Bicyclic phenolic compounds and their uses

Abstract

A series of phenolic compounds and uses thereof are disclosed, specifically, compounds represented by formula (III) and pharma- ceutically acceptable salts thereof. JPEG2024511015000078.jpg5776

Description

[Technical field]

[0001] The present invention relates to a series of bicyclic phenolic compounds and uses thereof, and specifically discloses compounds represented by formula (III) and pharma- ceutically acceptable salts thereof. [Background technology]

[0002] This application claims priority to: CN202110298570.3, filing date: March 19, 2021; CN202110443424.5, application date: April 23, 2021; CN202210107896.8, application date: January 28, 2022.

[0003] There are two subtypes of thyroid hormone receptors (THRs): THRα and THRβ. Over the past few decades, various THRβ agonists, including GC-1, KB141, KB2115, etc., have been developed for use in the treatment of metabolic disorders such as dyslipidemia, nonalcoholic fatty liver, and nonalcoholic steatohepatitis. However, side effects on the skeleton and heart have hindered further development; for example, KB2115 was withdrawn from Phase III clinical trials due to the discovery of cartilage damage in dogs. THRα is mainly distributed in the brain, heart, and skeletal muscles, and can increase osteoclast activity, leading to reduced bone density. Therefore, people believe that these side effects are caused by agonism of the THRα subtype, and hope to avoid side effects by increasing target selectivity and liver tissue selectivity. Representative agonists of this strategy are MGL-3196 and VK-2809, and both safety and efficacy have been initially verified through clinical trials. Therefore, the development of thyroid hormone analogs with specific distribution in liver tissue and high selectivity for thyroid hormone receptor subtypes would be of significant clinical value.

[0004] According to the literature (J. Med. Chem. 2014, 57, 3912-3923), the structure of the THRβ agonist MGL-3196 is as follows: [ka] Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention provides a compound represented by formula (III) or a pharma- ceutically acceptable salt thereof. [ka] however, Ring B is [ka] is selected from R 1 are independently H, F, Cl, Br, I and C 1-3 alkyl, 1-3 Alkyl is optionally one, two or three R a is replaced by R 2 and R 3 are independently H, F, Cl, Br, I, OH, and NH 2 , C.N.,C. 1-3 Alkyl and C 1-3 alkoxy, 1-3 Alkyl and C 1-3 Alkoxy optionally has one, two or three R b is replaced by R 4 is C 1-3 alkyl-phenyl; L is -O- or -CH 2 - selected from Ring A is phenyl, 5- to 6-membered heteroaryl, [ka] wherein said phenyl, 5- to 6-membered heteroaryl, [ka] Optionally, 1, 2 or 3 R c is replaced by n and m are each independently selected from 0, 1, and 2; R a and R b are each independently selected from F, Cl, Br, and I; R c are independently F, Cl, Br, I, =O, =NC 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 alkoxy, wherein =NC 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 The alkoxy is optionally substituted with 1, 2 or 3 halogen. In some embodiments of the present invention, the R 1 are independently H, F, Cl, Br, I and CH 3 wherein CH is selected from 3 Optionally, 1, 2 or 3 R a and other variables are as defined in the present invention.

[0006] In some embodiments of the present invention, the R 1 are independently H, F, Cl, Br, I, and CH 3 and CF 3 and the other variables are as defined herein. In some embodiments of the present invention, the R 2 and R 3 are independently H, F, Cl, Br, I, OH, and NH 2 , C.N., C.H. 3 and OCH 3 wherein CH is selected from 3 and OCH 3Optionally, 1, 2 or 3 R b and other variables are as defined in the present invention.

[0007] In some embodiments of the present invention, the R 2 and R 3 are independently H, F, Cl, Br, I, OH, and NH 2 , C.N., C.H. 3 , C.H. 2 F, CHF 2 , C.F. 3 and OCH 3 and the other variables are as defined herein. In some embodiments of the present invention, the R c are independently F, Cl, Br, I, =O, =NO-CH 3 , =NO-CH 2 CH 3 , C.H. 3 , O.C.H. 3 and OCH 2 CH 3 wherein =NO-CH 3 , =NO-CH 2 CH 3 , C.H. 3 , O.C.H. 3 and OCH 2 CH 3 is optionally substituted with 1, 2 or 3 halogens, and the other variables are as defined herein.

[0008] In some embodiments of the present invention, the R c are independently F, Cl, Br, I, =O, =NO-CH 3 , =NO-CH 2 CH 3 , C.H. 3 , O.C.H. 3 and OCH 2 CH 3 wherein =NO-CH 3 , =NO-CH 2 CH 3 , C.H. 3 , O.C.H. 3 and OCH 2 CH3 is optionally replaced by 1, 2 or 3 R, and the other variables are as defined herein. In some embodiments of the present invention, the R c are independently F, Cl, Br, I, =O, =NO-CH 3 , =NO-CH 2 CH 3 , C.H. 3 , O.C.H. 3 and OCH 2 CH 3 and the other variables are as defined herein.

[0009] In some embodiments of the invention, ring A is [ka] Optionally, 1, 2 or 3 R c and other variables are as defined in the present invention.

[0010] In some embodiments of the invention, ring A is [ka] and the other variables are as defined herein.

[0011] In some embodiments of the present invention, the R 4 teeth, [ka] and the other variables are as defined herein.

[0012] In some embodiments of the present invention, the structural unit [ka] and the other variables are as defined herein.

[0013] The present invention provides a compound represented by formula (I) or a pharma- ceutically acceptable salt thereof. [ka] however, R 1 are independently H, F, Cl, Br, I and C 1-3 alkyl, 1-3 Alkyl is optionally one, two or three R a is replaced by R 2 and R 3 are independently H, F, Cl, Br, I, OH, and NH 2 , C.N.,C. 1-3 Alkyl and C 1-3 alkoxy, 1-3 Alkyl and C 1-3 Alkoxy optionally has one, two or three R b is replaced by L is -O- or -CH 2 - selected from Ring A is phenyl, 5- to 6-membered heteroaryl, [ka] wherein said phenyl, 5- to 6-membered heteroaryl, [ka] Optionally, 1, 2 or 3 R c is replaced by n and m are each independently selected from 0, 1, and 2; R a and R b are each independently selected from F, Cl, Br, and I; R c are independently F, Cl, Br, I, =O, =NC 1-3 Alkoxy, C 1-3 Alkyl and C 1-3alkoxy, wherein =NC 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 The alkoxy is optionally substituted by 1, 2 or 3 R; R is independently selected from F, Cl, Br and I.

[0014] In some embodiments of the present invention, the R 1 are independently H, F, Cl, Br, I and CH 3 wherein CH is selected from 3 Optionally, 1, 2 or 3 R a and other variables are as defined in the present invention. In some embodiments of the present invention, the R 1 are independently H, F, Cl, Br, I, and CH 3 and CF 3 and the other variables are as defined herein.

[0015] In some embodiments of the present invention, the R 2 and R 3 are independently H, F, Cl, Br, I, OH, and NH 2 , C.N., C.H. 3 and OCH 3 wherein CH is selected from 3 and OCH 3 Optionally, 1, 2 or 3 R b and other variables are as defined in the present invention. In some embodiments of the present invention, the R 2 and R 3 are independently H, F, Cl, Br, I, OH, and NH 2 , C.N., C.H. 3 , C.H. 2 F, CHF 2 , C.F. 3 and OCH 3 and the other variables are as defined herein.

[0016] In some embodiments of the present invention, the R care independently F, Cl, Br, I, =O, =NO-CH 3 , =NO-CH 2 CH 3 , C.H. 3 , O.C.H. 3 and OCH 2 CH 3 wherein =NO-CH 3 , =NO-CH 2 CH 3 , C.H. 3 , O.C.H. 3 and OCH 2 CH 3 is optionally replaced by 1, 2 or 3 R, and the other variables are as defined herein.

[0017] In some embodiments of the present invention, the R c are independently F, Cl, Br, I, =O, =NO-CH 3 , =NO-CH 2 CH 3 , C.H. 3 , O.C.H. 3 and OCH 2 CH 3 and the other variables are as defined herein.

[0018] In some embodiments of the invention, ring A is [ka] Optionally, 1, 2 or 3 R c and other variables are as defined in the present invention.

[0019] In some embodiments of the invention, ring A is [ka] and the other variables are as defined herein.

[0020] In some embodiments of the present invention, the structural unit [ka] and the other variables are as defined herein.

[0021] In some embodiments of the invention, the compound or a pharma- ceutically acceptable salt thereof is selected from the following formula: [ka] however, [ka] is a single bond, R c are F, Cl, Br, I, and C. 1-3 Alkyl and C 1-3 Alkoxy, 1-3 Alkyl and C 1-3 The alkoxy is optionally substituted with 1, 2 or 3 halogens; [ka] If is a double bond, R c =O and =NC 1-3 Alkoxy, wherein =NC 1-3 The alkoxy is optionally substituted with 1, 2 or 3 halogens; R 1 , R 2 , R 3 , L and m are as defined in the present invention.

[0022] In some embodiments of the invention, the compound or a pharma- ceutically acceptable salt thereof is selected from the following formula: [ka] However, R 1 , R 2 , R 3 , L, m and n are as defined in the present invention.

[0023] Some aspects of the invention are further formed by any combination of the variables listed above. The present invention further provides a compound represented by the formula: or a pharma- ceutically acceptable salt thereof. [ka] [ka] In some embodiments of the invention, the compound or a pharma- ceutically acceptable salt thereof is selected from the following formula: [ka]

[0024] The present invention provides the use of the above compound, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating non-alcoholic steatohepatitis. The present invention further provides the following synthesis methods. [ka] [ka] however, -XYZ- is selected from cyclopentenyl, cyclohexenyl, phenyl, thienyl, thiazolyl, furyl and oxazolyl; R 2 and R 3 are independently H, F, Cl, Br, I, OH, and NH 2 , C.N.,C. 1-3 Alkyl and C 1-3 alkoxy, 1-3 Alkyl and C 1-3 Alkoxy optionally has one, two or three R b is replaced by R bare each independently selected from F, Cl, Br, and I.

[0025] [Definitions and Explanations] Unless otherwise stated, the following terms and phrases used herein have the following meanings. A particular term or phrase, unless otherwise defined, should be understood as being of ordinary definition, not indefinite or unclear. When a trade name is mentioned in this specification, it refers to the corresponding product or its active ingredient.

[0026] As used herein, "pharmacologically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are within the scope of sound medical judgment, suitable for contact with human and animal tissues, without significant toxicity, irritation, allergic response or other problem or complication, and consistent with a reasonable benefit / risk ratio.

[0027] The term "pharmaceutical acceptable salt" refers to a salt of a compound of the present invention, which is prepared with a relatively non-toxic acid or base with a compound having certain substituents discovered in this invention. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting these compounds with a sufficient amount of base in a separate solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting these compounds with a sufficient amount of acid in a separate solution or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include inorganic and organic acid salts, as well as salts of amino acids (such as arginine) and organic acids such as glucuronic acid, such as inorganic acids 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, and the like, and organic acids including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Certain compounds of the present invention contain both basic and acidic functional groups and can therefore be converted into any suitable base or acid addition salt.

[0028] The pharma- ceutically acceptable salts of the present invention can be synthesized in a conventional manner from the parent compound which contains an acidic or basic group. Typically, such salts are prepared by reacting the compound in its free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both.

[0029] 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, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as mixtures enriched in enantiomers or non-enantiomers, and all such mixtures are within the scope of the present invention. Other asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers and mixtures thereof are both within the scope of the present invention.

[0030] Unless otherwise stated, the terms "enantiomers" or "optical isomers" are stereoisomers that are mirror images of each other. Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" refer to the inability to freely rotate about double bonds or single bonds of ring carbon atoms. Unless otherwise explained, the term "diastereomer" is a stereoisomer in which the molecules have two or more centers of chirality and the molecules are not mirror-images of each other.

[0031] Unless otherwise specified, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic. [ka]

[0032] Unless otherwise defined, when a compound has a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom in the double bond has two different substituents bonded to it (in a double bond containing a nitrogen atom, the lone pair of electrons on the nitrogen atom is considered to be one substituent bonded to it), the atoms on the double bond of the compound and their substituents are represented by a wavy line ( [ka] ), it means the (Z) isomer, the (E) isomer, or a mixture of the two isomers of the compound. For example, the following formula (A) means that the compound exists in the form of a single isomer of formula (A-1) or formula (A-2), or in the form of two isomers of formula (A-1) and formula (A-2); the following formula (B) means that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2), or in the form of two isomers of formula (B-1) and formula (B-2). The following formula (C) means that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2), or in the form of two isomers of formula (C-1) and formula (C-2).

[0033] [ka]

[0034] Unless otherwise stated, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium and can be rapidly interconverted at room temperature. Tautomers can reach chemical equilibrium of tautomers when possible (e.g., in solution). For example, proton tautomers (also called prototropic tautomers) include interconversions via the transfer of a proton, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by rearrangement of some bond electrons. Among them, a specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxy-3-penten-2-one.

[0035] Unless otherwise explained, the terms "enriched in one isomer," "isomer-enriched," "enriched in one enantiomer," or "enantiomer-enriched" mean that the amount of one isomer or enantiomer is less than 100% and that the amount of such isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0036] Unless otherwise stated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, then the isomeric or enantiomeric excess (ee value) is 80%.

[0037] Optically active (R)- and (S)-isomers, as well as D- and L-isomers, can be prepared using asymmetric synthesis or chiral reagents or other conventional techniques. A single enantiomer of a compound of the invention can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary is resolved to provide the desired isolated enantiomer. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxyl) functional group, the diastereomeric salt can be formed with an appropriate optically active acid or base, and the diastereomers can be resolved by conventional methods known in the art, followed by recovery to provide the isolated enantiomers. Separation of enantiomers and diastereomers is also typically accomplished by chromatographic techniques using chiral stationary phases and any chemical derivatization techniques (e.g., carbamate formation from amines).

[0038] The compounds of the present invention may contain unnatural atomic isotopes at one or more atoms that constitute the compounds. For example, tritium (3 H), iodine-125( 125 I) or C-14( 14 Compounds can be labeled with radioisotopes such as radioisotopes C). Also, for example, deuterium can be replaced with hydrogen to form deuterated drugs, where the bond formed between deuterium and carbon is stronger than the bond formed between normal hydrogen and carbon, and compared to non-deuterated drugs, deuterated drugs have the advantages of reduced toxic side effects, increased drug stability, improved therapeutic efficacy, and extended biological half-life of the drug. Conversion of the isotopic composition of the compounds of the invention, whether radioactive or not, is within the scope of the invention.

[0039] The terms "optionally" and "optionally" refer to the event or circumstance described below that may, but does not necessarily, occur, and the description includes instances where the event or circumstance described does not occur.

[0040] The term "substituted" refers to the replacement of any one or more hydrogen atoms at a particular atom with a substituent, which may include deuterium and hydrogen variants, provided that the particular valence state is correct and the compound is stable after substitution. When a substituent is keto (i.e., =O), it means that two hydrogen atoms have been replaced. Keto group substitution does not occur on aromatic groups.

