TW202428285A - Phosphorus-containing compound and preparation method thereof and pharmaceutical application thereof - Google Patents

Abstract

The present invention discloses a phosphorus-containing compound and preparation method thereof and pharmaceutical application thereof. Specifically, the present invention discloses a compound represented by formula (I), optical isomers or pharmaceutically acceptable salts thereof, and application of the compounds as an androgen receptor (AR) inhibitor.

Description

Phosphorus-containing compounds and preparation methods and medical applications thereof

The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to a phosphorus-containing compound and a preparation method and medical application thereof.

This invention claims the following priority rights: 1) Application number CN 202211194169.6, application date September 28, 2022; 2) Application number CN 202211506143.0, application date November 28, 2022; 3) Application number CN 202310287532.7, application date March 21, 2023; 4) Application number CN 202310862597.X, application date July 13, 2023; 5) Application number CN 202311208427.6, application date September 18, 2023.

Prostate cancer is an androgen-dependent tumor. Androgens can stimulate the growth of prostate cancer cells and the progression of the disease through androgen receptors (AR). Endocrine therapy is one of the conventional treatment methods. For example, the standard treatment for advanced PCa is mainly androgen deprivation therapy (ADT), such as surgical castration (bilateral orchiectomy) or medical castration (such as injection of Noradrena). ADT therapy has a significant effect in the early stages of treatment, but as the disease progresses, AR mutates, and the mutated AR is more sensitive to low levels of androgens, driving the disease to castration-resistant prostate cancer (CRPC). Almost all patients with advanced prostate cancer will eventually progress to CRPC after receiving endocrine therapy. Additionally, up to 30% of prostate cancer patients will develop metastatic castration-resistant prostate cancer (mCRPC) within 10 years of initial treatment.

There are currently a number of oral drugs for the treatment of mCRPC, such as enzalutamide, apalutamide, and darolutamide, which mainly bind to the ligand binding domain (AR-LBD) of the androgen receptor, thereby blocking the interaction between AR and DNA and exerting their efficacy. However, after 2-3 years of treatment with these drugs, patients are prone to drug resistance. The emergence of androgen receptor variants (AR-Vs) lacking the LBD region and mutations in the LBD region are two important mechanisms of drug resistance.

Compared with the normal full-length AR, AR-Vs is a truncated AR. These splice variants lack LBD during the formation process, which results in the inability of androgens to bind to AR-Vs. However, because AR-Vs retain the N-terminal domain and DNA-binding domain (DBD), they can still bind to genomic DNA and regulate the expression of downstream target genes, showing androgen-independent structural activity, which is one of the important mechanisms of ADT resistance and CRPC disease progression.

The development of inhibitors targeting AR receptor NTD with good physicochemical properties and drugability, which inhibit the transcriptional function of androgen receptor AR by regulating the N-terminal domain of AR and block the conduction pathway of androgen receptor, is a new research direction for the treatment of prostate cancer. Inhibitors targeting AR-NTD will bring about deep and extensive AR inhibition by acting on the N-terminal domain of AR receptor. It has important clinical value for the treatment of AR-driven cancer diseases such as prostate cancer, especially the treatment of androgen-independent resistant prostate cancer.

In one aspect of the present invention, the present invention provides a compound represented by formula (I), an optical isomer thereof and a pharmaceutically acceptable salt thereof,

in,

R ₁ and R ₂ are each independently selected from H, OH, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 heteroalkyl and _3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;

Alternatively, _R1 and _R2 are linked together to form a 4-8 membered ring, and the 4-8 membered ring is optionally substituted by 1, 2 or 3 Rs;

R ₃ , R ₄ , and R ₅ are independently selected from H, CN, F, Cl, Br, OH, NH ₂ , _C1-6 alkyl, C1-6 alkyl-O—, _C1-6 alkyl-S—, _C1-6 alkyl-NH—, _C2-6 alkenyl-O—, _C2-6 alkenyl-S—, _C2-6 alkenyl-NH—, _C3-6 cycloalkyl-O—, _C3-6 cycloalkyl-S—, _C3-6 cycloalkyl-NH—, _4-6 membered heterocycloalkyl-O—, 4-6 membered heterocycloalkyl-S—, or 4-6 membered heterocycloalkyl-NH—, wherein the _C1-6 alkyl, C1-6 alkyl-O—, _C1-6 alkyl-S—, _C1-6 alkyl-NH—, C2-6 alkenyl-O—, _C2-6 alkenyl-S—, _C2-6 alkenyl-NH— C _2-6 alkenyl-S-, C _2-6 alkenyl-NH-, C _3-6 cycloalkyl-O-, C _3-6 cycloalkyl-S-, C _3-6 cycloalkyl-NH-, 4-6 membered heterocycloalkyl-O-, 4-6 membered heterocycloalkyl-S- and 4-6 membered heterocycloalkyl-NH- are optionally substituted with 1, 2 or 3 R;

R ₆ and R ₇ are independently selected from H, CN, F, Cl, Br, OH, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;

m and n are independently selected from 0, 1, 2 or 3;

Y is selected from O or S;

_L1 is selected _from a single bond, NH, O, _CH2 , _CH2CH2 or _OCH2 , wherein _CH2 , _CH2CH2 and _OCH2 are optionally substituted with 1 or ₂ R;

L ₂ and L ₃ are independently selected from -(CR ₈ R ₉ )x-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O) ₂ -, -NR ₁₀ -, -OR ₁₁ - or a 5-10 membered heterocycloalkyl group;

L ₄ is selected from -(CR ₈ R ₉ )x-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O) ₂ -, -NR ₁₀ -, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;

R ₈ and R ₉ are independently selected from H, CN, F, Cl, Br, OH, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;

or R ₈ and R ₉ are linked together to form a C _4-8 cycloalkyl or 4-8 membered heterocycloalkyl, wherein the C _4-8 cycloalkyl and 4-8 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;

R ₁₀ is selected from H or C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;

R ₁₁ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;

x is selected from 0, 1, 2 or 3;

Ring A is selected from phenyl or 5-10 membered heteroaryl;

Ring B and Ring C are independently selected from phenyl, 5-10 membered heteroaryl, benzo C _5-6 cycloalkyl, benzo 5-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C _5-6 cycloalkyl or 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl;

R is independently selected from H, halogen, =O, OH, NH ₂ , CN, , C _1-6 alkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, the C _1-6 alkyl, -C _1-6 alkyl-OH, C _3-6 heteroalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _{1-6 alkyl-C(=O)-, C 1-6 alkyl} -C(=O)O-, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-C(=O)NH-, C _1-6 alkyl-NH-C(=O)-, C _1-6 alkyl-S(=O) ₂ -, C _1-6 alkyl-S(=O) ₂ NH-, C _1-6 alkyl-NHS(=O) ₂ -, C _1-6 alkoxy, C _1-6 alkylthio and C _1-6 alkylamino is optionally substituted by 1, 2 or 3 R';

R' is selected from F, Cl, Br, I, OH, NH ₂ , CN, , , CH ₃ , CH ₂ F, CHF ₂ and CF ₃ ;

The heteroaryl, heteroalkyl or heterocycloalkyl group contains 1, 2 or 3 heteroatoms or heteroatoms independently selected from O, NH, S, C(=O), C(=O)O, C(=O)NH, S(=O), S(=O) ₂ , S(=O) ₂ NH and N;

And the compound of formula (I) is not selected from: .

In some embodiments of the present invention, the above R is independently selected from H, halogen, OH, NH ₂ , CN, =O, , C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkyl-C(=O)-, C _1-3 alkyl-S(=O) ₂ -, C _1-3 alkyl-C(=O)O-, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 alkylamino, said C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkyl-C(=O)-, C _1-3 alkyl-C(=O)O-, C _1-3 alkoxy, C _1-3 alkylthio and C _1-3 alkylamino are optionally substituted with 1, 2 or 3 R's, and the remaining variables are as defined in the present invention.

In some embodiments of the present invention, the above R is independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, =O, , , , , , , CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , , , , , , , , or , and the remaining variables are as defined in the present invention.

In some embodiments of the present invention, R ₁ and R ₂ are independently selected from C _1-3 alkyl or C _1-3 alkenyl, and the C _1-3 alkyl and C _1-3 alkenyl are optionally substituted by 1, 2 or 3 R, and the remaining variables are as defined in the present invention.

In some embodiments of the present invention, the above R ₁ and R ₂ are independently selected from Me, or , and the remaining variables are as defined in the present invention.

In some embodiments of the present invention, the above _R1 and _R2 are linked together to form a ring , , or , , , and is optionally substituted with 1, 2 or 3 R, and the remaining variables are as defined in the present invention.

In some embodiments of the present invention, the above _R1 and _R2 are linked together to form a ring , , , , , , , , or , and the remaining variables are as defined in the present invention.

In some embodiments of the present invention, R ₃ , R ₄ , and R ₅ are independently selected from H, CN, F, Cl, Br, OH, NH ₂ , CN, C _1-3 alkyl, C _1-3 alkyl-O-, C _1-3 alkyl-S-, C _1-3 alkyl-NH-, C _3-6 cycloalkyl-O-, C _3-6 cycloalkyl-S-, C _3-6 cycloalkyl-NH-, or oxocyclopropane-O-; the C _1-3 alkyl, C _1-3 alkyl-O-, C _1-3 alkyl-S-, C _1-3 alkyl-NH-, C _2-3 alkenyl-O-, C _2-3 alkenyl-S-, C _2-3 alkenyl-NH-, C _3-6 cycloalkyl-O-, C _3-6 cycloalkyl-S-, C _3-6 -cycloalkyl-NH- and oxacyclopropane-O- are optionally substituted with 1, 2 or 3 R, and the remaining variables are as defined herein.

In some embodiments of the present invention, R ₃ , R ₄ , and R ₅ are independently selected from H, CN, F, Cl, Br, OH, NH ₂ , CN, Me, , , , , , or , the Me, , , , , , and is optionally substituted with 1, 2 or 3 R, and the remaining variables are as defined in the present invention.

In some embodiments of the present invention, R ₃ , R ₄ , and R ₅ are independently selected from H, CN, F, Cl, Br, OH, NH ₂ , CN, Me, , , , , , , , , , , and , and the remaining variables are as defined in the present invention.

In some embodiments of the present invention, R ₈ and R ₉ are independently selected from H, CN, F, Cl, Br, OH, NH ₂ , Me or , and the remaining variables are as defined in the present invention.

In some embodiments of the present invention, the above R ₁₀ is selected from H, Me, , or , and the remaining variables are as defined in the present invention.

In some embodiments of the present invention, _L2 and _L3 are independently selected from a single bond, _-CH2- , -CH( _CH3 )-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O) _2- , -NH-, , , , , , , or , and the remaining variables are as defined in the present invention.

In some embodiments of the present invention, the above L ₄ is selected from -CH ₂ -, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O) ₂ -, -NH-, , or , and the remaining variables are as defined in the present invention.

In some embodiments of the present invention, the ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrrolidyl, thiazolyl, thienyl, oxazolyl and pyrimidinyl, and the remaining variables are as defined in the present invention.

In some embodiments of the present invention, the structural unit Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

In some embodiments of the present invention, the ring B is selected from phenyl, benzocyclopentyl, and benzocyclohexyl, and the remaining variables are as defined in the present invention.

In some embodiments of the present invention, the structural unit Selected from , , , , , , and .

In some embodiments of the present invention, the above ring C is selected from phenyl, benzocyclopentyl, benzocyclohexyl, 1H-indazolyl, 2H-indazolyl and 1H-benzo[d]imidazole, and the remaining variables are as defined in the present invention.

In some embodiments of the present invention, the structural unit Selected from , , , , , , , , , and , and the remaining variables are as defined in the present invention.

The present invention also provides compounds of the following formula, optical isomers thereof and pharmaceutically acceptable salts thereof, which are selected from: and .

In another aspect of the present invention, the present invention also provides the use of the aforementioned compound, its optical isomer or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating a disease related to androgen receptor (AR) activity or expression.

In some embodiments of the present invention, the above-mentioned androgen receptor (AR) activity or expression-related diseases are selected from prostate cancer, ovarian cancer, breast cancer, bladder cancer, pancreatic cancer, endometrial cancer, hepatocellular carcinoma, renal cell carcinoma, melanoma, mantle cell lymphoma, glioblastoma, salivary gland cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy and age-related macular degeneration.

Definition and description

Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered ambiguous or unclear in the absence of a specific definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to the corresponding product or its active ingredient.

As used in the present invention, the phrase "at least one" when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that elements other than the specifically identified elements in the list of elements to which the phrase "at least one" refers may optionally exist, whether related to or unrelated to those specifically identified elements.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent discovered by the present invention and a relatively non-toxic acid or base. When the compound of the present invention contains a relatively acidic functional group, the base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compound of the present invention contains a relatively basic functional group, the acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of acid in a solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, etc.; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups and can be converted into either base or acid addition salts.

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

"Pharmaceutically acceptable carrier" refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material, formulation aid or carrier commonly used with therapeutic agents in this art, which together constitute a "drug composition" for administration to a subject. Pharmaceutically acceptable carriers are non-toxic to recipients at the dosages and concentrations used and are compatible with the other ingredients of the formulation. The pharmaceutically acceptable carrier is suitable for the formulation used.

When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, and each occurrence of R has an independent choice. Furthermore, combinations of substituents and/or their variants are permitted only if such combinations result in stable compounds. For example, You can choose from , , and wait.

A hyphen ("-") not between two letters or symbols indicates the point of attachment of a substituent. For example, _{C1-6alkylcarbonyl-} refers to a _C1-6alkyl group attached to the rest of the molecule via the carbonyl group. However, when the point of attachment of the substituent is obvious to one of ordinary skill in the art, such as a halogen substituent, the "-" may be omitted.

When the group bond has a dotted line ", for example, in " ”, the dashed line represents the point of attachment of the group to the rest of the molecule.

The term "substituted" or "substituted by..." means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable. The term "optionally substituted" or "optionally substituted by..." means that it may be substituted or not substituted, and unless otherwise specified, the type and number of substituents can be any on a chemically feasible basis.

When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 1, 2, or 3 R's, then the group may optionally be substituted with 1 or 2 or 3 R's, and each occurrence of R' has an independent choice. Furthermore, combinations of substituents and/or their variants are permitted only if such combinations result in stable compounds.

When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected, such as When L ₁ represents a single bond, it means that the structure is actually .

When a substituent is listed without specifying the atom through which it is bonded to the substituted group, the substituent may be bonded through any atom thereof. For example, a pyridyl substituent may be bonded to the substituted group through any carbon atom on the pyridine ring.

When a linker group is listed without specifying its direction of attachment, the direction of attachment is arbitrary, e.g. The connecting group L is -CH ₂ O-. In this case, -CH ₂ O- can be connected to the phenyl group and the cyclopentyl group in the same direction as the reading order from left to right. , or by connecting phenyl and cyclopentyl groups in the opposite direction of the reading order from left to right. Combinations of linking groups, substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

The term "halogen" refers to fluorine, chlorine, bromine and iodine.

Unless otherwise specified, the number of atoms in a ring is usually defined as the ring member; for example, "3-6 membered ring" refers to a ring with 3-6 atoms arranged around it.

Unless otherwise specified, the term "C _1-6 alkyl" is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C _1-6 alkyl group includes C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ and C ₅ alkyl groups, etc.; it can be monovalent (such as CH ₃ ), divalent (-CH ₂ -) or polyvalent (such as divalent ). Examples of _{C 1-6} alkyl include but are not limited to CH ₃ , , , , , , , , , , , , wait.

Unless otherwise specified, the term "C _1-4 alkyl" is used to refer to a linear or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C _1-4 alkyl group includes C _1-2 , C _1-3 , C _3-4 and C _2-3 alkyl groups, etc.; it can be monovalent (such as CH ₃ ), divalent (-CH ₂ -) or polyvalent (such as divalent ). Examples of _{C 1-4} alkyl include but are not limited to CH ₃ , , , , , wait.

Unless otherwise specified, " _C2-6 alkenyl" is used to represent a linear or branched carbon hydrogen group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. The _C2-6 alkenyl includes _C2-4 , _C2-3 , _C4 , _C3 and _C2 alkenyl, etc.; it may be monovalent, divalent or polyvalent. Examples of _C2-6 alkenyl include but are not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, etc.

Unless otherwise specified, "C _2-3 alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. The C _2-3 alkenyl group includes C ₃ and C ₂ alkenyl groups; the C _2-3 alkenyl group may be monovalent, divalent or polyvalent. Examples of C _2-3 alkenyl groups include but are not limited to , , , , wait.

Unless otherwise specified, "C _2-6 alkynyl" is used to represent a linear or branched carbon hydrogen group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or polyvalent. The C _2-6 alkynyl group includes C _2-3 , C _2-4 , C 2-5, C _3-4 , C _3-5 , C _3-6 , C _4-5 , C _4-6 , C _5-6 , C ₆ , C ₅ , C ₄ , C ₃ and C ₂ alkynyl groups. Examples of _{C 2-6} alkynyl groups include but are not limited to , , , wait.

Unless otherwise specified, "C _2-3 alkynyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or polyvalent. The C _2-3 alkynyl group includes C ₃ and C ₂ alkynyl groups. Examples of C _2-3 alkynyl groups include but are not limited to , , , wait.

The term "heteroalkyl" by itself or in combination with another term refers to a stable linear or branched alkyl radical or combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- and -S(=O)N(H)-. In some embodiments, the heteroalkyl group is a C _1-6 heteroalkyl group; in other embodiments, the heteroalkyl group is a C _1-3 heteroalkyl group. The heteroatom or heteroatom group may be located at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the rest of the molecule, but the term "alkoxy" is a conventional expression and refers to those alkyl groups that are attached to the rest of the molecule through an oxygen atom. Examples of heteroalkyl groups include, but are not limited to _{, -OCH3} , _-OCH2CH3 , _-OCH2CH2CH3 , -OCH _{(CH3 ) 2} , _-CH2 - _CH2 - _O - _CH3 , _{-NHCH3 ,} -N(CH3) ₂ , _-NHCH2CH3 , -N( _CH3 )( _CH2CH3 ), -CH2 _- CH2-NH _- CH3, _-CH2 - _CH2 -N( _CH3 ) _-CH3 , _{-SCH3 , -SCH2CH3, -SCH2CH2CH3, -SCH(CH3)2 , -CH2 - S - CH2 - CH3 ,} -CH2 _{- CH2 - S- CH3} , -S(=O) _-CH3 , _-CH2 -CH ₂ -S(=O) ₂ -CH ₃ , and up to two impurity atoms may be consecutive, for example -CH ₂ -NH-OCH ₃ .

Unless otherwise specified, the term "C _1-6 alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through an oxygen atom. The C _1-6 alkoxy group includes C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ and C ₃ alkoxy groups, etc. Examples of C _1-6 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), pentoxy (including n -pentoxy, isopentoxy and neopentoxy), hexoxy, etc.

Unless otherwise specified, the term "C _1-3 alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms connected to the rest of the molecule through an oxygen atom. The C _1-3 alkoxy group includes C _1-3 , C _1-2 , C _2-3 , C ₁ , C ₂ and C ₃ alkoxy groups, etc. Examples of C _1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

Unless otherwise specified, the term "C _1-6 alkylamino" refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through an amine group. The C _1-6 alkylamino group includes C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ , C ₃ and C ₂ alkylamino groups, etc. Examples of C _1-6 alkylamino groups include, but are not limited to, -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -N(CH ₃ )CH ₂ CH ₃ , -N(CH ₂ CH ₃ )(CH ₂ CH ₃ ), -NHCH ₂ CH ₂ CH ₃ , -NHCH(CH ₃ ) ₂ , -NHCH ₂ CH ₂ CH ₂ CH ₃ , etc.

Unless otherwise specified, the term "C _1-3 alkylamino" refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an amine group. The C _1-3 alkylamino group includes C _1-3 , C _1-2 , C _2-3 , C ₁ , C ₂ and C ₃ alkylamino groups, etc. Examples of C _1-3 alkylamino groups include, but are not limited to, -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -N(CH ₃ )CH ₂ CH ₃ , -NHCH ₂ CH ₂ CH ₃ , -NHCH(CH ₃ ) ₂ , etc.

Unless otherwise specified, the term "C _1-6 alkylthio" refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through a sulfur atom. The C _1-6 alkylthio group includes C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ , C ₃ and C ₂ alkylthio groups, etc. Examples of C _1-6 alkylthio groups include, but are not limited to, -SCH ₃ , -SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH(CH ₃ ) ₂ , and the like.

Unless otherwise specified, the term "C _1-3 alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through a sulfur atom. The C _1-3 alkylthio group includes C _1-3 , C _1-2 , C _2-3 , C ₁ , C ₂ and C ₃ alkylthio groups, etc. Examples of C _1-3 alkylthio groups include, but are not limited to, -SCH ₃ , -SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH(CH ₃ ) ₂ , etc.

Unless otherwise specified, "C _3-6 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, and the C _3-6 cycloalkyl includes C _3-5 , C _4-5 and C _5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent. Examples of C _3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

Unless otherwise specified, the term "3-10 membered heterocyclic group" by itself or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 3 to 10 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen and sulfur atoms are independently optionally oxidized (i.e., C=O, NO and S(O) _p , p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, cyclic and bridged rings. In addition, with respect to the "3-10 membered heterocyclic group", the heteroatom may occupy the position of attachment of the heterocyclic group to the rest of the molecule. The 3-10 membered heterocyclic group includes 3-8 membered, 3-7 membered, 3-6 membered, 3-5 membered, 3-4 membered, 4-5 membered, 4-6 membered, 4-7 membered, 4-8 membered, 4-9 membered, 5-6 membered, 5-7 membered, 5-8 membered, 5-9 membered, 5-10 membered, 6-7 membered, 6-8 membered, 6-9 membered, 6-10 membered, 7-8 membered, 3 membered, 4 membered, 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, 10 membered heterocyclic group, etc. Examples of 3-9 membered heterocyclic groups include, but are not limited to, nitrogen heterocyclic group, oxygen heterocyclic group, thio heterocyclic group, 1,3-dioxolane, , , pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperidine (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxazolidinyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazolidinyl, 1, 2-thiazolyl, hexahydropyranyl, homopiperidinyl or homopiperidinyl, etc.

Unless otherwise specified, the term "5-6 membered heterocyclic group" by itself or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 5 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, cyclic and bridged rings. In addition, with respect to the "5-6 membered heterocyclic group", the heteroatom may occupy the position of attachment of the heterocyclic group to the rest of the molecule. The 5-6 membered heterocyclic group includes 5-membered and 6-membered heterocyclic groups. Examples of 5-6 membered heterocyclic groups include but are not limited to 1,3-dioxolane, , pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperidine (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxazolidinyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazolidinyl, 1, 2-thiazolyl, hexahydropyranyl, homopiperidinyl or homopiperidinyl, etc.

Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" of the present invention can be used interchangeably. The term "5-6 membered heteroaryl" means a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). The 5-6 membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N -pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N -imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl ( 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-isozolyl, 4-isozolyl and 5-isozolyl, 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.), pyridine or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

Unless otherwise specified, the term "C _6-10 aryl" by _itself or in combination with other terms refers to a monocyclic or bicyclic aromatic ring system having six to ten carbon atoms, respectively. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl.

Unless otherwise specified, the term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 5- to 8-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc.

Unless otherwise specified, _Cn-n+m or _Cn - _Cn+m includes any specific case of n to n+m carbon atoms, for example, _C1-12 includes _C1 , _C2 , _C3 , _C4 , _C5 , _C6 , _C7 , _C8 , _C9 , _C10 , _C11 , and _C12 , and also includes any range from n to n+m, for example, _C1-12 includes _C1-3 , _C1-6 , C1-9, _C3-6 , _C3-9 , _C3-12 , _C6-9 , _C6-12 , and C13 _{. Similarly} , n-membered to n+m-membered means that the number of atoms on the ring is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 5-10-membered ring, 6-7-membered ring, 6-8-membered ring, 6-9-membered ring and 6-10-membered ring, etc.

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound may be labeled with a radioactive isotope, such as tritium ( ^3H ), iodine-125 ( ^125I ) or C-14 ( ^14C ). For another example, deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic efficacy, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

"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 said event or circumstance does not occur.

The compounds of the present invention can be prepared by a variety of synthetic methods known to those of ordinary skill in the art to which the present invention belongs, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods known to those of ordinary skill in the art to which the present invention belongs. Preferred embodiments include but are not limited to the embodiments of the present invention.

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

Compounds were named according to conventional nomenclature in this field or using ChemDraw® software. Commercially available compounds were named according to the supplier's catalog name.

The compounds disclosed in the present invention may have one or more chiral centers, each of which independently has an R configuration or an S configuration, or a cis-configuration, or a trans-configuration. The chiral centers of some compounds disclosed in the present invention are marked with *R, *S, R*, S*, *Cis-, or *Trans-, indicating that the absolute configuration of the chiral center of the compound has not been identified, but the compound has been separated or chirally resolved and the chiral center is a chiral center of a single configuration, the compound is a single-configuration enantiomer monomer, or a single-configuration diastereoisomer monomer, or a diastereoisomer mixture with a single configuration of the chiral center (for example: other chiral center configurations have not been resolved), or a single-configuration monomer (for example, a single cis-configuration monomer, or a single trans-configuration monomer). When the absolute configuration (R configuration, S configuration, Cis-configuration, or Trans-configuration) of the chiral center of the compounds disclosed in the present invention has not been identified, such compounds can be confirmed based on the peak shape in the corresponding nuclear magnetic resonance ( ¹ H-NMR, ³¹ P-NMR) spectrum, or the corresponding retention time (RT or Rt) under the corresponding chromatographic column conditions (e.g., chromatographic column model, chromatographic column filling material, chromatographic column size, mobile phase, etc.).

The present invention is explained more specifically in the following examples. However, it should be understood that these examples are for the purpose of illustrating the present invention and are not intended to limit the scope of the present invention in any way. In the following examples, if no specific experimental conditions are specified, the conventional conditions of such reactions or the conditions recommended by the manufacturer are generally followed. Unless otherwise specified, percentages and parts are weight percentages and weight parts. Unless otherwise specified, the ratio of liquids is volume ratio.

Technical and scientific terms used herein without specific definition have the meaning commonly understood by one of ordinary skill in the art to which the present invention belongs.

The present application is described in detail below through embodiments, but it does not mean that there are any adverse limitations on the present application. The present application has been described in detail herein, and its specific embodiments are also disclosed. For those with ordinary knowledge in the technical field to which the present invention belongs, it will be obvious to make various changes and improvements to the specific embodiments of the present application without departing from the spirit and scope of the present application.

Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial sources.

In all examples, ¹ H NMR, ¹³ C NMR, ¹⁹ F NMR and ³¹ P NMR spectra were recorded using a Bruker Ascend 400 mHz NMR instrument, and the spectra were processed using Topspin software, with deuterated solvents as internal deuterium locks. ¹³ C NMR, ¹⁹ F NMR and ³¹ P NMR were decoupled from ¹ H. Assignments were made based on clear chemical shift/coupling patterns, or based on 2D Cosy, HMBC, HSQC or NOESY experiments. The multiplicity of the peaks was defined as: s singlet, d doublet, t triplet, q quartet, m multiplet, br broad peak, br.s broad singlet; the coupling constant ( J ) was accurate to 0.1 Hz. Mass spectra were recorded using an Agilent 1260 (ESI) or Shimadzu LC-MS-2020 (ESI) or Agilent 6215 (ESI) mass spectrometer; reversed-phase preparative HPLC separation was performed using an Agilent 1290 UV-guided fully automated purification system (Xtimate ^® Prep C18 OBDTM 21.2*250 mm 10μm column) or a Gilson GX281 UV-guided fully automated purification system (xBridge ^® Prep C18 OBDTM 19*250 mm 10μm column) or a Waters QDa-guided fully automated purification system (SunFire ^® Prep C18 OBD 29*250 mm 10μm column). Unless otherwise specified, the separation was performed using a SepaFlash pre-packed normal phase silica gel column (Sinopharm Chemical Reagent Co., Ltd.), a TLC analysis plate (Yantai Jiangyou Silica Gel Development Co., Ltd., model: HSGF254, specification: 2.5×5 cm), and the ratio of the eluent was by volume.

Among them, the Chinese names of the reagents represented by chemical formulas or English abbreviations are as follows:

CD ₃ OD represents deuterated methanol; DMSO -d6 represents deuterated dimethyl sulfoxide; Chloroform -d or CDCl ₃ represents deuterated chloroform; AcOH represents acetic acid; AlCl ₃ represents aluminum chloride; Aq represents aqueous solution; N ₂ represents nitrogen; Ar represents argon; B ₂ Pin ₂ represents diboric acid pinacol ester; BBr ₃ represents boron tribromide; BH ₃ represents borane; (Boc) ₂ O represents dibutyl dicarbonate; Et ₃ SiH represents triethylsilane; HATU represents 1-[bis(dimethylamino)methylene]-1H-1, 2, 3-triazolo[4, 5-b]pyridinium 3-oxide hexafluorophosphate; HOBt represents 1-hydroxybenzotriazole; K ₂ CO ₃ represents potassium carbonate; KOAc represents potassium acetate; MeONa represents sodium methoxide; LDA represents lithium diisopropylamide; LiHMDS represents lithium bis(trimethylsilyl)amide; LiOH represents lithium hydroxide; m -CPBA represents m-chloroperbenzoic acid; _Na2CO3 represents sodium carbonate; _NaBH4 represents sodium borohydride; _NaCl represents sodium chloride; _NaHCO3 represents sodium bicarbonate; _NaOH represents sodium hydroxide; _Na2SO4 represents sodium sulfate; NBS represents N-bromosuccinimide; NCS represents N-chlorosuccinimide; NIS represents N-iodosuccinimide; n -BuLi represents n-butyl lithium; _NH4Cl represents ammonium chloride; NMP represents N-methyl-2-pyrrolidone; PBr ₃ represents phosphorus tribromide; Pd(dppf)Cl ₂ or PdCl ₂ (dppf) represents 1, 1'-bis(diphenylphosphino)ferrocene dichloropalladium; Pd ₂ (dba) ₃ represents tri(dibenzylideneacetone)dipalladium (0); Pd(OAc) ₂ represents sodium acetate; conc. represents concentration; (COCl) ₂ represents oxalyl chloride; Cs ₂ CO ₃ represents cesium carbonate; CuCl represents cuprous chloride; CuI represents cuprous iodide; DCM represents dichloromethane; Dioxane or 1, 4-dioxane represents 1, 4-dioxane; MeCN, ACN or CH ₃ CN represents acetonitrile; MeOH or methanol represents methanol; EtOH or ethanol represents ethanol; DEA represents diethylamine; DIPEA or DIEA represents N, N-diisopropylethylamine; DIAD stands for diisopropyl azodicarboxylate; Xantphos stands for 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene; DMAP stands for 4-dimethylaminopyridine; DMF stands for N, N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EA or EtOAc stands for ethyl acetate; PE stands for petroleum ether; THF stands for tetrahydrofuran; Toluene or tol. stands for toluene; SOCl ₂ stands for dichlorosulfoxide; TFA stands for trifluoroacetic acid; FA stands for formic acid; TMSCN stands for trimethylsilyl cyanide; H ₂ O stands for water; HCl stands for hydrogen chloride gas; HCl aq. represents aqueous hydrochloric acid; °C represents degrees Celsius; rt or RT represents room temperature; h represents hour; min represents minute; g represents gram; mg represents milligram; mL represents milliliter; mmol represents millimole; M represents mole; cm represents centimeter; mm represents millimeter; µm represents micrometer; nm represents nanometer; mL/min represents milliliter per minute; Hz represents hertz; MHz represents megahertz; bar represents bar; psi represents pounds per square inch; _N2 represents nitrogen; HPLC represents high performance liquid chromatography; ID represents inner diameter; LCMS or LC-MS represents liquid chromatography-mass spectrometry; m/z represents mass-to-charge ratio; ESI represents electrospray ionization; CO ₂ stands for carbon dioxide; TLC stands for thin layer chromatography; UV stands for ultraviolet; IV stands for intravenous injection; PO stands for oral administration; rpm stands for revolutions per minute; ATCC stands for American type culture collection.

