CN114746400A

CN114746400A - Compounds useful as selective androgen receptor modulators

Info

Publication number: CN114746400A
Application number: CN202080081267.1A
Authority: CN
Inventors: 孙广龙; 沈春莉; 吴成德; 陈曙辉
Original assignee: Medshine Discovery Inc
Current assignee: Medshine Discovery Inc
Priority date: 2019-11-20
Filing date: 2020-11-20
Publication date: 2022-07-12
Also published as: WO2021098810A1

Abstract

A class of compounds as non-steroidal-selective androgen receptor modulators and their use in the manufacture of medicaments for the treatment of androgen receptor mediated disorders. Specifically disclosed is a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.

Description

Compounds useful as selective androgen receptor modulators

The present application claims priority as follows

CN 201911142843.4; application date: 2019-11-20.

Technical Field

The present invention relates to compounds as non-steroid selective androgen receptor modulators and their use in the preparation of medicaments for the treatment of androgen receptor mediated disorders. In particular to a compound shown in a formula (I) or pharmaceutically acceptable salt thereof.

Background

The Androgen Receptor (AR), also known as NR3C4, belongs to a steroid receptor in the nuclear receptor superfamily, and can stimulate protein anabolism, enhance muscles and bones, maintain hormone balance in the body, and the like by combining with androgen, and is a mediator for androgen to play important physiological roles. With the increase of age, the production of androgen in human body is decreased, and the diseases related to age, such as muscular atrophy, cachexia, osteoporosis, bone fracture, fatigue weakness, hypogonadism and other muscular and skeletal diseases, are happened, and although the corresponding androgen therapy can regulate the increase of muscle and skeleton by activating androgen receptor, and relieve a series of androgen deficiency diseases, it is easy to cause adverse side effects, such as acne, female virilization, facial and body hair excess, prostatic hyperplasia, cardiovascular related diseases, etc. The non-steroid Selective Androgen Receptor Modulators (SARMs) are used as partial agonists of androgen receptors, can selectively stimulate anabolic pathways of the androgen receptors in muscles and bones, increase the number and thickness of muscle fibers, enhance bone density and bone strength, and accelerate fracture recovery, thereby effectively treating various senile-related diseases such as muscular atrophy, fracture and the like, and avoiding serious side effects with high therapeutic index. The nonsteroidal-selective androgen receptor modulator VK5211(WO2009082437) developed by Viking Therapeutics is in the second clinical stage.

In view of the important role of selective androgen receptor modulators, it is of great importance to develop selective androgen receptor modulators that are useful as therapeutic drugs.

Disclosure of Invention

The invention provides a compound shown in a formula (I) or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

T ₁independently selected from N, CH and CR₅；

T ₂Independently selected from N, CH and CR₆；

R ₁Independently selected from H, F, Cl, Br, I, OH, NH₂、CN、C _1-3Alkyl and C_1-3Alkoxy radical, said C_1-3Alkyl and C_1-3Alkoxy is optionally substituted by 1, 2 or 3R_aSubstitution;

R ₂and R₃Each independently selected from F, Cl, Br, I, OH and NH₂；

Or, R₂、R ₃Together with the atoms to which they are attached form C_3-5Cycloalkyl radical, said C _3-5Cycloalkyl is optionally substituted by 1, 2 or 3R_bSubstitution;

R ₄independently selected from F, Cl, Br, I, OH, C_1-6Alkyl and C_1-6Alkoxy radical, said C_1-6Alkyl and C_1-6Alkoxy is optionally substituted by 1, 2 or 3R_cSubstitution;

R ₅independently selected from F, Cl, Br, I, CN, C_1-3Alkyl and C_1-3Alkoxy radical, said C_1-3Alkyl and C_1-3Alkoxy is optionally substituted by 1, 2 or 3R_dSubstitution;

R ₆independently selected from F, Cl, Br, I, OH, NH₂And CN;

R _a、R _band R_dEach independently selected from F, Cl, Br, I and OH;

R _cindependently selected from F, Cl, Br, I, OH, C_1-3Alkyl and C_1-3Alkoxy radical, said C_1-3Alkyl and C_1-3Alkoxy is optionally substituted with 1, 2 or 3R;

r is independently selected from F, Cl, Br and I.

In some embodiments of the invention, R is as defined above₁Independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CH ₃、CH ₂CH ₃、C(CH ₃) ₂And OCH₃Said CH₃、CH ₂CH ₃、C(CH ₃) ₂And OCH₃Optionally substituted by 1, 2 or 3R_aAnd, the other variables are as defined herein.

In some embodiments of the present invention, R is₁Independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CH ₃、CH ₂F、CHF ₂、CF ₃、CH ₂CH ₃、C(CH ₃) ₂And OCH₃The other variables are as defined herein.

In some embodiments of the invention, R is as defined above₂、R ₃And the atoms to which they are attached together form cyclopropyl, cyclobutyl and cyclopentyl optionally substituted by 1, 2 or 3R_bAnd the other variables are as defined herein.

In some embodiments of the invention, R is as defined above₂And R₃Together with the atoms to which they are attached

The other variables are as defined herein.

In some embodiments of the invention, R is as defined above_cIndependently selected from F, Cl, Br, I, OH, CH₃、CH ₂F、CHF ₂、CF ₃、CH ₂CH ₃、C(CH ₃) ₂And OCH₃And the other variables are as defined herein.

In some embodiments of the invention, R is as defined above₄Independently selected from F, Cl, Br, I, OH, C_1-3Alkyl and C_1-3Alkoxy radical, said C_1- ₃Alkyl and C_1-3Alkoxy is optionally substituted by 1, 2 or 3R_cAnd, the other variables are as defined herein.

In some embodiments of the present invention, R is₄Independently selected from F, Cl, Br, I, OH, CH₃、CH ₂CH ₃And OCH₃Said CH₃、CH ₂CH ₃And OCH₃Optionally substituted by 1, 2 or 3R_cAnd the other variables are as defined herein.

In some embodiments of the invention, R is as defined above₄Independently selected from F, Cl, Br, I,OH、CH ₃、CF ₃、CH ₂CH ₃、OCH ₃And

other variables are as defined herein.

In some embodiments of the invention, R is as defined above₄Is independently selected from

Other variables are as defined herein.

In some embodiments of the invention, R is as defined above₅Independently selected from F, Cl, Br, I, CN, CH₃And OCH₃The other variables are as defined herein.

In some embodiments of the invention, the structural unit

Is selected from

Other variables are as defined herein.

In some embodiments of the present invention, the structural unit

Is selected from

Other variables are as defined herein.

Further aspects of the invention are derived from any combination of the above variables.

In some embodiments of the invention, the compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

wherein the content of the first and second substances,

R ₁、R ₂、R ₃、R ₄、R ₅and R₆As defined herein.

wherein the content of the first and second substances,

R ₁、R ₂、R ₃、R ₄、R ₅and R₆As defined herein.

The invention also provides a compound shown as the following formula or a pharmaceutically acceptable salt thereof,

in some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is used for preparing a medicament for treating androgen receptor mediated diseases.

In some embodiments of the present invention, the use as described above, wherein said medicament is a non-steroid-selective androgen receptor modulator medicament.

In some embodiments of the present invention, the above-mentioned application is characterized in that the drug is a drug for various senile diseases such as muscular atrophy, bone fracture, osteoporosis, and the like.

Technical effects

The compounds of the present invention have selective androgen receptor modulating activity. The compound of the invention has certain oral exposure and oral bioavailability, and good oral PK property.

Definitions and explanations

As used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.

The term "pharmaceutically acceptable" as used herein is intended to refer to those 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.

The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amines or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid, either in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and salts of organic acids including acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like; also included are salts of amino acids such as arginine and the like, and salts of organic acids such as glucuronic acid and the like. Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains an acid or base, by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two.

Unless otherwise indicated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.

Unless otherwise indicated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.

Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" results from the inability of a double bond or a single bond to rotate freely within a ring-forming carbon atom.

Unless otherwise indicated, the term "diastereomer" refers to a stereoisomer in which the molecules have two or more chiral centers and a non-mirror image relationship between the molecules.

Unless otherwise indicated, "(+)" means dextrorotation, "(-) -means levorotation," (±) "means racemization.

Using solid wedge keys, unless otherwise indicated

And wedge dotted bond

Showing the absolute configuration of a solid centre, using straight solid keys

And straight dotted line bond

Showing the relative configuration of the centres of solids, by wavy lines

Indicating solid-line wedge-shaped keys

Or wedge dotted bond

Or by wavy lines

Indicating straight solid-line keys

Or straight dotted line bond

Unless otherwise indicated, the terms "enriched in one isomer", "isomer enriched", "enantiomer enriched" or "enantiomeric enrichment" refer to a content of one isomer or enantiomer of 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%.

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

Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the invention is desired, 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 pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).

The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioactive isotopes, such as tritium (A), (B), (C) and C)³H) Iodine-125 (¹²⁵I) Or C-14(¹⁴C) In that respect For example, deuterium can be used to replace hydrogen to form a deuterated drug, the bond formed by deuterium and carbon is stronger than the bond formed by common hydrogen and carbon, and compared with an undeuterated drug, the deuterated drug has the advantages of reducing toxic and side effects, increasing the stability of the drug, enhancing the curative effect, prolonging the biological half-life period of the drug and the like. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

The term "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

The term "substituted" means that any one or more hydrogen atoms on the specified atom is replaced with a substituent, and may include variations of deuterium and hydrogen, as long as the valence of the specified atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., ═ O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemical realizability.

When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

When the number of one linking group is 0, e.g. - (CRR)₀-, represents that the linking group is a single bond.

When the number of a substituent is 0, it means that the substituent is absent, such as-A- (R)₀Indicating that the structure is actually-a.

When a substituent is absent, it indicates that the substituent is absent, e.g., when X is absent in A-X, it indicates that the structure is actually A.

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, for example, where L represents a single bond in A-L-Z means that the structure is actually A-Z.

When a substituent bond can be cross-linked to more than two atoms of a ring, such substituent may be bonded to any atom of the ring, e.g. a building block

Means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. When no atom through which a substituent is attached to a substituted group is indicated in the listed substituents, such substituents may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be attached to a substituted group through any one of carbon atoms on the pyridine ring.

When the listed linking groups do not indicate their direction of attachment, the direction of attachment is arbitrary, for example,

wherein the linking group L is-M-W-, in which case-M-W-can be formed by connecting the ring A and the ring B in the same direction as the reading sequence from left to right

The ring A and the ring B may be connected in the reverse direction of the reading sequence from left to right

Combinations of the linking groups, substituents, and/or variants thereof are permissible only if such combinations result in stable compounds.

