WO2022053028A1 - 1,2,4-triazine-3,5(2h,4h)-diketone compound and application thereof - Google Patents

1,2,4-triazine-3,5(2h,4h)-diketone compound and application thereof Download PDF

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Publication number
WO2022053028A1
WO2022053028A1 PCT/CN2021/117786 CN2021117786W WO2022053028A1 WO 2022053028 A1 WO2022053028 A1 WO 2022053028A1 CN 2021117786 W CN2021117786 W CN 2021117786W WO 2022053028 A1 WO2022053028 A1 WO 2022053028A1
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compound
reaction
added
independently selected
pharmaceutically acceptable
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PCT/CN2021/117786
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French (fr)
Chinese (zh)
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张盛彬
于涛
吴成德
刘金鑫
胡国平
黎健
陈曙辉
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南京明德新药研发有限公司
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Publication of WO2022053028A1 publication Critical patent/WO2022053028A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-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
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines 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
    • C07D253/075—Two hetero atoms, in positions 3 and 5

Definitions

  • the present invention relates to a series of 1,2,4-triazine-3,5(2H,4H)-dione compounds and their applications, in particular to the compounds represented by formula (III) and their pharmaceutically acceptable salts.
  • THR ⁇ thyroid hormone receptor
  • THR ⁇ agonists can reduce body weight, regulate blood lipids, improve glucose tolerance and increase insulin sensitivity, so they become effective targets for the treatment of metabolic diseases such as obesity, dyslipidemia, diabetes and metabolic syndrome.
  • 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.
  • 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).
  • These side effects are thought to be due to agonism of the THR ⁇ isoform and are therefore expected to be avoided by improving target selectivity and liver tissue selectivity.
  • the representative variety of this strategy is MGL-3196, which has entered the third clinical phase, and its safety and efficacy have been further confirmed. Therefore, the development of thyroid hormone analogs with liver tissue distribution specificity and thyroid hormone receptor subtype selectivity is of great clinical value.
  • 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 OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy optionally being replaced by 1, 2 or 3 R a substitutions;
  • R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ; R 4 , R 5 and the carbon atoms attached to them form together
  • R is independently selected from H, F, Cl, Br and I;
  • T is selected from C(R 6 ) 2 ;
  • T 1 and T 2 are each independently selected from C(R 7 ) 2 , NR 8 and O, and T 1 and T 2 are not both C(R 7 ) 2 ;
  • n and m are independently selected from 0, 1 and 2;
  • L is selected from -CH 2 - and -O-;
  • R is independently selected from H and F ;
  • R 7 are each independently selected from H, 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 optional substituted with 1, 2 or 3 R c ;
  • 2 R 6 together with their common carbon atoms form a C 3-5 cycloalkyl optionally substituted with 1, 2 or 3 R ;
  • 2 R 7 together with their common carbon atoms form a C 3-5 cycloalkyl optionally substituted with 1, 2 or 3 R ;
  • R 6 and R 7 together with the carbon atoms to which they are attached form a C 3-5 cycloalkyl optionally substituted with 1, 2 or 3 R c ;
  • R 8 is independently selected from H and C 1-3 alkyl
  • Ring A is selected from a 5- to 6-membered heteroaryl group optionally substituted with 1, 2 or 3 R d ;
  • R a and R b are each independently selected from F, Cl, Br and I;
  • each R c is independently selected from F, Cl, Br and I;
  • Each R d is independently selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy.
  • 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 OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy optionally being replaced by 1, 2 or 3 R a substitutions;
  • R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ; R 4 , R 5 and the carbon atoms attached to them form together
  • R 9 is independently selected from H, F, Cl and Br;
  • T is selected from C(R 6 ) 2 ;
  • T 1 and T 2 are each independently selected from C(R 7 ) 2 , NR 8 and O, and T 1 and T 2 are not both C(R 7 ) 2 ;
  • n and m are independently selected from 0, 1 and 2;
  • L is selected from -CH 2 - and -O-;
  • R is independently selected from H and F ;
  • R 7 are each independently selected from H, 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 optional substituted with 1, 2 or 3 R c ;
  • 2 R 6 together with their common carbon atoms form a C 3-5 cycloalkyl optionally substituted with 1, 2 or 3 R ;
  • 2 R 7 together with their common carbon atoms form a C 3-5 cycloalkyl optionally substituted with 1, 2 or 3 R ;
  • R 6 and R 7 together with the carbon atoms to which they are attached form a C 3-5 cycloalkyl optionally substituted with 1, 2 or 3 R c ;
  • R 8 is independently selected from H and C 1-3 alkyl
  • Ring A is selected from a 5- to 6-membered heteroaryl group optionally substituted with 1, 2 or 3 R d ;
  • R a and R b are each independently selected from F, Cl, Br and I;
  • each R c is independently selected from F, Cl, Br and I;
  • Each R d is independently selected from F, Cl, Br, C 1-3 alkyl and C 1-3 alkoxy.
  • R 1 is independently selected from OH, NH 2 , CH 3 and OCH 3 , and the CH 3 and OCH 3 are optionally substituted by 1, 2 or 3 Ra , and other variables are as in the present invention defined.
  • R 1 is independently selected from OH, NH 2 , CH 3 , CF 3 , OCF 3 and OCH 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 and CH 3 , and other variables are as defined in the present invention.
  • R 7 is independently selected from H, F, Cl, Br, I, CH 3 , OCH 3 , OCH 2 CH 3 and OCH(CH 3 ) 2 , the CH 3 , OCH 3 , OCH 2 CH 3 and OCH(CH 3 ) 2 are optionally substituted with 1, 2 or 3 R c and other variables are as defined herein.
  • R 7 is independently selected from H, F, Cl, Br, I, CH 3 , CHF 2 , CF 3 , OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , OCH 2 CH 3 and OCH( CH3 ) 2 , other variables are as defined in the present invention.
  • R 7 is independently selected from H, F, Cl, Br, I, CH 3 , CHF 2 , CF 3 , OCH 3 , OCH 2 CH 3 and OCH(CH 3 ) 2 , other
  • the variables are as defined in the present invention.
  • the above-mentioned R 6 and R 7 together with the carbon atoms to which they are attached constitute a cyclopropyl group optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention .
  • the above-mentioned ring A is selected from pyrazolyl optionally substituted with 1, 2 or 3 Rd , and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from pyrazolyl, and other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from Other variables are as defined in the present invention.
  • the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • R 1 is independently selected from OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy optionally being replaced by 1, 2 or 3 R a substitutions;
  • R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ; R 4 , R 5 and the atoms connected to them together constitute
  • TR 9 is selected independently from C (R is selected as 6 ) 2 is selected from; H, F, Cl and Br;
  • T 1 and T 2 are each independently selected from C(R 7 ) 2 , NR 8 and O, and T 1 and T 2 are not both C(R 7 ) 2 ;
  • n and m are independently selected from 0, 1 and 2;
  • L is selected from -CH 2 - and -O-;
  • R is independently selected from H and F ;
  • R 7 are each independently selected from H, 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 optional substituted with 1, 2 or 3 R c ;
  • R 6 and R 7 together with the atoms to which they are attached form a C 3-5 cycloalkyl group optionally substituted with 1, 2 or 3 R c ;
  • R 8 is independently selected from H and C 1-3 alkyl
  • R a and R b are each independently selected from F, Cl, Br and I;
  • Each R c 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 selected from OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy optionally being surrounded by 1, 2 or 3 R a replace;
  • R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ; R 4 , R 5 and the atoms connected to them together constitute
  • T is selected from C(R 6 ) 2 ;
  • T 1 and T 2 are each independently selected from C(R 7 ) 2 , NR 8 and O, and T 1 and T 2 are not both C(R 7 ) 2 ;
  • n and m are independently selected from 0, 1 and 2;
  • L is selected from -CH 2 - and O;
  • R is independently selected from H and F ;
  • R 7 are each independently selected from H, 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 optional substituted with 1, 2 or 3 R c ;
  • R 6 and R 7 together with the atoms to which they are attached form a C 3-5 cycloalkyl group optionally substituted with 1, 2 or 3 R c ;
  • R 8 is independently selected from H and C 1-3 alkyl
  • R a and R b are each independently selected from F, Cl, Br and I;
  • Each R c is independently selected from F, Cl, Br and I.
  • R 1 is independently selected from OH, NH 2 , CH 3 and OCH 3 , and the CH 3 and OCH 3 are optionally substituted by 1, 2 or 3 Ra , and other variables are as in the present invention defined.
  • R 1 is selected from OH, NH 2 , CH 3 , CF 3 , OCF 3 and OCH 3 , and other variables are as defined herein.
  • R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH and CH 3 , and other variables are as defined in the present invention.
  • R 7 is independently selected from H, F, Cl, Br, I, CH 3 , OCH 3 , OCH 2 CH 3 and OCH(CH 3 ) 2 , the CH 3 , OCH 3 , OCH 2 CH 3 and OCH(CH 3 ) 2 are optionally substituted with 1, 2 or 3 R c and other variables are as defined herein.
  • R 7 are independently selected from H, F, Cl, Br, I, OH, CH 3 , CHF 2 , CF 3 , OCH 3 , OCH 2 CH 3 and OCH(CH 3 ) 2 , and other variables are as defined in the present invention.
  • R 6 and R 7 together with the atoms to which they are attached form a cyclopropyl group optionally substituted with 1, 2 or 3 R c , other variables are as defined herein.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • R 1 , R 2 , R 3 , R 6 , R 7 , R 9 , X and n are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • T 1 , T 2 , R 1 , R 2 , R 3 and R 6 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 group consisting of
  • 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 the neutral forms of 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 ammonia or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of 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 provided herein also exist in prodrug forms.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
  • 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 and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • 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.
  • tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature.
  • a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
  • proton tautomers also called prototropic tautomers
  • prototropic tautomers include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
  • the enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • 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.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituents When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A.
  • substituents do not specify 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 rings. The carbon atom is attached to the substituted group.
  • the listed linking group does not indicate its direction of attachment, 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.
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
  • Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C1-3alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like.
  • Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 3-5 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system, said C 3-5 cycloalkyl including C 3 -4 and C 4-5 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent.
  • Examples of C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 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 listed below, embodiments formed by their 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 stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl, which is an amine protecting group; BOC stands for tert-butoxycarbonyl, which is an amine protecting group; HOAc stands for acetic acid; rt stands 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-
  • the compound of the present invention has significant THR ⁇ activity or selectivity; the compound of the present invention has no inhibitory effect on CYP1A2, CYP2C19, CYP2D6 and CYP3A4, but has a moderate inhibitory effect on CYP2C9, and the risk of drug-drug interaction is low; the compound of the present invention has excellent Pharmacokinetic properties; the compounds of the present invention are distributed in higher proportions in the liver and less in the heart and plasma.
  • 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 dry the filtrate under reduced pressure.
  • reaction solution was poured into 50 mL of saturated aqueous sodium carbonate solution, extracted with dichloromethane (50 mL*3), the organic phases were combined, and the organic phase was washed with saturated brine (100 mL). Dry over sodium sulfate, filter, and spin dry the filtrate under reduced pressure.
  • WX001-7 (2.05 g, 11.30 mmol, 1.90 mL) in tetrahydrofuran (40 mL) was added WX001-6 (4 g, 10.27 mmol), cesium carbonate (5.02 g, 15.41 mmol), 2,2-bis(diphenylene) phosphino)-1,1-binaphthalene (319.87 mg, 513.71 ⁇ mol), palladium acetate (115.33 mg, 513.71 ⁇ mol), and reacted at 65° C. for 12 hours.
  • WX001-9 (2g, 6.15mmol) was added to the reaction flask, acetic acid (20mL) and hydrochloric acid (1.85g, 18.81mmol, 1.82mL, 37% concentration) were added, the temperature was lowered to 5°C, and sodium nitrite (449.45mg) was added. , 6.51 mmol) in water (5 mL), then stirred at 5 °C for 0.5 hours, added WX001-10 (1.06 g, 6.76 mmol), and stirred at 5 °C for 0.5 hours.
  • WX001-11 (2.3g, 4.67mmol) was added to the reaction flask, N,N-dimethylacetamide (20mL) was added to dissolve the substrate, potassium acetate (916.54mg, 9.34mmol) was added, and the temperature was raised to 120°C Stir for 1 hour. After the reaction was completed, 30 mL of water was added to the reaction solution, ethyl acetate (30 mL*3) was added for extraction, the organic phases were combined, and the organic phase was washed with 50 mL of saturated brine. After separation, the organic phase was dried with anhydrous sodium sulfate and filtered. , the filtrate was spin-dried under reduced pressure to obtain WX001-12.
  • WX002-2 (20 g, 82.96 mmol) and methanol (200 mL) were added to the pre-dried reaction flask, and sodium borohydride (3.77 g, 99.55 mmol) was added in batches at 0 °C, and the nitrogen was replaced three times.
  • the reaction solution was poured into water (200 mL) to quench , the aqueous phase (300 mL*3) was extracted with methyl tert-butyl ether, the organic phases were combined, the organic phase was washed with saturated brine (100 mL), after separation, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed Spin dry.
  • WX002-9 (8 g, 15.95 mmol), tetrahydrofuran (80 mL), and hydrochloric acid (2 M, 31.89 mL) were added to the pre-dried reaction flask, and the mixture was stirred at 25° C. for 1 hour.
  • 50 mL of saturated aqueous sodium carbonate solution was added to the reaction solution, ethyl acetate (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 Dry over sodium sulfate, filter, and spin dry the filtrate under reduced pressure.
  • WX002-11 (8.8g, 17.44mmol) and N,N-dimethylacetamide (90mL) were added to the pre-dried reaction flask, then potassium acetate (1.88g, 19.18mmol) was added, and the nitrogen was replaced three times. Stir at 115°C for 2hrs. After the reaction was completed, 300 mL of water was added to the reaction solution, ethyl acetate (500 mL*3) was added to extract the combined organic phase, washed with saturated brine (200 mL) and separated, the organic phase was dried with anhydrous sodium sulfate, filtered, and the The filtrate was spin-dried under reduced pressure to obtain WX002-12.
  • reaction solution was poured into saturated ammonium chloride solution (30 mL) to quench, then ethyl acetate (30 mL) was added to separate the layers, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (30 mL*2), and the combined The organic phase was washed successively with saturated brine (100 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 (10 mL), water (20 mL) was added for separation, the organic phase was collected, the aqueous phase was extracted with dichloromethane (20 mL*2), and the organic The phase was washed with saturated brine (80 mL*3), 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 (2 mL), water (10 mL) and ethyl acetate (10 mL) were added for separation, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate ( 10 mL*2), the organic phases were combined, washed with saturated brine (60 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • WX004-7 (0.5 g, 1.61 mmol, 1 eq) was added to the pre-dried reaction flask, then dissolved in tetrahydrofuran (5 mL), the reaction system was lowered to 0 °C, and then tert-butyl nitrite (331.13 mg, 3.21 mmol) was added. , 381.93 ⁇ L, 2eq) and tetrahydrofuran (5mL) mixed solution, the reaction was stirred at 0°C for 0.5 hours, WX001-10 (275.76mg, 1.77mmol, 1.1eq) was added, and the mixture was stirred at 0°C for 0.5 hours.
  • Extract with ethyl ester (5 mL*2), combine the organic phases, wash with saturated brine (20 mL*3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product.
  • the crude product was purified by (chromatographic column: Waters Xbridge BEH C18100*30mm*10 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; B(acetonitrile) %: 20%-50%, 8 minutes) to give WX004.
  • WX001-7 (494.30 mg, 2.73 mmol, 457.69 ⁇ L) in tetrahydrofuran (10 mL) was added WX005-1 (1 g, 2.48 mmol), cesium carbonate (1.21 g, 3.72 mmol), 2,2-bis(diphenyl) phosphino)-1,1-binaphthyl (77.20 mg, 123.97 ⁇ mol), palladium acetate (27.83 mg, 123.97 ⁇ mol), and reacted at 65° C. for 12 hours.
  • WX005-4 (0.26g, 513.28 ⁇ mol) was added to the reaction flask, N,N-dimethylacetamide (2mL) was added to dissolve the substrate, potassium acetate (100.75mg, 1.03mmol) was added, and the temperature was raised to 120°C Stir for 1 hour. After the reaction was completed, 30 mL of water was added to the reaction solution, ethyl acetate (30 mL*3) was added for extraction, the organic phases were combined, and the organic phase was washed with 50 mL of saturated brine. After separation, the organic phase was dried with anhydrous sodium sulfate and filtered. , the filtrate was spin-dried under reduced pressure to obtain WX005-5.
  • the reaction solution was poured into water (200 mL) to quench , the aqueous phase (300 mL*3) was extracted with methyl tert-butyl ether, the organic phases were combined, the organic phase was washed with saturated brine (100 mL), after separation, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed Spin dry.
  • WX006-3 (44.17 g, 123.64 mmol) and tetrahydrofuran (170 mL) were added to the pre-dried reaction flask, set at 0° C., then n-butyllithium (2.5 M, 46.16 mL) was slowly added dropwise, stirred for 1 hour, and then WX006-2 (17 g, 82.43 mmol) and tetrahydrofuran (170 mL) were added, and the temperature was naturally raised to 25° C. and stirred for 3 hours.
  • WX006-6 (4 g, 14.03 mmol) and tetrahydrofuran (40 mL) were added to the pre-dried reaction flask, then placed at -78°C and slowly added dropwise n-butyllithium (2.5 M, 6.17 mL), stirred for 1 hour, and then slowly WX001-4 (2.69 g, 12.62 mmol) and tetrahydrofuran (20 mL) were added dropwise, and the mixture was stirred at -78°C for 1 hour.
  • n-butyllithium 2.5 M, 6.17 mL
  • WX006-8 (3.4g, 8.43mmol) and 1-4 dioxane (35mL) were added to the pre-dried reaction flask, followed by cesium carbonate (4.12g, 12.64mmol) and WX001-7 (1.68g, 9.27mmol) , 1.56 mL), replaced nitrogen three times, added tris(dibenzylideneacetone)dipalladium (463.14 mg, 505.76 ⁇ mol) and Xantphos (390.19 mg, 674.35 ⁇ mol), replaced nitrogen again, and stirred at 100° C. for 16 hours.
  • WX006-11 (2.5g, 4.93mmol) and N,N-dimethylacetamide (25mL) were added to the pre-dried reaction flask, then potassium acetate (532.75mg, 5.43mmol) was added, and the nitrogen was replaced three times. Stir at 115°C for 2hrs. After the reaction was completed, 300 mL of water was added to the reaction solution, ethyl acetate (500 mL*3) was added to extract the combined organic phase, washed with saturated brine (200 mL) and separated, the organic phase was dried with anhydrous sodium sulfate, filtered, and the The filtrate was spin-dried under reduced pressure to obtain WX006-12.
  • 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.
  • dichloromethane 200 mL was added for liquid separation, and then dichloromethane (200 mL*2) was added for extraction. After liquid separation, the organic phase was collected, sequentially washed with saturated brine solution (200 mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. When concentrated to 50%, two drops of fractions were taken, and water (1 mL) was added for extraction. The aqueous phase was detected with starch potassium iodide test paper and did not turn blue. After complete concentration, take two drops of the product, add water (1 mL) for extraction, and the aqueous phase is detected with starch potassium iodide test paper and does not change blue.
  • WX011-3 (1 g, 2.83 mmol, 1 eq) and tetrahydrofuran (10 mL) were added to the pre-dried reaction flask. After dropping to 0 °C, tert-butyl nitrite (583.50 mg, 5.66 mmol, 673.01 ⁇ L, 2 eq) was added. The solution of tetrahydrofuran (5 mL) was reacted at 0°C for 0.5 hours, WX001-10 (662.63 mg, 4.24 mmol, 1.5eq) was added, and the reaction was performed at 0°C for 2.5 hours.
  • 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 calculation of the Z factor (>0.5) will be used to monitor the stability of each experiment.
  • the compounds of the present invention have significant THR ⁇ activity or selectivity.
  • 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 (10.0 mM) was serially diluted to prepare working solution (100 ⁇ final concentration), and the working solution concentrations were: 5.00, 1.50, 0.500, 0.150, 0.0500, 0.0150, 0.00500 mM, and P450 co-workers were prepared at the same time.
  • the working solution of each positive inhibitor of enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) and their specific substrate mixture (5 in 1); human liver microsomes stored in a refrigerator below -60 °C are placed on ice Thawed, until all human liver microsomes were dissolved, diluted with PB to prepare a working solution of a certain concentration (0.253 mg/mL).
  • the compound of the present invention has no inhibitory effect on CYP1A2, CYP2C19, CYP2D6 and CYP3A4, but has moderate inhibitory effect on CYP2C9, and the risk of drug-drug interaction is low.
  • test compound was mixed with 10% dimethyl sulfoxide/10% polyethylene glycol stearate in water, vortexed and sonicated to prepare a clear solution.
  • C57BL/6 male mice aged 7 to 10 weeks were selected, and the candidate compound solution was administered intravenously (IV) at a dose of 3 mg/kg.
  • IV intravenously
  • Whole blood was collected for a certain period of time, plasma was prepared, drug concentration was analyzed by LC-MS/MS method, and pharmacokinetic parameters were calculated by Phoenix WinNonlin software (Pharsight, USA).
  • test compound was mixed with 2% hydroxypropylmethylcellulose/0.1% aqueous Tween 80 solution, vortexed and sonicated to prepare a homogeneous suspension for later use.
  • C57BL/6 male mice aged 7 to 10 weeks were selected and administered the candidate compound solution orally (PO) at a dose of 5 mg/kg.
  • Whole blood was collected for a certain period of time, plasma was prepared, drug concentration was analyzed by LC-MS/MS method, and pharmacokinetic parameters were calculated by Phoenix WinNonlin software (Pharsight, USA).
  • IV intravenous injection
  • PO oral
  • DNAUC AUC/administered dose
  • the compounds of the present invention have good pharmacokinetic properties.
  • test compound was mixed with 2% hydroxypropyl methylcellulose/0.1% Tween 80 aqueous solution, vortexed and sonicated to prepare a WX001 homogeneous suspension for later use.
  • C57BL/6 male mice aged 7 to 10 weeks were selected and administered the candidate compound solution orally (PO) at a dose of 5 mg/kg.
  • Whole blood, liver and heart were collected for a certain period of time, samples were prepared, drug concentrations were analyzed by LC-MS/MS method, and pharmacokinetic parameters were calculated by Phoenix WinNonlin software (Pharsight, USA).
  • the compounds of the present invention are distributed in a higher proportion in the liver and less in the heart and plasma.

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Abstract

Disclosed are a series of 1,2,4-triazine-3,5(2H,4H)-diketone compounds and an application thereof. Specifically disclosed are a compound represented by formula (III) and a pharmaceutically acceptable salt thereof.

Description

1,2,4-三嗪-3,5(2H,4H)-二酮类化合物及其应用1,2,4-Triazine-3,5(2H,4H)-diketones and their applications
本申请主张如下优先权This application claims the following priority
CN202010945613.8，申请日：2020年09月10日；CN202010945613.8, application date: September 10, 2020;
CN202110258546.7，申请日：2021年03月09日；CN202110258546.7, application date: March 09, 2021;
CN202110522568.X，申请日：2021年05月13日。CN202110522568.X, application date: May 13, 2021.
技术领域technical field
本发明涉及一系列1,2,4-三嗪-3,5(2H,4H)-二酮类的化合物及其应用，具体涉及式(III)所示化合物及其药学上可接受的盐。The present invention relates to a series of 1,2,4-triazine-3,5(2H,4H)-dione compounds and their applications, in particular to the compounds represented by formula (III) and their pharmaceutically acceptable salts.
背景技术Background technique
甲状腺激素受体(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。THRβ激动剂可以降低体重，调节血脂，改善糖耐量以及增加胰岛素的敏感性，因此成为治疗肥胖，血脂异常，糖尿病和代谢综合症等代谢类疾病有效靶点。There are two subtypes of the thyroid hormone receptor (THR): THRα and THRβ. THRα is mainly distributed in the brain, heart and skeletal muscle, and can control the heart rate. THRβ 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. THRβ agonists can reduce body weight, regulate blood lipids, improve glucose tolerance and increase insulin sensitivity, so they become effective targets for the treatment of metabolic diseases such as obesity, dyslipidemia, diabetes and metabolic syndrome.
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。In the past decades, a variety of THRβ 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. However, 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). These side effects are thought to be due to agonism of the THRα isoform and are therefore expected to be avoided by improving target selectivity and liver tissue selectivity. The representative variety of this strategy is MGL-3196, which has entered the third clinical phase, and its safety and efficacy have been further confirmed. Therefore, the development of thyroid hormone analogs with liver tissue distribution specificity and thyroid hormone receptor subtype selectivity is of great clinical value.
基于文献(J.Med.Chem.2014,57,3912-3923)报道，THRβ激动剂MGL-3196结构如下：Based on literature (J.Med.Chem.2014,57,3912-3923) reports, the structure of THRβ agonist MGL-3196 is as follows:
Figure PCTCN2021117786-appb-000001
Figure PCTCN2021117786-appb-000001
发明内容SUMMARY OF THE INVENTION
本发明提供了式(III)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2021117786-appb-000002
Figure PCTCN2021117786-appb-000002
其中，in,
X选自O、CH 2和C(＝O)； X is selected from O, CH2 and C(=O);
环B选自
Figure PCTCN2021117786-appb-000003
Ring B is selected from
Figure PCTCN2021117786-appb-000003
R 1独立地选自OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R a取代； R 1 is independently selected from OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy optionally being replaced by 1, 2 or 3 R a substitutions;
R 2和R 3分别独立地选自H、F、Cl、Br、I、OH和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代；R 4、R 5和与它们相连的碳原子共同构成
Figure PCTCN2021117786-appb-000004
R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ; R 4 , R 5 and the carbon atoms attached to them form together
Figure PCTCN2021117786-appb-000004
R 9独立地选自H、F、Cl、Br和I； R is independently selected from H, F, Cl, Br and I;
T选自C(R 6) 2； T is selected from C(R 6 ) 2 ;
T 1和T 2分别独立地选自C(R 7) 2、NR 8和O，且T 1和T 2不同时为C(R 7) 2； T 1 and T 2 are each independently selected from C(R 7 ) 2 , NR 8 and O, and T 1 and T 2 are not both C(R 7 ) 2 ;
n和m分别独立地选自0、1和2；n and m are independently selected from 0, 1 and 2;
L选自-CH 2-和-O-； L is selected from -CH 2 - and -O-;
R 6独立地选自H和F； R is independently selected from H and F ;
R 7分别独立地选自H、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R c取代； R 7 are each independently selected from H, 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 optional substituted with 1, 2 or 3 R c ;
或者，2个R 6与它们共有的碳原子共同构成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R c取代； Alternatively, 2 R 6 together with their common carbon atoms form a C 3-5 cycloalkyl optionally substituted with 1, 2 or 3 R ;
或者，2个R 7与它们共有的碳原子共同构成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R c取代； Alternatively, 2 R 7 together with their common carbon atoms form a C 3-5 cycloalkyl optionally substituted with 1, 2 or 3 R ;
或者，R 6和R 7与它们相连的碳原子共同构成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R c取代； Alternatively, R 6 and R 7 together with the carbon atoms to which they are attached form a C 3-5 cycloalkyl optionally substituted with 1, 2 or 3 R c ;
R 8独立地选自H和C 1-3烷基； R 8 is independently selected from H and C 1-3 alkyl;
环A选自5～6元杂芳基，所述5～6元杂芳基任选被1、2或3个R d取代； Ring A is selected from a 5- to 6-membered heteroaryl group optionally substituted with 1, 2 or 3 R d ;
R a和R b分别独立地选自F、Cl、Br和I； R a and R b are each independently selected from F, Cl, Br and I;
各R c独立地选自F、Cl、Br和I； each R c is independently selected from F, Cl, Br and I;
各R d独立地选自F、Cl、Br、I、C 1-3烷基和C 1-3烷氧基。 Each R d is independently selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy.