Example 1: Preparation of Compound 1

Preparation of compound 1-2

Compound 1-1 (120.0 g, 643.1 mmol) was dissolved in MeCN (1.2 L), cooled to 0°C in an ice-water bath, and p-toluenesulfonic acid monohydrate (122.2 g, 643.1 mmol) was added and stirred at this temperature for 30 min; then NIS (173.6 g, 771.1 mmol) was added, and after the addition, the ice-water bath was removed, and the reaction system was stirred at room temperature for 16 h. Sodium sulfite was added to the reaction system to quench the reaction, and water (3 L) was added, extracted with ethyl acetate (2 L×2), the organic phase was washed with saturated brine (2 L×3), dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by normal phase silica gel chromatography column (EA/PE=0-30%) to obtain the title compound 1-2 (168.0 g, white solid, yield 84%).

Preparation of Compound 1-3

Compound 1-2 (163.0 g, 0.52 mol) was dissolved in DMF (800 mL), and cesium carbonate (338.9 g, 1.04 mol), compound 1-bromo-2-chloroethane (149.1 g, 1.04 mol) and H ₂ O (12 mL) were added in sequence, and the temperature was raised to 65°C for 16 h. After the reaction was completed, the filtrate was filtered, and water (3 L) was added to the filtrate, and ethyl acetate was extracted (2 L×2). The organic phase was washed with saturated brine (2 L×3), dried with anhydrous sodium sulfate, and the organic phase was concentrated and purified by normal phase silica gel chromatography column (EA/PE=0-30%) to obtain the title compound 1-3 (136.9 g, white solid, yield 70%).

Preparation of Compounds 1-4

Compound 1-3 (168.0 g, 448.0 mmol) was dissolved in DMF (1 L), and CuCN (100.3 g, 1120.0 mmol) and CuI (73.1 g, 385.4 mmol) were added and the temperature was raised to 140 °C for 4 hours. The reaction was completed by monitoring by TLC (PE/EA=5/1, product Rf≈0.5), and the filter cake was filtered through a thin layer of diatomaceous earth and eluted with ethyl acetate. The filtrate was collected and added with water (4 L), extracted with ethyl acetate (3 L × 2), the organic phase was washed with saturated brine (2 L × 3), dried over anhydrous sodium sulfate, concentrated and purified by normal phase silica gel chromatography (EA/PE = 0-20%) to obtain the title compound 1-4 (66.7 g, white solid, yield 54%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46 (d, J = 5.1 Hz, 1H), 6.93 (d, J = 5.0 Hz, 1H), 5.32 (s, 2H), 2.51 (s, 3H), 2.05 (s, 2H).

Preparation of Compounds 1-5

Compound 1-4 (5 g, 18 mmol) was added to a three-necked flask, replaced with nitrogen three times, anhydrous tetrahydrofuran (20 mL) was added, and methylmagnesium bromide (3.0 M, 18 mL, 54 mmol) was added dropwise at -10°C. The reaction system was stirred at 0°C for 2 hours, and the reaction was completed. Saturated ammonium chloride aqueous solution (50 mL) was slowly added to the reaction system under an ice bath, and extracted with EtOAc (50 mL×3). The organic phases were combined, washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (EtOAc/PE = 0-20%) to obtain the title compound 1-5 (3 g, light yellow liquid, yield 60%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 7.90 (d, J = 2.2 Hz, 1H), 7.83 (d, J = 2.2 Hz, 1H), 5.37 (s, 1H), 4.43 (t, J = 4.0 Hz, 2H), 3.97 (t, J = 4.0 Hz, 2H) ,1.43 (s, 6H).

Preparation of Compounds 1-6

Compound 1-5 (3 g, 10.9 mmol) was added to a three-necked flask, followed by anhydrous THF (30 mL) and phenol (3 g, 32.8 mmol), and then a boron trifluoride ether solution (9.71 g, 32.8 mmol) was added at 0°C. The reaction system was stirred at 0°C for 3 hours. After the reaction was completed, ice water (20 mL) was slowly added to quench the reaction, and the mixture was extracted with EtOAc (30 mL×3). The organic phases were combined, washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-20%) to obtain the title compound 1-6 (2.3 g, light yellow liquid, yield 57%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 9.29 (s, 1H), 7.61 (d, J = 2.2 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.04 (d, J = 8.6 Hz, 2H), 6.69 (d, J = 8.6 Hz, 2H), 4.41 (t, J =4.0 Hz, 2H), 3.95 (t, J = 4.0 Hz 2H), 1.60 (s, 6H).

Preparation of Compounds 1-7

Compound 1-6 (1.5 g, 4.3 mmol) was added to a single-necked bottle, and DMF (5 mL), anhydrous potassium carbonate (1.2 g, 8.6 mmol) and 2-chloro-4-(chloromethyl)pyrimidine (700 mg, 4.3 mmol) were added in sequence, and the reaction system was stirred for 1 hour. After the reaction was completed, water (10 mL) was added to the reaction system to quench the reaction, and EtOAc (20 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-30%) to obtain the title compound 1-7 (1.8 g, white solid, yield 88%). LC-MS (ESI): m/z 476.0 [M+H] ⁺ .

Preparation of compound 1

Compound 1-7 (300 mg, 0.63 mmol) was dissolved in DMF (5.0 mL), and dimethylphosphine oxide (245 mg, 3.2 mmol), triethylamine (191 mg, 1.9 mmol), tri(dibenzylideneacetone)dipalladium (115 mg, 0.13 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (73 mg, 0.13 mmol) were added in sequence. The reaction system was replaced with nitrogen three times and stirred in a microwave at 120°C for 2 hours. After the reaction was completed, the insoluble solid was filtered off, water (10 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was prepared, separated, and purified (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 1 (45 mg, yield 14%). LC-MS (ESI): m/z 518.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d6 ) δ 8.99 (d, J = 5.1 Hz, 1H), 7.71 (dd, J = 5.2, 3.2 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.20 (d, J = 8.9 Hz, 2H), 7.00 (d, J = 8.9 Hz, 2H), 5.28 (s, 2H), 4.52 – 4.34 (m, 2H), 4.05 – 3.86 (m, 2H), 1.76 (d, J = 1 3.7 Hz, 6H), 1.63 (s, 6H); ³¹ P NMR (162 MHz, DMSO- d6 ) δ 34.00 (s, 1P).

Example 2: Preparation of Compound 2

Preparation of compound 2-1

Compound 1-5 (1 g, 3.65 mmol) and compound 2-iodophenol (1.61 g, 7.3 mmol) were dissolved in anhydrous dichloromethane (20 mL), and a boron trifluoride ether solution (48%, 1.93 mL, 7.3 mmol) was slowly added dropwise at 0°C. After the addition, the mixture was reacted at room temperature for 2 hours. The reaction was followed by LCMS until it was complete and then quenched with water. The reaction system was extracted with DCM (50 mL×2), and the organic phases were combined, dried, concentrated, and the crude product was obtained. The title compound 2-1 (180 mg) was obtained by separation and purification on a normal phase silica gel column (EtOAc/PE = 0 - 30%). The yield was 10%. LC-MS (ESI): m/z 474.4 [MH] ^- .

Preparation of compound 2-2

Compound 2-1 (170 mg, 0.36 mmol) and cuprous cyanide (128 mg, 1.43 mmol) were dissolved in DMF (5 mL), replaced with nitrogen three times, and then microwaved at 120°C for 2 hours. After the reaction was complete as monitored by LCMS, water was added, and the mixture was extracted with EtOAc (50 mL×2). The organic phases were combined, dried, concentrated, and the crude product of the title compound 2-2 (130 mg) was obtained, which was used directly in the next step. LC-MS (ESI): m/z 373.0 [MH] ^- .

Preparation of compound 2-3

Compound 2-2 (130 mg, 0.35 mmol), compound (2-chloropyrimidin-4-yl)methanol (100 mg, 0.69 mmol) and triphenylphosphine (273 mg, 1 mmol) were dissolved in anhydrous tetrahydrofuran (8 mL), and diethyl azodicarboxylate (181 mg, 1 mmol) was slowly added dropwise at room temperature, and the mixture was reacted at 50°C for 4 hours. After the reaction was completed by LCMS tracking, water was added, and the reaction system was extracted with EtOAc (50 mL×2). The organic phases were combined, dried and concentrated to obtain 150 mg of the crude product of the title compound 2-3, which was directly used in the next step. LC-MS (ESI): m/z 501.0 [M+H] ⁺ .

Preparation of compound 2

Compound 2-3 (150 mg, 0.3 mmol) was dissolved in DMF (8.0 mL), and dimethylphosphine oxide (70 mg, 0.9 mmol), triethylamine (91 mg, 0.9 mmol), Pd ₂ (dba) ₃ (27 mg, 0.03 mmol) and Xantphos (35 mg, 0.06 mmol) were added in sequence. The mixture was replaced with nitrogen three times and then reacted at 100°C in a microwave oven for 2 hours. After the reaction was completed by LCMS tracking, the reaction solution was filtered, and the crude filtrate was purified by preparation separation (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/L NH ₄ HCO ₃ )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 2 (25 mg, yield 15%). LC-MS (ESI): m/z 543.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ 9.05 (d, J = 5.2 Hz, 1H), 7.76 – 7.69 (m, 2H), 7.70 – 7.62 (m, 2H), 7.49 (dd, J = 9.0, 2.6 Hz, 1H), 7.25 (d, J = 9.0 Hz, 1H), 5.49 (s, 2H), 4.42 (t, J = 6.2 Hz, 2H), 3.96 (t, J = 6.2 Hz, 2H), 1.73 (d, J = 13.6 Hz, 6H), 1.66 (s, 6H). ³¹ P NMR (162 MHz, DMSO- d6 ) δ 3 4.01 (s, 1P).

Example 3: Preparation of Compound 3

Preparation of compound 3-1

Compound 1-5 (300 mg, 1.1 mmol) was added to a three-necked flask, and then 5,6,7,8-tetrahydro-1-naphthol (486 mg, 3.3 mmol) and anhydrous dichloromethane (10 mL) were added. After nitrogen substitution three times, boron trifluoride ether solution (48%, 620 mg, 2.2 mmol) was added dropwise at a cooling temperature of 0°C. The reaction system was stirred at 0°C for 2 hours. After the reaction was completed, water was added to quench the reaction, and dichloromethane (50 mL×3) was used for extraction. The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-20%) to obtain the title compound 3-1 (200 mg) with a yield of 45%. ¹ H NMR (400 MHz, Chloroform- d ) δ 7.48 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 4.40 (t, J = 6. 3 Hz, 2H), 3.87 (t, J = 6.3 Hz, 2H), 2.77 (t, J = 6.2 Hz, 2H), 2.44 (t, J = 6.3 Hz, 2H), 1.90 – 1.81 (m, 2H), 1.76 (dq, J = 5.2, 3.0, 2.2 Hz, 2 H), 1.65 (s, 6H).

Preparation of compound 3-2

Compound 3-1 (200 mg, 0.5 mmol) was added to a three-necked flask, followed by anhydrous DCM (10 mL), (2-methylthiopyrimidin-4-yl)methanol (155 mg, 1.0 mmol), triphenylphosphine (260 mg, 1.0 mmol), replaced with nitrogen three times, and diisopropyl azodicarboxylate (200 mg, 1.0 mmol) was added at 0°C. The reaction was stirred at 25°C for 16 hours. After the reaction was completed, water (30 mL) was added, extracted with EtOAc (30 mL×3), the organic phases were combined, dried and concentrated to obtain a crude product, and separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 20%) to obtain the title compound 3-2 (100 mg) with a yield of 38%. LC-MS (ESI): 542.3 [M+H] ⁺ .

Preparation of compound 3-3

Compound 3-2 (100 mg, 0.2 mmol) was added to a single-necked bottle, and THF (5 mL) was added. 5 mL of water was added to the conical flask, potassium peroxymonosulfonate (427 g, 1.2 mmol) was added, and the mixture was slowly dripped into the single-necked bottle, and stirred at room temperature for 16 hours. After the reaction was completed, water (30 mL) was added to quench the reaction, and the mixture was extracted with DCM (20 mL×3). The organic phases were combined, dried, and concentrated to obtain the crude title compound 3-3 (110 mg), with a yield of 93%. LC-MS (ESI): 574.3 [M+H] ⁺ .

Preparation of compound 3

Compound 3-3 (100 mg, 0.18 mmol) was dissolved in acetonitrile (2.0 mL), and dimethylphosphine oxide (68 mg, 0.9 mmol) and potassium carbonate (73 mg, 0.54 mmol) were added in sequence. The reaction system was stirred at 80°C for 3 hours. After the reaction was completed, the reaction system was filtered and water (30 mL) was added, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was prepared, separated and purified (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 3 (2.2 mg, yield 2.2%). LC-MS (ESI): m/z 572.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ 9.01 (d, J = 5.2 Hz, 1H), 7.62 (dd, J = 5.1, 3.1 Hz, 1H), 7.45 (s, 2H), 7.35 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 4.23 (t, J = 5.9 Hz, 2H), 3.90 (t, J = 5.9 Hz, 2H), 3.85 (s, 2H), 2.76 (t, J = 6.4 Hz, 2H), 2.67 (q, J = 1.9 Hz, 2H), 1.75 (d, J = 13.6 Hz, 6H), 1.71 (m, 2H), 1.65 (s, 6H), 1.62 (m, 2H). ³¹ P NMR (162 MHz, DMSO- d6 ) δ 33.85 (s, 1P).

Example 4: Preparation of Compound 4

Preparation of compound 4-1

Compound 1-5 (300 mg, 1.1 mmol) was added to a three-necked flask, followed by 4-indanol (440 mg, 3.3 mmol) and anhydrous dichloromethane (10 mL). After nitrogen substitution three times, boron trifluoride ether solution (48%, 620 mg, 2.2 mmol) was added dropwise at 0°C. The reaction system was stirred at 0°C for 2 hours. After the reaction was completed, water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried, concentrated, and the crude product was obtained. The title compound 4-1 (200 mg) was obtained by separation and purification on a normal phase silica gel column (EtOAc/PE = 0 - 20%) with a yield of 45%. ¹ H NMR (400 MHz, DMSO- d6 ) δ 9.14 (s, 1H), 7.51 (d, J = 2.3 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 8.3 Hz, 1H), 4.43 (t, J = 5.0 Hz, 2H), 3.96 (t, J = 5.0 Hz, 2H), 2.61 (t, J = 7.3 Hz, 2H), 2.10 (t, J = 7.3 Hz, 2H), 1.76 – 1.66 (m, 2H), 1.56 (s, 6H).

Preparation of compound 4-2

Compound 4-1 (200 mg, 0.5 mmol) was added to a three-necked flask, followed by anhydrous DCM (10 mL), (2-methylthiopyrimidin-4-yl)methanol (155 mg, 1.0 mmol), triphenylphosphine (270 mg, 1.0 mmol), replaced with nitrogen three times, and diisopropyl azodicarboxylate (208 mg, 1.0 mmol) was added at 0°C. The reaction was stirred at 25°C for 16 hours. After the reaction was completed, water (40 mL) was added, extracted with EtOAc (30 mL×3), the organic phases were combined, dried and concentrated to obtain a crude product, and separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 20%) to obtain the title compound 4-2 (100 mg) with a yield of 36%. LC-MS (ESI): 528.0 [M+H] ⁺ .

Preparation of compound 4-3

Compound 4-2 (100 mg, 0.19 mmol) was added to a single-necked bottle, and then THF (5 mL) was added. 5 mL of water was added to the conical flask, and potassium peroxymonosulfonate (394 mg, 1.2 mmol) was added. After stirring and dissolving, the resulting solution was slowly dripped into the single-necked bottle. After the addition was completed, the reaction was stirred at room temperature for 16 hours. After the reaction was completed, sodium thiosulfate aqueous solution (20 mL) was slowly added to the reaction system under an ice bath, and extracted with DCM (20 mL×3). The organic phases were combined, dried and concentrated to obtain the crude title compound 4-3 (100 mg), with a yield of 94%. LC-MS (ESI): 560.5 [M+H] ⁺ .

Preparation of compound 4

Compound 4-3 (100 mg, 0.18 mmol) was dissolved in acetonitrile (2.0 mL), and dimethylphosphine oxide (68 mg, 0.9 mmol) and potassium carbonate (73 mg, 0.54 mmol) were added in sequence. The reaction system was stirred at 80°C for 3 hours. After the reaction was completed, the reaction system was filtered, water (20 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparation separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 4 (34 mg, yield 63%). LC-MS (ESI): m/z 558.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ 9.00 (d, J = 5.2 Hz, 1H), 7.72 (dd, J = 5.2, 3.1 Hz, 1H), 7.53 (d, J = 2.3 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 5.32 (s, 2H), 4.54 – 4.37 (t, J = 5.8 Hz, 2H), 3.96 (t, J = 5.8 Hz, 2H), 2.80 (t, J = 7.3 Hz, 2H), 2.16 (q, J = 7.4 Hz, 2H), 1.77 (d, J = 13.6 Hz, 6H), 1.77 (m, 2H), 1.59 (s, 6H). ³¹ P NMR (162 MHz, DMSO- d6 ) δ 34.01 (s, 1P) .

Example 5: Preparation of Compound 5

Preparation of compound 5-2

Add compound 5-1 (2 g, 15.56 mmol), NCS (2.08 g, 15.56 mmol) and AIBN (0.255 g, 1.56 mmol) to the sealed tube, dissolve in acetonitrile (20 mL), and react at 80°C overnight. Add water (50 mL), extract with ethyl acetate (20 mL×3), dry and concentrate to obtain a crude product, which is purified by normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate/petroleum ether = 0 ~ 100%) to obtain the title product 5-2 (0.8 g, yield 31%). LC-MS (ESI): m/z 162.9 [M+H] ⁺ .

Preparation of compound 5-3

Compound 5-2 (0.8 g, 4.91 mmol) and DCM (5 mL) were added to the reaction flask, followed by TEA (0.5 g, 4.91 mmol) and acetic acid (0.294 g, 2.91 mmol), and the mixture was reacted at 55°C overnight. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried, and concentrated to obtain a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate/petroleum ether = 0~100%) to obtain the title product 5-3 (0.5 g, yield 54%). LC-MS (ESI): m/z 187.0 [M+H] ⁺ .

Preparation of compound 5-4

Dissolve compound 5-3 (500 mg, 2.68 mmol) in DMF solution (1 mL), add compound dimethylphosphine oxide (209 mg, 2.68 mmol) and DIPEA (209 mg, 2.68 mmol). Stir the reaction system at 160°C for 1 hour. After the reaction system is cooled, filter, and add appropriate amount of lyophilize to the filtrate to obtain the crude title compound 5-4 (0.5 g) with a yield of 81%, which is directly used in the next reaction. LC-MS (ESI): m/z 229.4 [M+H] ⁺ .

Preparation of compound 5-5

Compound 5-4 (0.5 g, 2.19 mmol) and methanol (3 mL) were added to the reaction flask, and TEA (0.443 g, 4.38 mmol) was added, and the mixture was reacted at 55°C overnight. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried, and concentrated to obtain a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 20 g, UV254, dichloromethane/methanol = 0~100%) to obtain the title product 5-5 (0.25 g, yield 62%). LC-MS (ESI): m/z 187.2 [M+H] ⁺ .

Preparation of compound 5

Compound 5-5 (250 mg, 1.34 mmol), compound 1-6 (470 mg, 1.34 mmol) and tributylphosphine (815 mg, 4.03 mmol) were added to a three-necked flask, and dichloromethane (10 mL) was added as a solvent. Under nitrogen protection, N,N,N',N'-tetramethylazodicarbonamide (694 mg, 4.03 mmol) was added under ice-water bath, and the reaction system was stirred at room temperature for 16 hours. The reaction solution was filtered, and the crude filtrate was purified by preparation separation (preparation method: chromatographic column: Agilent 10 Prep-C18 250x21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% TFA)-acetonitrile; mobile phase acetonitrile ratio 50%-70% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 5 (190 mg, yield 27%). LC-MS (ESI): m/z 518.0 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 9.00 (t, J = 4.8 Hz, 1H), 8.00 (t, J = 5.1 Hz, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 7.13 – 7.03 (m, 2H), 6.95 – 6.89 (m, 2H), 5.36 (s, 2H), 4.42 (t, J = 6.2 Hz, 2H), 3.88 (t, J = 6.2 Hz, 2H), 1.73 (d, J = 13.6 Hz, 6H), 1.63 (s, 6H). ³¹ P NMR (162 MHz, Chloroform -d ) 36.12 (s, 1P).

Example 6: Preparation of Compound 6

Preparation of compound 6

Compound 1 (50 mg, 0.09 mmol) was dissolved in toluene (2.0 mL), and phosphorus pentasulfide (86 mg, 0.4 mmol) was added. The reaction system was stirred at 100 °C for 16 hours. After the reaction was completed, the reaction system was filtered, the filtrate was added with water, extracted with dichloromethane (20 mL×3), the organic phases were combined, dried and concentrated to obtain a crude product, which was prepared, separated and purified (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 6 (4 mg, yield 7%). LC-MS (ESI): m/z 534.5 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ 8.97 (d, J = 5.2 Hz, 1H), 7.69 (t, J = 4.5 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 5.27 (s, 2H), 4.41 (t, J = 5.1 Hz, 2H), 3.95 (t, J = 5.1 Hz, 2H), 2.05 (d, J = 14.0 Hz, 6H), 1.63 (s, 6H). ³¹ P NMR (162 MHz, DMSO- d6 ) δ 36.63 (s, 1P).

Example 7: Preparation of Compound 7

Preparation of compound 7-2

Compound 7-1 (140 mg, 0.968 mmol) was dissolved in DMSO solution (1 mL), and dimethylphosphine oxide (78 mg, 1.94 mmol) and DIPEA (376 mg, 2.91 mmol) were added. The reaction system was sealed and stirred at 150°C for 1 hour. After the reaction system was cooled, it was filtered, and an appropriate amount of lyophilized water was added to the filtrate. The residue was separated and purified by a normal phase silica gel column (MeOH/DCM = 0-5%) to obtain the title compound 7-2 (120 mg, yield 66%) as a white solid. LC-MS (ESI): m/z 187.0 [M+H] ⁺ .

Preparation of compound 7

Compound 7-2 (120 mg, 0.645 mmol), compound 1-6 (226 mg, 0.645 mmol) and tri-n-butylphosphine (391 mg, 1.93 mmol) were added to a three-necked flask, and dichloromethane (10 mL) was added as a solvent. Under nitrogen protection, N,N,N',N'-tetramethylazodicarbonamide (333 mg, 1.93 mmol) was added under ice-water bath, and the reaction system was stirred at room temperature for 16 hours. The reaction solution was filtered and spin-dried to obtain a crude product, which was purified by preparative separation (preparation method: chromatographic column: Agilent 10 Prep-C18 250x21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% TFA)-acetonitrile; mobile phase acetonitrile ratio 50%-70% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 7 (70 mg, yield 20%). LC-MS (ESI): m/z 518.2 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 9.22 (s, 1H), 8.98 (d, J = 3.2 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 5.27 (s, 2H), 4.43 (t, J = 6.2 Hz, 2H), 3.88 (t, J = 6.2 Hz, 2H), 1.83 (d, J = 13.6 Hz, 6H), 1.66 (s, 6H). ³¹ P NMR (162 MHz, Chloroform -d ) δ 35.95 (s, 1P).

Example 8: Preparation of Compound 8

Preparation of compound 8-2

Compound 8-1 (100 mg, 5.36 mmol) was dissolved in DMSO solution (1 mL), and dimethylphosphine (692 mg, 5.36 mmol) and DIPEA (376 mg, 5.36 mmol) were added. The reaction system was sealed and stirred at 150°C for 1 hour. After the reaction system was cooled, it was filtered, and an appropriate amount of lyophilized water was added to the filtrate. The residue was separated and purified by a normal phase silica gel column (MeOH/DCM = 0-5%) to obtain the title compound 8-2 (0.4 g, yield 32%). LC-MS (ESI): m/z 229.0 [M+H] ⁺ .

Preparation of compound 8-3

Compound 8-2 (400 mg, 1.75 mmol) was dissolved in THF solution (3 mL), and sodium borohydride (66 mg, 1.75 mmol) was added. The reaction system was stirred at 20°C for 1 hour. After the reaction system was cooled, it was filtered, and an appropriate amount of lyophilized water was added to the filtrate. The residue was separated and purified by a normal phase silica gel column (MeOH/DCM = 0-5%) to obtain the title compound 8-3 (0.04 g, yield 12%). LC-MS (ESI): m/z 187.2 [M+H] ⁺ .

Preparation of compound 8

Compound 8-3 (40 mg, 0.215 mmol), compound 1-6 (75 mg, 0.215 mmol) and tri-n-butylphosphine (43 mg, 0.214 mmol) were added to a three-necked flask, and dichloromethane (2 mL) was added as a solvent. Under nitrogen protection, N,N,N',N'-tetramethylazodicarbonamide (37 mg, 0.215 mmol) was added under ice-water bath, and the reaction system was stirred at room temperature for 16 hours. The reaction solution was filtered to obtain a crude product, which was purified by preparative separation (preparation method: chromatographic column: Agilent 10 Prep-C18 250x21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% TFA)-acetonitrile; mobile phase acetonitrile ratio 50%-70% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 8 (3 mg, yield 6%). LC-MS (ESI): m/z 518.2 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 9.29 (s, 1H), 8.41 (d, J = 5.7 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.13 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 5.21 (s, 2H), 4.43 (t, J = 6.2 Hz, 2H), 3.88 (t, J = 6.2 Hz, 2H), 1.82 (d, J = 13.7 Hz, 6H), 1.66 (s, 6H). ³¹ P NMR (162 MHz, Chloroform -d ) δ 36.42 (s, 1P).

Example 9: Preparation of Compound 9

Preparation of compound 9-2

Compound 9-1 (8 g, 49.01 mmol) was dissolved in dichloromethane (100 mL). Vinyl magnesium bromide (1.0 M, 98 mL, 98.20 mmol) was added dropwise at -70 °C, and the temperature was naturally raised to room temperature for reaction for 2 hours. Ethanol (100 mL) was added to quench the reaction system, and the mixture was extracted with ethyl acetate (200 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column 20 g, UV254, methanol/dichloromethane = 0~10%) to obtain the title product 9-2 (8 g, yield 83%). ¹ H NMR (400 MHz, Chloroform -d ) δ 6.36 – 6.06 (m, 6H), 4.04 (m, 2H), 1.30 (t, J = 7.0 Hz, 3H).

Preparation of compound 9-3

Compound 9-2 (2 g, 13.69 mmol) and 2,4-dimethoxybenzylamine (2.29 g, 13.69 mmol) were dissolved in ethanol (30 mL), and the reaction solution was stirred at 100°C for 1 hour. The crude product was spin-dried and the title compound 9-3 (1.4 g, yield 32%) was obtained by normal phase silica gel column (biotage, silica gel column 20 g, UV254, methanol/dichloromethane = 0~10%). ¹ H NMR (400 MHz, Chloroform- d ) δ 7.22 (d, J = 8.2 Hz, 1H), 6.48 (dd, J = 8.2, 2.4 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 4.10 – 4.03 (m, 2H), 3.80 (d, J = 7.0 Hz, 6H), 3.59 (s, 2H), 3.11 – 2.96 (m, 2H), 2.78 – 2.66 (m, 2H), 2.02 – 1.93 (m, 2H), 1.91 – 1.77 (m, 2H), 1.34 (t, J = 7.0 Hz, 3H). ³ 1P NMR (162 MHz, Chloroform- d ) δ 45.70 (s, 1P).

Preparation of compounds 9-4 and 9-5

Compound 9-3 (0.45 g, 1.44 mmol) was added to a three-necked flask, nitrogen was replaced, and THF (5 mL) was added. At -78°C, lithium aluminum hydroxide tetrahydrofuran solution (1 M, 1.44 mL) was added dropwise, and the reaction was carried out for 30 min after the addition was completed. The reaction system was quenched with solid sodium sulfate decahydrate (100 mg), filtered, and the filtrate was combined, dried and concentrated to obtain a mixture of crude title products 9-4 and 9-5 (0.27 g, yield 74%). LC-MS (ESI): m/z 253.8 [M+H] ⁺ , 269.8 [M+H] ⁺ .

Preparation of compound 9-6

A mixture of the above compounds 9-4 and 9-5 (0.270 g, about 1.07 mmol), 30% hydrogen peroxide (0.2 mL), and DCM (5 mL) were added to a three-necked flask and reacted at room temperature for 1 hour. After the reaction was completed, the crude product was concentrated and purified by a normal phase silica gel column (biotage, silica gel column 40 g, UV254, methanol/dichloromethane = 0~10%) to obtain the title compound 9-6 (0.160 g, yield 55%). LC-MS (ESI): m/z 269.8 [M+H] ⁺ .

Preparation of compound 9-7

Compound 9-6 (0.270 g, 1 mmol) was dissolved in DMF solution (2 mL), and compound (2-chloropyrimidin-4-yl)methanol (145 mg, 1 mmol), DIPEA (389 mg, 3.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (58 mg, 0.1 mmol), and Pd ₂ (dba) ₃ (92 mg, 0.1 mmol) were added. The reaction system was sealed and stirred at 150°C for 1 hour. After the reaction system was cooled, it was filtered, and an appropriate amount of freeze-dried water was added to the filtrate. The residue was separated and purified by a normal phase silica gel column (MeOH/DCM = 0-10%) to obtain the title compound 9-7 (0.15 g, yield 39%). LC-MS (ESI): m/z 377.8 [M+H] ⁺ .