Unless otherwise specified, when a group has one or more attachable sites, any one or more of the sites of the group may be attached to other groups by chemical bonds. When the chemical bond is not positioned and H atoms exist in the connectable sites, the number of the H atoms of the connectable sites is correspondingly reduced along with the number of the connected chemical bonds to become a group with corresponding valence number. The chemical bond linking said site to other groups may be a direct solid bond

Straight dotted line key

Or wavy lines

And (4) showing. For example-OCH₃The straight solid line bond in (a) represents a bond to another group via an oxygen atom in the group;

the straight dotted bond in (1) represents the linkage to the other group through both ends of the nitrogen atom in the group;

the wavy line in (a) indicates that the phenyl group is bonded to other groups through the carbon atoms at the 1-and 2-positions in the phenyl group;

means that any of the available attachment sites on the piperidinyl group can be attached to another group via 1 bond, including at least

These 4 linkages, even though the-N-atom is drawn as a H atom, are

Still comprise

The radical of this attachment mode, except that when 1 chemical bond is attached, the H at that site is reduced by 1 to become the corresponding monovalent piperidinyl group.

Unless otherwise specified, the number of atoms on a ring is generally defined as the number of ring members, e.g., "5-7 membered ring" means a "ring" around which 5-7 atoms are arranged.

Unless otherwise specified, the term "C_1-6Alkyl "is intended to mean a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. Said C is_1-6The alkyl group comprising C_1-5、C _1-4、C _1-3、C _1-2、C _2-6、C _2-4、C ₆And C₅Alkyl, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C_1-6Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, and the like.

Unless otherwise specified, the term "C_1-3Alkyl "is intended to mean a straight or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. Said C is_1-3The alkyl group comprising C_1-2And C_2-3Alkyl, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C_1-3Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

Unless otherwise specified, the term "C_1-6Alkoxy "denotes those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule through an oxygen atom. Said C is_1-6Alkoxy radicals comprising C_1-4、C _1-3、C _1-2、C _2-6、C _2-4、C ₆、C ₅、C ₄And C₃Alkoxy, and the like. C_1-6Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, and the like.

Unless otherwise specified, the term "C_1-3Alkoxy "refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom. Said C is_1-3Alkoxy radicals comprising C_1-2、C _2-3、C ₃And C₂Alkoxy, and the like. C_1-3Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

Unless otherwise specified, "C" is_3-5Cycloalkyl "denotes a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, being a monocyclic ring system, said C_3-5Cycloalkyl radicals including C_3-4And C_4-5Cycloalkyl groups and the like; it may be monovalent, divalent or polyvalent. C_3-5Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.

The term "protecting group" includes, but is not limited to, "amino protecting group," hydroxyl protecting group, "or" thiol protecting group. The term "amino protecting group" refers to a protecting group suitable for use in preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: a formyl group; acyl, for example alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), 1-bis- (4' -methoxyphenyl) methyl; silyl groups, such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for use in preventing side reactions of a hydroxy group. Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g. acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (benzhydryl, DPM); silyl groups, such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like.

The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention.

The compounds of the present invention may be structurally confirmed by conventional methods well known to those skilled in the art, and if the present invention relates to the absolute configuration of the compound, the absolute configuration may be confirmed by means of conventional techniques in the art. For example, single crystal X-ray diffraction method (SXRD), diffraction intensity data of the cultured single crystal is collected by a Bruker D8 venture diffractometer, a light source is CuK alpha radiation, and a scanning mode is as follows:

after scanning and collecting relevant data, the crystal structure is further analyzed by a direct method (Shelxs97), so that the absolute configuration can be confirmed.

The solvent used in the present invention can be commercially available.

The invention employs the following abbreviations: aq represents water; eq represents equivalent, equivalent; DCM represents dichloromethane; PE represents petroleum ether; DMSO represents dimethyl sulfoxide; EtOAc for ethyl acetate; EtOH represents ethanol; MeOH represents methanol; cbz represents benzyloxycarbonyl, an amine protecting group; BOC represents tert-butoxycarbonyl as an amine protecting group; r.t. represents room temperature; O/N stands for overnight; THF represents tetrahydrofuran; boc₂O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA stands for diisopropylethylamine; iPrOH represents 2-propanol; mp represents the melting point.

The compounds are used according to the conventional naming principle in the field

The software names, and the commercial compounds are under the supplier catalog name.

Detailed Description

The present invention is described in detail below by way of examples, but is not meant to be limited to any of the disadvantages of the present invention. Having described the invention in detail and having disclosed specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Example 1

The synthetic route is as follows:

1) synthesis of Compound 1-2

1-1(50g, 205.55mmol) and toluene (500mL) were added to a predried three-necked flask, the temperature was reduced to-78 deg.C, lithium triethylborohydride (1M, 209.66mL) was added dropwise to the system, and the system was stirred at-78 deg.C for 2 hours. N, N-diisopropylethylamine (158.08g, 1.22mol, 213.05mL), 4-dimethylaminopyridine (2.49g, 20.39mmol) and trifluoroacetic anhydride (51.38g, 244.63mmol, 34.03mL) were added dropwise and the system was allowed to warm to 15 ℃ naturally and stirred for 16 hours. Adding water (500mL), extracting with ethyl acetate (500mL), collecting the organic phase, washing the organic phase with saturated brine (500 mL. times.2), concentrating under reduced pressure to obtain crude product, and purifying the crude product with column to obtain compound 1-2. LCMS (ESI) M/z 172[ M-55 ]] ⁺。

2) Synthesis of Compounds 1-3

A predried 250mL three-necked flask was charged with diethylzinc (1M, 52.80mL), toluene (40mL), the system was cooled to 0 deg.C, chloroiodomethane (18.63g, 105.61mmol, 7.67mL) was added, the system was stirred at 0 deg.C for 0.5 h, then a solution of 1-2(4g, 17.60mmol) in toluene (40mL) was added dropwise and the system was stirred at 15 deg.C for 2 h. Adding 1M hydrochloric acid (80mL) into the system, extracting with ethyl acetate (80mL), collecting an organic phase, washing the organic phase with saturated saline (80mL × 2), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain the compound 1-3. LCMS (ESI) M/z 186[ M-55 ]] ⁺。

3) Synthesis of Compounds 1-4

1-3(1.5g, 6.22mmol) and tetrahydrofuran (10mL) were added to a pre-dried 100mL three-necked flask, the temperature was reduced to-60 deg.C, lithium aluminum hydride (943mg, 24.87mmol) was added, and the system was stirred at-60 deg.C for 3 hours. Adding 1M hydrochloric acid (10mL), extracting with ethyl acetate (10mL), collecting the organic phase, washing the organic phase with saturated brine (10 mL. times.2), drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain crude compounds 1-4. LCMS (ESI) M/z 158[ M-55 ]] ⁺。

4) Synthesis of Compounds 1-5

A predried 100mL three-necked flask was charged with 1-4(1.3g, 6.10mmol), ethyl acetate (10mL), N, N-diisopropylethylamine (4.73g, 36.57mmol, 6.37mL), cooled to 0 deg.C, and a solution of pyridine sulfur trioxide complex (2.91g, 18.29mmol) in dimethyl sulfoxide (10mL) was added dropwise, and the system was stirred at 0 deg.C for 1 hour. 1M hydrochloric acid (10mL) was added, extraction was performed with ethyl acetate (10mL), the organic phase was collected, washed with saturated brine (10 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compounds 1-5. LCMS (ESI) M/z 156[ M-55 ]] ⁺。

5) Synthesis of Compounds 1-6

1-5(1.2g, 5.68mmol), trifluoromethyltrimethylsilane (969mg, 6.82mmol), and tetrahydrofuran (15mL) were added to a predried 100mL three-necked flask, cooled to 0 deg.C, tetrabutylammonium fluoride (1M, 8.52mL) was added dropwise, and the system was stirred at 0 deg.C for 1 hour. 1M hydrochloric acid (15mL) was added to the system, and extraction was performed with ethyl acetate (15mL), and the organic phase was collected, washed with saturated brine (15 mL. times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compounds 1 to 6. LCMS (ESI) M/z 226[ M-55 ]] ⁺。

6) Synthesis of Compounds 1-7

A previously dried 50mL single neck flask was charged with 1-6(1.4g, 4.98mmol), hydrochloric acid/ethyl acetate (14mL) and the system was stirred at 25 ℃ for 1 hour. Water (15mL) is added into the system, the pH of the water phase is adjusted to 9 by sodium hydroxide, ethyl acetate (15mL) is added for extraction, the organic phase is collected, the organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and the filtrate is decompressed and concentrated to obtain crude compounds 1-7. LCMS (ESI) M/z 182[ M +1 ]] ⁺。

7) Synthesis of Compound 1A or 1B or 1C or 1D

A50 mL single-necked flask previously dried was charged with 1-8(983mg, 3.31mmol), 1-7(0.6g, 3.31mmol) dioxane (12mL), followed by tris (dibenzylideneacetone) dipalladium (303mg, 331.21. mu. mol), 2, 2-bis (diphenylphosphino) -1, 1-binaphthyl (206.23mg, 331.21. mu. mol), cesium carbonate (2.16g, 6.62mmol), and nitrogen replaced 3 times, and the system was stirred at 100 ℃ for 3 hours. Adding water (20mL), extracting with ethyl acetate (20mL), collecting organic phase, and collecting organic phaseWashing with saturated brine (20mL x 3), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain crude product, and purifying the crude product by preparative high performance liquid chromatography (acidic system) to obtain compound 1A. SFC detection (ee: 98.6%), column: chiralpak AD-310 x4.6mm I.D., 3 μm; mobile phase: a is supercritical carbon dioxide, B is 0.05 percent of isopropylamine methanol solution; gradient: b initial 10% hold for 0.5 min, from 10% to 40% in 2.0min, 40% hold for 2.0min, return to 10% in 0.7 min, 10% equilibrate for 0.8 min; flow rate: 2.5 mL/min; column temperature: 35 ℃; wavelength: 220nm, retention time: 1.19 min.¹HNMR(400MHz,CDCl ₃)δppm 7.59-7.61(m,1H),7.07(s,1H),6..82-6.85(m,1H),4.14-4.28(m,2H),3.23-3.25(m,1H),2.72-2.77(m,1H),2.60-2.61(m,1H),2.05-2.11(m,1H),1.90-1.91(m,1H),1.12-1.16(m,1H),0.35-0.36(m,1H)；LCMS(ESI)m/z:351[M+1] ⁺。