本发明提供了式(III)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2021117786-appb-000005
Figure PCTCN2021117786-appb-000005
其中，in,
X选自O、CH 2和C(＝O)； X is selected from O, CH2 and C(=O);
环B选自
Figure PCTCN2021117786-appb-000006
Ring B is selected from
Figure PCTCN2021117786-appb-000006
R 1独立地选自OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R a取代； R 1 is independently selected from OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy optionally being replaced by 1, 2 or 3 R a substitutions;
R 2和R 3分别独立地选自H、F、Cl、Br、I、OH和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代；R 4、R 5和与它们相连的碳原子共同构成
Figure PCTCN2021117786-appb-000007
R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ; R 4 , R 5 and the carbon atoms attached to them form together
Figure PCTCN2021117786-appb-000007
R 9独立地选自H、F、Cl和Br； R 9 is independently selected from H, F, Cl and Br;
T选自C(R 6) 2； T is selected from C(R 6 ) 2 ;
T 1和T 2分别独立地选自C(R 7) 2、NR 8和O，且T 1和T 2不同时为C(R 7) 2； T 1 and T 2 are each independently selected from C(R 7 ) 2 , NR 8 and O, and T 1 and T 2 are not both C(R 7 ) 2 ;
n和m分别独立地选自0、1和2；n and m are independently selected from 0, 1 and 2;
L选自-CH 2-和-O-； L is selected from -CH 2 - and -O-;
R 6独立地选自H和F； R is independently selected from H and F ;
R 7分别独立地选自H、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R c取代； R 7 are each independently selected from H, 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 optional substituted with 1, 2 or 3 R c ;
或者，2个R 6与它们共有的碳原子共同构成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R c取代； Alternatively, 2 R 6 together with their common carbon atoms form a C 3-5 cycloalkyl optionally substituted with 1, 2 or 3 R ;
或者，2个R 7与它们共有的碳原子共同构成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R c取代； Alternatively, 2 R 7 together with their common carbon atoms form a C 3-5 cycloalkyl optionally substituted with 1, 2 or 3 R ;
或者，R 6和R 7与它们相连的碳原子共同构成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R c取代； Alternatively, R 6 and R 7 together with the carbon atoms to which they are attached form a C 3-5 cycloalkyl optionally substituted with 1, 2 or 3 R c ;
R 8独立地选自H和C 1-3烷基； R 8 is independently selected from H and C 1-3 alkyl;
环A选自5～6元杂芳基，所述5～6元杂芳基任选被1、2或3个R d取代； Ring A is selected from a 5- to 6-membered heteroaryl group optionally substituted with 1, 2 or 3 R d ;
R a和R b分别独立地选自F、Cl、Br和I； R a and R b are each independently selected from F, Cl, Br and I;
各R c独立地选自F、Cl、Br和I； each R c is independently selected from F, Cl, Br and I;
各R d独立地选自F、Cl、Br、C 1-3烷基和C 1-3烷氧基。 Each R d is independently selected from F, Cl, Br, C 1-3 alkyl and C 1-3 alkoxy.
本发明的一些方案中，上述R 1独立地选自OH、NH 2、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。 In some embodiments of the present invention, the above R 1 is independently selected from OH, NH 2 , CH 3 and OCH 3 , and the CH 3 and OCH 3 are optionally substituted by 1, 2 or 3 Ra , and other variables are as in the present invention defined.
本发明的一些方案中，上述R 1独立地选自OH、NH 2、CH 3、CF 3、OCF 3和OCH 3，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 1 is independently selected from OH, NH 2 , CH 3 , CF 3 , OCF 3 and OCH 3 , and other variables are as defined in the present invention.
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和CH 3，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH and CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 7分别独立地选自H、F、Cl、Br、I、CH 3、OCH 3、OCH 2CH 3和OCH(CH 3) 2，所述CH 3、OCH 3、OCH 2CH 3和OCH(CH 3) 2任选被1、2或3个R c取代，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 7 is independently selected from H, F, Cl, Br, I, CH 3 , OCH 3 , OCH 2 CH 3 and OCH(CH 3 ) 2 , the CH 3 , OCH 3 , OCH 2 CH 3 and OCH(CH 3 ) 2 are optionally substituted with 1, 2 or 3 R c and other variables are as defined herein.
本发明的一些方案中，上述R 7分别独立地选自H、F、Cl、Br、I、CH 3、CHF 2、CF 3、OCH 3、OCH 2F、OCHF 2、OCF 3、OCH 2CH 3和OCH(CH 3) 2，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 7 is independently selected from H, F, Cl, Br, I, CH 3 , CHF 2 , CF 3 , OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , OCH 2 CH 3 and OCH( CH3 ) 2 , other variables are as defined in the present invention.
本发明的一些方案中，上述R 7分别独立地选自H、F、Cl、Br、I、CH 3、CHF 2、CF 3、OCH 3、OCH 2CH 3和OCH(CH 3) 2，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 7 is independently selected from H, F, Cl, Br, I, CH 3 , CHF 2 , CF 3 , OCH 3 , OCH 2 CH 3 and OCH(CH 3 ) 2 , other The variables are as defined in the present invention.
本发明的一些方案中，上述R 6和R 7与它们相连的碳原子共同构成环丙基，所述环丙基任选被1、2或3个R c取代，其他变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 6 and R 7 together with the carbon atoms to which they are attached constitute a cyclopropyl group optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention .
本发明的一些方案中，上述R 6和R 7与它们相连的碳原子共同构成
Figure PCTCN2021117786-appb-000008
其他变量如本发明所定义。 In some embodiments of the present invention, the above R 6 and R 7 together with the carbon atoms to which they are attached constitute
Figure PCTCN2021117786-appb-000008
Other variables are as defined in the present invention.
本发明的一些方案中，上述R 4、R 5和与它们相连的碳原子共同构成
Figure PCTCN2021117786-appb-000009
Figure PCTCN2021117786-appb-000010
其他变量如本发明所定义。 In some embodiments of the present invention, the above R 4 , R 5 and the carbon atoms to which they are attached together constitute
Figure PCTCN2021117786-appb-000009
Figure PCTCN2021117786-appb-000010
Other variables are as defined in the present invention.
本发明的一些方案中，上述R 4、R 5和与它们相连的碳原子共同构成
Figure PCTCN2021117786-appb-000011
Figure PCTCN2021117786-appb-000012
其他变量如本发明所定义。 In some embodiments of the present invention, the above R 4 , R 5 and the carbon atoms to which they are attached together constitute
Figure PCTCN2021117786-appb-000011
Figure PCTCN2021117786-appb-000012
Other variables are as defined in the present invention.
本发明的一些方案中，上述R 4、R 5和与它们相连的碳原子共同构成
Figure PCTCN2021117786-appb-000013
Figure PCTCN2021117786-appb-000014
Figure PCTCN2021117786-appb-000015
其他变量如本发明所定义。 In some embodiments of the present invention, the above R 4 , R 5 and the carbon atoms to which they are attached together constitute
Figure PCTCN2021117786-appb-000013
Figure PCTCN2021117786-appb-000014
Figure PCTCN2021117786-appb-000015
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2021117786-appb-000016
选自
Figure PCTCN2021117786-appb-000017
Figure PCTCN2021117786-appb-000018
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural units
Figure PCTCN2021117786-appb-000016
selected from
Figure PCTCN2021117786-appb-000017
Figure PCTCN2021117786-appb-000018
Other variables are as defined in the present invention.
本发明的一些方案中，上述环A选自吡唑基，所述吡唑基任选被1、2或3个R d取代，其他变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned ring A is selected from pyrazolyl optionally substituted with 1, 2 or 3 Rd , and other variables are as defined in the present invention.
本发明的一些方案中，上述环A选自吡唑基，其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned ring A is selected from pyrazolyl, and other variables are as defined in the present invention.
本发明的一些方案中，上述环B选自
Figure PCTCN2021117786-appb-000019
Figure PCTCN2021117786-appb-000020
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned ring B is selected from
Figure PCTCN2021117786-appb-000019
Figure PCTCN2021117786-appb-000020
Other variables are as defined in the present invention.
本发明提供了式(II)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2021117786-appb-000021
Figure PCTCN2021117786-appb-000021
其中，in,
X独立地选自CH 2和C(＝O)； X is independently selected from CH and C(=O);
R 1独立地选自OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R a取代； R 1 is independently selected from OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy optionally being replaced by 1, 2 or 3 R a substitutions;
R 2和R 3分别独立地选自H、F、Cl、Br、I、OH和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代；R 4、R 5和与它们相连的原子共同构成
Figure PCTCN2021117786-appb-000022
R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ; R 4 , R 5 and the atoms connected to them together constitute
Figure PCTCN2021117786-appb-000022
TR 9选独自立C地(R选 6) 2自；H、F、Cl和Br； TR 9 is selected independently from C (R is selected as 6 ) 2 is selected from; H, F, Cl and Br;
T 1和T 2分别独立地选自C(R 7) 2、NR 8和O，且T 1和T 2不同时为C(R 7) 2； T 1 and T 2 are each independently selected from C(R 7 ) 2 , NR 8 and O, and T 1 and T 2 are not both C(R 7 ) 2 ;
n和m分别独立地选自0、1和2；n and m are independently selected from 0, 1 and 2;
L选自-CH 2-和-O-； L is selected from -CH 2 - and -O-;
R 6独立地选自H和F； R is independently selected from H and F ;
R 7分别独立地选自H、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R c取代； R 7 are each independently selected from H, 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 optional substituted with 1, 2 or 3 R c ;
或者，2个R 6与它们共有的原子共同构成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R c取代； Alternatively, 2 R 6 together with the atoms they have in common form a C 3-5 cycloalkyl optionally substituted with 1, 2 or 3 R ;
或者，2个R 7与它们共有的原子共同构成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R c取代； Alternatively, 2 R7 together with the atoms they have in common form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 Rc ;
或者，R 6和R 7与它们相连的原子共同构成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R c取代； Alternatively, R 6 and R 7 together with the atoms to which they are attached form a C 3-5 cycloalkyl group optionally substituted with 1, 2 or 3 R c ;
R 8独立地选自H和C 1-3烷基； R 8 is independently selected from H and C 1-3 alkyl;
R a和R b分别独立地选自F、Cl、Br和I； R a and R b are each independently selected from F, Cl, Br and I;
各R c独立地选自F、Cl、Br和I。 Each R c is independently selected from F, Cl, Br and I.
本发明提供了式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2021117786-appb-000023
Figure PCTCN2021117786-appb-000023
其中，in,
R 1选自OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R a取代； R 1 is selected from OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy optionally being surrounded by 1, 2 or 3 R a replace;
R 2和R 3分别独立地选自H、F、Cl、Br、I、OH和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代；R 4、R 5和与它们相连的原子共同构成
Figure PCTCN2021117786-appb-000024
R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ; R 4 , R 5 and the atoms connected to them together constitute
Figure PCTCN2021117786-appb-000024
T选自C(R 6) 2； T is selected from C(R 6 ) 2 ;
T 1和T 2分别独立地选自C(R 7) 2、NR 8和O，且T 1和T 2不同时为C(R 7) 2； T 1 and T 2 are each independently selected from C(R 7 ) 2 , NR 8 and O, and T 1 and T 2 are not both C(R 7 ) 2 ;
n和m分别独立地选自0、1和2；n and m are independently selected from 0, 1 and 2;
L选自-CH 2-和O； L is selected from -CH 2 - and O;
R 6独立地选自H和F； R is independently selected from H and F ;
R 7分别独立地选自H、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R c取代； R 7 are each independently selected from H, 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 optional substituted with 1, 2 or 3 R c ;
或者，2个R 6与它们共有的原子共同构成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R c取代； Alternatively, 2 R 6 together with the atoms they have in common form a C 3-5 cycloalkyl optionally substituted with 1, 2 or 3 R ;
或者，2个R 7与它们共有的原子共同构成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R c取代； Alternatively, 2 R7 together with the atoms they have in common form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 Rc ;
或者，R 6和R 7与它们相连的原子共同构成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R c取代； Alternatively, R 6 and R 7 together with the atoms to which they are attached form a C 3-5 cycloalkyl group optionally substituted with 1, 2 or 3 R c ;
R 8独立地选自H和C 1-3烷基； R 8 is independently selected from H and C 1-3 alkyl;
R a和R b分别独立地选自F、Cl、Br和I； R a and R b are each independently selected from F, Cl, Br and I;
各R c独立地选自F、Cl、Br和I。 Each R c is independently selected from F, Cl, Br and I.
本发明的一些方案中，上述R 1独立地选自OH、NH 2、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。 In some embodiments of the present invention, the above R 1 is independently selected from OH, NH 2 , CH 3 and OCH 3 , and the CH 3 and OCH 3 are optionally substituted by 1, 2 or 3 Ra , and other variables are as in the present invention defined.
本发明的一些方案中，上述独立地R 1选自OH、NH 2、CH 3、CF 3、OCF 3和OCH 3，其他变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned independently R 1 is selected from OH, NH 2 , CH 3 , CF 3 , OCF 3 and OCH 3 , and other variables are as defined herein.
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和CH 3，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH and CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 7分别独立地选自H、F、Cl、Br、I、CH 3、OCH 3、OCH 2CH 3和OCH(CH 3) 2，所述CH 3、OCH 3、OCH 2CH 3和OCH(CH 3) 2任选被1、2或3个R c取代，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 7 is independently selected from H, F, Cl, Br, I, CH 3 , OCH 3 , OCH 2 CH 3 and OCH(CH 3 ) 2 , the CH 3 , OCH 3 , OCH 2 CH 3 and OCH(CH 3 ) 2 are optionally substituted with 1, 2 or 3 R c and other variables are as defined herein.
本发明的一些方案中，上述R 7分别独立地选自H、F、Cl、Br、I、OH、CH 3、CHF 2、CF 3、OCH 3、OCH 2CH 3和OCH(CH 3) 2，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 7 are independently selected from H, F, Cl, Br, I, OH, CH 3 , CHF 2 , CF 3 , OCH 3 , OCH 2 CH 3 and OCH(CH 3 ) 2 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 6和R 7与它们相连的原子共同构成环丙基，所述环丙基任选被1、2或3个R c取代，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 6 and R 7 together with the atoms to which they are attached form a cyclopropyl group optionally substituted with 1, 2 or 3 R c , other variables are as defined herein.
本发明的一些方案中，上述R 6和R 7与它们相连的原子共同构成
Figure PCTCN2021117786-appb-000025
其他变量如本发明所定义。 In some aspects of the present invention, the above R 6 and R 7 together with the atoms to which they are attached constitute
Figure PCTCN2021117786-appb-000025
Other variables are as defined in the present invention.
本发明的一些方案中，上述R 4、R 5和与它们相连的原子共同构成
Figure PCTCN2021117786-appb-000026
Figure PCTCN2021117786-appb-000027
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 4 , R 5 and the atoms connected to them form together
Figure PCTCN2021117786-appb-000026
Figure PCTCN2021117786-appb-000027
Other variables are as defined in the present invention.
本发明的一些方案中，上述R 4、R 5和与它们相连的原子共同构成
Figure PCTCN2021117786-appb-000028
Figure PCTCN2021117786-appb-000029
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 4 , R 5 and the atoms connected to them form together
Figure PCTCN2021117786-appb-000028
Figure PCTCN2021117786-appb-000029
Other variables are as defined in the present invention.
本发明的一些方案中，上述R 4、R 5和与它们相连的原子共同构成
Figure PCTCN2021117786-appb-000030
Figure PCTCN2021117786-appb-000031
Figure PCTCN2021117786-appb-000032
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 4 , R 5 and the atoms connected to them form together
Figure PCTCN2021117786-appb-000030
Figure PCTCN2021117786-appb-000031
Figure PCTCN2021117786-appb-000032
Other variables are as defined in the present invention.
本发明的一些方案中，上述R 4、R 5和与它们相连的原子共同构成
Figure PCTCN2021117786-appb-000033
Figure PCTCN2021117786-appb-000034
Figure PCTCN2021117786-appb-000035
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 4 , R 5 and the atoms connected to them form together
Figure PCTCN2021117786-appb-000033
Figure PCTCN2021117786-appb-000034
Figure PCTCN2021117786-appb-000035
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2021117786-appb-000036
选自
Figure PCTCN2021117786-appb-000037
Figure PCTCN2021117786-appb-000038
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural units
Figure PCTCN2021117786-appb-000036
selected from
Figure PCTCN2021117786-appb-000037
Figure PCTCN2021117786-appb-000038
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2021117786-appb-000039
选自
Figure PCTCN2021117786-appb-000040
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural units
Figure PCTCN2021117786-appb-000039
selected from
Figure PCTCN2021117786-appb-000040
Other variables are as defined in the present invention.
本发明还有一些方案是由上述各变量任意组合而来。There are still some solutions of the present invention which are obtained by any combination of the above variables.
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In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of
Figure PCTCN2021117786-appb-000041
Figure PCTCN2021117786-appb-000041
其中，in,
R 1、R 2、R 3、R 6、R 7、R 9、X和n如本发明所定义。 R 1 , R 2 , R 3 , R 6 , R 7 , R 9 , X and n are as defined in the present invention.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of
Figure PCTCN2021117786-appb-000042
Figure PCTCN2021117786-appb-000042
其中，in,
T 1、T 2、R 1、R 2、R 3和R 6如本发明所定义。 T 1 , T 2 , R 1 , R 2 , R 3 and R 6 are as defined in the present invention.
本发明还提供了下式所示化合物或其药学上可接受的盐，The present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
Figure PCTCN2021117786-appb-000043
Figure PCTCN2021117786-appb-000043
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In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of
Figure PCTCN2021117786-appb-000044
Figure PCTCN2021117786-appb-000044
本发明的一些方案中，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。In some aspects of the present invention, the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of nonalcoholic steatohepatitis.
定义和说明Definition and Explanation
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。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without specific definitions, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient. As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, 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.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。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。The term "pharmaceutically acceptable 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. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of 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 ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of 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 or acid addition salts.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present invention can be synthesized from the 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.
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被 转换到本发明的化合物。In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。Certain compounds of the present invention may exist in unsolvated as well as solvated forms, including hydrated forms. In general, solvated and unsolvated forms are equivalent and are intended to be included within the scope of the present invention.
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(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the 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 and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise indicated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise indicated, the term "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.
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。Unless otherwise specified, "(D)" or "(+)" means dextrorotatory, "(L)" or "(-)" means levorotatory, and "(DL)" or "(±)" means racemic.
除非另有说明，用楔形实线键
Figure PCTCN2021117786-appb-000045
和楔形虚线键
Figure PCTCN2021117786-appb-000046
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2021117786-appb-000047
和直形虚线键
Figure PCTCN2021117786-appb-000048
表示立体中心的相对构型，用波浪线
Figure PCTCN2021117786-appb-000049
表示楔形实线键
Figure PCTCN2021117786-appb-000050
或楔形虚线键
Figure PCTCN2021117786-appb-000051
或用波浪线
Figure PCTCN2021117786-appb-000052
表示直形实线键
Figure PCTCN2021117786-appb-000053
和直形虚线键
Figure PCTCN2021117786-appb-000054
Use solid wedge keys unless otherwise specified
Figure PCTCN2021117786-appb-000045
and wedge-dotted keys
Figure PCTCN2021117786-appb-000046
Indicate the absolute configuration of a stereocenter, using a straight solid key
Figure PCTCN2021117786-appb-000047
and straight dashed keys
Figure PCTCN2021117786-appb-000048
Indicate the relative configuration of the stereocenter, with a wavy line
Figure PCTCN2021117786-appb-000049
Represents a solid wedge key
Figure PCTCN2021117786-appb-000050
or wedge-dotted key
Figure PCTCN2021117786-appb-000051
or with wavy lines
Figure PCTCN2021117786-appb-000052
Represents a straight solid key
Figure PCTCN2021117786-appb-000053
and straight dashed keys
Figure PCTCN2021117786-appb-000054
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。The compounds of the present invention may exist in particular. Unless otherwise specified, the term "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). For example, proton tautomers (also called prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。Unless otherwise indicated, 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%.
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体 过量(ee值)为80％。Unless otherwise indicated, the terms "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% .
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。 Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the 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. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a 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. In addition, 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. For example, compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). For another example, 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.
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。The terms "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. .
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。The term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable. When the substituent is oxygen (ie =O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。 When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups connected to it are directly connected, for example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
当一个取代基为空缺时，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 PCTCN2021117786-appb-000055
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 PCTCN2021117786-appb-000056
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 PCTCN2021117786-appb-000057
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。 When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A. When the listed substituents do not specify 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 rings. The carbon atom is attached to the substituted group. When the listed linking group does not indicate its direction of attachment, the direction of attachment is arbitrary, for example,
Figure PCTCN2021117786-appb-000055
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.
Figure PCTCN2021117786-appb-000056
It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
Figure PCTCN2021117786-appb-000057
Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
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。 Unless otherwise specified, the term "C 1-3 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 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.
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。 Unless otherwise specified, the term " 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.
除非另有规定，“C 3-5环烷基”表示由3至5个碳原子组成的饱和环状碳氢基团，其为单环体系，所述C 3-5环烷基包括C 3-4和C 4-5环烷基等；其可以是一价、二价或者多价。C 3-5环烷基的实例包括，但不限于，环丙基、环丁基、环戊基等。 Unless otherwise specified, "C 3-5 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system, said C 3-5 cycloalkyl including C 3 -4 and C 4-5 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. Examples of C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
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)。 Unless otherwise specified, 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 π 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-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2- -pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).
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。 Unless otherwise specified, 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-membered ring, 9-membered ring , 10-membered ring, 11-membered ring, and 12-membered ring, also including any one range from n to n+m, for example, 3-12-membered ring includes 3-6 membered ring, 3-9 membered ring, 5-6 membered ring ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, etc.
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 PCTCN2021117786-appb-000058
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。 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 CuKα radiation, and the scanning mode is:
Figure PCTCN2021117786-appb-000058
After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by their 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.
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；HOAc代表乙酸；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。 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 stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl, which is an amine protecting group; BOC stands for tert-butoxycarbonyl, which is an amine protecting group; HOAc stands for acetic acid; rt stands 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.
化合物依据本领域常规命名原则或者使用
Figure PCTCN2021117786-appb-000059
软件命名，市售化合物采用供应商目录名称。技术效果 Compounds are named according to conventional nomenclature in the art or are used
Figure PCTCN2021117786-appb-000059
Software naming, commercially available compounds use supplier catalog names. technical effect
本发明化合物具有显著的THRβ活性或选择性；本发明化合物对CYP1A2、CYP2C19、CYP2D6和CYP3A4均无抑制作用，对CYP2C9有中等抑制作用，药物-药物相互作用风险较低；本发明化合物具有优异的药代动力学性质；本发明化合物在肝脏中分布比例较高，在心脏和血浆中较少。The compound of the present invention has significant THRβ activity or selectivity; the compound of the present invention has no inhibitory effect on CYP1A2, CYP2C19, CYP2D6 and CYP3A4, but has a moderate inhibitory effect on CYP2C9, and the risk of drug-drug interaction is low; the compound of the present invention has excellent Pharmacokinetic properties; the compounds of the present invention are distributed in higher proportions in the liver and less in the heart and plasma.
具体实施方式detailed description
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention will be described in detail by the following examples, but it does not mean any unfavorable limitation of the present invention. The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed. For those skilled in the art, various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention. will be obvious.
实施例1Example 1
Figure PCTCN2021117786-appb-000060
Figure PCTCN2021117786-appb-000060
合成路线：synthetic route:
Figure PCTCN2021117786-appb-000061
Figure PCTCN2021117786-appb-000061
步骤1：化合物WX001-2的合成Step 1: Synthesis of compound WX001-2
在预先干燥的反应瓶中加入WX001-1(5g,33.74mmol)和乙腈(50mL)，加入N-溴代丁二酰亚胺(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)。 Add WX001-1 (5 g, 33.74 mmol) and acetonitrile (50 mL) to the pre-dried reaction flask, add N-bromosuccinimide (6.61 g, 37.11 mmol), replace nitrogen three times, and place at 25°C Stir for 16 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the concentrate was added with methyl tert-butyl ether (200 mL) to make a slurry, slurried at 25° C. for 30 minutes, filtered, and the filtrate was collected. The filtrate was washed with saturated brine (200 mL*2), The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain WX001-2. 1 H NMR (400MHz, deuterated chloroform) δ 7.29-7.30 (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Step 2: Synthesis of compound WX001-3
在预先干燥的反应瓶中加入WX001-2(6.2g,27.30mmol)和N,N-二甲基甲酰胺(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)。 WX001-2 (6.2 g, 27.30 mmol) and N,N-dimethylformamide (140 mL) were added to the pre-dried reaction flask, cesium carbonate (22.24 g, 68.25 mmol) was added in batches at 0°C, and nitrogen was replaced. Three times, chloromethyl methyl ether (3.30 g, 40.95 mmol, 3.11 mL) was slowly added dropwise at 0 °C, stirring was continued at 0 °C for 2 hours, and additional chloromethyl methyl ether (1.76 g, 21.84 mmol, 1.66 mL) was added. , 0.8eq), and continued stirring at 0 °C for 1 hour. After the reaction was completed, the 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. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 20:1) to give WX001-3. 1 H NMR (400MHz, deuterated chloroform) 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Step 3: Synthesis of Compound WX001-5
在预先干燥的反应瓶中，加WX001-3(6g,22.13mmol)和四氢呋喃(60mL)，降温至-78℃，加入正丁基锂(2.5M,9.29mL)，保持-78℃搅拌1小时，加入四氢呋喃(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。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)。 In a pre-dried reaction flask, add WX001-3 (6g, 22.13mmol) and tetrahydrofuran (60mL), cool down to -78°C, add n-butyllithium (2.5M, 9.29mL), keep at -78°C and stir for 1 hour , a mixed solution of tetrahydrofuran (6 mL) and WX001-4 (4.71 g, 22.13 mmol) was added, and stirring was continued at -78° C. for 1 hour. After the reaction was completed, the 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 dry the filtrate under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=2% to 5%) to obtain WX001-5. 1 H NMR (400MHz, deuterated chloroform) δ 7.10 (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Step 4: Synthesis of compound WX001-6
在预先干燥的反应瓶中，加入WX001-5(8.4g,20.72mmol)和二氯甲烷(100mL)，降温至0℃，然后加入三乙基硅烷(3.61g,31.09mmol,4.97mL)，三氟乙酸(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，加入二氯甲烷(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。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)。 In a pre-dried reaction flask, add WX001-5 (8.4g, 20.72mmol) and dichloromethane (100mL), cool down to 0°C, then add triethylsilane (3.61g, 31.09mmol, 4.97mL), triethylsilane (3.61g, 31.09mmol, 4.97mL), triethylsilane Fluoroacetic acid (3.54 g, 31.09 mmol, 2.30 mL), the reaction system was stirred at 0 °C for 1 hour. After the reaction was completed, the reaction solution was poured into 50 mL of saturated aqueous sodium carbonate solution, extracted with dichloromethane (50 mL*3), the organic phases were combined, and the organic phase was washed with saturated brine (100 mL). Dry over sodium sulfate, filter, and spin dry the filtrate under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=2% to 5% to 10%) to give WX001-6. 1 H NMR (400MHz, deuterated chloroform) 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Step 5: Synthesis of Compound WX001-8
向WX001-7(2.05g,11.30mmol,1.90mL)的四氢呋喃(40mL)溶液中加入WX001-6(4g,10.27mmol)，碳酸铯(5.02g,15.41mmol)，2,2-双(二苯膦基)-1,1-联萘(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。To a solution of WX001-7 (2.05 g, 11.30 mmol, 1.90 mL) in tetrahydrofuran (40 mL) was added WX001-6 (4 g, 10.27 mmol), cesium carbonate (5.02 g, 15.41 mmol), 2,2-bis(diphenylene) phosphino)-1,1-binaphthalene (319.87 mg, 513.71 μmol), palladium acetate (115.33 mg, 513.71 μmol), and reacted at 65° C. for 12 hours. After the reaction was completed, water (50 mL) was added to the reaction solution, ethyl acetate (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 to obtain WX001-8.