Preparation of compound 9-8

Compound 9-7 (150 mg, 0.397 mmol) was dissolved in TFA (2 mL), and the reaction solution was stirred at 25°C for 1 hour, and then concentrated to obtain a residue. Methanol (2 mL) was added to the residue, and then triethylamine (40 mg, 0.397 mmol) and di-tri-butyl dicarbonate (87 mg, 0.397 mmol) were added, and the reaction solution was stirred at 25°C for 1 hour. TLC plate showed that the reaction was complete. The reaction solution was poured into water (50 mL), extracted with dichloromethane (50 mL×3), and the organic phase was vortexed to obtain a crude product. The crude product was purified by normal phase silica gel column (biotage, silica gel column 25 g, UV254, ethyl acetate/petroleum ether = 0-100%) to obtain the title compound 9-8 (0.120 g, yield 92%). LC-MS (ESI): m/z 327.8 [M+H] ⁺ .

Preparation of compound 9-9

Compound 9-8 (130 mg, 0.344 mmol), compound 1-6 (120 mg, 0.344 mmol) and tributyl phosphine (139 mg, 0.689 mmol) were added to a three-necked flask, and dichloromethane (2 mL) was added as a solvent. Under nitrogen protection, N,N,N',N'-tetramethylazodime (118 mg, 0.689 mmol) was added under ice-water bath, and the reaction system was stirred at room temperature for 16 hours. The reaction solution was filtered, and the crude filtrate was purified by normal phase silica gel column (biotage, silica gel column 25 g, UV254, MeOH/DCM = 0 - 10%) to obtain the title compound 9-9 (0.2 g, yield 88%), LC-MS (ESI): m/z 659.0 [M+H] ⁺ .

Preparation of compound 9

Compound 9-9 (200 mg, 0.303 mmol) was dissolved in DCM (3 mL), TFA (1 mL) was added, and the reaction system was reacted at room temperature for 1 hour. The reaction solution was vortexed to obtain a crude product (180 mg), which was prepared and separated (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 9 (5 mg, yield 12%). LC-MS (ESI): m/z 559.0 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.91 (d, J = 5.2 Hz, 1H), 7.70 (dd, J = 5.1, 3.2 Hz, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.3 1 (d, J = 2.3 Hz, 1H), 7.13 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 5.24 (s, 2H), 4.43 (t, J = 6.1 Hz, 2H), 3.88 (t, J = 6.1 Hz, 2H), 3.53 – 3.37 (m, 2H), 3.04 – 2.88 (m, 2H), 2.74-2.67 (m, 2H), 2.29 – 2.14 (m, 2H), 1.65 (s, 6H). ³¹ P NMR (162 MHz, Chloroform- d ) δ 30.19 (s, 1P).

Example 10: Preparation of Compound 10

Preparation of compound 10-2

Compound 1-6 (350 mg, 1 mmol), compound 10-1 (352 mg, 3mmol), triphenylphosphine (789 mg, 3 mmol), DIAD (606 mg, 3 mmol) and anhydrous tetrahydrofuran (10 mL) were added to a single-necked bottle, replaced with nitrogen three times, and stirred at 50°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, saturated sodium chloride aqueous solution (30 mL) was added to the reaction system, and extracted with EtOAc (50 mL×3), the organic phases were combined, dried and concentrated to obtain a crude product, and separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 30%) to obtain the title compound 10-2 (230 mg) with a yield of 48%. LC-MS (ESI): 476.2 [M+H] ⁺ .

Preparation of compound 10

Compound 10-2 (230 mg, 0.48 mmol) was dissolved in N,N-dimethylformamide (3.0 mL), and dimethylphosphine oxide (2 mg, 1.45 mmol), triethylamine (146 mg, 1.45 mmol), tri(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (30 mg, 0.05 mmol) were added in sequence. The atmosphere was replaced with nitrogen three times, and the reaction system was stirred in a microwave at 120°C for 2 hours. After the reaction was completed, the reaction system was filtered and extracted with dichloromethane (20 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparation separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 10 (3.86 mg, yield 1.5%). LC-MS (ESI): m/z 518.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ 8.81 – 8.83 (m, 2H) , 7.65 (d, J = 2.3 Hz, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.17 (d , J = 8. ³¹ P NMR (162 MHz, DMSO- d6 ) δ 39.24 (s, 1P).

Example 11: Preparation of Compound 11

Preparation of compound 11-1

Under nitrogen protection, the compound methyl p-hydroxybenzoate (3.0 g, 19.72 mmol) and diisopropylamine hydrochloride (542.8 mg, 3.94 mmol) were dissolved in toluene (30 mL). 1,3-dichloro-5,5-dimethylhydantoin (7.77 g, 9.44 mmol) was slowly added at 0°C and stirred at 0°C for 5 hours. After the reaction was completed, a saturated aqueous sodium sulfite solution (30 mL) was added to quench the reaction, and the reaction system was extracted with EtOAc (100 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-5%) to obtain the title compound 11-1 (1.5 g) with a yield of 34%. LC-MS (ESI): m/z 221.2 [M+H] ⁺ .

Preparation of compound 11-2

Compound 11-1 (1.3 g, 5.88 mmol), 1-bromo-2-chloroethane (1.69 g, 11.76 mmol), cesium carbonate (3.83 g, 11.76 mmol), and DMF (13 mL) were added to a 100 mL sealed tube and reacted at 120°C for 16 hours. After the reaction was completed, 60 mL of water was added, and the reaction system was extracted with EtOAc (30 mL×3). The organic phases were combined, dried, and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-10%) to obtain the title compound 11-2 (0.4 g) with a yield of 24%. LC-MS (ESI): m/z 283.1 [M+H] ⁺ .

Preparation of compound 11-3

Compound 11-2 (400 mg, 1.41 mmol) was added to a three-necked flask and replaced with nitrogen three times. Anhydrous tetrahydrofuran (5 mL) was added to the three-necked flask, and methyl magnesium bromide tetrahydrofuran solution (3.0 M, 1.88 mL, 4.65 mmol) was slowly added dropwise at a cooling temperature of 0°C. After the reaction system was stirred at 0°C for 60 minutes, a saturated ammonium chloride solution (5 mL) was added to the reaction system for quenching, and the reaction system was extracted with EtOAc (5 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-10%) to obtain the title compound 11-3 (280 mg) with a yield of 70%. LC-MS (ESI): m/z 264.8 [MH ₂ O+H] ⁺ .

Preparation of compound 11-4

Compound 11-3 (280 mg, 0.98 mmol) and phenol (185 mg, 1.97 mmol) were dissolved in dichloromethane (3 mL). After cooling to 0°C, a boron trifluoride ether solution (48%, 387 mg, 1.97 mmol) was added dropwise. The temperature was slowly raised to room temperature and stirred for 1 hour. Water (5 mL) was added to the reaction system for quenching, and the mixture was extracted with EtOAc (5 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-20%) to obtain the title compound 11-4 (180 mg) with a yield of 50%. LC-MS (ESI): m/z 357.0 [MH] ^- .

Preparation of compound 11-5

Compound 11-4 (180 mg, 0.5 mmol), triphenylphosphine (393 mg, 1.5 mmol), and compound (2-(methylthio)pyrimidin-4-yl)methanol (117 mg, 0.75 mmol) were dissolved in tetrahydrofuran (2 mL). The mixture was cooled to 0°C under nitrogen protection, and DIAD (303 mg, 1.5 mmol) was added dropwise. The mixture was slowly heated to room temperature and stirred for 16 hours. Water (5 mL) was added to the reaction system to quench the mixture, and the mixture was extracted with EtOAc (5 mL×3). The organic phases were combined, dried, and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 20%) to obtain the title compound 11-5 (160 mg) with a yield of 64%. LC-MS (ESI): m/z 497.0 [M+H] ⁺ .

Preparation of compound 11-6

Compound 11-5 (160 mg, 0.5 mmol) was dissolved in tetrahydrofuran (2 mL), potassium peroxymonosulfonate (445 mg, 1.29 mmol) in water (2 mL) was added, and stirred at room temperature for 16 hours. After the reaction was completed, water (5 mL) was added, and the mixture was extracted with EtOAc (15 mL×3). The organic phases were combined, dried, and concentrated to obtain the title compound 11-6 (120 mg) with a yield of 70%. LC-MS (ESI): m/z 529.2 [M+H] ⁺ .

Preparation of compound 11

Compound 11-6 (120 mg, 0.22 mmol), potassium carbonate (93 mg, 0.68 mmol), dimethylphosphine oxide (53 mg, 0.68 mmol) and acetonitrile (2 mL) were added to a sealed tube and stirred at 80 °C for 16 hours. Water (5 mL) was added to the reaction system for quenching, and the reaction was extracted with EtOAc (5 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparation, separation and purification (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 11 (40 mg, yield 33%). LC-MS (ESI): m/z 527.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ 8.99 (d, J = 5.2 Hz, 1H), 7.79 – 7.65 (m, 1H), 7.25 (s, 2H), 7.23 – 7.17 (m, 2H), 7. 03 – 6.95 (m, 2H), 5.28 (s, 2H), 4.30 – 4.16 (m, 2H), 3.98 – 3.90 (m, 2H), 1.75 (d, J = 13.7 Hz, 6H), 1.61 (s, 6H). ³¹ P NMR (162 MHz, DMSO- d6 ) δ 33.97 (s, 1P).

Example 12: Preparation of Compound 12

Preparation of compound 12-1

Under nitrogen protection, compound 1-3 (1.8 g, 4.8 mmol), methylboric acid (574 g, 9.6 mmol), potassium carbonate (1.33 g, 9.6 mmol), Pd(dppf)Cl ₂ (348 mg, 0.48 mmol), 1,4-dioxane (20 mL) and water (4 mL) were added to a 100 mL three-necked flask and reacted at 100°C for 16 hours. After the reaction was completed, 60 mL of water was added, and the reaction system was extracted with EtOAc (30 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-10%) to obtain the title compound 12-1 (0.6 g) with a yield of 47%. LC-MS (ESI): m/z 263.0 [M+H] ⁺ .

Preparation of compound 12-2

Compound 12-1 (600 mg, 2.28 mmol) was added to a three-necked flask and replaced with nitrogen three times. Anhydrous tetrahydrofuran (5 mL) was added to the three-necked flask, and methyl magnesium bromide tetrahydrofuran solution (3 M, 3.04 mL, 9.12 mmol) was slowly added dropwise at a cooling temperature of 0°C. After the reaction system was stirred at 0°C for 60 minutes, a saturated ammonium chloride solution (5 mL) was added to the reaction system for quenching, and the reaction system was extracted with EtOAc (5 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-10%) to obtain the title compound 12-2 (340 mg) with a yield of 70%. LC-MS (ESI): m/z 263.0 [M+H] ⁺ .

Preparation of compound 12-3

Compound 12-2 (340 mg, 1.29 mmol) and phenol (243 mg, 2.58 mmol) were dissolved in dichloromethane (5 mL). After cooling to 0°C, a boron trifluoride ether solution (48%, 2.58 mmol) was added dropwise. The temperature was slowly raised to room temperature and stirred for 1 hour. Water (5 mL) was added to the reaction system to quench, and the mixture was extracted with EtOAc (15 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-20%) to obtain the title compound 12-3 (300 mg) with a yield of 68%. LC-MS (ESI): m/z 337.0 [MH] ^- .

Preparation of compound 12-4

Compound 12-3 (300 mg, 0.88 mmol), triphenylphosphine (463 mg, 1.77 mmol), and compound (2-(methylthio)pyrimidin-4-yl)methanol (207 mg, 1.33 mmol) were dissolved in tetrahydrofuran (3 mL). The mixture was cooled to 0°C under nitrogen protection, and DIAD (357 mg, 1.77 mmol) was added dropwise. The mixture was slowly heated to room temperature and stirred for 16 hours. Water (5 mL) was added to the reaction system to quench the mixture, and the mixture was extracted with EtOAc (5 mL×3). The organic phases were combined, dried, and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-20%) to obtain the title compound 12-4 (180 mg) with a yield of 42%. LC-MS (ESI): m/z 477.0 [M+H] ⁺ .

Preparation of compound 12-5

Compound 12-4 (180 mg, 0.38 mmol) was dissolved in tetrahydrofuran (2 mL), and potassium peroxymonosulfonate (522 mg, 1.51 mmol) in water (2 mL) was added, and stirred at room temperature for 16 hours. After the reaction was completed, water (5 mL) was added, and the mixture was extracted with EtOAc (5 mL×3). The organic phases were combined, dried, and concentrated to obtain the title compound 12-5 (100 mg) with a yield of 52%. LC-MS (ESI): m/z 509.0 [M+H] ⁺ .

Preparation of compound 12

Compound 12-5 (100 mg, 0.20 mmol), potassium carbonate (81 mg, 0.59 mmol), dimethylphosphine oxide (46 mg, 0.59 mmol) and acetonitrile (2 mL) were added to a sealed tube and stirred at 80 °C for 16 hours. Water (5 mL) was added to the reaction system for quenching, and the reaction mixture was extracted with EtOAc (5 mL×3). The organic phases were combined, dried, and concentrated to obtain a crude product, which was purified by preparation, separation, and purification (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 50%-80% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 12 (45 mg, yield 45%). LC-MS (ESI): m/z 507.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ 8.99 (d, J = 5.2 Hz, 1H), 7.73 – 7.67 (m, 1H), 7.21 – 7.12 (m, 2H), 7.04 (s, 2H), 7. 01 – 6.93 (m, 2H), 5.27 (s, 2H), 4.17 – 4.05 (m, 2H), 3.99 – 3.84 (m, 2H), 2.25 (s, 3H), 1.75 (d, J = 13.7 Hz, 6H), 1.59 (s, 6H). ³¹ P NMR (1 62MHz, DMSO- d6 ) δ 33.97 (s, 1P).

Example 13: Preparation of Compound 13

Preparation of compound 13-2

Compound 13-1 (5 g, 37.3 mmol) and acetyl chloride (5.85 g, 74.6 mmol) were dissolved in dichloromethane (100 mL), and aluminum chloride (14.9 g, 111.9 mmol) was added thereto. After the addition, the system was stirred at room temperature for 16 h. After ice water (10 mL) was added to the system to quench the reaction, it was extracted with dichloromethane (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude title compound 13-2, which was used directly in the next reaction without purification. LC-MS (ESI): 218.6 [M+H] ⁺ .

Preparation of compound 13-3

Crude compound 13-2 (5.3 g, 24.3 mmol) was dissolved in a mixed solvent of methanol (50 mL) and water (50 mL), and lithium hydroxide (2.91 g, 121 mmol) was added thereto. After the addition, the system was stirred at room temperature for 2 h. Dilute hydrochloric acid was added to the system to adjust the solution to pH = 5, and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude title compound 13-3, which was used directly in the next reaction without purification. LC-MS (ESI): 176.6 [M+H] ⁺ .

Preparation of compound 13-4

The crude compound 13-3 (4.1 g, 23.3 mmol) was dissolved in dichloromethane (100 mL), and NBS (4.56 g, 25.6 mmol) was added thereto. After the addition, the system was stirred at room temperature for 16 h. After adding water (10 mL) to the system to quench the reaction, it was extracted with dichloromethane (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0 ~ 25%) to obtain the title compound 13-4. LC-MS (ESI): 254.6 [M+H] ⁺ .

Preparation of compound 13-5

Compound 13-4 (5.1 g, 20.0 mmol) and 1-bromo-2-chloroethane (5.7 g, 40.0 mmol) were dissolved in DMF (50 mL), and cesium carbonate (19.5 g, 60.0 mmol) was added thereto. After the addition, the system was stirred at 70°C for 16 h. After dilution with water (50 mL), the system was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0 ~ 25%) to obtain the title compound 13-5. LC-MS (ESI): 316.6 [M+H] ⁺ .

Preparation of compound 13-6

Compound 13-5 (2 g, 6.3 mmol) and zinc cyanide (1.5 g, 12.6 mmol) were dissolved in DMF (20 mL), and tetrakistriphenylphosphine palladium (0.7 g, 0.6 mmol) was added thereto. After the addition, the system was stirred at 120°C in a microwave reactor for 2 h. The system was filtered, diluted with water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0 ~ 25%) to obtain the title compound 13-6. LC-MS (ESI): 264.0 [M+H] ⁺ .

Preparation of compound 13-7

Compound 13-6 (1 g, 3.8 mmol) was dissolved in tetrahydrofuran (50 mL), and methylmagnesium bromide (1.0 M, 3.8 mL) was added thereto at -78°C. After the addition, the system was stirred at room temperature for 2 h. Saturated ammonium chloride solution (10 mL) was added to the system, the reaction was quenched, and then extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0 ~ 25%) to obtain the title compound 13-7.

Preparation of compound 13-8

Compound 13-7 (700 mg, 2.5 mmol) and phenol (282 mg, 3.0 mmol) were dissolved in dichloromethane (50 mL). Boron trifluoride etherate (48%, 1.42 mL) was added at 0°C. After the addition, the system was stirred at room temperature for 2 h. Water (10 mL) was added to the system to quench the reaction, and then extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0 ~ 25%) to obtain the title compound 13-8. LC-MS (ESI): 355.8 [M+H] ⁺ .

Preparation of compound 13-9

Compound 13-8 (230 mg, 0.65 mmol) and compound (2-(methylthio)pyrimidin-4-yl)methanesulfonic acid methyl ester (302 mg, 1.3 mmol) were dissolved in DMF (10 mL), and cesium carbonate (635 mg, 1.95 mmol) was added thereto. After the addition, the system was stirred at 80°C for 2 h. After dilution with water (10 mL), the system was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0 ~ 35%) to obtain the title compound 13-9. LC-MS (ESI): 493.8 [M+H] ⁺ .

Preparation of compound 13-10

Compound 13-9 (250 mg, 0.51 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperbenzoic acid (175 mg, 1.02 mmol) was added. After the addition, the system was stirred at room temperature for 2 h. After dilution with water (10 mL), the system was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated sodium bicarbonate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude title compound 13-10, which was used directly in the next reaction without purification. LC-MS (ESI): 525.8 [M+H] ⁺ .

Preparation of compound 13

The crude compound 13-10 (130 mg, 0.25 mmol) and dimethylphosphine oxide (192 mg, 2.5 mmol) were dissolved in acetonitrile (3 mL), and potassium carbonate (102 mg, 0.74 mmol) was added thereto. After addition, the system was stirred at 80°C for 8 h. After adding water (10 mL) to dilute the system, it was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated sodium bicarbonate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-performance preparative liquid phase (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 50%-70% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 13. LC-MS (ESI): 523.8 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.87 (s, 1H), 7.68 (s, 1H), 7.55 (s, 1H), 7.11 – 7.03 (m, 2H), 6.93 – 6.82 (m, 2H), 5 .23 (s, 2H), 4.42 (t, J = 5.8 Hz, 2H), 3.83 (t, J = 5.8 Hz, 2H), 2.84 (t, J = 7.4 Hz, 2H), 2.20 (t, J = 7.4 Hz, 2H), 1.90 (d, J = 13.5 Hz, 6H), 1 .84 – 1.80 (m, 2H), 1.62 (s, 6H). ³¹ P NMR (162 MHz, Chloroform- d ) δ 35.17 (s, 1P).

Example 14: Preparation of Compound 14

Preparation of compound 14-2

Compound 14-1 (900 mg, 4.09 mmol) was dissolved in tetrahydrofuran (30 mL), and diisobutylaluminum hydroxide (1.0 M, 8.18 mL) was added thereto at 0°C. After the addition, the system was stirred at room temperature for 16 h. Water (1 mL) and then an aqueous sodium hydroxide solution (15%, 1.5 mL) were added to the system to quench the reaction, and then the system was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude title compound 14-2, which was used directly in the next reaction without purification. LC-MS (ESI): 178.8 [M+H] ⁺ .

Preparation of compound 14-3

Compound 14-2 (230 mg, 1.29 mmol) and methanesulfonyl chloride (295 mg, 2.58 mmol) were dissolved in dichloromethane (20 mL). Triethylamine (392 mg, 3.88 mmol) was added thereto at 0°C. After the addition, the system was stirred at room temperature for 2 h. Water (10 mL) was added to the system to quench the reaction, and then extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound 14-3, which was used directly in the next step without purification. LC-MS (ESI): 256.8 [M+H] ⁺ .

Preparation of compound 14-4

Compound 14-3 (200 mg, 0.78 mmol) and compound 1-6 (200 mg, 0.57 mmol) were dissolved in DMF (20 mL), and cesium carbonate (555 mg, 1.71 mmol) was added thereto. After the addition, the system was stirred at 80°C for 2 h. After dilution with water (10 mL), the system was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0 ~ 30%) to obtain the title compound 14-4. LC-MS (ESI): 508.6 [M+H] ⁺ .

Preparation of compound 14

Compound 14-4 (200 mg, 0.39 mmol), dimethylphosphine oxide (304 mg, 3.9 mmol), Xantphos (45 mg, 0.078 mmol) and triethylamine (393 mg, 3.9 mmol) were dissolved in DMF (20 mL), and Pd ₂ (dba) ₃ (35.7 mg, 0.039 mmol) was added thereto. After the addition, the system was stirred at 120°C in a microwave reactor for 2 h. After adding water (10 mL) to dilute the system, it was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-efficiency preparative liquid phase (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 14. LC-MS (ESI): 507.0 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 7.97 (s, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 8.7 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 5.45 (s, 2H), 4.42 (t, J = 6.2 Hz, 2H), 3.87 (t, J = 6.2 Hz, 2H), 1.75 (d, J = 13.8 Hz, 6H), 1.63 (s, 6H). ³¹ P NMR (16 2 MHz, Chloroform- d ) δ 31.49 (s, 1P).

Example 15: Preparation of Compound 15

Preparation of compound 15-2

Compound 15-1 (1 g, 4.57 mmol) was dissolved in anhydrous dichloromethane (20 mL). Diisobutylaluminum hydroxide (1.0 M, 6.85 mL, 6.85 mmol) was slowly added dropwise at -60°C under nitrogen protection. The mixture was reacted at room temperature for 2 hours. After the reaction was completed by TLC tracking, water was added to quench the reaction system. The reaction system was extracted with DCM (50 mL×2). The organic phases were combined, dried and concentrated to obtain 330 mg of the crude product of the title compound 15-2, which was directly used in the next reaction. ¹ H NMR (400 MHz, DMSO- d6 ) δ 8.09 (s, 1H), 5.28 (t, J = 5.7 Hz, 1H), 4.34 (dd, J = 5.7, 1.2 Hz, 2H).

Preparation of compound 15-3

Compound 15-2 (320 mg, 1.81 mmol) was dissolved in dichloromethane (10 mL), triethylamine (0.38 mL, 2.71 mmol) was added dropwise at 0°C, and methanesulfonyl chloride (249 mg, 2.17 mmol) was added after 10 minutes of reaction, and the reaction was continued at room temperature for 4 hours. After the reaction was completed by LCMS tracking, the reaction system was extracted with DCM (50 mL×2), and the organic phases were combined, dried and concentrated to obtain the crude product of the title compound 15-3 (320 mg), which was directly used in the next reaction. ¹ H NMR (400 MHz, DMSO- d6 ) δ 8.44 (s, 1H), 5.17 (s, 2H), 3.24 (s, 3H).

Preparation of compound 15-4

Compound 15-3 (320 mg, 0.92 mmol) was dissolved in DMF (5 mL), and cesium carbonate (598 mg, 1.83 mmol) was added under stirring. After reacting for 5 minutes, compound 1-6 (304 mg, 1.19 mmol) was added and reacted at 80°C for 4 hours. After the reaction was completed by LCMS tracking, the reaction solution was poured into ice water and extracted with EtOAc (50 mL×2). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-30%) to obtain the title compound 15-4 (210 mg) with a yield of 45%. LC-MS (ESI): m/z 508.6 [M+H] ⁺ .

Preparation of compound 15

Compound 15-4 (210 mg, 0.41 mmol) was dissolved in N , N -dimethylformamide (3.0 mL), and dimethylphosphine oxide (97 mg, 1.24 mmol), triethylamine (125 mg, 1.24 mmol), tri(dibenzylideneacetone)dipalladium (38 mg, 0.04 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (48 mg, 0.08 mmol) were added in sequence. After replacing with nitrogen three times, the mixture was reacted at 100°C in a microwave oven for 2 hours. The reaction was followed by LCMS until the reaction was complete, and the reaction solution was filtered. The crude filtrate was purified by preparative separation (preparative method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/L NH ₄ HCO ₃ )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 15 (35 mg, yield 17%). LC-MS (ESI): m/z 507.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ 8.47 (s, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 2.2 Hz, 1H), 7.18 (d, J = 8.9 Hz, 2H), 6.97 (d, J = 8.9 Hz, 2H), 5.04 (s, 2H), 4.45 – 4.36 (m, 2H), 4.01 – 3.88 (m, 2H), 1.84 (d, J = 14.4 Hz, 6H), 1.63 (s, 6H). ³¹ P NMR (162 MHz, DMSO- d6 ) δ 25.57 (s, 1P).

Example 16: Preparation of Compound 16

Preparation of compound 16-1

Compound 1-6 (500 mg, 1.42 mmol) was dissolved in THF solution (10 mL), and compound (6-bromopyridin-3-yl)methanol (320 mg, 1.7 mmol) and triphenylphosphine (558 mg, 2.13 mmol) were added. The mixture was cooled to 0°C, and diethyl azodicarboxylate (494 mg, 2.84 mmol) was slowly added dropwise. The mixture was reacted at room temperature for 16 hours. After the reaction was completed, the crude product was purified by preparative separation (separation method, PE:EA=10:1 - 2:1) to obtain the title compound 16-1 (300 mg, yield 40.6%). LC-MS (ESI): 519.0 [M+H] ⁺ .

Preparation of compound 16

Compound 16-1 (250 mg, 0.48 mmol) was dissolved in DMF solution (5 mL), and dimethylphosphine oxide (187 mg, 2.4 mmol), triethylamine (250 mg, 0.48 mmol), Pd ₂ (dba) ₃ (18.3 mg, 0.02 mmol), and Xantphos (23.1 mg, 0.04 mmol) were added. The mixture was subjected to microwave reaction at 120°C for 16 hours. After the reaction, the crude filtrate was purified by preparation separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 16 (12 mg, 4.8%). LC-MS (ESI): 517.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ 8.76 (d, J = 5.0 Hz, 1H ) , 8.02 (d, J = 5.4 Hz, 1H) , 7.63 (d, J = 2.3 Hz, 1H) , 7.58 ( m, 1H), 1 .65 (d, J = 14.4 Hz, 6H), 1.64 (s, 6H). ³¹ P NMR (162 MHz, DMSO- d6 ) δ 34.22.

Example 17: Preparation of Compound 17

Preparation of compound 17-1

Compound 1-6 (500 mg, 1.42 mmol) was dissolved in THF solution (10 mL), and compound (2-iodophenyl)methanol (398 mg, 1.7 mmol) and triphenylphosphine (558 mg, 2.13 mmol) were added. The mixture was cooled to 0°C, and diethyl azodicarboxylate (494 mg, 2.84 mmol) was slowly added dropwise. The mixture was reacted at room temperature for 16 hours. After the reaction was completed, the crude product was purified by preparative separation (separation method, PE:EA=10:1-2:1) to obtain the title compound 17-1 (280 mg, yield 34.8%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 7.82 (t, J = 1.7 Hz, 1H), 7.69 (dt, J = 7.9, 1.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.05 (s, 2H), 4.41 (t, J = 5.2 HZ, 2H), 3.95 (t, J = 5.2 HZ, 2H), 1.63 (s, 6H).

Preparation of compound 17

Compound 17-1 (280 mg, 0.49 mmol) was dissolved in DMF solution (5 mL), and dimethylphosphine oxide (187 mg, 2.4 mmol), triethylamine (250 mg, 0.48 mmol), Pd ₂ (dba) ₃ (18.3 mg, 0.02 mmol), and Xantphos (23.1 mg, 0.04 mmol) were added. The mixture was subjected to microwave reaction at 120°C for 16 hours. After the reaction, the crude filtrate was purified by preparation separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 17 (12 mg, 4.7%). LC-MS (ESI): 516.5 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ 7.78 – 7.80 (m, 2H), 7.64 (d, J = 2.4 Hz, 1H), 7.58 (t, J = 2.0 Hz, 1H), 7.47 (dd, J = 4.9, 2 .3 Hz, 2H), 7.18 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 5.52 (s, 2H), 4.41 (t, J = 5.0 Hz, 2H), 3.95 (t, J = 5.0 Hz, 2H), 1.74 (d, J = 13 .3 Hz, 6H), 1.63 (s, 6H). ³¹ P NMR (162 MHz, DMSO- d6 ) δ 36.37.

Example 18: Preparation of Compound 18

Preparation of compound 18

Compound 9 (140 mg, about 0.75 mmol, crude product) was dissolved in MeOH (3.0 mL), and paraformaldehyde (68 mg, 0.75 mmol) was added, and the mixture was stirred at room temperature for 1 hour, followed by the addition of sodium cyanoborohydride (47 mg, 0.75 mmol). The reaction system was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and the crude filtrate was purified by preparation separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 18 (5 mg, yield 8%). LC-MS (ESI): m/z 573.0 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.89 (d, J = 5.2 Hz, 1H), 7.69 (t, J = 4.2 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.23 (s, 2H), 4.42 (t, J = 6.2 Hz, 2H), 3.87 (t, J = 6.2 Hz, 2H), 3.17-2.99 (m, 2H), 2.76-2.58 (m, 4H), 2.45 – 2.27 (m, 5H), 1.64 (s, 6H). ³¹ P NMR (162 MHz, Chloroform- d ) δ 29.02 (s, 1P).

Example 19: Preparation of Compound 19

Preparation of compound 19-2

Compound 1-6 (350 mg, 1 mmol), 19-1 (580 mg, 3 mmol), triphenylphosphine (789 mg, 3 mmol), DIAD (606 mg, 3 mmol) and anhydrous tetrahydrofuran (10 mL) were added to a single-necked bottle, replaced with nitrogen three times, and stirred at 50°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and a saturated sodium chloride aqueous solution (30 mL) was added to the reaction system, extracted with EtOAc (50 mL×3), the organic phases were combined, dried and concentrated to obtain a crude product, and separated and purified by a normal phase silica gel column (EtOAc/PE = 0-30%) to obtain the title compound 19-2 (250 mg) with a yield of 51%. LC-MS (ESI): 525.2 [M+H] ⁺ .

Preparation of compound 19

Compound 19-2 (250 mg, 0.48 mmol) was dissolved in N , N -dimethylformamide (3.0 mL), and dimethylphosphine oxide (114 mg, 1.45 mmol), triethylamine (146 mg, 1.45 mmol), tri(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (30 mg, 0.05 mmol) were added in sequence. The atmosphere was replaced with nitrogen three times, and the reaction system was stirred in a microwave at 120°C for 2 hours. After the reaction was completed, the reaction system was filtered and extracted with dichloromethane (20 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparation separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 19 (18.25 mg, yield 7.3%). LC-MS (ESI): m/z 523.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ 9.21 (s, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.3 Hz, 2H), 5.76 (s, 2H), 4.41 (t, J = 5.1 Hz, 2H), 3.95 (t, J = 5.1 Hz, 2H), 1.71 (d, J = 13.7 Hz, 6H), 1.62 (s, 6H). ³¹ P NMR (162 MHz, DMSO- d6 ) δ 33.66 (s, 1P).