[0041] The term "optionally substituted" means that the group may be substituted or unsubstituted, and unless otherwise defined, the type and number of the substituents are optional as long as they are chemically stable and can be realized.

[0042] When any variable (e.g., R) occurs more than once in a composition or structure of a compound, its definition is independent in each occurrence. Thus, for example, if a group is substituted with 0-2 R, then said group is optionally substituted with up to 2 R, and each occurrence of R is independently optional. Also, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0043] When the number of linking groups is 0, for example, -(CRR) 0 - means that the linking group is a single bond.

[0044] When one of the variables is a single bond, the two groups it links are directly linked; for example, when L in ALZ represents a single bond, the structure is actually AZ. The absence of a substituent represents that the substituent is not present, for example, the absence of X in AX represents that the structure is actually A. When no atom through which a substituent is substituted for a given substituent is specified, such a substituent may be bonded through any atom thereof, for example, pyridinyl as a substituent may be bonded to the substituent through any carbon atom of the pyridine ring.

[0045] [ka]

[0046] Unless otherwise specified, when a group has one or more bondable sites, any one or more sites of the group can be bonded to other groups by chemical bonds. When the bonding mode of the chemical bond is delocalized and there is an H atom at the bondable site, the number of H atoms at the site is reduced to a group with a corresponding valence according to the number of bonded chemical bonds. The chemical bond by which the site is bonded to another group is: [ka] For example, -OCH 3 A straight solid bond means that the group is bonded to another group via an oxygen atom of the group.

[0047] [ka]

[0048] Unless otherwise defined, the term "C 1―3"Alkyl" refers to a saturated hydrocarbon group consisting of 1 to 3 carbon atoms in a straight or branched chain. 1-3 Alkyl has C 1―2 and C. 2―3 Alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene) and polyvalent (e.g., methine). 1-3 Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl).

[0049] Unless otherwise defined, the term "C 1―3 "Alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms linked to the remainder of the molecule through an oxygen atom. 1-3 Alkoxy is C 1-2 , C 2-3 , C 3 and C 2 Alkoxy and the like are included. C 1-3 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy or isopropoxy), and the like.

[0050] Unless otherwise defined, the terms "5- to 6-membered heteroaromatic ring" and "5- to 6-membered heteroaryl" of the present invention can be used interchangeably, and the term "5- to 6-membered heteroaryl" refers to a monocyclic group having a conjugated π-electron system composed of 5 to 6 ring atoms, of which 1, 2, 3, and 4 ring atoms are independently selected from O, S, and N heteroatoms, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p, p is 1 or 2). The 5-6 membered heteroaryl is linked to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5- or 6-membered heteroaryl. Illustrative examples of 5-6 membered heteroaryl include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (including 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), and the like. -triazolyl, tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, 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 or 4-pyrimidinyl, etc.).

[0051] Unless otherwise defined, C n-n+m Or C n -C n+m includes any one specific embodiment of n to n+m carbons, for example, C 1-12 is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 Including any one of the ranges n to n+m, for example, C 1-12 is C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C3-12 , C 6-9 , C 6-12 , and C 9-12 Similarly, n-membered to n+m-membered rings indicate that the number of atoms in the ring is n to n+m, and for example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any one of the ranges of n to n+m, and for example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring, etc.

[0052] The structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art, and when the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means of those skilled in the art. For example, single crystal X-ray diffraction (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuKα radiation, the scanning method is φ / ω scanning, after collecting the relevant data, the absolute configuration can be confirmed by direct method (Shelxs97) crystal structure analysis.

[0053] The compounds of the present invention can be prepared by a variety of synthetic methods familiar to those skilled in the art, including the specific embodiments given below, embodiments in combination with other chemical synthetic methods, and equivalent alternative methods familiar to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

[0054] All solvents used in the present invention can be obtained from commercial sources. The present invention uses the following abbreviations: aq stands for water; eq stands for equivalent; DCM stands for dichloromethane; PE stands for petroleum ether; DMF stands for N,N-dimethylformamide; DMSO stands for dimethylsulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl, an amine protecting group; BOC stands for tert-butoxycarbonyl, an amine protecting group; rt stands for room temperature; O / N stands for run overnight; THF stands for tetrahydrofuran; Boc stands for tetrahydrofuran; 2O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; Xantphos stands for 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; NBS stands for N-bromosuccinimide; BINAP stands for 2,2-bis(diphenylphosphino)-1,1-binaphthyl; TEA stands for triethylamine; Pd 2 (dba) 3 represents tris(dibenzylideneacetone)dipalladium.

[0055] Compounds were named according to art-conventional names or ChemDraw® software; for commercially available compounds, manufacturer's catalog names were used. Effect of the Invention

[0056] The compounds of the present invention have no drug-drug interactions, have significant THRβ activity and selectivity, have high exposure and good oral bioavailability, and have excellent pharmacokinetic properties, and can significantly reduce LDL-C levels in rat plasma. [Brief description of the drawings]

[0057] [Figure 1] This is a prediction of the binding mode between compound A and MGL-3196. [Diagram 2] This is a prediction of the binding mode between compound B and MGL-3196. [Diagram 3] This is a prediction of the binding mode between compound C and MGL-3196. [Figure 4] This shows the rate of change in LDL-C in rats one week after administration compared to before administration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0058] The present invention will be specifically described below by way of examples, but is not intended to be an adverse restriction of the present invention. The present invention has been described in detail herein, and specific embodiments thereof have been disclosed. It is obvious to those skilled in the art that various changes and modifications can be made in the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0059] Calculation example 1 [ka]

[0060] The molecular docking process was carried out using GlideSP[1] and default options in Maestro (Schrodinger version 2017-2). MGL-3196 was selected as the docking template. To produce the protein, hydrogen atoms were added using the Protein Production Wizard module of Maestro[2], and the OPLS3 force field was used. In the production of the ligand, a 3D structure was generated and further energy minimization[3] was performed using LigPrep. A 30 Å docking grid was generated using the ligand centroid of the 1Q4X crystal structure. A complex model was generated by constraining the amino acid side chains within a range of 5A of the ligand center to move within the range of B factors by Induced Fit Docking. Then, the ligand was removed and the example compound was placed in the molecular docking process. The type of interaction between the protein receptor and the ligand was analyzed, and a reasonable docking conformation was selected and saved according to the calculated docking scrore and globalStrain values. The binding mode of compound AC and MGL-3196 is shown in Figures 1-3.

[0061] [1]Glide, Schrodinger, LLC, New York, NY, 2017. [2]Maestro, Schrodinger, LLC, New York, NY, 2017. [3]LigPrep, Schrodinger, LLC, New York, NY, 2017.

[0062] Conclusion: The compounds of the present invention have relatively good binding to THRβ protein. The compounds of the present invention occupy the binding pocket of thyroxine and THRβ, which is a closed hydrophobic pocket consisting of multiple α-helices, and above the pocket there is a positively charged subpocket composed of three arginines (Arg282, Arg316 and Arg320). The 6-azauracil acid group of the original reference compound MGL-3196 is bound to this subpocket, the cyano group forms a hydrogen bond with Arg316, the carbonyl atom and nitrogen atom of 6-azauracil form a hydrogen bond with Arg320, and the carbonyl oxygen of pyridazinone forms a hydrogen bond with His435. The middle benzene ring, the terminal pyridazinone and isopropyl can all form hydrophobic interactions with the surrounding amino acids. The polar head of the compound of the present invention, 1,2,4-oxadiazolin-5-one, is bound to this subpocket, and similarly forms hydrogen bonds with three arginines, and adjusts the angle of the dichlorobenzene through the amide, which favors the formation of a halogen bond with Phe272; the carbonyl or hydroxyl of the tail can form a hydrogen bond through interaction with His435, and the condensed ring effectively provides hydrophobic interaction, which has relatively good selectivity.

[0063] Example 1 [ka] Synthesis scheme: [ka]

[0064] Step 1: Synthesis of compound WX001-2 WX001-1 (5 g, 33.74 mmol) and acetonitrile (50 mL) were added to a pre-dried reaction flask, NBS (6.61 g, 37.11 mmol) was added, the mixture was purged with nitrogen gas three times, and stirred at 25° C. for 16 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the concentrate was slurried with methyl tert-butyl ether (200 mL), slurried at 25° C. for 30 minutes, filtered, the filtrate was collected, the filtrate was washed with saturated saline (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=2.4 Hz,1H), 6.55-6.57 (d, J=8.4 Hz,1H), 4.91 (s, 1H), 2.73-2.74 (m,2H), 2.66-2.68 (m,2H), 1.81-1.84 (m, 4H).

[0065] Step 2: Synthesis of compound WX001-3 WX001-2 (6.2 g, 27.30 mmol) and DMF (140 mL) were added to a pre-dried reaction flask, cesium carbonate (22.24 g, 68.25 mmol) was added in batches at 0 ° C., and the mixture was replaced with nitrogen gas three times. Chloromethyl methyl ether (3.30 g, 40.95 mmol, 3.11 mL) was slowly added dropwise at 0 ° C., stirring was continued for 2 hours at 0 ° C., and chloromethyl methyl ether (1.76 g, 21.84 mmol, 1.66 mL, 0.8 eq) was further added and stirring was continued for 1 hour at 0 ° C. After the reaction was completed, the reaction solution was poured into water (100 mL) to quench it, and the aqueous phase (100 mL × 3) was extracted with methyl tert-butyl ether, the organic phase was combined, washed with saturated saline (150 mL × 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 20:1) to obtain WX001-3. 1H NMR (400MHz, deuterated chloroform) δ 7.31-7.33 (d, J=8.4 Hz, 1H), 6.78-6.81 (d, J= 8.4 Hz, 1H), 5.18 (s, 2H), 3.48 (s, 3H), 2.68-2.74 (m, 4H), 1.76-1.79 (m, 4H).

[0066] Step 3: Synthesis of compound WX001-5 WX001-3 (6 g, 22.13 mmol) and THF (60 mL) were added to a pre-dried reaction flask, cooled to -78 ° C, n-butyl lithium (2.5 M, 9.29 mL) was added, and the mixture was stirred for 1 hour while maintaining the temperature at -78 ° C. A mixed solution of THF (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, and ethyl acetate (20 mL × 3) was added for extraction. The organic phase was combined, washed with 20 mL of saturated saline, and after separation, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure to obtain a crude product. 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=8.4 Hz, 1H), 6.67-6.69 (d, J=8.8 Hz, 1H), 6.13-6.14 (d, J=4.8 Hz, 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=4.4 Hz, 1H), 1.76-1.83 (m, 4H).

[0067] Step 4: Synthesis of compound WX001-6 WX001-5 (8.4 g, 20.72 mmol) and DCM (100 mL) were added to a pre-dried reaction flask and cooled to 0 ° C., then triethylsilane (3.61 g, 31.09 mmol, 4.97 mL), TFA (3.54 g, 31.09 mmol, 2.30 mL) were added, and the reaction system was stirred at 0 ° C. for 1 h. After the reaction was completed, the reaction solution was poured into 50 mL of saturated aqueous sodium carbonate solution, extracted by adding DCM (50 mL × 3), and the organic phase was combined, washed with saturated saline (100 mL), and separated. After the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 2% ~ 5% ~ 10%) to obtain WX001-6. 1 H NMR (400MHz, deuterated chloroform) δ 7.22 (s, 2H), 6.66-6.68 (d,J=8.4 Hz, 1H), 6.20-6.22 (d, J=8.4 Hz, 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).

[0068] Step 5: Synthesis of compound WX001-8 WX001-6 (4 g, 10.27 mmol), cesium carbonate (5.02 g, 15.41 mmol), BINAP (319.87 mg, 513.71 μmol), and palladium acetate (115.33 mg, 513.71 μmol) were added to a solution of WX001-7 (2.05 g, 11.30 mmol, 1.90 mL) in THF (40 mL), and the mixture was reacted at 65 ° C. for 12 hours. After the reaction was completed, water (50 mL) was added to the reaction solution, and ethyl acetate (50 mL × 3) was added for extraction, and the organic phase was combined, washed with saturated saline (50 mL), and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure to obtain WX001-8.

[0069] Step 6: Synthesis of compound WX001-9 WX001-8 (4.5 g, 9.19 mmol), HCl (8 mL), and THF (40 mL) were added to a pre-dried reaction flask and stirred at 25 ° C for 1 hour. After the reaction was completed, 50 mL of saturated aqueous sodium carbonate was added to the reaction solution, and ethyl acetate (50 mL × 3) was added for extraction, and the organic phases were combined and washed with saturated saline (50 mL). 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 = 5% ~ 10% ~ 20%) to obtain WX001-9. 1 H NMR (400MHz, deuterated chloroform) δ 6.66-6.68(d, J=8.4 Hz, 1H), 6.46 (s, 2H), 6.31-6.34 (d, J=8.4 Hz,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).

[0070] Step 7: Synthesis of compound WX001-11 WX001-9 (450 mg, 1.38 mmol, 1 eq) and THF (4 mL) were added in sequence to a dried reaction flask, and a solution of TEA (419.75 mg, 4.15 mmol, 577.37 μL, 3 eq) and WX001-10 (308.01 mg, 2.07 mmol, 1.5 eq) in THF (3 mL) was added and purged with nitrogen gas, and then stirred at 20 ° C for 1 hour. After the reaction was completed, the mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), separated, and the organic phase was collected, washed with saturated saline solution (10 mL × 3) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel TLC plate (DCM:MeOH = 20: 1) to obtain WX001-11. 1H NMR (400 MHz, deuterated chloroform) δ 8.51 (br s, 1H), 7.31 (s, 2H), 6.65 (d, J = 8.4 Hz, 1H), 6.24 (d, J = 8.4 Hz, 1H), 5.17 - 5.08 (m, 2H), 3.78 - 3.73 (m, 2H), 3.48 - 3.43 (m, 3H), 2.79 - 2.74 (m, 4H), 2.19 - 2.14 (m, 6H), 1.88 (br d, J = 4.5 Hz, 2H), 1.84 - 1.79 (m, 2H).

[0071] Step 8: Synthesis of compound WX001 WX001-11 (400 mg, 914.31 μmol, 1 eq), MeOH (4 mL) and HCl (0.8 mL, 37% purity) were added in sequence to a dried reaction flask, and the mixture was heated to 50° C. and stirred for 2 hours. After completion of the reaction, the mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL×3), and separated to collect the organic phase. The organic phase was washed with saturated aqueous sodium bicarbonate solution (20 mL) and saturated saline solution (10 mL×3) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (column: Waters Xbridge BEH C18 100×30 mm×10 μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 25%-55%, 10 min) to obtain WX001. 1 H NMR (400 MHz, deuterated methanol) δ 7.41 (s, 2H), 6.36 (d, J = 8.3 Hz, 1H), 6.05 (d, J = 8.3 Hz, 1H), 3.77 - 3.73 (m, 2H), 2.80 - 2.74 (m, 2H), 2.69 - 2.64 (m, 2H), 2.15 (s, 6H), 1.88 - 1.88 (m, 1H), 1.90 - 1.85 (m, 2H), 1.82 - 1.78 (m, 2H). MS-ESI m / z:392.5 [MH] - .

