Bicyclic phenolic compounds and uses thereof

Abstract

A series of phenolic compounds and their applications, specifically discloses compounds represented by formula (III) and pharmaceutically acceptable salts thereof.

Description

[0001] This application is a divisional application of patent application No. 202280016468.2, the filing date of which is March 18, 2022, and the title of which is "Bicyclic phenolic compounds and uses thereof".

[0002] This application claims priority to

[0003] CN202110298570.3, the filing date of which is March 19, 2021;

[0004] CN202110443424.5, the filing date of which is April 23, 2021;

[0005] CN202210107896.8, the filing date of which is January 28, 2022. TECHNICAL FIELD

[0006] The present application relates to a series of bicyclic phenolic compounds and uses thereof, and specifically discloses a compound represented by formula (III) and a pharmaceutically acceptable salt thereof. BACKGROUND

[0007] There are two subtypes of thyroid hormone receptors (THR), THRα and THRβ. In the past decades, various THRβ agonists have been developed for the treatment of metabolic diseases such as dyslipidemia, non-alcoholic fatty liver and non-alcoholic steatohepatitis, for example: GC-1, KB141, KB2115, etc. However, bone and heart side effects hindered further development, for example, KB2115 stopped the third phase of clinical research due to the discovery of cartilage damage in dogs. THRα is mainly distributed in the brain, heart and skeletal muscle, and it can enhance the activity of osteoclasts, causing a decrease in bone density. Therefore, it is believed that these side effects are caused by the activation of the THRα subtype, and it is hoped to avoid it by improving the target selectivity and liver tissue selectivity. Representative varieties of this strategy are MGL-3196 and VK-2809, and their safety and effectiveness have been preliminarily verified through clinical trials. Therefore, it has great clinical value to develop thyroid hormone analogs with high specificity of liver tissue distribution and thyroid hormone receptor subtype selectivity.

[0008] Based on the literature (J. Med. Chem. 2014, 57, 3912-3923), it is reported that the structure of the THRβ agonist MGL-3196 is as follows:

[0009] SUMMARY

[0010] The present application provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,

[0011]

[0012] wherein,

[0013] Ring B is selected from

[0014] R1is independently selected from H, F, Cl, Br, I and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2 or 3 R a ;

[0015] R2and R3are each independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy is optionally substituted with 1, 2 or 3 R b ;

[0016] R4is selected from C 1-3 alkyl-phenyl;

[0017] L is selected from -O- and -CH2-;

[0018] Ring A is selected from phenyl, 5-6 membered heteroaryl, said phenyl, 5-6 membered heteroaryl, optionally substituted with 1, 2 or 3 R c ;

[0019] n and m are each independently selected from 0, 1 and 2;

[0020] R a and R b are each independently selected from F, Cl, Br and I;

[0021] R c is independently selected from F, Cl, Br, I, =O, =N-C 1-3 alkoxy, C 1-3 alkyl and C 1-3 alkoxy, said =N-C 1-3 alkoxy, C 1-3 alkyl and C 1-3 alkoxy is optionally substituted with 1, 2 or 3 halogen.

[0022] In some embodiments of the application, R1is independently selected from H, F, Cl, Br, I and CH3, said CH3is optionally substituted with 1, 2 or 3 Ra, and the other variables are as defined in the application.

[0023] In some embodiments of the application, R1is independently selected from H, F, Cl, Br, I, CH3, and CF3, and the other variables are as defined in the Summary.

[0024] In some embodiments of the application, R2and R3are each independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, and OCH3, said CH3and OCH3are optionally substituted with 1, 2, or 3 R b and the other variables are as defined in the Summary.

[0025] In some embodiments of the application, R2and R3are each independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, CH2F, CHF2, CF3, and OCH3, and the other variables are as defined in the Summary.

[0026] In some embodiments of the application, R c is independently selected from F, Cl, Br, I, =0, =N-0-CH3, =N-0-CH2CH3, CH3, OCH3, and OCH2CH3, said =N-0-CH3, =N-0-CH2CH3, CH3, OCH3, and OCH2CH3are optionally substituted with 1, 2, or 3 halo, and the other variables are as defined in the Summary.

[0027] In some embodiments of the application, R c is independently selected from F, Cl, Br, I, =0, =N-0-CH3, =N-0-CH2CH3, CH3, OCH3, and OCH2CH3, said =N-0-CH3, =N-0-CH2CH3, CH3, OCH3, and OCH2CH3are optionally substituted with 1, 2, or 3 R, and the other variables are as defined in the Summary.

[0028] In some embodiments of the application, R c is independently selected from F, Cl, Br, I, =0, =N-0-CH3, =N-0-CH2CH3, CH3, OCH3, and OCH2CH3, and the other variables are as defined in the Summary.

[0029] In some embodiments of the application, ring A is selected from said is optionally substituted with 1, 2, or 3 R c and the other variables are as defined in the Summary.

[0030] In some embodiments of the application, ring A is selected from and the other variables are as defined in the Summary.

[0031] In some embodiments of the application, R4 is selected from The other variables are as defined in the application.

[0032] In some embodiments of the application, the structural unit is selected from The other variables are as defined in the application.

[0033] The present application provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0034]

[0035] wherein,

[0036] R1 is independently selected from H, F, Cl, Br, I and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2 or 3 R a ;

[0037] R2 and R3 are each independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy is optionally substituted with 1, 2 or 3 R b ;

[0038] L is selected from -O- and -CH2-;

[0039] Ring A is selected from phenyl, 5-6 membered heteroaryl, said phenyl, 5-6 membered heteroaryl, optionally substituted with 1, 2 or 3 R c ;

[0040] n and m are each independently selected from 0, 1 and 2;

[0041] R a and R b are each independently selected from F, Cl, Br and I;

[0042] R c is independently selected from F, Cl, Br, I, =O, =N-C 1-3 alkoxy, C 1-3 alkyl and C 1-3 alkoxy, said =N-C 1-3 alkoxy, C 1-3 alkyl and C 1-3 alkoxy is optionally substituted with 1, 2 or 3 R

[0043] R is independently selected from F, CI, Br, and I.

[0044] In some embodiments of the application, R1is independently selected from H, F, CI, Br, I, and CH3, said CH3being optionally substituted with 1, 2, or 3 R a and the other variables are as defined in the application.

[0045] In some embodiments of the application, R1is independently selected from H, F, CI, Br, I, CH3, and CF3, and the other variables are as defined in the application.

[0046] In some embodiments of the application, R2and R3are each independently selected from H, F, CI, Br, I, OH, NH2, CN, CH3, and OCH3, said CH3and OCH3being optionally substituted with 1, 2, or 3 R b and the other variables are as defined in the application.

[0047] In some embodiments of the application, R2and R3are each independently selected from H, F, CI, Br, I, OH, NH2, CN, CH3, CH2F, CHF2, CF3, and OCH3, and the other variables are as defined in the application.

[0048] In some embodiments of the application, R c is independently selected from F, CI, Br, I, =0, =N-0-CH3, =N-0-CH2CH3, CH3, OCH3, and OCH2CH3, said =N-0-CH3, =N-0-CH2CH3, CH3, OCH3, and OCH2CH3being optionally substituted with 1, 2, or 3 R and the other variables are as defined in the application.

[0049] In some embodiments of the application, R c is independently selected from F, CI, Br, I, =0, =N-0-CH3, =N-0-CH2CH3, CH3, OCH3, and OCH2CH3, and the other variables are as defined in the application.

[0050] In some embodiments of the application, ring A is selected from said being optionally substituted with 1, 2, or 3 R c and the other variables are as defined in the application.

[0051] In some embodiments of the application, ring A is selected from and the other variables are as defined in the application.

[0052] In some embodiments of the present application, the above structural unit is selected from The other variables are as defined in the present application.

[0053] In some embodiments of the present application, the above compound or pharmaceutically acceptable salt thereof is selected from:

[0054]

[0055] wherein,

[0056] R is a single bond, R c is F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted with 1, 2 or 3 halogens;

[0057] R is a double bond, R c is =O and =N-C 1-3 alkoxy, said =N-C 1-3 alkoxy are optionally substituted with 1, 2 or 3 halogens;

[0058] R1, R2, R3, L and m are as defined in the present application.

[0059] In some embodiments of the present application, the above compound or pharmaceutically acceptable salt thereof is selected from:

[0060]

[0061] wherein, R1, R2, R3, L, m and n are as defined in the present application.

[0062] The present application also provides some embodiments of the present application, which are any combination of the above variables.

[0063] The present application also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,

[0064]

[0065]

[0066] In some embodiments of the present application, the above compound or pharmaceutically acceptable salt thereof is selected from:

[0067]

[0068] The present application also provides use of the above-mentioned compound or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-alcoholic steatohepatitis.

[0069] The present application also provides the following synthetic method:

[0070]

[0071] wherein,

[0072] -X-Y-Z- is selected from the group consisting of cyclopentenyl, cyclohexenyl, phenyl, thienyl, thiazolyl, furanyl and oxazolyl;

[0073] R2and R3are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2, CN, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted with 1, 2 or 3 R b ;

[0074] R b are each independently selected from the group consisting of F, Cl, Br and I.

[0075] Definitions and Descriptions

[0076] The following terms and phrases, as used herein, are intended to have the following meanings unless otherwise indicated. A particular term or phrase should not be construed as being indefinite or unclear if not specifically defined, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0077] The term "pharmaceutically acceptable", as used herein, pertains to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0078] The term "pharmaceutically acceptable salt" means a salt of a compound of this application which is found to be suitable for use in pharmaceutical applications, due to the presence of specific substituents on the compounds discovered in this application, with a relatively non-toxic acid or base. When the compounds of this application contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base to provide the salt. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When the compounds of this application contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid to provide the salt. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, nitric, carbonic, boric, sulfuric, sulfamic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, and the like; and organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like; also salts of amino acids such as arginate, gluconate, and the like. Certain specific compounds of this application contain both basic and acidic functionalities, allowing the compounds to be converted into either base or acid addition salts.

[0079] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains an acidic or basic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two.

[0080] The compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as the racemic mixtures and other mixtures of the enantiomers or diastereomers, and all isomeric forms modified by substitution, including compounds having an N-oxide substitution. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are included within the scope of the present application.

[0081] The term "enantiomeric" or "optical isomer" means a stereoisomer that is a mirror image of the other and is not superimposable.

[0082] The term "cis- or trans-isomer" or "geometric isomer" is caused by the inability of a double bond or ring-forming carbon atom single bond to rotate freely.

