制备工作液(100×最终浓度)，工作液浓度为1.00mM，同时分别准备P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4(以咪达唑仑为探针底物)和CYP3A4(以睾酮为探针底物))各阳性抑制剂及其特异性探针底物的工作液；将保存在低于-60℃冰箱的人肝微粒体置于冰上解冻，待人肝微粒体全部溶解，用PB进行稀释，制备一定浓度工作液(0.127mg/ml)。先将20.0μL探针底物加至反应板中(Blank孔中加入20.0μL PB)，然后将158μL人肝微粒体工作液加入反应板中，将反应板置于冰上，待用；此时将2.00μL受试化合物(N＝1)及特异性抑制剂(N＝2)加入对应孔中，无抑制剂(受试化合物或阳性抑制剂)组加入对应的有机溶剂，受试化合物对照样品和阳性对照样品有机相分别为1:1DMSO:MeOH和1:9DMSO:MeOH；在37℃水浴预孵育10min后，将20.0μL辅酶因子(NADPH)溶液加入反应板中，对于以咪达唑仑为探针底物的CYP3A4代谢反应，反应时间为3分钟；以(S)-美芬妥英为探针底物的CYP2C19反应和以右美沙芬为探针底物的CYP2D6反应，反应时间为20分钟，其余反应均为10分钟；然后加入400μL预冷的乙腈溶液(含200ng/mL Tolbutamide和Labetalol的内标)终止反应；将反应板置于摇床，振荡混匀10min；然后在4℃、4000rpm条件下离心20min；取200μL上清加至100μL水中，进行样品稀释；最后封板，振荡，摇匀，进行LC/MS/MS检测。
实验结果：
如表2所示。
表2.受试化合物对人肝微粒体细胞色素P450同工酶活性的抑制作用结果
Figure PCTCN2022081686-appb-000093
实验结论：化合物WX001对CYP1A2、CYP2C19、CYP2D6和CYP3A4均无抑制作用，对CYP2C9有中等抑制作用。
实验三：体内药代动力学研究
大鼠口服及静脉注射WX001的药代动力学研究
选取雄性SD大鼠，按照表3给予受试物。
表3.本发明化合物的给药和采血
Figure PCTCN2022081686-appb-000094
收集一定时间的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数。实验结果如表4和表5所示：
表4.本发明化合物通过静脉给药的药代动力学结果
Figure PCTCN2022081686-appb-000095
表5.本发明化合物通过口服给药的药代动力学结果
Figure PCTCN2022081686-appb-000096
Figure PCTCN2022081686-appb-000097
实验结论：本发明化合物具有较高的暴露量以及较好的口服生物利用度。
实验四：体内药效学研究
实验目的：
利用胆固醇胆酸添加饲料诱导的大鼠模型检测待测化合物的体内药效。
实验方法：
选取9-10周龄雄性SD大鼠，到达设施后，适应3-7天。适应期内，每天观察动物的健康状况并提供正常饲料。适应期结束后，饲喂高胆固醇(1.5％胆固醇和0.5％胆酸)饲料进行造模，空白对照组大鼠继续饲喂正常饲料。将大鼠饲喂高胆固醇饲料两周后，采集血液，分离血清检测LDL-C水平。根据血清LDL-C水平将高胆固醇模型大鼠进行随机分组，随后连续7天口服给药，每天一次，参见表6。给药一周后采集大鼠血清检测LDL-C水平，评估药效。
表6动物分组情况
Figure PCTCN2022081686-appb-000098
实验结果：
见附图4，其中P<0.05代表给药组相对溶媒组在药效学指标上有统计学显著差异。
实验结论：本发明化合物能够显著降低大鼠血浆LDL-C水平。

Claims (16)

  1. 式(III)所示化合物或其药学上可接受的盐，
    Figure PCTCN2022081686-appb-100001
    其中，
    环B选自
    Figure PCTCN2022081686-appb-100002
    R 1独立地选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代；
    R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、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R b取代；
    R 4选自C 1-3烷基-苯基；
    L选自-O-和-CH 2-；
    环A选自苯基、5～6元杂芳基、
    Figure PCTCN2022081686-appb-100003
    所述苯基、5～6元杂芳基、
    Figure PCTCN2022081686-appb-100004
    任选被1、2或3个R c取代；
    n和m分别独立地选自0、1和2；
    R a和R b分别独立地选自F、Cl、Br和I；
    R c独立地选自F、Cl、Br、I、＝O、＝N-C 1-3烷氧基、C 1-3烷基和C 1-3烷氧基，所述＝N-C 1-3烷氧基、C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代。
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 1独立地选自H、F、Cl、Br、I和CH 3，所述CH 3任选被1、2或3个R a取代。
  3. 根据权利要求2所述化合物或其药学上可接受的盐，其中，R 1独立地选自H、F、Cl、Br、I、CH 3和CF 3。
  4. 根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和OCH 3，所述CH 3和OCH 3任选被1、2或3个R b取代。
  5. 根据权利要求4所述化合物或其药学上可接受的盐，其中，R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2F、CHF 2、CF 3和OCH 3。
  6. 根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，R c独立地选自F、Cl、Br、I、＝O、＝N-O-CH 3、＝N-O-CH 2CH 3、CH 3、OCH 3和OCH 2CH 3，所述＝N-O-CH 3、＝N-O-CH 2CH 3、CH 3、OCH 3和OCH 2CH 3任选被1、2或3个卤素取代。
  7. 根据权利要求6所述化合物或其药学上可接受的盐，其中，R c独立地选自F、Cl、Br、I、＝O、＝N-O-CH 3、＝N-O-CH 2CH 3、CH 3、OCH 3和OCH 2CH 3。
  8. 根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，环A选自
    Figure PCTCN2022081686-appb-100005
    Figure PCTCN2022081686-appb-100006
    所述
    Figure PCTCN2022081686-appb-100007
    Figure PCTCN2022081686-appb-100008
    任选被1、2或3个R c取代。
  9. 根据权利要求8所述化合物或其药学上可接受的盐，其中，环A选自
    Figure PCTCN2022081686-appb-100009
    Figure PCTCN2022081686-appb-100010
  10. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 4选自
    Figure PCTCN2022081686-appb-100011
  11. 根据权利要求1～3、9任意一项所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022081686-appb-100012
    选自
    Figure PCTCN2022081686-appb-100013
    Figure PCTCN2022081686-appb-100014
  12. 根据权利要求1～11任意一项所述化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2022081686-appb-100015
    其中，R 1、R 2、R 3、L、m和n如权利要求1～11任意一项所定义。
  13. 根据权利要求1～11任意一项所述化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2022081686-appb-100016
    其中，
    Figure PCTCN2022081686-appb-100017
    为单键时，R c为F、Cl、Br、I、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个卤素取代；
    Figure PCTCN2022081686-appb-100018
    为双键时，R c为＝O和＝N-C 1-3烷氧基，所述＝N-C 1-3烷氧基任选被1、2或3个卤素取代；
    R 1、R 2、R 3、L和m如权利要求1～11任意一项所定义。
  14. 下式化合物或其药学上可接受的盐，
    Figure PCTCN2022081686-appb-100019
    Figure PCTCN2022081686-appb-100020
    Figure PCTCN2022081686-appb-100021
  15. 根据权利要求14所述化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2022081686-appb-100022
  16. 根据权利要求1～15任意一项所述的化合物或其药学上可接受的盐在制备治疗非酒精性脂肪肝炎的药物中的应用。
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