Example 2

The synthesis route is as follows:

1) synthesis of Compound 2-2

A round-bottomed flask was charged with compound 2-1(3g, 15.30mmol), N-bromosuccinimide (5.99g, 33.67mmol), benzoyl peroxide (556mg, 2.30mmol), carbon tetrachloride (40mL) and reacted at 90 ℃ for 16 hours while substituting nitrogen three times. And (3) carrying out reduced pressure concentration on the reaction liquid to obtain a crude product, and purifying the crude product by column chromatography to obtain the compound 2-2.¹HNMR(400MHz,CDCl ₃)δppm 8.18(d,J＝1.88Hz,1H),7.60(dd,J＝8.28,1.88Hz,1H),7.48(d,J＝8.28Hz,1H),6.92(s,1H)。

2) Synthesis of Compounds 2-3

A round-bottom flask was charged with Compound 2-2(1g, 2.83 mmo)l), silver nitrate (2.40g, 14.13mmol), water (1mL), acetonitrile (8mL) three times with nitrogen, and reacted at 90 ℃ for 16 hours. And (3) carrying out reduced pressure concentration on the reaction liquid to obtain a crude product, and purifying the crude product by column chromatography to obtain a compound 2-3.¹HNMR(400MHz,CDCl ₃)δppm 10.31(s,1H),8.19(d,J＝2.01Hz,1H),7.90(dd,J＝8.16,2.01Hz,1H),7.71(d,J＝8.16Hz,1H)。

3) Synthesis of Compounds 2-4

Compound 2-3(300mg, 1.43mmol), ethanol (8.35. mu.L), dichloromethane (4mL), diethylaminosulfur trifluoride (460mg, 2.86mmol, 377.45. mu.L) were added to a thumb flask, and the mixture was reacted for 1 hour at 25 ℃ with nitrogen substitution three times. Adding saturated sodium bicarbonate solution (10mL), extracting with dichloromethane (10mL × 3), collecting organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain crude product, and purifying the crude product by column chromatography to obtain compound 2-4.¹HNMR(400MHz,CDCl ₃)δppm7.93(s,1H),7.78(dd,J＝8.28,0.88Hz,1H),7.63(d,J＝8.28Hz,1H),6.74-7.07(m,1H)。

4) Synthesis of Compounds 2A or 2B or 2C or 2D

In a thumb flask, compounds 1-7(50mg, 276.01. mu. mol), compounds 2-4(64mg, 276.01. mu. mol), cesium carbonate (224mg, 690.02. mu. mol), tris (dibenzylideneacetone) dipalladium (25mg, 27.60. mu. mol), 2, 2-bis (diphenylphosphino) -1, 1-binaphthyl (17mg, 27.60. mu. mol), dioxane (1mL) was added three times with nitrogen and reacted at 100 ℃ for 2 hours. And (3) carrying out reduced pressure concentration on the reaction liquid to obtain a crude product, and purifying the crude product by column chromatography and preparative high performance liquid chromatography (alkaline system) to obtain the compound 2A. SFC detection (ee: 96.68%), column: chiralpak AD-3150 x4.6mm I.D., 3 μm; mobile phase: a is supercritical carbon dioxide, B is 0.05 percent isopropyl amine isopropanol solution; gradient: b initial 10% hold for 0.5 min, from 10% to 40% in 2.0min, 40% hold for 2.0min, return to 10% in 0.7 min, 10% equilibrate for 0.8 min; flow rate: 2.5 mL/min; column temperature: 35 ℃; wavelength: 220nm, retention time: 1.77 min.¹HNMR(400MHz,CDCl ₃)δppm 7.56(d,J＝8.66Hz,1H),7.05(s,1H),6.71-7.02(m,2H),4.28(br s,1H),4.16(br d,J＝9.03Hz,1H),3.21-3.30(m,1H),2.68-2.79(m,1H),2.44(br s,1H),2.08(dd,J＝13.99,8.85Hz,1H),1.88(br s,1H),1.04-1.17(m,1H),0.34(s,1H)；LCMS(ESI)m/z:333.09[M+1] ⁺。

Example 3

The synthetic route is as follows:

1) synthesis of Compounds 3A or 3B or 3C or 3D

A50 mL single-neck flask previously dried was charged with 3-1(119mg, 552.01. mu. mol, 1eq), 1-7(0.1g, 552.01. mu. mol), dioxane (4mL), and then tris (dibenzylideneacetone) dipalladium (50mg, 55.20. mu. mol), 2, 2-bis (diphenylphosphino) -1, 1-binaphthyl (34.37mg, 55.20. mu. mol), cesium carbonate (359mg, 1.10mmol), replaced with nitrogen 3 times, and the system was stirred at 100 ℃ for 3 hours. Water (20mL) was added, extraction was performed with ethyl acetate (20mL), the organic phase was collected, washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product is purified by preparative high performance liquid chromatography (acidic system) and resolved by supercritical fluid chromatography (alkaline system) to obtain the compound 3A. SFC detection (ee: 100%), column: chiralpak AD-3150 x4.6mm i.d., 3 μm; mobile phase: a is supercritical carbon dioxide, B is 0.05 percent isopropyl amine isopropanol solution; gradient: b initial 10% hold for 0.5 min, from 10% to 40% in 2.0min, 40% hold for 2.0min, return to 10% in 0.7 min, 10% equilibrate for 0.8 min; flow rate: 2.5 mL/min; column temperature: 35 ℃; wavelength: 220nm, retention time: 2.18 min.¹HNMR(400MHz,CDCl ₃)δppm 7.34-7.36(m,1H),6.79-6.80(s,1H),6.57-6.59(m,1H),4.30-4.37(m,1H),4.08-4.10(m,1H),3.20-3.24(m,1H),3.05-3.07(m,1H),2.74-2.75(m,1H),2.05-2.08(m,1H),1.86-1.87(m,1H),1.08-1.11(m,1H),0.31-0.35(m,1H)；LCMS(ESI)m/z:317[M+1] ⁺。

Example 4

The synthesis route is as follows:

1) synthesis of Compounds 4A or 4B or 4C or 4D

Compound 4-1(0.08g, 377. mu. mol), compound 1-7(68mg, 377. mu. mol), cesium carbonate (307mg, 943. mu. mol), 2, 2-bis (diphenylphosphino) -1, 1-binaphthyl (23mg, 37. mu. mol) and 1, 4-dioxane (2mL) were charged into a reaction tube, and reacted at 100 ℃ for 16 hours under nitrogen protection with tris (dibenzylideneacetone) dipalladium (35mg, 38. mu. mol). And concentrating the reaction liquid under reduced pressure to obtain a crude product, and performing supercritical fluid chromatographic resolution (alkaline system) on the crude product to obtain the compound 4A. SFC detection (ee: 99.24%), column: chiralpak AS-3150 x4.6mm I.D., 3 μm; mobile phase: a is supercritical carbon dioxide, B is 0.05 percent isopropyl amine isopropanol solution; gradient: b initial 10% hold for 0.5 min, from 10% to 40% in 2.0min, 40% hold for 2.0min, return to 10% in 0.7 min, 10% equilibrate for 0.8 min; flow rate: 2.5 mL/min; column temperature: 35 ℃; wavelength: 220nm, retention time: 3.11 min.¹HNMR(400MHz,CDCl ₃)δppm 7.29(d,J＝8.61Hz,1H),6.31(dd,J＝8.61,2.15Hz,1H),6.20(d,J＝1.96Hz,1H),4.32-4.41(m,1H),4.10(br d,J＝8.41Hz,1H),3.88(s,3H),3.24(ddd,J＝7.19,5.04,2.45Hz,1H),2.84(d,J＝5.28Hz,1H),2.73(br dd,J＝13.69,8.02Hz,1H),2.03-2.11(m,1H),1.79-1.88(m,1H),1.05(dt,J＝8.66,5.26Hz,1H),0.34(td,J＝5.14,2.45Hz,1H)；LCMS(ESI)m/z:313[M+1] ⁺。

Example 5

The synthetic route is as follows:

1) synthesis of Compounds 5A or 5B or 5C or 5D

Compound 5-1(0.1g, 500. mu. mol), compound 1-7(91mg, 500. mu. mol), potassium phosphate (265mg, 1.25mmol), 2, 2-bis (diphenylphosphino) -1, 1-binaphthyl (31mg, 50. mu. mol) and 1, 4-dioxane (1mL) were added to a reaction tube, and under nitrogen protection, tris (dibenzylideneacetone) dipalladium (46mg, 50. mu. mol) was added and reacted at 100 ℃ for 16 hours. And concentrating the reaction solution under reduced pressure to obtain a crude product, purifying the crude product by column chromatography, and recrystallizing and purifying the purified product by using dichloromethane and petroleum ether again to obtain the compound 5A. SFC detection (ee: 92%), column: chiralpak AD-3150 x4.6mm I.D., 3 μm; mobile phase: a is supercritical carbon dioxide, B is 0.05 percent of isopropylamine methanol solution; gradient: b initial 10% hold for 0.5 min, from 10% to 40% in 2.0min, 40% hold for 2.0min, return to 10% in 0.7 min, 10% equilibrate for 0.8 min; flow rate: 2.5 mL/min; column temperature: 35 ℃; wavelength: 220nm, retention time: 1.98 min.¹HNMR(400MHz,CDCl ₃)δppm 7.35-7.42(m,1H),6.52(t,J＝2.45Hz,1H),6.49(s,1H),4.25-4.35(m,1H),4.09(br d,J＝8.61Hz,1H),3.20(ddd,J＝7.14,4.99,2.35Hz,1H),2.73(br dd,J＝12.13,8.41Hz,1H),2.55(d,J＝5.28Hz,1H),2.08(dd,J＝13.89,8.61Hz,1H),1.81-1.92(m,1H),1.10(dt,J＝8.75,5.40Hz,1H),0.34(td,J＝5.18,2.54Hz,1H)；LCMS(ESI)m/z:301[M+1] ⁺。

Example 6

The synthetic route is as follows:

1) synthesis of Compound 6-2

Compound 6-1(0.8g, 3.83mmol), ethanol (4mL), concentrated hydrochloric acid (4mL) were added to a three-necked flask, and the mixture was purged with nitrogen three times and reacted at 80 ℃ for 1.5 hours. And concentrating the reaction solution under reduced pressure to obtain a crude product, adjusting the pH value of the crude product to 8 by using a saturated sodium bicarbonate aqueous solution, extracting by using ethyl acetate (10mL & lt3 & gt), separating, combining organic phases, washing by using saturated saline solution (10mL & lt3 & gt), drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain the crude product, and purifying the crude product by using column chromatography to obtain the compound 6-2.¹HNMR(400MHz,CDCl ₃)δppm 7.32(d,J＝8.41Hz,1H),6.58(d,J＝8.41Hz,1H),4.17-4.27(m,2H),2.25(s,3H)。

