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WO2022194287A1 - 双环吡啶酮类化合物及其应用 - Google Patents

双环吡啶酮类化合物及其应用 Download PDF

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WO2022194287A1
WO2022194287A1 PCT/CN2022/081768 CN2022081768W WO2022194287A1 WO 2022194287 A1 WO2022194287 A1 WO 2022194287A1 CN 2022081768 W CN2022081768 W CN 2022081768W WO 2022194287 A1 WO2022194287 A1 WO 2022194287A1
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compound
independently selected
present
alkoxy
pharmaceutically acceptable
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PCT/CN2022/081768
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English (en)
French (fr)
Inventor
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 CN202280016736.0A priority Critical patent/CN116940566A/zh
Priority to CN202311769408.0A priority patent/CN117624154A/zh
Publication of WO2022194287A1 publication Critical patent/WO2022194287A1/zh

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    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a class of bicyclic pyridone compounds and applications thereof, and specifically discloses a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.
  • Thyroid hormones play an important role in growth, differentiation, development and maintaining metabolic balance. Its physiological action is carried out through thyroid hormone receptors.
  • Thyroid hormone (THR) has two subtypes: THR ⁇ and THR ⁇ .
  • THR ⁇ is mainly distributed in the brain, heart and skeletal muscle, and can control the heart rate.
  • THR ⁇ is widely distributed in various tissues, mainly in liver, brain, and less in heart. It is involved in energy metabolism and is the main receptor for lipid metabolism and glucose metabolism.
  • 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.
  • 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 (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is independently selected from H 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 ;
  • Each R 4 is independently selected from H, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are optionally separated by 1, 2 or 3 R c substitution;
  • 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 Rd ;
  • n and m are independently selected from 0, 1 and 2;
  • R a , R b and R c are each independently selected from F, Cl, Br and I;
  • R is independently selected from F, Cl, Br and I;
  • Ring A is phenyl or 6-membered heteroaryl
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is independently selected from H 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 independently selected from H, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy optionally surrounded by 1, 2 or 3 R c replace;
  • 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 Rd ;
  • n and m are independently selected from 0, 1 and 2;
  • R a , R b and R c are each independently selected from F, Cl, Br and I;
  • R is independently selected from F, Cl, Br and I.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is independently selected from H 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, -C(R 4 ) 2 and
  • R 4 is independently selected from H, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy optionally surrounded by 1, 2 or 3 R c replace;
  • 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 Rd ;
  • n and m are independently selected from 0, 1 and 2;
  • R a , R b and R c 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 and CH 3 , said CH 3 is optionally substituted with 1, 2 or 3 Ra , and other variables are as defined in the present invention.
  • R 1 is independently selected from H, 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 by 1, 2 or 3 Ra , 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.
  • R 4 is independently selected from H, CH 3 , OCH 3 and OCH 2 CH 3 , and said CH 3 , OCH 3 and OCH 2 CH 3 are optionally surrounded by 1, 2 or 3 R c
  • other variables are as defined in the present invention.
  • R 4 is independently selected from H, CH 3 , OCH 3 and OCH 2 CH 3 , and other variables are as defined in the present invention.
  • the above L is selected from -O-, -CH2- , -C( OCH2CH3 ) 2- 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 Rd , 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 ring A is selected from Other variables 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 present invention also provides following synthetic method:
  • the present invention also provides following test method:
  • test compounds The inhibitory effect of test compounds 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
  • the in vivo efficacy of the compounds to be tested was detected by using a rat model induced by dietary cholesterol cholic acid.
  • 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 diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • SXRD single crystal X-ray diffraction method
  • the cultured single crystal is collected by Bruker D8 venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • the 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; r.t. for room temperature; O/N for overnight; THF for tetrahydrofuran; TFA for trifluoroacetic acid; DIPEA for diisopropylethylamine; TEA for triethylamine.
  • the compound of the present invention has significant THR ⁇ activity and selectivity; the compound of the present invention has excellent pharmacokinetic properties; the compound of the present invention has no drug-drug interaction; the compound of the present invention can significantly reduce the level of plasma LDL-C in rats.
  • Figure 4 Prediction of the binding mode of Compound D to MGL-3196.
  • 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.
  • 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 compounds of the present invention have significant THR ⁇ activity and selectivity.
  • mice Male C57BL/6 mice were selected, and the test substances were administered according to Table 2.
  • the compounds of the present invention have good pharmacokinetic properties.