Example 20: Preparation of Compound 20

Preparation of compound 20-2

Compound 20-1 (350 mg, 1.8 mmol) and dichloromethane (5 mL) were added to a single-necked bottle, and Dess-Martin oxidant (955 mg, 2.7 mmol) was added under stirring. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered and the filter cake was rinsed with dichloromethane (10 mL). Saturated sodium chloride aqueous solution (15 mL) was added to the filtrate for washing, and it was extracted with dichloromethane (10 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 10%) to obtain the title compound 20-2 (300 mg) with a yield of 86%. LC-MS (ESI): 191.8 [M+H] ⁺ .

Preparation of compound 20-3

Compound 20-2 (300 mg, 1.56 mmol) and anhydrous tetrahydrofuran (6 mL) were added to a three-necked flask, replaced with nitrogen three times, stirred at -20°C for 0.5 hours, and then methylmagnesium bromide (3.0 M, 0.65 mL) was added dropwise, and stirred at -20°C for 2 hours. After the reaction was completed, saturated ammonium chloride aqueous solution (10 mL) was added to the reaction system, and the organic phases were extracted and combined with EtOAc (10 mL×3), dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-30%) to obtain the title compound 20-3 (260 mg), with a yield of 80%. LC-MS (ESI): 208.0 [M+H] ⁺ .

Preparation of compound 20-4

Compound 20-3 (260 mg, 1.25 mmol), triethylamine (253 mg, 2.5 mmol), and anhydrous dichloromethane (5 mL) were added to a three-necked flask, replaced with nitrogen three times, and methylsulfonyl chloride (178 mg, 1.56 mmol) was added dropwise at 0°C, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, a saturated sodium chloride aqueous solution (10 mL) was added to the reaction system, and extracted with dichloromethane (15 mL×3), and the organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 25%) to obtain the title compound 20-4 (310 mg) with a yield of 87%.

Preparation of compound 20-5

Compound 20-4 (100 mg, 0.48 mmol), compound 1-6 (168 mg, 0.48 mmol), cesium carbonate (319 mg, 0.96 mmol) and N, N-dimethylformamide (3.0 mL) were added to a single-necked bottle, replaced with nitrogen three times, and stirred at 80°C for 2 hours. After the reaction was completed, it was cooled to room temperature, and a saturated sodium chloride aqueous solution (10 mL) was added to the reaction system, and extracted with EtOAc (15 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 35%) to obtain the title compound 20-5 (192 mg) with a yield of 74%. LC-MS (ESI): 538.8 [M+H] ⁺ .

Preparation of Compound 20 Compound 20-5 (192 mg, 0.355 mmol) was dissolved in N, N-dimethylformamide (2 mL), and dimethylphosphine oxide (138 mg, 1.77 mmol), triethylamine (90 mg, 0.887 mmol), tri(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol) and 4, 5-bis(diphenylphosphino)-9, 9-dimethyloxanthracene (30 mg, 0.05 mmol) were added in sequence. The atmosphere was replaced with nitrogen three times, and the reaction system was stirred in a microwave at 120°C for 2 hours. After the reaction was completed, the reaction system was filtered and extracted with dichloromethane (20 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparation separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 20 (18.25 mg, yield 7.3%). LC-MS (ESI): m/z 537.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ 9.14 (s, 1H) , 7.61 ( d, J = 2.4 Hz, 1H) , 7.54 (d, J = 2.3 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2 1.65 (d, J = 6.3 Hz, 3H), 1.59 (s, 6H). ³¹ P NMR (162 MHz, DMSO- d6 ) δ 34.21 (s, 1P).

Example 21: Preparation of Compound 21

Preparation of compound 21-2

Under nitrogen protection, compound 21-1 (13.0 g, 76.47 mmol) and NCS (12.2 g, 91.76 mmol) were dissolved in acetonitrile (100 mL). Stir at room temperature for 12 hours. After the reaction was completed, saturated sodium chloride solution (15 mL) was added, and the reaction system was extracted with EtOAc (100 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 50%) to obtain the title compound 21-2 (10.2 g) with a yield of 65%. LC-MS (ESI): m/z 202.8 [MH] ^- .

Preparation of compound 21-3: DMF (150 mL) was added to compound 21-2 (12.2 g, 59.81 mmol), 1-bromo-2-chloroethane (17.1 g, 119.61 mmol), and cesium carbonate (39.1 g, 119.61 mmol), and the mixture was reacted at 120°C for 16 hours. After the reaction, water (300 mL) was added, and the reaction system was extracted with EtOAc (100 mL×3). The organic phases were combined, dried, and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-50%) to obtain the title compound 21-3 (3.3 g) with a yield of 25%. LC-MS (ESI): m/z 267.0 [M+H] ⁺ .

Preparation of compound 21-4

Compound 21-3 (3.3 g, 12.42 mmol) was added to a three-necked flask and replaced with nitrogen three times. Anhydrous tetrahydrofuran (50 mL) was added to the three-necked flask, and methyl magnesium bromide tetrahydrofuran solution (3 M, 12.4 mL, 37.26 mmol) was added dropwise at a cooling temperature of 0°C. After the reaction system was stirred at 0°C for 60 minutes, a saturated ammonium chloride solution (50 mL) was added to the reaction system for quenching, and the reaction system was extracted with EtOAc (50 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 50%) to obtain the title compound 21-4 (2.1 g) with a yield of 64%. LC-MS (ESI): m/z 249.2 [MH ₂ O+H] ⁺ .

Preparation of compound 21-5

Compound 21-4 (600 mg, 2.24 mmol) and phenol (633 mg, 6.75 mmol) were dissolved in dichloromethane (10 mL). After cooling to 0°C, a boron trifluoride ether solution (48%, 1.33 g, 6.75 mmol) was added dropwise. The temperature was slowly raised to room temperature and stirred for 1 hour. Water (10 mL) was added to the reaction system for quenching, and the mixture was extracted with EtOAc (5 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-50%) to obtain the title compound 21-5 (400 mg) with a yield of 52%. LC-MS (ESI): m/z 341.0 [MH] ^- .

Preparation of compound 21-6

Compound 21-5 (400 mg, 1.16 mmol), (2-chloropyrimidin-4-yl)methanol (501 mg, 3.48 mmol), triphenylphosphine (1.25 g, 3.48 mmol), DIAD (702 mg, 3.48 mmol) and anhydrous tetrahydrofuran (15 mL) were added to a single-necked bottle, replaced with nitrogen three times, and stirred at 50°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and a saturated sodium chloride aqueous solution (30 mL) was added to the reaction system, extracted with EtOAc (50 mL×3), and the organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-50%) to obtain the title compound 21-6 (200 mg) with a yield of 37%. LC-MS (ESI): 468.9 [M+H] ⁺ .

Preparation of compound 21

Compound 21-6 (200 mg, 0.45 mmol) was dissolved in N , N -dimethylformamide (3 mL), and dimethylphosphine oxide (105 mg, 1.35 mmol), triethylamine (136 mg, 1.35 mmol), tri(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (30 mg, 0.05 mmol) were added in sequence. The atmosphere was replaced with nitrogen three times, and the reaction system was stirred in a microwave at 120°C for 2 hours. After the reaction was completed, the reaction system was filtered and extracted with dichloromethane (20 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparation separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 21 (17.56 mg, yield 8.1%). LC-MS (ESI): m/z 511.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.99 (d, J = 5.2 Hz, 1H), 7.71 (dd, J = 5.2, 3.2 Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H), 7.1 0 (dd, J = 12.5, 2.3 Hz, 1H), 7.07 (dd, J = 3.7, 2.1 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 5.28 (s, 2H), 4.29 (t, J = 5.6 Hz, 2H), 3.89 (t, J = 5.6 Hz , 2H), 1.75 (d, J = 13.7 Hz, 6H), 1.60 (s, 6H). ³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 33.99 (s, 1P). ¹⁹ F NMR (377 MHz, DMSO- d6 ) δ -127.02 (s, 1F).

Example 22: Preparation of Compound 22

Preparation of compound 22-2

Dissolve compound 1-6 (1.0 g, 2.84 mmol) in THF solution (20 mL), add compound (6-bromopyridin-2-yl)methanol (640 mg, 3.4 mmol) and triphenylphosphine (1.11 mg, 4.26 mmol). Cool to 0 ^o C, slowly add diethyl azodicarboxylate (988 mg, 5.68 mmol), react at room temperature for 16 hours. After the reaction is completed, the crude product is purified by preparative separation (separation method, PE:EA= 10:1 - 2:1) to obtain the title compound 22-2 (700 mg, yield 47.3%). LC-MS (ESI): 519.0 [M+H] ⁺ .

Preparation of compound 22

Compound 22-2 (650 mg, 1.25 mmol) was dissolved in DMF solution (10 mL), and dimethylphosphine oxide (390 mg, 5 mmol), triethylamine (1.26 g, 12.5 mmol), Pd ₂ (dba) ₃ (36.6 mg, 0.04 mmol), and Xantphos (46.2 mg, 0.08 mmol) were added. The mixture was subjected to microwave reaction at 120°C for 16 hours. After the reaction, the crude filtrate was purified by preparation separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 minutes; flow rate: 30 mL/min), the obtained concentrate was separated by preparative TLC (DCM: MeOH = 15:1) to obtain the title compound 22 (150 mg, 4.8%). LC-MS (ESI): 517.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.01 (dd, J = 7.7, 3.5 Hz, 1H), 7.89 (t, J = 6.3 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 5.23 (s, 2H), 4.41 (t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.2 Hz, 2H), 1.64 (d, J = 13.6 Hz, 6H), 1.63 (s, 6H). ³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 33.81 (s, 1P).

Example 23: Preparation of Compound 23

Preparation of compound 23-2

Dissolve compound 1-6 in THF solution (10 mL), add compound (3-iodophenyl)methanol (398 mg, 1.7 mmol) and triphenylphosphine (558 mg, 2.13 mmol). Cool to 0 ^o C, slowly add diethyl azodicarboxylate (494 mg, 2.84 mmol), react at room temperature for 16 hours. After the reaction is completed, the crude product is purified by preparative separation (separation method, PE:EA=10:1 - 2:1) to obtain the title compound 23-2 (320 mg, yield 39.8%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.82 (s, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 5.05 (s, 2H), 4.41 (t, J =4.0 Hz, 2H), 3.95 (t, J =4.0 Hz, 2H), 1. 63 (s, 6H).

Preparation of compound 23

Compound 23-2 (300 mg, 0.53 mmol) was dissolved in DMF solution (5 mL), and dimethylphosphine oxide (187 mg, 2.4 mmol), triethylamine (250 mg, 0.48 mmol), Pd ₂ (dba) ₃ (18.3 mg, 0.02 mmol), and Xantphos (23.1 mg, 0.04 mmol) were added. The mixture was subjected to microwave reaction at 120°C for 16 hours. After the reaction, the crude filtrate was purified by preparation separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 minutes; flow rate: 30 mL/min), the concentrate was separated by preparative TLC (DCM: MeOH = 15: 1) to give the title compound 23 (14 mg, 5.1%). LC-MS (ESI): 516.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.85 (d, J = 11.8 Hz, 1H), 7.72 (t, J = 9.3 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.62 (s, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.54 (dt, J = 7.5, 2.8 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 31 P NMR( 1 ) 62 MHz, DMSO- d 6 ₎ ^δ 32.34 (s, 1P).

Example 24: Preparation of Compound 24

Preparation of compound 24-2

Add compound 24-1 (1.75 g, 6.86 mmol), DMF (25 mL), 1-bromo-2-chloroethane (1.51 g, 10.51 mmol, 875.00 μL), K ₂ CO ₃ (2.87 g, 20.77 mmol) to a 100 mL single-necked bottle, stir at room temperature (25 °C) for 21 hours. TLC (PE:EA=3:1) monitoring shows that there is a small amount of raw material remaining and there are two main spots. LCMS shows that there is no molecular ion peak of the raw material, and the main peak is the molecular ion peak of the target product. Add water (100 mL) and extract twice with ethyl acetate (80 mL). The organic phases were combined, washed with water (100 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a light yellow liquid. Purification by column chromatography (PE:EA = 1:0 ~ 10:1 ~ 5:1 ~3:1) gave 1.03 g of the title compound 24-2. LC-MS (ESI): m/z 317.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 (d, J = 1.6 Hz, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.17 (s, 1H), 5.15 (t, J = 6.8 Hz, 2H) , 3.96 (t, J = 6.8 Hz, 2H), 3.95 (s, 3H).

Preparation of compound 24-3

Add compound 24-2 (0.95 g, 2.99 mmol), Zn(CN) ₂ (703.00 mg, 5.99 mmol), Pd(PPh ₃ ) ₄ (694 mg, 600.57 μmol), and DMF (19 mL) to a 100 mL single-necked bottle, replace the atmosphere with nitrogen three times, and stir at 100 °C for 18 hours. LCMS monitoring shows that the reaction of the starting material is complete. Cool to room temperature. Add saturated ammonium chloride solution (60 mL) to the reaction system to quench, add ethyl acetate (60 mL), filter through diatomaceous earth to remove insoluble matter, and wash with ethyl acetate (40 mL). Combine the filtrate, mix, stand, and separate. Extract the aqueous phase with ethyl acetate (50 mL). The organic phases were combined, washed with water (80 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain 1.5 g of off-white solid. Crystallization was performed with ethyl acetate (5 mL) and PE (5 mL) to obtain 0.91 g of the title compound 24-3. LC-MS-ESI ⁺ : m/z [M+H] ⁺ 264.1.

Preparation of compound 24-4

Add compound 24-3 (0.91 g, 3.45 mmol) and THF (10 mL) to a 100 mL three-necked flask with a nitrogen balloon, stir to dissolve, and replace with nitrogen three times. Cool to 0 °C, add CH ₃ MgBr (3 M, 12.08 mmol, 4.03 mL) dropwise. After the addition is complete, stir and keep warm for 4 hours. TLC (PE:EA=1:1) monitoring shows that the reaction is complete. Saturated ammonium chloride solution (50 mL) is slowly added dropwise to quench the reaction, THF is evaporated under reduced pressure, water (30 mL) is added, and ethyl acetate is extracted (50 mL+30 mL). The organic phases are combined, washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated under reduced pressure to obtain 1 g of the title compound 24-4. It was used directly in the next step without purification.

Synthesis of compound 24-5

Add compound 24-4 (1 g, 3.79 mmol), phenol (714 mg, 7.59 mmol) and DCM (10 mL) to a 100 mL single-necked bottle, cool in an ice-water bath, dropwise add BF ₃ -Et ₂ O (1.15 g, 8.10 mmol, 1 mL), slowly warm to room temperature and stir overnight (16 hours). LCMS monitoring shows that the reaction is complete. Add saturated ammonium chloride solution (40 mL) to the reaction system for quenching, and extract with DCM (50 mL+25 mL). Combine the organic phases, wash with water (30 mL), concentrate under reduced pressure, and purify through a normal phase silica gel column (EA/PE = 0 ~ 20%) to obtain 0.52 g of the title compound 24-5. LC-MS (ESI): m/z 340.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (s, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.06 ~ 7.09 (m, 2H), 6 .75 ~ 6.75 (m, 2H), 5.02 (t, J = 6 Hz, 3H), 4.01 (t, J = 6 Hz, 3H), 1.71 (s, 6H).

Preparation of compound 24-6

Add compound 24-5 (0.38 g, 1.12 mmol), 2-methylthiopyrimidin-4-ylmethanol (265 mg, 1.70 mmol), DCM (14.99 mL) and TMAD (600 mg, 3.48 mmol) to a 25 mL single-necked bottle, protect with nitrogen, cool to 0 °C, add Bu ₃ P (696.60 mg, 3.44 mmol, 860 μL), slowly raise to room temperature (25 °C) and stir for 1 hour. LCMS monitoring shows that the raw material reaction is complete. Add saturated ammonium chloride solution (50 mL) to the reaction system for quenching, and extract with dichloromethane (50+30 mL). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and evaporate the filtrate under reduced pressure to obtain a yellow liquid. Purification by normal phase silica gel (EA/PE = 10 ~ 20%) gave 0.53 g of the title compound 24-6. LC-MS (ESI): m/z 478.0 [M+H] ⁺ .

Preparation of compound 24-7

Add compound 24-6 (0.48 g, 1.00 mmol) and DCM (10 mL) to a 100 mL single-necked bottle, stir to dissolve, add m-CPBA (615 mg, 3.03 mmol, 85% purity), and stir at 25°C for 16 hours. LCMS showed that the raw material was completely reacted. Add sodium carbonate solution (50 mL) to the reaction system to quench the reaction, and extract with DCM (50+30 mL). Combine the organic phases, wash with water (30 mL), and evaporate to dryness under reduced pressure to obtain a light yellow liquid. Purify by normal phase silica gel column (EA/PE = 10 ~ 50%) to obtain 0.43 g of the title compound 24-7. LC-MS (ESI): m/z 510.0 [M+H] ⁺ .

Synthesis of compound 24

Add compound 24-7 (0.38 g, 745.09 μmol), CH ₃ CN (10 mL), K ₂ CO ₃ (824 mg, 5.96 mmol) and dimethylphosphine oxide (471.20 mg, 6.04 mmol) to a 50 mL single-necked bottle, and stir at 80 °C for 16 hours. LCMS showed that the reaction was complete. Add saturated ammonium chloride solution (80 mL) to the reaction system for quenching, and extract with ethyl acetate (50 mL*3). Combine the organic phases, evaporate under reduced pressure, and purify through a normal phase silica gel column (MeOH/EA = 0 ~ 10%) to obtain a yellow liquid. Purify through preparative liquid phase to obtain 105 mg of the title compound 24. LC-MS (ESI): m/z 508.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.89 (d, J = 4.8 Hz, 1H), 8.10 (s, 1H), 7.92 (d, J = 1.6 Hz, 1H), 7.71 (t, J = 4 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 5.24 (s, 2H), 5.02 (t, J = 6 Hz, 2H), 4.01 (t, J = 6 Hz, 2H), 1.96 ( d, J = 14 Hz, 6H), 1.73 (s, 6H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 39.27 (s, 1P).

Example 25: Preparation of Compound 25

Synthesis of compound 25-2

Add compound 25-1 (0.88 g, 2.77 mmol), Pd(PPh ₃ ) ₄ (640 mg, 553.84 μmol), Zn(CN) ₂ (651 mg, 5.54 mmol) and DMF (18 mL) to a 50 mL single-necked bottle, replace the atmosphere with nitrogen three times, stir at 100 °C for 18 hours, LCMS shows that the reaction of the raw materials is complete. Cool to room temperature. Add water (80 mL) and ethyl acetate (60 mL), filter through diatomaceous earth to remove insoluble solids. Rinse the filter cake with ethyl acetate (40 mL). Combine the filtrate, mix, stand, and separate. Extract the aqueous phase with ethyl acetate (40 mL). The organic phases were combined, washed with water (80 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a yellow solid. Crystallization was performed with ethyl acetate/petroleum ether (10 mL/5 mL) to obtain 0.66 g of the title compound 25-2. LC-MS (ESI): m/z 264.2 [M+H] ⁺ .

Synthesis of compound 25-3

Add compound 25-2 (0.66 g, 2.50 mmol) and THF (10 mL) to a 100 mL three-necked flask, cool to 0 °C, add CH ₃ MgBr (3 M, 8.76 mmol, 2.92 mL) dropwise, and stir for 1 hour after the addition is complete. TLC (PE:EA = 1:1) shows that the reaction is complete. Slowly pour the reaction solution into an aqueous solution of ammonium chloride (80 mL) and extract with ethyl acetate (60+40 mL). Combine the organic phases, wash with water (30 mL), dry with anhydrous sodium sulfate, filter, and evaporate the filtrate under reduced pressure to obtain 0.86 g of a yellow liquid. Use it directly in the next step without purification.

Synthesis of compound 25-4

Under nitrogen atmosphere, add compound 25-3 (0.86 g, 3.26 mmol), phenol (614 mg, 6.52 mmol), and DCM (12 mL) to a 100 mL single-necked bottle, cool to 0 °C, add BF ₃ -Et ₂ O (1.93 g, 6.52 mmol, 1.68 mL, 48% mass fraction), and after the addition is complete, stir for 2 hours at room temperature. LCMS shows that the reaction is complete. Add saturated aqueous ammonium chloride solution (50 mL) to quench the reaction, and extract with DCM (80+50 mL). Combine the organic phases, wash with water (50 mL), and evaporate to dryness under reduced pressure to obtain a yellow liquid. Purify by normal phase silica gel column (EA/PE = 10 ~ 30%) to obtain 0.34 g of the title compound 25-4. LC-MS (ESI): m/z 340.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.07 ~ 7.09 (m, 2H), 6 .75 ~ 6.77 (m, 2H), 4.77 (t, J = 6 Hz, 2H), 4.07 (t, J = 6 Hz, 2H), 1.69 (s, 6H).

Synthesis of compound 25-5

Add compound 25-4 (0.34 g, 1.00 mmol), compound 2-methylthiopyrimidin-4-ylmethanol (235 mg, 1.50 mmol), TMAD (520 mg, 3.02 mmol) and DCM (10 mL) to a 100 mL single-necked bottle, cool to 0 °C, add Bu ₃ P (610 mg, 3.02 mmol), slowly warm to room temperature and stir for 16 hours. LCMS monitoring shows that the reaction is complete. Add saturated aqueous ammonium chloride solution (50 mL) to quench the reaction, and extract with dichloromethane (50+30 mL). Combine the organic phases, wash with water (30 mL), and evaporate to dryness under reduced pressure to obtain a yellow liquid. Purify by normal phase silica gel column (EA/PE = 0 ~ 25%) to obtain 0.44 g of the title compound 25-5. LC-MS (ESI): m/z 478.0 [M+H] ⁺ .

Synthesis of compound 25-6

Add compound 25-5 (0.44 g, 920.49 μmol) and DCM (10 mL) to a 100 mL single-necked bottle, cool to 0 °C in an ice-water bath, add m-CPBA (561 mg, 2.76 mmol, 85% purity), slowly warm to room temperature and stir for 20 hours. TLC (PE:EA= 1:1) shows that the reaction is complete. Add saturated aqueous ammonium chloride solution (50 mL) to quench the reaction, and extract with DCM (50+30 mL). Combine the organic phases, wash with sodium carbonate solution (30 mL), and evaporate under reduced pressure to obtain a light yellow liquid. Purify by normal phase silica gel column (EA/PE = 0 ~ 50%) to obtain 0.44 g of the title compound 25-6. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.93 (d, J = 5.2 Hz, 1H), 8.12 (s, 1H), 7.90 (d, J = 2 Hz, 1H), 7.85 (d, J = 4.8 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.15 ~ 7.18 (m, 2H), 6.87 ~ 6.90 (m, 2H), 5.29 (s, 2H), 4.77 (t, J = 5.6 Hz, 2H), 4.07 (t, J = 5.6 Hz, 2H), 3.39 (s, 3H), 1.71 (s, 6H).

Synthesis of compound 25

Add compound 25-6 (0.25 g, 490.19 μmol), K ₂ CO ₃ (545.00 mg, 3.94 mmol), CH ₃ CN (10 mL) and dimethylphosphine oxide (310.00 mg, 3.97 mmol) to a 100 mL single-necked bottle, and stir at 80 °C for 18 hours. LCMS monitoring shows that the reaction is complete. Cool to room temperature. Add saturated aqueous ammonium chloride solution (50 mL) to quench the reaction, and extract with ethyl acetate (100+50+50 mL) three times. Combine the organic phases and evaporate to dryness under reduced pressure to obtain a brown-yellow liquid. Purify by normal phase silica gel column (MeOH/EA = 0 ~ 10%) to obtain 155 mg of viscous material. Purify by preparative HPLC to obtain 40.5 mg of the title compound 25. LC-MS (ESI): m/z 508.4 [M+ H ] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.89 (s, 1H) , 8.13 (s, 1H), 7.90 (s, 1H) , 7.69 (s, 1H) , 7.45 (s, 1H), 7.15 (d, J = ^{8 31} P NMR (162 MHz, CDCl ₃ ) δ 35.08 (s, 1P).

Example 26: Preparation of Compound 26

Synthesis of compound 26-2

Add compound 26-1 (5 g, 20.40 mmol), anhydrous DMF (40 mL), triethyl orthoformate (4.54 g, 30.66 mmol, 5.10 mL) and p-toluenesulfonic acid monohydrate (400.00 mg, 2.10 mmol, 8.98 μL) to a 100 mL single-necked bottle and stir at room temperature for 2 hours. LCMS shows that the reaction is complete. Cool to room temperature, precipitate solid, filter, rinse the filter cake with ethyl acetate (3 mL), and evaporate to dryness under reduced pressure to obtain 1.07 g of the title compound. Combine the filtrate, add water (200 mL), and extract with ethyl acetate (150 mL*3) three times. The organic phases were combined, washed with water (150 mL*3) three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain 3.7 g of a gray solid. Crystallization was performed with ethyl acetate (30 mL) to obtain another 3.2 g of the title compound 26-2. LC-MS (ESI): m/z 255.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.52 (s, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 3.89 (s, 3H).

Synthesis of compounds 26-3 and 26-3A

Add compound 26-2 (4.1 g, 16.07 mmol), DMF (60 mL), K ₂ CO ₃ (6.68 g, 48.36 mmol), 1-bromo-2-chloroethane (3.53 g, 24.63 mmol, 2.05 mL) to a 50 mL single-necked bottle and stir at 25 °C for 22 hours. TLC (PE:EA=1:1 and PE:EA=0:1) showed that the reaction was complete. Cool to room temperature, add saturated ammonium chloride solution (150 mL) to quench the reaction, and extract with ethyl acetate (100+80 mL). The organic phases were combined, washed with water (150 mL*3), washed with saturated sodium chloride (30 mL), and evaporated under reduced pressure. The residue was purified by crystallization with ethyl acetate/methanol (9:1) to obtain 2.8 g of the title compound 26-3A. LC-MS (ESI): m/z 317.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.39 (d, J = 1.2 Hz, 1H), 8.01 (d, J = 1.2 Hz, 1H), 4.78 (t, J = 5.6 Hz, 2H), 4.08 (t, J = 5.6 Hz, 2H), 3.91 (s, 3H). The mother liquors were combined, evaporated under reduced pressure, and purified by normal phase silica gel column (PE/DCM = 0 ~ 50%) to obtain 0.93 g of the title compound 26-3. LC-MS (ESI): m/z 317.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.00 (d, J = 1.6 Hz, 1H), 4.91 (t, J = 6.0 Hz, 2H ), 4.09 (t, J = 6.0 Hz, 2H), 3.89 (s, 3H).

Synthesis of compound 26-4

Add compound 26-3A (2.6 g, 8.19 mmol), Zn(CN) ₂ (1.92 g, 16.38 mmol), Pd(PPh ₃ ) ₄ (1.90 g, 1.64 mmol) and DMF (52 mL) to a 100 mL single-necked bottle, replace the atmosphere with nitrogen three times, and stir at 145°C for 18 hours. TLC (PE:EA = 1:1) shows that the reaction is complete. LCMS shows that the reaction of the starting material is complete. Cool to room temperature. Add water (120 mL) and ethyl acetate (80 mL), mix, filter through diatomaceous earth to remove insoluble solids, and rinse the filter cake with ethyl acetate (60 mL). Combine the filtrate, mix, stand, separate, and separate. Extract the aqueous phase with ethyl acetate (60 mL). The organic phases were combined, washed with water (100 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain 3.6 g of a light yellow solid. Crystallization with ethyl acetate (40 mL) gave 1.21 g of the title compound 26-4. LC-MS (ESI): m/z 264.1 [M+H] ⁺ .

Synthesis of compound 26-5

Add compound 26-4 (1.2 g, 4.55 mmol) and THF (15 mL) to a 100 mL three-necked flask with a nitrogen balloon, stir to dissolve, and replace with nitrogen three times. Cool to 0 °C, and add CH ₃ MgBr (3 M, 15.93 mmol, 5.31 mL) dropwise. After the addition is complete, stir for 4 hours. TLC monitoring shows that the reaction is complete. Slowly pour the reaction solution into the ammonium chloride solution (50 mL), remove THF under reduced pressure, and extract with ethyl acetate (50 mL+30 mL). Combine the organic phases, wash with water (20 mL), dry with anhydrous sodium sulfate, filter, and evaporate the filtrate under reduced pressure to obtain 1.35 g of the title compound 26-5. Use it directly in the next step without purification.

Synthesis of Compound 26-6

Add compound 26-5 (1.35 g, 5.12 mmol), phenol (0.97 g, 10.31 mmol) and DCM (30 mL) to a 100 mL single-necked bottle, cool in an ice-water bath, dropwise add BF ₃ -Et ₂ O (1.45 g, 10.24 mmol, 1.26 mL), slowly warm to room temperature and stir for 16 hours. LCMS shows that the reaction is complete. Add saturated ammonium chloride solution to quench the reaction (80 mL), extract with DCM (80 mL+40 mL), combine the organic phases, wash with water (50 mL), and evaporate to dryness under reduced pressure to obtain a yellow viscous substance. Purify by normal phase silica gel column (EA/PE = 0 ~ 50%) to obtain 0.53 g of the title compound 26-6. LC-MS (ESI): m/z 340.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.06 ~ 7.09 (m, 2H), 6.75 ~ 6.79 (m, 2H), 5.02 (t, J = 6.0 Hz, 2H), 4.01 (t, J = 6.0 Hz, 2H), 1.71 (s, 6H).

Synthesis of compound 26-7

Under nitrogen atmosphere, add compound 26-6 (0.48 g, 1.41 mmol), compound 2-methylthiopyrimidin-4-ylmethanol (340.00 mg, 2.18 mmol), TMAD (730 mg, 4.24 mmol) and THF (10 mL) to a 100 mL single-necked bottle, stir to dissolve, cool to 0°C, and drop Bu ₃ P (900 mg, 4.45 mmol, 1.11 mL). After the addition is complete, slowly raise the temperature to 25 °C and stir for 3 hours. LCMS shows that the raw material has reacted completely. Add saturated ammonium chloride solution (60 mL) to the reaction system and extract with DCM (80+40 mL). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and evaporate the filtrate under reduced pressure to obtain a brown liquid. Purification by normal phase silica gel column (EA/PE = 0 ~ 50%) gave 0.92 g of the title compound 26-7. LC-MS (ESI): m/z 478.0 [M+H] ⁺ .

Synthesis of Compound 26-8

Add compound 26-7 (0.92 g, 1.92 mmol) and DCM (20 mL) to a 100 mL single-necked bottle, stir to dissolve, add m-CPBA (1.18 g, 5.81 mmol, 85% purity), and stir at 25 °C for 16 hours. TLC shows that the raw material has reacted completely. Add saturated sodium carbonate solution (50 mL) to quench the reaction, and extract with DCM (50+50 mL). Combine the organic phases, wash with water (50 mL), and evaporate to dryness under reduced pressure to obtain a brown-yellow liquid. Purify by normal phase silica gel (EA/PE = 0 ~ 75%) to obtain 0.42 g of the title compound 26-8. LC-MS (ESI): m/z 510.0 [M+H] ⁺ .