步骤6：化合物WX001-9的合成Step 6: Synthesis of Compound WX001-9
在预先干燥的反应瓶中，加入WX001-8(4.5g,9.19mmol)和盐酸(8mL)，四氢呋喃(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)。 In a pre-dried reaction flask, WX001-8 (4.5 g, 9.19 mmol), hydrochloric acid (8 mL) and tetrahydrofuran (40 mL) were added, and the mixture was stirred at 25° C. for 1 hour. After the reaction was completed, 50 mL of saturated aqueous sodium carbonate solution was added to the reaction solution, ethyl acetate (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 Dry over sodium sulfate, filter, and spin dry the filtrate under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=5% to 10% to 20%) to give WX001-9. 1 H NMR (400MHz, deuterated chloroform) δ 6.66-6.68(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Step 7: Synthesis of compound WX001-11
将WX001-9(2g,6.15mmol)加入到反应瓶中，加醋酸(20mL)和盐酸(1.85g,18.81mmol,1.82mL,37％浓度)，降温至5℃，加入亚硝酸钠(449.45mg,6.51mmol)的水(5mL)溶液，然后在5℃下搅拌0.5小时，加入WX001-10(1.06g,6.76mmol)，在5℃下搅拌0.5小时。反应完成后，向反应液中加入5 mL饱和乙酸钠水溶液，过滤，滤饼用5mL水洗涤，将滤饼减压旋干，得到WX001-11。 1H NMR(400MHz,氘代氯仿)δ9.36(s,1H),8.54(s,1H),7.03(s,2H),6.67-6.69(d,J＝8.4Hz,1H),6.18-6.21(d,J＝8.4Hz,1H),5.14(s,2H)，4.32-4.37(m,2H),3.77(s,2H),3.46(s,3H),2.74-2.80(m,4H),2.20(s,6H),1.82-1.89(m,4H),1.27-1.39(m,3H)。 WX001-9 (2g, 6.15mmol) was added to the reaction flask, acetic acid (20mL) and hydrochloric acid (1.85g, 18.81mmol, 1.82mL, 37% concentration) were added, the temperature was lowered to 5°C, and sodium nitrite (449.45mg) was added. , 6.51 mmol) in water (5 mL), then stirred at 5 °C for 0.5 hours, added WX001-10 (1.06 g, 6.76 mmol), and stirred at 5 °C for 0.5 hours. After the reaction was completed, 5 mL of saturated aqueous sodium acetate solution was added to the reaction solution, filtered, the filter cake was washed with 5 mL of water, and the filter cake was spin-dried under reduced pressure to obtain WX001-11. 1 H NMR (400MHz, deuterated chloroform) δ 9.36(s, 1H), 8.54(s, 1H), 7.03(s, 2H), 6.67-6.69(d, J=8.4Hz, 1H), 6.18-6.21 (d, J=8.4Hz, 1H), 5.14(s, 2H), 4.32-4.37(m, 2H), 3.77(s, 2H), 3.46(s, 3H), 2.74-2.80(m, 4H), 2.20(s, 6H), 1.82-1.89(m, 4H), 1.27-1.39(m, 3H).
步骤8：化合物WX001-12的合成Step 8: Synthesis of Compound WX001-12
将WX001-11(2.3g,4.67mmol)加入到反应瓶中，加入N,N-二甲基乙酰胺(20mL)将底物溶解，加入乙酸钾(916.54mg,9.34mmol)，升温至120℃搅拌1小时。反应完成后，向反应液中加入30mL水，加入乙酸乙酯(30mL*3)萃取，合并有机相，有机相用50mL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WX001-12。WX001-11 (2.3g, 4.67mmol) was added to the reaction flask, N,N-dimethylacetamide (20mL) was added to dissolve the substrate, potassium acetate (916.54mg, 9.34mmol) was added, and the temperature was raised to 120°C Stir for 1 hour. After the reaction was completed, 30 mL of water was added to the reaction solution, ethyl acetate (30 mL*3) was added for extraction, the organic phases were combined, and the organic phase was washed with 50 mL of saturated brine. After separation, the organic phase was dried with anhydrous sodium sulfate and filtered. , the filtrate was spin-dried under reduced pressure to obtain WX001-12.
步骤9：化合物WX001的合成Step 9: Synthesis of Compound WX001
向WX001-12(1.9g,4.26mmol)的甲醇(5mL)溶液中，加入盐酸(419.33mg,4.26mmol,411.11μL,37％浓度)，在50℃下反应0.5小时。反应完成后，反应液直接旋干，粗品通过制备高效液相色谱柱纯化(色谱柱:Phenomenex luna C18 250*50mm*10μm；流动相:[水(0.04％盐酸)-乙腈]；B(乙腈)％:45％-75％,10分钟)，得到WX001。 1H NMR(400MHz,氘代二甲基亚砜)δ12.98(s,1H),8.91(s,1H),7.17(s,2H),6.40-6.42(d,J＝8Hz,1H),5.92-5.94(d,J＝8.4Hz,1H),3.74(s,2H),2.73-2.74(m,2H),2.49-2.50(m,2H),2.07(s,6H),1.71-1.80(m,4H)。MS-ESI m/z:401.1[M-H] -。 To a solution of WX001-12 (1.9 g, 4.26 mmol) in methanol (5 mL), hydrochloric acid (419.33 mg, 4.26 mmol, 411.11 μL, 37% concentration) was added, and the reaction was carried out at 50° C. for 0.5 hour. After the reaction was completed, the reaction solution was directly spin-dried, and the crude product was purified by a preparative high performance liquid chromatography column (chromatographic column: Phenomenex luna C18 250*50mm*10μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; B (acetonitrile) %: 45%-75%, 10 minutes) to get WX001. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 12.98(s, 1H), 8.91(s, 1H), 7.17(s, 2H), 6.40-6.42(d, J=8Hz, 1H), 5.92-5.94(d, J=8.4Hz, 1H), 3.74(s, 2H), 2.73-2.74(m, 2H), 2.49-2.50(m, 2H), 2.07(s, 6H), 1.71-1.80( m, 4H). MS-ESI m/z: 401.1 [MH] - .
实施例2Example 2
Figure PCTCN2021117786-appb-000062
Figure PCTCN2021117786-appb-000062
合成路线：synthetic route:
Figure PCTCN2021117786-appb-000063
Figure PCTCN2021117786-appb-000063
步骤1：化合物WX002-2的合成Step 1: Synthesis of compound WX002-2
在预先干燥的反应瓶中加入WX002-1(15g,92.49mmol)和乙腈(150mL)，加入N-溴代丁二酰亚胺(18.11g,101.74mmol)，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WX002-2。 1H NMR(400MHz,氘代氯仿)δ12.56(s,1H),7.59(d,J＝8.9Hz,1H),6.74(d,J＝8.9Hz,1H),2.97(t,J＝6.2Hz,2H),2.73-2.64(m,2H),2.19-2.04(m,2H)。 Add WX002-1 (15 g, 92.49 mmol) and acetonitrile (150 mL) to the pre-dried reaction flask, add N-bromosuccinimide (18.11 g, 101.74 mmol), replace nitrogen three times, and place at 25°C Stir for 16 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the concentrate was added with methyl tert-butyl ether (200 mL) to make a slurry, slurried at 25° C. for 30 minutes, filtered, and the filtrate was collected. The filtrate was washed with saturated brine (200 mL*2), The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain WX002-2. 1 H NMR (400 MHz, deuterated chloroform) δ 12.56 (s, 1H), 7.59 (d, J=8.9 Hz, 1H), 6.74 (d, J=8.9 Hz, 1H), 2.97 (t, J=6.2 Hz, 2H), 2.73-2.64 (m, 2H), 2.19-2.04 (m, 2H).
步骤2：化合物WX002-3的合成Step 2: Synthesis of compound WX002-3
在预先干燥的反应瓶中加入WX002-2(20g,82.96mmol)和甲醇(200mL)，0℃下分批加入硼氢化钠(3.77g,99.55mmol)，置换氮气三次，置于0℃下继续搅拌0.5小时，反应完成后，将反应液倒入2M HCl(150mL)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，得到WX002-3。WX002-2 (20 g, 82.96 mmol) and methanol (200 mL) were added to the pre-dried reaction flask, and sodium borohydride (3.77 g, 99.55 mmol) was added in batches at 0 °C, and the nitrogen was replaced three times. Stir for 0.5 hours, after the reaction is completed, pour the reaction solution into 2M HCl (150mL) to quench, extract the aqueous phase (100mL*3) with methyl tert-butyl ether, combine the organic phases, wash with saturated brine (150mL*3) , the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain WX002-3.
步骤3：化合物WX002-4的合成Step 3: Synthesis of Compound WX002-4
在预先干燥的反应瓶中，加WX002-3(25g,102.84mmol)和四氢呋喃(250mL)，然后加入磷酸(151.17g,1.54mol,89.98mL)，置换氮气三次，置于80℃搅拌16hr。反应完成后，将反应液冷却至室温，将反应液缓慢倒入饱和碳酸氢钠水溶液(800mL)调pH至6-7，加入乙酸乙酯(500mL)分液，收集有机相，水相用乙酸乙酯萃取(500mL*2),合并有机相，用饱和食盐水洗涤(500mL*2)，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＝10％转50％)纯化，得到WX002-4。 1H NMR(400MHz,氘代氯仿)δ7.22(d,J＝8.6Hz,1H),6.71(td,J＝1.9,9.8Hz,1H),6.54(d,J＝8.6Hz,1H),6.13-6.06(m,1H),4.68(s,1H),2.88(t,J＝8.3Hz,2H),2.34(ddt,J＝1.9,4.5,8.3Hz,2H)。 In a pre-dried reaction flask, add WX002-3 (25 g, 102.84 mmol) and tetrahydrofuran (250 mL), then add phosphoric acid (151.17 g, 1.54 mol, 89.98 mL), replace nitrogen three times, and stir at 80° C. for 16 hr. After the reaction was completed, the reaction solution was cooled to room temperature, the reaction solution was slowly poured into saturated aqueous sodium bicarbonate solution (800 mL) to adjust pH to 6-7, ethyl acetate (500 mL) was added for separation, the organic phase was collected, and acetic acid was used for the aqueous phase. Ethyl ester extraction (500mL*2), combined organic phases, washed with saturated brine (500mL*2), after separation, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=10% to 50%) to obtain WX002-4. 1 H NMR (400MHz, deuterated chloroform) δ 7.22 (d, J=8.6Hz, 1H), 6.71 (td, J=1.9, 9.8Hz, 1H), 6.54 (d, J=8.6Hz, 1H), 6.13-6.06 (m, 1H), 4.68 (s, 1H), 2.88 (t, J=8.3Hz, 2H), 2.34 (ddt, J=1.9, 4.5, 8.3Hz, 2H).
步骤4：化合物WX002-5的合成Step 4: Synthesis of compound WX002-5
在预先干燥的反应瓶中，加入WX002-4(20g,88.86mmol)和N,N-二甲基甲酰胺(200mL)，0℃下分批加入碳酸铯(86.85g,266.57mmol)，置换氮气三次，0℃下缓慢滴入氯甲基甲醚(14.31g,177.71mmol,13.50mL)，置于0℃下继续搅拌2小时，反应完成后，将反应液倒入水(200mL)中淬灭，甲基叔丁基醚萃取水相(300mL*3)，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。粗品经柱层析(乙酸乙酯：石油醚＝2％转5％转30％)纯化，得到WX002-5。 1H NMR(400MHz,氘代氯仿)δ7.29(d,J＝8.9Hz,1H),6.88-6.79(m,2H),6.12-6.02(m,1H),5.17(s,2H),3.49(s,3H),2.88(t,J＝8.4Hz,2H),2.33(ddt,J＝1.9,4.5,8.4Hz,2H)。 In a pre-dried reaction flask, WX002-4 (20 g, 88.86 mmol) and N,N-dimethylformamide (200 mL) were added, and cesium carbonate (86.85 g, 266.57 mmol) was added in batches at 0°C to replace nitrogen. Three times, chloromethyl methyl ether (14.31 g, 177.71 mmol, 13.50 mL) was slowly added dropwise at 0 °C, and the stirring was continued at 0 °C for 2 hours. After the reaction was completed, the reaction solution was poured into water (200 mL) to quench , the aqueous phase (300 mL*3) was extracted with methyl tert-butyl ether, the organic phases were combined, the organic phase was washed with saturated brine (100 mL), after separation, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed Spin dry. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=2% to 5% to 30%) to give WX002-5. 1 H NMR (400 MHz, deuterated chloroform) δ 7.29 (d, J=8.9 Hz, 1H), 6.88-6.79 (m, 2H), 6.12-6.02 (m, 1H), 5.17 (s, 2H), 3.49 (s, 3H), 2.88 (t, J=8.4 Hz, 2H), 2.33 (ddt, J=1.9, 4.5, 8.4 Hz, 2H).
步骤5：化合物WX002-6的合成Step 5: Synthesis of compound WX002-6
在预先干燥的反应瓶中，加入二氯甲烷(300mL)，氮气置换三次，降温至-70℃，加入二乙基锌(1M,55.73mL)，然后加入二碘甲烷(29.85g,111.47mmol,8.99mL)，置于0℃搅拌30分钟后加入WX002-5(3g,11.15mmol)和二氯甲烷(50mL)的混合溶液，加料完成，升温至20℃搅拌8.5小时。反应完成后，反应液用2M柠檬酸水溶液中(1000mL)，加入二氯甲烷(800mL)分液，收集有机相，水相用二氯甲烷萃取(500mL*2)，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30％)纯化，得到WX002-6。 1H NMR(400MHz,氘代氯仿)δ7.27(s,1H),6.86(d,J＝4.3Hz,1H),5.21(d,J＝5.0Hz,2H),3.52(s,3H),3.03(dd,J＝5.3,16.1Hz,1H),2.38-2.35(m,1H),2.24-2.10(m,2H),1.80-1.68(m,1H),1.61-1.53(m,1H),0.92(dt,J＝4.8,8.5Hz,1H),0.78(q,J＝4.9Hz,1H)。 In the pre-dried reaction flask, add dichloromethane (300mL), replace with nitrogen three times, cool down to -70°C, add diethylzinc (1M, 55.73mL), then add diiodomethane (29.85g, 111.47mmol, 8.99 mL), placed at 0 °C and stirred for 30 minutes, and then added a mixed solution of WX002-5 (3 g, 11.15 mmol) and dichloromethane (50 mL), the addition was completed, and the temperature was raised to 20 °C and stirred for 8.5 hours. After the completion of the reaction, the reaction solution was used in 2M citric acid aqueous solution (1000mL), dichloromethane (800mL) was added to separate the layers, the organic phase was collected, the aqueous phase was extracted with dichloromethane (500mL*2), the organic phases were combined, and the organic phase used Washed with saturated brine (50 mL), after separation, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the crude product was subjected to column chromatography (ethyl acetate: petroleum ether=5% to 10% to 30 %) to obtain WX002-6. 1 H NMR (400MHz, deuterated chloroform) δ 7.27(s, 1H), 6.86(d, J=4.3Hz, 1H), 5.21(d, J=5.0Hz, 2H), 3.52(s, 3H), 3.03(dd, J＝5.3, 16.1Hz, 1H), 2.38-2.35(m, 1H), 2.24-2.10(m, 2H), 1.80-1.68(m, 1H), 1.61-1.53(m, 1H), 0.92 (dt, J=4.8, 8.5 Hz, 1H), 0.78 (q, J=4.9 Hz, 1H).
步骤6：化合物WX002-7的合成Step 6: Synthesis of Compound WX002-7
在预先干燥的反应瓶中，加入WX002-6(11g,38.85mmol)和四氢呋喃(110mL)，降温至-78℃，加入正丁基锂(2.5M,16.32mL)，保持-78℃搅拌1小时，加入四氢呋喃(40mL)和WX001-4(7.45g,34.96mmol)的混合溶液，继续在-78℃下搅拌1小时。反应完成后，向反应液中加入100mL饱和氯化铵水溶液，加入乙酸乙酯(200mL*3)萃取，合并有机相，有机相用饱和食盐水(200mL)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WX002-7。 1H NMR(400MHz,氘代氯仿)δ7.11(s,2H),6.88-6.77(m,2H),6.06-5.97(m,1H),5.13-5.08(m,2H),3.42(br d,J＝3.6Hz,3H),2.86-2.74(m,1H),2.61(td,J＝8.0,16.0Hz,1H),2.39-2.29(m,1H),2.18(d,J＝6.1Hz,6H),1.88-1.76(m,2H),1.74-1.56(m,1H),1.53-1.43(m,1H),0.92-0.77(m,2H)。 In a pre-dried reaction flask, WX002-6 (11 g, 38.85 mmol) and tetrahydrofuran (110 mL) were added, the temperature was lowered to -78 °C, n-butyllithium (2.5 M, 16.32 mL) was added, and the temperature was kept at -78 °C and stirred for 1 hour , a mixed solution of tetrahydrofuran (40 mL) and WX001-4 (7.45 g, 34.96 mmol) was added, and stirring was continued at -78° C. for 1 hour. After the reaction was completed, 100 mL of saturated aqueous ammonium chloride solution was added to the reaction solution, ethyl acetate (200 mL*3) was added for extraction, the organic phases were combined, and the organic phase was washed with saturated brine (200 mL). Dry over sodium sulfate, filter, and spin dry the filtrate under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=5% to 10% to 20%) to give WX002-7. 1 H NMR (400MHz, deuterated chloroform) δ 7.11(s, 2H), 6.88-6.77(m, 2H), 6.06-5.97(m, 1H), 5.13-5.08(m, 2H), 3.42(br d , J=3.6Hz, 3H), 2.86-2.74(m, 1H), 2.61(td, J=8.0, 16.0Hz, 1H), 2.39-2.29(m, 1H), 2.18(d, J=6.1Hz, 6H), 1.88-1.76 (m, 2H), 1.74-1.56 (m, 1H), 1.53-1.43 (m, 1H), 0.92-0.77 (m, 2H).
步骤7：化合物WX002-8的合成Step 7: Synthesis of Compound WX002-8
在预先干燥的反应瓶中，加入WX002-7(11.5g,27.56mmol l)和二氯甲烷(120mL)，置于0℃，加入三乙基硅氢(4.81g,41.33mmol,6.60mL)和三氟乙酸(4.71g,41.33mmol,3.06mL)，置于0℃搅拌0.5小时。反应完成后，向反应液中加入饱和碳酸氢钠水溶液(100mL)调pH至6-7，加入二氯甲烷(100mL)分液，收集有机相，水相用乙酸乙酯萃取(100mL*3),合并有机相，有机相用饱和食盐水(200mL)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WX002-8。 1H NMR(400MHz,氘代氯仿)δ7.22-7.20(m,2H),6.71(s,1H),6.26(d,J＝8.7Hz,1H),6.16(d,J＝8.6Hz,1H),5.20-5.14(m,2H),3.82(s,1H),3.75-3.65(m,1H),3.50(s,3H),2.99-2.91(m,1H),2.44-2.40(m,1H),2.25-2.21(m,1H),2.14(s,6H),1.86-1.79(m,1H),1.61-1.56(m,1H),0.93(dt,J＝4.7,8.5Hz,1H),0.82(q,J＝4.8Hz,1H)。 In a pre-dried reaction flask, add WX002-7 (11.5g, 27.56mmol l) and dichloromethane (120mL), place at 0°C, add triethylsilylhydrogen (4.81g, 41.33mmol, 6.60mL) and Trifluoroacetic acid (4.71 g, 41.33 mmol, 3.06 mL) was placed at 0°C and stirred for 0.5 hours. After the completion of the reaction, add saturated aqueous sodium bicarbonate solution (100 mL) to the reaction solution to adjust pH to 6-7, add dichloromethane (100 mL) to separate the layers, collect the organic phase, and extract the aqueous phase with ethyl acetate (100 mL*3) , the organic phases were combined, and the organic phase was washed with saturated brine (200 mL). After separation, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=5% to 10% to 20%) to give WX002-8. 1 H NMR (400MHz, deuterated chloroform) δ 7.22-7.20 (m, 2H), 6.71 (s, 1H), 6.26 (d, J=8.7Hz, 1H), 6.16 (d, J=8.6Hz, 1H) ), 5.20-5.14(m, 2H), 3.82(s, 1H), 3.75-3.65(m, 1H), 3.50(s, 3H), 2.99-2.91(m, 1H), 2.44-2.40(m, 1H ), 2.25-2.21(m, 1H), 2.14(s, 6H), 1.86-1.79(m, 1H), 1.61-1.56(m, 1H), 0.93(dt, J=4.7, 8.5Hz, 1H), 0.82 (q, J=4.8 Hz, 1H).
步骤8：化合物WX002-9的合成Step 8: Synthesis of Compound WX002-9
在预先干燥的反应瓶加入WX002-8(8g,19.93mmol)和1-4二氧六环(80mL)，再加入碳酸铯(19.48g,59.80mmol)和WX001-7(4.34g,23.92mmol,4.01mL)，置换氮气三次，加入三(二亚苄基丙酮)二钯(1.10g,1.20mmol)和Xantphos(922.71mg,1.59mmol)，再次置换氮气，置于100℃搅拌16小时。反应完成后，反应液用乙酸乙酯稀释后用垫有硅藻土的漏斗过滤，收集滤液，将滤液减压旋干。粗品经柱层析(乙酸乙酯：石油醚＝2％转5％转10％)纯化，得到WX002-9。 1H NMR(400MHz,氘代氯仿)δ.85-7.79(m,2H),7.66-7.61(m,1H),7.53-7.47(m,4H),7.30(br d,J＝1.6Hz,3H),6.69(d,J＝8.6Hz,2H),6.45(d,J＝4.6Hz,2H),5.23-5.16(m,2H),3.74-3.70(m,1H),3.68-3.61(m,1H),3.52(s,3H),2.96-2.88(m,1H),2.44-2.38(m,1H),2.24-2.20(m,1H),1.99(s,6H),1.86-1.74(m,1H),1.57(s,2H),0.91(dt,J＝4.7,8.4Hz,1H),0.80(q,J＝4.8Hz,1H)。 In the pre-dried reaction flask, add WX002-8 (8g, 19.93mmol) and 1-4 dioxane (80mL), then add cesium carbonate (19.48g, 59.80mmol) and WX001-7 (4.34g, 23.92mmol, 4.01 mL), replaced nitrogen three times, added tris(dibenzylideneacetone)dipalladium (1.10 g, 1.20 mmol) and Xantphos (922.71 mg, 1.59 mmol), replaced nitrogen again, and stirred at 100° C. for 16 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, filtered through a funnel with celite pads, the filtrate was collected, and the filtrate was spin-dried under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=2% to 5% to 10%) to give WX002-9. 1 H NMR (400MHz, deuterated chloroform) δ.85-7.79 (m, 2H), 7.66-7.61 (m, 1H), 7.53-7.47 (m, 4H), 7.30 (br d, J=1.6Hz, 3H ),6.69(d,J=8.6Hz,2H),6.45(d,J=4.6Hz,2H),5.23-5.16(m,2H),3.74-3.70(m,1H),3.68-3.61(m, 1H), 3.52(s, 3H), 2.96-2.88(m, 1H), 2.44-2.38(m, 1H), 2.24-2.20(m, 1H), 1.99(s, 6H), 1.86-1.74(m, 1H), 1.57 (s, 2H), 0.91 (dt, J=4.7, 8.4 Hz, 1H), 0.80 (q, J=4.8 Hz, 1H).
步骤9：化合物WX002-10的合成Step 9: Synthesis of Compound WX002-10
在预先干燥的反应瓶里加入WX002-9(8g,15.95mmol)和四氢呋喃(80mL)，盐酸(2M,31.89mL)，置于25℃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WX002-10。 1H NMR(400MHz,氘代氯仿)δ6.69(d,J＝8.6Hz,2H),6.45(br s,2H),6.34(d,J＝8.8Hz,1H),6.24(d,J＝8.6Hz,1H),5.18-5.12(m,2H),5.11(s,2H),3.49-3.47(m,3H),2.45-2.31(m,3H),2.08(s,6H),1.84-1.73(m,1H),1.61-1.49(m, 2H),0.89(dt,J＝4.8,8.4Hz,1H),0.79(q,J＝4.8Hz,1H)。 WX002-9 (8 g, 15.95 mmol), tetrahydrofuran (80 mL), and hydrochloric acid (2 M, 31.89 mL) were added to the pre-dried reaction flask, and the mixture was stirred at 25° C. for 1 hour. After the reaction was completed, 50 mL of saturated aqueous sodium carbonate solution was added to the reaction solution, ethyl acetate (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 Dry over sodium sulfate, filter, and spin dry the filtrate under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=5% to 10% to 20%) to give WX002-10. 1 H NMR (400 MHz, deuterated chloroform) δ 6.69 (d, J=8.6 Hz, 2H), 6.45 (br s, 2H), 6.34 (d, J=8.8 Hz, 1H), 6.24 (d, J= 8.6Hz, 1H), 5.18-5.12(m, 2H), 5.11(s, 2H), 3.49-3.47(m, 3H), 2.45-2.31(m, 3H), 2.08(s, 6H), 1.84-1.73 (m, 1H), 1.61-1.49 (m, 2H), 0.89 (dt, J=4.8, 8.4 Hz, 1H), 0.79 (q, J=4.8 Hz, 1H).