[0072] Example 2 [ka] Synthesis scheme: [ka]

[0073] Step 1: Synthesis of compound WX002-2 WX002-1 (1 g, 5.43 mmol, 1 eq) and chloroform (67 mL) were added to a pre-dried reaction flask, tetrabutylammonium tribromide (3.14 g, 6.51 mmol, 1.2 eq) was added, and the mixture was purged with nitrogen gas three times and stirred at 25 ° C for 3 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, the concentrate was diluted with ethyl acetate (30 mL), water (30 mL) was added, separated, the aqueous phase was extracted with ethyl acetate (30 mL × 2), the organic phase was combined, the organic phase was washed with 1N hydrochloric acid (30 mL) and saturated saline (30 mL) in sequence, the organic phase was collected, 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 20: 1 to 10: 1) to obtain WX002-2. 1 H NMR (400 MHz, deuterated chloroform) δ 7.35 - 7.29 (m, 2H), 7.27 - 7.20 (m, 5H), 6.71 - 6.66 (m, 1H), 4.74 (s, 1H), 3.96 (s, 2H).

[0074] Step 2: Synthesis of compound WX002-3 WX002-2 (2.46 g, 9.35 mmol, 66.63 mL, 1 eq) and DMF (24.6 mL) were added to a pre-dried reaction flask, which was then purged with nitrogen gas three times. At 0° C., cesium carbonate (13.07 g, 40.11 mmol, 4.29 eq) was added, and then chloromethyl methyl ether (2.15 g, 26.70 mmol, 2.03 mL, 2.86 eq) was added dropwise and stirred at 25° C. for 2 hours. After completion of the reaction, the reaction solution was poured into ice water (30 mL) to quench, ethyl acetate (20 mL) was added to separate, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (2×20 mL), the organic phase was combined, washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0-10:1-5:1) to obtain WX002-3. 1 H NMR (400 MHz, deuterated chloroform) δ 7.32 - 7.27 (m, 3H), 7.25 - 7.17 (m, 4H), 6.97 (d, J = 8.7 Hz, 1H), 5.15 (s, 2H), 3.96 (s, 2H), 3.37 (s, 3H) .

[0075] Step 3: Synthesis of compound WX002-4 WX002-3 (2.34 g, 7.62 mmol, 1 eq) and THF (23.4 mL) were added to a pre-dried reaction flask, and the flask was purged with nitrogen gas three times. At -78 ° C, n-butyl lithium (2.5 M, 3.35 mL, 1.1 eq) was slowly added dropwise, and the mixture was stirred at -78 ° C for 1 hour. Then, a mixed solution of WX001-4 (1.46 g, 6.86 mmol, 0.9 eq) and THF (23.4 mL) was added dropwise at -78 ° C, and stirring was continued at -78 ° C for 1 hour. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution (20 mL), and then ethyl acetate (20 mL) was added and separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (20 mL × 2), the organic phase was combined, washed successively with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0-20:1-10:1-5:1) to obtain WX002-4. 1 H NMR (400 MHz, deuterated chloroform) δ 7.18 - 7.14 (m, 2H), 7.12 - 7.05 (m, 5H), 6.99 (s, 1H), 6.93 - 6.86 (m, 2H), 6.14 (d, J = 4.1 Hz, 1H), 5.23 (s, 1H), 5.05 (s, 2H), 3.89 (d, J = 5.6 Hz, 2H), 3.26 (s, 3H), 2.15 (s, 6H).

[0076] Step 4: Synthesis of compound WX002-5 WX002-4 (2.23 g, 5.05 mmol, 1 eq) and DCM (23 mL) were added to a pre-dried reaction flask, and the flask was flushed with nitrogen gas three times. 3SiH (881.28 mg, 7.58 mmol, 1.21 mL, 1.5 eq) and trifluoroacetic acid (864.15 mg, 7.58 mmol, 561.13 μL, 1.5 eq) were added dropwise in sequence and 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 by adding DCM (50 mL × 3), and the organic phases were combined, washed with saturated saline (50 mL), and separated. After that, 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 (petroleum ether: ethyl acetate = 1: 0 to 20: 1 to 10: 1) to obtain WX002-5. 1 H NMR (400 MHz, deuterated chloroform) δ 7.24 (d, J = 7.4 Hz, 2H), 7.21 - 7.12 (m, 5H), 6.93 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 1.9 Hz, 1H), 6.72 (dd, J = 2.0, 8.4 Hz, 1H), 5.10 (s, 2H), 3.93 (s, 2H), 3.89 (s, 2H), 3.34 (s, 3H), 2.19 (s, 6H).

[0077] Step 5: Synthesis of compound WX002-6 WX002-5 (1.8 g, 4.23 mmol, 1 eq), WX001-7 (843.62 mg, 4.65 mmol, 781.13 μL, 1.1 eq) and dioxane (36 mL) were added to a pre-dried reaction flask, and cesium carbonate (2.07 g, 6.35 mmol, 1.5 eq) was added. The flask was purged with nitrogen gas three times, and Xantphos (195.89 mg, 338.54 μmol, 0.08 eq) and Pd 2 (dba) 3(232.51 mg, 253.90 μmol, 0.06 eq) was added in sequence, and the atmosphere was replaced with nitrogen gas three times, followed by stirring at 100° C. for 16 hours. After completion of the reaction, water (200 mL) and ethyl acetate (200 mL) were added to the reaction solution, separated, the aqueous phase was extracted with ethyl acetate (200 mL×3), the organic phase was combined, washed with saturated saline (300 mL×2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain WX002-6, which was used directly in the next step without purification.

[0078] Step 6: Synthesis of compound WX002-7 WX002-6 (2.22 g, 4.22 mmol, 1 eq) and THF (25 mL) were added to a pre-dried reaction flask, 2N hydrochloric acid (5.78 mL, 2.74 eq) was added, and the mixture was purged with nitrogen gas three times and stirred at 25 ° C for 1 hour. After completion of the reaction, the reaction solution was quenched with saturated sodium bicarbonate solution (100 mL), the aqueous phase was extracted with ethyl acetate (100 mL × 3), the organic phase was combined, washed with saturated saline (150 mL × 2), the organic phase was collected, 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 2: 1) to obtain WX002-7. 1 H NMR (400 MHz, deuterated chloroform) δ 7.24 (d, J = 7.2 Hz, 2H), 7.17 (d, J = 7.5 Hz, 3H), 6.91 (d, J = 8.3 Hz, 1H), 6.86 (d, J = 1.8 Hz, 1H), 6.76 (dd, J = 1.8, 8.3 Hz, 1H), 6.43 (s, 2H), 5.09 (s, 2H), 3.94 (s, 2H), 3.85 (s, 2H), 3.50 (br s, 2H), 3.33 (s, 3H), 2.14 (s, 6H).

[0079] Step 7: Synthesis of compound WX002-8 WX001-10 (474.51 mg, 3.20 mmol, 1.50 eq) and THF (8 mL) were added to a pre-dried reaction flask, and the flask was purged with nitrogen gas three times. A mixed solution of WX002-7 (770 mg, 2.13 mmol, 1 eq) and THF (8 mL) was added dropwise, and TEA (646.65 mg, 6.39 mmol, 889.48 μL, 3 eq) was added and stirred at 25 ° C for 1 hour. After the reaction was completed, the reaction solution was poured into water (30 mL) to quench the reaction, and the aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was combined and washed with saturated saline (50 mL × 2). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain WX002-8, which was used directly in the next step without purification.

[0080] Step 8: Synthesis of compound WX002 WX002-8 (1.09 g, 2.30 mmol, 1 eq) and MeOH (22 mL) were added to a pre-dried reaction flask, HCl (12 M, 4.36 mL, 22.73 eq) was added, and the mixture was replaced with nitrogen gas three times and stirred at 50 ° C for 3 hours. After the reaction was completed, the reaction solution was adjusted to pH 7 with saturated sodium bicarbonate solution, ethyl acetate (30 mL × 3) was added to extract, and the organic phase was collected after separation, the organic phase was combined, the organic phase was washed with saturated saline solution (40 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 high performance liquid chromatography (column: Waters Xbridge BEH C18 250 × 50 mm × 10 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile %: 25% to 65%, 10 min) to obtain WX002. 1 H NMR (400 MHz, deuterated methanol) δ 7.36 (s, 2H), 7.25 - 7.08 (m, 5H), 6.67 - 6.59 (m, 3H), 3.88 (s, 2H), 3.84 (s, 2H), 2.18 (s, 6H);MS-ESI m / z: 428.2 [MH] - .

[0081] Example 3 [ka] Synthesis scheme: [ka] [ka]

[0082] Step 1: Synthesis of compound WX003-2 Sodium hydride (5.82 g, 145.46 mmol, 60% content, 3 eq) and DMSO (35 mL) were added to a pre-dried reaction flask, which was then purged with nitrogen gas three times and stirred at 75 ° C for 10 minutes. Next, at 25 ° C, a solution of methyltriphenylphosphonium iodide (39.20 g, 96.98 mmol, 2 eq) in DMSO (25 mL) was slowly added and stirred at 25 ° C for 20 minutes. At 25 ° C, a solution of WX003-1 (10 g, 48.49 mmol, 1 eq) in DMSO (10 mL) was added dropwise, and the mixture was heated to 65 ° C and stirred for 12 hours. After the reaction was completed, the reaction solution was poured into ice water (200 mL), methyl tert-butyl ether (200 mL) was added to separate, the organic phase was collected, the aqueous phase was extracted with methyl tert-butyl ether (200 mL x 2), the organic phase was combined, washed with saturated saline (600 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by an automatic column chromatography apparatus (petroleum ether: ethyl acetate = 1:0 to 5:1) to obtain WX003-2. 1H NMR (400MHz, deuterated chloroform) δ 7.14 - 7.06 (m, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 5.94 (d, J = 2.4 Hz, 1H), 5.33 - 5.27 (m, 1H), 5.23 (s, 2H), 3.52 (s, 2H), 3.56 - 3.48 (m, 1H), 2.90 - 2.83 (m, 1H), 2.87 (t, J = 6.4 Hz, 1H), 2.56 - 2.50 (m, 1H), 2.57 - 2.48 (m, 1H), 1.89 (quin, J = 6.4 Hz, 1H), 1.96 - 1.84 (m, 1H).

[0083] Step 2: Synthesis of compound WX003-3 Under a nitrogen gas environment, ethyl acetate (300 mL) and Pd / C (2.32 g, 20.56 mmol, 10% content, 1 eq) were sequentially added to a pre-dried hydrogenation flask, and WX003-2 (4.2 g, 20.56 mmol, 1 eq) was added, and the mixture was purged with hydrogen gas three times, placed in a hydrogen gas environment at 15 psi pressure, and stirred at 25° C. for 2 hours. After the reaction was completed, the reaction solution was directly filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain WX003-3. 1 H NMR (400MHz, deuterated chloroform) δ 7.09 - 7.02 (m, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 5.23 (s, 2H), 3.51 (s, 2H), 3.57 (s, 1H), 3.30 - 3.16 (m, 1H), 2.88 - 2.67 (m, 2H), 1.93 - 1.70 (m, 3H), 1.96 - 1.64 (m, 1H), 1.25 (d, J = 7.0 Hz, 3H).

[0084] Step 3: Synthesis of compound WX003-4 WX003-3 (4 g, 19.39 mmol, 1 eq) and THF (40 mL) were added to a pre-dried reaction flask, NBS (3.45 g, 19.39 mmol, 1 eq) was added, and the mixture was purged with nitrogen gas three times and stirred at -78 °C for 0.5 h. After the reaction was completed, water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution to separate, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (100 mL x 2), the organic phase was combined, washed with saturated saline (400 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by an automatic column chromatography apparatus (petroleum ether: ethyl acetate = 1: 0 to 10: 1) to obtain WX003-4. 1 H NMR (400MHz, deuterated chloroform) δ 7.36 - 7.30 (m, 1H), 6.83 (d, J = 8.6 Hz, 1H), 5.20 (d, J = 0.9 Hz, 2H), 3.55 - 3.46 (m, 1H), 3.49 (s, 2H), 3.29 - 3.18 (m, 1H), 2.95 - 2.83 (m, 1H), 2.62 - 2.48 (m, 1H), 1.92 - 1.79 (m, 2H), 1.76 - 1.67 (m, 2H), 1.23 (d, J = 7.0 Hz, 3H).

[0085] Step 4: Synthesis of compound WX003-5 WX003-4 (4.9 g, 17.18 mmol, 1 eq) and THF (50 mL) were added to a pre-dried reaction flask, and then n-butyl lithium (2.5 M, 7.56 mL, 1.1 eq) was slowly added dropwise at -78 ° C. and stirred for 1 hour, and then a solution of WX001-4 (3.29 g, 15.46 mmol, 0.9 eq) in THF (25 mL) was slowly added dropwise and stirred for 1 hour at -78 ° C. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution (200 mL), and then ethyl acetate (200 mL) was added and separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (200 mL × 2), the organic phase was combined, washed successively with saturated brine (600 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified using an automatic column chromatography system (petroleum ether:ethyl acetate=1:0-10:1-5:1) to obtain WX003-5. 1 H NMR (400MHz, deuterated chloroform) δ 7.19 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 8.6 Hz, 1H), 6.86 - 6.74 (m, 1H), 6.21 (dd, J = 4.4, 10.0 Hz, 1H), 5.27 - 5.14 (m, 2H), 3.57 - 3.43 (m, 3H), 3.34 - 3.19 (m, 1H), 3.10 - 3.00 (m, 1H), 2.92 - 2.72 (m, 1H), 2.47 - 2.35 (m, 1H), 2.26 (d, J = 6.9Hz, 6H), 1.92 - 1.84 (m, 1H), 1.79 - 1.69 (m, 2H), 1.29 - 1.22 (m, 3H).

[0086] Step 5: Synthesis of compound WX003-6 A pre-dried reaction flask was charged with WX003-5 (2.45 g, 5.84 mmol, 1 eq) and DCM (25 mL), and the mixture was cooled to -10 °C with Et 3SiH (1.02g, 8.76mmol, 1.40mL, 1.5eq) and TFA (999.25mg, 8.76mmol, 648.86μL, 1.5eq) were added and stirred at -10℃ for 1h. After completion of the reaction, the reaction solution was adjusted to pH 6-7 with saturated aqueous sodium bicarbonate, water (30mL) and dichloromethane (30mL) were added and separated, the organic phase was collected, the aqueous phase was extracted with dichloromethane (30mL×2), the organic phase was combined, the organic phase was washed with saturated brine (150mL×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 an automatic column chromatography apparatus (petroleum ether:ethyl acetate=1:0-10:1-5:1) to obtain WX003-6. 1 H NMR (400MHz, deuterated chloroform) δ 7.23 (s, 1H), 7.25 - 7.20 (m, 1H), 6.69 (d, J = 8.6 Hz, 1H), 6.21 (d, J = 8.4 Hz, 1H), 5.16 (s, 2H), 3.82 - 3.62 (m, 2H), 3.48 (s, 3H), 3.28 (td, J = 3.5, 6.8 Hz, 1H), 2.93 - 2.83 (m, 1H), 2.67 - 2.57 (m, 1H), 2.15 (s, 6H), 1.92 (br dd, J = 4.8, 10.1 Hz, 2H), 1.78 (td, J = 4.5, 9.4 Hz, 2H), 1.27 (d, J = 7.0 Hz, 3H).