[0083] The term "diastereomer" means a stereoisomer having two or more chiral centers and which is not a mirror image of the other. Unless otherwise indicated, the term "diastereomer" is intended to encompass any type of stereoisomerism, including, but not limited to, R and S configurations, as well as C and D configurations.

[0084] Unless otherwise indicated, "(+)" means dextrorotary, "(-)" means levorotary, and "(±)" means racemic.

[0085] Unless otherwise indicated, a wedge-shaped solid line bond and a wedge-shaped dashed line bond indicate the absolute configuration of a stereocenter, a straight solid line bond and a straight dashed line bond indicate the relative configuration of a stereocenter, and a wavy line indicates a wedge-shaped solid line bond or a wedge-shaped dashed line bond or a wavy line indicates a straight solid line bond and a straight dashed line bond

[0086] Unless otherwise indicated, when a compound contains a double bond, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom of the double bond is attached to two different substituents (in the case of a double bond containing a nitrogen atom, the pair of unshared electrons on the nitrogen atom is considered to be one substituent), if the atoms of the double bond and their substituents are connected by a wavy line in the compound, it indicates the (Z) isomer, the (E) isomer, or a mixture of the two isomers. For example, the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or formula (A-2), or as a mixture of the two isomers of formula (A-1) and formula (A-2); the following formula (B) indicates that the compound exists as a single isomer of formula (B-1) or formula (B-2), or as a mixture of the two isomers of formula (B-1) and formula (B-2). The following formula (C) indicates that the compound exists as a single isomer of formula (C-1) or formula (C-2), or as a mixture of the two isomers of formula (C-1) and formula (C-2).

[0087]

[0088]

[0089] Unless otherwise stated, the terms "tautomer" or "tautomer form" refer to isomers with different functional groups in dynamic equilibrium at room temperature, capable of rapidly interconverting into each other. Tautomers can be chemically equilibrated if possible (e.g., in solution). For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions involving the rearrangement of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the tautomers pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0090] Unless otherwise stated, the terms "rich in one isomer," "isomer enrichment," "rich in one enantiomer," or "enantiomer enrichment" mean that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0091] Unless otherwise stated, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomer excess (ee value) is 80%.

[0092] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0093] The compounds of the present application can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). For example, deuterium can be substituted for hydrogen to form deuterated drugs, which have advantages over non-deuterated drugs, such as reduced toxicity, increased stability, enhanced efficacy, and increased biological half-life. All isotopic variations of the compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application.

[0094] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0095] The term "substituted" means that any one or more hydrogen atoms on the particular atom is replaced with a substituent group, which can include variations of deuterium and hydrogen, as long as the valency of the particular atom is normal and the resulting compound is stable. When the substituent is oxygen (i.e., =0), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.

[0096] The term "optionally substituted" means that the moiety can or can not be substituted and that the types and number of substituents are any that are chemically possible, unless otherwise specified.

[0097] When any variable (e.g., R) occurs more than one time in a compound, its definition in each instance is independent of the definition of the other occurrences. Thus, for example, if a group is substituted with 0-2 R groups, then the group can optionally be substituted with up to two R groups, and each R group is selected independently of the other. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0098] When the number of occurrences of a linking group is zero, such as -(CRR)0-, it means that the linking group is a single bond.

[0099] When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly connected, such as L represents a single bond in A-L-Z means that the structure is actually A-Z.

[0100] When a substituent is null, it means that the substituent is absent, such as X is null in A-X, which means that the structure is actually A. When a listed substituent does not specify through which atom of the substituent it is attached to the substituted group, the substituent can be bonded through any of its atoms, for example, a pyridyl group as a substituent can be attached to the substituted group through any of the carbon atoms of the pyridyl ring.

[0101] When a listed linking group does not specify its direction of attachment, its direction of attachment is arbitrary, for example, In the case of L is -M-W- in -M-W- can attach ring A and ring B to form -M-W- can attach ring A and ring B to form

[0102] Unless otherwise specified, when a group has one or more available sites for attachment, any one or more of the sites of the group can be attached to other groups by a chemical bond. When the chemical bond is not directional and there is an H atom at the site, the number of H atoms at the site will correspondingly decrease by one for each chemical bond attached to it, becoming a group of the corresponding valence. The chemical bond by which the site is attached to other groups can be represented by a straight solid line bond a straight dashed line bond or a wavy line For example, the straight solid line bond in -OCH3represents attachment to other groups through the oxygen atom in the group; the straight dashed line bond in -NH2represents attachment to other groups through both ends of the nitrogen atom in the group; the wavy line in -Ph represents attachment to other groups through both the 1 and 2 carbon atoms in the phenyl group; represents that any available site on the piperidinyl group can be attached to other groups by one chemical bond, including at least the four ways of attachment, even though H atoms are drawn on -N-, but still include groups of this type of attachment, only when one chemical bond is attached, the H at the site will correspondingly decrease by one to become a corresponding monovalent piperidinyl group.

[0103] Unless otherwise specified, the term "C 1-3 alkyl" is used to mean a straight or branched chain saturated carbon hydride group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0104] Unless otherwise specified, the term "C" 1-3 "Alkoxy" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 C 2-3 C3 and C2 alkoxy groups, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0105] Unless otherwise specified, the terms "5-6 membered heteroaryl" and "5-6 membered heteroaryl" are used interchangeably in this invention. The term "5-6 membered heteroaryl" refers to a monocyclic group with a conjugated π-electron system consisting of 5 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). The 5-6 membered heteroaryl group can be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl group includes both 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), and triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl). (and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), 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 and 4-pyrimidinyl, etc.).

[0106] Unless otherwise specified, C n-n+m Or C n -C n+m This includes any specific case with n to n+m carbons, such as C 1-12Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It also includes any range from n to n+m, such as C 1-12 Including C 1-3 C 1-6 C 1-9 C 3-6 C 3-9 C 3-12 C 6-9 C 6-12 and C 9-12 Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

[0107] The structures of the compounds of this invention can be confirmed by conventional methods well known to those skilled in the art. If this invention relates to the absolute configuration of a compound, that absolute configuration can be confirmed by conventional techniques in the art. For example, single-crystal X-ray diffraction (SXRD) is used, where the cultured single crystal is used to collect diffraction intensity data using a Bruker D8 venture diffractometer with CuKα radiation as the light source. The scanning method is as follows: After collecting relevant data by scanning / ω, the crystal structure can be further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0108] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0109] The solvents used in the present application are commercially available. The following abbreviations are used in the present application: aq stands for water; eq stands for equivalent, equivalent amount; DCM stands for dichloromethane; PE stands for petroleum ether; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; CBz stands for carbobenzyloxy, which is an amine protecting group; BOC stands for tert-butyloxycarbonyl, which is an amine protecting group; r.t. stands for room temperature; O / N stands for overnight; THF stands for tetrahydrofuran; Boc2O 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; Pd2(dba)3 stands for tris(dibenzylideneacetone)dipalladium.

[0110] The compounds are named according to the principles of nomenclature in the art or using software nomenclature, and commercially available compounds are named using the supplier's catalog name.

[0111] Technical effects

[0112] The compounds of the present application have significant THRβ activity and selectivity, no drug-drug interaction; the compounds of the present application have high exposure and good oral bioavailability, and have excellent pharmacokinetic properties; the compounds of the present application can significantly reduce the rat plasma LDL-C level. BRIEF DESCRIPTION OF DRAWINGS

[0113] Figure 1 : Compound A and MGL-3196 binding mode prediction;

[0114] Figure 2 : Compound B and MGL-3196 binding mode prediction;

[0115] Figure 3 : Compound C and MGL-3196 binding mode prediction;

[0116] Figure 4 : Change rate of rat LDL-C after one week of administration relative to rat LDL-C before administration. DETAILED DESCRIPTION

[0117] The present application is described in detail below by way of examples, but it does not mean any unfavorable limitation of the present application. The present application has been described in detail herein, and specific implementation manners thereof are also disclosed, and it will be obvious to those skilled in the art that various changes and improvements can be made to the specific implementation manners of the present application without departing from the spirit and scope of the present application. ​

[0118] Calculation Example 1

[0119]

[0120] Molecular docking process: using Maestro ( The process was performed using GlideSP[1] and the default options in version 2017-2). MGL-3196 was selected as the docking template. To prepare the protein, hydrogen atoms were added using the protein preparation wizard module of Maestro[2] and the OPLS3 force field was used. For the preparation of the ligand, a 3D structure was generated and energy minimization was performed using LigPrep[3]. The ligand centroid was generated using the 1Q4X crystal structure. Docking grid. Using InducedFit Docking, amino acid side chains within a 5A range around the ligand center were constrained to move within a B-factor range to generate a complex model. The ligand was then removed, and example compounds were placed during molecular docking. The interaction types between the protein receptor and ligand were analyzed, and reasonable docking conformations were selected and preserved based on calculated docking scrore and global Strain values. The binding mode of compound AC with MGL-3196 is shown in the appendix. Figures 1-3 .

[0121] [1] Glide, LLC, New York, NY, 2017.

[0122] [2] Maestro, LLC, New York, NY, 2017.

[0123] [3]LigPrep, LLC, New York, NY, 2017.

[0124] Conclusion: The compound of the present application has good binding with THR beta protein. The compound of the present application occupies the binding pocket of THR beta and thyroid hormone, the binding pocket is a closed and hydrophobic pocket composed of multiple alpha helixes, and the upper part of the pocket is a positively charged sub-pocket composed of three arginines (Arg282, Arg316 and Arg320). The 6-azauracil acid group of the original reference compound MGL-3196 is combined in this sub-pocket, the cyano group forms a hydrogen bond with Arg316, the carbonyl 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 the isopropyl can form hydrophobic interaction with the surrounding amino acids. The 1,2,4-oxadiazol-5-ketone polar head of the compound of the present application is combined in this sub-pocket, also forms a hydrogen bond with the three arginines, improves the angle of dichlorobenzene through amide, is easier to form halogen bond with Phe272, and the tail carbonyl or hydroxyl can form a hydrogen bond with His435 through mutual influence, and the ring effectively provides hydrophobic interaction. It has good selectivity.

[0125] Example 1

[0126]

[0127] Synthetic route:

[0128]

[0129] Step 1: Synthesis of compound WX001-2

[0130] WX001-1 (5 g, 33.74 mmol) and acetonitrile (50 mL) were added to a pre-dried reaction bottle, NBS (6.61 g, 37.11 mmol) was added, replaced with nitrogen three times, and stirred at 25°C for 16 hours. After the reaction was completed, the reaction liquid was directly concentrated under reduced pressure, the concentrate was slurried with methyl tert-butyl ether (200 mL), and the slurry was stirred at 25°C for 30 minutes, filtered, and the filtrate was collected. The filtrate was washed with saturated brine (200 mL*2), the organic phase was collected, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain WX001-2. 1 H NMR (400 MHz, chloroform-d) 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).