步骤10：化合物WX002-11的合成Step 10: Synthesis of Compound WX002-11
在预先干燥的反应瓶中加入WX002-10(4.6g,13.63mmol)，四氢呋喃(50mL)，将反应体系降至0℃，然后加入亚硝酸叔丁酯(2.81g,27.26mmol,3.24mL)和四氢呋喃(20mL)的混合溶液，在0℃下搅拌反应0.5hr，加入WX001-10(4.26g,27.26mmol)，0℃搅拌1小时。反应完成后，将反应液中加入水(200mL)和乙酸乙酯(250mL)分液，收集有机相，水相用乙酸乙酯萃取(2*250mL),合并有机相，用饱和食盐水洗涤(3*200mL)，无水硫酸钠干燥，过滤，减压浓缩得到粗品。得到WX002-11。In the pre-dried reaction flask was added WX002-10 (4.6g, 13.63mmol), tetrahydrofuran (50mL), the reaction system was lowered to 0°C, then tert-butyl nitrite (2.81g, 27.26mmol, 3.24mL) and The mixed solution of tetrahydrofuran (20 mL) was stirred at 0 °C for 0.5 hr, WX001-10 (4.26 g, 27.26 mmol) was added, and the mixture was stirred at 0 °C for 1 hour. After the reaction was completed, water (200 mL) and ethyl acetate (250 mL) were added to the reaction solution for separation, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (2*250 mL), the organic phases were combined and washed with saturated brine ( 3*200mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Get WX002-11.
步骤11：化合物WX002-12的合成Step 11: Synthesis of compound WX002-12
在预先干燥的反应瓶里加入WX002-11(8.8g,17.44mmol)和N,N-二甲基乙酰胺(90mL)，然后加入乙酸钾(1.88g,19.18mmol)，置换氮气三次，置于115℃搅拌2hr。反应完成后，将反应液中加入300mL水，加入乙酸乙酯(500mL*3)萃取合并有机相，用饱和食盐水洗涤(200mL)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WX002-12。WX002-11 (8.8g, 17.44mmol) and N,N-dimethylacetamide (90mL) were added to the pre-dried reaction flask, then potassium acetate (1.88g, 19.18mmol) was added, and the nitrogen was replaced three times. Stir at 115°C for 2hrs. After the reaction was completed, 300 mL of water was added to the reaction solution, ethyl acetate (500 mL*3) was added to extract the combined organic phase, washed with saturated brine (200 mL) and separated, the organic phase was dried with anhydrous sodium sulfate, filtered, and the The filtrate was spin-dried under reduced pressure to obtain WX002-12.
步骤12：化合物WX002-13的合成Step 12: Synthesis of Compound WX002-13
在预先干燥的反应瓶里加入WX002-12(2g,4.36mmol)和甲醇(20mL)，然后加入盐酸(12M,363.50μL)，置换氮气三次，置于50℃搅拌0.5hr。反应完毕后，将反应液用饱和碳酸氢钠水溶液(50mL)调pH至6-7，加入水(50mL)和乙酸乙酯(100mL*3)萃取，合并有机相，用饱和食盐水洗涤(150mL)，分液后，有机相用无水硫酸钠干燥，过滤，将滤液减压旋干，粗品通过制备高效液相色谱柱纯化(色谱柱:Phenomenex luna C18(250*70mm,15μm)；流动相:[水(0.1％三氟乙酸)-乙腈]；B(乙腈)％:40％-70％,20分钟)，得到WX002-13。 1H NMR(400MHz,氘代氯仿)δ8.95-8.31(m,1H),7.18(s,2H),6.47(d,J＝8.3Hz,1H),6.12(d,J＝8.4Hz,1H),4.91-4.51(m,1H),3.96-3.75(m,2H),2.98-2.85(m,1H),2.45-2.30(m,1H),2.23(s,6H),2.18-2.05(m,2H),1.99-1.82(m,1H),1.38-1.21(m,1H),1.02(dt,J＝4.7,8.3Hz,1H),0.77(q,J＝4.8Hz,1H)。 WX002-12 (2 g, 4.36 mmol) and methanol (20 mL) were added to the pre-dried reaction flask, then hydrochloric acid (12 M, 363.50 μL) was added, nitrogen was replaced three times, and stirred at 50° C. for 0.5 hr. After the reaction was completed, the pH of the reaction solution was adjusted to 6-7 with saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL) and ethyl acetate (100 mL*3) were added for extraction, the organic phases were combined and washed with saturated brine (150 mL). ), after liquid separation, the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the crude product was purified by a preparative high performance liquid chromatography column (chromatographic column: Phenomenex luna C18 (250*70mm, 15 μm); mobile phase : [water (0.1% trifluoroacetic acid)-acetonitrile]; B (acetonitrile) %: 40%-70%, 20 minutes) to give WX002-13. 1 H NMR (400MHz, deuterated chloroform) δ 8.95-8.31 (m, 1H), 7.18 (s, 2H), 6.47 (d, J=8.3Hz, 1H), 6.12 (d, J=8.4Hz, 1H) ),4.91-4.51(m,1H),3.96-3.75(m,2H),2.98-2.85(m,1H),2.45-2.30(m,1H),2.23(s,6H),2.18-2.05(m , 2H), 1.99-1.82 (m, 1H), 1.38-1.21 (m, 1H), 1.02 (dt, J=4.7, 8.3Hz, 1H), 0.77 (q, J=4.8Hz, 1H).
步骤13：化合物WX002和WX003的合成Step 13: Synthesis of Compounds WX002 and WX003
将WX002-13(0.3g,723.84μmol)进行手性分离色谱柱:DAICEL CHIRALPAK IG(250mm*30mm,10μm)；流动相:[0.1％氨水乙醇]；B(0.1％氨水乙醇)％:35％-35％,分钟。得到WX002(ee％＝100％，保留时间为1.494分钟)和WX003(ee％＝97.06％,保留时间为1.607分钟)。Chiral separation of WX002-13 (0.3g, 723.84μmol) column: DAICEL CHIRALPAK IG (250mm*30mm, 10μm); mobile phase: [0.1% ammonia ethanol]; B (0.1% ammonia ethanol)%: 35% -35%, min. WX002 (ee%=100%, retention time 1.494 minutes) and WX003 (ee%=97.06%, retention time 1.607 minutes) were obtained.
WX002： 1H NMR(400MHz,氘代二甲基亚砜)δ13.00(br s,1H),9.01(s,1H),7.15(s,2H),6.44(d,J＝8.3Hz,1H),5.89(d,J＝8.3Hz,1H),3.94-3.81(m,1H),3.69(d,J＝16.3Hz,1H),2.92(br dd,J＝3.7,16.2Hz,1H),2.24(dt,J＝4.3,8.5Hz,2H),2.14(s,6H),1.70-1.62(m,1H),1.51(br d,J＝5.3Hz,1H),0.81(dt,J＝4.4,8.3Hz,1H),0.72(q,J＝4.5Hz,1H)； WX002: 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 13.00(br s, 1H), 9.01(s, 1H), 7.15(s, 2H), 6.44(d, J=8.3Hz, 1H ),5.89(d,J＝8.3Hz,1H),3.94-3.81(m,1H),3.69(d,J＝16.3Hz,1H),2.92(br dd,J＝3.7,16.2Hz,1H), 2.24(dt,J=4.3,8.5Hz,2H),2.14(s,6H),1.70-1.62(m,1H),1.51(br d,J=5.3Hz,1H),0.81(dt,J=4.4 ,8.3Hz,1H),0.72(q,J=4.5Hz,1H);
WX003： 1H NMR(400MHz,氘代二甲基亚砜)δ13.07-12.87(m,1H),9.00(s,1H),7.15(s,2H),6.44(d,J＝ 8.3Hz,1H),5.90(d,J＝8.3Hz,1H),3.86(br d,J＝16.4Hz,1H),3.69(d,J＝16.3Hz,1H),2.92(br dd,J＝4.2,16.2Hz,1H),2.24(dt,J＝4.4,8.5Hz,2H),2.13(s,6H),1.70-1.62(m,1H),1.54-1.48(m,1H),0.81(dt,J＝4.3,8.3Hz,1H),0.72(q,J＝4.5Hz,1H)。 WX003: 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 13.07-12.87(m, 1H), 9.00(s, 1H), 7.15(s, 2H), 6.44(d, J=8.3Hz, 1H), 5.90(d, J＝8.3Hz, 1H), 3.86(br d, J＝16.4Hz, 1H), 3.69(d, J＝16.3Hz, 1H), 2.92(br dd, J＝4.2, 16.2 Hz, 1H), 2.24(dt, J=4.4, 8.5Hz, 2H), 2.13(s, 6H), 1.70-1.62(m, 1H), 1.54-1.48(m, 1H), 0.81(dt, J= 4.3, 8.3 Hz, 1H), 0.72 (q, J=4.5 Hz, 1H).
实施例3Example 3
Figure PCTCN2021117786-appb-000064
Figure PCTCN2021117786-appb-000064
合成路线：synthetic route:
Figure PCTCN2021117786-appb-000065
Figure PCTCN2021117786-appb-000065
步骤1：化合物WX004-2的合成Step 1: Synthesis of compound WX004-2
在预先干燥的反应瓶里加入WX004-1(3g,22.36mmol,1eq)和N,N-二甲基甲酰胺(30mL)，置于0℃加入碳酸铯(21.85g,67.08mmol,3eq)和氯甲醚(3.60g,44.72mmol,3.40mL,2eq)，自然升温至25℃搅拌2小时。反应完毕后，将反应液倒入冰水(30mL)中，加入乙酸乙酯(30mL)分液，收集有机相，水相用乙酸乙酯萃取(30mL*2)，合并有机相，用饱和食盐水洗涤(3*100mL)，无水硫酸钠干燥，过滤，滤 液减压浓缩得到粗品。粗品通过柱层析分离纯化(石油醚:乙酸乙酯＝1:0至10:1至5:1)得到WX004-2。 1H NMR(400MHz,氘代氯仿)δ2.00-2.14(m,3H),2.92(d,J＝9.51Hz,3H),3.50(s,3H),5.21(s,2H),6.90(dd,J＝13.51,7.75Hz,2H),7.07-7.14(m,1H)。 Add WX004-1 (3g, 22.36mmol, 1eq) and N,N-dimethylformamide (30mL) to a pre-dried reaction flask, place at 0°C and add cesium carbonate (21.85g, 67.08mmol, 3eq) and Chloromethyl ether (3.60 g, 44.72 mmol, 3.40 mL, 2 eq) was naturally heated to 25° C. and stirred for 2 hours. After the completion of the reaction, the reaction solution was poured into ice water (30 mL), ethyl acetate (30 mL) was added to separate the layers, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (30 mL*2), the organic phases were combined, and saturated common salt was used. Wash with water (3*100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 10:1 to 5:1) to obtain WX004-2. 1 H NMR (400MHz, deuterated chloroform) δ 2.00-2.14(m, 3H), 2.92(d, J=9.51Hz, 3H), 3.50(s, 3H), 5.21(s, 2H), 6.90(dd , J=13.51, 7.75Hz, 2H), 7.07-7.14 (m, 1H).
步骤2：化合物WX004-3的合成Step 2: Synthesis of compound WX004-3
在预先干燥的反应瓶里加入WX004-2(2g,11.22mmol,1eq)和四氢呋喃(20mL)，然后加入溴代丁二酰亚胺(2.20g,12.34mmol,1.1eq)，置换氮气三次，置于-78℃搅拌2小时。反应完毕后，将反应液倒入冰水(10mL)中，加入乙酸乙酯(10mL)分液，收集有机相，水相用乙酸乙酯萃取(10mL*2)，合并有机相，用饱和食盐水洗涤(30mL*3)，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品通过柱层析分离纯化(石油醚:乙酸乙酯＝1:0转10:1转5:1)得到WX004-3。 1H NMR(400MHz,氘代氯仿)δ2.06-2.15(m,2H),2.97(t,J＝17.37,7.65Hz,4H),3.48(s,3H),5.17(s,2H),6.79(d,J＝8.77Hz,1H),7.23(d,J＝8.77Hz,1H)。 In the pre-dried reaction flask, add WX004-2 (2g, 11.22mmol, 1eq) and tetrahydrofuran (20mL), then add bromosuccinimide (2.20g, 12.34mmol, 1.1eq), replace nitrogen three times, set Stir at -78°C for 2 hours. After the reaction was completed, the reaction solution was poured into ice water (10 mL), ethyl acetate (10 mL) was added to separate the layers, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (10 mL*2), the organic phases were combined, and saturated common salt was used for extraction. Washed with water (30 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 10:1 to 5:1) to obtain WX004-3. 1 H NMR (400MHz, deuterated chloroform) δ 2.06-2.15(m, 2H), 2.97(t, J=17.37, 7.65Hz, 4H), 3.48(s, 3H), 5.17(s, 2H), 6.79 (d, J=8.77Hz, 1H), 7.23 (d, J=8.77Hz, 1H).
步骤3：化合物WX004-4的合成Step 3: Synthesis of Compound WX004-4
在预先干燥的反应瓶里加入WX004-3(2.2g,8.56mmol,1eq)和四氢呋喃(22mL)，然后置于-78℃缓慢滴入正丁基锂(2.5M,3.76mL,1.1eq)，-78℃搅拌1小时，然后缓慢滴入WX001-4(1.64g,7.70mmol,0.9eq)和四氢呋喃(10mL)，置于-78℃搅拌1小时。反应完毕后，将反应液倒入饱和氯化铵溶液中(30mL)淬灭，然后加入乙酸乙酯(30mL)分液，收集有机相，水相用乙酸乙酯(30mL*2)萃取，合并有机相，依次用饱和食盐水(100mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品通过柱层析分离纯化(石油醚:乙酸乙酯＝1:0转10:1转5:1)得到WX004-4。 1H NMR(400MHz,氘代氯仿)δ1.95-2.12(m,3H),2.26(s,6H),2.89(t,J＝7.50Hz,3H),3.48(s,3H),5.13-5.22(m,2H),6.21(d,J＝4.25Hz,1H),6.81(d,J＝8.38Hz,1H),6.97(d,J＝8.50Hz,1H),7.18(s,2H)。 Add WX004-3 (2.2g, 8.56mmol, 1eq) and tetrahydrofuran (22mL) to the pre-dried reaction flask, then place at -78°C and slowly drop n-butyllithium (2.5M, 3.76mL, 1.1eq), Stir at -78 °C for 1 hour, then slowly dropwise add WX001-4 (1.64 g, 7.70 mmol, 0.9 eq) and tetrahydrofuran (10 mL), place at -78 °C and stir for 1 hour. After the reaction was completed, the reaction solution was poured into saturated ammonium chloride solution (30 mL) to quench, then ethyl acetate (30 mL) was added to separate the layers, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (30 mL*2), and the combined The organic phase was washed successively with saturated brine (100 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 10:1 to 5:1) to obtain WX004-4. 1 H NMR (400MHz, deuterated chloroform) δ 1.95-2.12(m, 3H), 2.26(s, 6H), 2.89(t, J=7.50Hz, 3H), 3.48(s, 3H), 5.13-5.22 (m, 2H), 6.21 (d, J=4.25 Hz, 1H), 6.81 (d, J=8.38 Hz, 1H), 6.97 (d, J=8.50 Hz, 1H), 7.18 (s, 2H).
步骤4：化合物WX004-5的合成Step 4: Synthesis of compound WX004-5
在预先干燥的反应瓶里加入WX004-4(2.6g,6.64mmol,1eq)和二氯甲烷(26mL)，置于-10℃，加入三乙基硅氢(1.16g,9.97mmol,1.59mL,1.5eq)和三氟乙酸(1.14g,9.97mmol,737.93μL,1.5eq)，置于-10℃搅拌1小时。反应完毕后，将反应液用饱和碳酸氢钠水溶液(10mL)调pH至6-7，加入水(20mL)分液，收集有机相，水相用二氯甲烷萃取(20mL*2)，合并有机相，用饱和食盐水洗涤(80mL*3)，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗产品通过柱层析分离纯化(石油醚:乙酸乙酯＝1:0至10:1至5:1)得到WX004-5。 1H NMR(400MHz,氘代氯仿)δ2.11-2.16(m,2H),2.18(s,6H),2.96(t,J＝7.50Hz,4H),3.43-3.50(m,3H),3.81(s,2H),5.14(s,2H),6.28(d,J＝8.25Hz,1H),6.69(d,J＝8.25Hz,1H),7.22(s,2H)。 In a pre-dried reaction flask, add WX004-4 (2.6g, 6.64mmol, 1eq) and dichloromethane (26mL), place at -10°C, add triethylsilylhydrogen (1.16g, 9.97mmol, 1.59mL, 1.5eq) and trifluoroacetic acid (1.14g, 9.97mmol, 737.93μL, 1.5eq), placed at -10°C and stirred for 1 hour. After the completion of the reaction, the pH of the reaction solution was adjusted to 6-7 with saturated aqueous sodium bicarbonate solution (10 mL), water (20 mL) was added for separation, the organic phase was collected, the aqueous phase was extracted with dichloromethane (20 mL*2), and the organic The phase was washed with saturated brine (80 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 10:1 to 5:1) to obtain WX004-5. 1 H NMR (400MHz, deuterated chloroform) δ 2.11-2.16 (m, 2H), 2.18 (s, 6H), 2.96 (t, J=7.50Hz, 4H), 3.43-3.50 (m, 3H), 3.81 (s, 2H), 5.14 (s, 2H), 6.28 (d, J=8.25Hz, 1H), 6.69 (d, J=8.25Hz, 1H), 7.22 (s, 2H).
步骤5：化合物WX004-6的合成Step 5: Synthesis of compound WX004-6
在预先干燥的反应瓶里加入WX004-5(1.5g,4.00mmol,1eq)和1,4-二氧六环(15mL)，然后加入碳 酸铯(1.95g,6.00mmol,1.5eq)和WX001-7(796.79mg,4.40mmol,737.77μL,1.1eq)，置换氮气三次，加入三(二亚苄基丙酮)二钯(219.60mg,239.81μmol,0.06eq)和4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(185.01mg,319.75μmol,0.08eq)，再次置换氮气，置于100℃搅拌12小时。反应完毕后，将反应液冷却至室温，加入水(20mL)和乙酸乙酯(20mL)分液，收集有机相，水相用乙酸乙酯萃取(20mL*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WX004-6。In a pre-dried reaction flask was added WX004-5 (1.5g, 4.00mmol, 1eq) and 1,4-dioxane (15mL), followed by cesium carbonate (1.95g, 6.00mmol, 1.5eq) and WX001- 7 (796.79mg, 4.40mmol, 737.77μL, 1.1eq), replace nitrogen three times, add tris(dibenzylideneacetone)dipalladium (219.60mg, 239.81μmol, 0.06eq) and 4,5-bis(diphenyl) phosphine)-9,9-dimethylxanthene (185.01 mg, 319.75 μmol, 0.08 eq), replaced with nitrogen again, and stirred at 100° C. for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (20 mL) and ethyl acetate (20 mL) were added to separate the layers, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (20 mL*2), the organic phases were combined, and saturated common salt was used for extraction. Washed with water (100 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain WX004-6.
步骤6：化合物WX004-7的合成Step 6: Synthesis of Compound WX004-7
在预先干燥的反应瓶里加入WX004-6(1.5g,3.15mmol,1eq)和四氢呋喃(15mL)，加入盐酸(2M,1.58mL,1eq)，置于25℃搅拌1小时。反应完毕后，将反应液用饱和碳酸氢钠水溶液(2mL)调pH至6-7，加入水(10mL)和乙酸乙酯(10mL)分液，收集有机相，水相用乙酸乙酯萃取(10mL*2)，合并有机相，用饱和食盐水洗涤(60mL*2)，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品通过柱层析分离纯化(石油醚:乙酸乙酯＝1:0转10:1转5:1转3:1)得到WX004-7。WX004-6 (1.5g, 3.15mmol, 1eq) and tetrahydrofuran (15mL) were added to a pre-dried reaction flask, hydrochloric acid (2M, 1.58mL, 1eq) was added, and the mixture was stirred at 25°C for 1 hour. After completion of the reaction, the pH of the reaction solution was adjusted to 6-7 with saturated aqueous sodium bicarbonate solution (2 mL), water (10 mL) and ethyl acetate (10 mL) were added for separation, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate ( 10 mL*2), the organic phases were combined, washed with saturated brine (60 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 10:1 to 5:1 to 3:1) to obtain WX004-7.
步骤7：化合物WX004-8的合成Step 7: Synthesis of Compound WX004-8
在预先干燥的反应瓶中加入WX004-7(0.5g,1.61mmol,1eq)，之后用四氢呋喃(5mL)溶解，将反应体系降至0℃，然后加入亚硝酸叔丁酯(331.13mg,3.21mmol,381.93μL,2eq)和四氢呋喃(5mL)的混合溶液，在0℃下搅拌反应0.5小时，加入WX001-10(275.76mg,1.77mmol,1.1eq)，0℃搅拌0.5小时。反应完毕后，将反应液中加入水(10mL)和乙酸乙酯(10mL)分液，收集有机相，水相用乙酸乙酯萃取(10mL*2)，合并有机相，用饱和食盐水洗涤(50mL*3)，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗产品通过薄层色谱硅胶板(石油醚:乙酸乙酯＝2:1)纯化得到WX004-8。 1H NMR(400MHz,氘代氯仿)δ1.36-1.41(m,3H),2.15-2.20(m,2H),2.22-2.28(m,6H),2.97(s,4H),3.47(s,3H),3.87(s,2H),4.31-4.39(m,2H),5.12-5.17(m,2H),6.27(d,J＝8.50Hz,1H),6.63-6.74(m,1H),7.01(s,2H)。 WX004-7 (0.5 g, 1.61 mmol, 1 eq) was added to the pre-dried reaction flask, then dissolved in tetrahydrofuran (5 mL), the reaction system was lowered to 0 °C, and then tert-butyl nitrite (331.13 mg, 3.21 mmol) was added. , 381.93 μL, 2eq) and tetrahydrofuran (5mL) mixed solution, the reaction was stirred at 0°C for 0.5 hours, WX001-10 (275.76mg, 1.77mmol, 1.1eq) was added, and the mixture was stirred at 0°C for 0.5 hours. After the completion of the reaction, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution for separation, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (10 mL*2), the organic phases were combined and washed with saturated brine ( 50mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin layer chromatography on silica gel plate (petroleum ether:ethyl acetate=2:1) to obtain WX004-8. 1 H NMR (400MHz, deuterated chloroform) δ 1.36-1.41(m, 3H), 2.15-2.20(m, 2H), 2.22-2.28(m, 6H), 2.97(s, 4H), 3.47(s, 3H), 3.87(s, 2H), 4.31-4.39(m, 2H), 5.12-5.17(m, 2H), 6.27(d, J=8.50Hz, 1H), 6.63-6.74(m, 1H), 7.01 (s, 2H).
步骤8：化合物WX004-9的合成Step 8: Synthesis of Compound WX004-9
在预先干燥的反应瓶里加入WX004-8(330mg,689.60μmol,1eq)和氮，氮-二甲基乙酰胺(3mL)，然后加入醋酸钾(74.44mg,758.56μmol,1.1eq)，置换氮气三次，置于115℃搅拌2小时。反应完毕后，将反应液冷却至室温，加入水(10mL)和乙酸乙酯(10mL)分液，收集有机相，水相用乙酸乙酯萃取(10mL*2),合并有机相，用饱和食盐水洗涤(50mL*3)，无水硫酸钠干燥，过滤，滤液减压浓缩得到WX004-9。To the pre-dried reaction flask was added WX004-8 (330mg, 689.60μmol, 1eq) and nitrogen, nitrogen-dimethylacetamide (3mL), then potassium acetate (74.44mg, 758.56μmol, 1.1eq) was added to replace nitrogen Three times, placed at 115°C and stirred for 2 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, water (10 mL) and ethyl acetate (10 mL) were added to separate the layers, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (10 mL*2), the organic phases were combined, and saturated common salt was used to combine the organic phases. Washed with water (50 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain WX004-9.
步骤9：化合物WX004的合成Step 9: Synthesis of Compound WX004
在预先干燥的反应瓶里加入WX004-9(0.3g,693.69μmol,1eq)和甲醇(1mL)，然后加入盐酸(68.36mg,693.69μmol,67.02μL,37％纯度,1eq)，置换氮气三次，置于50℃搅拌0.5小时。反应完毕后，将反应液冷却至室温，用饱和碳酸氢钠水溶液(2mL)调pH至6-7，加入水(5mL)和乙酸乙酯(5mL)分液，收集有机相，水相用乙酸乙酯萃取(5mL*2)，合并有机相，用饱和食盐水洗涤(20mL*3)，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品通过(色谱柱:Waters Xbridge BEH C18100*30mm*10μm；流动相:[水 (10mM碳酸氢铵)-乙腈]；B(乙腈)％:20％-50％,8分钟)纯化得到WX004。 1H NMR(400MHz,氘代二甲基亚砜)δ2.04(t,J＝7.47Hz,2H),2.17(s,6H),2.78(t,J＝7.38Hz,2H),2.90(t,J＝7.32Hz,2H),3.80(s,2H),6.05(d,J＝8.25Hz,1H),6.40(d,J＝8.13Hz,1H),7.02-7.11(m,1H),7.14(s,2H),8.94(s,1H)。MS-ESI m/z:387.2[M-H] -。 Add WX004-9 (0.3g, 693.69μmol, 1eq) and methanol (1mL) to the pre-dried reaction flask, then add hydrochloric acid (68.36mg, 693.69μmol, 67.02μL, 37% purity, 1eq), replace nitrogen three times, It was placed at 50°C and stirred for 0.5 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, and the pH was adjusted to 6-7 with saturated aqueous sodium bicarbonate solution (2 mL), water (5 mL) and ethyl acetate (5 mL) were added to separate the layers, the organic phase was collected, and the aqueous phase was treated with acetic acid. Extract with ethyl ester (5 mL*2), combine the organic phases, wash with saturated brine (20 mL*3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was purified by (chromatographic column: Waters Xbridge BEH C18100*30mm*10μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; B(acetonitrile) %: 20%-50%, 8 minutes) to give WX004. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 2.04(t, J=7.47Hz, 2H), 2.17(s, 6H), 2.78(t, J=7.38Hz, 2H), 2.90(t , J＝7.32Hz, 2H), 3.80(s, 2H), 6.05(d, J＝8.25Hz, 1H), 6.40(d, J＝8.13Hz, 1H), 7.02-7.11(m, 1H), 7.14 (s, 2H), 8.94 (s, 1H). MS-ESI m/z: 387.2 [MH] - .