2) Synthesis of Compound 6-3

A dry three-necked flask was charged with 6-2(0.4g, 2.40mmol) and concentrated hydrochloric acid (12M, 4.00mL), cooled to 0 deg.C, added with an aqueous solution (1mL) of sodium nitrite (182mg, 2.64mmol), stirred for 30 minutes, added with sodium iodide (395mg, 2.64mmol), and allowed to warm to 25 deg.C naturally for 1 hour. And adding saturated sodium bisulfite aqueous solution (15mL) into the reaction solution to adjust the pH value to 8, adding ethyl acetate (15mL) for extraction, concentrating the organic phase under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain a compound 6-3.¹HNMR(400MHz,CDCl ₃)δppm 7.84-7.90(m,1H),7.19(s,1H),2.66(s,3H)。

3) Synthesis of Compound 6A or 6B or 6C or 6D

In a previously dried single neck flask were added compound 6-3(100mg, 360.37. mu. mol), compound 1-7(65mg, 360.37. mu. mol), cesium carbonate (234mg, 720.75. mu. mol), 2, 2-bis (diphenylphosphino) -1, 1-binaphthyl (22mg, 36.04. mu. mol), tris (dibenzylideneacetone) dipalladium (33mg, 36.04. mu. mol), followed by dioxane (2mL), nitrogen purge three times, and stirring in an oil bath at 100 ℃ for 16 hours. The solvent was concentrated to dryness under reduced pressure. Ethyl acetate (5mL) and saturated brine (5mL) were added to the mixture to separate the mixture, and the organic phase was dried over anhydrous sodium sulfateFiltering, concentrating the filtrate under reduced pressure to obtain crude product, and purifying the crude product by preparative thin-layer chromatography silica gel plate and preparative high performance liquid chromatography (alkaline system) to obtain the compound 6A. SFC detection (ee: 98%), column: chiralpak OD-3150 x4.6mm I.D., 3 μm; mobile phase: a is supercritical carbon dioxide, B is 0.05 percent of isopropylamine methanol solution; gradient: b initial 10% hold for 0.5 min, from 10% to 40% in 2.0min, 40% hold for 2.0min, return to 10% in 0.7 min, 10% equilibrate for 0.8 min; flow rate: 2.5 mL/min; column temperature: 35 ℃; wavelength: 220nm, retention time: 2.15 min.¹HNMR(400MHz,CDCl ₃)δppm 7.54(d,J＝8.4Hz,1H),7.01(d,J＝8.4Hz,1H),3.90-3.79(m,1H),3.66(s,1H),3.25(br d,J＝2.1Hz,1H),2.53(s,3H),2.50-2.43(m,1H),2.24-2.13(m,1H),1.56(s,2H),0.60(br s,1H),0.33-0.23(m,1H)；LCMS(ESI)m/z:331.1[M+1] ⁺。

Example 7

The synthesis route is as follows:

1) synthesis of Compound 7-2

To a dry thumb bottle, compound 7-1(5g, 31.73mmol) and dichloromethane (50mL) were added followed by water (50mL), sodium bicarbonate (5.50g, 65.47mmol, 2.55mL) and elemental iodine (8.05g, 31.72mmol, 6.39mL) and the reaction was heated to 50 ℃ under reflux for 22 hours. Diluting the reaction solution with ethyl acetate (50mL), washing with saturated sodium thiosulfate (50mL), washing with sodium bisulfite (50mL), drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain the compound 7-2.¹HNMR(400MHz,CDCl ₃)δppm 7.34-7.38(m,1H),6.45-6.46(m,1H),3.81-3.84(m,3H)。

2) Synthesis of Compound 7-3

To a dry three-necked flask, a solution of compound 7-2(3g, 10.58mmol) in N, N dimethylformamide (30mL), zinc cyanide (0.8g, 6.81mmol, 432. mu.L), 1, 1' -bis (diphenylphosphino) ferrocene (586mg, 1.06mmol), nitrogen blanket, and finally tris (dibenzylideneacetone) dipalladium (969mg, 1.06mmol) were added, nitrogen replaced three times, and reacted at 120 ℃ for 1.5 hours. Adding water (30mL) and ethyl acetate (30mL) into the reaction solution in sequence, separating, collecting an organic phase, washing the organic phase with saturated saline (30mL x 3), filtering with kieselguhr, washing with saturated saline (100mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain the compound 7-3.¹HNMR(400MHz,CDCl ₃)δppm 7.23(d,J＝8.41Hz,1H),6.63(d,J＝8.61Hz,1H),4.45(br s,2H),3.87(s,3H)。

3) Synthesis of Compound 7-4

To a dry three-necked flask, compound 7-3(0.3g, 1.64mmol), concentrated hydrochloric acid (12M, 3.00mL) was added, the temperature was reduced to 0 deg.C, a solution of sodium nitrite (124mg, 1.81mmol) in water (1mL) was added, the mixture was stirred for 30 minutes, and finally sodium iodide (270mg, 1.81mmol) was added, and the temperature was naturally raised to 25 deg.C and reacted for 30 minutes. Adding saturated sodium bicarbonate aqueous solution (10mL) and ethyl acetate (10mL) into the reaction solution in sequence, filtering by using diatomite, collecting filtrate, extracting and separating liquid, washing an organic phase by using saturated saline solution (10mL), drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying the crude product by using column chromatography to obtain the compound 7-4.¹HNMR(400MHz,CDCl ₃)δppm 7.82(d,J＝8.22Hz,1H),7.16(d,J＝8.22Hz,1H),3.92(s,3H)。

4) Synthesis of Compounds 7A or 7B or 7C or 7D

In a pre-dried single neck flask were added compound 7-4(100mg, 340.73. mu. mol), compound 1-7(61mg, 340.73. mu. mol), cesium carbonate (222mg, 681.46. mu. mol), 2, 2-bis (diphenylphosphino) -1, 1-binaphthyl (21.22mg, 34.07. mu. mol), tris (dibenzylideneacetone) dipalladium (31mg, 34.07. mu. mol), followed by dioxane (2mL), nitrogen purged three times, and stirred in an oil bath at 100 ℃ for 16 hours. After vacuum concentrationAdding ethyl acetate (5mL) and saturated saline solution (5mL) for separating, drying the organic phase by anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and sequentially purifying the crude product by a preparative thin-layer chromatography silica gel plate and performing supercritical fluid chromatography (alkaline system) to obtain the compound 7A. SFC detection (ee: 98.88%), column: chiralpak AS-3150 x4.6mm I.D., 3 μm; mobile phase: a is supercritical carbon dioxide, B is 0.05 percent isopropyl amine isopropanol solution; gradient: b initial 10% hold for 0.5 min, from 10% to 40% in 2.0min, 40% hold for 2.0min, return to 10% in 0.7 min, 10% equilibrate for 0.8 min; flow rate: 2.5 mL/min; column temperature: 35 ℃; wavelength: 220nm, retention time: 2.53 min.¹HNMR(400MHz,CDCl ₃)δ7.31(d,J＝8.6Hz,1H),6.85(d,J＝8.8Hz,1H),4.31-4.20(m,1H),4.02-3.93(m,1H),3.85(s,3H)3.72(ddd,J＝2.5,5.6,6.7Hz,1H),2.65-2.57(m,1H),2.53(d,J＝4.7Hz,1H),2.11(dd,J＝8.1,13.2Hz,1H),1.69(br d,J＝1.8Hz,1H),0.72-0.65(m,1H),0.41(dt,J＝2.5,5.3Hz,1H)；LCMS(ESI)m/z:347[M+1] ⁺。

Example 8

The synthetic route is as follows:

1) synthesis of Compound 8-2

The compound 8-1(0.7g, 4.10mmol), hydrochloric acid (12M, 8.75mL) was added to a three-necked flask, and after cooling to 0 ℃ and adding a solution of sodium nitrite (311mg, 4.51mmol) in water (2mL), sodium iodide (676mg, 4.51mmol) was added thereto and stirring was carried out at 0 ℃ for 30 minutes, sodium iodide (676mg, 4.51mmol) was added, and after completion of the addition, the temperature was naturally raised to 25 ℃ and stirred for 30 minutes. The reaction solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (10 mL. times.3), the organic phases were combined, washed with saturated brine (10 mL. times.3), dried over anhydrous sodium sulfate, filtered, and filteredConcentrating the solution under reduced pressure to obtain crude product, and purifying the crude product by column chromatography to obtain compound 8-2.¹HNMR(400MHz,CDCl ₃)δppm 7.81(dd,J＝8.31,5.58Hz,1H),,7.23(dd,J＝8.22,1.37Hz,1H)。

2) Synthesis of Compounds 8A or 8B or 8C or 8D

In a thumb flask, compounds 1-7(100mg, 552.01. mu. mol), compounds 8-2(170.90mg, 607.21. mu. mol), tris (dibenzylideneacetone) dipalladium (50mg, 55.20. mu. mol), cesium carbonate (449mg, 1.38mmol), 2, 2-bis (diphenylphosphino) -1, 1-binaphthyl (34mg, 55.20. mu. mol), dioxane (1mL) was added three times with nitrogen and reacted at 100 ℃ for 2 hours. And concentrating the reaction solution under reduced pressure to obtain a crude product, and purifying the crude product by a preparative high performance liquid chromatography (alkaline system) to obtain the compound 8A. SFC detection (ee: 96.8%), column: chiralpak AD-3150 x4.6mm I.D., 3 μm; mobile phase: a is supercritical carbon dioxide, B is 0.05 percent of isopropylamine methanol solution; gradient: b initial 10% hold 0.5 min, from 10% to 40% in 2.0min, 40% hold 2.0min, return to 10% in 0.7 min, 10% equilibrate 0.8 min; flow rate: 2.5 mL/min; column temperature: 35 ℃; wavelength: 220nm, retention time: 2.04 min.¹HNMR(400MHz,CDCl ₃)δppm 7.32(dd,J＝8.91,1.38Hz,1H),6.91(t,J＝8.47Hz,1H),4.32-4.41(m,1H),4.23-4.31(m,1H),3.35-3.42(m,1H),2.64-2.75(m,1H),2.51(d,J＝4.77Hz,1H),2.04(dd,J＝14.24,8.34Hz,1H),1.76-1.86(m,1H),0.98(dt,J＝8.44,5.38Hz,1H),0.37(td,J＝5.18,2.70Hz,1H)；LCMS(ESI)m/z:335[M+1] ⁺。