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Abstract

一类双环吡啶酮类化合物及其应用，具体公开了式(I)所示化合物及其药学上可接受的盐。

Description

双环吡啶酮类化合物及其应用
本申请主张如下优先权
CN202110299530.0，申请日：2021年03月19日；
CN202110443443.8，申请日：2021年04月23日。
技术领域
本发明涉及一类双环吡啶酮类化合物及其应用，具体公开了式(I)所示化合物及其药学上可接受的盐。
背景技术
甲状腺激素对于生长、分化、发育和维持代谢平衡具有重要作用。它的生理作用通过甲状腺激素受体进行。甲状腺激素(THR)有两种亚型：THRα和THRβ。THRα主要分布在大脑、心脏和骨骼肌，能够控制心率。THRβ广泛分布在各个组织中，主要分布在肝，脑中，在心脏中较少。其参与能量代谢，是脂代谢和糖代谢的主要受体。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)。人们认为这些副作用是由于激动THRα亚型导致的，因此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，其已进入临床三期，安全性和有效性得到进一步的证实。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 PCTCN2022081768-appb-000001
发明内容
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2022081768-appb-000002
其中，
R 1独立地选自H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-、-C(＝O)-、-S-、-S(＝O) 2、-S(＝O)-、-C(R 4) 2-和
Figure PCTCN2022081768-appb-000003
各R 4分别独立地选自H、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 c取代；
环A选自苯基、5～6元杂芳基、
Figure PCTCN2022081768-appb-000004
所述苯基、5～6元杂芳基、
Figure PCTCN2022081768-appb-000005
任选被1、2或3个R d取代；
n和m分别独立地选自0、1和2；
R a、R b和R c分别独立地选自F、Cl、Br和I；
各R d分别独立地选自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；
当环A为苯基或6元杂芳基时，L选自-C(＝O)-、-S-、-S(＝O) 2、-S(＝O)-、-C(R 4) 2-和
Figure PCTCN2022081768-appb-000006
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2022081768-appb-000007
其中，
R 1独立地选自H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-、-C(＝O)-、-S-、-S(＝O) 2、-S(＝O)-、-C(R 4) 2-和
Figure PCTCN2022081768-appb-000008
R 4独立地选自H、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 c取代；
环A选自苯基、5～6元杂芳基、
Figure PCTCN2022081768-appb-000009
所述苯基、5～6元杂芳基、
Figure PCTCN2022081768-appb-000010
任选被1、2或3个R d取代；
n和m分别独立地选自0、1和2；
R a、R b和R c分别独立地选自F、Cl、Br和I；
R d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。
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2022081768-appb-000011
其中，
R 1独立地选自H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、-C(R 4) 2和
Figure PCTCN2022081768-appb-000012
R 4独立地选自H、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 c取代；
环A选自苯基、5～6元杂芳基、
Figure PCTCN2022081768-appb-000013
所述苯基、5～6元杂芳基、
Figure PCTCN2022081768-appb-000014
任选被1、2或3个R d取代；
n和m分别独立地选自0、1和2；
R a、R b和R c分别独立地选自F、Cl、Br和I；
R d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、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 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 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 4独立地选自H、CH 3、OCH 3和OCH 2CH 3，所述CH 3、OCH 3和OCH 2CH 3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R 4独立地选自H、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L选自-O-、-CH 2-、-C(OCH 2CH 3) 2-和
Figure PCTCN2022081768-appb-000015
其他变量如本发明所定义。
本发明的一些方案中，上述R d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 d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 PCTCN2022081768-appb-000016
Figure PCTCN2022081768-appb-000017
所述
Figure PCTCN2022081768-appb-000018
Figure PCTCN2022081768-appb-000019
任选被1、2或3个R d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 PCTCN2022081768-appb-000020
Figure PCTCN2022081768-appb-000021
Figure PCTCN2022081768-appb-000022
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 PCTCN2022081768-appb-000023
Figure PCTCN2022081768-appb-000024
Figure PCTCN2022081768-appb-000025
其他变量如本发明所定义。
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 PCTCN2022081768-appb-000026
Figure PCTCN2022081768-appb-000027
本发明还提供了下述合成方法：
方法1：
Figure PCTCN2022081768-appb-000028
Figure PCTCN2022081768-appb-000029