实施例4Example 4
Figure PCTCN2021117786-appb-000066
Figure PCTCN2021117786-appb-000066
合成路线：synthetic route:
Figure PCTCN2021117786-appb-000067
Figure PCTCN2021117786-appb-000067
步骤1：化合物WX005-1的合成Step 1: Synthesis of compound WX005-1
在预先干燥的反应瓶中，加入WX001-5(3.5g,8.64mmol)和二氯甲烷(30mL)，降温至0℃，加入氯铬酸吡啶(2.79g,12.95mmol)，升温至25℃搅拌12小时。反应完成后，向反应液中加入饱和硫代硫酸钠(30mL)和二氯甲烷(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，将滤液减压旋干。粗品用快速过柱机纯化，洗脱剂极性，乙酸乙酯：石油 醚＝4％转6％转10％，得到WX005-1。 1H NMR(400MHz,氘代二甲基亚砜)δ7.35(s,2H),7.09-7.11(d,J＝8.4Hz,1H),6.86-6.88(d,J＝8.4Hz,1H),5.27(s,2H),3.37(s,3H),3.12-3.13(m,2H),2.65-2.66(m,2H),2.02(s,6H),1.72-1.74(m,4H)。 In a pre-dried reaction flask, WX001-5 (3.5g, 8.64mmol) and dichloromethane (30mL) were added, the temperature was lowered to 0°C, pyridine chlorochromate (2.79g, 12.95mmol) was added, the temperature was raised to 25°C and stirred 12 hours. After the reaction was completed, saturated sodium thiosulfate (30 mL) and dichloromethane (30 mL*3) were added to the reaction solution for extraction, the organic phases were combined, and the organic phase was washed with saturated brine (30 mL). Dry over anhydrous sodium sulfate, filter, and spin dry the filtrate under reduced pressure. The crude product was purified by a rapid column machine, the eluent was polar, ethyl acetate: petroleum ether=4% to 6% to 10% to obtain WX005-1. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 7.35 (s, 2H), 7.09-7.11 (d, J=8.4Hz, 1H), 6.86-6.88 (d, J=8.4Hz, 1H) , 5.27(s, 2H), 3.37(s, 3H), 3.12-3.13(m, 2H), 2.65-2.66(m, 2H), 2.02(s, 6H), 1.72-1.74(m, 4H).
步骤2：化合物WX005-2的合成Step 2: Synthesis of Compound WX005-2
向WX001-7(494.30mg,2.73mmol,457.69μL)的四氢呋喃(10mL)溶液中加入WX005-1(1g,2.48mmol)，碳酸铯(1.21g,3.72mmol)，2,2-双(二苯膦基)-1,1-联萘(77.20mg,123.97μmol)，醋酸钯(27.83mg,123.97μmol)，在65℃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。粗品用快速过柱机纯化，洗脱剂极性，乙酸乙酯：石油醚＝5％转10％转20％，得到WX005-2。To a solution of WX001-7 (494.30 mg, 2.73 mmol, 457.69 μL) in tetrahydrofuran (10 mL) was added WX005-1 (1 g, 2.48 mmol), cesium carbonate (1.21 g, 3.72 mmol), 2,2-bis(diphenyl) phosphino)-1,1-binaphthyl (77.20 mg, 123.97 μmol), palladium acetate (27.83 mg, 123.97 μmol), and reacted at 65° C. for 12 hours. After the reaction was completed, water (50 mL) was added to the reaction solution, ethyl acetate (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. The crude product was purified by a rapid column machine, the eluent was polar, ethyl acetate: petroleum ether=5% to 10% to 20% to obtain WX005-2.
步骤3：化合物WX005-3的合成Step 3: Synthesis of Compound WX005-3
在预先干燥的反应瓶中，加入WX005-2(0.4g,794.23μmol)和盐酸(1mL)，四氢呋喃(5mL)，室温(25℃)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)，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。粗品通过快速硅胶柱纯化，洗脱剂极性，乙酸乙酯：石油醚＝5％转10％转20％，得到WX005-3。 1H NMR(400MHz,氘代二甲基亚砜)δ7.07-7.09(d,J＝8.4Hz,1H),6.83-6.85(d,J＝8.4Hz,1H),6.23(s,2H),5.25(s,2H),5.27(s,2H),3.38(s,3H),2.98-3.01(m,2H),2.64-2.67(m,2H),1.88(s,6H),1.68-1.74(m,4H)。 In a pre-dried reaction flask, add WX005-2 (0.4 g, 794.23 μmol), hydrochloric acid (1 mL), tetrahydrofuran (5 mL), and stir at room temperature (25° C.) for 1 hour. After the reaction was completed, 50 mL of saturated aqueous sodium carbonate solution was added to the reaction solution, ethyl acetate (50 mL*3) was added, 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. The crude product was purified by flash silica gel column, polar eluent, ethyl acetate:petroleum ether=5% to 10% to 20% to give WX005-3. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 7.07-7.09 (d, J=8.4 Hz, 1H), 6.83-6.85 (d, J=8.4 Hz, 1H), 6.23 (s, 2H) ,5.25(s,2H),5.27(s,2H),3.38(s,3H),2.98-3.01(m,2H),2.64-2.67(m,2H),1.88(s,6H),1.68-1.74 (m, 4H).
步骤4：化合物WX005-4的合成Step 4: Synthesis of compound WX005-4
将WX005-3(0.15g,441.92μmol)加入到反应瓶中，加冰乙酸(2mL)和盐酸(133.25mg,1.35mmol,130.64μL,37％纯度)，降温至5℃，加入亚硝酸钠(32.32mg,468.44μmol)的水(2mL)溶液，然后在5℃下搅拌0.5小时，加入WX001-10(75.90mg,486.11μmol)，在5℃下搅拌0.5小时。反应完成后，向反应液中加入5mL饱和乙酸钠水溶液，有大量固体析出，过滤，滤饼用5mL水洗涤，将滤饼减压旋干，得到WX005-4。Add WX005-3 (0.15g, 441.92μmol) to the reaction flask, add glacial acetic acid (2mL) and hydrochloric acid (133.25mg, 1.35mmol, 130.64μL, 37% purity), cool to 5°C, add sodium nitrite ( 32.32 mg, 468.44 μmol) in water (2 mL), then stirred at 5°C for 0.5 hours, added WX001-10 (75.90 mg, 486.11 μmol), and stirred at 5°C for 0.5 hours. After the reaction was completed, 5 mL of saturated aqueous sodium acetate solution was added to the reaction solution, a large amount of solid was precipitated, filtered, and the filter cake was washed with 5 mL of water, and the filter cake was spin-dried under reduced pressure to obtain WX005-4.
步骤5：化合物WX005-5的合成Step 5: Synthesis of compound WX005-5
将WX005-4(0.26g,513.28μmol)加入到反应瓶中，加入N,N-二甲基乙酰胺(2mL)将底物溶解，加入乙酸钾(100.75mg,1.03mmol)，升温至120℃搅拌1小时。反应完成后，向反应液中加入30mL水，加入乙酸乙酯(30mL*3)萃取，合并有机相，有机相用50mL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WX005-5。WX005-4 (0.26g, 513.28μmol) was added to the reaction flask, N,N-dimethylacetamide (2mL) was added to dissolve the substrate, potassium acetate (100.75mg, 1.03mmol) was added, and the temperature was raised to 120°C Stir for 1 hour. After the reaction was completed, 30 mL of water was added to the reaction solution, ethyl acetate (30 mL*3) was added for extraction, the organic phases were combined, and the organic phase was washed with 50 mL of saturated brine. After separation, the organic phase was dried with anhydrous sodium sulfate and filtered. , the filtrate was spin-dried under reduced pressure to obtain WX005-5.
步骤6：化合物WX005的合成Step 6: Synthesis of Compound WX005
向WX005-5(0.2g,434.33μmol)的甲醇(2mL)溶液中加入盐酸(0.3mL,37％纯度)，在50℃反应0.5小时，反应完成后，反应液直接减压旋干，粗品通过高效液相色谱柱纯化(色谱柱:Welch Xtimate C18  100*25mm*3μm；流动相:[水(0.05％盐酸)-乙腈]；乙腈％:30％-70％,8分钟，得到WX005。 1H NMR(400MHz,氘代二甲基亚砜)δ8.62(s,1H),7.19(s,2H),7.15-7.17(d,J＝8Hz,1H),6.57-6.55(d,J＝8.4Hz,1H),5.22(s,1H),3.29-3.32(m,2H),2.69-2.72(m,2H),2.20(s,6H),1.84-1.89(m,4H)。MS-ESI m/z:417.1[M+H] +。 To the methanol (2 mL) solution of WX005-5 (0.2 g, 434.33 μmol), hydrochloric acid (0.3 mL, 37% purity) was added, and the reaction was carried out at 50° C. for 0.5 hour. High performance liquid chromatography column purification (chromatographic column: Welch Xtimate C18 100*25mm*3μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 30%-70%, 8 minutes, to obtain WX005. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ8.62 (s, 1H), 7.19 (s, 2H), 7.15-7.17 (d, J=8Hz, 1H), 6.57-6.55 (d, J=8.4 Hz, 1H), 5.22(s, 1H), 3.29-3.32(m, 2H), 2.69-2.72(m, 2H), 2.20(s, 6H), 1.84-1.89(m, 4H). MS-ESI m /z:417.1[M+H] + .
实施例5Example 5
Figure PCTCN2021117786-appb-000068
Figure PCTCN2021117786-appb-000068
合成路线：synthetic route:
Figure PCTCN2021117786-appb-000069
Figure PCTCN2021117786-appb-000069
步骤1：化合物WX006-2的合成Step 1: Synthesis of compound WX006-2
在预先干燥的反应瓶中，加入WX006-1(20g,123.32mmol)和N,N-二甲基甲酰胺(200mL)，0℃下分批加入碳酸铯(120.54g,369.95mmol)，置换氮气三次，0℃下缓慢滴入氯甲基甲醚(19.86g,246.63mmol,18.73mL)，置于0℃下继续搅拌4小时，反应完成后，将反应液倒入水(200mL)中淬灭，甲基叔丁基醚萃取水相(300mL*3)，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。粗品经柱层析(乙酸乙酯：石油醚＝2％转5％转30％)纯化，得到WX006-2。 1H NMR(400MHz,氘代氯仿)δ7.37(d,J＝8.1Hz,1H),7.05(d,J＝8.4Hz,1H),6.90(d,J＝7.5Hz,1H),5.26(s,2H),3.53(s,3H),2.95-2.91(m,2H),2.64(t,J＝6.6Hz,2H),2.10-2.05(m,2H)。 In a pre-dried reaction flask, WX006-1 (20 g, 123.32 mmol) and N,N-dimethylformamide (200 mL) were added, and cesium carbonate (120.54 g, 369.95 mmol) was added in batches at 0°C to replace nitrogen. Three times, chloromethyl methyl ether (19.86 g, 246.63 mmol, 18.73 mL) was slowly added dropwise at 0 °C, and the stirring was continued at 0 °C for 4 hours. After the reaction was completed, the reaction solution was poured into water (200 mL) to quench , the aqueous phase (300 mL*3) was extracted with methyl tert-butyl ether, the organic phases were combined, the organic phase was washed with saturated brine (100 mL), after separation, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed Spin dry. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=2% to 5% to 30%) to obtain WX006-2. 1 H NMR (400 MHz, deuterated chloroform) δ 7.37 (d, J=8.1 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.90 (d, J=7.5 Hz, 1H), 5.26 ( s, 2H), 3.53 (s, 3H), 2.95-2.91 (m, 2H), 2.64 (t, J=6.6Hz, 2H), 2.10-2.05 (m, 2H).
步骤2：化合物WX006-4的合成Step 2: Synthesis of compound WX006-4
在预先干燥的反应瓶中加入WX006-3(44.17g,123.64mmol)和四氢呋喃(170mL)，置于0℃，然后缓慢滴入正丁基锂(2.5M，46.16mL)，搅拌1小时，然后加入WX006-2(17g，82.43mmol)和四氢呋喃(170mL)，自然升温至25℃搅拌3小时。反应完成后，将反应液倒入饱和氯化铵水溶液(300mL)中，加入乙酸乙酯(300mL)分液，收集有机相，水相用乙酸乙酯萃取(300mL*2)，合并有机相，用饱和食盐水洗涤(3*100mL)，无水硫酸钠干燥，过滤，将滤液减压浓缩，粗品经柱层析(乙酸乙酯：石油醚＝1％转10％转20％)纯化，得到WX006-4。 1H NMR(400MHz,氘代氯仿)δ7.13-7.05(m,1H),7.03-6.96(m,1H),6.90-6.77(m,1H),5.99-5.80(m,1H),5.20(d,J＝18.5Hz,2H),3.52(d,J＝1.3Hz,3H),2.87(t,J＝6.4Hz,1H),2.73-2.61(m,1H),2.58-2.49(m,1H),2.26(q,J＝1.5Hz,2H),2.17-2.07(m,1H),1.98-1.83(m,1H)。 WX006-3 (44.17 g, 123.64 mmol) and tetrahydrofuran (170 mL) were added to the pre-dried reaction flask, set at 0° C., then n-butyllithium (2.5 M, 46.16 mL) was slowly added dropwise, stirred for 1 hour, and then WX006-2 (17 g, 82.43 mmol) and tetrahydrofuran (170 mL) were added, and the temperature was naturally raised to 25° C. and stirred for 3 hours. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution (300 mL), ethyl acetate (300 mL) was added to separate the layers, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (300 mL*2), and the organic phases were combined, Washed with saturated brine (3*100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether=1% to 10% to 20%) to obtain WX006-4. 1 H NMR (400MHz, deuterated chloroform) δ 7.13-7.05 (m, 1H), 7.03-6.96 (m, 1H), 6.90-6.77 (m, 1H), 5.99-5.80 (m, 1H), 5.20 ( d, J=18.5Hz, 2H), 3.52 (d, J=1.3Hz, 3H), 2.87 (t, J=6.4Hz, 1H), 2.73-2.61 (m, 1H), 2.58-2.49 (m, 1H) ), 2.26 (q, J=1.5Hz, 2H), 2.17-2.07 (m, 1H), 1.98-1.83 (m, 1H).
步骤3：化合物WX006-5的合成Step 3: Synthesis of compound WX006-5
在预先干燥的反应瓶中，钯/碳(5g,24.48mmol,10％含量)和乙酸乙酯(300mL)，加入WX006-4(5g,24.48mmol)，置换氢气三次，置于25℃，50Psi搅拌16小时。反应完成后，将反应液经过硅藻土过滤，滤饼用乙酸乙酯(3*20mL)洗涤，将滤液减压旋干。得到WX006-5。 1H NMR(400MHz,氘代氯仿)δ7.09-6.99(m,1H),6.89(d,J＝8.1Hz,1H),6.75(d,J＝7.6Hz,1H),5.23(s,2H),3.51(s,3H),3.31-3.17(m,1H),2.81-2.65(m,2H),1.88-1.71(m,4H),1.25(d,J＝6.9Hz,3H)。 In a pre-dried reaction flask, palladium/carbon (5g, 24.48mmol, 10% content) and ethyl acetate (300mL), add WX006-4 (5g, 24.48mmol), replace hydrogen three times, place at 25°C, 50Psi Stir for 16 hours. After the reaction was completed, the reaction solution was filtered through celite, the filter cake was washed with ethyl acetate (3*20 mL), and the filtrate was spin-dried under reduced pressure. Get WX006-5. 1 H NMR (400MHz, deuterated chloroform) δ 7.09-6.99 (m, 1H), 6.89 (d, J=8.1Hz, 1H), 6.75 (d, J=7.6Hz, 1H), 5.23 (s, 2H) ), 3.51(s, 3H), 3.31-3.17(m, 1H), 2.81-2.65(m, 2H), 1.88-1.71(m, 4H), 1.25(d, J=6.9Hz, 3H).
步骤4：化合物WX006-6的合成Step 4: Synthesis of compound WX006-6
在预先干燥的反应瓶中，加入WX006-5(3.8g,18.42mmol)和四氢呋喃(40mL)，分批加入N-溴代丁二酰亚胺(3.61g,20.26mmol)，置于-78℃搅拌2小时，反应完成后，将反应液倒入水(50mL)中淬灭，乙酸乙酯(50mL*3)，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＝2％转5％转30％)纯化，得到WX006-6。 1H NMR(400MHz,氘代氯仿)δ7.32(d,J＝8.8Hz,1H),6.82(d,J＝8.8Hz,1H),5.26-5.15(m,2H),3.49(s,3H),3.24(td,J＝3.5,6.8Hz,1H),2.95-2.83(m,1H),2.62-2.46(m,1H),1.88-1.80(m,2H),1.74-1.66(m,2H),1.22(d,J＝6.9Hz,3H)。 In a pre-dried reaction flask, add WX006-5 (3.8g, 18.42mmol) and tetrahydrofuran (40mL), add N-bromosuccinimide (3.61g, 20.26mmol) in batches, place at -78°C Stir for 2 hours, after the reaction is completed, pour the reaction solution into water (50 mL) to quench, ethyl acetate (50 mL*3), combine the organic phases, wash the organic phase with saturated brine (50 mL), after separation, organic The phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=2% to 5% to 30%) to give WX006-6. 1 H NMR (400MHz, deuterated chloroform) δ 7.32 (d, J=8.8Hz, 1H), 6.82 (d, J=8.8Hz, 1H), 5.26-5.15 (m, 2H), 3.49 (s, 3H) ), 3.24(td, J＝3.5, 6.8Hz, 1H), 2.95-2.83(m, 1H), 2.62-2.46(m, 1H), 1.88-1.80(m, 2H), 1.74-1.66(m, 2H) ), 1.22 (d, J=6.9 Hz, 3H).
步骤5：化合物WX006-7的合成Step 5: Synthesis of compound WX006-7
在预先干燥的反应瓶里加入WX006-6(4g,14.03mmol)和四氢呋喃(40mL)，然后置于-78℃缓慢滴入正丁基锂(2.5M,6.17mL)，搅拌1小时，然后缓慢滴入WX001-4(2.69g,12.62mmol)和四氢呋喃(20mL)，置于-78℃搅拌1小时。反应完毕后，将反应液倒入饱和氯化铵溶液中(100mL)，然后加入乙酸乙酯(200mL)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，粗品经柱层析(乙酸乙酯：石油醚＝5％转10％转30％)纯化，得到WX006-7。WX006-6 (4 g, 14.03 mmol) and tetrahydrofuran (40 mL) were added to the pre-dried reaction flask, then placed at -78°C and slowly added dropwise n-butyllithium (2.5 M, 6.17 mL), stirred for 1 hour, and then slowly WX001-4 (2.69 g, 12.62 mmol) and tetrahydrofuran (20 mL) were added dropwise, and the mixture was stirred at -78°C for 1 hour. After the reaction was completed, the reaction solution was poured into saturated ammonium chloride solution (100 mL), then ethyl acetate (200 mL) was added for extraction, the organic phases were combined, and the organic phase was washed with saturated brine (100 mL). Dry with anhydrous sodium sulfate, filter, spin dry the filtrate under reduced pressure, and purify the crude product by column chromatography (ethyl acetate: petroleum ether=5% to 10% to 30%) to obtain WX006-7.
步骤6：化合物WX006-8的合成Step 6: Synthesis of Compound WX006-8
在预先干燥的反应瓶中，加入WX006-7(5.3g,12.64mmol)和二氯甲烷(70mL)，置于-10℃然后加入三乙基硅氢(2.2g,18.96mmol,3.03mL)和三氟乙酸(2.16g,18.96mmol,1.4mL)，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(100mL)调pH至6-7，加入二氯甲烷(300mL)萃取，合并有机相，有机相用饱和食盐水(200mL)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WX006-8。 1H NMR(400MHz,氘代氯仿)δ7.22(s,2H),6.69(d,J＝8.5Hz,1H),6.21(d,J＝8.5Hz,1H),5.16(s,2H),3.83-3.73(m,1H),3.70-3.59(m,1H),3.47(s,3H),3.32-3.21(m,1H),2.95-2.82(m,1H),2.70-2.55(m,1H),2.15(s,6H),1.92(br dd,J＝4.8,9.8Hz,2H),1.82-1.73(m,2H),1.27(d,J＝6.9Hz,3H)。 In a pre-dried reaction flask, add WX006-7 (5.3g, 12.64mmol) and dichloromethane (70mL), place at -10°C and then add triethylsilylhydrogen (2.2g, 18.96mmol, 3.03mL) and Trifluoroacetic acid (2.16 g, 18.96 mmol, 1.4 mL) was placed at -10°C and stirred for 1 hour. After the completion of the reaction, the pH of the reaction solution was adjusted to 6-7 with saturated aqueous sodium bicarbonate solution (100 mL), and dichloromethane (300 mL) was added for extraction. , the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=5% to 10% to 20%) to give WX006-8. 1 H NMR (400MHz, deuterated chloroform) δ 7.22(s, 2H), 6.69(d, J=8.5Hz, 1H), 6.21(d, J=8.5Hz, 1H), 5.16(s, 2H), 3.83-3.73(m,1H), 3.70-3.59(m,1H), 3.47(s,3H), 3.32-3.21(m,1H), 2.95-2.82(m,1H), 2.70-2.55(m,1H) ), 2.15(s, 6H), 1.92(br dd, J=4.8, 9.8Hz, 2H), 1.82-1.73(m, 2H), 1.27(d, J=6.9Hz, 3H).
步骤7：化合物WX006-9的合成Step 7: Synthesis of compound WX006-9
在预先干燥的反应瓶加入WX006-8(3.4g,8.43mmol)和1-4二氧六环(35mL)，再加入碳酸铯(4.12g,12.64mmol)和WX001-7(1.68g,9.27mmol,1.56mL)，置换氮气三次，加入三(二亚苄基丙酮)二钯(463.14mg,505.76μmol)和Xantphos(390.19mg,674.35μmol)，再次置换氮气，置于100℃搅拌16小时。反应完成后，反应液用乙酸乙酯稀释后用垫有硅藻土的漏斗过滤，收集滤液，将滤液减压旋干。粗品经柱层析(乙酸乙酯：石油醚＝2％转5％转10％)纯化，得到WX006-9。 1H NMR(400MHz,氘代氯仿)δ7.85-7.80(m,1H),7.67-7.57(m,1H),7.54-7.45(m,3H),7.32-7.29(m,3H),6.96-6.86(m,1H),6.73(d,J＝7.4Hz,1H),6.67(d,J＝8.5Hz,1H),6.46(s,2H),6.14(d,J＝8.5Hz,1H),5.31(s,1H),3.75-3.67(m,1H),3.63-3.55(m,1H),3.49(s,3H),3.31-3.21(m,1H),2.91-2.81(m,1H),2.66-2.53(m,1H),2.00(s,6H),1.95-1.86(m,2H),1.81-1.71(m,3H),1.26(d,J＝7.0Hz,3H)。 WX006-8 (3.4g, 8.43mmol) and 1-4 dioxane (35mL) were added to the pre-dried reaction flask, followed by cesium carbonate (4.12g, 12.64mmol) and WX001-7 (1.68g, 9.27mmol) , 1.56 mL), replaced nitrogen three times, added tris(dibenzylideneacetone)dipalladium (463.14 mg, 505.76 μmol) and Xantphos (390.19 mg, 674.35 μmol), replaced nitrogen again, and stirred at 100° C. for 16 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, filtered through a funnel with celite pads, the filtrate was collected, and the filtrate was spin-dried under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=2% to 5% to 10%) to give WX006-9. 1 H NMR (400MHz, deuterated chloroform) δ 7.85-7.80 (m, 1H), 7.67-7.57 (m, 1H), 7.54-7.45 (m, 3H), 7.32-7.29 (m, 3H), 6.96- 6.86(m, 1H), 6.73(d, J=7.4Hz, 1H), 6.67(d, J=8.5Hz, 1H), 6.46(s, 2H), 6.14(d, J=8.5Hz, 1H), 5.31(s, 1H), 3.75-3.67(m, 1H), 3.63-3.55(m, 1H), 3.49(s, 3H), 3.31-3.21(m, 1H), 2.91-2.81(m, 1H), 2.66-2.53 (m, 1H), 2.00 (s, 6H), 1.95-1.86 (m, 2H), 1.81-1.71 (m, 3H), 1.26 (d, J=7.0Hz, 3H).
步骤8：化合物WX006-10的合成Step 8: Synthesis of Compound WX006-10
在预先干燥的反应瓶里加入WX006-9(3g,5.96mmol)和四氢呋喃(30mL)，盐酸(2M,11.91mL)，置于25℃搅拌1小时。反应完成后，向反应液中加入50mL饱和碳酸钠水溶液调pH至6-7，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WX006-10。 1H NMR(400MHz,氘代氯仿)δ6.69(d,J＝8.5Hz,1H),6.47(s,2H),6.32(d,J＝8.5Hz,1H),5.16(s,2H), 3.78-3.68(m,1H),3.64-3.59(m,1H),3.48(s,3H),3.32-3.24(m,1H),2.94-2.84(m,1H),2.70-2.53(m,1H),2.09(s,6H),2.00-1.87(m,2H),1.83-1.73(m,2H),1.28(d,J＝6.9Hz,3H)。 WX006-9 (3 g, 5.96 mmol), tetrahydrofuran (30 mL) and hydrochloric acid (2 M, 11.91 mL) were added to the pre-dried reaction flask, and the mixture was stirred at 25° C. for 1 hour. After the reaction was completed, 50 mL of saturated aqueous sodium carbonate solution was added to the reaction solution to adjust the pH to 6-7, ethyl acetate (50 mL*3) was added for extraction, the organic phases were combined, and the organic phase was washed with saturated brine (50 mL), and the solution was separated. , the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=5% to 10% to 20%) to give WX006-10. 1 H NMR (400MHz, deuterated chloroform) δ 6.69(d, J=8.5Hz, 1H), 6.47(s, 2H), 6.32(d, J=8.5Hz, 1H), 5.16(s, 2H), 3.78-3.68(m,1H), 3.64-3.59(m,1H), 3.48(s,3H), 3.32-3.24(m,1H), 2.94-2.84(m,1H), 2.70-2.53(m,1H) ), 2.09(s, 6H), 2.00-1.87(m, 2H), 1.83-1.73(m, 2H), 1.28(d, J=6.9Hz, 3H).