[0131] Step 2: Synthesis of compound WX001-3

[0132] WX001-2 (6.2 g, 27.30 mmol) and DMF (140 mL) were added into a pre-dried reaction flask, cesium carbonate (22.24 g, 68.25 mmol) was added portionwise at 0 °C, the reaction flask was purged with nitrogen for three times, chloromethyl methyl ether (3.30 g, 40.95 mmol, 3.11 mL) was added dropwise slowly at 0 °C, the reaction was continued to stir at 0 °C for 2 hours, chloromethyl methyl ether (1.76 g, 21.84 mmol, 1.66 mL, 0.8 eq) was added, the reaction was continued to stir at 0 °C for 1 hour. After the reaction was completed, the reaction solution was poured into water (100 mL) to quench, the aqueous phase was extracted with methyl tert-butyl ether (100 mL*3), the combined organic phase was washed with saturated brine (150 mL*3), 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. 1 H NMR (400 MHz, Chloroform-d) 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).

[0133] Step 3: Synthesis of compound WX001-5

[0134] WX001-3 (6 g, 22.13 mmol) and THF (60 mL) were added into a pre-dried reaction flask, the reaction flask was cooled to -78 °C, n-butyllithium (2.5 M, 9.29 mL) was added, the reaction was continued to stir at -78 °C for 1 hour, a mixture solution of THF (6 mL) and WX001-4 (4.71 g, 22.13 mmol) was added, the reaction was continued to stir at -78 °C for 1 hour. After the reaction was completed, the reaction solution was poured into 20 mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate (20 mL*3), the combined organic phase was washed with 20 mL of saturated brine, after the liquid was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 2% to 5%) to obtain WX001-5. 1H NMR (400 MHz, Chloroform-d) 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).

[0135] Step 4: Synthesis of compound WX001-6

[0136] WX001-5 (8.4 g, 20.72 mmol) and DCM (100 mL) were added into a pre-dried reaction flask, which was cooled to 0 °C, then triethylsilane (3.61 g, 31.09 mmol, 4.97 mL) and TFA (3.54 g, 31.09 mmol, 2.30 mL) were added, the reaction system was stirred at 0 °C for 1 h. After the reaction was completed, the reaction liquid was poured into 50 mL saturated aqueous sodium carbonate solution, DCM (50 mL*3) was added for extraction, the combined organic phase was washed with saturated brine (100 mL), after separation, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 2% to 5% to 10%) to obtain WX001-6. 1 H NMR (400 MHz, Chloroform-d) 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).

[0137] Step 5: Synthesis of compound WX001-8

[0138] To a solution of WX001-7 (2.05 g, 11.30 mmol, 1.90 mL) in THF (40 mL) was added WX001-6 (4 g, 10.27 mmol), cesium carbonate (5.02 g, 15.41 mmol), BINAP (319.87 mg, 513.71 μmol), palladium acetate (115.33 mg, 513.71 μmol) and the reaction was stirred at 65 °C for 12 h. After the reaction was completed, water (50 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (50 mL*3). The organic phase was combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give WX001-8.

[0139] Step 6: Synthesis of compound WX001-9

[0140] WX001-8 (4.5 g, 9.19 mmol) and HCl (8 mL) were added to a pre-dried reaction flask and THF (40 mL) was added. The mixture was stirred at 25 °C for 1 h. After the reaction was completed, 50 mL of saturated aqueous sodium carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate (50 mL*3). The organic phase was combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 5% to 10% to 20%) to give WX001-9. 1 H NMR (400 MHz, Chloroform-d) 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).

[0141] Step 7: Synthesis of compound WX001-11

[0142] In a dry reaction flask, WX001-9 (450 mg, 1.38 mmol, 1 eq), THF (4 mL), 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) were added successively, and the nitrogen was replaced. The reaction was stirred at 20 °C for 1 h. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (10 mL*3) was added for extraction. After the liquid was separated, the organic phase was collected, washed successively with saturated brine solution (10 mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin layer chromatography on a silica gel plate (DCM:MeOH = 20:1). WX001-11 was obtained. 1 H NMR (400 MHz, Chloroform-d) 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).

[0143] Step 8: Synthesis of compound WX001

[0144] In a dry reaction flask, WX001-11 (400 mg, 914.31 μmol, 1 eq), MeOH (4 mL) and HCl (0.8 mL, 37% purity) were added successively, and the temperature was raised to 50 °C. The reaction was stirred for 2 h. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (10 mL*3) was added for extraction. After the liquid was separated, the organic phase was collected. The organic phase was washed successively with saturated sodium bicarbonate aqueous solution (20 mL) and saturated brine solution (10 mL*3), 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 (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. 1H NMR (400 MHz, Methanol-d4) 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 [M-H] - .

[0145] Example 2

[0146]

[0147] Synthesis route:

[0148]

[0149] Step 1: Synthesis of compound WX002-2

[0150] WX002-1 (1 g, 5.43 mmol, 1 eq) and chloroform (67 mL) were added into a pre-dried reaction flask, tetrabutylammonium tribromide (3.14 g, 6.51 mmol, 1.2 eq) was added, replaced with nitrogen for 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, the liquid was separated, the water phase was extracted with ethyl acetate (30 mL*2), the organic phase was collected, and the organic phase was washed with 1N hydrochloric acid (30 mL) and saturated brine (30 mL) in turn, 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, Chloroform-d) 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).

[0151] Step 2: Synthesis of compound WX002-3

[0152] Into a pre-dried reaction flask, WX002-2 (2.46 g, 9.35 mmol, 66.63 mL, 1 eq) and DMF (24.6 mL) were added, replaced with nitrogen for three times, placed at 0 °C, cesium carbonate (13.07 g, 40.11 mmol, 4.29 eq) was added, then chloromethyl methyl ether (2.15 g, 26.70 mmol, 2.03 mL, 2.86 eq) was added dropwise, stirred at 25 °C for 2 hours. After the reaction was completed, the reaction solution was poured into ice water (30 mL) to quench, then partitioned with ethyl acetate (20 mL), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (2*20 mL), the combined organic phase was washed with saturated brine (20 mL*3), 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 to 10:1 to 5:1) to obtain WX002-3. 1 H NMR (400 MHz, Chloroform-d) d 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).

[0153] Step 3: Synthesis of compound WX002-4

[0154] Into a pre-dried reaction flask, WX002-3 (2.34 g, 7.62 mmol, 1 eq) and THF (23.4 mL) were added, replaced with nitrogen for three times, placed at -78 °C, n-butyllithium (2.5 M, 3.35 mL, 1.1 eq) was slowly added dropwise, 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, continued to stir at -78 °C for 1 hour. After the reaction was completed, the reaction solution was poured into saturated ammonium chloride solution (20 mL), then partitioned with ethyl acetate (20 mL), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (20 mL*2), the combined organic phase was washed with saturated brine (20 mL*2) in turn, 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 to 20:1 to 10:1 to 5:1) to obtain WX002-4. 1 H NMR (400 MHz, Chloroform-d) d 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).

[0155] Step 4: Synthesis of compound WX002-5

[0156] WX002-4 (2.23 g, 5.05 mmol, 1 eq) and DCM (23 mL) were added into a pre-dried reaction flask, replaced with nitrogen for three times, placed at 0 °C, Et3SiH (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 slowly drop by drop in turn, continued to stir at 0 °C for 1 h. After the reaction was completed, the reaction solution was poured into 50 mL saturated aqueous sodium carbonate solution, extracted with DCM (50 mL*3), the organic phase was combined, washed with saturated brine (50 mL), after separation, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0 to 20:1 to 10:1) to give WX002-5. 1 H NMR (400 MHz, Chloroform-d) 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).

[0157] Step 5: Synthesis of compound WX002-6

[0158] 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 into a pre-dried reaction flask, cesium carbonate (2.07 g, 6.35 mmol, 1.5 eq) was added, replaced with nitrogen for three times, Xantphos (195.89 mg, 338.54 μmol, 0.08 eq) and Pd2(dba)3 (232.51 mg, 253.90 μmol, 0.06 eq) were added in turn, replaced with nitrogen for three times again, placed at 100 °C and stirred for 16 h. After the reaction was completed, water (200 mL) and ethyl acetate (200 mL) were added into the reaction solution, separated, the aqueous phase was extracted with ethyl acetate (200 mL*3), the organic phase was combined, washed with saturated brine (300 mL*2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give WX002-6 without purification, which was directly used in the next step.

[0159] Step 6: Synthesis of compound WX002-7

[0160] WX002-6 (2.22 g, 4.22 mmol, 1 eq) and THF (25 mL) were added into a pre-dried reaction flask, 2N hydrochloric acid (5.78 mL, 2.74 eq) was added, replaced with nitrogen for three times, and stirred at 25 °C for 1 hour. After the reaction was completed, 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 phases were combined, washed with saturated brine (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, Chloroform-d) d 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).

[0161] Step 7: Synthesis of compound WX002-8

[0162] WX001-10 (474.51 mg, 3.20 mmol, 1.50 eq) and THF (8 mL) were added into a pre-dried reaction flask, replaced with nitrogen for three times, a mixed solution of WX002-7 (770 mg, 2.13 mmol, 1 eq) and THF (8 mL) was added dropwise, 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 quenched by pouring into water (30 mL), the aqueous phase was extracted with ethyl acetate (30 mL*3), the organic phases were combined, washed with saturated brine (50 mL*2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain WX002-8 without purification, which was directly used in the next step.

[0163] Step 8: Synthesis of compound WX002

[0164] Into a pre-dried reaction flask was added WX002-8 (1.09 g, 2.30 mmol, 1 eq) and MeOH (22 mL), HCl (12 M, 4.36 mL, 22.73 eq) was added, replaced nitrogen for three times, stirred at 50 °C for 3 hours. After the reaction was completed, the reaction solution was adjusted to pH about 7 with saturated sodium bicarbonate solution, extracted with ethyl acetate (30 mL*3), the organic phase was collected after separation, the organic phase was combined, washed with saturated brine 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 (chromatography column: Waters Xbridge BEH C18 250*50mm*10μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile%: 25%-65%, 10 min) to obtain WX002. 1 H NMR (400 MHz, Methanol-d4) 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 [M-H] - .