[0087] Step 6: Synthesis of compound WX003-7 WX003-6 (1.9 g, 4.71 mmol, 1 eq) and dioxane (20 mL) were added to a pre-dried reaction flask, followed by cesium carbonate (2.30 g, 7.07 mmol, 1.5 eq) and WX001-7 (939.07 mg, 5.18 mmol, 869.51 μL, 1.1 eq). The flask was flushed with nitrogen gas three times, and Xantphos (218.05 mg, 376.84 μmol, 0.08 eq) and Pd 2 (dba) 3(258.81 mg, 282.63 μmol, 0.06 eq) was added, and the mixture was further purged with nitrogen gas, followed by stirring at 100° C. for 12 hours. After completion of the reaction, the reaction solution was cooled to room temperature, water (50 mL) and ethyl acetate (50 mL) were added and separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (50 mL×2), the organic phase was combined, the organic phase was washed with saturated saline (300 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain WX003-7, and the crude product was used directly in the next step.

[0088] Step 7: Synthesis of compound WX003-8 WX003-7 (2.3 g, 4.57 mmol, 1 eq) and THF (25 mL) were added to a pre-dried reaction flask, hydrochloric acid (2N, 2.28 mL, 1 eq) was added, and the mixture was stirred at 25 °C for 1 h. After the reaction was completed, the reaction solution was adjusted to pH 6-7 with saturated aqueous sodium bicarbonate, water (30 mL) and ethyl acetate (30 mL) were added and separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (30 mL x 2), the organic phase was combined, the organic phase was washed with saturated brine (120 mL x 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 an automatic column chromatography apparatus (petroleum ether: ethyl acetate = 1: 0-10: 1-5: 1-3: 1) to obtain WX003-8. 1 H NMR (400MHz, deuterated chloroform) δ 6.68 (d, J = 8.4 Hz, 1H), 6.53 (s, 2H), 6.30 (d, J = 8.5 Hz, 1H), 5.15 (s, 2H), 3.81 - 3.57 (m, 2H), 3.54 - 3.41 (m, 3H), 3.36 - 3.21 (m, 1H), 2.96 - 2.82 (m, 1H), 2.70 - 2.55 (m, 1H), 2.22 - 2.02 (m, 6H), 1.99 - 1.85 (m, 2H), 1.84 - 1.69 (m, 2H), 1.27 (d, J = 7.0 Hz, 3H).

[0089] Step 8: Synthesis of compounds WX003-9-1 and WX003-9-2 WX003-8 (250 mg, 736.44 μmol, 1 eq) was subjected to chiral separation to obtain WX003-9-1 and WX003-9-2 using the following separation method: (Column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm); A: food-grade supercritical carbon dioxide; B: mobile phase: [0.1% ammonia water + isopropanol]; B%: 35% to 35%, 10 min). The retention time of WX003-9-1 is 3.671 min, and the retention time of WX003-9-2 is 4.112 min. Analysis method (Instrument: CAS-TJ-ANA-SFC-C (Waters UPCC with PDA); Column: Chiralpak OJ-3, 150×4.6 mm ID, 3 μm; Mobile phase: A: food grade supercritical carbon dioxide; B: isopropanol (0.1% isopropylamine, volume ratio); Gradient: The content of B increases from 10% to 50% in 3.5 min, maintains for 1 min, then increases from 50% to 10% in 0.5 min; Flow rate: 2.5 mL / min; Column temperature: 35° C.; Detection wavelength: 220 nm; System back pressure: 100 bar). WX003-9-1: 1 H NMR (400MHz, deuterated chloroform) δ 6.68 (d, J = 8.4 Hz, 1H), 6.47 (s, 2H), 6.32 (d, J = 8.5 Hz, 1H), 5.15 (s, 2H), 3.79 - 3.57 (m, 2H), 3.47 (s, 3H), 3.32 - 3.23 (m, 1H), 2.93 - 2.84 (m, 1H), 2.62 (ddd, J = 7.3, 10.6, 17.6 Hz, 1H), 2.09 (s, 6H), 1.95 - 1.86 (m, 2H), 1.80 - 1.74 (m, 2H), 1.30 - 1.25 (d, J = 7.0 Hz, 3H). WX003-9-2: 1H NMR (400MHz, deuterated chloroform) δ 6.68 (d, J = 8.5 Hz, 1H), 6.47 (s, 2H), 6.32 (d, J = 8.5 Hz, 1H), 5.15 (s, 2H), 3.77 - 3.58 (m, 2H), 3.47 (s, 3H), 3.32 - 3.23 (m, 1H), 2.94 - 2.84 (m, 1H), 2.62 (ddd, J = 7.4, 10.5, 17.5 Hz, 1H), 2.09 (s, 6H), 1.96 - 1.87 (m, 2H), 1.81 - 1.74 (m, 2H), 1.27 (d, J = 7.0 Hz, 3H).

[0090] Step 9: Synthesis of compounds WX003-10-1 and WX003-10-2 A solution of WX001-10 (46.59 mg, 313.72 μmol, 1.5 eq) in THF (1 mL) was added to a dried reaction flask, and WX003-9-1 (71 mg, 209.15 μmol, 1 eq) was dissolved in THF (1 mL) and then added to the reaction flask, and TEA (63.49 mg, 627.45 μmol, 87.33 μL, 3 eq) was added and stirred at 20 ° C for 1 hour. After the reaction was completed, the reaction solution was added to water (5 mL), extracted by adding ethyl acetate (5 mL), separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (5 mL × 2), the organic phase was combined, the organic phase was washed successively with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain WX003-10-1.

[0091] A solution of WX001-10 (46.59 mg, 313.72 μmol, 1.5 eq) in THF (1 mL) was added to a dried reaction flask, and WX003-9-2 (71 mg, 209.15 μmol, 1 eq) was dissolved in THF (1 mL), and then added to the reaction flask, TEA (63.49 mg, 627.45 μmol, 87.33 μL, 3 eq) was added, and the mixture was stirred at 20 ° C for 1 hour. After the reaction was completed, the reaction solution was added to water (5 mL), and ethyl acetate (5 mL) was added to extract, separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (5 mL × 2), the organic phase was combined, the organic phase was washed successively with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain WX003-10-2.

[0092] Step 10: Synthesis of compounds WX003 and WX004 WX003-10-1 (100.00 mg, 221.48 μmol, 1 eq) and DMA (1 mL) were added to a pre-dried reaction flask, then HCl (0.2 mL, 37% purity) was added, and the mixture was replaced with nitrogen gas three times and stirred at 50 ° C for 6 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), the pH was adjusted to neutral with saturated sodium bicarbonate solution, ethyl acetate (10 mL × 3) was added for extraction, and the organic phase was collected after separation, the organic phase was combined, the organic phase was washed with saturated saline (50 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 high performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 25% to 55%, 8 min) to obtain WX003. 1H NMR (400MHz, deuterated dimethyl sulfoxide) δ 10.34 (br s, 1H), 8.93 (s, 1H), 7.45 (s, 2H), 6.40 (d, J = 8.3 Hz, 1H), 5.96 (d, J = 8.3 Hz, 1H), 3.70 (s, 1H), 3.62 (s, 1H), 3.10 (td, J = 3.5, 6.8 Hz, 1H), 2.88 - 2.79 (m, 1H), 2.58 (br s, 1H), 2.09 (s, 6H), 1.89 - 1.78 (m, 2H), 1.68 (br d, J = 3.1 Hz, 2H), 1.18 (d, J = 6.9 Hz, 3H);MS-ESI m / z: 406.2 [MH] - .

[0093] WX003-10-2 (100.00 mg, 221.48 μmol, 1 eq) and DMA (1 mL) were added to a pre-dried reaction flask, then HCl (0.2 mL, 37% purity) was added, and the mixture was replaced with nitrogen gas three times and stirred at 50 ° C for 6 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), the pH was adjusted to neutral with saturated sodium bicarbonate solution, ethyl acetate (10 mL × 3) was added for extraction, and the organic phase was collected after separation, the organic phase was combined, the organic phase was washed with saturated saline (50 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 high performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [A: water (ammonium bicarbonate)-B: acetonitrile]; acetonitrile %: 25% to 55%, 8 min) to obtain WX004. 1H NMR (400MHz, deuterated dimethyl sulfoxide) δ 10.23 (s, 1H), 8.92 (s, 1H), 7.45 (s, 2H), 6.39 (d, J = 8.3 Hz, 1H), 5.95 (d, J = 8.3 Hz, 1H), 3.69 (s, 1H), 3.60 (br s, 1H), 3.08 (td, J = 3.5, 6.8 Hz, 1H), 2.87 - 2.78 (m, 1H), 2.62 - 2.53 (m, 1H), 2.07 (s, 6H), 1.89 - 1.77 (m, 2H), 1.66 (br d, J = 3.3 Hz, 2H), 1.17 (d, J = 6.9 Hz, 3H);MS-ESI m / z: 406.2 [MH] - .

[0094] Example 4 [ka] Synthesis scheme: [ka]

[0095] Step 1: Synthesis of compound WX005 WX001 (50 mg, 127.09 μmol, 1 eq) and THF (2.8 mL) were added to a pre-dried reaction flask, TEA (0.28 mL) was added, and the mixture was purged with nitrogen gas three times. Iodine monochloride (24.76 mg, 152.50 μmol, 7.78 μL, 1.20 eq) was added at -78 ° C., and the mixture was stirred at -78 ° C. for 2 hours. After the reaction was completed, the reaction solution was adjusted to pH 6-7 with 2N hydrochloric acid, washed with saturated sodium thiosulfate solution (10 mL × 2), the organic phase was collected, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance liquid chromatography (column: Phenomenex Luna 80 × 30 mm × 3 μm; mobile phase: [water (HCl)-acetonitrile]; acetonitrile %: 60%-80%, 8 min) to obtain WX005. 1H NMR (400 MHz, deuterated methanol) δ 7.44 (s, 2H), 6.51 (s, 1H), 3.76 (s, 2H), 2.81 - 2.66 (m, 4H), 2.17 (s, 6H), 1.91 - 1.77 (m, 4H);MS-ESI m / z: 518.0 [MH] - .

[0096] Example 5 [ka] Synthesis scheme: [ka]

[0097] Step 1: Synthesis of compound WX006-3 WX006-1 (5.5 g, 38.15 mmol, 13.75 mL, 1 eq) and isopropanol (250 mL) were added to a pre-dried reaction flask, and WX006-2 (12.14 g, 41.96 mmol, 1.1 eq) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (20.27 g, 57.22 mmol, 1.5 eq) were added, and the mixture was purged with nitrogen gas three times and stirred at 80 ° C for 12 hours. After the reaction was completed, the reaction solution was directly 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 WX006-3. 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).

[0098] Step 2: Synthesis of compound WX006-4 WX006-3 (3.0 g, 18.50 mmol, 1 eq) and ethanol (100 mL) were added to a pre-dried reaction flask, palladium on carbon (1 g, 18.50 mmol, 10% content, 1 eq) was added, and the mixture was purged with hydrogen gas three times, placed in a 50 psi hydrogen gas (373.70 mg, 185.00 mmol, 10 eq) environment, and stirred at 60 ° C for 16 hours. After the reaction was completed, the reaction solution was directly filtered through diatomaceous earth, 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 obtain WX006-4. 1 H NMR (400 MHz, deuterated chloroform) δ 6.78-6.91 (m, 1H), 6.58 (dd, J=5.38, 8.38 Hz, 1H), 5.03 (d, J=5.13 Hz, 1H), 2.71 (s, 4H), 1.75-1.81 (m, 4H). 19 F NMR (376 MHz, deuterated chloroform) δ -145.84 (s, 1F).

[0099] Step 3: Synthesis of compound WX006-5 WX006-4 (4 g, 24.07 mmol, 1 eq) and acetonitrile (80 mL) were added to a pre-dried reaction flask, NBS (4.71 g, 26.48 mmol, 1.1 eq) was added, and the mixture was replaced with nitrogen gas three times and stirred at 25 ° C for 2 hours. After the reaction was completed, water (150 mL) and ethyl acetate (150 mL) were added to the reaction solution to separate, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (200 mL × 2), the organic phase was combined, washed with saturated saline (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 WX006-5. 1H NMR (400 MHz, deuterated chloroform) δ 7.17 (d, J=9.51 Hz, 1H), 5.04 (s, 1H), 2.69 (td, J=5.85, 15.82 Hz, 4H), 1.73-1.85 (m, 1H), 1.77 (d, J=5.25 Hz, 3H). 19 F NMR (377 MHz, deuterated dimethylsulfoxide) δ 0.00 (s, 1F).

[0100] Step 4: Synthesis of compound WX006-6 WX006-5 (6 g, 24.48 mmol, 1 eq) and DMF (120 mL) were added to a pre-dried reaction flask, and the flask was purged with nitrogen gas three times. At 0° C., cesium carbonate (23.93 g, 73.44 mmol, 3 eq) was added, and then chloromethyl methyl ether (3.94 g, 48.96 mmol, 3.72 mL, 2 eq) 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 and separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (100 mL×2), the organic phase was combined, washed with saturated saline (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 silica gel TLC plate (petroleum ether: ethyl acetate = 10:1) to obtain WX006-6. 1 H NMR (400 MHz, deuterated chloroform) δ 7.20 (d, J=10.38 Hz, 1H), 5.11 (s, 2H), 3.53-3.65 (m, 3H), 2.78 (t, J=6.07 Hz, 2H), 2.67 (t, J=6.00 Hz, 2H), 1.70-1.82 (m, 4H). 19 F NMR (376 MHz, deuterated chloroform) δ -132.23 (s, 1F).

[0101] Step 5: Synthesis of compound WX006-7 WX006-6 (1g, 3.46mmol, 1eq) and tetrahydrofuran (10mL) were added to a pre-dried reaction flask, and the flask was purged with nitrogen gas three times. At -78°C, n-butyllithium (2.5M, 1.52mL, 1.1eq) was slowly added dropwise, and the mixture was stirred at -78°C for 1 hour. Then, a mixed solution of WX001-4 (663.22mg, 3.11mmol, 0.9eq) and tetrahydrofuran (10mL) was added dropwise at -78°C, and stirring was continued at -78°C for 1 hour. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution (50mL), and then ethyl acetate (50mL) was added and separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (50mL x 2), the organic phase was combined, washed successively with saturated brine (50mL x 2), dried over anhydrous sodium sulfate, filtered, 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=1:0-10:1-5:1) to obtain WX006-7. 1 H NMR (400 MHz, deuterated chloroform) δ 7.19 (s, 2H), 6.88 (d, J=12.88 Hz, 1H), 6.17 (d, J=3.50 Hz, 1H), 5.13 (s, 2H), 3.58 (s, 3H), 2.80 (d, J=3.00 Hz, 2H), 2.72-2.76 (m, 1H), 2.58 (d, J=17.64 Hz, 1H), 2.38 (s, 1H), 2.34 (s, 1H), 2.25 (s, 6H), 1.92 (d, J=4.00 Hz, 1H), 1.79 (d, J=5.63 Hz, 1H). 19 F NMR (376 MHz, deuterated chloroform) δ -134.26 (s, 1F).