步骤9：化合物WX006-11的合成Step 9: Synthesis of compound WX006-11
在预先干燥的反应瓶中加入WX006-10(0.9g,2.65mmol)，四氢呋喃(10mL)，将反应体系降至0℃，然后加入亚硝酸叔丁酯(546.78mg,5.30mmol,630.66μL)和四氢呋喃(10mL)的混合溶液，在0℃下搅拌反应0.5hr，加入WX001-10(620.93mg,3.98mmol)，0℃搅拌1小时。反应完成后，将反应液中加入水(200mL)和乙酸乙酯(250mL)分液，收集有机相，水相用乙酸乙酯萃取(250mL*2)，合并有机相，用饱和食盐水洗涤(200mL*3)，无水硫酸钠干燥，过滤，减压浓缩得到粗品。得到WX006-11。In the pre-dried reaction flask was added WX006-10 (0.9 g, 2.65 mmol), tetrahydrofuran (10 mL), the reaction system was lowered to 0 °C, and then tert-butyl nitrite (546.78 mg, 5.30 mmol, 630.66 μL) and The mixed solution of tetrahydrofuran (10 mL) was stirred at 0°C for 0.5 hr, WX001-10 (620.93 mg, 3.98 mmol) was added, and the mixture was stirred at 0°C for 1 hour. After the reaction was completed, water (200 mL) and ethyl acetate (250 mL) were added to the reaction solution for separation, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (250 mL*2), the organic phases were combined and washed with saturated brine ( 200 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Get WX006-11.
步骤10：化合物WX006-12的合成Step 10: Synthesis of Compound WX006-12
在预先干燥的反应瓶里加入WX006-11(2.5g,4.93mmol)和N,N-二甲基乙酰胺(25mL)，然后加入乙酸钾(532.75mg,5.43mmol)，置换氮气三次，置于115℃搅拌2hr。反应完成后，将反应液中加入300mL水，加入乙酸乙酯(500mL*3)萃取合并有机相，用饱和食盐水洗涤(200mL)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WX006-12。WX006-11 (2.5g, 4.93mmol) and N,N-dimethylacetamide (25mL) were added to the pre-dried reaction flask, then potassium acetate (532.75mg, 5.43mmol) was added, and the nitrogen was replaced three times. Stir at 115°C for 2hrs. After the reaction was completed, 300 mL of water was added to the reaction solution, ethyl acetate (500 mL*3) was added to extract the combined organic phase, washed with saturated brine (200 mL) and separated, the organic phase was dried with anhydrous sodium sulfate, filtered, and the The filtrate was spin-dried under reduced pressure to obtain WX006-12.
步骤11：化合物WX006-13的合成Step 11: Synthesis of compound WX006-13
在预先干燥的反应瓶里加入WX006-12(0.5g,1.09mmol)和甲醇(5mL)，然后加入盐酸(12M,90.48μL)，置换氮气三次，置于50℃搅拌0.5小时。反应完毕后，将反应液用饱和碳酸氢钠水溶液(50mL)调pH至6-7，加入水(50mL)和乙酸乙酯(100mL*3)萃取，合并有机相，用饱和食盐水洗涤(150mL)，分液后，有机相用无水硫酸钠干燥，过滤，将滤液减压旋干，粗品通过制备高效液相色谱柱纯化(色谱柱:Phenomenex luna C18 250*50mm*10μm；流动相:[水(0.04％盐酸)-乙腈]；B(乙腈)％:50％-90％,10分钟]得到WX006-13。 1H NMR(400MHz,氘代氯仿)δ8.62(br s,1H),7.19(s,2H),6.42(d,J＝8.3Hz,1H),6.16(d,J＝8.0Hz,1H),4.64-4.47(m,1H),3.91-3.68(m,2H),3.18(td,J＝3.6,7.0Hz,1H),2.94-2.80(m,1H),2.72-2.56(m,1H),2.24(s,6H),2.01-1.90(m,2H),1.86-1.76(m,2H),1.30(d,J＝7.0Hz,3H)。 WX006-12 (0.5 g, 1.09 mmol) and methanol (5 mL) were added to the pre-dried reaction flask, then hydrochloric acid (12 M, 90.48 μL) was added, nitrogen was replaced three times, and stirred at 50° C. for 0.5 hour. After the reaction was completed, the pH of the reaction solution was adjusted to 6-7 with saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL) and ethyl acetate (100 mL*3) were added for extraction, the organic phases were combined and washed with saturated brine (150 mL). ), after liquid separation, the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the crude product was purified by a preparative high-performance liquid chromatography column (chromatographic column: Phenomenex luna C18 250*50mm*10 μm; mobile phase: [ Water (0.04% hydrochloric acid)-acetonitrile]; B (acetonitrile) %: 50%-90%, 10 min] to give WX006-13. 1 H NMR (400 MHz, deuterated chloroform) δ 8.62 (br s, 1H), 7.19(s, 2H), 6.42(d, J=8.3Hz, 1H), 6.16(d, J=8.0Hz, 1H), 4.64-4.47(m, 1H), 3.91-3.68(m, 2H), 3.18 (td, J＝3.6, 7.0Hz, 1H), 2.94-2.80(m, 1H), 2.72-2.56(m, 1H), 2.24(s, 6H), 2.01-1.90(m, 2H), 1.86-1.76 (m, 2H), 1.30 (d, J=7.0 Hz, 3H).
步骤12：化合物WX006和WX007的合成Step 12: Synthesis of Compounds WX006 and WX007
将WX006-13(70mg，168.08μmol)进行手性分离色谱柱:DAICEL CHIRALPAK IG(250mm*30mm,10μm)；流动相:[0.1％氨水乙醇]；B(0.1％氨水乙醇)％:35％-35％,分钟。得到WX006(ee％＝100％,保留时间为1.422分钟)和WX007(ee％＝95.18％,保留时间为1.505分钟)。The WX006-13 (70mg, 168.08μmol) was subjected to chiral separation Column: DAICEL CHIRALPAK IG (250mm*30mm, 10μm); mobile phase: [0.1% ammonia ethanol]; B (0.1% ammonia ethanol)%: 35%- 35%, min. WX006 (ee%=100%, retention time 1.422 minutes) and WX007 (ee%=95.18%, retention time 1.505 minutes) were obtained.
WX006： 1H NMR(400MHz,氘代氯仿)δ8.78(br s,1H),7.27(s,2H),6.50(d,J＝8.3Hz,1H),6.24(d,J＝8.1Hz,1H),4.64(br s,1H),3.96-3.89(m,1H),3.85-3.78(m,1H),3.27(td,J＝3.4,7.0Hz,1H),3.02-2.90(m,1H),2.80-2.65(m,1H),2.32(s,6H),2.02(br dd,J＝4.5,9.6Hz,2H),1.95-1.85(m,2H),1.39(d,J＝7.0Hz,3H)； WX006: 1 H NMR (400 MHz, deuterated chloroform) δ 8.78 (br s, 1H), 7.27 (s, 2H), 6.50 (d, J=8.3 Hz, 1H), 6.24 (d, J=8.1 Hz, 1H), 4.64(br s, 1H), 3.96-3.89(m, 1H), 3.85-3.78(m, 1H), 3.27(td, J=3.4, 7.0Hz, 1H), 3.02-2.90(m, 1H) ),2.80-2.65(m,1H),2.32(s,6H),2.02(br dd,J=4.5,9.6Hz,2H),1.95-1.85(m,2H),1.39(d,J=7.0Hz ,3H);
WX007： 1H NMR(400MHz,氘代氯仿)δ7.27(s,2H),6.50(br d,J＝8.1Hz,1H),6.31-6.13(m,1H),5.12- 4.40(m,1H),3.98-3.78(m,2H),3.35-3.20(m,1H),2.97(br d,J＝17.3Hz,1H),2.79-2.65(m,1H),2.32(s,6H),2.08-1.99(m,2H),1.89(br s,2H),1.39(br d,J＝6.9Hz,3H)。 WX007: 1 H NMR (400 MHz, deuterated chloroform) δ 7.27 (s, 2H), 6.50 (br d, J=8.1 Hz, 1H), 6.31-6.13 (m, 1H), 5.12- 4.40 (m, 1H) ),3.98-3.78(m,2H),3.35-3.20(m,1H),2.97(br d,J=17.3Hz,1H),2.79-2.65(m,1H),2.32(s,6H),2.08 -1.99 (m, 2H), 1.89 (br s, 2H), 1.39 (br d, J=6.9Hz, 3H).
实施例6Example 6
Figure PCTCN2021117786-appb-000070
Figure PCTCN2021117786-appb-000070
合成路线：synthetic route:
Figure PCTCN2021117786-appb-000071
Figure PCTCN2021117786-appb-000071
步骤1：化合物WX008的合成Step 1: Synthesis of compound WX008
在干躁的反应瓶中，将WX001-12(300mg,671.90μmol,1eq)，加入到AcOH(3mL)，加入NCS(98.69mg,739.09μmol,1.1eq)，在50℃下反应10小时。反应完成后，加入碳酸氢钠水溶液中和，加入乙酸乙酯(10mL*3)萃取，分液后收集有机相，依次用饱和食盐水溶液(10mL*3)，无水硫酸钠干燥，减压浓缩。通过制备高效液相色谱柱纯化(色谱柱:Phenomenex luna C18 250*50mm*10μm；流动相:[水(0.04％盐酸)-乙腈]；B(乙腈)％:50％-70％,10分钟)，得到WX008。 1H NMR(400MHz,氘代甲醇)δ7.26(s,2H),6.13(s,1H),3.84(s,2H),2.82-2.68(m,4H),2.22(s,6H),1.92-1.75(m,4H)。MS-ESI m/z:435.0[M-H] -。 In a dry reaction flask, add WX001-12 (300 mg, 671.90 μmol, 1 eq) to AcOH (3 mL), add NCS (98.69 mg, 739.09 μmol, 1.1 eq), and react at 50° C. for 10 hours. After the completion of the reaction, add aqueous sodium bicarbonate solution to neutralize, add ethyl acetate (10 mL*3) for extraction, collect the organic phase after separation, successively use saturated brine solution (10 mL*3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure . Purification by preparative high performance liquid chromatography column (chromatographic column: Phenomenex luna C18 250*50mm*10μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; B(acetonitrile)%: 50%-70%, 10 minutes) , get WX008. 1 H NMR (400MHz, deuterated methanol) δ 7.26(s, 2H), 6.13(s, 1H), 3.84(s, 2H), 2.82-2.68(m, 4H), 2.22(s, 6H), 1.92 -1.75(m, 4H). MS-ESI m/z: 435.0 [MH] - .
实施例7Example 7
Figure PCTCN2021117786-appb-000072
Figure PCTCN2021117786-appb-000072
合成路线：synthetic route:
Figure PCTCN2021117786-appb-000073
Figure PCTCN2021117786-appb-000073
步骤1：化合物WX009-3的合成Step 1: Synthesis of compound WX009-3
在预先干燥的反应瓶中加入WX009-1(5.5g,38.15mmol,13.75mL,1eq)和异丙醇(250mL)，加入WX009-2(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WX009-3。 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)。 In the pre-dried reaction flask, add WX009-1 (5.5g, 38.15mmol, 13.75mL, 1eq) and isopropanol (250mL), add WX009-2 (12.14g, 41.96mmol, 1.1eq) and 1-chloromethane Alkyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (20.27g, 57.22mmol, 1.5eq), replaced nitrogen three times, and stirred at 80°C for 12 Hour. After the completion of the reaction, the reaction solution was directly concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 50:1) to obtain WX009-3. 1 H NMR (400 MHz, deuterated chloroform) δ 8.21 (d, J=8.19 Hz, 1H), 7.80 (d, J=8.19 Hz, 1H), 7.46-7.55 (m, 2H), 7.39 (dd, J = 5.20, 8.99 Hz, 1H), 7.28-7.32 (m, 1H), 5.48 (d, J=4.40 Hz, 1H). 19 F NMR (377 MHz, deuterated chloroform) δ-145.48 (s, 1F).
步骤2：化合物WX009-4的合成Step 2: Synthesis of compound WX009-4
在预先干燥的反应瓶中加入WX009-3(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小试。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WX009-4。 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)。 WX009-3 (3.0g, 18.50mmol, 1eq) and ethanol (100mL) were added to the pre-dried reaction flask, palladium carbon (1g, 18.50mmol, 10% content, 1eq) was added, hydrogen was replaced three times, and placed in hydrogen ( 373.70mg, 185.00mmol, 10eq) in a 50psi environment, stirred at 60°C for 16 hours. After completion of the reaction, the reaction solution was directly filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0) to obtain WX009-4. 1 H NMR (400MHz, deuterated chloroform) δ 6.78-6.91 (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). 19 F NMR (376 MHz, deuterated chloroform) δ-145.84 (s, 1F).
步骤3：化合物WX009-5的合成Step 3: Synthesis of compound WX009-5
在预先干燥的反应瓶中加入WX009-4(4g,24.07mmol,1eq)和乙腈(80mL)，加入N-溴代丁二酰亚 胺(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WX009-5。 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)。 In the pre-dried reaction flask, add WX009-4 (4g, 24.07mmol, 1eq) and acetonitrile (80mL), add N-bromosuccinimide (4.71g, 26.48mmol, 1.1eq), replace nitrogen three times, Stir at 25°C for 2 hours. After the completion of the reaction, water (150 mL) and ethyl acetate (150 mL) were added to the reaction solution for separation, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (200 mL*2), the organic phases were combined and washed with saturated brine ( 300 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 50:1) to obtain WX009-5. 1 H NMR (400MHz, deuterated chloroform) δ 7.17 (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). 19 F NMR (377 MHz, deuterated dimethyl sulfoxide) δ 0.00 (s, 1F).
步骤4：化合物WX009-6的合成Step 4: Synthesis of compound WX009-6
在预先干燥的反应瓶中加入WX009-5(6g,24.48mmol,1eq)和N,N-二甲基甲酰胺(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WX009-6。 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)。 Add WX009-5 (6g, 24.48mmol, 1eq) and N,N-dimethylformamide (120mL) to the pre-dried reaction flask, replace nitrogen three times, place at 0 ℃, add cesium carbonate (23.93g, 73.44mmol, 3eq), then chloromethyl ether (3.94g, 48.96mmol, 3.72mL, 2eq) was added dropwise, and the mixture was stirred at 25°C for 2 hours. After the reaction was completed, 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. The crude product was purified by thin layer chromatography on silica gel plate (petroleum ether:ethyl acetate=10:1) to give WX009-6. 1 H NMR (400MHz, deuterated chloroform) δ 7.20 (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). 19 F NMR (376 MHz, deuterated chloroform) δ-132.23 (s, 1F).
步骤5：化合物WX009-7的合成Step 5: Synthesis of compound WX009-7
在预先干燥的反应瓶中加入WX009-6(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WX009-7。 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)。 Add WX009-6 (1 g, 3.46 mmol, 1 eq) and tetrahydrofuran (10 mL) to the pre-dried reaction flask, replace nitrogen three times, place at -78 ° C, slowly drop n-butyl lithium (2.5 M, 1.52 mL, 1.1eq), stirred at -78°C for 1 hour, then added dropwise a mixed solution of WX001-4 (663.22mg, 3.11mmol, 0.9eq) and tetrahydrofuran (10mL) at -78°C, and continued stirring at -78°C for 1 hour . After the reaction was completed, the 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. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 10:1 to 5:1) to obtain WX009-7. 1 H NMR (400MHz, deuterated chloroform) δ 7.19(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). 19 F NMR (376 MHz, deuterated chloroform) δ-134.26 (s, 1F).
步骤6：化合物WX009-8的合成Step 6: Synthesis of compound WX009-8
在预先干燥的反应瓶中加入WX009-7(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4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(87.48mg,151.19μmol,0.08eq)和三(二亚苄基丙酮)二钯(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WX009-8。 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)。 Add WX009-7 (800mg, 1.89mmol, 1eq), WX001-7 (376.75mg, 2.08mmol, 348.84μL, 1.1eq) and 1,4-dioxane (16mL) to a pre-dried reaction flask, add Cesium carbonate (923.62mg, 2.83mmol, 1.5eq), replaced nitrogen three times, followed by adding 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (87.48mg, 151.19μmol, 0.08eq) ) and tris(dibenzylideneacetone)dipalladium (103.83 mg, 113.39 μmol, 0.06 eq), replaced with nitrogen three times again, and stirred at 100° C. for 16 hours. After completion of the reaction, the reaction solution was directly filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 20:1 to 10:1 to 3:1) to obtain WX009-8. 1 H NMR (400MHz, deuterated chloroform) δ 7.84-7.92 (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=5.14 Hz, 1H), 1.55 (s, 1H). 19 F NMR (376 MHz, deuterated chloroform) δ-133.29 (s, 1F).
步骤7：化合物WX009-9的合成Step 7: Synthesis of compound WX009-9
在预先干燥的反应瓶中加入WX009-8(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WX009-9。 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,5H),1.66-1.76(m,4H)。 19F NMR(377MHz,氘代氯仿)δ-134.74(s,1F)。 WX009-8 (600 mg, 1.15 mmol, 1 eq) and tetrahydrofuran (12 mL) were added to the pre-dried reaction flask, hydrochloric acid (2 M, 572.92 μL, 1 eq) was added, nitrogen was replaced three times, and the mixture was stirred at 25° C. for 1 hour. After the reaction was completed, the pH of the reaction solution was adjusted to about 7 with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (20mL*3), the organic phases were combined, washed with saturated brine (20mL*2), the organic phase was collected, no Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was purified by thin layer chromatography on silica gel plate (petroleum ether:ethyl acetate=1:1) to obtain WX009-9. 1 H NMR (400MHz, deuterated chloroform) δ 7.05(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, 5H), 1.66-1.76(m, 4H). 19 F NMR (377 MHz, deuterated chloroform) δ-134.74 (s, 1F).
步骤8：化合物WX009-10的合成Step 8: Synthesis of compound WX009-10
在预先干燥的反应瓶中加入WX009-9(130mg,361.68μmol,1eq)和甲醇(5mL)，醋酸(5mL)，加入钯碳(10mg,3.62mmol,10％含量,10eq)，置换氢气三次，置于氢气(7.31mg,3.62mmol,10eq)，50psi下，25℃搅拌16小时。反应完毕后，将反应液直接过滤，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＝3:1)得到WX009-10。 1H NMR(400MHz,氘代氯仿)δ6.50(s,2H),6.09-6.19(m,1H),5.07(s,2H),3.67(s,2H),3.58(s,3H),2.81(t,J＝5.82Hz,2H),2.69-2.76(m,2H),2.08(s,6H),1.78-1.89(m,4H)。 19F NMR(376MHz,氘代氯仿)δ-134.95(s,1F)。 Add WX009-9 (130mg, 361.68μmol, 1eq) and methanol (5mL), acetic acid (5mL) to the pre-dried reaction flask, add palladium carbon (10mg, 3.62mmol, 10% content, 10eq), replace hydrogen three times, Place under hydrogen (7.31 mg, 3.62 mmol, 10 eq) and stir at 25°C for 16 hours under 50 psi. After completion of the reaction, the reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin layer chromatography on silica gel (petroleum ether:ethyl acetate=3:1) to give WX009-10. 1 H NMR (400MHz, deuterated chloroform) δ 6.50(s, 2H), 6.09-6.19(m, 1H), 5.07(s, 2H), 3.67(s, 2H), 3.58(s, 3H), 2.81 (t, J=5.82 Hz, 2H), 2.69-2.76 (m, 2H), 2.08 (s, 6H), 1.78-1.89 (m, 4H). 19 F NMR (376 MHz, deuterated chloroform) δ-134.95 (s, 1F).
步骤9：化合物WX009-11的合成Step 9: Synthesis of compound WX009-11
在预先干燥的反应瓶中加入WX009-10(100mg,291.18μmol,1eq)和醋酸(1mL)，盐酸(12M,74.98μL,3.09eq)，置于0℃缓慢滴入亚硝酸钠(21.30mg,308.65μmol,1.06eq)和水(1mL)的混合溶液，0℃搅拌0.5小时，0℃下加入WX001-10(45.46mg,291.18μmol,1eq)，0℃继续搅拌0.5小时。反应完毕后，将反应液用醋酸钠(3eq)的水溶液(30mL)淬灭，过滤，收集滤饼，滤饼减压浓缩得到WX009-11。 1H NMR(400MHz,氘代氯仿)δ9.25(s,1H),8.53(s,1H),7.03(s,2H),6.02(d,J＝12.72Hz,1H),5.08(s,2H),4.35(q,J＝7.23Hz,2H),3.75-3.79(m,2H),3.59(s,3H),2.82(br s,2H),2.73(d,J＝5.92Hz,2H),2.23(s,4H),2.18-2.20(m,2H),1.79-1.90(m,4H),1.39(t,J＝7.13Hz,3H)。 Add WX009-10 (100mg, 291.18μmol, 1eq), acetic acid (1mL), hydrochloric acid (12M, 74.98μL, 3.09eq) to the pre-dried reaction flask, and slowly add sodium nitrite (21.30mg, 3.09eq) at 0°C. A mixed solution of 308.65μmol, 1.06eq) and water (1mL) was stirred at 0°C for 0.5 hours, WX001-10 (45.46mg, 291.18μmol, 1eq) was added at 0°C, and stirring was continued at 0°C for 0.5 hours. After the reaction was completed, the reaction solution was quenched with an aqueous solution of sodium acetate (3eq) (30 mL), filtered, and the filter cake was collected and concentrated under reduced pressure to obtain WX009-11. 1 H NMR (400MHz, deuterated chloroform) δ 9.25(s, 1H), 8.53(s, 1H), 7.03(s, 2H), 6.02(d, J=12.72Hz, 1H), 5.08(s, 2H) ), 4.35(q, J＝7.23Hz, 2H), 3.75-3.79(m, 2H), 3.59(s, 3H), 2.82(br s, 2H), 2.73(d, J＝5.92Hz, 2H), 2.23(s, 4H), 2.18-2.20(m, 2H), 1.79-1.90(m, 4H), 1.39(t, J=7.13Hz, 3H).
步骤10：化合物WX009-12的合成Step 10: Synthesis of Compound WX009-12
在预先干燥的反应瓶中加入WX009-11(100mg,195.86μmol,1eq)和N,N-二甲基乙酰胺(1.5mL)，加入醋酸钾(21.14mg,215.45μmol,1.1eq)，置换氮气三次，置于115℃下搅拌5小时。反应完毕后，反应液冷却至室温，乙酸乙酯(10mL)和水(10mL)稀释反应液，水相用乙酸乙酯萃取(2*15mL)，合并有机相，有机相用饱和食盐水洗涤(3*30mL)，无水硫酸钠干燥，过滤，滤液减压浓缩得到WX009-12。MS-ESI m/z: 463.2[M-H] -。 Add WX009-11 (100mg, 195.86μmol, 1eq) and N,N-dimethylacetamide (1.5mL) to a pre-dried reaction flask, add potassium acetate (21.14mg, 215.45μmol, 1.1eq), replace nitrogen Three times, it was stirred at 115°C for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with ethyl acetate (10 mL) and water (10 mL), the aqueous phase was extracted with ethyl acetate (2*15 mL), the organic phases were combined, and the organic phase was washed with saturated brine ( 3*30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain WX009-12. MS-ESI m/z: 463.2[MH] - .
步骤11：化合物WX009的合成Step 11: Synthesis of Compound WX009
在预先干燥的反应瓶中加入WX009-12(90mg,193.76μmol,1eq)和甲醇(1mL)，加入盐酸(12M,16.15μL,1eq)，置换氮气三次，置于50℃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溶液淬灭，用乙酸乙酯(30mL)稀释，加入水(30mL)，分液，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，滤液减压浓缩得粗产品。粗产品经高效液相色谱分离(色谱柱:Welch Xtimate C18 100*25mm*3μm；流动相:[水(0.04％盐酸)-乙腈]；B(乙腈)％:30％-55％,8分钟)得到WX009。 1H NMR(400MHz,氘代甲醇)δ7.26(s,2H),5.92(d,J＝12.42Hz,1H),3.85(s,2H),2.68-2.78(m,4H),2.22(s,6H),1.77-1.91(m,4H)。 19F NMR(377MHz,氘代甲醇)δ-144.45(s,1F)。MS-ESI m/z:419.2[M-H] -。 Add WX009-12 (90 mg, 193.76 μmol, 1 eq) and methanol (1 mL) to a pre-dried reaction flask, add hydrochloric acid (12 M, 16.15 μL, 1 eq), replace nitrogen three times, and stir at 50° C. for 0.5 hours. After the completion of the reaction, the reaction solution was quenched with saturated sodium bicarbonate solution, diluted with ethyl acetate (30 mL), water (30 mL) was added, the layers were separated, the aqueous phase (30 mL*3) was extracted with ethyl acetate, and the organic phases were combined. , washed with saturated brine (30 mL*2), collected the organic phase, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (chromatographic column: Welch Xtimate C18 100*25mm*3μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; B (acetonitrile)%: 30%-55%, 8 minutes) Get WX009. 1 H NMR (400MHz, deuterated methanol) δ7.26(s, 2H), 5.92(d, J=12.42Hz, 1H), 3.85(s, 2H), 2.68-2.78(m, 4H), 2.22(s , 6H), 1.77-1.91 (m, 4H). 19 F NMR (377 MHz, deuterated methanol) δ-144.45 (s, 1F). MS-ESI m/z: 419.2 [MH] - .
实施例8Example 8
Figure PCTCN2021117786-appb-000074
Figure PCTCN2021117786-appb-000074
合成路线：synthetic route:
Figure PCTCN2021117786-appb-000075
Figure PCTCN2021117786-appb-000075
Figure PCTCN2021117786-appb-000076
Figure PCTCN2021117786-appb-000076
步骤1：化合物WX010-2的合成Step 1: Synthesis of compound WX010-2
在干燥的反应瓶中，加入WX010-1(5g,33.96mmol,4.72mL,1eq)和乙醇(15mL)，置换氮气，降温至0℃，接着加入醋酸酐(6.93g,67.93mmol,6.36mL,2eq)的乙醇(60mL)溶液，升温至20℃，搅拌2小时。反应完成后，将反应液直接减压浓缩，加入醋酸30mL溶解再次减压浓缩。得到WX010-2。 1H NMR(400MHz,氘代氯仿)δ7.58(br d,J＝7.8Hz,1H),7.12(t,J＝7.7Hz,1H),6.93(br d,J＝7.6Hz,2H),2.80-2.77(m,2H),2.59(br t,J＝6.1Hz,2H),2.20(s,3H),1.85-1.76(m,4H)。 In a dry reaction flask, add WX010-1 (5g, 33.96mmol, 4.72mL, 1eq) and ethanol (15mL), replace nitrogen, cool down to 0°C, then add acetic anhydride (6.93g, 67.93mmol, 6.36mL, 2eq) in ethanol (60 mL), warmed to 20° C. and stirred for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and 30 mL of acetic acid was added to dissolve it and concentrated under reduced pressure again. Get WX010-2. 1 H NMR (400MHz, deuterated chloroform) δ 7.58 (br d, J=7.8Hz, 1H), 7.12 (t, J=7.7Hz, 1H), 6.93 (br d, J=7.6Hz, 2H), 2.80-2.77 (m, 2H), 2.59 (br t, J=6.1 Hz, 2H), 2.20 (s, 3H), 1.85-1.76 (m, 4H).