方法2：
Figure PCTCN2022081768-appb-000030
方法3：
Figure PCTCN2022081768-appb-000031
方法4：
Figure PCTCN2022081768-appb-000032
本发明还提供了如下测试方法：
细胞色素P450同工酶抑制性研究
实验目的：
测定受试化合物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。
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，溶媒对照组和受试化合物组饲喂高胆固醇(1.5％胆固醇和0.5％胆酸)饲料进行造模，溶媒为0.5％羧甲基纤维素钠+0.2％吐温80水溶液，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。给药一周后采集大鼠血清检测LDL-C水平，评估药效。
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 PCTCN2022081768-appb-000033
和楔形虚线键
Figure PCTCN2022081768-appb-000034
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022081768-appb-000035
和直形虚线键
Figure PCTCN2022081768-appb-000036
表示立体中心的相对构型，用波浪线
Figure PCTCN2022081768-appb-000037
表示楔形实线键
Figure PCTCN2022081768-appb-000038
或楔形虚线键
Figure PCTCN2022081768-appb-000039
或用波浪线
Figure PCTCN2022081768-appb-000040
表示直形实线键
Figure PCTCN2022081768-appb-000041
和直形虚线键
Figure PCTCN2022081768-appb-000042
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 PCTCN2022081768-appb-000043
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 PCTCN2022081768-appb-000044
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 PCTCN2022081768-appb-000045
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 PCTCN2022081768-appb-000046
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 PCTCN2022081768-appb-000047
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 PCTCN2022081768-appb-000048
直形虚线键
Figure PCTCN2022081768-appb-000049
或波浪线
Figure PCTCN2022081768-appb-000050
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 PCTCN2022081768-appb-000051
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 PCTCN2022081768-appb-000052
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 PCTCN2022081768-appb-000053
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 PCTCN2022081768-appb-000054
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2022081768-appb-000055
仍包括
Figure PCTCN2022081768-appb-000056
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：
Figure PCTCN2022081768-appb-000057
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；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；TFA代表三氟 乙酸；DIPEA代表二异丙基乙基胺；TEA代表三乙胺。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2022081768-appb-000058
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；本发明化合物具有优异的药代动力学性质；本发明化合物无药物-药物相互作用；本发明化合物能显著降低大鼠血浆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：化合物D与MGL-3196结合模式预测。
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 PCTCN2022081768-appb-000059
分子对接过程：通过使用Maestro(
Figure PCTCN2022081768-appb-000060
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 PCTCN2022081768-appb-000061
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-D与MGL-3196结合模式见附图1-4。
[1]Glide,
Figure PCTCN2022081768-appb-000062
LLC,New York,NY,2017.
[2]Maestro,
Figure PCTCN2022081768-appb-000063
LLC,New York,NY,2017.
[3]LigPrep,
Figure PCTCN2022081768-appb-000064
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 PCTCN2022081768-appb-000065
合成路线：
Figure PCTCN2022081768-appb-000066
步骤1：化合物WX001-2的合成
在干燥的反应瓶中，依次加入WX001-1(5g,37.85mmol,1eq)，1,4-二氧六环(50mL)，1-环已基-2-吗啉乙基碳二亚胺对甲苯磺酸盐(6.75g,41.63mmol,1.1eq)和DBU(6.34g,41.63mmol,6.27mL,1.1eq)，将反应体系升温至80℃，搅拌2小时。反应完全后，加入水(100mL)稀释，加入1N HCl调pH至3～4，加乙酸乙酯(3*100mL)萃取，分液后收集有机相。有机相依次用饱和食盐水溶液(100mL*3)洗涤，无水硫酸钠干燥，减压浓缩，得到WX001-2。 1H NMR(400MHz,氘代氯仿)δ4.51(q,J＝7.1Hz,2H),1.45(t,J＝7.1Hz,3H)。
步骤2：化合物WX001-3的合成