[0102] Step 6: Synthesis of compound WX006-8 WX006-7 (800 mg, 1.89 mmol, 1 eq), WX001-7 (376.75 mg, 2.08 mmol, 348.84 μL, 1.1 eq) and 1,4-dioxane (16 mL) were added to a pre-dried reaction flask, followed by addition of cesium carbonate (923.62 mg, 2.83 mmol, 1.5 eq). The flask was purged with nitrogen gas three times, and then Xantphos (87.48 mg, 151.19 μmol, 0.08 eq) and Pd 2 (dba) 3 (103.83 mg, 113.39 μmol, 0.06 eq) were added in sequence, and the mixture was purged with nitrogen gas three times 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=1:0-20:1-10:1-3:1) to obtain WX006-8. 1 H NMR (400 MHz, deuterated chloroform) δ 7.84-7.92 (m, 1H), 7.87 (d, J=6.90 Hz, 1H), 7.62 (d, J=6.90 Hz, 2H), 7.48-7.54 (m, 3H), 7.32-7.38 (m, 3H), 7.21 (d, J=8.41 Hz, 2H), 6.85 (d, J=13.55 Hz, 1H), 6.11 (s, 1H), 5.13 (s, 2H), 3.59 (s, 3H), 2.79 (d, J=7.28 Hz, 3H), 2.62 (s, 1H), 2.12 (s, 6H), 1.81 (dd, J=3.39, 6.27 Hz, 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).

[0103] Step 7: Synthesis of compound WX006-9 WX006-8 (600 mg, 1.15 mmol, 1 eq) and tetrahydrofuran (12 mL) were added to a pre-dried reaction flask, hydrochloric acid (2 M, 572.92 μL, 1 eq) was added, and the mixture was replaced with nitrogen gas three times and stirred at 25 ° C for 1 hour. After the reaction was completed, the reaction solution was adjusted to pH 7 with saturated sodium bicarbonate solution, the aqueous phase (20 mL × 3) was extracted with ethyl acetate, the organic phase was combined, washed with saturated saline (20 mL × 2), the organic phase was collected, 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 silica gel TLC plate (petroleum ether: ethyl acetate = 1: 1) to obtain WX006-9. 1 H NMR (400 MHz, deuterated chloroform) δ 7.05 (d, J=13.13 Hz, 1H), 6.47 (s, 2H), 6.12 (s, 1H), 5.12 (s, 2H), 3.59 (s, 3H), 2.78 (d, J=5.75 Hz, 2H), 2.25-2.32 (m, 2H), 2.23-2.24 (m, 1H), 2.19 (s, 6H), 1.66-1.76 (m, 4H). 19 F NMR (377 MHz, deuterated chloroform) δ -134.74 (s, 1F).

[0104] Step 8: Synthesis of compound WX006-10 MeOH (30 mL), glacial acetic acid (25 mL) and wet Pd / C (50 mg, 10% content) were added to a pre-dried reaction flask, and WX006-9 (500 mg, 1.39 mmol, 1 eq) was added, purged with hydrogen gas three times, placed under a hydrogen gas environment of 50 psi pressure, and stirred at 25°C for 16 hours. After completion of the reaction, the reaction solution was filtered through diatomaceous earth and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 20: 1 to 10: 1) to obtain WX006-10. 1H NMR (400 MHz, deuterated chloroform) δ 6.47 - 6.37 (m, 2H), 6.15 (d, J = 13.0 Hz, 1H), 5.10 - 5.06 (m, 2H), 3.67 - 3.62 (m, 2H), 3.59 - 3.56 (m, 3H), 2.81 (br t, J = 6.1 Hz, 2H), 2.72 (br t, J = 6.1 Hz, 2H), 2.08 (s, 6H), 1.90 - 1.84 (m, 2H), 1.82 - 1.77 (m, 2H).

[0105] Step 9: Synthesis of compound WX006-11 A solution of WX006-10 in THF (2 mL) was added to a dried reaction flask, and the atmosphere was replaced with nitrogen gas three times. WX001-10 was dissolved in THF (2 mL) and then added to the reaction flask. TEA (150.27 mg, 1.49 mmol, 206.70 μL, 3 eq) was added and stirred at 20 ° C. for 1 hour. After the reaction was completed, the reaction solution was added to water (5 mL), extracted with ethyl acetate (5 mL), separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (5 mL × 2), the organic phase was combined, the organic phase was washed with saturated saline (20 mL × 2) in succession, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to obtain the crude product of WX006-11, which was used directly in the next step.

[0106] Step 10: Synthesis of compound WX006 WX006-11 and MeOH (5 mL) were added to a pre-dried reaction flask, HCl (12N, 60.19 μL, 1 eq) was added, and the mixture was replaced with nitrogen gas three times and stirred at 50 °C for 0.5 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, diluted with ethyl acetate (30 mL), water (30 mL) was added and separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated saline (30 mL x 2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC high-performance liquid chromatography (column: Phenomenex luna C18 80 x 40 mm x 3 μm; mobile phase: [water (HCl)-acetonitrile]; acetonitrile %: 49% to 69%, 7 min) to obtain WX006. 1 H NMR (400 MHz, deuterated methanol) δ 7.42 (s, 2H), 5.89 (d, J = 12.3 Hz, 1H), 3.77 (s, 2H), 2.76 - 2.67 (m, 4H), 2.17 (s, 6H), 1.90 - 1.77 (m, 4H);MS-ESI m / z: 410.1 [MH] - .

[0107] Example 6 [ka] Synthesis scheme: [ka]

[0108] Step 1: Synthesis of compound WX007-2 In a nitrogen gas environment, EtOH (1000mL) and Pd / C (10g, 312.17mmol, 10% content, 1eq) were sequentially added to two pre-dried hydrogenation flasks, and WX007-1 (50g, 312.17mmol, 1eq) was added to each flask. The mixture was replaced with hydrogen gas three times, placed in a hydrogen gas environment at 50psi pressure, and stirred at 60°C for 4 hours. After the reaction was completed, 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=1:0-10:1-5:1) to obtain WX007-2. 1 H NMR (400MHz, deuterated chloroform) δ 12.43 (s, 1H), 7.39 - 7.35 (m, 1H), 6.81 - 6.80 (m, 1H), 6.73 - 6.71 (m, 1H), 2.95 - 2.92 (m, 2H), 2.71 - 2.69 (m, 2H), 2.15 - 2.08 (m, 2H).

[0109] Step 2: Synthesis of compound WX007-3 WX007-2 (10 g, 61.66 mmol, 1 eq), methoxyamine hydrochloride (5.66 g, 67.82 mmol, 1.1 eq) and EtOH (100 mL) were added to a pre-dried reaction flask, potassium carbonate (25.56 g, 184.97 mmol, 3 eq) was added, and the mixture was purged with nitrogen gas three times and stirred at 60 ° C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (200 mL) was added, the aqueous phase was extracted with ethyl acetate (200 mL × 3), the organic phase was combined, the organic phase was washed with saturated saline (300 mL × 1), dried over anhydrous sodium sulfate, filtered, 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 5: 1) to obtain WX007-3. 1H NMR (400MHz, deuterated chloroform) δ 11.33 (s, 1H), 7.17 - 7.13 (m, 1H), 6.82-6.80 (d, 1H), 6.68 - 6.66 (d, 1H), 4.00 (s, 3H), 2.83 - 2.76 (m, 4H), 1.90 - 1.83 (m, 2H).

[0110] Step 3: Synthesis of compound WX007-4 WX007-3 (11 g, 57.52 mmol, 1 eq) and DCM (200 mL) were added to a pre-dried reaction flask, 2,6-lutidine (24.65 g, 230.09 mmol, 26.80 mL, 4 eq) was added, triisopropylsilyl trifluoromethanesulfonate (52.88 g, 172.57 mmol, 46.38 mL, 3 eq) was added, and the mixture was purged with nitrogen gas three times and stirred at 25 ° C for 6 hours. After the reaction was completed, the reaction solution was quenched by adding water (200 mL), the aqueous phase was extracted with dichloromethane (500 mL × 3), the organic phase was combined, the organic phase was washed with saturated saline (550 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=1:0-20:1-10:1-5:1) to obtain WX007-4. 1 H NMR (400MHz, deuterated chloroform) δ 7.07 - 7.03 (m, 1H), 6.77- 6.72 (m, 2H), 3.97 (s, 3H), 2.76 - 2.72 (m, 2H), 2.61 - 2.58 (m, 2H), 1.75 - 1.70 (m, 2H), 1.35 - 1.29 (m, 3H), 1.28 - 1.10 (m, 18H).

[0111] Step 4: Synthesis of compound WX007-5 WX007-4 (4 g, 11.51 mmol, 1 eq) and acetonitrile (40 mL) were added to a pre-dried reaction flask, NBS (2.25 g, 12.66 mmol, 1.1 eq) was added, and the mixture was purged with nitrogen gas three times and stirred at 25 ° C for 2 hours. After the reaction was completed, the reaction solution was quenched by adding water (50 mL), the aqueous phase was extracted with ethyl acetate (60 mL × 3), the organic phase was combined, washed with saturated saline (100 mL × 2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1: 0 to 20: 1 to 10: 1) to obtain WX007-5. 1 H NMR (400MHz, deuterated chloroform) δ 7.32 - 7.30 (m, 1H), 6.67 - 6.65 (d, 1H), 3.97 (s, 3H), 2.75 - 2.71 (m, 4H), 1.75 - 1.72 (m, 2H),1.33 - 1.25 (m, 3H), 1.11 - 1.09 (m, 18H).

[0112] Step 5: Synthesis of compound WX007-6 WX007-5 (0.5 g, 1.17 mmol, 1 eq) and THF (5 mL) were added to a pre-dried reaction flask, and the flask was purged with nitrogen gas three times. At -78 ° C, n-butyl lithium (2.5 M, 515.87 μL, 1.1 eq) was slowly added dropwise, and the mixture was stirred at -78 ° C for 1 hour. Then, a mixed solution of WX001-4 (249.81 mg, 1.17 mmol, 1 eq) and THF (5 mL) was added dropwise at -78 ° C, and stirring was continued at -78 ° C for 1 hour. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution (5 mL) to quench the reaction, and then ethyl acetate (5 mL) was added to separate the reaction, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (2 × 5 mL), the organic phase was combined, the organic phase was washed successively with saturated brine (2 × 5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0-20:1-10:1) to obtain WX007-6. 1H NMR (400MHz, deuterated dimethyl sulfoxide) δ 7.18 (s, 3H), 6.95 - 6.93 (m, 1H), 6.70 - 6.68 (m, 1H), 6.24 - 6.23 (d, 1H), 3.97 (s, 3H), 2.74 - 2.70 (m, 3H), 2.63 (m, 1H), 2.23 (s, 6H), 1.70 - 1.66 (m, 2H), 1.30 - 1.26 (m, 3H), 1.24 - 1.08 (m, 18H).

[0113] Step 6: Synthesis of compound WX007-7 WX007-6 (470 mg, 838.33 μmol, 1 eq) and DCM (10 mL) were added to a pre-dried reaction flask, and the flask was flushed with nitrogen gas three times. 3 SiH (146.22 mg, 1.26 mmol, 200.85 μL, 1.5 eq) and TFA (143.38 mg, 1.26 mmol, 93.10 μL, 1.5 eq) were added dropwise in sequence and stirred at 0 ° C for 1 hour. After completion of the reaction, the reaction solution was poured into (30 mL) saturated aqueous sodium carbonate solution, extracted by adding DCM (30 mL × 3), and the organic phases were combined, washed with saturated saline (30 mL), and separated. After that, the organic phase was dried over anhydrous sodium sulfate, filtered, 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 obtain WX007-7. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 11.25 (s, 1H), 7.30 (s, 2H), 6.58 - 6.56 (m, 1H), 6.23 - 6.21 (m, 1H), 3.96 (s, 3H), 3.78 (s, 2H), 2.88 - 2.80 (m, 4H), 2.11 (s, 6H), 1.88 - 1.85 (m, 2H).

[0114] Step 7: Synthesis of compound WX007-8 WX007-7 (320 mg, 824.11 μmol, 1 eq) and DCM (6.4 mL) were added to a pre-dried reaction flask, 2,6-lutidine (353.21 mg, 3.30 mmol, 383.93 μL, 4 eq), triisopropylsilyl trifluoromethanesulfonate (757.57 mg, 2.47 mmol, 664.54 μL, 3 eq) were added, and the mixture was purged with nitrogen gas three times and stirred at 25 ° C for 1 hour. After the reaction was completed, the reaction solution was quenched by adding water (200 mL), the aqueous phase was extracted with dichloromethane (500 mL × 3), the organic phase was combined, the organic phase was washed successively with saturated saline (550 mL × 2), dried over anhydrous sodium sulfate, filtered, 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=1:0-20:1-10:1-5:1) to obtain WX007-8. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 7.21 (s, 2H), 6.57 - 6.55 (d, 1H), 6.25 - 6.23 (m, 1H), 3.97 (s, 3H), 3.80 (s, 2H), 2.78 - 2.69 (m, 4H), 2.13 (s, 6H), 1.82 - 1.80 (m, 2H), 1.27 - 1.21 (m, 3H), 1.08 (m, 18H).

[0115] Step 8: Synthesis of compound WX007-9 WX007-8 (518 mg, 951.09 μmol, 1 eq), WX001-7 (189.61 mg, 1.05 mmol, 175.56 μL, 1.1 eq) and dioxane (10 mL) were added to a pre-dried reaction flask, followed by addition of cesium carbonate (464.83 mg, 1.43 mmol, 1.5 eq). The flask was purged with nitrogen gas three times, and then Xantphos (44.03 mg, 76.09 μmol, 0.08 eq) and Pd 2 (dba) 3 (52.26 mg, 57.07 μmol, 0.06 eq) were added successively, and the mixture was purged with nitrogen gas three times and stirred at 100° C. for 6 hours. After the reaction was completed, the reaction solution was directly filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain WX007-9.

[0116] Step 9: Synthesis of compound WX007-10 WX007-9 (615 mg, 953.55 μmol, 1 eq) and THF (10 mL) were added to a pre-dried reaction flask, HCl (2N, 1.91 mL, 4 eq) was added, and the mixture was purged with nitrogen gas three times and stirred at 25 ° C for 1 hour. After completion of the reaction, the reaction solution was quenched with saturated sodium bicarbonate solution (100 mL), the aqueous phase was extracted with ethyl acetate (100 mL × 3), the organic phase was combined, washed with saturated saline (150 mL × 2), the organic phase was collected, 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 2: 1) to obtain WX007-10. 1 H NMR (400MHz, deuterated chloroform) δ 6.64 - 6.62 (m, 1H), 6.47 - 6.45 (m, 3H), 3.99 (s, 3H), 3.72 (s, 2H), 3.53 (s, 1H), 2.89 - 2.83 (m, 4H), 2.08 (s, 6H), 1.96 - 1.95(m, 2H).