Synthesis of compound 26

Add compound 26-8 (370 mg, 725.48 μmol), K ₂ CO ₃ (814.00 mg, 5.89 mmol), CH ₃ CN (10 mL) and dimethylphosphine oxide (458 mg, 5.87 mmol) to a 100 mL single-necked bottle and reflux for 17 hours. LCMS showed that the reaction was complete. Add saturated ammonium chloride solution (50 mL) to quench the reaction and extract with ethyl acetate (60 mL*3) three times. Combine the organic phases and evaporate to dryness under reduced pressure to obtain a light brown viscous product. Purify by normal phase silica gel column (MeOH/EA = 0 ~ 15%) and preparative HPLC to obtain 5.5 mg of the title compound 26. LC-MS (ESI): m/z 508.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.874 (d, J = 5.2 Hz, 1H), 8.09 (s, 1H), 7.687 (t, J = 4.4 Hz, 1H), 7.51 (s, 1H), 7.47 ( s, 1H), 7.15 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 5.25 (d, 2H), 4.54 (t, J = 5.6 Hz, 2H), 3.85 (t, J = 5.6 Hz, 2H), 1.88 (d, J = 13.6 Hz, 6H), 1.74 (s, 6H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 34.98 (s, 1P).

Example 27: Preparation of Compound 27

Preparation of compound 27-2

Add the compound magnesium (2.45 g, 101.8 mmol) and iodine (20 mg, 78 μmol) to a dry three-necked flask, add dry THF (100 mL) to the flask, replace the reaction system with nitrogen three times, and heat to 75°C for reaction. Slowly add the compound 1,4-dibromopentane (10.0 g, 46.3 mmol) to the reaction system, and react at room temperature for 1 hour. Cool the reaction body to -20°C, and add the compound diethyl phosphite (5.4 g, 39.3 mmol). The reaction was monitored by LCMS until the reaction was complete, and ethanol (100 mL) was added dropwise to quench the reaction. The reaction system was concentrated under reduced pressure to obtain a crude product, which was first separated and purified by a normal phase silica gel column (DCM/MeOH = 0 ~ 15%) to obtain 1.2 g of the crude product, and then separated and purified by reverse phase (ACN/H ₂ O = 0 ~ 10%) to obtain 50 mg of the title compound 27-2, with a yield of 0.98%. LC-MS (ESI): m/z 119.3 [M+H] ⁺ .

Preparation of compound 27-3

Compound 1-6 (200 mg, 0.5 mmol) was added to a three-necked flask, followed by anhydrous DCM (10 mL), (2-methylthiopyrimidin-4-yl)methanol (155 mg, 1.0 mmol), triphenylphosphine (260 mg, 1.0 mmol), replaced with nitrogen three times, and diisopropyl azodicarboxylate (200 mg, 1.0 mmol) was added at 0°C. The reaction was stirred at 25°C for 16 hours. After the reaction was completed, water (30 mL) was added, extracted with EtOAc (30 mL×3), the organic phases were combined, dried and concentrated to obtain a crude product, and separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 20%) to obtain the title compound 27-3 (100 mg) with a yield of 38%. LC-MS (ESI): 488.12 [M+H] ⁺ .

Preparation of compound 27-4

Compound 27-3 (1.2 g, 2.46 mmol) was added to a dry three-necked flask, and dry DCM (50 mL) and m-chloroperbenzoic acid (1.2 g, 6.15 mmol, 85% purity) were added to the flask. The reaction was allowed to proceed at room temperature for 3 hours. The reaction was followed by LCMS until completion. Saturated sodium thiosulfate (50 mL) was added to quench the reaction. The organic phase was then washed with saturated sodium carbonate (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 27-4, which was used directly in the next step without purification. LC-MS (ESI): m/z 521.8 [M+H] ⁺ .

Preparation of compound 27

Dissolve the crude compound 27-3 (300 mg, 0.57 mmol) in tetrahydrofuran (4 mL), add potassium carbonate (406 mg, 1.25 mmol), and compound 27-2 (50 mg, 0.42 mmol), replace the reaction system with nitrogen three times, heat to 85 ° C and react for 6 hours. Monitor the reaction by LCMS until the end of the reaction, filter, add water (10 mL) to the filtrate, extract with ethyl acetate (10 mL×2), and combine the organic phases. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 15%-55% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 9 mg of the title compound 27 with a yield of 3.8%. LC-MS (ESI): m/z 557.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 5.2 Hz, 1H), 7.74 (dd, J = 5.2, 2.3 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.58 ( d, J = 2.3 Hz, 1H), 7.18 – 7.20 (m, 2H), 6.99 – 7.01 (m, 2H), 5.31 (s, 2H), 4.41 (t, J = 4.0 Hz, 2H), 3.95 (t, J = 4.0 Hz, 2H), 2.38-2.46 (m, 2H), 1.83-1.98 (m, 4H), 1.63 (s, 6H), 1.23 – 1.36 (m, 4H). ³¹ P NMR (162 MHz, DMSO- d6 ) δ 34.16 (s, 1P).

Example 28: Preparation of Compound 28

Preparation of compound 28

Compound 9 (0.25 g, 0.446 mmol) and TEA (90 mg, 0.894 mmol) were added to a three-necked flask, the atmosphere was replaced with nitrogen, and DCM (5 mL) was added. At 0°C, a solution of acetyl chloride (70 mg, 0.894 mmol) in dichloromethane (0.5 mL) was slowly added dropwise to the reaction system, and the reaction lasted for 30 minutes after the addition was completed. The reaction system was saturated and quenched with sodium bicarbonate (10 mL), the organic phase was separated, dried and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent10Prep-C18250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 110 mg of the title compound 28 with a yield of 40%. LC-MS (ESI): m/z 601.0 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d) δ 8.92 (s, 1H), 7.75 (s, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.13 ( d, J = 7.8 Hz, 2H), 6.91 (d, J = 7.8 Hz, 2H), 5.24 (s, 2H), 4.42 (t, J = 6.1 Hz, 2H), 4.35-4.20 (m, 1H), 4.13-3.90 (m, 1H), 3.87 (t, J = 6.1 Hz, 2H), 3.59 – 5.67 (m, 2H), 2.75-2.55(m, 2H), 2.35-2.28 (m, 2H), 2.19 (s, 3H), 1.65 (s, 6H) . ³¹ P NMR (162 MHz, Chloroform-d) δ 29.93 (s, 1P).

Example 29: Preparation of Compound 29

Preparation of compound 29

Compound 9 (60 mg, 0.107 mmol) and TEA (22 mg, 0.214 mmol) were added to a three-necked flask, nitrogen was replaced, and DCM (2 mL) was added. At 0°C, a solution of methylsulfonyl chloride (24 mg, 0.214 mmol) in dichloromethane (0.5 mL) was slowly added dropwise to the reaction system. After the addition was complete, the reaction was allowed to proceed for 30 minutes. The reaction system was quenched with saturated sodium bicarbonate (10 mL), and the organic phase was separated, dried, and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 30 mg of the title compound 29 with a yield of 47%. LC-MS (ESI): m/z 637.0 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d) δ 8.87 (d, J = 5.2 Hz, 1H), 7.72 (dd, J = 5.2, 3.2 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.06 – 7.08 (m, 2H), 6.83 – 6.85 (m, 2H), 5.16 (s, 2H), 4.35 (t, J = 6.2 Hz, 2H), 3.80 (t, J = 6.2 Hz, 2H), 2.85 (s, 3H) , 2.63 - 2.71 (m, 2H), 2.31 – 2.46 (m, 2H), 1.58 (s, 6H). ³¹ P NMR (162 MHz, Chloroform-d) δ 32.56 (s, 1P).

Example 30: Preparation of Compound 30

For detailed experimental steps, please refer to Example 9. LC-MS (ESI): m/z 659.2 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.90 (d, J = 5.2 Hz, 1H), 7.71 (dd, J = 5.2, 3.1 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.3 0 (d, J = 2.4 Hz, 1H), 7.10 – 7.14 (m, 2H), 6.88 – 6.91 (m, 2H), 5.23 (s, 2H), 4.41 (t, J = 6.1 Hz, 2H), 4.21-4.05 (m, 2H), 3.87 (t, J = 6.1 Hz, 2H), 3.34-3.31 (m, 2H), 2.65-2.58 (m, 2H), 2.30-2.10 (m, 2H), 1.64 (s, 6H), 1.48 (s, 9H). ³¹ P NMR (162 MHz, Chloroform-d) δ 29.83 (s, 1P).

Example 31: Preparation of Compound 31

Preparation of compound 31-3

Compound 31-1 (1 g, 4.46 mmol), compound 31-2 (1.71 g, 5.80 mmol), cesium carbonate (2.91 g, 8.92 mmol), Xantphos (516.40 mg, 892.47 μmol), tri(dibenzylideneacetone)palladium (408.63 mg, 446.24 μmol) and 1,4-dioxane (5 mL) were added to a reaction bottle and reacted at 100°C for 16 hours under nitrogen protection. After the reaction was completed, saturated ammonium chloride solution (20 mL) was added to quench the reaction. The reaction system was filtered and extracted with dichloromethane (20 mL) three times. The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 ~ 50%) to obtain 1.7 g of the title compound 31-3, with a yield of 87%. LC-MS (ESI): m/z 436.9 [M+H] ⁺ .

Preparation of compound 31-4

Compound 31-3 (900 mg, 2.05 mmol), iodine (3.91 g, 15.41 mmol), NaHCO ₃ (1.73 g, 20.54 mmol), THF (10 mL) and water (3 mL) were added to the reaction bottle and stirred at 50°C for 2 hours. The reaction was complete as monitored by LCMS. Saturated aqueous sodium sulfite solution (10 mL) was added to quench the reaction. The reaction system was filtered and extracted three times with dichloromethane (10 mL). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 ~ 50%) to obtain 580 mg of the title compound 31-4, with a yield of 62%. LC-MS (ESI): m/z 450.9 [M+H] ⁺ .

Preparation of compound 31-5

Compound 31-4 (580 mg, 1.28 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (II) (93.09 mg, 128.28 μmol), pinacol diboron (488.64 mg, 1.92 mmol), potassium acetate (377.70 mg, 3.85 mmol) and dioxane (12 mL) were added to the reaction bottle. Under nitrogen protection, the reaction was carried out at 100°C for 4 hours. After filtration and spin drying, dioxane (5 mL) was added, and hydrogen peroxide (1.45 g, 12.83 mmol, 30%) was added dropwise at 0°C. After the addition, the mixture was stirred at room temperature for 20 minutes. The reaction was complete as monitored by LCMS. Sodium sulfite aqueous solution (30 ml) was slowly added dropwise to quench the reaction. The reaction system was filtered and extracted three times with dichloromethane (10 mL). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-50%) to obtain 400 mg of the title compound 31-5, with a yield of 80%. LC-MS (ESI): m/z 389.0 [M+H] ⁺ .

Preparation of compound 31-6

Under nitrogen protection, compound 31-5 (300 mg, 770.75 μmol), (2-(methylphenyl)pyrimidin-4-yl)methanol (180.59 mg, 1.16 mmol), TMAD (398.13 mg, 2.31 mmol), and DCM (2 mL) were added to the reaction flask. Tributylphosphine (467.80 mg, 2.31 mmol) was added dropwise at 0°C and stirred at room temperature for 1 hour. The reaction was complete as monitored by LCMS. Add water (10 mL), extract with dichloromethane (10 mL) three times, combine the organic phases, dry and concentrate to obtain a crude product, separate and purify by normal phase silica gel column (EtOAc/PE = 0 ~ 50%) to obtain 400 mg of the title compound 31-6, with a yield of 54%. LC-MS (ESI): m/z 527.0 [M+H] ⁺ .

Preparation of compound 31-7

Compound 31-6 (220 mg, 417.12 μmol), potassium peroxymonosulfonate (722.27 mg, 2.09 mmol), water (2 mL) and THF (2 mL) were added to a reaction bottle and reacted at 30°C for 16 hours. Water (10 mL) was added, and then extracted three times with dichloromethane (10 mL). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 ~ 50%) to obtain 200 mg of the title compound 31-7, with a yield of 54%. LC-MS (ESI): m/z 559.0 [M+H] ⁺ .

Preparation of compound 31

Compound 31-7 (110 mg, 196.63 μmol), dimethylphosphine oxide (76.74 mg, 983.16 μmol), potassium carbonate (135.88 mg, 983.16 μmol) and acetonitrile (2 mL) were reacted at 80°C for 5 hours. The reaction was complete as monitored by LCMS. Water (10 mL) was added, and then extracted three times with dichloromethane (10 mL). The organic phases were combined, dried and concentrated to obtain a crude product. The crude product was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 35%-95% acetonitrile in 20 min; flow rate: 30 mL/min) to obtain 10 mg of the title compound 31, yield 9%. LC-MS (ESI): m/z 557.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.01 (s, 1H), 8.07 (d, J = 2.5 Hz, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.73 (dd, J = 5.1, 3.0 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 6.90 – 6.96 (m, 2H), 5.27 (s, 2H), 4.53 (t, J = 8 Hz, 2H), 4.02 (t, J = 8 Hz, 2H), 1.77 (d, J = 13.7 Hz, 6H), 1.69 – 1.61 (m, 2H). ³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 34.07 (s, 1P).

Example 32: Preparation of Compound 32

Preparation of compound 32

Compound 1-7 (300 mg, 0.63 mmol) was dissolved in DMF (5.0 mL), and dimethylphosphine oxide (333 mg, 3.2 mmol), triethylamine (191 mg, 1.9 mmol), tri(dibenzylideneacetone)dipalladium (115 mg, 0.13 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (73 mg, 0.13 mmol) were added in sequence. The reaction system was replaced with nitrogen three times and stirred in a microwave at 120°C for 2 hours. After the reaction was completed, the insoluble solid was filtered out, water (10 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was prepared, separated, and purified (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 10 mg of the title compound 32 with a yield of 3%. LC-MS (ESI): m/z 546.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ 8.98 (d, J = 5.2 Hz, 1H) , 7.71 ( dd , J1 = 4.9, J2 = 3.1 Hz, 1H), 7.64 (d, J = 2.3 Hz , 1H), 1 .97 - 2.06 (m, 4H), 1.63 (s, 6H), 1.23 (s, 6H). ³¹ P NMR (162 MHz, DMSO- d6 ) δ 42.35 (s, 1P).

Example 33: Preparation of Compound 33

Preparation of compound 33-2

Compound 31-2 (1.76 g, 5.98 mmol) was dissolved in 1,4-dioxane (20.0 mL), and 5-methoxyindole (800 mg, 5.44 mmol), cesium carbonate (3.54 g, 10.87 mmol), tris(dibenzylideneacetone)dipalladium (498 mg, 0.54 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (628 mg, 1.09 mmol) were added in sequence. The reaction system was replaced with nitrogen three times, and the reaction was stirred in a microwave at 120°C for 2 hours. After the reaction, the insoluble solid was filtered out, water (20 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (20 mL) twice. The organic phases were combined, washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by normal phase silica gel chromatography (EA/PE = 0 ~ 30%) to obtain 800 mg of the title compound 33-2 with a yield of 41%. LC-MS (ESI): m/z 361.0 [M+H] ⁺ .

Preparation of compound 33-3 Compound 33-2 (800 mg, 2.21 mmol) was dissolved in dichloromethane (15 mL), and boron tribromide (2.22 g, 8.86 mmol, 17% DCM solution) was added dropwise under nitrogen protection at -60°C. The mixture was allowed to react overnight at room temperature. After LCMS monitoring until the reaction was complete, water (20 mL) was added to quench the mixture, and dichloromethane (20 mL) was used for extraction twice. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by normal phase silica gel chromatography (EA/PE = 0 ~ 30%) to obtain 150 mg of the title compound 33-3, with a yield of 20%. LC-MS (ESI): m/z 347.0 [M+H] ⁺ .

Preparation of compound 33-4

Compound 33-3 (150 mg, 0.43 mmol) was dissolved in DMF (5 mL), and potassium carbonate (119 mg, 0.86 mmol) was added under stirring. After reacting for 5 minutes, 2-chloro-4-chloromethylpyrimidine (85 mg, 0.52 mmol) was added and reacted at 80°C for 4 hours. LCMS monitored the reaction until it was complete, and the reaction solution was poured into a saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL×2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Purification was performed on a normal phase silica gel column (EA/PE = 0 ~ 30%) to obtain 100 mg of the title compound 33-4, with a yield of 49%. LC-MS (ESI): m/z 473.2 [M+H] ⁺ .

Preparation of compound 33

Compound 33-4 (50 mg, 0.11 mmol) was dissolved in N , N -dimethylformamide (3.0 mL), and dimethylphosphine oxide (25 mg, 0.32 mmol), N , N -diisopropylethylamine (41 mg, 0.32 mmol), tris(dibenzylideneacetone)dipalladium (10 mg, 0.01 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (12 mg, 0.02 mmol) were added in sequence. After replacing with nitrogen three times, the reaction was carried out at 110°C in a microwave oven for 2 hours. The reaction was monitored by LCMS until completion. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure. The crude product was purified by preparative separation (preparative method: chromatographic column: Welch Xtimate C18 250 x 21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/L NH ₄ HCO ₃ )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 10 mg of the title compound 33 with a yield of 18%. LC-MS (ESI): m/z 473.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.99 (d, J = 8 Hz, 1H), 8.11 – 8.14 (m, 2H), 7.71 – 7.76 (m, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 2.6 Hz, 1H), 7.04 (dd, J = 8.0, 2.6 Hz, 1H), 6.66 (d, J = 3.4 Hz, 1H), 5.34 (s, 2H), 4.50 (t, J = 4 Hz, 2H), 4.02 (t, J = 4 Hz, 2H), 1.78 (d, J = 16 Hz, 6H). ³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 34.12 (s, 1P).

Example 34: Preparation of Compound 34

Preparation of compound 34-2

Compound 34-1 (5 g, 16 mmol) and cesium carbonate (10.43 g, 32 mmol) were dissolved in DMF (50 mL), and iodomethane (1.5 mL, 24 mmol) was added thereto. After the addition, the system was stirred at room temperature for 16 h. After ice water (100 mL) was added to the system to quench the reaction, it was extracted with ethyl acetate (50 mL) three times, the organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by normal phase silica gel column chromatography (EtOAc/PE = 0 ~ 10%) to obtain 4.2 g of the title compound 34-2, with a yield of 80%.

Preparation of compound 34-3

Compound 34-2 (4.2 g, 12.9 mmol) was dissolved in DMF (50 mL), and cuprous cyanide (2.3 g, 25.8 mmol) was added thereto. After the addition, the system was stirred at 120°C for 16 h. After dilution with water (50 mL), the system was extracted with ethyl acetate (50 mL) three times, the organic phases were combined, washed with saturated brine (50 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by normal phase silica gel column chromatography (EtOAc/PE (v/v) = 0 ~ 10%) to obtain 2.5 g of the title compound 34-3, with a yield of 86%.

Preparation of compound 34-4

Compound 34-3 (2.5 g, 11.1 mmol) was dissolved in tetrahydrofuran (50 mL), and methylmagnesium bromide (3.0 M, 11.1 mL) was added thereto at -78°C. After the addition, the system was stirred at room temperature for 2 h. Saturated ammonium chloride solution (50 mL) was added to the reaction system, and after quenching the reaction, it was extracted with ethyl acetate (50 mL) three times, the organic phases were combined, washed with saturated brine (50 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by normal phase silica gel column chromatography (EtOAc/PE (v/v) = 0 ~ 25%) to obtain 2.3 g of the title compound 34-4, with a yield of 92%.

Preparation of compound 34-5

Compound 34-4 (2.3 g, 10.2 mmol) and phenol (1.2 g, 12.2 mmol) were dissolved in dichloromethane (50 mL). Boron trifluoride etherate (48%, 2.68 mL) was added at 0°C. After the addition, the system was stirred at room temperature for 2 h. Water (50 mL) was added to the system to quench the reaction, and then extracted with ethyl acetate (50 mL) three times. The organic phases were combined and washed with saturated brine (50 mL) three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by normal phase silica gel column chromatography (EtOAc/PE (v/v) = 0 ~ 25%) to obtain the title compound 34-5 with a yield of 49%. LC-MS (ESI): 300.2 [MH] ^- .

Preparation of compound 34-6

Compound 34-5 (1.2 g, 3.98 mmol) and compound (2-(methylthio)pyrimidin-4-yl)methanesulfonic acid methyl ester (1.86 g, 7.96 mmol) were dissolved in DMF (30 mL), and cesium carbonate (3.88 g, 11.94 mmol) was added thereto. After the addition, the system was stirred at 80°C for 2 h. After diluting the system with water (50 mL), extract with ethyl acetate (50 mL) three times, combine the organic phases, wash with saturated brine (50 mL) twice, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. The crude product was purified by normal phase silica gel column chromatography (EtOAc/PE (v/v) = 0 ~ 35%) to obtain the title compound 34-6 with a yield of 74.3%. LC-MS (ESI): 439.8[M+H] ⁺ .

Preparation of compound 34-7

Compound 34-6 (1.2 g, 2.73 mmol) was dissolved in dichloromethane (30 mL), and m-chloroperbenzoic acid (1.41 g, 8.19 mmol) was added. After the addition, the system was stirred at room temperature for 2 h. Saturated sodium carbonate solution (50 mL) was added to the system to quench the reaction, and the mixture was extracted with dichloromethane (50 mL) three times. The organic phases were combined, washed with saturated sodium bicarbonate (50 mL) three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude title compound 34-7 with a yield of 93%. It was used directly in the next reaction without purification. LC-MS (ESI): 471.8 [M+H] ⁺ .

Preparation of compound 34

The crude compound 34-7 (1.2 g, 2.54 mmol) and dimethylphosphine oxide (1.92 g, 25.4 mmol) were dissolved in acetonitrile (30 mL), and potassium carbonate (1.04 g, 7.6 mmol) was added thereto. After the addition, the system was stirred at 80°C for 8 h. After adding water (50 mL) to dilute the system, it was extracted with ethyl acetate (50 mL) three times, the organic phases were combined, washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-efficiency preparative liquid phase (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 34. LC-MS (ESI): 469.8 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d) δ 8.88 (s, 1H), 7.69 (s, 1H), 7.43 (d, J = 2.3 Hz, 1H), 7.30 (d, J = 2.3 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 5.25 (s, 2H), 4.05 (s, 3H), 1.91 (d, J = 13.5 Hz, 6H), 1.64 (s, 6H). ³¹ P NMR (162 MHz, Chloroform- d ) δ 35.2 2 (s, 1P).

Example 35: Preparation of Compound 35

Preparation of compound 35

Compound 34 (850 mg, 1.81 mmol) was dissolved in dichloromethane (30 mL), and boron tribromide (3.62 mL, 3.62 mmol) was added thereto at 0°C. After the addition, the system was stirred at 0°C for 3 h. After adding water (10 mL) to dilute the system, it was extracted with dichloromethane (50 mL) three times, the organic phases were combined, washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-efficiency preparative liquid phase (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (10mM/L NH ₄ HCO ₃ )-acetonitrile; the mobile phase acetonitrile ratio was 45%-65% in 12 minutes, gradient elution; flow rate 30 mL/min) to obtain the title compound 35. LC-MS (ESI): 456.0 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d) δ 8.89 (s, 1H), 7.70 (s, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 5.22 (s, 2H), 1.93 (d, J = 8 Hz, 6H), 1.63 (s, 6H). ³¹ P NMR (162 MHz, Chloroform- d ) δ 35.82 (s, 1P).

Example 36: Preparation of Compound 36

Preparation of compound 36

Compound 35 (100 mg, 0.22 mmol) and allyl bromide (0.047 mL, 0.66 mol) were dissolved in DMF (5 mL), and cesium carbonate (360 mg, 1.11 mmol) was added. After the addition, the system was stirred at 70 °C for 16 h. Saturated ammonium chloride solution (10 mL) was added to the system to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL) three times. The organic phases were combined, washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-performance preparative liquid chromatography (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 50%-70% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 36. LC-MS (ESI): 495.8[M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d) δ 8.89 (d, J = 5.0 Hz, 1H), 7.69 (t, J = 4.0 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.11 – 7.4 (m, 2H), 6.89 – 6.91 (m, 2H), 6.10 – 6.17 (m, 1H), 5.43 (dt, J = 17.2, 1.4 Hz, 1H), 5.32 (dq, J = 10.3, 1.2 Hz, 1H), 5 .25 (s, 2H), 4.71 (dt, J = 6.0, 1.3 Hz, 2H), 1.92 (d, J = 13.7 Hz, 6H), 1.64 (s, 6H). ³¹ P NMR (162 MHz, Chloroform- d ) δ 36.13 (s, 1P).

Example 37: Preparation of Compound 37

Preparation of compound 37

Compound 36 (100 mg, 0.22 mmol) and epichlorohydrin (0.051 mL, 0.66 mol) were dissolved in DMF (5 mL), and cesium carbonate (360 mg, 1.11 mmol) was added thereto. After the addition, the system was stirred at 70°C for 16 h. Saturated ammonium chloride solution (10 mL) was added to the system to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL) three times. The organic phases were combined, washed with saturated brine (50 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-efficiency preparative liquid chromatography (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% FA) -acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 37. LC-MS (ESI): 512.2 [M+H] ⁺ . ^1H NMR (400 MHz, Chloroform-d) δ 8.88 (s, 1H), 7.68 (s, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.18 – 7.10 (m, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.25 (s, 2H) , 4.40 (dd, J = 11.2, 3.5 Hz, 1H), 4.17 (dd, J = 11.2, 6.1 Hz, 1H), 3.46 (ddd, J = 6.2, 5.0, 3.3 Hz, 1H), 2.90 (t, J = 4.5 Hz, 1H), 2.74 (dd, J = 4 .8, 2.6 Hz, 1H), 1.90 (d, J = 13.5 Hz, 6H), 1.64 (s, 6H). ³¹ P NMR (162 MHz, Chloroform-d) δ 35.27(s, 1P).

Example 38: Preparation of Compound 38

Preparation of compound 38-2

Compound 38-1 (500 mg, 1.9 mmol) was dissolved in tetrahydrofuran (30 mL), and methylmagnesium bromide (3.0 M, 1.9 mL) was added thereto at -78°C. After the addition, the system was stirred at room temperature for 2 h. Saturated ammonium chloride solution (20 mL) was added to the system to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL) three times. The organic phases were combined, washed with saturated brine (50 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by normal phase silica gel column chromatography (EtOAc/PE (v/v) = 0 ~ 25%) to obtain 500 mg of the title compound 38-2, with a yield of 98%. LC-MS (ESI): m/z 264.2 [MH] ⁺ .

Preparation of compound 38-3

Compound 38-2 (450 mg, 1.71 mmol) and phenol (193 mg, 2.05 mmol) were dissolved in dichloromethane (50 mL). Boron trifluoride etherate (48%, 0.9 mL) was added at 0°C. After the addition, the system was stirred at room temperature for 2 h. Water (20 mL) was added to the system to quench the reaction, and then extracted with ethyl acetate (50 mL) three times. The organic phases were combined and washed with saturated brine (50 mL) three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by normal phase silica gel medium pressure column chromatography (EtOAc/PE (v/v) = 0 ~ 25%) to obtain 400 mg of the title compound 38-3, with a yield of 68%. LC-MS (ESI): m/z 340.0 [M+H] ⁺ .

Preparation of compound 38-4

Compound 38-3 (350 mg, 1.03 mmol) and compound (2-(methylthio)pyrimidin-4-yl)methanesulfonic acid methyl ester (481 mg, 2.06 mmol) were dissolved in DMF (20 mL), and cesium carbonate (1.00 g, 3.09 mmol) was added thereto. After the addition, the system was stirred at 80°C for 2 h. After diluting the system with water (20 mL), extract with ethyl acetate (50 mL) three times, combine the organic phases, wash with saturated brine (50 mL) twice, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. The crude product was purified by normal phase silica gel column chromatography (EtOAc/PE (v/v) = 0 ~ 35%) to obtain 250 mg of the title compound 38-4, with a yield of 50.8%. LC-MS (ESI): m/z 478.2[M+H] ⁺ .

Preparation of compound 38-5

Compound 38-4 (200 mg, 0.42 mmol) was dissolved in dichloromethane (30 mL), and m-chloroperbenzoic acid (216 mg, 1.26 mmol) was added. After the addition, the system was stirred at room temperature for 2 h. Saturated sodium carbonate solution (20 mL) was added to the system to quench the reaction, and the mixture was extracted with dichloromethane (50 mL) three times. The organic phases were combined, washed with saturated sodium bicarbonate (50 mL) three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 200 mg of crude title compound 38-5 with a yield of 93.7%. It was used directly in the next reaction without purification. LC-MS (ESI): m/z 510.2 [M+H] ⁺ .

Preparation of compound 38

The crude compound 38-5 (150 mg, 0.29 mmol) and dimethylphosphine oxide (223 mg, 2.9 mmol) were dissolved in acetonitrile (5 mL), and potassium carbonate (120 mg, 0.87 mmol) was added thereto. After the addition, the system was stirred at 80°C for 8 h. Saturated ammonium chloride solution (10 mL) was added to the system for quenching, and the mixture was extracted with ethyl acetate (50 mL) three times. The organic phases were combined, washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-performance preparative liquid chromatography (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% 10mM/L NH ₄ HCO ₃ )-acetonitrile; the mobile phase acetonitrile ratio was 40%-40% in gradient elution within 12 minutes; flow rate was 30 mL/min) to obtain the title compound 38. LC-MS (ESI): m/z 508.2 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol- d4 ) δ 8.84 (d, J = 5.2 Hz, 1H), 8.27 (s, 1H), 7.79 (d, J = 1.6 Hz, 1H), 7.66 (t, J = 1.6 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.14 – 7.10 (m, 2H), 6.85 – 6.89 (m, 2H), 5.19 (s, 2H), 4.78 (d, J = 8 Hz, 2H), 3.95 (d, J = 8 Hz, 2H), 1.81 (d , J = 13.9 Hz, 6H), 1.65 (s, 6H). ³¹ P NMR (162 MHz, Chloroform- d ) δ 41.18 (s, 1P).

Example 39: Preparation of Compound 39

Preparation of compound 39-2

Compound 39-1 (2 g, 10.7 mmol) and triethylamine (4.5 mL, 32.1 mmol) were dissolved in dichloromethane (60 mL). Methylsulfonyl chloride (2.45 g, 21.4 mmol) was added thereto at 0°C. After the addition, the system was stirred at room temperature for 2 h. Saturated ammonium chloride solution (30 mL) was added to the system to quench the reaction, and the mixture was extracted with dichloromethane (50 mL) three times. The organic phases were combined and washed with saturated brine (50 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 2.1 g of crude title compound 39-2, with a yield of 74.1%. LC-MS (ESI): m/z 210.0 [M-55] ⁺ .