[0165] Example 3

[0166]

[0167] Synthesis route:

[0168]

[0169] Step 1: Synthesis of compound WX003-2

[0170] In a pre-dried reaction flask, sodium hydride (5.82 g, 145.46 mmol, 60% content, 3 eq) and DMSO (35 mL) were added, replaced with nitrogen for three times, and stirred at 75 °C for 10 minutes. Then, it was placed at 25 °C, and 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. A solution of WX003-1 (10 g, 48.49 mmol, 1 eq) in DMSO (10 mL) was added dropwise, and the reaction was continued to stir at 65 °C for 12 hours. After the reaction was completed, the reaction solution was poured into ice water (200 mL), and methyl tert-butyl ether (200 mL) was added to separate the liquid, and the organic phase was collected, and the aqueous phase was extracted with methyl tert-butyl ether (200 mL*2), and the combined organic phase was washed with saturated brine (600 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by automatic column separation (petroleum ether: ethyl acetate = 1:0 to 5:1) to obtain WX003-2. 1 H NMR (400 MHz, Chloroform-d) 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).

[0171] Step 2: Synthesis of compound WX003-3

[0172] Under a nitrogen 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, replaced with hydrogen for three times, and placed in a hydrogen pressure environment of 15 psi, and stirred at 25 °C for 2 hours. After the reaction was completed, the reaction solution was directly filtered through diatomite, and the filtrate was concentrated under reduced pressure to obtain WX003-3. 1H NMR (400 MHz, Chloroform-d) 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).

[0173] Step 3: Synthesis of compound WX003-4

[0174] WX003-3 (4 g, 19.39 mmol, 1 eq) and THF (40 mL) were added into a pre-dried reaction flask, NBS (3.45 g, 19.39 mmol, 1 eq) was added, replaced with nitrogen for three times, and stirred at -78 °C for 0.5 h. After the reaction was completed, the reaction solution was divided into water (100 mL) and ethyl acetate (100 mL), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (100 mL*2), the combined organic phase was washed with saturated brine (400 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by automatic column separation (petroleum ether: ethyl acetate = 1:0 to 10:1) to obtain WX003-4. 1 H NMR (400 MHz, Chloroform-d) 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).

[0175] Step 4: Synthesis of compound WX003-5

[0176] Into a pre-dried reaction flask was placed WX003-4 (4.9 g, 17.18 mmol, 1 eq) and THF (50 mL), then was slowly added n-butyllithium (2.5 M, 7.56 mL, 1.1 eq) at -78 °C, stirred for 1 h, then slowly added a solution of WX001-4 (3.29 g, 15.46 mmol, 0.9 eq) in THF (25 mL) at -78 °C, stirred for 1 h. After the reaction was completed, the reaction solution was poured into saturated ammonium chloride solution (200 mL), then was separated with ethyl acetate (200 mL), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (200 mL*2), the combined organic phase was washed with saturated brine (600 mL*2) in turn, 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 automatic column separation (petroleum ether: ethyl acetate = 1:0 to 10:1 to 5:1) to obtain WX003-5. 1 H NMR (400 MHz, Chloroform-d) 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 = 6.9 Hz, 6H), 1.92-1.84 (m, 1H), 1.79-1.69 (m, 2H), 1.29-1.22 (m, 3H).

[0177] Step 5: Synthesis of compound WX003-6

[0178] Into a pre-dried reaction flask was placed WX003-5 (2.45 g, 5.84 mmol, 1 eq) and DCM (25 mL), then was stirred at -10 °C, and then was added Et3SiH (1.02 g, 8.76 mmol, 1.40 mL, 1.5 eq) and TFA (999.25 mg, 8.76 mmol, 648.86 μL, 1.5 eq), and was stirred at -10 °C for 1 h. After the reaction was completed, the reaction solution was adjusted to pH 6-7 with saturated aqueous sodium bicarbonate solution, and then was separated with water (30 mL) and dichloromethane (30 mL), the organic phase was collected, the aqueous phase was extracted with dichloromethane (30 mL*2), the combined organic phase was washed with saturated brine (150 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by automatic column separation (petroleum ether: ethyl acetate = 1:0 to 10:1 to 5:1) to obtain WX003-6. 1H NMR (400 MHz, Chloroform-d) 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).

[0179] Step 6: Synthesis of compound WX003-7

[0180] Into a pre-dried reaction bottle was added WX003-6 (1.9 g, 4.71 mmol, 1 eq) and dioxane (20 mL), then 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) were added, replaced with nitrogen for three times, Xantphos (218.05 mg, 376.84 μmol, 0.08 eq) and Pd2(dba)3(258.81 mg, 282.63 μmol, 0.06 eq) were added, replaced with nitrogen again, stirred at 100 °C for 12 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, separated with water (50 mL) and ethyl acetate (50 mL), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (50 mL*2), the organic phase was combined, washed with saturated brine (300 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain WX003-7. The crude product was directly used in the next step.

[0181] Step 7: Synthesis of compound WX003-8

[0182] WX003-7 (2.3 g, 4.57 mmol, 1 eq) and THF (25 mL) were added into a pre-dried reaction flask, hydrochloric acid (2 N, 2.28 mL, 1 eq) was added, and it 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 solution, 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*2), the combined organic phase was washed with saturated brine (120 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by automatic column separation (petroleum ether: ethyl acetate = 1:0 to 10:1 to 5:1 to 3:1) to obtain WX003-8. 1 H NMR (400 MHz, Chloroform-d) 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).

[0183] Step 8: Synthesis of compounds WX003-9-1 and WX003-9-2

[0184] WX003-8 (250 mg, 736.44 μmol, 1 eq) was subjected to chiral separation, and the separation method was as follows: (chromatographic column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 μm); A: food-grade supercritical carbon dioxide; B: mobile phase: [0.1% ammonia water + isopropyl alcohol]; B%: 35%-35%, 10 min) to obtain WX003-9-1 and WX003-9-2. The retention time of WX003-9-1 was 3.671 minutes, and the retention time of WX003-9-2 was 4.112 minutes, and the analysis method (instrument: CAS-TJ-ANA-SFC-C (Waters UPC C with PDA); chromatographic column: Chiralpak OJ-3, 150 x 4.6 mm I.D., 3 μm; mobile phase: A: food-grade supercritical carbon dioxide; B: isopropyl alcohol (0.1% isopropylamine, by volume); gradient: B content increased from 10% to 50% in 3.5 minutes and maintained for 1 minute, and then increased from 50% to 10% in 0.5 minute; 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 (400 MHz, Chloroform-d) 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: 1 H NMR (400 MHz, Chloroform-d) 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:

[0185] Step 9: Synthesis of compounds WX003-10-1 and WX003-10-2

[0186] In a dry reaction bottle, WX001-10 (46.59 mg, 313.72 umol, 1.5 eq) was dissolved in THF (1 mL), and WX003-9-1 (71 mg, 209.15 umol, 1 eq) was added to the reaction bottle, and then TEA (63.49 mg, 627.45 umol, 87.33 uL, 3 eq) was added. The mixture was stirred at 20 °C for 1 h. After the reaction was completed, the reaction solution was added to water (5 mL), and extracted with ethyl acetate (5 mL) to separate the organic phase. The aqueous phase was extracted with ethyl acetate (5 mL*2), and the organic phase was combined and washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give WX003-10-1.

[0187] In a dry reaction bottle, WX001-10 (46.59 mg, 313.72 umol, 1.5 eq) was added in THF (1 mL), WX003-9-2 (71 mg, 209.15 umol, 1 eq) was dissolved in THF (1 mL) and added into the reaction bottle, TEA (63.49 mg, 627.45 umol, 87.33 uL, 3 eq) was added, and the mixture was stirred at 20 °C for 1 h. After the reaction was completed, the reaction solution was added to water (5 mL), extracted with ethyl acetate (5 mL) and separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (5 mL*2), the organic phase was collected, and the organic phase was dried 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.

[0188] Step 10: Synthesis of compounds WX003 and WX004

[0189] In a previously dried reaction bottle, WX003-10-1 (100.00 mg, 221.48 umol, 1 eq) and DMA (1 mL) were added, then HCl (0.2 mL, 37% purity) was added, replaced with nitrogen for three times, and stirred at 50 °C for 6 h. 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, extracted with ethyl acetate (10 mL*3), separated to collect the organic phase, and the organic phase was washed with saturated brine (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 (chromatography column: Waters Xbridge BEH C18 100*30 mm*10 um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 25%-55%, 8 min) to obtain WX003. 1 H NMR (400 MHz, Deuterated dimethyl sulfoxide) d 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 [M-H] - .

[0190] Into a pre-dried reaction flask was added WX003-10-2 (100.00 mg, 221.48 μmol, 1 eq) and DMA (1 mL), then HCl (0.2 mL, 37% purity) was added, replaced with nitrogen for three times, and stirred at 50 °C for 6 hours. After the reaction was completed, the reaction solution was added to water (10 mL) for dilution, the pH was adjusted to neutral with saturated sodium bicarbonate solution, extracted with ethyl acetate (10 mL*3), the organic phase was collected after separation, the combined organic phase was washed with saturated brine (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 (chromatography column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [A: water (ammonium bicarbonate)-B: acetonitrile]; acetonitrile%: 25%-55%, 8 min) to obtain WX004. 1 H NMR (400 MHz, 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 [M-H] - .

[0191] Example 4

[0192]

[0193] Synthetic route:

[0194]

[0195] Step 1: Synthesis of compound WX005

[0196] In a pre-dried reaction flask, WX001 (50 mg, 127.09 μmol, 1 eq) and THF (2.8 mL) were added, TEA (0.28 mL) was added, replaced with nitrogen for three times, and iodine monochloride (24.76 mg, 152.50 μmol, 7.78 μL, 1.20 eq) was added at -78 °C. After stirring at -78 °C for 2 hours, 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), and 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 (chromatography column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-acetonitrile]; acetonitrile%: 60%-80%, 8 min) to obtain WX005. 1 H 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-ES Im / z: 518.0 [M-H] - .

[0197] Example 5

[0198]

[0199] Synthetic route:

[0200]

[0201] Step 1: Synthesis of compound WX006-3

[0202] In a pre-dried reaction flask, WX006-1 (5.5 g, 38.15 mmol, 13.75 mL, 1 eq) and isopropanol (250 mL) were added, WX006-2 (12.14 g, 41.96 mmol, 1.1 eq) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (20.27 g, 57.22 mmol, 1.5 eq) were added, replaced with nitrogen for 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. 1H NMR (400 MHz, Chloroform-d) d 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, Chloroform-d) d -145.48 (s, 1F).