Example 9

The synthesis route is as follows:

1) synthesis of Compound 9-2

Compound 9-1(0.3g, 1.60mmol), aqueous hydrochloric acid (1M, 2mL) were added to a three-necked flask, and an aqueous solution (1mL) of sodium nitrite (121mg, 1.76mmol) was added thereto after cooling to 0 ℃, and sodium iodide (264mg, 1.76mmol) was added thereto after stirring at 0 ℃ for 0.5 hour, and then the mixture was stirred at 25 ℃ for 0.5 hour. Adjusting pH of the reaction solution to 8 with saturated sodium bicarbonate aqueous solution, extracting with ethyl acetate (10mL x 3), combining organic phases, washing the organic phases with saturated saline solution (10mL x 3), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain the compound 9-2.¹HNMR(400MHz,CDCl ₃)δppm 7.93(d,J＝8.28Hz,1H),7.28(s,0.5H),7.26(s,0.5H)。

2) Synthesis of Compounds 9A or 9B or 9C or 9D

In a thumb flask, compound 1-7(80mg, 441.61. mu. mol), compound 9-2(144mg, 485.77. mu. mol), cesium carbonate (360mg, 1.10mmol), 2, 2-bis (diphenylphosphino) -1, 1-binaphthyl (27mg, 44.16. mu. mol), tris (dibenzylideneacetone) dipalladium (40mg, 44.16. mu. mol), dioxane (1mL) was added and reacted for 2 hours at 100 ℃ with nitrogen substitution three times. And concentrating the reaction solution under reduced pressure to obtain a crude product, and purifying the crude product by preparative high performance liquid chromatography (alkaline system) to obtain a compound 9A or 9B or 9C or 9D. SFC detection (ee: 100%), column: chiralpak OJ-3150 x4.6mm I.D., 3 μm; mobile phase: a is supercritical carbon dioxide, B is 0.05 percent of isopropylamine methanol solution; gradient: b initial 10% hold for 0.5 min, from 10% to 40% in 2.0min, 40% hold for 2.0min, return to 10% in 0.7 min, 10% equilibrate for 0.8 min; flow rate: 2.5 mL/min; column temperature: 35 ℃; wavelength: 220nm, retention time: 2.23 min.¹HNMR(400MHz,CDCl ₃)δppm 7.59(d,J＝8.53Hz,1H),7.07(d,J＝8.53Hz,1H),3.87(q,J＝7.15Hz,1H),3.71-3.80(m,2H),2.42-2.62(m,2H),2.19(dd,J＝13.18,7.78Hz,1H),1.59-1.72(m,1H),0.51-0.63(m,1H),0.33-0.45(m,1H)；LCMS(ESI)m/z:351.02[M+1] ⁺。

Example 10

The synthesis route is as follows:

1) synthesis of Compound 10-2

Compound 10-1(1.00g, 6.87mmol) and acetonitrile (10mL) were added to a three-necked flask, and a solution of N-bromosuccinimide (1.22g, 6.87mmol) in acetonitrile (10mL) was added thereto at 0 ℃ to conduct replacement with nitrogen three times, followed by reaction at 0 ℃ for 2 hours. And (3) carrying out reduced pressure concentration on the reaction liquid to obtain a crude product, and purifying the crude product by column chromatography to obtain the compound 10-2.¹HNMR(400MHz,CDCl ₃)δppm 6.61(dd,J＝2.20,1.57Hz,1H),6.37(dd,J＝9.91,2.51Hz,1H),3.86(br s,2H)。

2) Synthesis of Compound 10-3

Compound 10-2(300mg, 1.34mmol) and hydrochloric acid (2mL) were added to a three-necked flask, the mixture was cooled to 0 ℃ and a solution of sodium nitrite (101mg, 1.47mmol) in water (0.5mL) was added, followed by stirring at 0 ℃ for 1 hour, followed by addition of sodium iodide (220mg, 1.47mmol) and stirring at 0 ℃ for 1 hour. Extracting the reaction solution with ethyl acetate (20mL x 3), collecting the organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain the compound 10-3.¹HNMR(400MHz,CDCl ₃)δppm 7.63(t,J＝1.69Hz,1H),7.39(dd,J＝7.28,1.88Hz,1H)。

3) Synthesis of Compound 10-4

To a reaction tube dried in advance were added compound 10-3(185mg, 552.01. mu. mol), compound 1-7(0.1g, 552.01. mu. mol) dioxane (4mL), followed by tris (dibenzylideneacetone) dipalladium (50mg, 55.20. mu. mol), 2, 2-bis (diphenylphosphino) -1, 1-binaphthyl (34mg, 55.20. mu. mol) cesium carbonate (539mg, 1.66mmol), nitrogen-substituted 3 times, and the system was stirred at 100 ℃ for 2 hours. Adding water (10mL) and ethyl acetate (10mL) into the reaction solution for extraction, collecting an organic phase, concentrating the organic phase under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain a compound 10-4.

4) Synthesis of Compounds 10A or 10B or 10C or 10D

Compound 10-4(40mg, 102.94. mu. mol), zinc cyanide (6mg, 51.47. mu. mol, 3.27. mu.L), tetrakis (triphenylphosphine) palladium (17mg, 15.44. mu. mol), N-methylpyrrolidone (2mL) nitrogen sparged for 1 minute and reacted at 130 ℃ for 2 hours in a thumb bottle. Ethyl acetate (5mL) was added to the reaction solution, the organic phase was washed with saturated brine solution (5mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by preparative high performance liquid chromatography (basic system) to give compound 10A. SFC detection (ee: 90.48%), column: chiralpak AS-3150 x4.6mm I.D., 3 μm; mobile phase: a is supercritical carbon dioxide, B is 0.05 percent of isopropylamine methanol solution; gradient: b initial 10% hold for 0.5 min, from 10% to 40% in 2.0min, 40% hold for 2.0min, return to 10% in 0.7 min, 10% equilibrate for 0.8 min; flow rate: 2.5 mL/min; column temperature: 35 ℃; wavelength: 220nm, retention time: 1.63 min.¹HNMR(400MHz,CDCl ₃)δppm 6.60(s,1H),6.39(dd,J＝11.84,2.25Hz,1H),4.29(br s,1H),4.08(br d,J＝8.61Hz,1H),3.12-3.25(m,1H),2.69-2.77(m,1H),2.62(br s,1H),2.06(br dd,J＝13.40,8.51Hz,1H),1.90(br d,J＝5.67Hz,1H),1.09-1.19(m,1H),0.31-0.40(m,1H)；LCMS(ESI)m/z:335.05[M+1] ⁺。

Example 11

The synthetic route is as follows:

1) synthesis of Compounds 11A or 11B or 11C or 11D

A predried 50mL single-neck flask was charged with 11-1(69mg, 276.01. mu. mol), 1-7(50mg, 276.01. mu. mol) dioxane (5mL), followed by 2,2Bis (diphenylphosphino) -1, 1-binaphthyl (17mg, 27.60. mu. mol), cesium carbonate (179mg, 552.02. mu. mol) tris (dibenzylideneacetone) dipalladium (25mg, 27.60. mu. mol), nitrogen substitution 3 times, and the system was stirred at 100 ℃ for 2 hours. Adding water (20mL), extracting with ethyl acetate (20mL), collecting the organic phase, washing the organic phase with saturated brine (20mL x 3), drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying the crude product by preparative high performance liquid chromatography (basic system) to obtain the compound 11A. SFC detection (ee: 96.84%), column: chiralpak OJ-3150 x4.6mm I.D., 3 μm; mobile phase: a is supercritical carbon dioxide, B is 0.05 percent isopropyl amine isopropanol solution; gradient: b initial 10% hold for 0.5 min, from 10% to 40% in 2.0min, 40% hold for 2.0min, return to 10% in 0.7 min, 10% equilibrate for 0.8 min; flow rate: 2.5 mL/min; column temperature: 35 ℃; wavelength: 220nm, retention time: 2.08 min.¹HNMR(400MHz,CDCl ₃)δppm 6.67(s,2H),4.33-4.36(m,1H),4.08-4.10(m,1H),3.20- 3.22(m,1H),3.05-3.19(m,1H),2.71-2.75(m,1H),2.04-2.07(m,1H),1.89-2.02(m,1H),1.12-1.16(m,1H),0.34-0.36(m,1H)；LCMS(ESI)m/z:351[M+1] ⁺。

Example 12

The synthetic route is as follows:

1) synthesis of Compound 12-2

A round-bottomed flask was charged with compound 12-1(3.00g, 23.34mmol), N-iodosuccinimide (5.25g, 23.34mmol), and N, N-dimethylformamide (30mL) and reacted for 16 hours at 25 ℃ with nitrogen substitution three times. Ethyl acetate (40mL) was added to the reaction mixture, the organic phase was washed with saturated brine (20 mL. times.3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was reducedConcentrating under reduced pressure to obtain crude product, and purifying by column chromatography to obtain compound 12-2.¹HNMR(400MHz,CDCl ₃)δppm 7.75(d,J＝8.41Hz,1H),6.21(d,J＝8.41Hz,1H),4.60(br s,2H)。

2) Synthesis of Compound 12-3

Compound 12-2(1.00g, 3.93mmol), zinc cyanide (230mg, 1.96mmol, 124.72. mu.L), tris (dibenzylideneacetone) dipalladium (359mg, 393.00. mu. mol), 1, 1' -bis (diphenylphosphino) ferrocene (217mg, 393.00. mu. mol), N, N-dimethylformamide (10mL) were added to a round-bottomed flask and nitrogen-substituted three times, and reacted at 120 ℃ for 16 hours. Adding ethyl acetate (30mL) into the reaction solution, washing the organic phase with saturated saline (20mL x 3), collecting the organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain the compound 12-3.¹HNMR(400MHz,CDCl ₃)δppm 7.63(d,J＝8.41Hz,1H),6.43(d,J＝8.41Hz,1H),5.10(br s,2H)。