步骤2：化合物WX010-3的合成Step 2: Synthesis of Compound WX010-3
在干燥的反应瓶中，加入WX010-2(6g,31.70mmol,4.72mL,1eq)和醋酸(60mL)，置换氮气，降温至0℃，接着加入液溴(15.20g,95.11mmol,4.90mL,3eq)的醋酸(5mL)溶液，在0℃，搅拌2小时。反应完成后，将反应液倒入冰水(100mL)中淬灭，加二氯甲烷(100mL*3)萃取，分液后收集有机相，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WX010-3。 1H NMR(400MHz,氘代氯仿)δ7.58-7.51(m,1H),7.39(s,1H),2.77-2.56(m,4H),2.26(s,3H),1.82-1.75(m,4H),1.74-1.65(m,1H)。 In a dry reaction flask, add WX010-2 (6g, 31.70mmol, 4.72mL, 1eq) and acetic acid (60mL), replace nitrogen, cool down to 0°C, then add liquid bromine (15.20g, 95.11mmol, 4.90mL, 3eq) in acetic acid (5mL), stirred at 0°C for 2 hours. After the completion of the reaction, the reaction solution was poured into ice water (100 mL) to quench, and dichloromethane (100 mL*3) was added for extraction. After separation, the organic phase was collected, and then saturated brine solution (100 mL*3), anhydrous sulfuric acid were used successively. Dry over sodium and concentrate under reduced pressure to give WX010-3. 1 H NMR (400MHz, deuterated chloroform) δ 7.58-7.51(m, 1H), 7.39(s, 1H), 2.77-2.56(m, 4H), 2.26(s, 3H), 1.82-1.75(m, 4H), 1.74-1.65 (m, 1H).
步骤3：化合物WX010-4的合成Step 3: Synthesis of Compound WX010-4
在干燥的反应瓶中，依次加入WX010-3(7g,26.10mmol,4.72mL,1eq)，丙酮(181mL)，硫酸镁(4.34g,36.02mmol,1.38eq)的水溶液(25mL)和高锰酸钾(12.38g,78.31mmol,3eq)，在20℃下搅拌2小时。反应完成后，将反应液过滤，用饱和亚硫酸钠水溶液(200mL)洗涤，滤液搅拌0.5小时。加二氯甲烷(200mL)分液后加入二氯甲烷(200mL*2)萃取，分液后收集有机相，依次用饱和食盐水溶液(200mL*3)，无水硫酸钠干燥，减压浓缩。浓缩50％时取两滴馏分，加入水(1mL)萃取，水相用淀粉碘化钾试纸检测不变蓝。完全浓缩后取两滴产品，加入水(1mL)萃取，水相用淀粉碘化钾试纸检测不变蓝。水相用饱和亚硫酸钠水溶液洗涤，直至淀粉碘化钾试纸不再变蓝，液体放置过夜，再次检测淀粉碘化钾试纸不变蓝后丢弃。得到WX010-4。 1H NMR(400MHz,氘代氯仿)δ8.56(d,J＝9.1Hz,1H),7.70(d,J＝9.3Hz,1H),3.04(t, J＝6.2Hz,2H),2.70(br d,J＝6.6Hz,2H),2.24(s,3H),2.14-2.09(m,2H)。 In a dry reaction flask, add WX010-3 (7g, 26.10mmol, 4.72mL, 1eq), acetone (181mL), magnesium sulfate (4.34g, 36.02mmol, 1.38eq) aqueous solution (25mL) and permanganic acid in turn Potassium (12.38 g, 78.31 mmol, 3 eq), stirred at 20°C for 2 hours. After completion of the reaction, the reaction solution was filtered, washed with saturated aqueous sodium sulfite solution (200 mL), and the filtrate was stirred for 0.5 hour. Dichloromethane (200 mL) was added for liquid separation, and then dichloromethane (200 mL*2) was added for extraction. After liquid separation, the organic phase was collected, sequentially washed with saturated brine solution (200 mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. When concentrated to 50%, two drops of fractions were taken, and water (1 mL) was added for extraction. The aqueous phase was detected with starch potassium iodide test paper and did not turn blue. After complete concentration, take two drops of the product, add water (1 mL) for extraction, and the aqueous phase is detected with starch potassium iodide test paper and does not change blue. The aqueous phase was washed with a saturated aqueous sodium sulfite solution until the starch potassium iodide test paper no longer turned blue, the liquid was placed overnight, and the starch potassium iodide test paper did not turn blue again after being discarded. Get WX010-4. 1 H NMR (400 MHz, deuterated chloroform) δ 8.56 (d, J=9.1 Hz, 1H), 7.70 (d, J=9.3 Hz, 1H), 3.04 (t, J=6.2 Hz, 2H), 2.70 ( br d, J=6.6Hz, 2H), 2.24 (s, 3H), 2.14-2.09 (m, 2H).
步骤4：化合物WX010-5的合成Step 4: Synthesis of Compound WX010-5
在干燥的反应瓶中，加入WX010-4(7g,24.81mmol,4.72mL,1eq)和盐酸溶液(6M,351.49mL,85eq)，升温至90℃，搅拌10小时。反应完成后，将反应液降温至0℃，加入2N氢氧化钠水溶液，调pH至7～8，加乙酸乙酯(500mL*3)萃取，分液后收集有机相，依次用饱和食盐水溶液(500mL*3)，无水硫酸钠干燥，减压浓缩。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0至3:1)。得到WX010-5。 1H NMR(400MHz,氘代氯仿)δ7.39(s,1H),7.36(s,1H),6.48(br d,J＝8.7Hz,1H),6.42(d,J＝8.9Hz,1H),2.95(t,J＝6.2Hz,2H),2.69-2.56(m,2H),2.05(s,2H)。 In a dry reaction flask, WX010-4 (7g, 24.81mmol, 4.72mL, 1eq) and hydrochloric acid solution (6M, 351.49mL, 85eq) were added, the temperature was raised to 90°C, and the mixture was stirred for 10 hours. After the completion of the reaction, the reaction solution was cooled to 0°C, 2N aqueous sodium hydroxide solution was added, the pH was adjusted to 7-8, ethyl acetate (500mL*3) was added for extraction, the organic phase was collected after separation, and the solution was successively mixed with saturated saline solution ( 500 mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 3:1). Get WX010-5. 1 H NMR (400 MHz, deuterated chloroform) δ 7.39 (s, 1H), 7.36 (s, 1H), 6.48 (br d, J=8.7Hz, 1H), 6.42 (d, J=8.9Hz, 1H) , 2.95(t, J=6.2Hz, 2H), 2.69-2.56(m, 2H), 2.05(s, 2H).
步骤5：化合物WX010-6的合成Step 5: Synthesis of Compound WX010-6
在干燥的反应瓶中，加入WX010-5(1.68g,24.16mmol,2eq)，盐酸羟胺(1.68g,24.16mmol,2eq)，吡啶(10mL)和乙醇(50mL)，升温至85℃，搅拌10小时。反应完成后，将反应液减压浓缩后加水(50mL)洗涤，加乙酸乙酯(50mL*3)萃取，分液后收集有机相，依次用饱和食盐水溶液(50mL*3)，无水硫酸钠干燥，减压浓缩。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0至3:1)。得到WX010-6。 1H NMR(400MHz,氘代氯仿)δ7.25(s,1H),6.46(d,J＝8.8Hz,1H),2.91-2.79(m,4H),1.83(m,J＝6.4Hz,2H)。 In a dry reaction flask, add WX010-5 (1.68g, 24.16mmol, 2eq), hydroxylamine hydrochloride (1.68g, 24.16mmol, 2eq), pyridine (10mL) and ethanol (50mL), warm to 85°C, stir for 10 Hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, washed with water (50 mL), and extracted with ethyl acetate (50 mL*3). Dry and concentrate under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 3:1). Get WX010-6. 1 H NMR (400MHz, deuterated chloroform) δ 7.25 (s, 1H), 6.46 (d, J=8.8Hz, 1H), 2.91-2.79 (m, 4H), 1.83 (m, J=6.4Hz, 2H) ).
步骤6：化合物WX010-7的合成Step 6: Synthesis of Compound WX010-7
在干燥的反应瓶中，加入WX010-6(3.32g,18.03mmol,2eq)，三乙胺(3.65g,36.06mmol,5.02mL,4eq)和二氯甲烷(30mL)，置换氮气，降温至0℃，接着加入对甲苯磺酰氯(1.89g,9.92mmol,1.1eq)，在0℃，搅拌1小时。反应完成后，将反应液加入水(30mL)洗涤，加入1N盐酸调节pH到7～8，加乙酸乙酯(50mL*3)萃取，分液后收集有机相，依次用饱和食盐水溶液(50mL*3)，无水硫酸钠干燥，减压浓缩。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0至3:1)。得到WX010-7。 1H NMR(400MHz,氘代氯仿)δ7.44(d,J＝8.6Hz,1H),7.14(d,J＝8.6Hz,1H),3.01(t,J＝6.3Hz,2H),2.94(t,J＝6.0Hz,2H),2.21(m,J＝6.2Hz,2H)。 In a dry reaction flask, add WX010-6 (3.32g, 18.03mmol, 2eq), triethylamine (3.65g, 36.06mmol, 5.02mL, 4eq) and dichloromethane (30mL), replace nitrogen, and cool to 0 °C, followed by adding p-toluenesulfonyl chloride (1.89 g, 9.92 mmol, 1.1 eq), and stirring at 0 °C for 1 hour. After the reaction was completed, the reaction solution was washed with water (30 mL), 1N hydrochloric acid was added to adjust the pH to 7-8, and ethyl acetate (50 mL*3) was added for extraction. 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 3:1). Get WX010-7. 1 H NMR (400 MHz, deuterated chloroform) δ 7.44 (d, J=8.6 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H), 3.01 (t, J=6.3 Hz, 2H), 2.94 ( t, J=6.0Hz, 2H), 2.21 (m, J=6.2Hz, 2H).
步骤7：化合物WX010-8的合成Step 7: Synthesis of Compound WX010-8
在干燥的反应瓶中，依次加入WX010-7(2g,8.44mmol,4.72mL,1eq)，三乙胺(1.02g,10.12mmol,1.41mL,1.2eq)，四氢呋喃(20mL)，BOC酸酐(2.21g,10.12mmol,2.33mL,1.2eq)和4-二甲氨基吡啶(103.05mg,843.54μmol,0.1eq)，置换氮气，在20℃，搅拌2小时。反应完成后，向反应液加碳酸氢钠水溶液(50mL)洗涤，加乙酸乙酯(50mL*3)萃取，分液后收集有机相，依次用饱和食盐水溶液(50mL*3)，无水硫酸钠干燥，减压浓缩。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0至3:1)。得到WX010-8。 1H NMR(400MHz,氘代氯仿)δ7.65(br s,1H),7.60-7.55(m,1H),3.00(t,J＝6.4Hz,2H),2.92(t,J＝6.0Hz,2H),2.21-2.17(m,2H),1.72(s,9H)。 In a dry reaction flask, sequentially add WX010-7 (2g, 8.44mmol, 4.72mL, 1eq), triethylamine (1.02g, 10.12mmol, 1.41mL, 1.2eq), tetrahydrofuran (20mL), BOC anhydride (2.21 g, 10.12 mmol, 2.33 mL, 1.2 eq) and 4-dimethylaminopyridine (103.05 mg, 843.54 μmol, 0.1 eq), replaced with nitrogen, and stirred at 20° C. for 2 hours. After the completion of the reaction, add aqueous sodium bicarbonate solution (50mL) to the reaction solution for washing, add ethyl acetate (50mL*3) for extraction, collect the organic phase after separation, use saturated saline solution (50mL*3), anhydrous sodium sulfate in turn Dry and concentrate under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 3:1). Get WX010-8. 1 H NMR (400MHz, deuterated chloroform) δ 7.65 (br s, 1H), 7.60-7.55 (m, 1H), 3.00 (t, J=6.4Hz, 2H), 2.92 (t, J=6.0Hz, 2H), 2.21-2.17 (m, 2H), 1.72 (s, 9H).
步骤8：化合物WX010-10的合成Step 8: Synthesis of Compound WX010-10
在干燥的反应瓶中，依次加入WX010-8(500mg,1.48mmol,1eq)，N,N-二甲基甲酰胺(5mL)，乙酸钾(436.55mg,4.45mmol,3eq)，[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(181.63mg,222.41μmol,0.15eq)和WX010-9(753.05mg,2.97mmol,2eq)，反应在80℃下搅拌4小时。反应完成后，将反应液加到水(10mL)中淬灭，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)，无水硫酸钠干燥，减压浓缩。得到WX010-10。In a dry reaction flask, add WX010-8 (500mg, 1.48mmol, 1eq), N,N-dimethylformamide (5mL), potassium acetate (436.55mg, 4.45mmol, 3eq), [1,1 -Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (181.63mg, 222.41μmol, 0.15eq) and WX010-9 (753.05mg, 2.97mmol, 2eq), the reaction was stirred at 80°C for 4 Hour. After the completion of the reaction, the reaction solution was added to water (10 mL) to quench, and ethyl acetate (10 mL*3) was added for extraction. After separation, the organic phase was collected, followed by saturated saline solution (10 mL*3), anhydrous sodium sulfate. Dry and concentrate under reduced pressure. Get WX010-10.
步骤9：化合物WX010-11的合成Step 9: Synthesis of Compound WX010-11
在干燥的反应瓶中，加入WX010-10(500mg,1.30mmol,1eq)和四氢呋喃(5mL)，置换氮气，降温至0℃，接着加入氢氧化钠(1M,2.60mL,2eq)和过氧化氢(221.29mg,1.95mmol,187.53μL,30％纯度,1.5eq)，在0℃，搅拌2小时。反应完全后，将反应液加入到硫代硫酸钠水溶液(10mL)中淬灭，调节PH到7～8，淀粉碘化钾试纸不在变蓝，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)，无水硫酸钠干燥，减压浓缩。浓缩到50％时，取一滴反应液加入1mL水稀释，萃取，淀粉碘化钾试纸检测不再变蓝。浓缩到完全时，取一滴反应液加入1mL水稀释，萃取，淀粉碘化钾试纸检测不再变蓝。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0至3:1)，得到WX010-11。 1H NMR(400MHz,氘代氯仿)δ7.63(br s,1H),7.02(d,J＝8.8Hz,1H),3.02-2.96(m,2H),2.85(t,J＝6.0Hz,2H),2.18-2.14(m,2H),1.72-1.70(m,9H)。 In a dry reaction flask, add WX010-10 (500mg, 1.30mmol, 1eq) and tetrahydrofuran (5mL), replace nitrogen, cool down to 0°C, then add sodium hydroxide (1M, 2.60mL, 2eq) and hydrogen peroxide (221.29 mg, 1.95 mmol, 187.53 μL, 30% purity, 1.5 eq), stirred at 0° C. for 2 hours. After the reaction was completed, the reaction solution was added to an aqueous solution of sodium thiosulfate (10 mL) to quench, and the pH was adjusted to 7 to 8. The starch potassium iodide test paper did not turn blue. Add ethyl acetate (10 mL*3) for extraction, and collect after separation. The organic phase was successively dried with saturated saline solution (10 mL*3), anhydrous sodium sulfate, and concentrated under reduced pressure. When concentrated to 50%, take a drop of the reaction solution and add 1 mL of water to dilute and extract, and the starch potassium iodide test paper will no longer turn blue. When the concentration is complete, take a drop of the reaction solution and add 1 mL of water to dilute and extract, and the starch potassium iodide test paper will no longer turn blue. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 3:1) to give WX010-11. 1 H NMR (400MHz, deuterated chloroform) δ 7.63 (br s, 1H), 7.02 (d, J=8.8Hz, 1H), 3.02-2.96 (m, 2H), 2.85 (t, J=6.0Hz, 2H), 2.18-2.14 (m, 2H), 1.72-1.70 (m, 9H).
步骤10：化合物WX010-13的合成Step 10: Synthesis of Compound WX010-13
在干燥的反应瓶中，加入WX010-11(640mg,2.33mmol,1eq)，WX010-12(538.20mg,2.56mmol,1.1eq)，N,N-二甲基甲酰胺(7mL)和碳酸钾(644.06mg,4.66mmol,2eq)，置换氮气，在100℃下搅拌1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。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0至3:1)。得到WX010-13。 1H NMR(400MHz,氘代氯仿)δ8.33(s,2H),7.62(br d,J＝7.1Hz,1H),6.62(d,J＝8.8Hz,1H),3.05(dt,J＝2.9,6.0Hz,4H),2.22(quin,J＝6.2Hz,2H),1.70(s,9H)。 In a dry reaction flask, add WX010-11 (640mg, 2.33mmol, 1eq), WX010-12 (538.20mg, 2.56mmol, 1.1eq), N,N-dimethylformamide (7mL) and potassium carbonate ( 644.06 mg, 4.66 mmol, 2 eq), replaced with nitrogen, and stirred at 100° C. for 1 hour. After the reaction was completed, water (20 mL) was added to dilute, and ethyl acetate (20 mL*3) was added for extraction. After separation, the organic phase was collected, sequentially washed with saturated brine solution (20 mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 3:1). Get WX010-13. 1 H NMR (400 MHz, deuterated chloroform) δ 8.33 (s, 2H), 7.62 (br d, J=7.1 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 3.05 (dt, J= 2.9, 6.0 Hz, 4H), 2.22 (quin, J=6.2 Hz, 2H), 1.70 (s, 9H).
步骤11：化合物WX010-14的合成Step 11: Synthesis of Compound WX010-14
在干燥的反应瓶中，依次加入WX010-13(450mg,969.21μmol,1eq)，乙醇(6mL)，盐酸(3mL,37％纯度)和二氯化锡二水合物(984.16mg,4.36mmol,4.5eq)，置换氮气，在75℃下搅拌2小时。反应完全后，加入水(20mL)稀释，加入饱和碳酸钠水溶液调pH至7～8，加乙酸乙酯(3*30mL)萃取，分液后收集有机相，依次用饱和食盐水溶液(30mL*3)，无水硫酸钠干燥，减压浓缩。得到WX010-14。In a dry reaction flask, WX010-13 (450mg, 969.21μmol, 1eq), ethanol (6mL), hydrochloric acid (3mL, 37% purity) and tin dichloride dihydrate (984.16mg, 4.36mmol, 4.5ml) were added sequentially eq), replaced with nitrogen, and stirred at 75°C for 2 hours. After the reaction is complete, add water (20 mL) to dilute, add saturated aqueous sodium carbonate solution to adjust the pH to 7-8, add ethyl acetate (3*30 mL) for extraction, collect the organic phase after separation, and sequentially add saturated saline solution (30 mL*3 ), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Get WX010-14.
步骤12：化合物WX010-15的合成Step 12: Synthesis of Compound WX010-15
在干燥的反应瓶中，加入WX010-14(350mg,1.05mmol,1eq)，醋酸(4mL)和水(4mL)，降温至0℃，接着加入盐酸(1.23g,3.20mmol,539.20μL,37％纯度,3.06eq)和亚硝酸钠(76.60mg,1.11mmol,1.06eq)的水(1mL)溶液，在0℃下搅拌0.5小时。加入WX001-10(179.87mg,1.15mmol,1.1eq)，置换 氮气，在0℃下搅拌0.5小时。反应完全后，加入乙酸钠溶液(20mL)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(20mL*3)，无水硫酸钠干燥，减压浓缩。得到WX010-15。In a dry reaction flask, add WX010-14 (350mg, 1.05mmol, 1eq), acetic acid (4mL) and water (4mL), cool down to 0°C, then add hydrochloric acid (1.23g, 3.20mmol, 539.20μL, 37% Purity, 3.06eq) and sodium nitrite (76.60mg, 1.11mmol, 1.06eq) in water (1mL) and stirred at 0°C for 0.5h. WX001-10 (179.87 mg, 1.15 mmol, 1.1 eq) was added, nitrogen was replaced, and the mixture was stirred at 0°C for 0.5 hours. After the reaction is complete, add sodium acetate solution (20mL) to quench, add ethyl acetate (20mL*3) for extraction, collect the organic phase after liquid separation, sequentially use saturated brine solution (20mL*3), dry over anhydrous sodium sulfate, reduce pressure concentrate. Get WX010-15.
步骤13：化合物WX010的合成Step 13: Synthesis of Compound WX010
在干燥的反应瓶中，加入WX010-15(400mg,797.89μmol,1eq)，N,N-二甲基乙酰胺(4mL)和乙酸钾(156.61mg,1.60mmol,2eq)，升温至120℃，搅拌2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。通过制备高效液相色谱柱纯化(色谱柱:Phenomenex Luna 80*30mm*3μm；流动相:[水(0.04％盐酸)-乙腈]；B(乙腈)％:30％-60％,8分钟)，得到WX010。 1H NMR(400MHz,氘代甲醇)δ7.75(s,2H),7.13(d,J＝8.9Hz,1H),6.65(d,J＝8.9Hz,1H),3.02(td,J＝6.1,19.7Hz,4H),2.21(quin,J＝6.0Hz,2H),1.29(s,1H)。MS-ESI m/z:454.9[M+H] +。 In a dry reaction flask, add WX010-15 (400mg, 797.89μmol, 1eq), N,N-dimethylacetamide (4mL) and potassium acetate (156.61mg, 1.60mmol, 2eq), warm to 120°C, Stir for 2 hours. After the reaction was completed, water (20 mL) was added to dilute, and ethyl acetate (20 mL*3) was added for extraction. After separation, the organic phase was collected, sequentially washed with saturated brine solution (20 mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by preparative high performance liquid chromatography (chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; B (acetonitrile)%: 30%-60%, 8 minutes), Get WX010. 1 H NMR (400MHz, deuterated methanol) δ 7.75 (s, 2H), 7.13 (d, J=8.9 Hz, 1H), 6.65 (d, J=8.9 Hz, 1H), 3.02 (td, J=6.1 , 19.7Hz, 4H), 2.21 (quin, J=6.0Hz, 2H), 1.29 (s, 1H). MS-ESI m/z: 454.9 [M+H] + .
实施例9Example 9
Figure PCTCN2021117786-appb-000077
Figure PCTCN2021117786-appb-000077
合成路线：synthetic route:
Figure PCTCN2021117786-appb-000078
Figure PCTCN2021117786-appb-000078
步骤1：化合物WX011-1的合成Step 1: Synthesis of Compound WX011-1
在预先干燥的反应瓶中加入WX006-7(3.2g,7.63mmol,1eq)和二氯甲烷(40mL)，然后加入氯铬酸吡啶(2.47g,11.45mmol,1.5eq)，20℃反应12小时。反应完成后，向反应液中加入饱和硫代硫酸钠水溶液(30mL)，用二氯甲烷(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。粗产品经柱层析纯化(石油醚:乙酸乙酯＝20:1至10:1),纯化得到WX011-1。 1H NMR(400MHz,氘代氯仿)δ7.23-7.15(m,3H),6.84-6.77(m,1H),5.27-5.23(m,2H),3.50(s,3H),3.48-3.41(m,1H),3.34-3.22(m,1H),3.14-3.02(m,1H),2.13-2.07(m,6H),1.89-1.74(m,4H),1.28-1.25(m,3H)。 Add WX006-7 (3.2g, 7.63mmol, 1eq) and dichloromethane (40mL) to the pre-dried reaction flask, then add pyridine chlorochromate (2.47g, 11.45mmol, 1.5eq), and react at 20°C for 12 hours . After the reaction was completed, saturated aqueous sodium thiosulfate solution (30 mL) was added to the reaction solution, extracted with dichloromethane (30 mL*3), the organic phases were combined, and the organic phases were washed with saturated brine (30 mL). The phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=20:1 to 10:1) to obtain WX011-1. 1 H NMR (400MHz, deuterated chloroform) δ 7.23-7.15 (m, 3H), 6.84-6.77 (m, 1H), 5.27-5.23 (m, 2H), 3.50 (s, 3H), 3.48-3.41 ( m, 1H), 3.34-3.22 (m, 1H), 3.14-3.02 (m, 1H), 2.13-2.07 (m, 6H), 1.89-1.74 (m, 4H), 1.28-1.25 (m, 3H).
步骤2：化合物WX011-2的合成Step 2: Synthesis of Compound WX011-2
在预先干燥的反应瓶中加入WX011-1(2.6g,6.23mmol,1eq)和二氧六环(30mL)，然后加入碳酸铯(3.04g,9.35mmol,1.5eq)和WX001-7(1.24g,6.85mmol,1.15mL,1.1eq)，置换氮气三次后，加入三(二亚苄基丙酮)二钯(570.49mg,623.00μmol,0.1eq)和4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(360.48mg,623.00μmol,0.1eq)，再次置换氮气三次后，升温至100℃反应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*3)，分液，收集有机相，用饱和食盐水洗涤(50mL*3)，无水硫酸钠干燥，过滤，减压浓缩。粗产品经柱层析纯化(石油醚:乙酸乙酯＝20:1至5:1)纯化得到WX011-2。In a pre-dried reaction flask was added WX011-1 (2.6g, 6.23mmol, 1eq) and dioxane (30mL), followed by cesium carbonate (3.04g, 9.35mmol, 1.5eq) and WX001-7 (1.24g) , 6.85mmol, 1.15mL, 1.1eq), after replacing nitrogen three times, add tris(dibenzylideneacetone)dipalladium (570.49mg, 623.00μmol, 0.1eq) and 4,5-bis(diphenylphosphorus)- 9,9-Dimethylxanthene (360.48 mg, 623.00 μmol, 0.1 eq) was replaced with nitrogen three times, and then the temperature was raised to 100° C. to react for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 50 mL of water and ethyl acetate (50 mL*3) were added, the layers were separated, the organic phase was collected, washed with saturated brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, Concentrate under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=20:1 to 5:1) to obtain WX011-2.