[0203] Step 2: Synthesis of compound WX006-4

[0204] WX006-3 (3.0 g, 18.50 mmol, 1 eq) and ethanol (100 mL) were added to a pre-dried reaction flask, palladium carbon (1 g, 18.50 mmol, 10% content, 1 eq) was added, hydrogen was replaced for three times, and the reaction was stirred at 60 °C for 16 hours under the environment of hydrogen (373.70 mg, 185.00 mmol, 10 eq) at 50 psi. After the reaction was completed, the reaction solution was directly filtered through diatomite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0) to obtain WX006-4. 1 H NMR (400 MHz, Chloroform-d) d 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, Chloroform-d) d -145.84 (s, 1F).

[0205] Step 3: Synthesis of compound WX006-5

[0206] 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, nitrogen was replaced for three times, and the reaction was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction solution was divided into water (150 mL) and ethyl acetate (150 mL), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (200 mL*2), the combined organic phase was washed with saturated brine (300 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 purified by column chromatography (petroleum ether: ethyl acetate = 1:0 to 50:1) to obtain WX006-5. 1H NMR (400 MHz, Chloroform-d) d 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, Chloroform-d) d -132.23 (s, 1F).

[0207] Step 4: Synthesis of compound WX006-6

[0208] WX006-5 (6 g, 24.48 mmol, 1 eq) and DMF (120 mL) were added into a pre-dried reaction flask, replaced with nitrogen for three times, placed at 0 °C, then cesium carbonate (23.93 g, 73.44 mmol, 3 eq) was added, followed by dropwise addition of methyl carbonate (3.94 g, 48.96 mmol, 3.72 mL, 2 eq), stirred at 25 °C for 2 hours. After the reaction was completed, the reaction solution was poured into ice water (100 mL), and ethyl acetate (100 mL) was added to separate the liquid, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (100 mL*2), the combined organic phase was washed with saturated brine (100 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 purified by thin layer chromatography on silica gel plate (petroleum ether: ethyl acetate = 10: 1) to obtain WX006-6. 1 H NMR (400 MHz, Chloroform-d) d 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, Chloroform-d) d -132.23 (s, 1F).

[0209] Step 5: Synthesis of compound WX006-7

[0210] WX006-6 (1 g, 3.46 mmol, 1 eq) and tetrahydrofuran (10 mL) were added into a pre-dried reaction flask, replaced with nitrogen for three times, and then placed at -78 °C. n-Butyllithium (2.5 M, 1.52 mL, 1.1 eq) was slowly dropped in. After stirring at -78 °C for 1 h, a mixture of WX001-4 (663.22 mg, 3.11 mmol, 0.9 eq) and tetrahydrofuran (10 mL) was dropped in at -78 °C. The reaction was continued to stir at -78 °C for 1 h. After the reaction was completed, the reaction solution was poured into saturated ammonium chloride solution (50 mL), and then separated into two phases by adding ethyl acetate (50 mL). The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (50 mL*2). The combined organic phase was washed with saturated brine (50 mL*2) successively, dried over anhydrous sodium sulfate, filtered, and then 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 10:1 to 5:1) to obtain WX006-7. 1 H NMR (400 MHz, Chloroform-d) d 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, Chloroform-d) d -134.26 (s, 1F).

[0211] Step 6: Synthesis of compound WX006-8

[0212] 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 into a pre-dried reaction flask, and then cesium carbonate (923.62 mg, 2.83 mmol, 1.5 eq) was added. After replacing with nitrogen for three times, Xantphos (87.48 mg, 151.19 μmol, 0.08 eq) and Pd2(dba)3(103.83 mg, 113.39 μmol, 0.06 eq) were added successively. After replacing with nitrogen for three times again, the reaction was stirred at 100 °C for 16 h. After the reaction was completed, the reaction solution was directly filtered through diatomite, and then the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0 to 20:1 to 10:1 to 3:1) to obtain WX006-8.1 H NMR (400 MHz, Chloroform-d) d 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, Chloroform-d) d -133.29 (s, 1F).

[0213] Step 7: Synthesis of compound WX006-9

[0214] WX006-8 (600 mg, 1.15 mmol, 1 eq) and tetrahydrofuran (12 mL) were added into a pre-dried reaction flask, hydrochloric acid (2 M, 572.92 μί, 1 eq) was added, replaced with nitrogen for three times, and stirred at 25 °C for 1 h. After the reaction was completed, the reaction solution was adjusted to pH about 7 with saturated sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate (20 mL*3), the combined organic phase was washed with saturated brine (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 thin layer chromatography on silica gel plate (petroleum ether: ethyl acetate = 1: 1) to obtain WX006-9. 1 H NMR (400 MHz, Chloroform-d) d 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, Chloroform-d) d -134.74 (s, 1F).

[0215] Step 8: Synthesis of compound WX006-10

[0216] WX006-9 (500 mg, 1.39 mmol, 1 eq) was added, hydrogen was replaced for three times, and the reaction was stirred at 25 °C under a hydrogen pressure of 50 psi for 16 hours. After the reaction was completed, the reaction solution was filtered using diatomite, 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. 1 H NMR (400 MHz, Chloroform-d) 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).

[0217] Step 9: Synthesis of compound WX006-11

[0218] WX006-10 in THF (2 mL) was added to a dry reaction bottle, replaced with nitrogen three times, and WX001-10 was dissolved in THF (2 mL) and added to the reaction bottle. TEA (150.27 mg, 1.49 mmol, 206.70 μL, 3 eq) was added, and the reaction was 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) to separate the liquid, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (5 mL*2), the combined organic phase was washed with saturated brine (20 mL*2) in turn, dried over anhydrous sodium sulfate, filtered, and rotary evaporated under reduced pressure to obtain the crude product of WX006-11, which was directly used in the next step.

[0219] Step 10: Synthesis of compound WX006

[0220] WX006-11 and MeOH (5 mL) were added into a pre-dried reaction flask, HCl (12 N, 60.19 μL, 1 eq) was added, replaced with nitrogen for three times, and stirred at 50 °C for 0.5 h. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, diluted with ethyl acetate (30 mL), separated with water (30 mL), and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (30 mL*3), and the combined organic phase was washed with saturated brine (30 mL*2), 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 HPLC high phase liquid chromatography (chromatographic column: Phenomenex luna C18 80*40 mm*3 μm; mobile phase: [water (HCl)-acetonitrile]; acetonitrile%: 49%-69%, 7 min) to obtain WX006. 1 H NMR (400 MHz, Methanol-d4) 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 [M-H] - .

[0221] Example 6

[0222]

[0223] Step 1: Synthesis of compound WX007-2

[0224] WX007-1 (50 g, 312.17 mmol, 1 eq) was added into two pre-dried hydrogenation flasks, respectively, and Pd / C (10 g, 312.17 mmol, 10% content, 1 eq) was added into each flask, respectively, under nitrogen environment. Hydrogen was replaced for three times, and the flasks were stirred at 60 °C under hydrogen pressure of 50 psi for 4 h. After the reaction was completed, the reaction solution was directly filtered through diatomite, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0 to 10:1 to 5:1) to obtain WX007-2. 1 H NMR (400 MHz, Chloroform-d) 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).

[0225] Step 2: Synthesis of compound WX007-3

[0226] Into a pre-dried reaction flask was placed WX007-2 (10 g, 61.66 mmol, 1 eq), methoxyamine hydrochloride (5.66 g, 67.82 mmol, 1.1 eq) and EtOH (100 mL), potassium carbonate (25.56 g, 184.97 mmol, 3 eq) was added, replaced with nitrogen for three times, and stirred at 60 °C for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, water (200 mL) was added, and the aqueous phase was extracted with ethyl acetate (200 mL*3), the organic phases were combined, washed with saturated brine (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. 1 H NMR (400 MHz, Chloroform-d) d 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).

[0227] Step 3: Synthesis of compound WX007-4

[0228] Into a pre-dried reaction flask was placed WX007-3 (11 g, 57.52 mmol, 1 eq) and DCM (200 mL), 2,6-dimethylpyridine (24.65 g, 230.09 mmol, 26.80 mL, 4 eq) was added, triisopropylsilyl (trifluoromethyl sulfate) (52.88 g, 172.57 mmol, 46.38 mL, 3 eq) was added, replaced with nitrogen for three times, and stirred at 25 °C for 6 h. After the reaction was completed, water (200 mL) was added to quench the reaction, and the aqueous phase was extracted with dichloromethane (500 mL*3), the organic phases were combined, washed with saturated brine (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 to 20:1 to 10:1 to 5:1) to obtain WX007-4. 1 H NMR (400 MHz, Chloroform-d) d 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).

[0229] Step 4: Synthesis of compound WX007-5

[0230] Into a pre-dried reaction flask was added WX007-4 (4 g, 11.51 mmol, 1 eq) and acetonitrile (40 mL), NBS (2.25 g, 12.66 mmol, 1.1 eq) was added, replaced with nitrogen for three times, and stirred at 25 °C for 2 hours. After the reaction was completed, water (50 mL) was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (60 mL*3), the combined organic phase was 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 to 20:1 to 10:1) to obtain WX007-5. 1 H NMR (400 MHz, Chloroform-d) d 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).

[0231] Step 5: Synthesis of compound WX007-6

[0232] Into a pre-dried reaction flask was added WX007-5 (0.5 g, 1.17 mmol, 1 eq) and THF (5 mL), replaced with nitrogen for three times, and stirred at -78 °C, then n-butyllithium (2.5 M, 515.87 μL, 1.1 eq) was slowly added dropwise, stirred at -78 °C for 1 hour, then a mixture of WX001-4 (249.81 mg, 1.17 mmol, 1 eq) and THF (5 mL) was added dropwise at -78 °C, and the stirring was continued at -78 °C for 1 hour. After the reaction was completed, the reaction solution was poured into saturated ammonium chloride solution (5 mL) to quench the reaction, then ethyl acetate (5 mL) was added to separate the phases, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (2*5 mL), the combined organic phase was washed with saturated brine (2*5 mL) in turn, 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 WX007-6. 1 H NMR (400 MHz, Chloroform-d) d 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).

[0233] Step 6: Synthesis of compound WX007-7

[0234] WX007-6 (470 mg, 838.33 pmol, 1 eq) and DCM (10 mL) were added into a pre-dried reaction flask, replaced with nitrogen for three times, placed at 0 °C, Et3SiH (146.22 mg, 1.26 mmol, 200.85 pL, 1.5 eq) and TFA (143.38 mg, 1.26 mmol, 93.10 pL, 1.5 eq) were added slowly dropwise in turn, and stirring was continued at 0 °C for 1 h. After the reaction was completed, the reaction solution was poured into (30 mL) saturated aqueous sodium carbonate solution, DCM (30 mL*3) was added for extraction, the combined organic phase was washed with saturated brine (30 mL), after separation, 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 5:1) to obtain WX007-7. 1 H NMR (400 MHz, Deuterated dimethyl sulfoxide) d 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).