3) Synthesis of Compound 12-4

Compound 12-3(500mg, 3.26mmol) and acetonitrile (5mL) were added to a three-necked flask, the mixture was cooled to 0 ℃, cuprous iodide (620mg, 3.26mmol) was added, tert-butyl nitrite (839mg, 8.14mmol, 968.12. mu.L) was added dropwise, and after the addition was completed, the mixture was quickly added to a previously heated oil bath at 60 ℃ and stirred for 1 hour. And (3) carrying out reduced pressure concentration on the reaction liquid to obtain a crude product, and purifying the crude product by column chromatography to obtain the compound 12-4.¹HNMR(400MHz,CDCl ₃)δppm 7.85(d,J＝8.03Hz,1H),7.58(d,J＝8.03Hz,1H)。

4) Synthesis of Compounds 12A or 12B or 12C or 12D

In a thumb flask, compound 1-7(100mg, 552.01. mu. mol), compound 12-4(145mg, 552.01. mu. mol), 2, 2-bis (diphenylphosphino) -1, 1-binaphthyl (34mg, 55.20. mu. mol), tris (dibenzylideneacetone) dipalladium (50mg, 55.20. mu. mol), potassium phosphate (351mg, 1.66mmol), dioxane (2mL) was charged with nitrogen and reacted at 100 ℃ for 16 hours. And concentrating the reaction solution under reduced pressure to obtain a crude product, and purifying the crude product by preparative high performance liquid chromatography (alkaline system) to obtain the compound 12A. SFC detection (ee: 81.88%), column: chiralpak AD-3150x4.6mm i.d., 3 μm; mobile phase: a is supercritical carbon dioxide, B is 0.05 percent isopropyl amine isopropanol solution; gradient: b initial 10% hold for 0.5 min, from 10% to 40% in 2.0min, 40% hold for 2.0min, return to 10% in 0.7 min, 10% equilibrate for 0.8 min; flow rate: 2.5 mL/min; column temperature: 35 ℃; wavelength: 220nm, retention time: 2.32 min.¹HNMR(400MHz,CDCl ₃)δppm 7.64-7.76(m,1H),6.83(d,J＝8.78Hz,1H),5.64(br d,J＝8.16Hz,1H),4.40(br s,1H),4.28(br t,J＝7.09Hz,1H),3.20-3.32(m,1H),2.50(br d,J＝6.65Hz,1H),2.33-2.43(m,1H),1.87-1.96(m,1H),1.07-1.17(m,1H),0.36(br s,1H)；LCMS(ESI)m/z:318[M+1] ⁺。

Example 13

The synthetic route is as follows:

1) synthesis of Compounds 13A or 13B or 13C or 13D

In a thumb flask, compound 13-1(100mg, 459.88. mu. mol), compound 1-7(83mg, 459.88. mu. mol), cesium carbonate (374mg, 1.15mmol), tris (dibenzylideneacetone) dipalladium (42mg, 45.99. mu. mol), 2, 2-bis (diphenylphosphino) -1, 1-binaphthyl (28mg, 45.99. mu. mol), dioxane (2mL) was added for three nitrogen replacements, and reacted at 100 ℃ for 2 hours. And (3) carrying out reduced pressure concentration on the reaction liquid to obtain a crude product, and purifying the crude product by a preparative high performance liquid chromatography (alkaline system) and carrying out supercritical fluid chromatography (alkaline system) to obtain the compound 13A. SFC detection (ee: 99.78%), column: chiralpak AS-3150 x4.6mm I.D., 3 μm; mobile phase: a is supercritical carbon dioxide, B is 0.05 percent of isopropylamine methanol solution; gradient: b initial 10% hold for 0.5 min, from 10% to 40% in 2.0min, 40% hold for 2.0min, return to 10% in 0.7 min, 10% equilibrate for 0.8 min; flow rate of flow: 2.5 mL/min; column temperature: 35 ℃; wavelength: 220nm, retention time: 1.75 min.¹HNMR(400MHz,CDCl ₃)δppm 8.10(d,J＝2.54Hz,1H),7.05(d,J＝2.54Hz,1H),4.25-4.32(m,1H),4.12-4.17(m,1H),3.25(ddd,J＝7.09,5.04,2.54Hz,1H),2.62-2.81(m,2H),2.00-2.14(m,1H),1.87-1.99(m,1H),1.17(dt,J＝8.51,5.43Hz,1H),0.30-0.42(m,1H)；LCMS(ESI)m/z:318[M+1] ⁺。

Example 14

The synthetic route is as follows:

1) synthesis of Compounds 14A or 14B or 14C or 14D

1-7(100mg, 552.01. mu. mol), 14-1(208mg, 828.02. mu. mol), cesium carbonate (449mg, 1.38mmol), 2, 2-bis (diphenylphosphino) -1, 1-binaphthyl (34mg, 55.20. mu. mol), dioxane (2mL) was added to a thumb flask, tris (dibenzylideneacetone) dipalladium (50mg, 55.20. mu. mol) was added three times with nitrogen substitution, and reaction was carried out at 100 ℃ for 16 hours three times with nitrogen substitution. And (3) carrying out reduced pressure concentration on the reaction liquid to obtain a crude product, and purifying the crude product by using a preparative high performance liquid chromatography (alkaline system) and carrying out supercritical fluid chromatography to obtain the compound 14A. SFC detection (ee: 99.62%), column: chiralpak IC-3150 x4.6mm I.D., 3 μm; mobile phase: a is supercritical carbon dioxide, B is 0.05 percent isopropyl amine isopropanol solution; gradient: b initial 10% hold for 0.5 min, from 10% to 40% in 2.0min, 40% hold for 2.0min, return to 10% in 0.7 min, 10% equilibrate for 0.8 min; flow rate: 2.5 mL/min; column temperature: 35 ℃; wavelength: 220nm, retention time: 2.14 min.¹HNMR(400MHz,CDCl ₃)δppm 8.34(d,J＝2.93Hz,1H),7.26(d,J＝2.93Hz,1H),4.25-4.34(m,1H),4.22(br d,J＝8.61Hz,1H),3.29(ddd,J＝7.24,5.09,2.54Hz,1H),2.69-2.83(m,2H),2.06-2.15(m,1H),1.91-2.02(m,1H),1.22(dt,J＝8.56,5.50Hz,1H),0.34-0.42(m,1H)；LCMS(ESI)m/z:352[M+1] ⁺。

Example 15

The synthetic route is as follows:

1) synthesis of Compound 15-2

Ethanol (100mL), 15-1(10g, 39.92mmol), tetrahydrofuran (100mL), calcium chloride (6.65g, 59.89mmol) were added to the pre-dried reaction flask, followed by addition of sodium borohydride (2.42g, 63.88mmol) in portions and stirring of the system at 15 deg.C for 16 hours. Filtering, adding 1M hydrochloric acid (100mL) into the filtrate, extracting with ethyl acetate (100mL), collecting the organic phase, washing the organic phase with saturated brine (100mL × 3), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain compound 15-2. LCMS (ESI) M/z 224[ M +1 ]] ⁺。

2) Synthesis of Compound 15-3

A previously dried reaction flask was charged with 15-2(5g, 22.48mmol), ethyl acetate (50mL), diisopropylethylamine (17.43g, 134.85mmol, 23.49mL), cooled to 0 deg.C, then a solution of pyridine sulfur trioxide complex (10.73g, 67.43mmol) in dimethyl sulfoxide (50mL) was added dropwise and the system stirred at 0 deg.C for 1 hour. 1M hydrochloric acid (100mL) was added, extraction was performed with ethyl acetate (50mL), the organic phase was collected, washed with saturated brine (50 mL. times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 15-3. LCMS (ESI) M/z 222[ M +1 ]] ⁺。

3) Synthesis of Compound 15-4

The pre-dried reaction flask was charged with 15-3(4.5g, 20.41mmol) and dichloromethane (10mL), cooled to 0 deg.C, and then added with diethylaminoSulfur trifluoride (6.58g, 40.83mmol, 5.39mL) was stirred at 0 ℃ for 1 hour. The system was poured into saturated sodium bicarbonate (50mL), separated, the organic phase was collected, washed with saturated brine (50mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 15-4. LCMS (ESI) M/z 244[ M +1 ]] ⁺。

4) Synthesis of Compound 15-5

A previously dried 50mL single-neck flask was charged with 15-4(3.6g, 14.85mmol), p-methoxybenzylamine (3.26g, 23.76mmol, 3.07mL), dioxane (80mL), then 2, 2-bis (diphenylphosphino) -1, 1-binaphthyl (924.57mg, 1.48mmol), tris (dibenzylideneacetone) dipalladium (1.36g, 1.48mmol), cesium carbonate (9.68g, 29.70mmol), nitrogen purged 3 times, and the system was stirred at 100 ℃ for 2 hours. Adding water (60mL) into the system, extracting with ethyl acetate (60mL), collecting the organic phase, washing the organic phase with saturated saline (50mL × 3), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain the compound 15-5. LCMS (ESI) M/z 299[ M +1 ]] ⁺。

5) Synthesis of Compound 15-6

To the pre-dried reaction flask were added 15-5(1.2g, 4.02mmol), N, N dimethylformamide (20mL), followed by zinc cyanide (566mg, 4.82mmol, 305.98. mu.L), 1, 1-bis (diphenylphosphino) ferrocene (445mg, 803.44. mu. mol), tris (dibenzylideneacetone) dipalladium (183mg, 200.86. mu. mol), and the system was stirred in an oil bath at 180 ℃ for 2 hours. Cooling the system to room temperature, adding saturated saline solution (20mL), extracting with ethyl acetate (20mL), collecting the organic phase, washing the organic phase with saturated saline solution (10mL x 3), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain the compound 15-6. LCMS (ESI) M/z 290[ M +1 ]] ⁺。

6) Synthesis of Compounds 15-7

To the pre-dried reaction flask were added 15-6(0.6g, 2.07mmol), dichloromethane (4mL), trifluoroacetic acid (4mL), and the system was stirred at 15 ℃ for 3 hours. Adding saturated sodium bicarbonate to adjust pH to 7, extracting with dichloromethane (10mL), collecting organic phase, concentrating under reduced pressure to obtain crude product, and performing column chromatographyPurifying to obtain the compound 15-7. LCMS (ESI) M/z 170[ M +1 ]] ⁺。

7) Synthesis of Compounds 15-8

15-7(80mg, 473.01. mu. mol) and hydrochloric acid (1mL) were added to a reaction flask which had been previously washed, and the mixture was cooled to 0 ℃ and then a solution of sodium nitrite (65mg, 946.01. mu. mol) and sodium iodide (141mg, 946.01. mu. mol) in water (1mL) was added thereto, and the mixture was stirred at 0 ℃ for 1 hour. Adding saturated sodium bisulfite (10mL), adjusting pH to 7 with saturated sodium bicarbonate, extracting with ethyl acetate (10mL), collecting organic phase, concentrating the organic phase under reduced pressure to obtain crude product, and purifying by column chromatography to obtain compound 15-8. LCMS (ESI) M/z 281[ M +1 ]] ⁺。