[0117] Step 10: Synthesis of compound WX007 A solution of WX001-10 (32.96 mg, 221.94 μmol, 0.8 eq) in THF (1 mL) was added to a dried reaction flask, and WX007-10 (90 mg, 277.42 μmol, 1 eq) was dissolved in THF (1 mL) and then added to the reaction flask, and TEA (84.22 mg, 832.27 μmol, 115.84 μL, 3 eq) was added and stirred at 20 ° C for 1 hour. After the reaction was completed, the reaction solution was added to water (5 mL), and ethyl acetate (5 mL) was added to extract, separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (5 mL × 2), the organic phase was combined, the organic phase was washed successively with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile%: 35%-55%, 8 min) to obtain a column chromatography solution, extracted with column chromatography solution, collected the organic phase, dried the organic phase over anhydrous sodium sulfate, filtered, and concentrated the filtrate under reduced pressure to obtain WX007. 1 H NMR (400MHz, deuterated methanol) δ 7.41 (s, 2H), 6.51 (d, J = 8.5 Hz, 1H), 6.32 (d, J = 8.6 Hz, 1H), 3.98 (s, 3H), 3.85 (s, 2H), 2.92 - 2.85 (m, 4H), 2.16 (s, 6H), 1.97 - 1.91 (m, 2H); MS-ESI m / z:437.2 [M + H] +.

[0118] Example 7 [ka] Synthesis scheme: [ka] [ka]

[0119] Step 1: Synthesis of compound WX008-4 WX007-2 (113 g, 696.74 mmol, 1 eq) and DMF (1050 mL) were added to a pre-dried reaction flask, WX008-3 (214.50 g, 1.25 mol, 148.96 mL, 1.8 eq) and potassium carbonate (173.33 g, 1.25 mol, 1.8 eq) were added, and the mixture was purged with nitrogen gas three times and stirred at 25 ° C for 16 hours. After the reaction was completed, water (1000 mL) was added to the reaction system, followed by extraction with methyl tert-butyl ether (500 mL × 3), and the organic phases were combined after separation. The organic phase was washed with saturated saline (500 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure with a water pump at 50 ° C to obtain a crude product as a pale yellow solid. The crude product was separated and purified by flash column chromatography (silica gel mesh: 100-200 mesh; petroleum ether:ethyl acetate=1:0-100:2) to obtain WX008-4.

[0120] Step 2: Synthesis of compound WX008-5 WX008-4 (90 g, 356.71 mmol, 1 eq) and MeOH (900 mL) were added to a pre-dried reaction flask, and sodium borohydride (16.19 g, 428.05 mmol, 1.2 eq) was slowly added at 0 °C, and stirring was continued for 0.5 h at 0 °C. After completion of the reaction, the reaction solution was quenched with saturated ammonium chloride solution (900 mL), ethyl acetate (900 mL) was added, separated, the aqueous phase was extracted with ethyl acetate (900 mL x 2), the organic phase was combined, washed with saturated brine (900 mL x 2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by flash column chromatography (petroleum ether:ethyl acetate = 1:0 to 100:1) to obtain WX008-5. 1H NMR (400MHz, deuterated chloroform) δ 7.48 - 7.32 (m, 5H), 7.16 (t, J = 8.0 Hz, 1H), 6.80 (dd, J = 8.1, 10.1 Hz, 2H), 5.20 - 5.08 (m, 3H), 3.10 (s, 1H), 2.88 - 2.77 (m, 1H), 2.75 - 2.63 (m, 1H), 2.10 - 1.98 (m, 1H), 1.98 - 1.88 (m, 2H), 1.80 - 1.70 (m, 1H).

[0121] Step 3: Synthesis of compound WX008-7 WX008-5 (20 g, 78.64 mmol, 1 eq) and THF (200 mL) were added to a pre-dried reaction flask, and sodium hydride (12.58 g, 314.56 mmol, 60% content, 4 eq) was slowly added at 0° C., and stirring was continued at 0° C. for 0.5 h. WX008-6 (36.80 g, 235.92 mmol, 18.87 mL, 3 eq) was added dropwise at 0° C., and stirring was continued at 0° C. for 0.5 h. The temperature was raised to 25° C., and stirring was continued for 15 h. After the reaction was completed, the reaction solution was quenched with water (100 mL), the aqueous phase was extracted with ethyl acetate (100 mL×3), the organic phase was combined, washed with saturated brine (100 mL×3), the organic phase was collected, 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=1:0-20:1-10:1-5:1) to obtain WX008-7. 1H NMR (400MHz, deuterated chloroform) δ 7.48 - 7.39 (m, 2H), 7.33 - 7.37 (m, 3H), 7.14 - 7.12 (m, 1H), 6.76 - 6.72 (m, 2H), 5.14 - 5.05 (m, 2H), 4.72 - 4.70 (m, 1H), 3.68 - 3.64 (m, 1H), 3.52 - 3.48 (m, 1H), 2.86 - 2.81 (m, 1H), 2.71 - 2.68 (m, 1H), 2.24 - 2.23 (m, 1H), 2.21 - 2.20 (m, 1H), 1.74 - 1.73 (m, 1H), 1.54 - 1.51 (m, 1H), 1.17 - 1.13 (m, 3H).

[0122] Step 4: Synthesis of compound WX008-8 Ethyl acetate (300 mL) and Pd / C (2 g, 10% content) were added to a pre-dried reaction flask, and WX008-7 (14.36 g, 50.85 mmol, 1 eq) was added. The mixture was purged with hydrogen gas three times, placed under a hydrogen gas environment at 15 psi pressure, and stirred at 25°C for 16 hours. After completion of the reaction, the reaction solution was filtered through diatomaceous earth and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0-20:1-10:1) to obtain WX008-8. 1 H NMR (400MHz, deuterated chloroform) δ 8.33 (s, 1H), 7.11 - 7.07 (m, 1H), 6.73 - 6.71 (m, 1H), 6.65 - 6.63 (m, 1H), 4.91 - 4.88 (m, 1H), 3.80 - 3.76 (m, 1H), 3.63 - 3.59 (m, 1H), 2.79 - 2.76 (m, 1H), 2.71 - 2.69 (m, 1H), 2.25 (m, 1H), 1.92 - 1.91 (m, 2H), 1.86 - 1.72 (m, 1H), 1.34 - 1.30 (m, 3H).

[0123] Step 5: Synthesis of compound WX008-10 WX008-8 (6.35 g, 33.03 mmol, 1 eq) and DCM (120 mL) were added to a pre-dried reaction flask, purged with hydrogen gas three times, 2,6-lutidine (8.85 g, 82.57 mmol, 9.62 mL, 2.5 eq) was slowly added dropwise, and then WX008-9 (20.24 g, 66.06 mmol, 17.76 mL, 2 eq) was added dropwise and stirred at 25 ° C for 16 hours. After the reaction was completed, the reaction solution was quenched by adding water (120 mL), the aqueous phase was extracted with dichloromethane (150 mL × 3), the organic phase was combined, washed with saturated brine (100 mL × 2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0-20:1-10:1) to obtain WX008-10. 1 H NMR (400MHz, deuterated chloroform) δ 7.04 - 7.00 (m, 1H), 6.68 - 6.63 (m, 2H), 4.78 - 4.77 (m, 1H), 3.72 - 3.68 (m, 1H), 3.52 - 3.48 (m, 1H), 2.84 (m, 1H), 2.70 - 2.68 (m, 1H), 2.31 - 2.28 (m, 1H), 2.10 (m, 1H), 1.69 (m, 1H), 1.47 (m, 1H), 1.36 - 1.34 (m, 3H), 1.21 - 1.19 (m, 3H), 1.17 - 1.12 (m, 18H).

[0124] Step 6: Synthesis of compound WX008-11 WX008-10 (11 g, 31.56 mmol, 1 eq) and acetonitrile (220 mL) were added to a pre-dried reaction flask, NBS (6.18 g, 34.71 mmol, 1.1 eq) was added, and the mixture was purged with nitrogen gas three times and stirred at 25 ° C for 2 hours. After the reaction was completed, the reaction solution was quenched by adding water (50 mL), the aqueous phase was extracted with ethyl acetate (60 mL × 3), the organic phase was combined, washed with saturated saline (100 mL × 2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1: 0 to 20: 1 to 10: 1) to obtain WX008-11. 1 H NMR (400MHz, deuterated chloroform) δ 7.31 - 7.29 (m, 1H), 6.58 - 6.56 (m, 1H), 4.77 - 4.75 (m, 1H), 3.72 - 3.68 (m, 1H), 3.51 - 3.47 (m, 1H), 2.90 - 2.88 (m, 1H), 2.51 (m, 1H), 2.30 - 2.29 (m, 1H), 2.26 (m, 1H), 1.75 (m, 1H), 1.55 (s, 1H), 1.44 - 1.32 (m, 3H), 1.21 - 1.18 (m, 3H), 1.17 - 1.11 (m, 18H).

[0125] Step 7: Synthesis of compound WX008-12 WX008-11 was added to a dried reaction flask, THF (20 mL) was added, and the mixture was replaced with nitrogen gas. The mixture was then cooled to -78°C, n-BuLi (2.5 M, 2.06 mL, 1.1 eq) was added dropwise, and the mixture was reacted at -78°C for 1 hour. WX001-4 in THF (10 mL) was added, and the mixture was reacted at -78°C for 1 hour. After the reaction was completed, the reaction solution was quenched by adding 20 mL of saturated ammonium chloride solution, and 30 mL of ethyl acetate was added for extraction. After separation, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed successively with saturated saline (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified using an automatic column chromatography apparatus (petroleum ether: ethyl acetate = 1:0 to 5:1) to obtain WX008-12.

[0126] Step 8: Synthesis of compound WX008-13 WX008-12 (680 mg, 1.21 mmol, 1 eq) and dioxane (7 mL) were added to a reaction flask, followed by WX001-7 (241.36 mg, 1.33 mmol, 223.48 μL, 1.1 eq) and cesium carbonate (591.70 mg, 1.82 mmol, 1.5 eq). After replacing with nitrogen gas, Pd 2 (dba) 3 (49.89 mg, 54.48 μmol, 0.045 eq), Xantphos (31.52 mg, 54.48 μmol, 0.045 eq) were added, and the atmosphere was replaced with nitrogen gas three times. The temperature was then raised to 100°C and the mixture was stirred for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified using an automatic column chromatography apparatus (petroleum ether: ethyl acetate = 1:0 to 5:1) to obtain WX008-13.

[0127] Step 9: Synthesis of compound WX008-14 WX008-13 (470 mg, 709.99 μmol, 1 eq) and THF (8 mL) were added to a pre-dried reaction flask, which was then purged with nitrogen gas three times and cooled to 0°C. Dilute hydrochloric acid (2 M, 354.99 μL, 1 eq) was then added and stirred at 20°C for 0.5 hours. After completion of the reaction, the pH of the reaction solution was adjusted to about 7 with saturated sodium bicarbonate solution, the aqueous phase (10 mL x 3) was extracted with ethyl acetate, the organic phase was combined, washed with saturated saline (10 mL x 2), the organic phase was collected, 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 an automatic column chromatography apparatus (petroleum ether:ethyl acetate = 1:0 to 3:1 to 2:1) to obtain WX008-14.

[0128] Step 10: Synthesis of compound WX008-15 A pre-dried reaction flask was purged with argon gas, Pd / C (10 mg, 10% content) was added, ethyl acetate (18 mL), glacial acetic acid (2 mL), WX008-14 (175 mg, 351.56 μmol, 1 eq) was added, and the mixture was replaced with hydrogen gas and stirred at 25°C and 15 psi for 4 hours. After the reaction was completed, 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 directly used in the next reaction. WX008-15 was obtained. 1H NMR (400 MHz, deuterated chloroform) δ 6.50 - 6.44 (m, 3H), 6.27 (d, J = 8.3 Hz, 1H), 4.81 (s, 1H), 3.77 - 3.73 (m, 1H), 3.73 - 3.68 (m, 1H), 3.65 (s, 1H), 3.59 (s, 1H), 3.56 - 3.51 (m, 1H), 2.92 (dd, J = 5.8, 17.2 Hz, 1H), 2.58 (ddd, J = 6.7, 11.6, 17.7 Hz, 1H), 2.37 - 2.26 (m, 1H), 2.17 - 2.09 (m, 1H), 2.07 (s, 6H), 1.89 - 1.76 (m, 1H), 1.30 - 1.26 (m, 3H), 1.22 (t, J = 7.1 Hz, 3H), 1.11 (dd, J = 7.5, 11.2 Hz, 18H).

[0129] Step 11: Synthesis of compound WX008-16 WX008-15 (260 mg, 539.66 μmol, 1 eq) and THF (0.3 mL) were added to a dried reaction flask, a solution of WX001-10 (120.21 mg, 809.49 μmol, 1.5 eq) in THF (0.3 mL) was added, triethylamine (163.82 mg, 1.62 mmol, 225.34 μL, 3 eq) was added, and the mixture was stirred at 20 ° C for 1 hour. After the reaction was completed, the reaction solution was quenched by adding 10 mL of saturated sodium bicarbonate solution, extracted by adding 30 mL of ethyl acetate, and the organic phase was collected after separation, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed successively with saturated brine (20 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 using an automatic column chromatography system (petroleum ether:ethyl acetate=1:0 to 2:1) to obtain WX008-16. 1H NMR (400 MHz, deuterated chromium) δ 8.49 (br s, 1H), 7.23 (br s, 2H), 6.42 (br d, J = 8.4 Hz, 1H), 6.16 (br d, J = 8.4 Hz, 1H), 4.78 (br s, 1H), 3.77 - 3.68 (m, 1H), 3.67 - 3.59 (m, 1H), 3.58 - 3.47 (m, 2H), 3.27 (q, J = 7.4 Hz, 1H), 2.89 - 2.79 (m, 1H), 2.29 (br d, J = 12.9 Hz, 2H), 2.10 (br s, 1H), 2.05 (br d, J = 3.1 Hz, 6H), 1.81 (br d, J = 1.6 Hz, 1H), 1.26 (td, J = 3.8, 7.3 Hz, 3H), 1.22 - 1.18 (m, 3H), 1.06 (dd, J = 7.4, 11.6 Hz, 18H).