[0235] Step 7: Synthesis of compound WX007-8

[0236] WX007-7 (320 mg, 824.11 pmol, 1 eq) and DCM (6.4 mL) were added into a pre-dried reaction flask, 2,6-dimethylpyridine (353.21 mg, 3.30 mmol, 383.93 pL, 4 eq) was added, triisopropylsilyl (trifluoromethyl sulfate) (757.57 mg, 2.47 mmol, 664.54 pL, 3 eq) was added, replaced with nitrogen for three times, and stirring was continued at 25 °C for 1 h. After the reaction was completed, water (200 mL) was added to quench the reaction, and the aqueous phase was extracted with dichloromethane (500 mL*3), the combined organic phase was washed with saturated brine (550 mL*2) in turn, 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 WX007-8. 1H NMR (400 MHz, Deuterated Dimethyl Sulfoxide) d 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).

[0237] Step 8: Synthesis of compound WX007-9

[0238] Into a pre-dried reaction bottle, was added 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), cesium carbonate (464.83 mg, 1.43 mmol, 1.5 eq) was added, replaced with nitrogen for three times, Xantphos (44.03 mg, 76.09 µmol, 0.08 eq) and Pd2(dba)3 (52.26 mg, 57.07 µmol, 0.06 eq) were added in sequence, replaced with nitrogen for three times again, stirred at 100 °C for 6 hours. After the reaction was completed, the reaction solution was directly filtered through celite, and the filtrate was concentrated under reduced pressure to obtain WX007-9.

[0239] Into a pre-dried reaction bottle, was added WX007-9 (615 mg, 953.55 µmol, 1 eq) and THF (10 mL), HCl (2 N, 1.91 mL, 4 eq) was added, replaced with nitrogen for three times, stirred at 25 °C for 1 hour. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution (100 mL), the aqueous phase was extracted with ethyl acetate (100 mL*3), the combined organic phase was washed with saturated brine (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 (400 MHz, Deuterated Chloroform) d 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).

[0240] Step 10: Synthesis of compound WX007

[0241] In a dry reaction bottle, WX001-10 (32.96 mg, 221.94 umol, 0.8 eq) was added in THF (1 mL), WX007-10 (90 mg, 277.42 umol, 1 eq) was dissolved in THF (1 mL) and added into the reaction bottle, TEA (84.22 mg, 832.27 umol, 115.84 uL, 3 eq) was added, and the mixture was stirred at 20 °C for 1 h. After the reaction was completed, the reaction solution was added to water (5 mL), and extracted with ethyl acetate (5 mL) to separate the organic phase, and the aqueous phase was extracted with ethyl acetate (5 mL*2), and the combined organic phase was washed with saturated brine (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 high performance liquid chromatography (chromatography column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile%: 35%-55%, 8 min) to obtain the product WX007. 1 H NMR (400 MHz, Methanol-d4) d 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-ES Im / z: 437.2 [M+H] + .

[0242] Example 7

[0243]

[0244] Synthetic route:

[0245]

[0246] Step 1: Synthesis of compound WX008-4

[0247] 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 system was replaced with nitrogen three times. The mixture was stirred at 25 °C for 16 h. After the reaction was completed, water (1000 mL) was added to the system, followed by extraction with methyl tert-butyl ether (500 mL*3), separation, and then combination of the organic phases. The organic phase was washed with saturated brine (500 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 50 °C using a water pump to obtain a yellow solid crude product. The crude product was purified by flash column chromatography (silica gel mesh: 100-200 mesh; petroleum ether: ethyl acetate = 1:0 to 100:2) to obtain WX008-4.

[0248] Step 2: Synthesis of compound WX008-5

[0249] WX008-4 (90 g, 356.71 mmol, 1 eq) and MeOH (900 mL) were added to a previously dried reaction flask, and sodium borohydride (16.19 g, 428.05 mmol, 1.2 eq) was slowly added at 0 °C. The mixture was continuously stirred at 0 °C for 0.5 h. After the reaction was completed, the reaction solution was quenched with a saturated ammonium chloride solution (900 mL), and ethyl acetate (900 mL) was added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (900 mL*2). The combined organic phase was washed with saturated brine (900 mL*2), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petroleum ether: ethyl acetate = 1:0 to 100:1) to obtain WX008-5. 1 H NMR (400 MHz, Chloroform-d) d 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).

[0250] Step 3: Synthesis of compound WX008-7

[0251] WX008-5 (20 g, 78.64 mmol, 1 eq) and THF (200 mL) were added into a pre-dried reaction flask, and sodium hydride (12.58 g, 314.56 mmol, 60% content, 4 eq) was slowly added at 0 °C. The mixture was stirred 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 the mixture was stirred at 0 °C for 0.5 h. The temperature was raised to 25 °C, and the mixture was stirred for 15 h. After the reaction was completed, the reaction solution was quenched with water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with saturated brine (100 mL*3), and the organic phase was collected, 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 to 20:1 to 10:1 to 5:1) to obtain WX008-7. 1 H NMR (400 MHz, Chloroform-d) 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).

[0252] Step 4: Synthesis of compound WX008-8

[0253] WX008-7 (14.36 g, 50.85 mmol, 1 eq) was added into a pre-dried reaction flask, and Pd / C (2 g, 10% content) was added. The hydrogen gas was replaced for three times, and the mixture was stirred at 25 °C under a hydrogen pressure of 15 psi for 16 h. After the reaction was completed, the reaction solution was filtered using diatomite, and 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 WX008-8. 1H NMR (400 MHz, Chloroform-d) 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).

[0254] Step 5: Synthesis of compound WX008-10

[0255] WX008-8 (6.35 g, 33.03 mmol, 1 eq) and DCM (120 mL) were added into a pre-dried reaction flask, replaced with hydrogen three times, 2,6-dimethylpyridine (8.85 g, 82.57 mmol, 9.62 mL, 2.5 eq) was added slowly dropwise, then WX008-9 (20.24 g, 66.06 mmol, 17.76 mL, 2 eq) was added dropwise, stirred at 25 °C for 16 hours. After the reaction was completed, water (120 mL) was added to quench the reaction, and the aqueous phase was extracted with dichloromethane (150 mL*3), the organic phases were 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 to 20:1 to 10:1) to obtain WX008-10. 1 H NMR (400 MHz, Chloroform-d) 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).

[0256] Step 6: Synthesis of compound WX008-11

[0257] WX008-10 (11 g, 31.56 mmol, 1 eq) and acetonitrile (220 mL) were added into a pre-dried reaction flask, NBS (6.18 g, 34.71 mmol, 1.1 eq) was added, and the nitrogen was replaced for three times, and then the reaction was stirred at 25 °C for 2 h. After the reaction was completed, water (50 mL) was added into the reaction solution to quench the reaction, and the water phase was extracted with ethyl acetate (60 mL*3), and then the organic phases were combined and washed with saturated brine (100 mL*2), and then the organic phase was collected, 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 to 10:1) to obtain WX008-11. 1 H NMR (400 MHz, Chloroform-d) 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).

[0258] Step 7: Synthesis of compound WX008-12

[0259] WX008-11, THF (20 mL) were added into a dried reaction flask, and then the nitrogen was replaced, and then the temperature was lowered to -78 °C, and then n-BuLi (2.5 M, 2.06 mL, 1.1 eq) was added dropwise, and then the reaction was carried out at -78 °C for 1 h, and then a THF (10 mL) solution of WX001-4 was added, and then the reaction was carried out at -78 °C for 1 h. After the reaction was completed, 20 mL of saturated ammonium chloride solution was added into the reaction solution to quench the reaction, and then 30 mL of ethyl acetate was added to extract the water phase, and then the organic phase was collected after separation, and then the water phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine (20 mL*3) in sequence, dried over anhydrous sodium sulfate, filtered, and then the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by an automatic column machine (petroleum ether: ethyl acetate = 1:0 to 5:1) to obtain WX008-12.

[0260] Step 8: Synthesis of compound WX008-13

[0261] WX008-12 (680 mg, 1.21 mmol, 1 eq), dioxane (7 mL), then WX001-7 (241.36 mg, 1.33 mmol, 223.48 μL, 1.1 eq), cesium carbonate (591.70 mg, 1.82 mmol, 1.5 eq), after replacing nitrogen three times, Pd2(dba)3 (49.89 mg, 54.48 μmol, 0.045 eq), Xantphos (31.52 mg, 54.48 μmol, 0.045 eq), then replacing nitrogen three times, and then increasing the temperature to 100 °C and stirring for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by automatic column machine (petroleum ether: ethyl acetate = 1:0 to 5:1) to obtain WX008-13.

[0262] Step 9: Synthesis of compound WX008-14

[0263] WX008-13 (470 mg, 709.99 μmol, 1 eq), THF (8 mL), replacing nitrogen three times, reducing the temperature to 0 °C, then adding dilute hydrochloric acid (2 M, 354.99 μL, 1 eq), and stirring at 20 °C for 0.5 hours. After the reaction was completed, the reaction liquid was adjusted to pH about 7 with saturated sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate (10 mL*3), the combined organic phase was washed with saturated brine (10 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 separated by automatic column machine (petroleum ether: ethyl acetate = 1:0 to 3:1, then 2:1), and purified to obtain WX008-14.

[0264] Step 10: Synthesis of compound WX008-15

[0265] WX008-14 (175 mg, 351.56 μmol, 1 eq), ethyl acetate (18 mL), glacial acetic acid (2 mL), replacing hydrogen, and stirring at 25 °C under 15 psi for 4 hours. After the reaction was completed, the reaction liquid was directly filtered through diatomite, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was directly used in the next reaction. WX008-15 was obtained. 1H NMR (400 MHz, Chloroform-d) 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).

[0266] Step 11: Synthesis of compound WX008-16

[0267] In a dry reaction bottle, WX008-15 (260 mg, 539.66 μmol, 1 eq) and THF (0.3 mL) were added, 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 stirring was performed at 20 °C for 1 h. After the reaction was completed, 10 mL of saturated sodium bicarbonate solution was added to quench the reaction, 30 mL of ethyl acetate was added for extraction, and after separation, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with saturated brine (20 mL*3) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by automatic column separation (petroleum ether: ethyl acetate = 1:0 to 2:1) to obtain WX008-16. 1H NMR (400 MHz, Chloroform-d) 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).