Preparation of compound 39-3

Compound 39-2 (906 mg, 3.42 mmol) and compound 1-6 (800 mg, 2.29 mmol) were dissolved in DMF (20 mL), and cesium carbonate (1.5 g, 4.58 mol) was added thereto. After the addition, the system was stirred at 80°C for 2 h. After dilution with water (20 mL), the system was extracted with ethyl acetate (50 mL) three times, the organic phases were combined, washed with saturated brine (50 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by normal phase silica gel column chromatography (EtOAc/PE (v/v) = 0 ~ 50%) to obtain 800 mg of the title compound 39-3, with a yield of 68.5%. LC-MS (ESI): m/z 463.2 [M-55] ⁺ .

Preparation of compound 39-4

Compound 39-3 (800 mg, 1.54 mmol) was dissolved in ethyl acetate (2 mL), and a solution of hydrogen chloride in ethyl acetate (1 M, 20 mL) was added thereto. After the addition, the system was stirred at room temperature for 16 h. After concentration, 550 mg of crude title compound 39-4 was obtained, with a yield of 85%. LC-MS (ESI): m/z 419.2 [M+H] ⁺ .

Preparation of compound 39-5

Compound 39-3 (550 mg, 1.31 mmol) and compound 4-chloro-2-methanesulfonylpyrimidine (252 mg, 1.31 mmol) were dissolved in tetrahydrofuran (20 mL), and triethylamine (132 mg, 1.31 mmol) was added thereto. After the addition, the system was stirred at room temperature for 16 h. After diluting the system with water (10 mL), extract with ethyl acetate (50 mL) three times, combine the organic phases, wash with saturated brine (50 mL) twice, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. The crude product was purified by normal phase silica gel column chromatography (EtOAc/PE (v/v) = 0 ~ 60%) to obtain 500 mg of the title compound 39-5, with a yield of 72.8%. LC-MS (ESI): m/z 575.2 [M+H] ⁺ .

Preparation of compound 39

The crude compound 39-5 (200 mg, 0.35 mmol) and dimethylphosphine oxide (269 mg, 3.5 mmol) were dissolved in acetonitrile (10 mL), and potassium carbonate (145 mg, 1.05 mmol) was added thereto. After the addition, the system was stirred at 80°C for 16 h. After adding saturated ammonium chloride solution (20 mL) to dilute the system, extract with ethyl acetate (50 mL) three times, combine the organic phases, wash with saturated brine (50 mL) twice, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. The crude product was purified by high-performance preparative liquid chromatography (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% 10mM/L NH ₄ HCO ₃ )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 39, LC-MS (ESI): m/z 573.2 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.32 (s, 1H), 7.46 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.38 (s, 1H), 5.06 (s, 1H), 4.42 (t, J = 6.1 Hz, 2H), 4.04 (s, 1H), 3.88 (t, J = 6.1 Hz, 3H), 3.61 – 3.75 (m, 3H), 2.25 – 2.44 (m, 2H), 1.85 (d, J = 1 3.6 Hz, 6H), 1.64 (s, 7H). ³¹ P NMR (162 MHz, Chloroform- d ) δ 35.46 (s, 1P).

Preparation of compounds 39A and 39B

Compound 39 (38.55 mg, 0.067 mmol) was chirally separated by SFC (preparation method: chromatographic column: ChiralPak AD, 250×30 mm ID, 10µm; column temperature: 38°C; mobile phase: A is CO ₂ , B is ethanol (containing 0.1% ammonia water); mobile phase B ratio 30% in 8 min; flow rate 150 mL/min) to obtain 11.11 mg of the title compound 39A (chiral column retention time of 11.11 min) and 17.34 mg of compound 39B (chiral column retention time of 7.60 min). Compound 39A: LC-MS (ESI): 573.2 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.34 – 8.19 (m, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.10 – 7.12 (m, 2H), 6.81 – 6.82 (m, 2H), 6.34 (m, 1H), 5.05 (m, 1H), 4.42 (t, J = 6.2 Hz, 2H), 4.03 (m, 1H), 3.88 (t, J = 6.2 Hz, 2H), 3.60 (m, 3H), 2.26 – 2.42 (m, 2H), 1.82 (d, J = 13.4 Hz, 6H), 1.64 (s, 6H). ³¹ P NMR (162 MHz, Chloroform- d ) δ 35.20 (s, 1P).

Compound 39B: LC-MS (ESI): 573.2[M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d) δ 8.33 (s, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.09 – 7.11 (m, 2H), 6.81 – 6.83 (m, 2H), 6.37 (s, 1H), 5.04 (s, 1H), 4.42 (t, J = 6.1 Hz, 2H), 3.99 (m, 1H), 3.87 (t, J = 6.1 Hz, 2H), 3.58 – 3.71 (m, 3H), 2.28 – 2.41 (m, 2H), 1.83 (d, J = 13.6 Hz, 6H), 1.64 (s, 6H). ³¹ P NMR (162 MHz, Chloroform- d ) δ 36.84 (s, 1P).

Example 40: Preparation of Compound 40

Preparation of compound 40-3

Compound 40-2 (500 mg, 3.62 mmol) was dissolved in THF (5 mL), the reaction system was replaced with nitrogen three times, cooled to -20°C in a dry ice bath, allyl magnesium bromide (1 M, 9.05 mL, 9.05 mmol) was added dropwise, the reaction system was stirred at -5°C for 2 hours, and the reaction was completed. Saturated aqueous ammonium chloride solution (20 mL) was slowly added to the reaction system in an ice bath to quench the reaction. The reaction solution was concentrated and freeze-dried, the crude product was dissolved in EA (10 mL), filtered, and the organic phase was concentrated to obtain a crude product, which was separated and purified by normal phase silica gel column chromatography (DCM/MeOH = 0 ~ 10%) to obtain 364 mg of the title compound 40-3, with a yield of 77%. LC-MS (ESI): m/z 131.1 [M+H] ⁺ .

Preparation of compound 40

Dissolve compound 27-3 (100 mg, 192 umol) in 2-methyltetrahydrofuran (2 mL), add cesium carbonate (156 mg, 480 umol) and compound 40-3 (37.5 mg, 288 umol) in sequence, and replace the reaction system with nitrogen three times. Heat the reaction system to 85°C and react for 1.5 h. After the reaction is completed, filter, add water (4 mL) to the filtrate, extract with ethyl acetate (10 mL) twice, and combine the organic phases. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile elution for 12 minutes; flow rate: 30 mL/min) to obtain 45 mg of the title compound 40 in a yield of 14%. LC-MS (ESI): m/z 570.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.99 (d, J = 5.2 Hz, 1H), 7.72 (dd, J = 5.1, 3.2 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.5 7 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 8.3 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 5.70-5.78 (m, 2H), 5.30 (s, 2H), 5.03 –5.19 (m, 4H), 4.41 (t, J = 5. 1 Hz, 2H), 3.95 (t, J = 5.1 Hz, 2H), 2.91 – 3.06 (m, 4H), 1.63 (s, 6H). ³¹ P NMR (162 MHz, DMSO- d6 ) δ 34.13 (s, 1P).

Example 41: Preparation of Compound 41

Preparation of compound 41-2

Add magnesium (2.45 g, 101.8 mmol) and iodine (20 mg, 78 umol) to a dry three-necked flask, add dry THF (100 mL) to the flask, replace the reaction system with nitrogen three times, and heat to 35°C for reaction. Slowly add 1,4-dibromobutane (10.0 g, 46.3 mmol) to the reaction system, and react at room temperature for 1 hour. Cool the reaction to -20°C, and add diethyl phosphite (5.4 g, 39.3 mmol). The reaction was monitored by LCMS until it was complete. Ethanol (100 mL) was added dropwise to quench the reaction. The reaction system was concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (DCM/MeOH = 0 ~ 15%) to obtain 320 mg of the title compound 41-2, with a yield of 6.6%. LC-MS (ESI): m/z 105.2 [M+H] ⁺ .

Preparation of compound 41

Compound 27-3 (322 mg, 0.62 mmol) was dissolved in 2-methyltetrahydrofuran (4 ml), potassium carbonate (406 mg, 1.25 mmol) and compound 41-2 (130 mg, 1.25 mmol) were added, the reaction system was replaced with nitrogen three times, the temperature was raised to 85°C and the reaction was carried out for 1.5 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was filtered, water (20 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (20 mL) twice, and the organic phases were combined. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 15%-55% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 21 mg of the title compound 41 with a yield of 6.2%. LC-MS (ESI): m/z 544.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ 8.99 (d, J = 5.1 Hz, 1H), 7.71 (dd, J = 5.2, 3.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.18 - 7.22 (m, 2H), 6.97 - 7.01 (m, 2H), 5.30 (s, 2H), 4.41 (t, J = 5.8 Hz, 2H), 3.96 (t, J = 5.8 Hz, 2H), 2.27 - 2.34 ( m, 2H), 1.91 - 1.97 (m, 2H), 1.66 - 1.87 (m, 4H), 1.63 (s, 6H). ³¹ P NMR (162 MHz, DMSO- d6 ) δ 59.94 (s, 1P).

Example 42: Preparation of Compound 42

Preparation of compound 42-1

Compound 34-6 (600 mg, 2.2 mmol) was added to a three-necked flask, and then DCM (10 mL) was added. The reaction system was replaced with argon three times, and boron tribromide (1 M, 4.4 mL, 4.4 mmol) was added dropwise at -15°C. The mixture was stirred for 2 hours in an ice bath. After the reaction was completed, sodium bicarbonate (4 mL, 1 M) was added, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, dried, concentrated, and the crude product was obtained. The crude product was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 30%) to obtain 460 mg of the title compound 42-1, with a yield of 85%. LC-MS (ESI): m/z 426.2 [M+H] ⁺ .

Preparation of compound 42-2

Compound 42-1 (460 mg, 1.082 mmol) and anhydrous THF (5 mL) were added to a three-necked flask, the reaction system was replaced with argon three times, sodium hydride (54 mg, 1.35 mmol, 60%) was added under ice bath, methyl 2,3-dichloropropionate (255 mg, 1.624 mmol) was added dropwise, and the reaction system was stirred at room temperature for 4 hours. After the reaction was completed, ammonium chloride aqueous solution (10 mL) was slowly added to the reaction system under ice bath, and extracted three times with DCM (10 mL), the organic phases were combined, dried and concentrated to obtain a crude product, and purified by normal phase silica gel column (EtOAc/PE = 0 ~ 40%) to obtain 280 mg of the title compound 42-2, with a yield of 47%. LC-MS (ESI): 546.3 [M+H] ⁺ .

Preparation of compound 42-3

Compound 42-2 (280 mg, 0.514 mmol) was added to a three-necked flask, and tetrahydrofuran (10 mL) was added. 5 mL of water was added to a conical flask, and potassium peroxymonosulfonate (788 mg, 2.4 mmol) was added, stirred to dissolve, and then added dropwise to the above reaction system under an ice bath, and stirred at room temperature for 16 hours. The reaction solution was filtered and spun to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 ~ 60%) to obtain 230 mg of the title compound 42-3, with a yield of 77%. LC-MS (ESI): m/z 578.2[M+H] ⁺ .

Preparation of compound 42-4

Compound 42-3 (230 mg, 0.399 mmol) was dissolved in 2-methyltetrahydrofuran (4 mL), and dimethylphosphine oxide (78 mg, 1.0 mmol) and potassium carbonate (325 mg, 1.0 mmol) were added in sequence. The reaction system was stirred at 80°C for 1.5 hours. After the reaction was completed, the reaction system was filtered, water (20 mL) was added to the filtrate, and the mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparation separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 110 mg of the title compound 42-4, with a yield of 46%. LC-MS (ESI): m/z 576.3 [M+H] ⁺ .

Preparation of compound 42

Compound 42-4 (110 mg, 0.191 mmol) was dissolved in MeOH (5 ml), and after nitrogen substitution three times, sodium borohydride (14.5 mg, 0.382 mmol) was added portionwise at 0°C. The reaction system was stirred at 0°C for 2 hours. After the reaction was completed, water (10 mL) was added to quench the reaction, and the mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparation separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 15%-45% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 29 mg of the title compound 42 with a yield of 28%. LC-MS (ESI): m/z 548.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.99 (d, J = 5.2 Hz, 1H), 7.72 (dd, J = 5.2, 3.2 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.5 6 (d, J = 2.4 Hz, 1H), 7.19 - 7.22 (m, 2H), 6.98 - 7.03 (m, 2H), 5.61 (d, J = 5.3 Hz, 1H), 5.29 (s, 2H), 4.18 (d, J = 5.4 Hz, 2H), 4.06 (m, J = 5.3 Hz, 1H), 3.83 (dd, J = 11.2, 4.6 Hz, 1H), 3.72 (dd, J = 11.2, 5.6 Hz, 1H), 1.74 (d, J = 18.7 Hz, 3H), 1.63 (s, 6H).

Example 43: Preparation of Compounds 43A and 43B

Preparation of compound 43-3

Under nitrogen protection, compound 43-1 (12 g, 68.12 mmol), compound 43-2 (25.78 g, 108.99 mmol), DCM (60 mL), n-hexane (300 mL), trifluoromethanesulfonic anhydride (960.93 mg, 3.41 mmol) were added to the reaction bottle in sequence. Stir at room temperature for 16 hours. LCMS monitoring showed that the reaction was complete. Filter, and wash the filtrate twice with saturated sodium bicarbonate aqueous solution (300 mL). The filtrate was concentrated and dried, and the concentrated residue was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 10%) to obtain 15 g of the title compound 43-3, with a yield of 82%. LC-MS (ESI): 267.2 [M+H] ⁺ .

Preparation of compound 43-4

Compound 43-3 (13 g, 48.82 mmol) and THF (150 mL) were added to a reaction flask. Lithium aluminum hydroxide (5.56 g, 146.46 mmol) was added in batches at 0°C and stirred at room temperature for 16 hours. The reaction was complete as monitored by LCMS. After the reaction system was cooled to 0°C, ice water (5.56 mL) was slowly added dropwise to quench the reaction. A 15% aqueous sodium hydroxide solution (5.56 mL) was added, and water (16.68 mL) was added after stirring for 20 minutes. The reaction system was filtered, and the filter cake was washed twice with DCM (50 mL). The filtrate was dried over anhydrous sodium sulfate, concentrated and cyclohexane to obtain 6.3 g of crude title compound 43-4, with a yield of 61%. LC-MS (ESI): 211.2 [M+H] ⁺ .

Preparation of compound 43-5

Under nitrogen protection, compound 43-4 (6 g, 28.53 mmol), anhydrous dichloromethane (30 mL), and triethylamine (6.35 g, 62.78 mmol) were added to the reaction flask. After cooling to 0°C, methanesulfonyl chloride (7.19 g, 62.78 mmol) was added dropwise to the reaction flask, and the temperature was raised to room temperature and stirred for 16 hours. TLC monitored the reaction to be complete. The reaction solution was directly concentrated and cyclohexane-dried, and the concentrated residue was dissolved in acetone (30 mL). KBr (9.91 g, 114.41 mmol) was added to the reaction system, and the temperature was raised to 40°C and stirred for 16 hours. After the reaction was completed, water (50 mL) was added, and then extracted three times with dichloromethane (50 mL). The organic phases were combined, dried and concentrated to obtain a crude product. The crude product was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 10%) to obtain 2.1 g of the title compound 43-5, with a yield of 21%. LC-MS (ESI): 335.0 [M+H] ⁺ .

Preparation of compound 43-6

Under nitrogen protection, add ammonium hypophosphite (778.23 mg, 9.37 mmol) and hexamethyldisilamine (3.8 mL) to the reaction bottle, heat to 120°C and stir for 4 hours, then cool to 0°C. Add compound 43-5 (2.1 g, 6.25 mmol) to the reaction system at 0°C, heat to 120°C and continue stirring for 4 hours. After cooling the system to 0°C, add anhydrous ethanol (12 mL) dropwise. Heat to reflux and stir for 1 hour. Cool the system to room temperature, filter, and wash the filter cake twice with DCM (10 mL). The filtrate was concentrated and cyclohexane dried to give 1.5 g of crude title compound 43-6, with a yield of 100%. LC-MS (ESI): 241.2 [M+H] ⁺ .

Preparation of compound 43-7

Under nitrogen protection, compound 43-6 (2.5 g, 10.41 mmol) and anhydrous dichloromethane (40 mL) were added to the reaction bottle, cooled to ℃, and oxalyl chloride (3.96 g, 31.22 mmol) was added dropwise. The temperature was slowly raised to room temperature and stirred for 16 hours. The reaction solution was concentrated to dryness, and the concentrated residue was dissolved in toluene (25 mL) and then vortexed. The concentrated residue was dissolved in dichloromethane (40 mL), and diisobutylaluminum hydroxide (1 M, 15.61 mmol, 15.61 mL) was added dropwise at -78℃. After stirring at -78℃ for two hours, methanol (8 mL) was added dropwise to quench the reaction. After the temperature was raised to 0°C, 10% acetic acid aqueous solution (25 mL) was added to the system and stirred at room temperature for 10 minutes. The system was extracted with dichloromethane (20 mL) for 5 times. The organic phases were combined and spun down. The concentrated residue was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-75% acetonitrile in 20 minutes; flow rate: 30 mL/min) to obtain 120 mg of the title compound 43-7, with a yield of 5%. LC-MS (ESI): 225.0 [M+H] ⁺ .

Preparation of compound 43-8

Under nitrogen protection, compound 43-7 (60 mg, 267.58 μmol) and anhydrous dichloromethane (1 mL) were added to a reaction bottle, and BBr ₃ (1 M, 2.00 mmol, 2 mL) was slowly added at 0°C and stirred at room temperature for 20 minutes. LCMS monitored the reaction to be complete. Methanol (12 mL) was slowly added dropwise at 0°C to quench the reaction. The reaction system was directly concentrated and cyclorotated to obtain 35 mg of the crude title compound 43-8 with a yield of 97%. LC-MS (ESI): 135.0 [M+H] ⁺ .

Preparation of compounds 43A and 43B

Compound 43-8 (35 mg, 260.97 μmol), compound 1-7 (200 mg, 419.48 μmol), DIPEA (216.86 mg, 1.68 mmol), Xantphos (48.54 mg, 83.90 μmol), Pd ₂ (dba) ₃ (38.41 mg, 41.95 μmol) and DMF (2 mL) were added to a microwave tube. Stir at 120 °C for 6 hours under nitrogen protection. The reaction was complete as monitored by LCMS. Water (10 mL) was added, and then extracted three times with dichloromethane (10 mL). The organic phases were combined, dried and concentrated to obtain a crude product. The crude product was purified by preparation, separation and purification (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-95% acetonitrile in 20 minutes; flow rate: 30 mL/min) to obtain 5 mg of the title compound 43A (yield 2%) and 10 mg of the title compound 43B (yield 4%).

Compound 43A: (HPLC analysis method: chromatographic column: Agilent ZORBAX Extend-C18 4.6*150 mm, 3.5 µm; column temperature: 30°C; mobile phase: water (0.1 mL/1 L trifluoroacetic acid)-acetonitrile (0.4 mL/4 L trifluoroacetic acid); acetonitrile: 5%-95% 8 min, 95% 7 min; flow rate: 1 mL/min, retention time Rt: 7.685 min). LC-MS (ESI): 574.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.03 (d, J = 5.2 Hz, 1H), 7.75 (dd, J = 5.2, 2.9 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.20 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 5.31 (s, 2H), 4.69 (br.s, 1H), 4.41 (t, J = 5.1 Hz, 2H), 3.95 (t, J = 5 .1 Hz, 2H), 3.77 – 3.62 (m, 1H), 2.49 – 2.36 (m, 2H), 2.07 – 1.87 (m, 4H), 1.63 (s, 6H), 1.44 – 1.28 (m, 2H). ³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 3 3.84 (s, 1P).

Compound 43B: (HPLC analysis method: chromatographic column: Agilent ZORBAX Extend-C18 4.6*150 mm, 3.5 µm; column temperature: 30°C; mobile phase: water (0.1 mL/1 L trifluoroacetic acid)-acetonitrile (0.4 mL/4 L trifluoroacetic acid); acetonitrile: 5%-95% 8 min, 95% 7 min; flow rate: 1 mL/min, retention time Rt: 7.816 min). LC-MS (ESI)：574.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.01 (d, J = 5.2 Hz, 1H), 7.74 (dd, J = 5.2, 3.0 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 5.29 (s, 2H) , 4.82 (d, J = 3.4 Hz, 1H), 4.41 (t, J = 5.3 Hz, 2H), 3.95 ³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 32.90 (s, 1P).

Example 44: Preparation of Compound 44

Preparation of compound 44-1

Under nitrogen protection, compound (2-chloropyrimidin-4-yl)methanol (1 g, 6.92 mmol), TBSCl (1.15 g, 7.61 mmol), and acetonitrile (10 mL) were added to the reaction bottle. Imidazole (941.86 mg, 13.84 mmol) was added at 0°C and stirred for 10 minutes, then the temperature was raised to room temperature and DMF (3 mL) was added. After stirring at room temperature for 1 hour, the reaction was complete as determined by LCMS. Water (30 mL) was added to quench the reaction, and then the mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 10%) to obtain the title compound 44-1 (1.63 g) with a yield of 91%. LC-MS (ESI): 259.0 [M+H] ⁺ .

Preparation of compound 44-2

Compound 44-1 (771.94 mg, 2.98 mmol), compound 43-8 (400 mg, 2.98 mmol), DIPEA (1.54 g, 11.93 mmol, 2.08 mL), Xantphos (345.15 mg, 596.51 μmol), Pd ₂ (dba) ₃ (273.12 mg, 298.26 μmol) and DMF (8 mL) were added to a microwave tube. Stir at 120 °C for 6 hours under nitrogen protection. LC-MS detected that the reaction was complete. Add water (30 mL), then extract with dichloromethane (10 mL) three times, combine the organic phases, dry and concentrate to obtain a crude product. The crude product was separated and purified by normal phase silica gel column (EtOAc/PE = 0 - 100%) to obtain the title compound 44-2 (240 mg) with a yield of 22%. LC-MS (ESI): 356.5 [M+H] ⁺ .

Preparation of compound 44-3

Compound 44-2 (200 mg, 561.06 μmol), DMP (475.93 mg, 1.12 mmol), and DCM (2 mL) were added to the reaction flask and stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. Water (20 mL) was added to quench the reaction and the mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 100%) to obtain the title compound 44-3 (100 mg) with a yield of 50%. LC-MS (ESI): 355.0 [M+H] ⁺ .

Preparation of compound 44-4

Compound 44-3 (200 mg, 564.25 μmol) and DCM (2 mL) were added to the reaction bottle, and DAST (136.43 mg, 846.37 μmol) was added dropwise at 0°C. After stirring at room temperature for 2 hours, the reaction was complete as detected by TLC, and water (20 mL) was added to quench the reaction. The mixture was then extracted three times with dichloromethane (20 mL), and the organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 100%) to obtain the title compound 44-4 (90 mg) with a yield of 42%.

Preparation of compound 44-5

Compound 44-4 (24 mg, 63.75 μmol), TBAF (1 M, 63.75 μmol, 63.75 μL) and THF were added to the reaction bottle and stirred at room temperature for 1 hour. LCMS detected that the reaction was complete. Water (5 mL) was added to quench the reaction, and then extracted with dichloromethane (10 mL) three times. The organic phases were combined, dried and concentrated to obtain a crude product. The crude product was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 100%) to obtain the title compound 44-5 (10 mg) with a yield of 59%. LC-MS (ESI): 263.0 [M+H] ⁺ .

Preparation of compound 44

Under nitrogen protection, compound 1-6 (53.43 mg, 152.56 μmol), compound 44-5 (20 mg, 76.28 μmol), TMAD (65.67 mg, 381.40 μmol), and DCM (2 mL) were added to the reaction bottle, and tributylphosphine (77.16 mg, 381.40 μmol) was added dropwise at 0°C and stirred for 20 minutes. LCMS detected that the reaction was complete. Water (10 mL) was added, and then extracted with dichloromethane (10 mL) three times, and the organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was prepared, separated and purified (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-80% acetonitrile elution for 30 min; flow rate: 30 mL/min) to obtain the title compound 44 (3 mg) in a yield of 6%. LC-MS (ESI): 594.0 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.93 (brs, 1H), 7.76 (brs, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.12 – 7.15 (m, 2H), 6.90 – 6.92 (m, 2H), 5.26 (s, 2H), 4.42 (t, J = 6.1 Hz, 2H), 3.88 (t, J = 6.1 Hz, 2H), 2.70 – 2.58 (m, 2H), 2.58 – 2.47 (m, 2H ), 2.46 – 2.36 (m, 2H), 2.36 – 2.27 (m, 2H), 1.65 (s, 6H). ¹⁹ F NMR (376 MHz, Chloroform- d ) δ -97.07 (d, J = 246.3 Hz, 1F), -98.73 (d, J = 246.3 Hz, 1F).

Example 45: Preparation of Compound 45

Preparation of compound 45-1

Add 1-6 (1 g, 2.86 mmol), DCM (15 mL) and pyridine (451.69 mg, 5.71 mmol, 460.02 μL) to a 100 ml single-necked bottle, cool to 0°C, replace with nitrogen, and dropwise add Tf2O (1.21 g, 4.28 mmol, 720.54 μL). Warm to room temperature and stir for 18 hours. TLC monitors the reaction to be complete (PE:EA = 3:1). Pour the reaction solution into water (50 ml) and extract twice with DCM (60 ml). Combine the organic phases, wash with water (50 ml), and concentrate under reduced pressure to obtain a yellow oil. Purify by flash chromatography column (EA/PE = 0 ~ 100%) to obtain 1.2 g of the title compound with a yield of 87%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 (d, J = 8 Hz, 1H), 7.34 (d, J = 8 Hz, 1H), 7.21 – 7.27 (m, 4H), 4.44 t(, J = 4 Hz, 2H), 3.88 (t, J = 4 Hz, 2H), 1.6 8 (s, 3H).

Preparation of compound 45-3

Compound 45-1 (500 mg, 1.04 mmol) was dissolved in 1, 4-dioxane (5 mL), and 45-2 (290 mg, 1.56 mmol), cesium carbonate (676 mg, 2.08 mmol), sodium acetate (23 mg, 0.1 mmol) and Xantphos (30 mg, 0.05 mmol) were added in sequence. The atmosphere was replaced with nitrogen three times, and the reaction system was stirred in a microwave at 100°C for 2 hours. After the reaction was completed, the reaction system was filtered and 10 mL of saturated sodium chloride aqueous solution was added to the filtrate to quench the reaction. The mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 35%) to obtain 110 mg of the title compound with a yield of 20%. LC-MS (ESI): 518.1 [M+H] ⁺ .

Preparation of compound 45-4

Compound 45-3 (110 mg, 0.212 mmol) was dissolved in dichloromethane (3.0 mL), trifluoroacetic acid (0.1 mL) was added dropwise, and the reaction system was stirred at room temperature for 2 hours. After the reaction was completed, 10 mL of saturated sodium bicarbonate solution was added to the filtrate to quench the reaction, and the mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried and concentrated to obtain 85 mg of the title compound, with a yield of 96%. LC-MS (ESI): 418.2 [M+H] ⁺ .

Preparation of compound 45-5

Compound 45-4 (85 mg, 203 umol) was dissolved in tetrahydrofuran (2.0 mL), triethylamine (51 mg, 507 umol) and 2-chloro-4-bromopyrimidine (39 mg, 203 mmol) were added under ice bath, and stirred at room temperature for 4 hours. After the reaction was completed, 10 mL of saturated sodium chloride aqueous solution was added to the reaction solution to quench the reaction, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 20 - 70%) to obtain 60 mg of the title compound with a yield of 20%. LC-MS (ESI): 530.3 [M+H] ⁺ .

Preparation of compound 45

Compound 45-5 (60 mg, 113 umol) was dissolved in N , N -dimethylformamide (1 mL), and dimethylphosphine oxide (44 mg, 565 umol), triethylamine (35 mg, 282 umol), Pd ₂ (dba) ₃ (4.6 mg, 5 umol) and Xantphos (3 mg, 5 μmmol) were added in sequence. The atmosphere was replaced with nitrogen three times, and the reaction system was stirred in a microwave at 120°C for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the reaction solution was filtered, water (20 mL) was added to the filtrate, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparation separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-45% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 7.2 mg of the title compound with a yield of 11%. LC-MS (ESI): m/z 572.0 [M+H] ⁺ . ³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 33.47 . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.16 (s, 1H), 7.99 (d, J = 6.5 Hz, 1H), 7.60 (d, J = ( t, J = 4 Hz, 2H), 3.59 – 3.63 (m, 1H), 3.49-3.22 (m, 2H), 3.12-3.15 (m, 1H), 2.28 – 2.33 (m, 1H), 1.99 – 2.04 (m, 1H), 1.67 (d, J = 13.5 Hz, 6 H), 1.60 (s, 6H).

Example 46: Preparation of Compound 46

Preparation of compound 46-2

Compound 45-1 (1 g, 2.07 mmol), 46-1 (734 mg, 2.49 mmol), Pd(dppf)Cl ₂ (152 mg, 0.21 mmol) and sodium carbonate (440 mg, 4.15 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (20.0 mL) and water (4.0 mL). The reaction system was replaced with nitrogen three times and stirred in a microwave at 90°C for 2 hours. After the reaction, the insoluble solid was filtered out, water (20 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (20 mL) twice. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by normal phase silica gel chromatography (EA/PE = 0 - 30%) to obtain 720 mg of the title compound with a yield of 69%. LC-MS (ESI): m/z 445.0 [M+H-56] ⁺ .

Preparation of compound 46-3

Compound 46-2 (700 mg, 1.40 mmol) was dissolved in ethyl acetate (15 mL), and 10% wet palladium on carbon (70 mg) was added. After replacing with a hydrogen balloon three times, the mixture was reacted at room temperature overnight. The reaction was followed by LCMS until the reaction was complete. The insoluble solid was filtered out and the crude product was concentrated. The crude product was purified by normal phase silica gel chromatography (EA/PE = 0 - 30%) to obtain 470 mg of the title compound with a yield of 67%. LC-MS (ESI): m/z 447.0 [M+H-56] ⁺ .

Preparation of compound 46-4

Compound 46-3 (430 mg, 0.85 mmol) was dissolved in 1, 4-dioxane (5.0 mL), and 4 M hydrogen chloride/1, 4-dioxane solution (2.13 mL, 8.54 mmol) was added dropwise under stirring, and the mixture was allowed to react overnight at room temperature. The next day, LCMS was used to track the reaction until it was complete, and the crude product of the title compound (320 mg) was obtained by concentration, with a yield of 93%. It was used directly in the next step without purification. LC-MS (ESI): m/z 403.0 [M+H] ⁺ .

Preparation of compound 46-5

Compound 46-4 (300 mg, 0.74 mmol) and DIPEA (240 mg, 1.86 mmol) were dissolved in tetrahydrofuran (8.0 mL), stirred for 5 minutes, and then 2, 4-dichloropyrimidine (122 mg, 0.82 mmol) was added, and the mixture was stirred at 60°C for 2 hours. After the reaction was completed, the reaction solution was poured into ice water (20 mL) to quench the reaction, extracted twice with ethyl acetate (20 mL), the organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by normal phase silica gel chromatography (EA/PE = 0 - 30%) to obtain 220 mg of the title compound with a yield of 57%. LC-MS (ESI): m/z 515.0 [M+H] ⁺ .