在干燥的反应瓶中，依次加入WX001-2(1g,6.32mmol,1eq)，水(2mL)，乙醇(10mL)和氢氧化锂一水合物(318.49mg,7.59mmol,2eq)，将反应至于20℃下搅拌1小时。反应完全后，向反应液中加入水(20mL)稀释，加入2M盐酸调节pH至4～6，加乙酸乙酯(30mL*3)萃取，分液后收集有机相。向水相加入2M盐酸调节pH至1，加乙酸乙酯(30mL*3)萃取，加入氯仿：异丙醇＝3:1(30mL*18)萃取，分液后收集有机相，无水硫酸钠干燥，减压浓缩，得到WX001-3。
步骤3：化合物WX001-4的合成
在干燥的反应瓶中，依次加入WX001-3(100mg,768.88μmol,1eq)，THF(1mL)，草酰氯(117.11mg,922.66μmol,80.77μL,1.2eq)和DMF(5.62mg,76.89μmol,5.92μL,0.1eq)，在20℃下搅拌1小时。反应完全后，反应液直接减压浓缩，得到WX001-4。
步骤4：化合物WX001-7的合成
在干燥的反应瓶中，依次加入WX001-5(5g,24.62mmol,1eq)，WX001-6(5.83g,32.75mmol,1.33eq)， N,N-二甲基乙酰胺(50mL)和碳酸铯(16.04g,49.24mmol,2eq)，升温至80℃，搅拌10小时。反应完全后，加入水(100mL)稀释，加乙酸乙酯(100mL*3)萃取，分液后收集有机相。有机相依次用饱和食盐水溶液(100mL*3)洗涤，无水硫酸钠干燥，减压浓缩得到粗品。粗品经柱层析(石油醚：乙酸乙酯＝1:0至2:1)纯化，得到WX001-7。 1H NMR(400MHz,氘代氯仿)δ6.66(s,2H),2.87-2.83(m,2H),2.77-2.69(m,2H),1.92-1.88(m,4H)。
步骤5：化合物WX001-8的合成
在干燥的反应瓶中，加入NaOH(16.25g,406.24mmol,20eq)和水(70mL)，DMSO(70mL)，WX001-7(7g,20.31mmol,1eq)，升温至120℃，搅拌2小时。反应完全后，加入水(100mL)稀释，加乙酸乙酯(100mL*3)萃取，分液后收集有机相。有机相依次用饱和食盐水溶液(100mL*3)，无水硫酸钠干燥，减压浓缩得到粗品。粗品经柱层析分离(石油醚：乙酸乙酯＝1:0至2:1)纯化，得到WX001-8。 1H NMR(400MHz,氘代氯仿)δ6.67(s,2H),2.84-2.52(m,4H),1.93-1.71(m,4H)。
步骤6：化合物WX001的合成
在干燥的反应瓶中，依次加入WX001-8(150.34mg,460.91μmol,1eq)，THF(2mL)，TEA(139.92mg,1.38mmol,192.46μL,3eq)和WX001-4(102.67mg,691.36μmol,1.5eq)的THF(2mL)溶液，在20℃下搅拌1小时。反应完全后，将反应液减压浓缩，通过高效液相色谱柱纯化(色谱柱:Phenomenex Gemini-NX80*40mm*3μm；流动相:[水(10mM碳酸氢铵)-乙腈]；乙腈％:10％-40％,8分钟)，得到WX001。 1H NMR(400MHz,氘代甲醇)δ7.92(s,2H),2.79-2.74(m,2H),2.59-2.54(m,2H),1.89-1.85(m,4H)。MS-ESI m/z:436.4[M-H] -。
实施例2
Figure PCTCN2022081768-appb-000067
合成路线：
Figure PCTCN2022081768-appb-000068
步骤1：化合物WX002-2的合成
在干燥的反应瓶中，依次加入WX002-1(1.18g,7.97mmol,2.6eq)，WX001-8(1g,3.07mmol,1eq)，DMF(10mL)和TEA(620.46mg,6.13mmol,853.45μL,2eq)，升温至100℃，搅拌10小时。反应完全后，加入水(50mL)打浆，过滤，滤饼水(10mL*2)洗涤后减压浓缩，得到WX002-2。 1H NMR(400MHz,氘代氯仿)δ9.46(br s,1H),7.99(dd,J＝3.0,5.4Hz,2H),7.85(dd,J＝3.1,5.4Hz,2H),7.60(s,2H),2.77(br s,2H),2.63(br s,2H),1.89-1.84(m,4H)。
步骤2：化合物WX002-3的合成
在干燥的反应瓶中，依次加入WX002-2(300mg,654.60μmol,1eq)，DMF(12mL)，碳酸钾(180.95mg,1.31mmol,2eq)和碘甲烷(185.83mg,1.31mmol,81.50μL,2eq)，在20℃，搅拌10小时。反应完全后，加入水(20mL)稀释，加乙酸乙酯(20mL*3)萃取，分液后收集有机相，依次用饱和食盐水溶液(20mL*3)，无水硫酸钠干燥，减压浓缩得到粗品。粗品经柱层析(DCM：MeOH＝20:1)纯化，得到WX002-3。 1H NMR(400MHz,氘代氯仿)δ8.04-7.96(m,2H),7.90-7.80(m,2H),7.60(s,2H),3.53(s,3H),2.80-2.58(m,4H),1.90-1.78(m,4H)。
步骤3：化合物WX002-4的合成
在干燥的反应瓶中，依次加入WX002-3(290mg,613.99μmol,1eq)，THF(3mL)和水合肼(108.48mg,1.84mmol,105.32μL,85％纯度,3eq)，升温至40℃，搅拌3小时。反应完全后，反应液加入氯化铵水溶液(10mL)淬灭，加乙酸乙酯(20mL*3)萃取，分液后收集有机相，依次用饱和食盐水溶液(10mL*3)，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WX002-4。 1H NMR(400MHz,氘代氯仿)δ6.68(s,2H),3.58-3.43(m,3H),2.77-2.55(m,4H),1.81(br t,J＝2.8Hz,4H)。
步骤4：化合物WX002的合成
在干燥的反应瓶中，依次加入WX002-4(150mg,440.91μmol,1eq)，THF(2mL)，TEA(133.85mg, 1.32mmol,184.11μL,3eq)和WX001-4(98.22mg,661.37μmol,1.5eq)的THF(2mL)溶液，20℃，搅拌1小时。反应完全后，反应液减压浓缩得到粗品。粗品通过制备高效液相色谱柱纯化(色谱柱:Gemini-NX80*40mm*3μm；流动相:[水(10mM碳酸氢铵)-乙腈]；乙腈％:15％-45％,8分钟)，得到WX002。 1H NMR(400MHz,氘代甲醇)δ7.93(s,2H),3.48(s,3H),2.79-2.73(m,2H),2.61-2.55(m,2H),1.86(br t,J＝3.1Hz,4H)。MS-ESI m/z:450.1[M-H] -。
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 PCTCN2022081768-appb-000069
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。
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
WX002 11524，29％ 4151，85％
结论：本发明化合物具有显著的THRβ活性和选择性。
实验二：体内药代动力学研究
小鼠口服及静脉注射WX002的药代动力学研究
选取雄性C57BL/6小鼠，按照表2给予受试物。
表2.本发明化合物的给药和采血
Figure PCTCN2022081768-appb-000070
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3和表4所示：
表3.本发明化合物通过静脉给药的药代动力学结果
Figure PCTCN2022081768-appb-000071
表4.本发明化合物通过口服给药的药代动力学结果
Figure PCTCN2022081768-appb-000072
结论：本发明化合物具有良好的药代动力学性质。