[0268] Step 12: Synthesis of compound WX008-17

[0269] In a dry reaction bottle, WX008-16 (270 mg, 454.68 μmol, 1 eq) and THF (0.3 mL) were added, triethylamine trifluorohydrofluoride (366.49 mg, 2.27 mmol, 370.57 μL, 5 eq) was added, replaced with nitrogen three times, and placed in a 50°C water bath for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature, 30 mL of water was added to quench the reaction, 20 mL of ethyl acetate was added for extraction, and the organic phase was collected after separation. The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with saturated brine (20 mL*3) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was found to have poor solubility in dichloromethane and ethyl acetate, so it was dissolved in a little methanol. The obtained solution was concentrated and dried by rotary evaporation. It was found that the ethoxy group was changed to methoxy group by detection. The crude product was purified by (column: Phenomenex C18 80*40mm*3μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile%: 25%-45%, 8 min) to obtain WX008-17.

[0270] Step 13: Synthesis of compounds WX008 and WX009

[0271] WX008-17 (60 mg, 101.04 pmol) was subjected to chiral separation (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 pm); mobile phase: A: carbon dioxide B: [0.1% ammonia water - ethanol]; B%: 35% - 35%, 14 min) to give WX008 and WX009. Chiral method check (method: column Chiralpak AD-3, 50 x 4.6 mm I.D., 3 pm; 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 that WX008 (ee% = 98.64%, retention time 3.482 min) and WX009 (ee% = 97.98%, retention time 3.831 min). Product WX009 was further purified by (column: Phenomenex C18 75*30 mm*3 pm; mobile phase: [water (ammonia water + ammonium bicarbonate) - acetonitrile]; acetonitrile%: 15% - 45%, 8 min) to give WX009.

[0272] WX008: 1 H NMR (400 MHz, Methanol-d4) d 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).

[0273] WX009: 1 H NMR (400 MHz, Methanol-d4) d 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).

[0274] Example 8

[0275]

[0276] Synthesis route:

[0277]

[0278] Step 1: Synthesis of compound WX010-1

[0279] Into a pre-dried reaction flask, WX008-16 (200 mg, 336.80 pmol, 1 eq), THF (5 mL) and tetrabutylammonium fluoride (1 M, 404.16 pL, 1.2 eq) were added successively, replaced with nitrogen for three times, and stirred at 20 °C for 1 hour. 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 pre-TLC (dichloromethane:methanol = 10:1) to obtain WX010-1.

[0280] Step 2: Synthesis of compounds WX010-2-1 and WX010-2-2

[0281] Into a pre-dried reaction flask, WX010-1 (70 mg, 160.00 pmol, 1 eq) and pyridine (2 mL) were added, acetic anhydride (245.02 mg, 2.40 mmol, 224.79 pL, 15 eq) was added, and stirred at 25 °C for 1 hour. After the reaction was completed, the reaction solution was adjusted to pH 4-5 with 0.5N 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, washed successively with 0.5M hydrochloric acid (10 mL*2), saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Then purified by supercritical chromatography separation (chromatographic column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 pm); mobile phase: A: carbon dioxide B: [0.1% ammonia water-ethanol]; B%: 25%-25%, 11 minutes) to obtain WX010-2-1 and WX010-2-2. Chiral method detection (method: chromatographic column Chiralpak AD-3, 150*4.6 mm I.D., 3 pm; 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) showed that the retention time of WX010-2-1 was 2.893 minutes, and the ee% was 100%; the retention time of WX010-2-2 was 3.190 minutes, and the ee% was 91.06%.

[0282] Step 3: Synthesis of compounds WX010 and WX011

[0283] In a pre-dried reaction flask, WX010-2-1 (16 mg, 33.37 μmol, 1 eq) and MeOH (4 mL) were added in turn, potassium carbonate (9.22 mg, 66.73 μmol, 2 eq) was added, nitrogen was replaced for three times, and it was stirred at 20 °C for 4 hours. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (chromatographic column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile%: 25%-55%, 8 min) to obtain WX010. 1 HNMR (400 MHz, 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 [M-H] + .

[0284] In a pre-dried reaction flask, WX010-2-2 (10.00 mg, 20.85 μmol, 1 eq) and MeOH (2.5 mL) were added in turn, potassium carbonate (5.76 mg, 41.71 μmol, 2 eq) was added, nitrogen was replaced for three times, and it was stirred at 20 °C for 4 hours. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (chromatographic column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile%: 25%-55%, 8 min) to obtain WX011. 1H NMR (400 MHz, Methanol-d4) 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 - ES Im / z: 436.1 [M-H] - .

[0285] Example 9

[0286]

[0287] Synthesis route:

[0288]

[0289] Step 1: Synthesis of compound WX012-1

[0290] WX008-11 (5 g, 11.70 mmol, 1 eq) and THF (100 mL) were added into a pre-dried reaction flask, replaced with nitrogen for three times, placed at -78 °C, slowly dropped with DMF (3.42 g, 46.78 mmol, 3.60 mL, 4 eq), stirred at -78 °C for 0.5 h, then dropped with n-butyllithium (2.5 M, 5.15 mL, 1.1 eq) at -78 °C, continued to stir at -78 °C for 1 h. After the reaction was completed, the reaction solution was poured into saturated ammonium chloride solution (20 mL), then divided into two layers with ethyl acetate (20 mL), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (20 mL*2), the combined organic phase was washed with saturated brine (20 mL*2) in turn, 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 to 20:1 to 10:1 to 5:1) to obtain WX012-1. 1H NMR (400 MHz, Chloroform-d) 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).

[0291] Step 2: Synthesis of compound WX012-2

[0292] WX012-1 (1 g, 2.66 mmol, 1 eq) and DCM (10 mL) were added into a pre-dried reaction flask, m-chloroperoxybenzoic acid (1.13 g, 6.55 mmol, 2.47 eq) was added, replaced with nitrogen for three times, continued to stir at 25 °C for 16 hours. After the reaction was completed, saturated sodium bicarbonate solution (20 mL) was added into the reaction solution to quench (20 mL), stirred for 30 min, then dichloromethane (20 mL) was added to separate the solution, the organic phase was collected, the aqueous phase was extracted with dichloromethane (20 mL*2), the combined organic phase was washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an intermediate. The intermediate (1 g, 2.66 mmol, 1 eq), DCM (5 mL) and MeOH (5 mL) were added into a pre-dried reaction flask, TEA (1.42 g, 14.07 mmol, 1.96 mL, 5.3 eq) was added, replaced with nitrogen for three times, continued to stir at 25 °C for 40 min. After the reaction was completed, 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 brine (20 mL), 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 to 20:1 to 10:1 to 5:1) to obtain WX012-2. 1 H NMR (400 MHz, Chloroform-d) 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).

[0293] Step 3: Synthesis of compound WX012-4

[0294] WX012-2 (690 mg, 1.89 mmol, 1 eq) and DMF (14 mL) were added into a pre-dried reaction flask, potassium carbonate (392.34 mg, 2.84 mmol, 1.5 eq) was added, replaced with nitrogen for three times, stirred for 0.5 h at 25 °C, slowly added WX012-3 (516.63 mg, 2.46 mmol, 1.3 eq), replaced with nitrogen for three times, stirred at 100 °C for 15.5 h. After the reaction was completed, quenched with water (30 mL), separated, the aqueous phase was extracted with ethyl acetate (50 mL*3), the organic phases were 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 a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0 to 10:1 to 5:1) to obtain WX012-4. 1 H NMR (400 MHz, Chloroform-d) d 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).

[0295] Step 4: Synthesis of compounds WX012-5-1 and WX012-5-2

[0296] WX012-4 (500 mg, 1.26 mmol, 1 eq) was purified by supercritical chromatography (Chromatography column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 pm); Mobile phase: A: Carbon dioxide B: [0.1% Ammonia water + Isopropyl alcohol]; B%: 30%-30%, 10 min) to give WX012-5-1 and WX012-5-2. Chiral method detection (Instrument: CAS-TJ-ANA-SFC-H (Waters UPC with SQ Detector2); Chromatography column: Chiralpak AD-3, 50 x 4.6 mm I.D., 3 pm; Mobile phase: A: Food grade supercritical carbon dioxide; B: Isopropyl alcohol (0.1% isopropyl amine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 min and kept 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 with an ee% of 100%; WX012-5-2 had a retention time of 1.295 with an ee% of 98.56%. WX012-5-1: 1 H NMR (400 MHz, Deuterated dimethyl sulfoxide) d 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: 1 H NMR (400 MHz, Deuterated dimethyl sulfoxide) d 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:

[0297] Step 5: Synthesis of compounds WX012-6-1 and WX012-6-2

[0298] WX012-5-1 and glacial acetic acid (1 mL), isopropyl alcohol (2 mL), water (1 mL) were added into a pre-dried reaction flask, which was placed at 50 °C, iron powder (98.17 mg, 1.76 mmol, 7 eq) was added slowly in batches, replaced with nitrogen for 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 diatomite, the filtrate was concentrated under reduced pressure, the concentrate was adjusted to pH 7-8 with saturated sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate (10 mL*3), and the organic phases were combined; the organic phase was successively washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by pre-TLC (petroleum ether: ethyl acetate = 1:1) to obtain WX012-6-1. 1 H NMR (400 MHz, 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).

[0299] WX012-5-2 (150 mg, 376.66 μmol, 1 eq) and glacial acetic acid (1.5 mL), isopropyl alcohol (3 mL), water (1.5 mL) were added into a pre-dried reaction flask, which was placed at 50 °C, iron powder (147.26 mg, 2.64 mmol, 7 eq) was added slowly in batches, replaced with nitrogen for 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 diatomite, the filtrate was concentrated under reduced pressure, the concentrate was adjusted to pH 7-8 with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (10 mL*3), and the organic phases were combined; the organic phase was successively washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by pre-TLC (petroleum ether: ethyl acetate = 1:1) to obtain WX012-6-2. 1H NMR (400 MHz, Deuterated dimethyl sulfoxide) d 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).

[0300] Step 6: Synthesis of compounds WX012 and WX013

[0301] In a dry reaction bottle, WX001-10 (48.39 mg, 325.86 μmol, 1.5 eq) was dissolved in THF (1.6 mL), and WX012-6-1 (80 mg, 217.24 μmol, 1 eq) was added to the reaction bottle, followed by the addition of TEA (65.95 mg, 651.72 μmol, 90.71 μL, 3 eq). The mixture was stirred at 20 °C for 1 h. After the reaction was completed, the reaction solution was added to water (5 mL), and ethyl acetate (5 mL) was added for extraction. The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL*2). The combined organic phase was washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (chromatography column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile%: 20%-65%, 10 min) to obtain WX012. 1 H NMR (400 MHz, Deuterated dimethyl sulfoxide) d 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).