[0130] ステップ12: Synthesis of compound WX008-17 WX008-16 (270 mg, 454.68 μmol, 1 eq) and THF (0.3 mL) were added to a dried reaction flask, triethylamine trihydrofluoride (366.49 mg, 2.27 mmol, 370.57 μL, 5 eq) was added, and the mixture was purged with nitrogen gas three times and stirred at 50 ° C for 12 hours. After completion of the reaction, the reaction system was cooled to room temperature, quenched by adding 30 mL water to the reaction solution, extracted by adding 20 mL ethyl acetate, separated, and the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed successively with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was mixed with dichloromethane and ethyl acetate in an inverted bottle, and found to have low solubility. It was dissolved in a small amount of methanol, and the resulting solution was concentrated and spun dry, and detection revealed that ethoxy had been converted to methoxy. The crude product was purified by (column: Phenomenex C18 80×40 mm×3 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile%: 25%-45%, 8 min) to obtain WX008-17.

[0131] Step 13: Synthesis of compounds WX008 and WX009 WX008-17 (60 mg, 101.04 μmol) was separated by chiral separation (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: A: carbon dioxide B: [0.1% aqueous ammonia-ethanol]; B%: 35%-35%, 14 min) to give WX008 and WX009. Detection by chiral method (method: column Chiralpak AD-3, 50 × 4.6 mm ID, 3 μm; mobile phase: A: carbon dioxide B: ethanol (0.1% IPAm, v / v), flow rate: 2.5 mL / min; column temperature: 35 °C; pressure: 2000 psi) showed WX008 (ee% = 98.64%, retention time 3.482 min) and WX009 (ee% = 97.98%, retention time 3.831 min). The product WX009 was further purified by (column: Phenomenex C18 75×30 mm×3 μm; mobile phase: [water (aqueous ammonia + ammonium bicarbonate)-acetonitrile]; acetonitrile %: 15%-45%, 8 min) to obtain WX009.

[0132] WX008: 1 H NMR (400 MHz, deuterated methanol) δ 7.41 (s, 2H), 6.44 (d, J = 8.1 Hz, 1H), 6.19 (d, J = 8.6 Hz, 1H), 4.67 (t, J = 3.2 Hz, 1H), 3.86 - 3.67 (m, 2H), 3.47 (s, 3H), 2.97 - 2.87 (m, 1H), 2.67 - 2.54 (m, 1H), 2.29 - 2.22 (m, 1H), 2.14 (s, 6H), 2.03 - 1.94 (m, 1H), 1.91 - 1.84 (m, 1H), 1.65 - 1.55 (m, 1H). WX009: 1H NMR (400 MHz, deuterated methanol) δ 7.42 (s, 2H), 6.45 (d, J = 8.3 Hz, 1H), 6.20 (d, J = 8.3 Hz, 1H), 4.67 (t, J = 2.8 Hz, 1H), 3.86 - 3.66 (m, 2H), 3.47 (s, 3H), 2.98 - 2.86 (m, 1H), 2.61 (ddd, J = 6.2, 11.4, 17.6 Hz, 1H), 2.32 - 2.20 (m, 1H), 2.14 (s, 6H), 2.05 - 1.96 (m, 1H), 1.92 - 1.80 (m, 1H), 1.66 - 1.55 (m, 1H).

[0133] Example 8 [ka] Synthesis scheme: [ka] [ka]

[0134] Step 1: Synthesis of compound WX010-1 WX008-16 (200 mg, 336.80 μmol, 1 eq), THF (5 mL), and tetrabutylammonium fluoride (1 M, 404.16 μL, 1.2 eq) were added sequentially to a pre-dried reaction flask, purged with nitrogen gas three times, and stirred at 20° C. for 1 hour. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure to obtain the crude product. The crude product was purified by pre-TLC (dichloromethane:methanol=10:1) to obtain WX010-1.

[0135] Step 2: Synthesis of compounds WX010-2-1 and WX010-2-2 WX010-1 (70 mg, 160.00 μmol, 1 eq) and pyridine (2 mL) were added to a pre-dried reaction flask, and acetic anhydride (245.02 mg, 2.40 mmol, 224.79 μL, 15 eq) was added and stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was adjusted to pH 4-5 with 0.5 N hydrochloric acid, extracted with dichloromethane (5 mL), the organic phase was collected, the aqueous phase was extracted with dichloromethane (5 mL × 2), the organic phase was combined, the organic phase was washed successively with 0.5 M hydrochloric acid (10 mL × 2), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Next, WX010-2-1 and WX010-2-2 were obtained by separation and purification using supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: A: carbon dioxide B: [0.1% aqueous ammonia-ethanol]; B%: 25% to 25%, 11 min). Detection was performed using a chiral method (column: Chiralpak AD-3, 150 × 4.6 mm ID, 3 μm; mobile phase: A: carbon dioxide B: methanol (0.1% IPAm, v / v), flow rate: 2.5 mL / min; column temperature: 35 °C; pressure: 2000 psi). WX010-2-1 showed a retention time of 2.893 min and an ee% of 100%; WX010-2-2 showed a retention time of 3.190 min and an ee% of 91.06%.

[0136] Step 3: Synthesis of compounds WX010 and WX011 WX010-2-1 (16 mg, 33.37 μmol, 1 eq) and MeOH (4 mL) were added in sequence to a pre-dried reaction flask, potassium carbonate (9.22 mg, 66.73 μmol, 2 eq) was added, and the mixture was purged with nitrogen gas three times and stirred at 20 ° C for 4 hours. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (column: Phenomenex C18 75 × 30 mm × 3 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile %: 25% to 55%, 8 min) to obtain WX010. 1H NMR (400MHz, deuterated methanol) δ 7.42 (s, 2H), 6.44 (d, J = 8.3 Hz, 1H), 6.19 (d, J = 8.1 Hz, 1H), 4.78 (t, J = 2.9 Hz, 1H), 3.85 - 3.75 (m, 2H), 3.75 - 3.67 (m, 2H), 2.98 - 2.88 (m, 1H), 2.68 - 2.56 (m, 1H), 2.26 - 2.18 (m, 1H), 2.16 - 2.12 (m, 6H), 2.08 - 1.99 (m, 1H), 1.92 - 1.83 (m, 1H), 1.68 - 1.58 (m, 1H), 1.21 (t, J = 7.0 Hz, 3H);MS-ESI m / z: 436.2 [MH] + .

[0137] WX010-2-2 (10.00 mg, 20.85 μmol, 1 eq) and MeOH (2.5 mL) were added in sequence to a pre-dried reaction flask, potassium carbonate (5.76 mg, 41.71 μmol, 2 eq) was added, and the mixture was purged with nitrogen gas three times and stirred at 20 ° C for 4 hours. After completion of the reaction, the reaction solution was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (column: Phenomenex C18 75 × 30 mm × 3 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile %: 25% to 55%, 8 min) to obtain WX011. 1H NMR (400 MHz, deuterated metal) δ 7.42 (s, 2H), 6.44 (d, J = 8.4 Hz, 1H), 6.19 (d, J = 8.4 Hz, 1H), 4.78 (t, J = 3.1 Hz, 1H), 3.84 - 3.76 (m, 2H), 3.74 - 3.68 (m, 2H), 3.00 - 2.87 (m, 1H), 2.69 - 2.55 (m, 1H), 2.25 - 2.19 (m, 1H), 2.14 (s, 6H), 2.07 - 2.00 (m, 1H), 1.93 - 1.82 (m, 1H), 1.67 - 1.59 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H); MS-ESI m / z: 436.1 [MH] - .

[0138] Example 9

change

change

change

[0139] ステップ1: Synthesis of compound WX012-1 WX008-11 (5 g, 11.70 mmol, 1 eq) and THF (100 mL) were added to a pre-dried reaction flask, and the flask was purged with nitrogen gas three times. DMF (3.42 g, 46.78 mmol, 3.60 mL, 4 eq) was slowly added dropwise at -78 ° C. and stirred at -78 ° C. for 0.5 hours. Then, n-butyllithium (2.5 M, 5.15 mL, 1.1 eq) was added dropwise at -78 ° C. and stirring was continued at -78 ° C. for 1 hour. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution (20 mL), and then ethyl acetate (20 mL) was added and separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (20 mL × 2), the organic phase was combined, washed successively with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0-20:1-10:1-5:1) to obtain WX012-1. 1 H NMR (400MHz, deuterated chloroform) δ 10.107 (s, 1H), 7.66 - 7.63 (m , 1H), 6.80 - 6.78 (m, 1H), 4.79 (s, 1H), 3.74 - 3.71 (m, 1H), 3.54 - 3.48 (m, 1H), 2.94 (m, 1H), 2.34 (m, 1H), 2.05 (m, 1H), 1.80 (m, 1H), 1.55 (s, 1H), 1.45 - 1.39 (m, 3H), 1.37 - 1.35 (m, 3H), 1.22 - 1.19 (m, 18H).

[0140] Step 2: Synthesis of compound WX012-2 WX012-1 (1 g, 2.66 mmol, 1 eq) and DCM (10 mL) were added to a pre-dried reaction flask, followed by m-chloroperbenzoic acid (1.13 g, 6.55 mmol, 2.47 eq), purged with nitrogen gas three times, and continued stirring at 25° C. for 16 h. After completion of the reaction, the reaction solution was quenched by adding saturated sodium bicarbonate solution (20 mL), stirred for 30 minutes, then added dichloromethane (20 mL) to separate, the organic phase was collected, the aqueous phase was extracted with dichloromethane (20 mL x 2), the organic phase was combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the intermediate, the intermediate (1 g, 2.66 mmol, 1 eq), DCM (5 mL) and MeOH (5 mL) were added to a pre-dried reaction flask, TEA (1.42 g, 14.07 mmol, 1.96 mL, 5.3 eq) was added, purged with nitrogen gas three times, and stirring was continued at 25 ° C for 40 minutes. After completion of the reaction, the reaction solution was diluted with dichloromethane (10 mL), then washed with 2N hydrochloric acid (10 mL), the organic phase was collected, the organic phase was washed with saturated sodium bicarbonate solution (10 mL), washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0-20:1-10:1-5:1) to obtain WX012-2. 1 H NMR (400MHz, deuterated chloroform) δ 6.56 - 6.55 (m, 2H), 4.76 - 4.75 (s , 1H), 4.34 (s, 1H), 3.73 - 3.69 (m, 1H), 3.53 - 3.49 (m, 1H), 2.77 (m, 1H), 2.46 - 2.44 (m, 1H), 2.29 - 2.26 (m, 1H), 2.06 (m, 1H), 1.75 (m, 1H), 1.55 (s, 1H), 1.42 - 1.31 (m, 3H), 1.22 - 1.20 (m, 3H), 1.18 - 1.11 (m, 18H).

[0141] Step 3: Synthesis of compound WX012-4 WX012-2 (690 mg, 1.89 mmol, 1 eq) and DMF (14 mL) were added to a pre-dried reaction flask, potassium carbonate (392.34 mg, 2.84 mmol, 1.5 eq) was added, the mixture was purged with nitrogen gas three times, and the mixture was stirred at 25 ° C for 0.5 hours, WX012-3 (516.63 mg, 2.46 mmol, 1.3 eq) was slowly added, the mixture was purged with nitrogen gas three times, and the mixture was stirred at 100 ° C for 15.5 hours. After the reaction was completed, the mixture was quenched with water (30 mL), separated, the aqueous phase was extracted with ethyl acetate (50 mL × 3), the organic phase was combined, washed with saturated saline (100 mL × 3), the organic phase was collected, 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=1:0-10:1-5:1) to obtain WX012-4. 1 H NMR (400MHz, deuterated chloroform) δ 8.31(m, 1H), 8.28 (m, 2H), 6.03 - 6.01 (m, 1H), 5.97- 5.95 (m, 1H), 4.90 (s, 1H), 3.85 - 3.81 (m, 1H), 3.73 - 3.69 (m, 1H), 3.23 - 3.18 (m, 1H), 2.72 - 2.71 (m, 1H), 2.37 - 2.33 (m, 1H), 2.15 (m, 1H), 1.95 - 1.94 (m, 1H), 1.70 - 1.68 (m, 1H), 1.29 - 1.26 (m, 3H).

[0142] Step 4: Synthesis of compounds WX012-5-1 and WX012-5-2 WX012-4 (500 mg, 1.26 mmol, 1 eq) was taken and purified by supercritical chromatography (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: A: carbon dioxide B: [0.1% aqueous ammonia + isopropanol]; B%: 30% to 30%, 10 min) to obtain WX012-5-1 and WX012-5-2. Detected by chiral method (Instrument: CAS-TJ-ANA-SFC-H (Waters UPCC with SQ Detector 2); Column: Chiralpak AD-3, 50×4.6 mm ID, 3 μm; Mobile phase: A: food grade supercritical carbon dioxide; B: isopropanol (0.1% isopropylamine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 min, maintained for 1 min, then increased from 50% to 5% in 0.4 min; Flow rate: 3.4 mL / min; Column temperature: 35° C.; Detection wavelength: 220 nm; System back pressure: 100 ba.) WX012-5-1 had a retention time of 1.197, ee% was 100%; WX012-5-2 had a retention time of 1.295, ee% was 98.56%. WX012-5-1: 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 8.52 (s, 2H), 8.50 - 8.48 (m, 1H), 6.29 - 6.21 (m, 1H), 6.19 - 6.14 (m, 1H), 4.80 (s, 1H), 3.82 - 3.68 (m, 1H), 3.65 - 3.52 (m, 1H), 3.06 (br dd, J = 3.1, 17.8 Hz, 1H), 2.74 - 2.64 (m, 1H), 2.33 (td, J = 1.8, 3.6 Hz, 1H), 2.29 - 2.18 (m, 1H), 1.99 - 1.79 (m, 1H), 1.69 - 1.54 (m, 1H), 1.14 (t, J = 7.0 Hz, 3H). WX012-5-2: 1H NMR (400MHz, deuterated dimethyl sulfoxide) δ 8.51 (s, 2H), 8.51 - 8.47 (m, 1H), 6.29 - 6.21 (m, 1H), 6.20 - 6.11 (m, 1H), 4.80 (s, 1H), 3.83 - 3.69 (m, 1H), 3.60 (dd, J = 7.1, 8.9 Hz, 1H), 3.06 (br dd, J = 3.4, 17.9 Hz, 1H), 2.72 - 2.59 (m, 1H), 2.35 - 2.21 (m, 1H), 1.97 - 1.80 (m, 2H), 1.67 - 1.56 (m, 1H), 1.14 (t, J = 6.9 Hz, 3H).

[0143] Step 5: Synthesis of compounds WX012-6-1 and WX012-6-2 WX012-5-1, glacial acetic acid (1 mL), isopropanol (2 mL), and water (1 mL) were added to a pre-dried reaction flask, and iron powder (98.17 mg, 1.76 mmol, 7 eq) was slowly added in batches at 50°C. The mixture was purged with nitrogen gas three times and stirred at 90°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, the pH of the concentrate was adjusted to 7-8 with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (10 mL x 3), and the organic phase was combined; the organic phase was washed successively with saturated saline (20 mL x 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 pre-TLC (petroleum ether: ethyl acetate = 1:1) to obtain WX012-6-1. 1H NMR (400MHz, deuterated dimethyl sulfoxide) δ 6.67 (s, 2H), 6.15 - 6.07 (m, 1H), 6.05 - 5.96 (m, 1H), 5.58 (s, 2H), 4.76 (br s, 1H), 3.78 - 3.66 (m, 1H), 3.65 - 3.55 (m, 1H), 3.00 (br dd, J = 4.3, 18.0 Hz, 1H), 2.70 - 2.57 (m, 1H), 2.24 - 2.11 (m, 1H), 1.93 - 1.72 (m, 2H), 1.59 - 1.46 (m, 1H), 1.12 (t, J = 7.0 Hz, 3H).