Claims (13)

  1. 式(I)所示化合物或其药学上可接受的盐，
    Figure PCTCN2022081768-appb-100001
    其中，
    R 1独立地选自H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-、-C(＝O)-、-S-、-S(＝O) 2、-S(＝O)-、-C(R 4) 2-和
    Figure PCTCN2022081768-appb-100002
    各R 4分别独立地选自H、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 c取代；
    环A选自苯基、5～6元杂芳基、
    Figure PCTCN2022081768-appb-100003
    所述苯基、5～6元杂芳基、
    Figure PCTCN2022081768-appb-100004
    任选被1、2或3个R d取代；
    n和m分别独立地选自0、1和2；
    R a、R b和R c分别独立地选自F、Cl、Br和I；
    各R d分别独立地选自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；
    当环A为苯基或6元杂芳基时，L选自-C(＝O)-、-S-、-S(＝O) 2、-S(＝O)-、-C(R 4) 2-和
    Figure PCTCN2022081768-appb-100005
  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、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 a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 4独立地选自H、CH 3、OCH 3和OCH 2CH 3，所述CH 3、OCH 3和OCH 2CH 3任选被1、2或3个R c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 4独立地选自H、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，L选自-O-、-CH 2-、-C(OCH 2CH 3) 2-和
    Figure PCTCN2022081768-appb-100006
  9. 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 d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。
  10. 根据权利要求9所述化合物或其药学上可接受的盐，其中，R d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。
  11. 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 PCTCN2022081768-appb-100007
    Figure PCTCN2022081768-appb-100008
    所述
    Figure PCTCN2022081768-appb-100009
    Figure PCTCN2022081768-appb-100010
    任选被1、2或3个R d取代。
  12. 根据权利要求11所述化合物或其药学上可接受的盐，其中，环A选自
    Figure PCTCN2022081768-appb-100011
    Figure PCTCN2022081768-appb-100012
  13. 下式化合物或其药学上可接受的盐，
    Figure PCTCN2022081768-appb-100013
    Figure PCTCN2022081768-appb-100014
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