Preparation of compound 46

Compound 46-5 (60 mg, 0.12 mmol) was dissolved in 1, 4-dioxane (3 mL), and dimethylphosphine oxide (18 mg, 0.23 mmol), DIPEA (38 mg, 0.29 mmol), Pd ₂ (dba) ₃ (11 mg, 0.01 mmol) and Xantphos (13 mg, 0.02 mmol) were added in sequence. After replacing with nitrogen three times, the reaction was stirred at 100°C in a microwave for 3 hours. After the reaction was completed by LCMS tracking, the reaction solution was filtered and evaporated under reduced pressure. The crude filtrate was purified by preparation separation (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (10mM/L _NH4HCO3 )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 18 mg _of the title compound with a yield of 28%. LC-MS (ESI): m/z 557.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.27 (t, J = 7.2 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.61 (dd, J = 6.2, 3.2 Hz, 1H), 4.42(t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.2 Hz, 2H), 3.92 – 3.78 (m, 1H) , 3.64 – 3.38 (m, 3H), 2.48 – 2.25 (m, 2H), 2.20 – 1.99 (m, 1H), 1.74 – 1.58 (m, 12H). ³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 33.35 (s, 1P).

Example 47: Preparation of Compound 47

Preparation of compound 47-2

Compound 47-1 (3.0 g, 12.8 mmol), compound bromochloroethane (2.7 g, 19.2 mmol) and cesium carbonate (8.3 g, 25.6 mmol) were dissolved in anhydrous DMF (50 mL) and reacted at 80°C for 4 hours. LCMS monitored the reaction until it was complete, and water (20 mL) was added to quench the reaction. The reaction system was extracted twice with EtOAc (50 mL). The organic phases were combined, dried and concentrated, and separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 20%) to obtain 1.8 g of the title compound with a yield of 47.5%. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.91 (s, 1H), 8.16 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 4.36 (t, J = 4.0 Hz, 2H), 4.01 (t, J = 4.0 Hz, 2H)

Preparation of compound 47-4

Compound 47-2 (1.8 g, 5.06 mmol) was added to a three-necked flask, and then anhydrous THF (20 mL) and LiHMDS (6 mL, 6 mmol) were added. After stirring at room temperature for 0.5 hours, 47-3 (1.0 g, 6.0 mmol) was added and reacted at 50°C. TLC monitoring showed that the reaction was complete after 2 hours. Ammonium chloride (50 mL) was added to quench the reaction and EA (50 mL) was used for extraction. The organic phases were combined, dried and concentrated, and separated and purified by normal phase silica gel column (EtOAc/PE = 0 - 50%) to obtain 620 mg of the title compound with a yield of 33.5%. LC-MS (ESI): m/z 365.9 [M+H] ⁺ .

Preparation of compound 47-5

Compound 47-4 (620 mg, 1.7 mmol) was dissolved in anhydrous DMF (10.0 mL), zinc cyanide (994 mg, 8.5 mmol) was added, and then Pd(PPh ₃ ) ₄ (346 mg, 0.3 mmol) was added. After nitrogen replacement three times, the reaction was carried out at 150°C for 3 hours under microwave. The reaction was complete. The organic phase was poured into water (50 mL) and extracted twice with EA (50 mL). The organic phases were combined, dried and concentrated, and separated and purified by a normal phase silica gel column (EtOAc/PE = 20 - 50%) to obtain 330 mg of the title compound with a yield of 62%. LC-MS (ESI): m/z 313.0 [M+H] ⁺ .

Preparation of compound 47-7

Compound 47-5 (330 mg, 1.05 mmol) was dissolved in anhydrous 1, 4-dioxane (10 mL), and 47-6 (335 mg, 1.26 mmol, CuI (19 mg, 0.1 mmol), and 1, 2-cyclohexanediamine (19 mg, 0.2 mmol) were added. After nitrogen replacement three times, the mixture was reacted at 150 °C for 2 hours. After the reaction was completed, the reaction solution was poured into water and extracted twice with EA (30 mL). The organic phases were combined, dried, concentrated, and separated and purified by normal phase silica gel column (EtOAc/PE = 20 - 40%) to obtain 210 mg of the title compound with a yield of 44%. LC-MS (ESI): m/z 449.2 [M+H] ⁺ .

Preparation of compound 47-8

Dissolve compound 47-7 (210 mg, 0.46 mmol) in THF (10 mL), add concentrated hydrochloric acid (5 ml), react at room temperature for 2 hours, and monitor by TLC until the reaction is complete. Pour the reaction solution into water (30 mL), then extract twice with EA (20 mL), combine the organic phases, dry and concentrate to obtain 180 mg of the crude title compound. Use it directly in the next reaction without purification.

Preparation of compound 47-9

Compound 47-8 (180 mg, crude product) was dissolved in DMF (10.0 mL), cesium carbonate (218 mg, 0.66 mmol) and 2-chloro-4-(chloromethyl)pyrimidine (91 mg, 0.5 mmol) were added, and the mixture was reacted at 50°C for 2 hours. After the reaction, the organic phase was poured into water (30 mL) and extracted twice with EA (20 mL). The organic phases were combined, dried and concentrated, and separated and purified by a normal phase silica gel column (EtOAc/PE = 10 - 40%) to obtain 110 mg of the title compound, with a two-step yield of 44%. LC-MS (ESI): m/z 531.2 [M+H] ⁺ .

Preparation of compound 47

Compound 47-9 (110 mg, 0.20 mmol) was dissolved in DMF (10 mL), and dimethylphosphine oxide (78 mg, 1 mmol), DIEA (129 mg, 1 mmol), Pd ₂ (dba) ₃ (27 mg, 0.03 mmol) and Xantphos (35 mg, 0.06 mmol) were added in sequence. After replacing with nitrogen three times, the reaction was carried out at 120°C in a microwave oven for 2 hours. The reaction was monitored by LCMS until the reaction was complete. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparative method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/L NH ₄ HCO ₃ )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 45 mg of the title compound 47, with a yield of 33%. LC-MS (ESI): m/z 573.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 5.2 Hz, 1H) , 7.74-7.69 (m, 3H) , 7.22-7.20 (m, 2H), 7.07-7.05 (m, 2H) , ³¹ P NMR (162 MHz, DMSO- d6 ) δ 34.04 (s, 1P).

Example 48: Preparation of Compound 48

Synthesis of compound 48-2:

Add compound 48-1 (2.5 g, 16.00 mmol), DMF (10 mL), imidazole (2.20 g, 32.32 mmol), and TBDPSCl (4.83 g, 17.57 mmol, 4.57 mL) to a 100 ml single-necked bottle and stir at room temperature for 3 hours. LCMS showed that the reaction was complete. Add ethyl acetate (200 mL) to dilute the reaction solution, wash with water (100 mL) three times, dry over anhydrous sodium sulfate, filter, and evaporate the filtrate under reduced pressure to obtain 6.8 g of the crude title compound. Use it directly in the next step without purification. LC-MS (ESI): 395.0 [M+H] ⁺ .

Synthesis of compound 48-3:

Add compound 48-2 (6.8 g, 17.23 mmol) and DCM (100 mL) to a 250 mL single-necked bottle, cool to 0°C in an ice-water bath, add m-CPBA (10.50 g, 51.70 mmol, 85% purity) in 4 batches, slowly raise the temperature to room temperature (20 °C) and stir for 16 hours. TLC (PE: EA = 3:1) shows that the reaction is complete. Add saturated sodium carbonate solution (100 ml) to quench the reaction, and extract with ethyl acetate (100 ml) twice. Combine the organic phases, wash once with saturated sodium carbonate solution (30 ml), wash once with water (30 ml), dry over anhydrous sodium sulfate, filter, and evaporate the filtrate under reduced pressure to obtain 6.28 g of the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.93 (d, J = 5.2 Hz, 1H), 7.95 (d, J = 5.2 Hz, 1H), 7.63 -7.66 (m, 4H), 7.44 – 7.48 (m, 2H), 7.37 -7.41 (4, H), 4.92 (s , 2H), 3.30 (s, 3H), 1.15 (s, 9H).

Synthesis of compound 48-4:

Add trimethylphosphine oxide (330.00 mg, 3.58 mmol) and THF (20 mL) to a 100 mL three-necked flask, cool to -60°C with stirring, add n-BuLi (2 M, 4.69 mmol, 2.34 mL) dropwise, and stir at room temperature for 0.5 hours after the addition is complete. Add a solution of compound 48-3 (1 g, 2.34 mmol) in THF (10 mL) dropwise at -60°C, and stir at room temperature for 3 hours after the addition is complete. TLC (PE: EA = 3:1 and EA: MeOH = 3:1) shows that the raw material has reacted completely. Add ammonium chloride solution (50 mL) dropwise at low temperature to quench the reaction, evaporate tetrahydrofuran under reduced pressure, and extract with ethyl acetate (40 mL) twice. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a light yellow liquid. Automatic column purification (EA:MeOH = 1:0 ~ 10:1 ~ 5:1) was performed to obtain 210 mg of the title compound. LC-MS (ESI): 439.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (d, J = 5.2 Hz, H), 7.64 – 7.67 (m, 4H), 7.60 (d, J = 5.2 Hz, 1H), 7.27 -7.47 (m, 6H), 4. 78 (s, 2H), 3.54 (d, J = 16.8 Hz, 2H), 1.53 (d, J = 13.2 Hz, 6H), 1.14 (s, 9H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 41.91 (s, 1P).

Synthesis of compound 48-5:

Add compound 48-4 (210 mg, 478.83 μmol), THF (2 mL), and TBAF (1 M, 1.00 mmol, 1 mL) to a 50 ml single-necked bottle and stir at room temperature (20 °C) for 16 hours. TLC (EA: MeOH = 3:1) showed that the reaction was complete. Evaporate THF under reduced pressure and purify with an automatic column machine (EA: MeOH = 1:0 ~ 10:1) to obtain 157 mg of the title compound. LC-MS (ESI): 201.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.63 (d, J = 5.2 Hz, 1H), 7.44 (d, J = 5.2 Hz, H), 4.74 (s, 2H), 3.59 (d, J = 16.8 Hz, 2H), 1.5 7 (d, J = 13.2 Hz, 6H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 41.76 (s, 1P).

Synthesis of compound 48:

Add compound 48-5 (100 mg, 499.56 μmol), compound 1-6 (174.00 mg, 496.80 μmol), TMAD (260.00 mg, 1.51 mmol) and DCM (4 mL) to a 50 mL single-necked bottle, replace with nitrogen three times, cool to 0°C, add Bu ₃ P (307.80 mg, 1.52 mmol, 380.00 μL) dropwise, warm to room temperature and stir for 16 hours, and monitor the reaction by LCMS. Evaporate under reduced pressure and prepare liquid phase purification to obtain 24.45 mg of the title compound. LC-MS (ESI): 532.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6 ) δ 8.77 (d, J = 5.2 Hz, 1H), 7.64 (s, 1H), 7.57 (s, 1H), 7.46 (d, J = 5.2 Hz, 1H), 7.18 – 7.20 (m, 2H), 6.96 – 6.98 (m, 2H), 5.18 (s, 2H), 4.41 (t, J = 5.2 Hz, 2H), 3.95 (t, J = 5.2 Hz, 2H), 3.52 (d, J = 16 Hz, 2H), 1.62 (s, 6H), 1.46 ( d, J = 13.2 Hz, 6H). ³¹ P NMR (162 MHz, DMSO-d6 ) δ 39.49 (s, 1P).

Example 49: Preparation of Compound 49

Preparation of compound 49-2

Under nitrogen protection, compound 45-1 (600 mg, 1.24 mmol), 49-1 (264.09 mg, 1.24 mmol), cesium carbonate (810.66 mg, 2.49 mmol), BINAP (193.66 mg, 311.01 μmol), Pd(OAc) ₂ (27.93 mg, 124.40 μmol) and dioxane (6 mL) were added to the reaction bottle. The temperature was raised to 70°C and stirred for 16 hours. LCMS detected that the reaction was complete. Water (5 mL) was added to quench the reaction, and then extracted with dichloromethane (5 mL) three times. The organic phases were combined, dried and concentrated to obtain a crude product. The crude product was separated and purified by normal phase silica gel column (EtOAc/PE = 0 - 10%) to obtain 350 mg of the title compound with a yield of 51%. LC-MS (ESI): 544.3 [M+H] ⁺ .

Preparation of compound 49-3

Compound 49-2 (350 mg, 642.78 μmol) was dissolved in DCM (6 mL), TFA (3 mL) was added dropwise to the reaction system at room temperature, and stirred for 2 hours. LCMS detected that the reaction was complete, and the reaction solution was concentrated to dryness to obtain 260 mg of the crude title compound, with a yield of 91%. LC-MS (ESI): 444.0 [M+H] ⁺ .

Preparation of compound 49-4

4-Chloro-2-methylsulfonyl-pyrimidine (260.07 mg, 1.35 mmol), compound 49-3 (150 mg, 337.54 μmol), triethylamine (341.55 mg, 3.38 mmol, 470.78 μL) and THF (2 mL) were added to the reaction bottle. Stir at room temperature for 2 hours. LCMS detected that the reaction was complete. Add water (5 mL), extract with dichloromethane (5 mL) three times, combine the organic phases, dry and concentrate to obtain the crude product. The crude product was separated and purified by normal phase silica gel column (EtOAc/PE = 0 - 30%) to obtain 120 mg of the title compound with a yield of 59%. LC-MS (ESI): 600.0 [M+H] ⁺ .

Preparation of compound 49

Compound 49-4 (60 mg, 99.91 μmol), K ₂ CO ₃ (69.04 mg, 499.54 μmol), dimethylphosphine oxide (39 mg, 499.54 μmol) and acetonitrile (2 mL) were added to the reaction bottle. The reaction was carried out at 80° C. for 16 hours. The reaction was complete as determined by LCMS. Water (5 mL) was added to the reaction system to quench the reaction, and the mixture was extracted three times with ethyl acetate (5 mL). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparation, separation and purification (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-80% acetonitrile in 20 minutes; flow rate: 30 mL/min) to obtain 10 mg of the title compound with a yield of 16%. LC-MS (ESI): 598.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.28 (d, J = 6.0 Hz, 1H), 7.60 (d, J = 2.2 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.04 – 7.07 (d , J = 8.8 Hz, 2H), 6.47 – 6.49 (m, 3H), 4.39 – 4.42 (m, 2H), 4.13 – 4.01 (m, 4H), 3.94 – 3.96 (m, 2H), 3.48 (s, 2H), 3.29 – 3.31 (m, 2H), 2.25(t, J = 6.8 Hz, 2H), 1.65 (d, J = 13.6 Hz, 6H), 1.60 (s, 6H).

Example 50: Preparation of Compound 50

Preparation of compound 50-1

Compound 2, 4-pyrimidine (2 g, 13.42 mol) was dissolved in DMF (80 mL), and NaH (537 mg, 13.42 mol) and compound 4-iodo-1H-imidazole (2.6 g, 13.42 μmol) were added in sequence, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the filtrate was filtered, and water (200 mL) was added to the filtrate, and ethyl acetate (200 mL) was extracted twice, and the organic phase was washed three times with saturated brine (200 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified using a normal phase silica gel chromatography column (EA/PE = 0 - 30%) to obtain 1.3 g of the title compound with a yield of 31%. ¹ H NMR (400 MHz, DMSO- d6 ) δ 8.91 (d, J = 5.6 Hz, 1H), 8.63 (d, J = 1.4 Hz, 1H), 8.27 (d, J = 1.4 Hz, 1H), 7.97 (d, J = 5.6 Hz, 1H).

Preparation of compound 50-2

Compound 45-1 (800 mg, 1.66 mmol) was dissolved in anhydrous dioxane solution (5 mL), and B ₂ Pin ₂ (547 mg, 2.16 mmol), potassium acetate (488 mg, 4.98 mmol), and Pd(dppf)Cl ₂ (361 mg) were added. The atmosphere was replaced with nitrogen, and the reaction system was stirred at 80°C for 36 hours. After the reaction is completed, the system is cooled to room temperature, ethyl acetate is added for dilution (50 mL), and the mixture is washed twice with saturated brine (300 mL) and twice with water (300 mL). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain a crude product. The crude product is purified by medium pressure column chromatography (methanol/dichloromethane (v/v) = 0 ~5%) to obtain 400 mg of the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 – 7.75 (m, 2H), 7.41 (d, J = 2.3 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 7.20 – 7.18 (m, 2H), 4.41 (t, J = 6.2 Hz, 2H), 3.87 (t, J = 6.2 Hz, 2H), 1.66 (s, 6H), 1.34 (s, 12H).

Preparation of compound 50-3

Compound 50-1 (800 mg, 2.61 mmol) was dissolved in 1, 4-dioxane (50 mL) and water (10 mL), and compound 50-2 (1.2 g, 2.61 mmol), potassium carbonate (1.08 g, 7.83 mmol), and Pd(dppf)Cl ₂ (189 mg, 0261 mmol) were added in sequence. The reaction system was replaced with nitrogen three times and stirred at 90°C for 2 hours. After the reaction, the insoluble solid was filtered out, water (10 mL) was added to the filtrate, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 270 mg of the title compound with a yield of 20%. LC-MS (ESI): m/z 512.08 [M+H] ⁺ .

Preparation of compound 50

Compound 50-3 (110 mg, 0.214 mmol) was dissolved in DMF (5.0 mL), and dimethylphosphine oxide (50 mg, 0.643 mmol), DIEA (83 mg, 0.643 mmol), Pd ₂ (dba) ₃ (20 mg, 0.021 mmol) and Xantphos (12 mg, 0.021 mmol) were added in sequence. The reaction system was replaced with nitrogen three times, and the reaction was stirred in a microwave at 120°C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, the insoluble solid was filtered out, water (10 mL) was added to the filtrate, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by preparation separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 50 mg of the title compound 6 with a yield of 42%. LC-MS (ESI): m/z 554.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO - d6 ) δ 9.12 (s, 1H), 8.86 (d, J = 1.3 Hz, 1H), 8.60 (d, J = 1.3 Hz, 1H), 8.05 – 8.08 (m, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 2.3 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.33 (d, J = 8.5 Hz, 2H), 4.43 (t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.2 Hz 2H), 1.85 (d, J = 13.6 Hz, 6H), 1.69 (s, 6H). ³¹ P NMR (162 MHz, DMSO-d6 ) δ 34.85 (s, 1P).

Example 51: Preparation of Compound 51

Preparation of compound 51-1

The compound 2-iodoaniline (1 g, 4.57 mmol) was dissolved in DMF (5 mL), and dimethylphosphine oxide (356 mg, 4.57 mmol), DIEA (1.77 g, 13.70 mmol), Pd ₂ (dba) ₃ (418 mg, 0.456 mmol) and Xantphos (264 mg, 0.456 mmol) were added in sequence. The reaction system was replaced with nitrogen three times and stirred in a microwave at 120°C for 2 hours. After the reaction was completed, the insoluble solid was filtered off, water (50 mL) was added to the filtrate, and the mixture was extracted twice with dichloromethane (30 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by preparation separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 600 mg of the title compound with a yield of 77%. LC-MS (ESI): m/z 170.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.23 - 7.19 (m, 1H), 7.08 - 7.02 (m, 1H), 6.70 - 6.62 (m, 2H), 1.74 (d, J = 13.0 Hz, 6H ). ³¹ P NMR (162 MHz, DMSO-d6 ) δ 42.07 (s, 1P).

Preparation of compound 51-2

Compound 45-1 (1.0 g, 2.1 mmol) and solvent DMF (20 mL) were added to the autoclave, stirred to dissolve, and then triethylsilane (366 mg, 3.2 mmol), triethylamine (425 mg, 4.2 mmol) and Pd(dppf)Cl ₂ (146 mg, 0.2 mmol) were added. The reaction system was replaced with carbon monoxide four times (pressure 2.0 MPa), and heated to 80°C under 2.0 MPa carbon monoxide pressure and stirred for 16 hours. TLC detection showed that the reaction was complete. After the reaction system was cooled to room temperature, water (60 mL) was added, and the mixture was extracted three times with ethyl acetate (100 mL). The organic phases were combined, washed three times with saturated brine (150 mL), and dried over anhydrous sodium sulfate. The concentrated residue was purified by column chromatography (ethyl acetate/petroleum ether = 0 - 30%) to obtain 680 mg of the title compound with a yield of 75.6%. ¹ H NMR (400 MHz, DMSO-d6 ) δ 9.98 (s, 1H), 7.84 – 7.87 (m, 2H), 7.69 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.48 – 7.50 (m, 2H), 4.43 (t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.2 Hz, 2H), 1.70 (s, 6H).

Preparation of compound 51

Compound 51-2 (100 mg, 0.276 mmol) was dissolved in MeOH (3.0 mL), and compound 51-1 (47 mg, 0.276 mmol) was added. After stirring at room temperature for 1 hour, sodium acetate borohydride (58 mg, 0276 mmol) was added. The reaction system was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 20 mg of the title compound with a yield of 14%. LC-MS (ESI): m/z 515.5 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d) δ 7.64 (s, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 7.25 – 7.18 (m, 3H), 7.06 – 6.99 (m, 3H), 6.58 (t, J = 7.4 Hz, 1H), 6.51 – 6.54 (m, 1H), 4.34 (t, J = 6.0 Hz, 2H), 4.29 (s, 2H), 3.80 (t, J = 6.0 Hz, 2H), 1.72 (d , J = 12.8 Hz, 6H), 1.57 (s, 6H). ³¹ P NMR (162 MHz, DMSO-d6 ) δ 43.94 (s, 1P).

Example 52: Preparation of Compound 52

Preparation of compound 52-2

Compound 52-1 (1 g, 5.79 mmol) and triethylamine (0.645 g, 6.37 mmol) were added to a three-necked flask, nitrogen was replaced, and THF (15 mL) was added. Isobutyl chloroformate (0.870 g, 6.37 mmol) was added dropwise at 0°C, and the reaction was continued for 30 min after the addition was completed. The reaction system was quenched with saturated brine (15 mL), extracted three times with ethyl acetate (15 mL), and the organic phases were combined, dried, and concentrated to obtain a colorless oil. Dichloromethane (15 mL) and water (3 mL) were added, cooled to 0°C, and sodium borohydride (0.438 g, 11.59 mmol) was added in batches. After the reaction system was stirred at room temperature for 2 hours, the reaction was completed by LCMS detection, silica gel was added to stir the sample, and the product was separated and purified by normal phase silica gel column (MeOH/DCM = 0 - 5%) to obtain 0.4 g of the title compound with a yield of 43%. LC-MS (ESI): m/z 159.0 [M+H] ⁺ .

Preparation of compound 52-3

Dissolve compound 52-2 (400 mg, 2.52 mmol) in DMF solution (1 mL), add dimethylphosphine oxide (590 mg, 7.57 mmol) and DIEA (590 mg, 7.57 mmol). Stir the reaction system at 150°C for 1 hour. After the reaction system is cooled, filter, add appropriate amount of lyophilized water to the filtrate, and separate and purify the residue by normal phase silica gel column (MeOH/DCM = 0 - 5%) to obtain the title compound (50 mg) as a yellow solid with a yield of 9%. LC-MS (ESI): m/z 201.4 [M+H] ⁺ .

Preparation of compound 52

Compound 52-3 (50 mg, 0.249 mmol), compound 1-6 (96 mg, 0.274 mmol) and Bu ₃ P (126 mg, 0.624 mmol) were added to a three-necked flask, and dichloromethane (10 mL) was added. Under nitrogen protection, TMAD (624 mg, 0.624 mmol) was added under ice-water bath, and the reaction system was stirred at room temperature for 16 hours. The reaction solution was filtered, and the crude filtrate was purified by preparation separation (preparation method: chromatographic column: Agilent 10 Prep-C18 250x21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% TFA)-acetonitrile; mobile phase acetonitrile ratio 50%-70% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 10 mg of the title compound with a yield of 7%. LC-MS (ESI): m/z 532.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.69 (s, 1H), 7.44 (d, J = 2.4 Hz, 1H) , 7.29 (d, J = 2.4 Hz, 1H) , 7.08 – 7.10 (m, 2H), ^{6 3} 1P NMR (162 MHz, DMSO-d6 ) δ 35.33 (s, 1P).

Example 53: Preparation of Compound 53

Preparation of compound 53-2

Compound 53-1 (500 mg, 2.48 mmol), compound 1-6 (868 mg, 2.48 mmol) and triphenylphosphine (974 mg, 3.72 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL), and diethyl azodicarboxylate (863 mg, 4.96 mmol) was slowly added dropwise at room temperature, and the mixture was reacted at 50°C for 4 hours. After the reaction was completed by LCMS tracking, water (20 mL) was added to quench the reaction, and the reaction system was extracted twice with EtOAc (50 mL×2), the organic phases were combined, dried and concentrated, and separated and purified by normal phase silica gel column (EtOAc/PE = 0-30%) to obtain 420 mg of the title compound 53-2 with a yield of 31.8%. LC-MS (ESI): m/z 477.0 [M-56] ⁺ .

Preparation of compound 53-3

Dissolve compound 53-2 (420 mg, 0.78 mmol) in DCM (10 mL), add trifluoroacetic acid (10 mL), and stir at room temperature for 1 hour. After the reaction, combine the organic phases, dry and concentrate to obtain the crude title compound 53-3 (580 mg). It was used directly in the next step without purification. LC-MS (ESI): 433.0 [M+H] ⁺ .

Preparation of compound 53-4

The crude compound 53-3 (580 mg) was dissolved in anhydrous methanol (10 mL), and DIPEA (516 mg, 4 mmol) was added. After stirring at 0°C for 5 minutes, compound 2, 4-dichloropyrimidine (325 mg, 2.2 mmol) was added, and the temperature was raised to 25°C for 1 hour. After the reaction was completed, saturated ammonium chloride solution (10 mL) was added to quench the reaction, and ethyl acetate (30 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by normal phase silica gel column (EtOAc/PE = 0 - 50%) to obtain 150 mg of the title compound 53-4, with a two-step yield of 35%. LC-MS (ESI): 544.9 [M+H] ⁺ .

Preparation of compound 53

Compound 53-4 (100 mg, 0.18 mmol) was dissolved in DMF (10.0 mL), and dimethylphosphine oxide (140 mg, 1.8 mmol), triethylamine (182 mg, 1.8 mmol), Pd ₂ (dba) ₃ (27 mg, 0.03 mmol) and Xantphos (35 mg, 0.06 mmol) were added in sequence. The mixture was replaced with nitrogen three times and then reacted at 100°C in a microwave oven for 12 hours. After the reaction was completed by LCMS tracking, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/L NH ₄ HCO ₃ )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 20 mg of the title compound 53 with a yield of 18.8%. LC-MS (ESI): m/z 586.8 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.30 – 8.28 (m, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.18 – 7.15 ( m, 2H), 6.97 – 6.93 (m, 3H), 4.66 – 4.65 (m, 1H), 4.41 (t, J = 5.2 Hz, 2H), 4.07 – 3.99 (m, 2H), 3.96 (t, J = 5.2 Hz, 2H), 3.53-3.34 (m, 2H ), 1.96 – 2.03 (m, 2H), 1.69 (d, J = 13.2 Hz, 6H), 1.63 (s, 6H), 1.62-1.57 (m, 2H). ³¹ P NMR (162 MHz, DMSO- d6 ) δ 33.42 (s, 1P).

Example 54: Preparation of Compound 54

Preparation of compound 54-2

Compound 1-6 (250 mg, 0.71 mmol) was dissolved in DMF (5 mL), and then compound 54-1 (213 mg, 0.85 mmol) and cesium carbonate (326 mg, 1.06 mmol) were added and reacted at 50°C for 4 hours. After the reaction was complete as monitored by LCMS, water (20 mL) was added to quench the reaction. The reaction system was extracted twice with EtOAc (50 mL), and the organic phases were combined, dried and concentrated, and separated and purified by normal phase silica gel column (EtOAc/PE = 0 - 30%) to obtain 160 mg of the title compound 54-2, with a yield of 43.5%. LC-MS (ESI): m/z 463.0 [M-56] ⁺ .

Preparation of compound 54-3

Dissolve compound 54-2 (160 mg, 0.30 mmol) in DCM (10 mL), add trifluoroacetic acid (8 mL), and stir at room temperature for 1 hour. After the reaction, combine the organic phases, dry and concentrate to obtain 180 mg of the crude title compound 54-3. Use it directly in the next reaction without purification. LC-MS (ESI): 419.0 [M+H] ⁺ .

Preparation of compound 54-5

The crude compound 54-3 (180 mg) was dissolved in anhydrous methanol (10 mL), and DIPEA (516 mg, 4 mmol) was added. After stirring at 0°C for 5 minutes, compound 2, 4-dichloropyrimidine (300 mg, 2.0 mmol) was added, and the temperature was raised to 25°C for 1 hour. After the reaction was completed, saturated ammonium chloride solution (10 mL) was added to quench the reaction, and ethyl acetate (30 mL) was added to extract twice. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified on a normal phase silica gel column (EtOAc/PE = 0 - 50%) to obtain 120 mg of the title compound 54-5, with a two-step yield of 75%. LC-MS (ESI): 531.0 [M+H] ⁺ .

Preparation of compound 54

Compound 54-5 (100 mg, 0.19 mmol) was dissolved in DMF (10 mL), and dimethylphosphine oxide (140 mg, 1.8 mmol), triethylamine (182 mg, 1.8 mmol), Pd ₂ (dba) ₃ (27 mg, 0.03 mmol) and Xantphos (35 mg, 0.06 mmol) were added in sequence. After replacing with nitrogen three times, the mixture was reacted at 120°C in a microwave oven for 12 hours. The reaction was monitored by LCMS until completion. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparative method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/L NH ₄ HCO ₃ )-acetonitrile; mobile phase acetonitrile ratio 35%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 4.67 mg of the title compound 54, with a yield of 4.29%. LC-MS (ESI): m/z 573.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.26 – 8.27 (m, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.18 – 7.15 ( m, 2H), 6.91-6.88 (m, 2H), 6.51 – 6.49 (m, 1H), 4.41 (t, J = 5.2 Hz, 2H), 4.23 – 4.18 (m, 4H), 3.95 (t, J = 5.2 Hz, 2H), 3.89 – 3.93 (m, 2H ), 2.03-1.96 (m, 1H), 1.64 (d, J = 13.6 Hz, 6H), 1.62 (s, 6H). ³¹ P NMR (162 MHz, DMSO- d6 ) δ 33.45 (s, 1P).

Example 55: Preparation of Compound 55

Preparation of compound 55-2

Compound 31-2 (1.83 g, 6.20 mmol) was dissolved in 1,4-dioxane (20.0 mL), and 5-methoxy-2-methylindole (1 g, 6.2 mmol), cesium carbonate (4.04 g, 10.87 mmol), tris(dibenzylideneacetone)dipalladium (498 mg, 0.54 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (628 mg, 12.41 mmol) were added in sequence. The reaction system was replaced with nitrogen three times, and the reaction was stirred at 110°C for 12 hours. After the reaction, the insoluble solid was filtered out, water (20 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (20 mL) twice. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by normal phase silica gel chromatography (EA/PE = 0 ~ 30%) to obtain 500 mg of the title compound 55-2, with a yield of 21%. LC-MS (ESI): m/z 375.2 [M+H] ⁺ .