[0144] WX012-5-2 (150 mg, 376.66 μmol, 1 eq) and glacial acetic acid (1.5 mL), isopropanol (3 mL), and water (1.5 mL) were added to a pre-dried reaction flask, and iron powder (147.26 mg, 2.64 mmol, 7 eq) was slowly added in batches at 50 °C, purged with nitrogen gas three times, and stirred at 90 °C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, the pH of the concentrate was adjusted to 7-8 with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (10 mL × 3), and the organic phase was combined; the organic phase was washed successively with saturated saline (20 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 pre-TLC (petroleum ether: ethyl acetate = 1:1) to obtain WX012-6-2. 1H NMR (400MHz, deuterated dimethyl sulfoxide) δ 6.67 (s, 2H), 6.19 - 6.07 (m, 1H), 6.05 - 5.96 (m, 1H), 5.58 (s, 2H), 4.76 (br s, 1H), 3.79 - 3.52 (m, 2H), 3.00 (br dd, J = 3.9, 17.8 Hz, 1H), 2.69 - 2.53 (m, 1H), 2.18 (br d, J = 12.8 Hz, 1H), 1.95 - 1.73 (m, 2H), 1.61 - 1.47 (m, 1H), 1.17 - 1.05 (m, 3H).

[0145] Step 6: Synthesis of compounds WX012 and WX013 A solution of WX001-10 (48.39 mg, 325.86 μmol, 1.5 eq) in THF (1.6 mL) was added to a dried reaction flask, and WX012-6-1 (80 mg, 217.24 μmol, 1 eq) was dissolved in THF (1 mL) and then added to the reaction flask, and TEA (65.95 mg, 651.72 μmol, 90.71 μL, 3 eq) was added and stirred at 20 ° C for 1 hour. After the reaction was completed, the reaction solution was added to water (5 mL), and ethyl acetate (5 mL) was added to extract, separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (5 mL × 2), the organic phase was combined, the organic phase was washed successively with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile %: 20% to 65%, 10 min) to obtain WX012. 1H NMR (400MHz, deuterated methanol) δ 7.94 (br s, 2H), 6.21 - 6.14 (m, 1H), 6.13 - 6.06 (m, 1H), 5.00 (br s, 1H), 3.92 - 3.78 (m, 2H), 3.22 (br dd, J = 5.0, 17.9 Hz, 1H), 2.73 (ddd, J = 6.0, 11.9, 18.2 Hz, 1H), 2.40 - 2.31 (m, 1H), 2.13 - 1.91 (m, 2H), 1.76 - 1.63 (m, 1H), 1.31 - 1.22 (m, 3H).

[0146] A solution of WX001-10 (66.54 mg, 448.06 μmol, 1.5 eq) in THF (2 mL) was added to a dried reaction flask, and WX012-6-2 (110 mg, 298.71 μmol, 1 eq) was dissolved in THF (1 mL) and then added to the reaction flask, and TEA (90.68 mg, 896.12 μmol, 124.73 μL, 3 eq) was added and stirred at 20 ° C for 1 hour. After the reaction was completed, the reaction solution was added to water (5 mL), and ethyl acetate (5 mL) was added to extract, separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (5 mL × 2), the organic phase was combined, the organic phase was washed successively with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile %: 20% to 65%, 10 min) to obtain WX013. 1H NMR (400MHz, deuterated methanol) δ 7.94 (br s, 2H), 6.22 - 6.15 (m, 1H), 6.12 - 6.12 (m, 1H), 6.15 - 6.09 (m, 1H), 5.00 (br s, 1H), 3.92 - 3.77 (m, 2H), 3.22 (br dd, J = 4.5, 18.1 Hz, 1H), 2.73 (ddd, J = 6.3, 11.9, 18.0 Hz, 1H), 2.43 - 2.29 (m, 1H), 2.14 - 1.91 (m, 2H), 1.77 - 1.63 (m, 1H), 1.31 - 1.24 (m, 3H).

[0147] Biological testing Experiment 1: Activation test of the compounds of the present invention against thyroid hormone receptors at the cellular level Experimental principle: In this experiment, the GeneBLAzer® TR alpha / beta-UAS-bla HEK 293T Cell-based Assay method developed by ThermoFisher was used. The principle is: TR alpha-UAS-bla HEK 293T Cell and TR beta-UAS-bla HEK 293T Cell expresses β-lactamase, and the reporter gene is controlled by 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, and activates β-lactamase expression using the GAL4-UAS system to decompose the substrate CCF4-AM (coumarin). The product emits fluorescence at a wavelength of 447 nm when excited at 409 nm, but when β-lactamase is not expressed, it emits fluorescence at a wavelength of 520 nm through FRET under excitation at 409 nm. The binding state of the compound to the protein can be determined by detecting the ratio of the two fluorescences (447 nm / 520 nm), and the EC 50 can be calculated.

[0148] Testing Method: Using an ECHO liquid handling workstation, compounds were transferred to 384-well plates with 10 gradient concentrations, 3-fold dilutions, and replicate wells for each compound. 4 Cell (TR beta-UAS-bla HEK 293T Cell) or 1.0×10 4 Cells (TR alpha-UAS-bla HEK 293T Cell) were seeded in a 384-well plate. HEK 293T-TR beta was cultured in a 37°C incubator for 16 hours, and HEK 293T-TR alpha was cultured for 22 hours. LiveBLAzer™-FRET B / G (CCF4-AM) substrate was added to the cell plate and cultured at room temperature in the dark for 2 hours. The fluorescence value of the product emitted at wavelengths of 460 nm / 530 nm under excitation at 409 nm was detected using a Flexstation3 instrument, and the EC of the compound was calculated using Graphpad Prism software by detecting the ratio of the two fluorescence (460 nm / 530 nm). 50 was calculated. In each experiment, the reference compound triiodothyronine (T3) was used as a positive control. The Z factor (>0.5) was calculated to monitor the stability of each experiment.

[0149] [Table 1] Conclusion: The compounds of the present invention have significant THRβ activity and selectivity.

[0150] Experiment 2: Inhibition studies of cytochrome P450 isozymes Purpose of the test: The objective of the present invention is to determine the inhibitory effect of the test compound WX001 on the activity of human hepatic microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4).

[0151] Experimental Procedure: First, the test compound (10.0 mM) was diluted to prepare a working solution (100x final concentration), the concentration of the working solution was 1.00 mM. At the same time, the working solutions of each positive inhibitor of P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (using midazolam as probe substrate) and CYP3A4 (using testosterone as probe substrate)) and its specific probe substrate were prepared, respectively. Human liver microsomes stored in a refrigerator below -60°C were thawed on ice, and after all human liver microsomes were dissolved, they were diluted with PB to prepare a working solution of a given concentration (0.127 mg / ml). First, 20.0 μL of the probe substrate was added to the reaction plate (20.0 μL of PB was added to the blank well), then 158 μL of human liver microsome working solution was added to the reaction plate, and the reaction plate was placed on ice for use; at this time, 2.00 μL of the test compound (N=1) and specific inhibitor (N=2) were added to the corresponding wells, and organic solvent corresponding to the group without inhibitor (test compound or positive inhibitor) was added, and the organic phase of the test compound control sample and the positive control sample were 1:1 DMSO:MeOH and 1:9 DMSO:MeOH, respectively; after incubation in a 37°C water bath for 10 minutes, 20.0 μL of coenzyme factor (NADPH) solution was added to the reaction plate, and in the case of CYP3A4 metabolic reaction with midazolam as the probe substrate, , the reaction time was 3 minutes; for the CYP2C19 reaction using (S)-mephenytoin as the probe substrate and the CYP2D6 reaction using dextromethorphan as the probe substrate, the reaction time was 20 minutes, and all other reactions were 10 minutes; then, 400μL of pre-cooled acetonitrile solution (containing 200ng / mL of tolbutamide and labetalol as internal standards) was added to stop the reaction; , the reaction plate was placed on a shaker and shaken for 10 minutes to mix uniformly; then, it was centrifuged at 4℃ and 4000rpm for 20 minutes; 200μL of the supernatant was taken and added to 100μL of water to dilute the sample. Finally, the plate was sealed, shaken uniformly, and LC / MS / MS detection was performed.

[0152] Test Results: As shown in Table 2. [Table 2] Experimental Conclusion: Compound WX001 shows no inhibitory effect on CYP1A2, CYP2C19, CYP2D6 and CYP3A4, but shows moderate inhibition on CYP2C9.

[0153] Experiment 3: Pharmacokinetic study Pharmacokinetic study of oral and intravenous injection of WX001 in rats Male SD rats were selected and administered the test substances according to Table 3.

[0154] [Table 3]

[0155] Whole blood was collected at a given time and plasma was prepared, and the drug concentration was analyzed by LC-MS / MS method, and pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight, USA). The experimental results are shown in Tables 4 and 5:

[0156] [Table 4]

[0157] [Table 5] Experimental Conclusion: The compounds of the present invention have higher exposure and better oral bioavailability.

[0158] Experiment 4: In vivo pharmacokinetic study Purpose of the test: A rat model induced by a cholesterol and bile acid supplemented diet is used to test the in vivo efficacy of test compounds.

[0159] Testing Method: Male SD rats aged 9-10 weeks were selected and adapted for 3-7 days after arriving at the facility. During the adaptation period, the animals were observed for health every day and fed with normal chow. After the adaptation period, the rats were fed with high cholesterol (1.5% cholesterol and 0.5% bile acid) chow for modeling, while the rats in the blank control group continued to feed with normal chow. After feeding the rats with the high cholesterol diet for 2 weeks, blood was collected and serum was separated to detect LDL-C levels. The high cholesterol model rats were randomly divided into groups according to serum LDL-C levels and orally administered once a day for 7 consecutive days as detailed in Table 6. One week after administration, serum from the rats was collected to detect LDL-C levels and evaluate the efficacy of the drug.

[0160] [Table 6]

[0161] Test Results: As shown in FIG. 4, P<0.05 indicated that there was a statistically significant difference in pharmacodynamic index between the treatment group and the vehicle group. Experimental conclusion: The compounds of the present invention can significantly reduce the plasma LDL-C level in rats. [1] A compound represented by formula (III) or a pharma- ceutically acceptable salt thereof. [ka] (however, Ring B is [ka] is selected from R 1 are independently H, F, Cl, Br, I and C 1-3 alkyl, 1-3 Alkyl is optionally one, two or three R a is replaced by R 2 and R 3 are independently H, F, Cl, Br, I, OH, and NH 2 , C.N.,C. 1-3 Alkyl and C 1-3 alkoxy, 1-3 Alkyl and C 1-3 Alkoxy optionally has one, two or three R b is replaced by R 4 is C 1-3 alkyl-phenyl; L is -O- or -CH 2 - selected from Ring A is phenyl, 5- to 6-membered heteroaryl,

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[10] R 4 teeth,

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[11] Structural Units

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[12] The compound according to any one of the above [1] to

[11] , which is selected from the following formulae, or a pharma- ceutically acceptable salt thereof.

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[11] above.)

[13] The compound according to any one of the above [1] to

[11] , which is selected from the following formulae, or a pharma- ceutically acceptable salt thereof.

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[11] .)

[14] A compound represented by the following formula or a pharma- ceutically acceptable salt thereof:

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[15] The compound according to the above

[14] , which is selected from the following formulas, or a pharma- ceutically acceptable salt thereof.

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[16] Use of the compound according to any one of the above-mentioned [1] to

[15] or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating nonalcoholic steatohepatitis.

Claims

1. A compound represented by formula (I) or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】 (however, R １ is independently selected from H, F, Cl, Br, and I; R ２ and R ３ are each independently H, F, Cl, Br, I, OH, or NH ２ , C.N., and C. １－３ alkyl, １－３ Alkyl is optionally one, two or three R ｂ is replaced by L is -O- or -CH ２ - selected from Ring A is 【Chemistry 3】 and 【Chemistry 4】 optionally 1, 2 or 3 R ｃ is replaced by m is independently selected from 0, 1 and 2; R ｂ are each independently selected from F, Cl, Br, and I; R ｃ are independently F, Cl, Br, I, ═O, C １－３ Alkyl and C １－３ alkoxy, １－３ Alkyl and C １－３ The alkoxy is optionally substituted with 1, 2 or 3 R, where R is independently selected from F, Cl, Br, and I.

2. R １ is independently selected from H, F, Cl, and Br, or a pharma- ceutically acceptable salt thereof.

3. R ２ and R ３ are each independently H, F, Cl, Br, I, OH, or NH ２ , C.N., and C.H. ３ wherein said CH ３ optionally 1, 2 or 3 R ｂ or a pharma- ceutically acceptable salt thereof.

4. R ２ and R ３ are each independently H, F, Cl, Br, I, OH, or NH ２ , C.N., C.H. ３ , C.H. ２ F, C.H.F. ２ , and C.F. ３ 4. The compound of claim 3, selected from:

5. R ｃ are independently F, Cl, Br, I, ═O, CH ３ , O.C.H. ３ and O.C.H. ２ CH ３ wherein said CH ３ , O.C.H. ３ and O.C.H. ２ CH ３ is optionally substituted by 1, 2 or 3 R, or a pharma- ceutically acceptable salt thereof.

6. R ｃ are independently F, Cl, Br, I, ═O, CH ３ , O.C.H. ３ and O.C.H. ２ CH ３ 6. The compound of claim 5, selected from:

7. Ring A is 【Chemistry 5】 and 【Chemistry 6】 optionally 1, 2 or 3 R ｃ or a pharma- ceutically acceptable salt thereof.

8. Ring A is 【Chemistry 7】 8. The compound of claim 7, selected from:

9. Structural Units 【Chemistry 9】 2. The compound of claim 1, selected from:

10. 2. The compound of claim 1 selected from the following formulas: or a pharma- ceutically acceptable salt thereof. 【Chemistry 10】 (However, R １ , R ２ , R ３ , L, and m are as defined in claim 1.

11. 2. The compound of claim 1 selected from the following formulas: or a pharma- ceutically acceptable salt thereof. 【Chemistry 11】 (however, 【Chemistry 12】 is a single bond, R ｃ are F, Cl, Br, I, C １－３ Alkyl and C １－３ Alkoxy, １－３ Alkyl and C １－３ The alkoxy is optionally substituted with 1, 2 or 3 halogens; 【Chemistry 13】 is a double bond, R ｃ is =O, R １ , R ２ , R ３ , L and m are as defined in claim 1.

12. A compound selected from the formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 14】 【Chemistry 15】

13. 13. The compound of claim 12 selected from the following formulas: or a pharma- ceutically acceptable salt thereof. 【Chemistry 16】 【Chemistry 17】

14. 14. Use of a pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating non-alcoholic steatohepatitis.

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