[0302] In a dry reaction bottle, WX001-10 (66.54 mg, 448.06 μmol, 1.5 eq) was added in THF (2 mL), WX012-6-2 (110 mg, 298.71 μmol, 1 eq) was dissolved in THF (1 mL) and added to the reaction bottle, TEA (90.68 mg, 896.12 μmol, 124.73 μL, 3 eq) was added, and stirring was carried out 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), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (5 mL*2), the organic phase was collected, and the organic phase was successively washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product crude. The crude product was purified by high performance liquid chromatography (chromatographic column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile%: 20%-65%, 10 minutes) to obtain WX013. 1 H NMR (400 MHz, Methanol-d4) 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).

[0303] Biological test

[0304] Experiment one: Test of the activity of the compound of the present application in activating thyroid hormone receptors at the cellular level

[0305] Experimental principle:

[0306] In this experiment, the ThermoFisher-developed TR alpha / beta-UAS-bla HEK293T Cell-based Assay method, the principle of which is that TR alplha-UAS-bla HEK 293T Cell and TR beta-UAS-bla HEK 293T Cell express beta-lactamase, which is controlled by the upstream UAS sequence. When the compound enters the cell and binds to the THR, the receptor binds to the DNA binding region to form a complete GAL4 dimer, which activates the expression of beta-lactamase using the GAL4-UAS system, decomposes the substrate CCF4-AM (coumarin), and the product produces fluorescence at a wavelength of 447 nm under excitation at 409 nm. If there is no expression of beta-lactamase, fluorescence at a wavelength of 520 nm is directly generated by FRET under excitation at 409 nm. The binding of the compound to the protein is determined by detecting the ratio of the two fluorescence (447 nm / 520 nm), and the EC 50 .

[0307] Experimental method:

[0308] The compound was transferred to a 384-well plate using an ECHO liquid workstation, 10 gradient concentrations of each compound, 3-fold dilution, double duplicate wells. 1.5 x 10 4 cells (TR beta-UAS-bla HEK 293T Cell) or 1.0 x 10 4 cells (TR alpha-UAS-bla HEK 293T Cell) were plated in a 384-well plate. HEK 293T-TR beta was incubated in a 37°C incubator for 16 hours, and HEK 293T-TR alpha was incubated for 22 hours. LiveBLAzer TM FRETB / G (CCF4-AM) substrate was added to the cell plate, and the plate was incubated at room temperature for 2 hours in the dark. The Flexstation 3 instrument was used to detect the fluorescence value of the product at 460 nm / 530 nm under excitation at 409 nm. The ratio of the two fluorescence (460 nm / 530 nm) was detected, and the software Graphpad Prism was used to calculate the EC 50 In each experiment, the reference compound triiodothyronine (T3) will be used as a positive control for the experiment. The calculation of Z factor (>0.5) will be used to monitor the stability of each experiment.

[0309] THR alpha and THR beta activity of each example in Table 1

[0310]

[0311]

[0312] Experimental conclusion: The compound of the present application has significant THRβ activity and selectivity.

[0313] Experiment two: Cytochrome P450 isozyme inhibition study

[0314] Experimental purpose:

[0315] The inhibition effect of the test compound WX001 on the activity of human liver microsomal cytochrome P450 isozyme (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) was determined.

[0316] Experimental operation:

[0317] First, the test compound (10.0 mM) was diluted to prepare a working solution (100x final concentration) with a working solution concentration of 1.00 mM, and a working solution of each positive inhibitor and its specific probe substrate for P450 isozyme (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (with midazolam as a probe substrate) and CYP3A4 (with testosterone as a probe substrate)) was prepared; human liver microsomes stored in a refrigerator below -60°C were thawed on ice, and when the human liver microsomes were completely dissolved, they were diluted with PB to prepare a working solution (0.127 mg / ml) of a certain concentration. 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), and then 158 μL of the human liver microsomal working solution was added to the reaction plate, which was placed on ice for use; at this time, 2.00 μL of the test compound (N=1) and the specific inhibitor (N=2) were added to the corresponding wells, and the non-inhibitor (test compound or positive inhibitor) group was added to the corresponding organic solvent. The organic phase of the test compound control sample and the positive control sample was 1:1 DMSO:MeOH and 1:9 DMSO:MeOH, respectively; after pre-incubation at 37°C for 10 min, 20.0 μL of coenzyme factor (NADPH) solution was added to the reaction plate, and for the CYP3A4 metabolic reaction with midazolam as a probe substrate, the reaction time was 3 min; for the CYP2C19 reaction with (S)-mephenytoin as a probe substrate and the CYP2D6 reaction with dextromethorphan as a probe substrate, the reaction time was 20 min, and the rest of the reactions were 10 min; then 400 μL of pre-cooled acetonitrile solution (containing 200 ng / mL of internal standard Tolbutamide and Labetalol) was added to terminate the reaction; the reaction plate was placed on a shaker and shaken for 10 min; then centrifuged at 4°C and 4000 rpm for 20 min; 200 μL of supernatant was added to 100 μL of water for sample dilution; finally, the plate was sealed, shaken and mixed well, and subjected to LC / MS / MS detection.

[0318] Experimental results:

[0319] As shown in Table 2.

[0320] Table 2. Inhibition of human liver microsomal cytochrome P450 isozyme activities by test compounds

[0321]

[0322] Experimental conclusion: Compound WX001 has no inhibitory effect on CYP1A2, CYP2C19, CYP2D6 and CYP3A4, and has a moderate inhibitory effect on CYP2C9.

[0323] Experiment three: in vivo pharmacokinetic study

[0324] Pharmacokinetic study of oral and intravenous administration of WX001 in rats

[0325] Male SD rats were selected and administered with test substances according to Table 3.

[0326] Table 3. Administration and blood sampling of compounds of the present application

[0327]

[0328] Whole blood was collected for a certain period of time, and plasma was prepared, and the drug concentration was analyzed by LC-MS / MS method, and the pharmacokinetic parameters were calculated by Phoenix WinNonlin software (Pharsight Corporation, USA). The experimental results are shown in Tables 4 and 5:

[0329] Table 4. Pharmacokinetic results of compounds of the present application by intravenous administration

[0330]

[0331] Table 5. Pharmacokinetic results of compounds of the present application by oral administration

[0332]

[0333] Experimental conclusion: The compound of the present application has a high exposure and good oral bioavailability.

[0334] Experiment four: in vivo pharmacodynamic study

[0335] Experimental purpose:

[0336] The in vivo efficacy of the test compound was detected by using a rat model induced by cholecalciferol cholic acid supplemented feed.

[0337] Experimental method:

[0338] 9-10 weeks old male SD rats were selected, and after arriving at the facility, they were adapted for 3-7 days. During the adaptation period, the health status of the animals was observed every day and normal feed was provided. After the end of the adaptation period, the rats were fed with high cholesterol (1.5% cholesterol and 0.5% cholic acid) feed for modeling, and the blank control group rats continued to be fed with normal feed. After the rats were fed with high cholesterol feed for two weeks, blood was collected, and serum was separated to detect the LDL-C level. According to the serum LDL-C level, the high cholesterol model rats were randomly grouped, and then orally administered for 7 consecutive days, once a day, see Table 6. After one week of administration, the serum of the rats was collected to detect the LDL-C level, and the efficacy was evaluated.

[0339] Table 6 Animal grouping

[0340]

[0341]

[0342] Experimental results:

[0343] See the attached Figure 4 Wherein P<0.05 represents that the pharmacodynamic index of the administration group has a statistically significant difference relative to the solvent group.

[0344] Experimental conclusion: The compound of the present application can significantly reduce the plasma LDL-C level of rats.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, ###0001### wherein, ， L is -CH2-; R1is independently selected from H, F, Cl, Br, I and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2, or 3 R a substituents; R2and R3are each independently selected from the group consisting of H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy optionally substituted with 1, 2, or 3 R b substituents; m is selected from 1 and 2; Ring A is , said optionally substituted with 1, 2, or 3 R c substituents; R is independently selected from F, CI, Br and I. R a and R b are each independently selected from F, Cl, Br, and I; R c independently selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy optionally substituted with 1, 2 or 3 R; R1 is independently selected from H, F, CI, Br, I, CH3 and CF3.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R1is independently selected from H, F, CI, Br, I, and CH3, said CH3being optionally substituted with 1, 2, or 3 R a substituted.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, R2 and R3 are each independently selected from H, F, CI, Br, I, CH3, CH2F, CHF2, CF3 and OCH3.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R2and R3are each independently selected from the group consisting of H, F, Cl, Br, I, CH3, and OCH3, said CH3and OCH3being optionally substituted with 1, 2, or 3 R b substituted.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, 14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, which is: ###0006### 6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R c independently selected from F, CI, Br, I, CH3, OCH3, and OCH2CH3, said CH3, OCH3, and OCH2CH3 being optionally substituted with 1, 2, or 3 R.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R c independently selected from F, CI, Br, I, CH3, OCH3, and OCH2CH3.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, Ring A is , said optionally substituted with 1, 2, or 3 R c substituents.

9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, Ring A is , said optionally substituted with 1, 2, or 3 R c substituents.

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from , , , , , , and .

11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, Structural unit selected from , , , , , , , , and .

12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from .

13. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, Structural unit selected from , and . R1, R2, R3, L and m are as defined in any one of claims 1 to 13; ， wherein, or, it is selected from: ###0007### ###0008### ###0009### ###0010### ###0011### ###0012### ###0013### ###0014### ###0015### ###0016### ###0017### ###0018### ###0019### ###0020### ###0021### ###0022### ###0023### ###0024### ###0025### ###0026### ###0027### ###0028### ###0029### ###0030### ###0031### ###0032### ###0033### ###0034### ###0035### ###0036### ###0037### ###0038### ###0039### ###0040### ###0041### ###0042### ###0043### ###0044### ###0045### ###0046### ###0047### ###0048### ###0049### ###0050### ###0051### ###0052### ###0053### ###0054### ###0055### ###0056### ###0057### ###0058### ###0059### ###0060### ###0061### ###0062### ###0063### ###0064### ###0065### ###0066### ###0067### ###0068### ###0069### ###0070### ###0071### ###0072### ###0073### ###0074### ###0075### ###0076### ###0077### ###0078### ###0079### ###0080### ###0081### ###0082### ###0083### ###0084### ###0085### ###0086### ###0087### ###0088### ###0089### ###0090### ###0091### ###0092### ###0093### ###0094### ###0095### ###0096### ###0097### ###0098### ###0099### ###0100### ###0101### ###0102### ###0103### ###0104### ###0105### ###0106### ###0107### ###0108### ###0109### ### ​ ， ​ is a single bond, R c is F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy is optionally substituted with 1, 2, or 3 R, R is independently selected from the group consisting of F, Cl, Br, and I; ​ ​ or . ​ and . ​

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