Preparation of compound 55-3

Compound 55-2 (250 mg, 0.666 mmol) was dissolved in dichloromethane (15 mL). Boron tribromide (1.11 g, 4.43 mmol, 17% DCM solution) was added dropwise at -60°C under nitrogen protection. After the addition, the mixture was reacted at -5°C for 2 hours. After the reaction was completed by LCMS monitoring, water (20 mL) was added to quench the mixture. The mixture was extracted with dichloromethane (20 mL) twice. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by normal phase silica gel chromatography (EA/PE = 0 ~ 30%) to obtain 150 mg of the title compound 55-3 with a yield of 62%. LC-MS (ESI): m/z 361.2 [M+H] ⁺ .

Preparation of compound 55-4

Compound 55-3 (200 mg, 0.55 mmol) was dissolved in DMF (2 mL), and potassium carbonate (229 mg, 1.66 mmol) was added under stirring. After reacting for 5 minutes, 2-chloro-4-(chloromethyl)pyrimidine (135 mg, 0.830 mmol) was added and reacted at 80°C for 4 hours. LCMS monitored the reaction until it was complete, and the reaction solution was poured into a saturated ammonium chloride solution (20 mL). The mixture was extracted twice with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by normal phase silica gel chromatography (EA/PE = 0 ~ 30%) to obtain 135 mg of the title compound 55-4 with a yield of 50%. LC-MS (ESI): m/z 487.0 [M+H] ⁺ .

Preparation of compound 55

Compound 55-4 (120 mg, 0.246 mmol) was dissolved in N , N -dimethylformamide (3.0 mL), and dimethylphosphine oxide (58 mg, 0.738 mmol), N , N -diisopropylethylamine (95 mg, 0.738 mmol), tris(dibenzylideneacetone)dipalladium (22 mg, 0.024 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (28 mg, 0.049 mmol) were added in sequence. After replacing the atmosphere with nitrogen three times, the reaction was carried out at 120°C in a sealed tube for 3 hours. The reaction was monitored by LCMS until completion. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure. The crude product was purified by preparative separation (preparative method: chromatographic column: Welch Xtimate C18 250 x 21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/L NH ₄ HCO ₃ )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 35 mg of the title compound 55, with a yield of 27%. LC-MS (ESI): m/z 529.0 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.86 (s, 1H), 7.71 (s, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.51 (d, J = 2.5 Hz, 1H), 7.05 (d, J = 2.3 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.87 (dd, J = 9.0, 2.3 Hz, 1H), 6.35 (s, 1H), 5.29 (s, 2H), 4.57 (t, J = 6.0 Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 2.30 (s, 3H), 1.91 (d, J = 12.9 Hz, 6H).

Example 56: Preparation of Compound 56

Preparation of compound 56-1

Compound 53-3 (350 mg, 0.810 mmol) and tetrahydrofuran (5 mL) were added to a single-necked bottle, and N , N -diisopropylethylamine (209 mg, 1.62 mmol), HATU (615 mg, 1.62 mmol), and 2-chloropyrimidin-4-ylcarboxylic acid (134 mg, 0.97 mmol) were added under stirring, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, 10 mL of saturated sodium chloride aqueous solution was added to the reaction system, and the mixture was extracted with EtOAc (10 mL) three times. The organic phases were combined, dried, concentrated, and the crude product was obtained, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-30%) to obtain 390 mg of the title compound 56-1. LC-MS (ESI): 573.2 [M+H] ⁺ .

Preparation of compound 56

Compound 56-1 (120 mg, 217 umol) was dissolved in N , N -dimethylformamide (2.0 mL), and dimethylphosphine oxide (67.6 mg, 868 mmol), triethylamine (55 mg, 542 umol), tri(dibenzylideneacetone)dipalladium (27 mg, 30 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (18 mg, 30 mmol) were added in sequence. The atmosphere was replaced with nitrogen three times, and the reaction system was stirred in a microwave at 120°C for 2 hours. After the reaction was completed, the reaction system was filtered and extracted with dichloromethane (20 mL) three times. The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparation separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 min; flow rate: 30 mL/min) to obtain 23.4 mg of the title compound 56. LC-MS (ESI): m/z 615.2[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d 6) δ 9.06 (d, J = 5.2 Hz, 1H), 7.30 – 7.75 (m, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 2 .4 Hz, 1H), 7.0 – 7.10 (m, 2H), 6.85 – 6.88 (m, 2H), 4.59 – 4.61 (m, 1H), 4.34 (d, J = 5.2 Hz, 2H), 3.88 (d, J = 5.2 Hz, 2H), 3.45 – 3.50 (m, 2H), 3.24 – 3.28 (m, 1H), 2.06-1.93 (m, 1H), 1.85 – 2.01 (m, 2H), 1.70 (d, J = 13.8 Hz, 6H), 1.59 – 1.63 (m, 2H), 1.56 (s, 6H). ³¹ P NMR (162 MHz , DMSO- d6 ) δ 34.46 (s, 1P).

Example 57: Preparation of Compound 57

Preparation of compound 57-2

Compound 1-6 (400 mg, 1.14 mmol), 57-1 (231 mg, 1.018 mmol), and tetrahydrofuran (6 mL) were added to a single-necked bottle, and triphenylphosphine (598 mg, 2.28 mmol) was added under stirring. The reaction system was replaced with nitrogen three times, and diethyl azodicarboxylate (397 mg, 2.28 mmol) was added dropwise under ice bath. After 30 minutes, the reaction was stirred at room temperature for 8 hours. After the reaction was completed, 13 mL of saturated sodium chloride aqueous solution was added to the reaction system. Extracted three times with ethyl acetate (15 mL), the organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 25%) to obtain 265 mg of the title compound 57-2. LC-MS (ESI): 559.2 [M+H] ⁺ .

Preparation of compound 57-3 Compound 57-2 (265 mg, 475 μmol) and dichloromethane (4 mL) were added to a single-necked bottle, trifluoroacetic acid (0.5 mL) was added dropwise under ice bath, stirred for 30 minutes, and then heated to room temperature for stirring and reacting for 2 hours. After the reaction was completed, 260 mg of the title compound 57-3 was obtained by concentration. LC-MS (ESI): 459.3 [M+H] ⁺ .

Preparation of compound 57-4

Compound 57-3 (260 mg, 453 μmol) and dichloromethane (4 mL) were added to a single-necked bottle, and triethylamine (92 mg, 906 μmol) and 4-chloro-2-methylsulfonylpyrimidine (95 mg, 495 μmol) were added under stirring. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, 15 mL of saturated sodium chloride aqueous solution was added to the reaction system, and the system was extracted with EtOAc (8 mL) for 3 times. The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0 - 50%) to obtain 248 mg of the title compound 57-4. LC-MS (ESI): 615.3 [M+H] ⁺ .

Preparation of compound 57

Compound 57-4 (160 mg, 260 μmol) was dissolved in acetonitrile (5.0 mL), and dimethylphosphine oxide (81.1 mg, 1.04 mmol) and cesium carbonate (169 mg, 520 μmol) were added in sequence. The atmosphere was replaced with nitrogen three times, and the reaction system was stirred at 85°C for 2 hours. After the reaction was completed, the reaction system was filtered and extracted with dichloromethane (20 mL) three times. The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparation separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 25%-45% acetonitrile in 12 min; flow rate: 30 mL/min) to obtain 42 mg of the title compound 57. LC-MS (ESI): m/z 613.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.31 (s, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.15 – 7.18 (m, 2H) , 6.82 – 6.86 (m, 3H), 4.43 – 4.93 (m, 2H), 4.61 – 4.63 (m, 1H), 4.42 (t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.2 Hz, 2H), 2.21 – 2.23 (m, 2H), 2. 00 – 2.21 (m, 4H), 1.87 – 1.93 (m, 2H), 1.67 (d, J = 13.3 Hz, 6H), 1.64 (s, 6H). ³¹ P NMR (162 MHz, DMSO- d6 ) δ 33.37 (s, 1P).

Example 58: Preparation of Compound 58

Preparation of compound 58-2

Dissolve the compounds triethylamine (3.03 g, 30 mmol) and 2,4-dichloropyrimidine (2.96 g, 20 mmol) in anhydrous methanol (10 mL), cool to 0°C, add 58-1 (2.0 g, 10.7 mmol) in batches, and react at room temperature for 2 hours. After the reaction is complete as monitored by LCMS, add water (20 mL), extract the reaction system twice with EtOAc (50 mL), combine the organic phases, dry and concentrate, and separate and purify by normal phase silica gel column (EtOAc/PE = 0-30%) to obtain 1.3 g of the title compound 58-2. LC-MS (ESI): m/z 243.8 [M+H- t Bu] ⁺ .

Preparation of compound 58-3

Dissolve compound 58-2 (600 mg, 2.0 mmol) in DCM (10 mL), add trifluoroacetic acid (10 mL), and stir at room temperature for 1 hour. After the reaction of the raw material is completed, concentrate to obtain the title compound 58-3 (620 mg), and the crude product is directly used for the next step. LC-MS (ESI): m/z 199.2 [M+1] ⁺ .

Preparation of compound 58-4

Compound 45-1 (1.2 g, 2.28 mmol) was dissolved in anhydrous methanol (10.0 mL), and DMSO (10 mL), triethylamine (1.01 g, 10 mmol), sodium acetate (100 mg, 0.44 mmol), 1,3-diphenylphosphinopropane (181 mg, 0.44 mmol), and dicobalt octacarbonyl (3.42 g, 10 mmol) were added. After nitrogen replacement three times, the temperature was raised to 75°C and the reaction was carried out for 12 hours. After the reaction was completed, saturated sodium chloride solution (100.0 mL) was added, and ethyl acetate (50.0 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by a normal phase silica gel column (EtOAc/PE = 0-50%) to obtain 340 mg of the title compound 58-4. LC-MS (ESI): 392.0 [M+H] ⁺ .

Preparation of compound 58-5

Compound 58-4 (340 mg, 0.86 mmol) was dissolved in a mixture of methanol (10.0 mL) and water, and then NaOH (344 mg, 8.6 mmol) was added. The reaction was allowed to proceed at room temperature for 2 hours. TLC detection (PE:EA = 3:1) indicated that the reaction of the raw material was complete. The reaction solution was adjusted to pH 5 with dilute hydrochloric acid (1 mol/L), extracted with ethyl acetate (50 ml), and the organic phase was concentrated to obtain 290 mg of the title compound 58-5.

Preparation of compound 58-6

Compound 58-5 (290 mg, 0.76 mmol) was dissolved in anhydrous DMF (10.0 mL), and then 58-3 (198 mg, 1 mmol) DIEA (303 mg, 2.2 mmol), HATU (418 mg, 1.1 mmol) were added. The reaction mixture was reacted at room temperature for 2 hours. The mixture was poured into water (100 mL), extracted with ethyl acetate (50 ml), the organic phase was concentrated, and column chromatography was used to separate 230 mg of the title compound 58-6. LC-MS (ESI): 558.2 [M+H] ⁺ .

Preparation of compound 58

Compound 58-6 (230 mg, 0.41 mmol) was dissolved in DMF (10.0 mL), and dimethylphosphine oxide (140 mg, 1.8 mmol), DIEA (138 mg, 1 mmol), Pd ₂ (dba) ₃ (27 mg, 0.03 mmol) and Xantphos (35 mg, 0.06 mmol) were added in sequence. The atmosphere was replaced with nitrogen three times and then reacted at 120°C in a microwave oven for 5 hours. After the reaction was completed by LCMS tracking, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparative method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/L NH ₄ HCO ₃ )-acetonitrile; mobile phase acetonitrile ratio 45%-65% in 12 min; flow rate 30 mL/min) to obtain 57.5 mg of the title compound 58. LC-MS (ESI): m/z 598.8 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.26 (d, J = 6.4 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.33 – 7. 35 (m, 2H), 7.26 – 7.28 (m, 2H), 6.83 – 6.85 (m, 1H), 4.36 (t, J = 5.2 Hz ,2H), 3.89 (t, J = 5.2 Hz 2H), 3.53 – 3.74 (m, 6H), 3.36 – 3.48 (m, 2H), 1.61 (s, 6H), 1.60 (d, J = 16.4 Hz, 6H). ³¹ P NMR (162 MHz, DMSO- d6 ) δ33.59 (s, 1P).

Example 59: Preparation of Compound 59

Preparation of compound 59-2

Under nitrogen protection, compound 45-1 (500 mg, 1.04 mmol), compound 59-1 (467 mg, 2.07 mmol), TEA (1.05 g, 10.37 mmol, 1.45 mL), Pd(dppf)Cl ₂ (75.86 mg, 103.67 μmol, 80.36 μL), Co(CO) ₈ (354.50 mg, 1.04 mmol) and DMF (5 mL) were added to the reaction bottle and stirred at 80°C for 5 hours. Water (10 mL) was added, and then extracted with dichloromethane (10 mL) for 3 times, and the organic phases were combined, dried and concentrated to obtain a crude product. The crude product was separated and purified by normal phase silica gel column (EtOAc/PE = 0-100%) to obtain 90 mg of the title compound 59-2. LC-MS (ESI): 585.2 [M+H] ⁺ .

Preparation of compound 59-3

Compound 59-2 (90 mg, 153.70 μmol), m-CPBA (79.57 mg, 461.11 μmol) and DCM (3 mL) were added to the reaction bottle and stirred at room temperature for 2 hours. Saturated sodium carbonate aqueous solution (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic phases were combined, dried and concentrated to obtain a crude product. The crude product was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-100%) to obtain 90 mg of the title compound 59-3. LC-MS (ESI): 617.0 [M+H] ⁺ .

Preparation of compound 59

Dimethylphosphine oxide (56.87 mg, 728.70 μmol), compound 59-3 (150 mg, 242.90 μmol), Cs ₂ CO ₃ (237.42 mg, 728.70 μmol), and acetonitrile (1 mL) were added to the reaction bottle. Stirred at 80°C for 3 hours. Filtered and concentrated to obtain a crude product. The crude product was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 20%-90% acetonitrile in 40 min; flow rate: 30 mL/min) to obtain 12 mg of the title compound 59. LC-MS (ESI): 615.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.68 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.36 – 7.39 (m, 2H), 7.26 – 7.35 (m, 2H), 7.04 – 7.06 (m, 1H), 5.38 – 5.42 (m, 1H), 4.43 (t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.2 Hz, 2H), 3.37 – 3.67 (m, 4H), 2.00 – 2. 08 (m, 2H), 1.72 – 1.75 (m, 8H), 1.68 (s, 6H). ³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 34.09 (s, 1P).

Test Example 1: Mouse Pharmacokinetics Test

Dosage: The dosing solution was prepared on the day. Weigh 2 mg of the compound and dissolve it with dosing type A: 3% DMSO + 1.5% Tween80 + 95.5% Saline to prepare an intravenous dosing solution with a concentration of 0.1 mg/mL; weigh 2 mg of the compound and dissolve it with dosing type B: 3% DMSO + 1.5% Tween80 + 95.5% Saline to obtain a 0.5 mg/mL oral dosing solution; weigh 3 mg of the compound and dissolve it with dosing type C: 5% DMSO + 5% NMP + 10% Solutol + 80% PEG400 to obtain a 3.0 mg/mL oral dosing solution.

Six healthy male naïve ICR mice weighing 25-30 g were divided into two groups (intravenous and oral groups), three mice in each group, and given a single dose. After three days of adaptive feeding, the mice were fasted overnight (10-12 h) before the experiment. They were allowed to drink water freely during the experiment and resumed eating 4 h after drug administration. After intravenous and oral administration, the timing began. Blood was collected through the orbital venous train at the planned time points (IV&PO 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24h). At each point, 30μL of whole blood was collected into a 1.5mL EP tube containing sodium heparin. The collected whole blood was placed on a vortexer and shaken twice to mix, placed on wet ice, and centrifuged at 8000 rpm for 5min at 4℃ within 1h. The supernatant plasma was taken and stored in a -80℃ refrigerator until processing and analysis. Table 1: Pharmacokinetics in mice Compound No. How to give medicine Dosage type C ₀ (IV) or C _max (PO) (ng/mL) CL (mL/min/kg, IV) AUC _i (ng*hr/mL) T _1/2 (hr) T _max (hr, PO) Bioavailability (%) 1 IV-0.5mpk A 2071 1.37 6128 1.77 / / PO-5mpk B 10795 / 37510 1.76 0.42 61% PO-30mpk C 41600 / 281021 2.1 1.7 76% 33 PO-30mpk C 34850 / 380653 3.2 2.0 / 41 PO-30mpk C 15888 / 72817 2.5 1.7 / 53 IV-0.5mpk A / 4.6 1841 5.1 / / PO-30mpk C 20900 / 209653 2.9 3.3 190% 57 PO-30mpk C 10849 / 1097345 68.8 6.7 /

Test Example 2: Pharmacokinetics test in rats

Dosage: The dosing solution was prepared on the day of administration. Weigh 2 mg of the compound and dissolve it in 3% DMSO + 1.5% Tween80 + 95.5% Saline to prepare a 0.1 mg/mL intravenous dosing solution; weigh 6 mg of the compound and dissolve it in 3% DMSO + 1.5% Tween80 + 95.5% Saline to obtain a 0.5 mg/mL oral dosing solution.

Six healthy male SD rats weighing 220-300 g were divided into two groups (intravenous and oral groups), three rats in each group, and given a single dose. After three days of adaptive feeding, the rats were fasted overnight (10-12 h) before the experiment, and were allowed to drink water freely during the experiment. They were allowed to eat 4 h after the drug was administered. After intravenous and oral administration, the timing began. Blood was collected through the orbital venous system at the planned time points (IV&PO 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24h). 150μL of whole blood was collected at each point and placed in an EP tube containing sodium heparin. The collected whole blood was placed on a vortexer and mixed twice, placed on wet ice, and centrifuged at 8000 rpm for 5min at 4℃ within 1h. The supernatant plasma was taken and stored in a -80℃ refrigerator until processing and analysis. Table 2: Pharmacokinetics in rats Compound No. How to give medicine C ₀ (IV) or C _max (PO) (ng/mL) CL (mL/min/kg, IV) AUC _i (ng*hr/mL) T _1/2 (hr) T _max (hr, PO) Bioavailability (%) 1 IV-0.5mpk 1025 2.78 3038 2.12 / / PO-5mpk 4380 / 29050 2.39 1.0 96%

Test Example 3: Cell proliferation inhibition test of LNCaP cells

1. Adenocarcinoma cell line LNCaP was purchased from ATCC. The cell culture medium was RPMI-1640 + 10% FBS. The cells were cultured at 37 ℃, 100% relative humidity, and 5% CO ₂ in an incubator.

2. Collect cells in logarithmic growth phase one day, count them, resuspend the cells in RPMI-1640 medium without phenol red containing 10% CD-FBS, adjust the cell concentration to the appropriate concentration (determined according to the results of the cell density optimization test), inoculate 96-well plates, add 100μl of cell suspension, and make the cell number 3000/well. Incubate the cells in a 37℃, 5% _CO2 incubator for 24 hours.

3. On the second day, different concentrations of the test compound were added. After 1 hour, 0.2 nM DHT was added and the cells were incubated in a 37°C, 5% CO ₂ incubator for 4 days.

4. After the incubation, add CellTiter-Glo assay reagent in an amount equal to the volume of culture medium to each well, shake and mix for 5 minutes, incubate at room temperature for 10 minutes, and read using a PerkinElmer EnVision microplate reader.

5. Calculate the inhibition rate of drug on the growth of each cell according to the following formula: Cell growth inhibition rate % = [(Ac-As)/(Ac-Ab)] × 100% As: OA of sample (cells + test compound) Ac: OA of normal growth cell control (cells + DMSO) Ab: OA of blank control (culture medium + DMSO) Use Graphpad Prism 8 software and the calculation formula XY-analysis/Nonlinear regression (curve fit)/Dose response-Inhibition/ log (inhibitor) vs. normalized response-Variable slope to perform _IC50 curve fitting and calculate the _IC50 value.

The results showed that the compound of the present invention exhibited good cell activity in the LNCaP cell proliferation inhibition experiment.

In the description of this specification, reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily need to be directed to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in an appropriate manner. In addition, in the absence of mutual contradiction, a person having ordinary knowledge in the technical field to which the present invention belongs may combine and combine different embodiments or examples described in this specification and the features of different embodiments or examples.

Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and cannot be understood as limitations of the present invention. A person having ordinary knowledge in the technical field to which the present invention belongs can change, modify, replace and modify the above embodiments within the scope of the present invention.

without

without

Claims (23)

A compound represented by formula (I), its optical isomers and pharmaceutically acceptable salts thereof, wherein R ₁ and R ₂ are independently selected from H, OH, NH ₂ , C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted by 1, ₂ or 3 R; or, R ₁ and R ₂ are connected together to form a 4-8 membered ring, and the 4-8 membered ring is optionally substituted by 1, 2 or 3 R; R ₃ , R ₄ and R ₅ are independently selected from H, CN, F, Cl, Br, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 alkyl-O-, C _1-6 alkyl-S-, C _{1-6 alkyl-NH-, C 2-6 alkenyl} -O-, C _2-6 alkenyl-S-, C _2-6 alkenyl-NH-, C _3-6 cycloalkyl-O-, C _3-6 cycloalkyl-S-, C _3-6 cycloalkyl-NH-, 4-6 membered heterocycloalkyl-O-, 4-6 membered heterocycloalkyl-S- or 4-6 membered heterocycloalkyl-NH-, the C _1-6 alkyl, C 1-6 C _1-6 alkyl-O-, C _1-6 alkyl-S-, C _1-6 alkyl-NH-, C _2-6 alkenyl-O-, C _2-6 alkenyl-S-, C _2-6 alkenyl-NH-, C _3-6 cycloalkyl-O-, C _3-6 cycloalkyl-S-, C _3-6 cycloalkyl-NH-, 4-6 membered heterocycloalkyl-O-, 4-6 membered heterocycloalkyl-S- and 4-6 membered heterocycloalkyl-NH- are optionally substituted by 1, 2 or 3 R; R ₆ and R ₇ are independently selected from H, CN, F, Cl, Br, OH, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C wherein the C _1-6 heteroalkyl group, C _3-6 cycloalkyl group, C _6-10 aryl group, _5-10 membered heteroaryl group, C _1-6 heteroalkyl group and 3-10 membered heterocycloalkyl group are optionally substituted by 1, 2 or 3 R groups; m and n are independently selected from 0, 1, 2 or 3; Y is selected from O or S; L ₁ is selected from a single bond, NH, O, CH ₂ , CH ₂ CH ₂ or OCH ₂ , wherein CH ₂ , CH ₂ CH ₂ and OCH ₂ are optionally substituted by 1 or 2 R groups; L ₂ and L ₃ are independently selected from -(CR ₈ R ₉ )x-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O) ₂ -, -NR ₁₀ -, -OR ₁₁ - or 5-10 membered heterocycloalkyl, the 5-10 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; L ₄ is selected from -(CR ₈ R ₉ )x-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O) ₂ -, -NR ₁₀ -, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, the C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R; R ₈ and R ₉ are independently selected from H, CN, F, Cl, Br, OH, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, _5-10 membered heteroaryl, C _1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R; or R ₈ and R ₉ are linked together to form a C _4-8 cycloalkyl or 4-8 membered heterocycloalkyl, wherein the C _4-8 cycloalkyl and 4-8 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R; R ₁₀ is selected from H or C _1-6 alkyl, C 3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C _3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C _1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C _1-6 alkyl, C C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R; R ₁₁ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 heteroalkyl or 3-10 membered heterocycloalkyl, and the C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R; x is selected from 0, 1, 2 or 3; Ring A is selected from phenyl or 5-10 membered heteroaryl; Ring B and Ring C are independently selected from phenyl, 5-10 membered heteroaryl, benzo C _5-6 cycloalkyl, benzo 5-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C _5-6 cycloalkyl or 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl; R are independently selected from H, halogen, =O, OH, NH ₂ , CN, , C _1-6 alkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, the C _1-6 alkyl, -C _1-6 alkyl-OH, C _3-6 heteroalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _{1-6 alkyl-C(=O)-, C 1-6 alkyl} -C(=O)O-, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-C(=O)NH-, C _1-6 alkyl-NH-C(=O)-, C _1-6 alkyl-S(=O) ₂ -, C _1-6 alkyl-S(=O) ₂ NH-, C _1-6 alkyl-NHS(=O) ₂ -, C _1-6 alkoxy, C _1-6 alkylthio and C _1-6 alkylamino groups are optionally substituted by 1, 2 or 3 R';R' is selected from F, Cl, Br, I, OH, _NH2 , CN, , , CH ₃ , CH ₂ F, CHF ₂ and CF ₃ ; the above heteroaryl, heteroalkyl or heterocycloalkyl contains 1, 2 or 3 heteroatoms or heteroatomic groups independently selected from O, NH, S, C(=O), C(=O)O, C(=O)NH, S(=O), S(=O) ₂ , S(=O) ₂ NH and N; and the compound of formula (I) is not selected from: . The compound as claimed in claim 1, its optical isomers and pharmaceutically acceptable salts thereof, wherein R is independently selected from H, halogen, OH, NH ₂ , CN, , =O, C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkyl-C(=O)-, C _1-3 alkyl-S(=O) ₂ -, C _1-3 alkyl-C(=O)O-, C _1-3 alkoxy, C _1-3 alkylthio and C _1-3 alkylamino, wherein the C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkyl-C(=O)-, C _1-3 alkyl-S(=O) ₂ -, C _1-3 alkyl-C(=O)O-, C _1-3 alkoxy, C _1-3 alkylthio and C _1-3 alkylamino are optionally substituted by 1, 2 or 3 R'. According to claim 2, the compound, its optical isomers and pharmaceutically acceptable salts thereof, wherein R is independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, =O, , , , , , , CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , , , , , , , , or . The compound, optical isomers thereof and pharmaceutically acceptable salts thereof according to any one of claims 1 to 3, wherein R ₁ and R ₂ are independently selected from C _1-3 alkyl or C _1-3 alkenyl, and the C _1-3 alkyl and C _1-3 alkenyl are optionally substituted by 1, 2 or 3 Rs. According to claim 4, the compound, its optical isomers and pharmaceutically acceptable salts thereof, wherein R ₁ and R ₂ are independently selected from Me, or . The compound according to any one of claims 1 to 3, its optical isomers and pharmaceutically acceptable salts thereof, wherein _R1 and _R2 are linked together to form a ring , , or , , , and Optionally replaced by 1, 2 or 3 Rs. According to claim 6, the compound, its optical isomer and its pharmaceutically acceptable salt, wherein _R1 and _R2 are linked together to form a ring , , , , , , , , , or . The compound according to any one of claims 1 to 3, its optical isomer and its pharmaceutically acceptable salt, wherein R ₃ , R ₄ and R ₅ are independently selected from H, CN, F, Cl, Br, OH, NH ₂ , CN, C _1-3 alkyl, C _1-3 alkyl-O-, C 1-3 alkyl-S-, C _1-3 alkyl-NH-, C _2-3 alkenyl-O-, C 2-3 alkenyl-S-, C _2-3 alkenyl-NH-, C _3-6 cycloalkyl-O-, C _3-6 cycloalkyl-S-, C _3-6 cycloalkyl-NH- or oxacyclopropane-O-; the C _1-3 alkyl, C 1-3 alkyl-O-, C 1-3 alkyl-S-, C 1-3 alkyl-NH-, C 2-3 alkenyl-O-, C _2-3 alkenyl-S-, C _2-3 alkenyl-NH-, C _3-6 cycloalkyl-O-, C _3-6 cycloalkyl-S-, C _3-6 cycloalkyl-NH- or oxacyclopropane-O-. C _3-6 cycloalkyl-O-, C _3-6 cycloalkyl-S-, C _3-6 cycloalkyl-NH- and oxacyclopropane-O- are optionally substituted with 1, 2 or 3 R. The compound, its optical isomer and its pharmaceutically acceptable salt according to claim 8, wherein R ₃ , R ₄ and R ₅ are independently selected from H, CN, F, Cl, Br, OH, NH ₂ , CN, Me, , , , , , or , the Me, , , , , , and Optionally replaced by 1, 2 or 3 Rs. The compound, its optical isomer and its pharmaceutically acceptable salt according to claim 9, wherein R ₃ , R ₄ and R ₅ are independently selected from H, CN, F, Cl, Br, OH, NH ₂ , CN, Me, , , , , , , , , , , and . The compound according to any one of claims 1 to 3, its optical isomers and pharmaceutically acceptable salts thereof, wherein R ₈ and R ₉ are independently selected from H, CN, F, Cl, Br, OH, NH ₂ , Me or . The compound according to any one of claims 1 to 3, its optical isomers and pharmaceutically acceptable salts thereof, wherein R ₁₀ is selected from H, Me, , or . The compound according to any one of claims 1 to 3, its optical isomer and its pharmaceutically acceptable salt, wherein _L2 and _L3 are independently selected from a single bond, _-CH2- , -CH( _CH3 )-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O) _2- , -NH-, , , , , , or . The compound according to any one of claims 1 to 3, its optical isomer and its pharmaceutically acceptable salt, wherein L ₄ is selected from -CH ₂ -, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O) ₂ -, -NH-, , or . The compound according to any one of claims 1 to 3, its optical isomers and pharmaceutically acceptable salts thereof, wherein Ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, thienyl, oxazolyl and pyrimidinyl. According to claim 15, the compound, its optical isomers and pharmaceutically acceptable salts thereof, wherein the structural unit Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . The compound according to any one of claims 1 to 3, its optical isomers and pharmaceutically acceptable salts thereof, wherein ring B is selected from phenyl, benzocyclopentyl, benzocyclohexyl, indolyl and spiro[cyclopropane-1,3'-dihydroindol]-2'-one. According to claim 17, the compound, its optical isomers and pharmaceutically acceptable salts thereof, wherein the structural unit Selected from , , , , , , and . According to claim 1, the compound, its optical isomers and pharmaceutically acceptable salts thereof, wherein ring C is selected from phenyl, benzocyclopentyl, benzocyclohexyl, 1H-indazolyl, 2H-indazolyl and 1H-benzo[d]imidazole. The compound according to claim 10 or 19, its optical isomers and pharmaceutically acceptable salts thereof, wherein the structural unit Selected from , , , , , , , , , , , , , , , , and . A compound of the following formula, its optical isomers and pharmaceutically acceptable salts thereof, which are selected from: and . A use of a compound according to any one of claims 1 to 21, an optical isomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating a disease associated with androgen receptor (AR) activity or expression. The androgen receptor (AR) activity or expression-related disease according to claim 22, which is selected from prostate cancer, ovarian cancer, breast cancer, bladder cancer, pancreatic cancer, endometrial cancer, hepatocellular carcinoma, renal cell carcinoma, melanoma, mantle cell lymphoma, glioblastoma, salivary gland cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy and age-related macular degeneration.