8) Synthesis of Compounds 15A or 15B or 15C or 15D

A50 mL single-neck flask dried in advance was charged with 15-8(50mg, 214.58. mu. mol), 1-7(39mg, 214.58. mu. mol), dioxane (2mL), and then tris (dibenzylideneacetone) dipalladium (19mg, 21.46. mu. mol), 2, 2-bis (diphenylphosphino) -1, 1-binaphthyl (1mg, 21.46. mu. mol), potassium phosphate (136mg, 643.74. mu. mol), and the mixture was replaced with nitrogen gas 3 times, and the system was stirred at 100 ℃ for 3 hours. Adding water (10mL) and ethyl acetate (10mL) for extraction, collecting an organic phase, concentrating the organic phase under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography and preparative high performance liquid chromatography (hydrochloric acid system) to obtain the hydrochloride of the compound 15A. SFC detection (ee: 91.24%), column: chiralpak AD-3150 x4.6mm I.D., 3 μm; mobile phase: a is supercritical carbon dioxide, B is 0.05 percent of isopropylamine methanol solution; gradient: b initial 10% hold for 0.5 min, from 10% to 40% in 2.0min, 40% hold for 2.0min, return to 10% in 0.7 min, 10% equilibrate for 0.8 min; flow rate: 2.5 mL/min; column temperature: 35 ℃; wavelength: 220nm, retention time: 1.39 min.¹HNMR(400MHz,CDCl ₃)δppm 8.30-8.31(m,1H),7.23-7.24(m,1H),6.76-7.03(m,1H),4.20-4.29(m,2H),3.27-3.31(m,1H),2.64-2.75(m,2H),1.93-2.12(m,2H),1.18-1.20(m,1H),0.35-0.38(m,1H)；LCMS(ESI)m/z:334[M+1] ⁺。

Example 16

The synthesis route is as follows:

1) synthesis of Compound 16-2

A reaction flask dried in advance was charged with 16-1(4g, 12.76mmol), dibromofluoromethane (12.97g, 67.62mmol), dichloromethane (16 mL)/ethanol (0.05mL) and benzyltriethylammonium chloride (435mg, 1.91mmol), cooled to 0 deg.C, and 50% aqueous sodium hydroxide solution (16mL) was added dropwise, followed by natural warming to 25 deg.C and stirring for 12 hours. Dichloromethane (25mL × 3) and water (25mL) are added into the reaction solution, liquid separation is carried out, an organic phase is collected, the organic phase is washed by saturated saline solution (30mL) in sequence, dried by anhydrous sodium sulfate, filtered, the filtrate is decompressed and concentrated to obtain a crude product, and the crude product is purified by column chromatography to obtain the compound 16-2. LCMS (ESI) M/z 368[ M-55 ]] ⁺。

2) Synthesis of Compound 16-3

Lithium aluminum hydride (608mg, 16.02mmol) and tetrahydrofuran (10mL) were added to a reaction flask which had been previously dried, a solution of 16-2(3.4g, 8.01mmol) in tetrahydrofuran (10mL) was added at 25 ℃ under nitrogen, the reaction solution was heated from 25 ℃ to 50 ℃ three times while displacing nitrogen, and the reaction solution was stirred at 25 ℃ to 50 ℃ for 1 hour. Saturated potassium sodium tartrate solution (1mL) was slowly added dropwise to the reaction mixture, the mixture was stirred for 15 minutes after completion of the addition, the mixture was filtered through a five-hole funnel with celite, the filter cake was washed with ethyl acetate (50mL), the filtrate was collected, and the mixture was concentrated under reduced pressure to give compound 16-3. LCMS (ESI) M/z 290[ M-55 ]] ⁺。

3) Synthesis of Compound 16-4

A reaction flask dried in advance was charged with 16-3(1.5g, 4.34mmol) and tetrahydrofuran (10mL), and a solution of tetrabutylammonium fluoride (1M, 5.21mL) in tetrahydrofuran was added dropwise under nitrogen, and the reaction mixture was stirred at 25 ℃ for 1 hour. Aqueous hydrochloric acid (1M, 10mL) was added to the reaction mixture, and extraction was performed with ethyl acetate (10 mL. multidot.3)Collecting and collecting an organic phase, washing the organic phase by using saturated saline solution (10mL), drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain the compound 16-4. LCMS (ESI) M/z 176[ M-55 ]] ⁺。

4) Synthesis of Compound 16-5

16-4(0.5g, 2.16mmol), ethyl acetate (10mL) and N, N-diisopropylethylamine (1.68g, 12.97mmol) were added to a pre-dried reaction flask, the temperature was lowered to 0 deg.C and a solution of pyridine sulfur trioxide complex (516mg, 3.24mmol) in dimethyl sulfoxide (5mL) was added dropwise, and the mixture was stirred from 0 deg.C to 20 deg.C for 12 hours. The reaction mixture was added with water (10mL), extracted with ethyl acetate (10mL × 2), and the organic phase was collected, washed successively with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude 16-5. MS (ESI) M/z 174[ M-55 ]] ⁺。

5) Synthesis of Compound 16-6

16-5(0.4g, 1.74mmol), trifluoromethyltrimethylsilane (297mg, 2.09mmol) and tetrahydrofuran (5mL) were added to a pre-dried reaction flask, and tetrabutylammonium fluoride tetrahydrofuran solution (1M, 2.62mL) was added dropwise at 0 ℃ and stirred at 15 ℃ for 12 hours. Adding hydrochloric acid aqueous solution (1M, 5mL) into the reaction solution, extracting with ethyl acetate (10mL), collecting an organic phase, washing the organic phase with saturated saline solution (10mL) in sequence, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain the compound 16-6. LCMS (ESI) M/z 244[ M-55 ]] ⁺。

6) Synthesis of Compounds 16-7

16-6(10mg, 33.42. mu. mol) and ethyl acetate hydrochloride (4M, 2mL) were added to a reaction flask dried in advance, and the reaction mixture was reacted at 20 ℃ for 5 hours. The reaction mixture was extracted with water (2mL) and the aqueous phase was collected. Adding sodium carbonate solid into the water phase to adjust pH to 9, extracting with ethyl acetate (5 mL. times.5), collecting organic phase, and concentrating the organic phase under reduced pressure to obtain compound 16-7.¹HNMR(400MHz,CDCl ₃)δppm 4.14-4.10(m,1H),3.68-3.64(m,1H),3.22-3.10(m,1H),2.30-2.24(m,4H),1.90-1.80(m,1H),0.89-0.86(m,1H)。

7) Synthesis of Compounds 16A or 16B or 16C or 16D

16-7(73mg, 369.58. mu. mol), 4-bromo-2-chlorobenzonitrile (80mg, 369.58. mu. mol), cesium carbonate (240mg, 739.16. mu. mol), 2, 2-bis (diphenylphosphino) -1, 1-binaphthyl (23mg, 36.96. mu. mol), tris (dibenzylideneacetone) dipalladium (34mg, 36.96. mu. mol) and 1, 4-dioxane (3mL) were added to a pre-dried reaction flask, and the reaction was stirred at 105 ℃ for 10 hours under nitrogen. The reaction solution is decompressed and concentrated to obtain a crude product, and the crude product is separated by preparative high performance liquid chromatography (neutral system) to obtain the compound 16A. SFC detection (ee: 95.6%), column: chiralpak AD-3150 x4.6mm I.D., 3 μm; mobile phase: a is supercritical carbon dioxide, B is 0.05 percent of isopropylamine methanol solution; gradient: b initial 10% hold for 0.5 min, from 10% to 40% in 2.0min, 40% hold for 2.0min, return to 10% in 0.7 min, 10% equilibrate for 0.8 min; flow rate: 2.5 mL/min; column temperature: 35 ℃; wavelength: 220nm, retention time: 2.06 min.¹HNMR(400MHz,CDCl ₃)δppm 7.46(d,J＝8.80Hz,1H),6.81(d,J＝2.40Hz,1H),6.63(d,J＝11.20Hz,1H),4.30-4.20(m,1H),4.25-3.94(m,2H),3.51-3.47(m,1H),2.87-2.82(m,1H),2.72-2.60(m,1H),2.31-2.24(m,1H),2.22-2.06(m,1H)；LCMS(ESI)m/z:335[M+1] ⁺。

Example 17

The synthesis route is as follows:

1) synthesis of Compounds 17A or 17B or 17C or 17D

To a previously dried reaction flask were added 16-7(43mg, 219.12. mu. mol), 5-bromo-2-cyano-3- (trifluoromethyl) pyridine (55mg, 219.12. mu. mol), potassium phosphate (139mg, 657.36. mu. mol), tris (dibenzylideneacetone) dipalladium (40mg, 43.82. mu. mol), 2, 2-bis (diphenylphosphino) -1, 1-binaphthyl (27mg,43.82. mu. mol) and 1, 4-dioxane (3mL), and the reaction mixture was stirred at 110 ℃ for 12 hours. The reaction solution is decompressed and concentrated to obtain a crude product, and the crude product is purified by a preparative high performance liquid chromatography (a neutral system) and is resolved by a supercritical fluid chromatography (an alkaline system) to obtain the compound 17A. SFC detection (ee: 100%), column: chiralpak AD-3150 x4.6mm I.D., 3 μm; mobile phase: a is supercritical carbon dioxide, B is 0.05 percent of isopropylamine methanol solution; gradient: b initial 10% hold for 0.5 min, from 10% to 40% in 2.0min, 40% hold for 2.0min, return to 10% in 0.7 min, 10% equilibrate for 0.8 min; flow rate: 2.5 mL/min; column temperature: 35 ℃; wavelength: 220nm, retention time: 1.67 min.¹HNMR(400MHz,MeOD)δppm 8.41(d,J＝2.80Hz,1H),7.42(d,J＝2.80Hz,1H),4.29-4.13(m,3H),3.76-3.72(m,1H),2.80-2.71(m,1H),2.28-2.24(m,1H),2.14-2.09(m,1H)；LCMS(ESI)m/z:370[M+1] ⁺。

Experimental example 1: test Compounds for Androgen Receptor (AR) agonism

1. Compound preparation, plating:

1.1 preparation of the Compounds: diluting a compound to be detected to a working concentration, diluting each compound by 10 concentration gradients according to 4-fold proportion by using Echo, and adding the compound into a 384-well cell plate according to a layout diagram of a microporous plate, wherein each well is 200 nL;

1.2AR cell assay Medium: 87% Opti-MEM (reduced serum medium), 10% Dialyzed FBS (Dialyzed fetal bovine serum), 1% NEAA (non-essential amino acids), 1% sodium pyruvate, and 1% penicillin-streptomycin;

1.3 placing the culture medium, trypsin and Du's phosphate buffer solution in a water bath at 37 ℃ for preheating;

1.4 removing the original culture medium in the cell culture flask, and washing the cells once by using 6mL of Du's phosphate buffer solution;

1.5 adding 3.5mL of pancreatin into a cell culture flask, gently shaking to make pancreatin fully contact with cells, removing pancreatin, sucking out pancreatin, and placing the flask into a culture flask containing 5% CO₂About 1 minute at 37 ℃;

1.6 resuspend cells with 10mL cell assay medium, remove approximately 0.8mL cell suspension count (ViCell XR)

Cells	Cell algebra	Cell viability	Cell density (per mL)
AR	20	95.1％	1.53×10 ⁶

1.7 dilution of the cell suspension to 2.5X 10 with culture Medium⁵Per ml of individual cells;

1.8 Add 40. mu.L of cell suspension to each well of the cell plate, add 40. mu.L of cell culture medium to the other wells, and put 5% CO₂Was cultured in an incubator at 37 ℃ for 16 hours.