步骤3：化合物WX011-3的合成Step 3: Synthesis of Compound WX011-3
在预先干燥的反应瓶里加WX011-2(2.1g,4.06mmol,1eq)和四氢呋喃(20mL)，然后加入稀盐酸(2M,8.11mL,4eq)，25℃反应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(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，用饱和食盐水洗涤(20mL*3)，无水硫酸钠干燥，过滤，减压浓缩。粗产品经柱层析纯化(石油醚:乙酸乙酯＝20:1至5:1),得到WX011-3。 1H NMR(400MHz,氘代二甲基亚砜)δ7.08(d,J＝8.8Hz,1H),6.84(d,J＝8.6Hz,1H),6.22(s,2H),5.34-5.18(m,4H),3.41-3.38(m,3H),3.24-3.11(m,2H),2.92-2.78(m,1H),1.91-1.84(m,6H),1.77-1.67(m,4H),1.20(d,J＝7.0Hz,3H)。 In a pre-dried reaction flask, add WX011-2 (2.1g, 4.06mmol, 1eq) and tetrahydrofuran (20mL), then add dilute hydrochloric acid (2M, 8.11mL, 4eq), and react at 25°C for 1 hour. After the reaction was completed, the pH of the reaction solution was adjusted to 6-7 with saturated aqueous sodium bicarbonate solution, water (50 mL) and ethyl acetate (50 mL) were added, the layers were separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (50 mL* 2), the organic phases were combined, washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=20:1 to 5:1) to give WX011-3. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 7.08 (d, J=8.8Hz, 1H), 6.84 (d, J=8.6Hz, 1H), 6.22 (s, 2H), 5.34-5.18 (m,4H), 3.41-3.38(m,3H), 3.24-3.11(m,2H), 2.92-2.78(m,1H), 1.91-1.84(m,6H), 1.77-1.67(m,4H) , 1.20 (d, J=7.0 Hz, 3H).
步骤4：化合物WX011-4的合成Step 4: Synthesis of Compound WX011-4
在预先干燥的反应瓶中加入WX011-3(1g,2.83mmol,1eq)和四氢呋喃(10mL)，降至0℃后，加入亚硝酸叔丁酯(583.50mg,5.66mmol,673.01μL,2eq)的四氢呋喃(5mL)溶液，0℃反应0.5小时后，加入WX001-10(662.63mg,4.24mmol,1.5eq)，0℃反应2.5小时。反应完全后，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(100mL*2)萃取，合并有机相，用饱和食盐水洗涤(100mL*3)，无水硫酸钠干燥，过滤，减压浓缩。粗产品经柱层析纯化(石油醚:乙酸乙酯＝5:1至0:1)，得到WX011-4。WX011-3 (1 g, 2.83 mmol, 1 eq) and tetrahydrofuran (10 mL) were added to the pre-dried reaction flask. After dropping to 0 °C, tert-butyl nitrite (583.50 mg, 5.66 mmol, 673.01 μL, 2 eq) was added. The solution of tetrahydrofuran (5 mL) was reacted at 0°C for 0.5 hours, WX001-10 (662.63 mg, 4.24 mmol, 1.5eq) was added, and the reaction was performed at 0°C for 2.5 hours. After the reaction was completed, water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, the layers were separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (100 mL*2), the organic phases were combined, and washed with saturated brine ( 100 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=5:1 to 0:1) to give WX011-4.
步骤5：化合物WX011-5的合成Step 5: Synthesis of Compound WX011-5
在预先干燥的反应瓶里加入WX011-4(500mg,960.48μmol,1eq)和N,N-二甲基乙酰胺(10mL)，然后加入乙酸钾(188.53mg,1.92mmol,2eq)，置换氮气三次后，115℃反应2小时。反应完成后，向反应液中加入水(30mL)和乙酸乙酯(50mL)分液，收集有机相，水相用乙酸乙酯(50mL*2)萃取,合并有机相，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WX011-5。Add WX011-4 (500mg, 960.48μmol, 1eq) and N,N-dimethylacetamide (10mL) to the pre-dried reaction flask, then add potassium acetate (188.53mg, 1.92mmol, 2eq), replace nitrogen three times After that, the reaction was carried out at 115°C for 2 hours. After the reaction was completed, water (30 mL) and ethyl acetate (50 mL) were added to the reaction solution for separation, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (50 mL*2), the organic phases were combined and washed with saturated brine ( 20 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain WX011-5.
步骤6：化合物WX011-6的合成Step 6: Synthesis of Compound WX011-6
向WX011-5(460mg,969.43μmol,1eq)的甲醇(8mL)溶液中加入浓盐酸(938.40mg,9.52mmol,920.00μL,37％,9.82eq)，50℃反应0.5小时。反应完成后，将反应液减压浓缩，粗产品经制备高效液相色谱纯化(色谱柱:Welch Xtimate C18 100*25mm*3μm；流动相:[水(0.04％盐酸)-乙腈]；B(乙腈)％:30％-70％,8分钟)，得到WX011-6。 1H NMR(400MHz,氘代氯仿)δ9.23-9.02(m,1H),7.24-7.07(m,3H),6.55-6.41(m,1H),5.76-5.40(m,1H),3.57-3.44(m,1H),3.26-3.03(m,2H),2.25-2.11(m,6H),1.93-1.73(m,4H),1.30(d,J＝7.0Hz,3H)。 To a solution of WX011-5 (460 mg, 969.43 μmol, 1 eq) in methanol (8 mL) was added concentrated hydrochloric acid (938.40 mg, 9.52 mmol, 920.00 μL, 37%, 9.82 eq), and reacted at 50° C. for 0.5 hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography (chromatographic column: Welch Xtimate C18 100*25mm*3 μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; B (acetonitrile) )%: 30%-70%, 8 minutes) to obtain WX011-6. 1 H NMR (400MHz, deuterated chloroform) δ 9.23-9.02 (m, 1H), 7.24-7.07 (m, 3H), 6.55-6.41 (m, 1H), 5.76-5.40 (m, 1H), 3.57- 3.44 (m, 1H), 3.26-3.03 (m, 2H), 2.25-2.11 (m, 6H), 1.93-1.73 (m, 4H), 1.30 (d, J=7.0Hz, 3H).
步骤7：化合物WX011-7的合成Step 7: Synthesis of Compound WX011-7
在预先干燥的反应瓶中，加入WX011-6(170mg,394.93μmol,1eq)，吡啶(2mL)和乙酸酐(0.5mL)。氮气置换三次，20℃反应1小时。反应完成后，将反应液减压浓缩。粗产品经柱层析纯化(石油醚:乙酸乙酯＝0:1)，得到160mg产物。产物经手性分离(色谱柱:REGIS(S,S)WHELK-O1(250mm*25mm,10μm)；流动相:[Neu-甲醇]；B％:50％-50％,12分钟)，得到WX011-7(ee％＝100％，Rt＝1.650分钟)和WX012-1(ee％＝100％，Rt＝1.838分钟)。In a pre-dried reaction vial, WX011-6 (170 mg, 394.93 μmol, 1 eq), pyridine (2 mL) and acetic anhydride (0.5 mL) were added. The nitrogen was replaced three times, and the reaction was carried out at 20°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=0:1) to obtain 160 mg of product. The product was separated by chiral (chromatographic column: REGIS(S, S) WHELK-O1 (250mm*25mm, 10μm); mobile phase: [Neu-methanol]; B%: 50%-50%, 12 minutes) to obtain WX011- 7 (ee%=100%, Rt=1.650 min) and WX012-1 (ee%=100%, Rt=1.838 min).
步骤8：化合物WX011的合成Step 8: Synthesis of Compound WX011
将WX011-7(60mg,126.99μmol,1eq)溶于甲醇(10mL)，加入浓盐酸(2.04g,20.70mmol,2mL,37％纯度,163.03eq)，70℃反应4小时。反应完成后，将反应液减压浓缩。粗产品经制备高效液相色谱纯化(色谱柱:Phenomenex Luna 80*30mm*3μm；流动相:[水(0.04％盐酸)-乙腈]；B(乙腈)％:30％-70％,8分钟)，得到WX011。 1H NMR(400MHz,氘代氯仿)δ9.17-8.93(m,1H),7.19-7.07(m,3H),6.50-6.42(m,1H),5.68-5.35(m,1H),3.54-3.42(m,1H),3.22(br d,J＝0.9Hz,2H),2.20-2.10(m,6H),1.89-1.70(m,4H),1.27(d,J＝7.0Hz,3H)。MS-ESI m/z:431.1[M+H] +。 Dissolve WX011-7 (60 mg, 126.99 μmol, 1 eq) in methanol (10 mL), add concentrated hydrochloric acid (2.04 g, 20.70 mmol, 2 mL, 37% purity, 163.03 eq), and react at 70° C. for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; B (acetonitrile)%: 30%-70%, 8 minutes) , get WX011. 1 H NMR (400MHz, deuterated chloroform) δ 9.17-8.93 (m, 1H), 7.19-7.07 (m, 3H), 6.50-6.42 (m, 1H), 5.68-5.35 (m, 1H), 3.54- 3.42 (m, 1H), 3.22 (br d, J=0.9Hz, 2H), 2.20-2.10 (m, 6H), 1.89-1.70 (m, 4H), 1.27 (d, J=7.0Hz, 3H). MS-ESI m/z: 431.1 [M+H] + .
步骤9：化合物WX012的合成Step 9: Synthesis of Compound WX012
将WX012-1(50mg,105.82μmol,1eq)溶于甲醇(10mL)，加入浓盐酸(2.04g,20.70mmol,2mL,37％纯度,195.63eq)，70℃搅拌4小时。反应完成后，将反应液减压浓缩。粗产品经高效液相色谱纯化(色谱柱:Phenomenex Luna 80*30mm*3μm；流动相:[水(0.04％盐酸)-乙腈]；B(乙腈)％:30％-70％,8分钟)，得到WX012。 1H NMR(400MHz,氘代氯仿)δ9.20-8.97(m,1H),7.21-7.08(m,3H),6.53-6.43(m,1H),5.68-5.49(m,1H),3.56-3.45(m,1H),3.25-3.03(m,2H),2.26-2.14(m,6H),1.93-1.73(m,4H),1.27(s,3H) WX012-1 (50 mg, 105.82 μmol, 1 eq) was dissolved in methanol (10 mL), concentrated hydrochloric acid (2.04 g, 20.70 mmol, 2 mL, 37% purity, 195.63 eq) was added, and the mixture was stirred at 70° C. for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; B (acetonitrile)%: 30%-70%, 8 minutes), Get WX012. 1 H NMR (400MHz, deuterated chloroform) δ9.20-8.97(m,1H), 7.21-7.08(m,3H), 6.53-6.43(m,1H), 5.68-5.49(m,1H), 3.56- 3.45(m, 1H), 3.25-3.03(m, 2H), 2.26-2.14(m, 6H), 1.93-1.73(m, 4H), 1.27(s, 3H)
MS-ESI m/z:431.1[M+H] +。 MS-ESI m/z: 431.1 [M+H] + .
生物测试biological test
实验一：化合物对甲状腺激素受体在细胞水平激活活性测试Experiment 1: Activation activity test of compounds on thyroid hormone receptors at the cellular level
实验原理：Experimental principle:
本实验采用ThermoFisher开发的
Figure PCTCN2021117786-appb-000079
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。 This experiment uses ThermoFisher developed
Figure PCTCN2021117786-appb-000079
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 β-lactamase, this reporter gene is controlled In the upstream UAS sequence, when the compound enters the cell and binds to THR, the receptor binds to the DNA-binding region to form a complete GAL4 dimer, using the GAL4-UAS system to activate the expression of β-lactamase and decompose the substrate CCF4- AM (coumarin), the product generates fluorescence at 447 nm under excitation at 409 nm. If β-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.
实验方法：experimental method:
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。Z因子的计算(>0.5)将用于监控每次实验的稳定性。 Compounds were transferred to a 384-well plate using an ECHO liquid workstation, with 10 gradient concentrations per compound, 3-fold dilution, and double wells. Plate 1.5×10 4 cells (TR beta-UAS-bla HEK 293T Cell) or 1.0×10 4 cells (TR alpha-UAS-bla HEK 293T Cell) in 384-well plates. 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 calculation of the Z factor (>0.5) will be used to monitor the stability of each experiment.
表1各实施例的THRα例和THRβ例活性Table 1 THRα and THRβ activity of each example
Figure PCTCN2021117786-appb-000080
Figure PCTCN2021117786-appb-000080
结论：本发明化合物具有显著的THRβ活性或选择性。Conclusion: The compounds of the present invention have significant THRβ activity or selectivity.
实验二：细胞色素P450同工酶抑制性研究Experiment 2: Cytochrome P450 isoenzyme inhibitory study
实验目的：Purpose:
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。The inhibitory effect of test compounds on the activity of human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) was determined.
实验操作：Experimental operation:
首先将受试化合物(10.0mM)进行梯度稀释，制备工作液(100×最终浓度)，且工作液浓度分别为：5.00,1.50,0.500,0.150,0.0500,0.0150,0.00500mM，同时准备P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)各阳性抑制剂及其特异性底物混合物(5合1)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(0.253mg/mL)。先将20.0μL底物混合液加至反应板中(空白孔中加入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各个浓度的受试化合物(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，作为对照组样品(受试化合物对照样品为1:1DMSO:MeOH，阳性对照样品均为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，置于37℃水浴孵育反应10min；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：First, the test compound (10.0 mM) was serially diluted to prepare working solution (100× final concentration), and the working solution concentrations were: 5.00, 1.50, 0.500, 0.150, 0.0500, 0.0150, 0.00500 mM, and P450 co-workers were prepared at the same time. The working solution of each positive inhibitor of enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) and their specific substrate mixture (5 in 1); human liver microsomes stored in a refrigerator below -60 °C are placed on ice Thawed, until all human liver microsomes were dissolved, diluted with PB to prepare a working solution of a certain concentration (0.253 mg/mL). First add 20.0 μL of the substrate mixture to the reaction plate (add 20.0 μL of PB to the blank wells), then add 158 μL of the working solution of human liver microsomes to the reaction plate, and put the reaction plate on ice for later use; 2.00 μL of each concentration of test compound (N=1) and specific inhibitor (N=2) were added to the corresponding wells, and no inhibitor (test compound or positive inhibitor) group was added to the corresponding organic solvent as a control Group samples (the test compound control sample was 1:1 DMSO:MeOH, and the positive control samples were all 1:9 DMSO:MeOH); after pre-incubating in a 37°C water bath for 10 min, 20.0 μL of coenzyme factor (NADPH) solution was added to the reaction plate, Incubate the reaction in a water bath at 37 °C for 10 min; add 400 μL of pre-cooled acetonitrile solution (internal standard containing 200 ng/mL Tolbutamide and Labetalol) to terminate the reaction; place the reaction plate on a shaker, shake and mix for 10 min; then at 4 °C, 4000 rpm Centrifuge for 20 min under conditions; add 200 μL of supernatant to 100 μL of water for sample dilution; finally seal the plate, shake, shake well, and perform LC/MS/MS detection. The experimental results are shown in Table 2:
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Table 2. Results of the inhibitory effect of test compounds on human liver microsomal cytochrome P450 isoenzyme activity
Figure PCTCN2021117786-appb-000081
Figure PCTCN2021117786-appb-000081
实验结论：本发明化合物对CYP1A2、CYP2C19、CYP2D6和CYP3A4均无抑制作用，对CYP2C9有中等抑制作用，药物-药物相互作用风险较低。Experimental conclusion: The compound of the present invention has no inhibitory effect on CYP1A2, CYP2C19, CYP2D6 and CYP3A4, but has moderate inhibitory effect on CYP2C9, and the risk of drug-drug interaction is low.
实验三：C57BL/6小鼠口服及静脉注射本发明化合物的药代动力学研究Experiment 3: Pharmacokinetic study of the compounds of the present invention by oral and intravenous injection in C57BL/6 mice
受试化合物与10％二甲基亚砜/10％聚乙二醇硬脂酸酯水溶液混合，涡旋并超声，制备得到澄清溶液。选取7至10周龄的C57BL/6雄性小鼠，静脉注射(IV)给予候选化合物溶液，剂量为3mg/kg。收集一定时间的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数。The test compound was mixed with 10% dimethyl sulfoxide/10% polyethylene glycol stearate in water, vortexed and sonicated to prepare a clear solution. C57BL/6 male mice aged 7 to 10 weeks were selected, and the candidate compound solution was administered intravenously (IV) at a dose of 3 mg/kg. Whole blood was collected for a certain period of time, plasma was prepared, drug concentration was analyzed by LC-MS/MS method, and pharmacokinetic parameters were calculated by Phoenix WinNonlin software (Pharsight, USA).
受试化合物与2％羟丙甲基纤维素/0.1％吐温80水溶液混合，涡旋并超声，制备得到均一混悬液备用。选取7至10周龄的C57BL/6雄性小鼠，口服(PO)给予候选化合物溶液，剂量为5mg/kg。收集一定时间的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin软件(美国Pharsight 公司)计算药代参数。The test compound was mixed with 2% hydroxypropylmethylcellulose/0.1% aqueous Tween 80 solution, vortexed and sonicated to prepare a homogeneous suspension for later use. C57BL/6 male mice aged 7 to 10 weeks were selected and administered the candidate compound solution orally (PO) at a dose of 5 mg/kg. Whole blood was collected for a certain period of time, plasma was prepared, drug concentration was analyzed by LC-MS/MS method, and pharmacokinetic parameters were calculated by Phoenix WinNonlin software (Pharsight, USA).
实验结果如表3所示：The experimental results are shown in Table 3:
表3.本发明化合物的药代动力学结果Table 3. Pharmacokinetic Results of Compounds of the Invention
Figure PCTCN2021117786-appb-000082
Figure PCTCN2021117786-appb-000082
注：IV：静脉注射；PO：口服；DNAUC＝AUC/给药剂量；Note: IV: intravenous injection; PO: oral; DNAUC=AUC/administered dose;
结论：本发明化合物具有良好的药代动力学性质。Conclusion: The compounds of the present invention have good pharmacokinetic properties.
实验四：化合物口服给药后药物在小鼠体内组织分布研究Experiment 4: Study on the tissue distribution of the drug in mice after oral administration of the compound
受试化合物与2％羟丙甲基纤维素/0.1％吐温80水溶液混合，涡旋并超声，制备得到WX001均一混悬液备用。选取7至10周龄的C57BL/6雄性小鼠，口服(PO)给予候选化合物溶液，剂量为5mg/kg。收集一定时间的全血，肝脏和心脏，制备样品，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。The test compound was mixed with 2% hydroxypropyl methylcellulose/0.1% Tween 80 aqueous solution, vortexed and sonicated to prepare a WX001 homogeneous suspension for later use. C57BL/6 male mice aged 7 to 10 weeks were selected and administered the candidate compound solution orally (PO) at a dose of 5 mg/kg. Whole blood, liver and heart were collected for a certain period of time, samples were prepared, drug concentrations were analyzed by LC-MS/MS method, and pharmacokinetic parameters were calculated by Phoenix WinNonlin software (Pharsight, USA).
实验结果如表4所示：The experimental results are shown in Table 4:
Figure PCTCN2021117786-appb-000083
Figure PCTCN2021117786-appb-000083
Figure PCTCN2021117786-appb-000084
Figure PCTCN2021117786-appb-000084
结论：本发明化合物在肝脏中分布比例较高，在心脏和血浆中较少。Conclusion: The compounds of the present invention are distributed in a higher proportion in the liver and less in the heart and plasma.

Claims (19)

  1. 式(III)所示化合物或其药学上可接受的盐，A compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2021117786-appb-100001
    Figure PCTCN2021117786-appb-100001
    其中，in,
    X选自O、CH 2和C(＝O)； X is selected from O, CH2 and C(=O);
    环B选自
    Figure PCTCN2021117786-appb-100002
    Ring B is selected from
    Figure PCTCN2021117786-appb-100002
    R 1独立地选自OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R a取代； R 1 is independently selected from OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy optionally being replaced by 1, 2 or 3 R a substitutions;
    R 2和R 3分别独立地选自H、F、Cl、Br、I、OH和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代； R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ;
    R 4、R 5和与它们相连的碳原子共同构成
    Figure PCTCN2021117786-appb-100003
    R 4 , R 5 and the carbon atoms attached to them form together
    Figure PCTCN2021117786-appb-100003
    R 9独立地选自H、F、Cl、Br和I； R is independently selected from H, F, Cl, Br and I;
    T选自C(R 6) 2； T is selected from C(R 6 ) 2 ;
    T 1和T 2分别独立地选自C(R 7) 2、NR 8和O，且T 1和T 2不同时为C(R 7) 2； T 1 and T 2 are each independently selected from C(R 7 ) 2 , NR 8 and O, and T 1 and T 2 are not both C(R 7 ) 2 ;
    n和m分别独立地选自0、1和2；n and m are independently selected from 0, 1 and 2;
    L选自-CH 2-和-O-； L is selected from -CH 2 - and -O-;
    R 6独立地选自H和F； R is independently selected from H and F ;
    R 7分别独立地选自H、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R c取代； R 7 are each independently selected from H, 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 optional substituted with 1, 2 or 3 R c ;
    或者，2个R 6与它们共有的碳原子共同构成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R c取代； Alternatively, 2 R 6 together with their common carbon atoms form a C 3-5 cycloalkyl optionally substituted with 1, 2 or 3 R ;
    或者，2个R 7与它们共有的碳原子共同构成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R c取代； Alternatively, 2 R 7 together with their common carbon atoms form a C 3-5 cycloalkyl optionally substituted with 1, 2 or 3 R ;
    或者，R 6和R 7与它们相连的碳原子共同构成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R c取代； Alternatively, R 6 and R 7 together with the carbon atoms to which they are attached form a C 3-5 cycloalkyl optionally substituted with 1, 2 or 3 R c ;
    R 8独立地选自H和C 1-3烷基； R 8 is independently selected from H and C 1-3 alkyl;
    环A选自5～6元杂芳基，所述5～6元杂芳基任选被1、2或3个R d取代； Ring A is selected from a 5- to 6-membered heteroaryl group optionally substituted with 1, 2 or 3 R d ;
    R a和R b分别独立地选自F、Cl、Br和I； R a and R b are each independently selected from F, Cl, Br and I;
    各R c独立地选自F、Cl、Br和I； each R c is independently selected from F, Cl, Br and I;
    各R d独立地选自F、Cl、Br、I、C 1-3烷基和C 1-3烷氧基。 Each R d is independently selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy.
  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OH、NH 2、CH 3和OCH 3，所述CH 3和OCH 3任选被1、2或3个R a取代。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is independently selected from OH, NH 2 , CH 3 and OCH 3 , wherein CH 3 and OCH 3 are optionally separated by 1, 2, or 3 substituted with Ra .
  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OH、NH 2、CH 3、CF 3、OCF 3和OCH 3。 The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is independently selected from OH, NH 2 , CH 3 , CF 3 , OCF 3 and OCH 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和CH 3。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH and CH 3 .
  5. 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 7分别独立地选自H、F、Cl、Br、I、CH 3、OCH 3、OCH 2CH 3和OCH(CH 3) 2，所述CH 3、OCH 3、OCH 2CH 3和OCH(CH 3) 2任选被1、2或3个R c取代。 The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 7 is independently selected from H, F, Cl, Br, I, CH 3 , OCH 3 , OCH 2 CH 3 and OCH( CH3 ) 2 , said CH3 , OCH3 , OCH2CH3 and OCH( CH3 ) 2 optionally substituted with 1, 2 or 3 Rc .
  6. 根据权利要求5所述化合物或其药学上可接受的盐，其中，R 7分别独立地选自H、F、Cl、Br、I、CH 3、CHF 2、CF 3、OCH 3、OCH 2F、OCHF 2、OCF 3、OCH 2CH 3和OCH(CH 3) 2。 The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 7 is independently selected from H, F, Cl, Br, I, CH 3 , CHF 2 , CF 3 , OCH 3 , OCH 2 F , OCHF 2 , OCF 3 , OCH 2 CH 3 and OCH(CH 3 ) 2 .
  7. 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，R 6和R 7与它们相连的碳原子共同构成环丙基，所述环丙基任选被1、2或3个R c取代。 According to the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, R 6 and R 7 and the carbon atoms to which they are attached together form a cyclopropyl group, and the cyclopropyl group is optionally substituted by 1, 2 or 3 R c substitutions.
  8. 根据权利要求7所述化合物或其药学上可接受的盐，其中，R 6和R 7与它们相连的碳原子共同构成
    Figure PCTCN2021117786-appb-100004
    Figure PCTCN2021117786-appb-100005
    The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 together with the carbon atom to which they are attached constitute
    Figure PCTCN2021117786-appb-100004
    Figure PCTCN2021117786-appb-100005
  9. 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、R 5和与它们相连的碳原子共同构成
    Figure PCTCN2021117786-appb-100006
    The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 and the carbon atom to which they are attached together constitute
    Figure PCTCN2021117786-appb-100006
  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 4、R 5和与它们相连的碳原子共同构成
    Figure PCTCN2021117786-appb-100007
    The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 and the carbon atom to which they are attached together constitute
    Figure PCTCN2021117786-appb-100007
  11. 根据权利要求1所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2021117786-appb-100008
    选自
    Figure PCTCN2021117786-appb-100009
    Figure PCTCN2021117786-appb-100010
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2021117786-appb-100008
    selected from
    Figure PCTCN2021117786-appb-100009
    Figure PCTCN2021117786-appb-100010
  12. 根据权利要求1所述化合物或其药学上可接受的盐，其中，环A选自吡唑基，所述吡唑基任选被1、2或3个R d取代。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from pyrazolyl optionally substituted with 1, 2 or 3 Rd .
  13. 根据权利要求12所述化合物或其药学上可接受的盐，其中，环A选自吡唑基。The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from pyrazolyl.
  14. 根据权利要求1、11或13任意一项所述化合物或其药学上可接受的盐，其中，环B选自
    Figure PCTCN2021117786-appb-100011
    Figure PCTCN2021117786-appb-100012
    The compound according to any one of claims 1, 11 or 13, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from
    Figure PCTCN2021117786-appb-100011
    Figure PCTCN2021117786-appb-100012
  15. 根据权利要求1～8任意一项所述化合物或其药学上可接受的盐，其化合物选自The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
    Figure PCTCN2021117786-appb-100013
    Figure PCTCN2021117786-appb-100013
    其中，in,
    R 1、R 2、R 3、R 6、R 7、R 9、X和n如权利要求1～8任意一项所定义。 R 1 , R 2 , R 3 , R 6 , R 7 , R 9 , X and n are as defined in any one of claims 1 to 8 .
  16. 根据权利要求1～4任意一项所述化合物或其药学上可接受的盐，其化合物选自The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
    Figure PCTCN2021117786-appb-100014
    Figure PCTCN2021117786-appb-100014
    其中，in,
    T 1、T 2和R 6如权利要求1所定义； T 1 , T 2 and R 6 are as defined in claim 1;
    R 1如权利要求1～3任意一项所定义； R 1 is as defined in any one of claims 1 to 3;
    R 2和R 3如权利要求1或4所定义。 R 2 and R 3 are as defined in claim 1 or 4.
  17. 下式化合物或其药学上可接受的盐，A compound of the formula or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2021117786-appb-100015
    Figure PCTCN2021117786-appb-100015
  18. 根据权利要求17所述化合物或其药学上可接受的盐，其选自：The compound according to claim 17, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
    Figure PCTCN2021117786-appb-100016
    Figure PCTCN2021117786-appb-100016
  19. 根据权利要求1～18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。Use of the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating nonalcoholic steatohepatitis.
PCT/CN2021/117786 2020-09-10 2021-09-10 1,2,4-triazine-3,5(2h,4h)-diketone compound and application thereof WO2022053028A1 (en)

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