2. Reading the plate, analyzing data:

2.1 preparation of solution A: add 182. mu.L DMSO to 200. mu.g LiveBLAzer^TMA FRET B/G substrate (CCF 4-AM). Subpackaging and storing in a refrigerator at-20 ℃;

2.2 preparation of 6 × substrate buffer: adding 15. mu.L of solution A to 150. mu.L of solution B and vortexing uniformly, adding 2335. mu.L of solution C to the above solution and vortexing uniformly;

2.3 taking out the cell culture plate, adding 8 μ L of 6 Xsubstrate buffer solution into each well, shaking for 1 minute, and centrifuging at 1000rpm for 10 seconds; after membrane sealing, incubate for 2 hours at 23 ℃ and read the plate with Envision, fit curve EC by Prism software ₅₀The value is obtained. The results of the Androgen Receptor (AR) agonistic activity test of the compounds are shown in table 1 below.

Results of androgen receptor agonistic activity test of the compounds of Table 1

Compound numbering	EC ₅₀(nM)	Compound numbering	EC ₅₀(nM)
Compound 1A	2.04	Compound 9A	1.66
Compound 2A	2.57	Compound 10A	0.27
Compound 3A	0.24	Compound 11A	2.36
Compound 4A	0.72	Compound 12A	19.22
Compound 5A	5.61	Compound 13A	10.14
Compound 6A	9.68	Compound 14A	7.08
Compound 7A	8.98	Compound 16A	0.43
Compound 8A	0.67	Compound 17A	5.08

And (4) experimental conclusion: the compound of the invention has remarkable Androgen Receptor (AR) agonism activity.

Experimental example 2: pharmacokinetic testing of Compounds of the invention

1. Abstract

The drug concentrations in the plasma of male SD rats at different times after intravenous and intragastric administration of Compound 1A, Compound 3A and Compound 14A were determined by LC-MS/MS method using the rats as test animals. The pharmacokinetic behavior of the compounds in rats was studied and evaluated for their pharmacokinetic profile.

2. Experimental protocol

2.1 test drugs: compound 1A, compound 3A and compound 14A

2.2 test animals: healthy adult male SD rats were 12 divided into 6 groups of 2 rats each. Animals were purchased from Shanghai Sphere-BiKai laboratory animals Co., Ltd, animal production license number: SCXK (Shanghai) 2013-0016.

2.3 pharmaceutical formulation

Weighing a proper amount of sample, sequentially adding a proper amount of DMSO, polyethylene glycol-15 hydroxystearate and water according to the volume ratio of 10:10:80, stirring and ultrasonically treating to reach a clear state of 0.2mg/mL for intravenous administration.

Weighing a proper amount of sample, dissolving the sample in a solution of 5% Tween 80, 90% polyethylene glycol 400 and 5% polyvinylpyrrolidone K30, stirring and ultrasonically treating the solution to reach a clear state of 1mg/mL for intragastric administration.

2.4 administration

12 male SD rats are divided into 6 groups, and after fasting overnight, the 1 st group to the 3 rd group are subjected to intravenous administration, wherein the administration volume is 5 mL/kg; and the groups 4-6 are subjected to intragastric administration, and the administration volume is 10 mL/kg.

3. Operation of

After intravenous administration of Compound 1A, Compound 3A and Compound 14A to each group of male SD rats, 40. mu.L of blood was collected at 0.0833, 0.25, 0.5, 1, 2, 4, 8 and 24 hours, respectively, and placed in a container containing 2. mu.L of EDTA-K₂In a test tube of (1). After administration of Compound 1A, Compound 3A and Compound 14A in the gavage group, 40. mu.L of blood was collected at 0.25, 0.5, 1, 2, 4, 8 and 24 hours, respectively, and placed in a container containing 2. mu.L of EDTA-K₂In a test tube of (1). The tubes were centrifuged at 4000rpm for 15 minutes to separate the plasma and stored at-60 ℃. Animals may eat food 2 hours after administration.

The LC-MS/MS method is used for determining the content of the compound to be tested in the blood plasma of rats after intravenous and intragastric administration. The linear range of the method is 2.00-6000 nmol/L; plasma samples were analyzed after treatment with acetonitrile to precipitate proteins. The results of the pharmacokinetic testing of compound 1A, compound 3A and compound 14A are shown in table 2 below.

TABLE 2 results of pharmacokinetic testing of Compound 1A, Compound 3A and Compound 14A

Note: "-" indicates that the item was not detected, and "ND" indicates that it was not detected.

The experimental conclusion is that: the compound of the invention has good oral absorption, certain oral exposure and oral bioavailability.

Claims

A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein, the first and the second end of the pipe are connected with each other,

T ₁independently selected from N, CH and CR₅；

T ₂Independently selected from N, CH and CR₆；

R ₁Independently selected from H, F, Cl, Br, I, OH, NH₂、CN、C _1-3Alkyl and C_1-3Alkoxy radical, said C_1-3Alkyl and C_1- ₃Alkoxy is optionally substituted by 1, 2 or 3R_aSubstitution;

R ₂and R₃Each independently selected from F, Cl, Br, I, OH and NH₂；

Or, R₂、R ₃Together with the atoms to which they are attached form C_3-5Cycloalkyl radical, said C_3-5Cycloalkyl is optionally substituted by 1, 2 or 3R_bSubstitution;

R ₄independently selected from F, Cl, Br, I, OH, C_1-6Alkyl and C_1-6Alkoxy radical, said C_1-6Alkyl and C_1-6Alkoxy is optionally substituted by 1, 2 or 3R_cSubstitution;

R ₅independently selected from F, Cl, Br, I, CN, C_1-3Alkyl and C_1-3Alkoxy radical, said C_1-3Alkyl and C_1-3Alkoxy is optionally substituted by 1, 2 or 3R_dSubstitution;

R ₆independently selected from F, Cl, Br, I, OH, NH₂And CN;

R _a、R _band R_dEach independently selected from F, Cl, Br, I and OH;

R _cindependently selected from F, Cl, Br, I, OH, C_1-3Alkyl and C_1-3Alkoxy radical, said C_1-3Alkyl and C_1-3Alkoxy is optionally substituted with 1, 2 or 3R;

r is independently selected from F, Cl, Br and I.
A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R₁Independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CH ₃、CH ₂CH ₃、C(CH ₃) ₂And OCH₃Said CH₃、CH ₂CH ₃、C(CH ₃) ₂And OCH₃Optionally substituted by 1, 2 or 3R_aAnd (4) substitution.
A compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R₁Independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CH ₃、CH ₂F、CHF ₂、CF ₃、CH ₂CH ₃、C(CH ₃) ₂And OCH₃。
A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R₂、R ₃And the atoms to which they are attached together form a cyclopropyl groupCyclobutyl and cyclopentyl optionally substituted by 1, 2 or 3R_bAnd (4) substitution.
A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein R₂And R₃Together with the atoms to which they are attached
A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R_cIndependently selected from F, Cl, Br, I, OH, CH₃、CH ₂F、CHF ₂、CF ₃、CH ₂CH ₃、C(CH ₃) ₂And OCH₃。
A compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein R₄Independently selected from F, Cl, Br, I, OH, C_1-3Alkyl and C_1-3Alkoxy radical, said C_1-3Alkyl and C_1-3Alkoxy is optionally substituted by 1, 2 or 3R_cAnd (4) substitution.
A compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R₄Independently selected from F, Cl, Br, I, OH, CH₃、CH ₂CH ₃And OCH₃Said CH₃、CH ₂CH ₃And OCH₃Optionally substituted by 1, 2 or 3R_cAnd (4) substitution.
The compound of claim 8 or a pharmaceutically acceptable salt thereofA salt of (I), wherein R₄Independently selected from F, Cl, Br, I, OH, CH₃、CF ₃、CH ₂CH ₃、OCH ₃And
a compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein R₄Is independently selected from
A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R₅Independently selected from F, Cl, Br, I, CN, CH₃And OCH₃Said CH₃And OCH₃Optionally substituted by 1, 2 or 3R_dAnd (4) substitution.
A compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein R₅Independently selected from F, Cl, Br, I, CN, CH₃And OCH₃。
A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the building block
Is selected from
A compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein the building block
Is selected from
A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, selected from:

wherein, the first and the second end of the pipe are connected with each other,

R ₁as defined in claims 1 to 3;

R ₂、R ₃as defined in claim 1,4 or 5;

R ₄as defined in claims 1, 7 to 10;

R ₅as defined in claim 1, 11 or 12;

R ₆as defined in claim 1.
The compound according to claim 15, or a pharmaceutically acceptable salt thereof, selected from:

wherein, the first and the second end of the pipe are connected with each other,

R ₁、R ₂、R ₃、R ₄、R ₅and R₆As defined in claim 15.
A compound of the formula or a pharmaceutically acceptable salt thereof,
the compound according to claim 17, or a pharmaceutically acceptable salt thereof, selected from:
the use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a condition mediated by the androgen receptor.
The use according to claim 19, wherein the medicament is a medicament for a plurality of senile diseases such as muscular dystrophy, bone fracture, osteoporosis, etc.