Linked ring compound as well as preparation method and medical application thereof

Abstract

The invention discloses a linked ring compound as well as a preparation method and medical application thereof, and particularly discloses a compound as shown in a formula (I), an optical isomer or pharmaceutically acceptable salt of the compound, and application of the compound as an androgen receptor (AR) inhibitor and the like. # imgabs0 #

Description

[0001] This application claims the priority of Chinese Patent Application No. 2023117906582 with an application date of December 22, 2023. This application incorporates the entire text of the above-mentioned Chinese patent application by reference. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to bicyclic compounds, their preparation methods, and pharmaceutical applications. Background Art

[0003] Prostate cancer is an androgen-dependent tumor. Androgens can bind to the androgen receptor (AR) and thereby stimulate the growth of prostate cancer cells and disease progression. Endocrine therapy is one of the conventional treatment methods. For example, the treatment standard for advanced PCa is mainly androgen deprivation therapy (ADT), such as surgical castration (bilateral orchiectomy) or medical castration (such as injection of Zoladex). ADT therapy has significant effects in the initial stage of treatment. However, as the disease progresses, AR mutates, and the mutated AR is more sensitive to low levels of androgens, thereby driving the disease to progress to castration-resistant prostate cancer (CRPC). Almost all advanced prostate cancer patients will eventually progress to CRPC after receiving endocrine therapy. In addition, up to 30% of prostate cancer patients will transform into metastatic castration-resistant prostate cancer (mCRPC) within 10 years of initial treatment.

[0004] Currently, there are several oral drugs for the treatment of mCRPC, such as enzalutamide, apalutamide, and darolutamide, etc. They mainly bind to the ligand-binding domain (AR-LBD) of the androgen receptor, thereby blocking the interaction between AR and DNA and then exerting their medicinal effects. However, after 2 - 3 years of treatment with these drugs, patients are prone to develop drug resistance. The emergence of androgen receptor variants (AR-Vs) lacking the LBD region and mutations in the LBD region are two important drug resistance mechanisms.

[0005] Compared with normal full-length AR, AR-Vs are truncated forms of AR. These splicing variants lack the LBD during formation, which results in the inability of androgens to bind to AR-Vs. However, since AR-Vs retain the N-terminal domain and the DNA-binding domain (DBD), they can still bind to genomic DNA and regulate the expression of downstream target genes, presenting androgen-independent constitutive activity, which is one of the important mechanisms for ADT resistance and CRPC disease progression.

[0006] Developing inhibitors targeting the NTD of the AR receptor with good physicochemical properties and drugability, inhibiting the transcriptional function of the androgen receptor AR by regulating the N-terminal domain of AR, and blocking the conduction pathway of the androgen receptor, is a new direction in the treatment research of prostate cancer. Inhibitors targeting AR-NTD, by acting on the N-terminal domain of the AR receptor, will bring in-depth and extensive AR inhibition. It has important clinical value for the treatment of AR-driven cancer diseases such as prostate cancer, especially for the treatment of androgen-independent resistant prostate cancer. Summary of the Invention

[0007] In one aspect of the present invention, the present invention provides a compound represented by formula (I), its optical isomers or its pharmaceutically acceptable salts,

[0008]

[0009] wherein,

[0010] R1 is selected from H, halogen, OH, CN, NH2, 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, and 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;

[0011] R2, R3, and R4 are each independently selected from H, CN, halogen, OH, NH2, C 1-6 alkyl, C 3-6 cycloalkyl, 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-, and the C 1-6 alkyl, C3-6 Cycloalkyl, 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;

[0012] R5, R6, R7 are each independently selected from H, CN, halogen, OH, NH2, C 1-6 Alkyl, C 3-6 Cycloalkyl, 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-, 4-6 membered heterocycloalkyl-NH-, C 6-10 Aryl, 5-10 membered heteroaryl or 3-10 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 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-, 4-6 membered heterocycloalkyl-NH-, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;

[0013] m, n, y are each independently selected from 0, 1, 2, 3 or 4;

[0014] L1 is selected from a single bond, -NH-, =N-, -O-, -C≡C-, -CH2-, -CH2CH2-, -OCH2-, C 3-6 cycloalkyl or 3- to 10-membered heterocycloalkyl, where the -NH-, -CH2-, -CH2CH2-, -OCH2-, C 3-6 cycloalkyl and 3- to 10-membered heterocycloalkyl are optionally substituted by 1 or 2 R;

[0015] selected from and when selected from then, L1 is selected from =N- or 3- to 10-membered heterocycloalkyl;

[0016] L2 is selected from a single bond, -CH=CH-, -C≡C-, -CH=CH-, -(CR8R9)x-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR 10 -,

[0017] C 3-6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, where the C 3-6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted by 1, 2 or 3 R;

[0018] L3 is selected from a single bond, -CH=CH-, -C≡C-, -(CR8R9)x-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR 10 - or -(CR8R9)x-O-;

[0019] and, L2 and L3 are not simultaneously selected from a single bond;

[0020] and, when L2 is selected from C 3-6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, L3 is not selected from a single bond;

[0021] R8 and R9 are each independently selected from H, CN, F, Cl, Br, OH, NH2, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 1-6 heteroalkyl or 3- to 10-membered heterocycloalkyl, where the C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 1-6The heteroalkyl and 3- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 R groups;

[0022] R 10 is selected from H or C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 1-6 heteroalkyl or 3- to 10-membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 1-6 The heteroalkyl and 3- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 R groups;

[0023] x is selected from 0, 1, 2 or 3;

[0024] Ring A is selected from C 4-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, phenyl or 5- to 10-membered heteroaryl;

[0025] Ring B, Ring C and Ring D are each independently selected from C 4-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, benzoC 5-6 cycloalkyl, benzo 5- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl fused to C 5-6 cycloalkyl or 5- to 6-membered heteroaryl fused to 5- to 6-membered heterocycloalkyl;

[0026] Each R is independently selected from H, halogen, ═O, ═NR', OH, NH2, CN, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkyl-S(═O)2-, C 1-6 alkyl-C(═O)-, C 1-6 alkyl-C(═O)O-, C 1-6 alkyl-O-C(═O)-, C 1-6 alkyl-C(═O)NH-, C 1-6 alkyl-NH-C(═O)-C 1-6 alkyl-S(═O)2NH-, C 1-6 alkyl-NHS(═O)2-, C 1-6 alkyl-O-, C 1-6 alkyl-S- or 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 3-6Cycloalkyl-S-, C 3-6 cycloalkyl-NH-, 4- to 6-membered heteroalkyl-O-, 4- to 6-membered heteroalkyl-S-, or 4- to 6-membered heteroalkyl-NH-, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl, C 1-6 alkyl-S(=O)2-, C 1-6 alkyl-C(=O)-, C 1-6 alkyl-C(=O)O-, C 1-6 alkyl-O-C(=O)-, C 1-6 alkyl-C(=O)NH-, C 1-6 alkyl-NH-C(=O)-, C 1-6 alkyl-S(=O)2NH-, C 1-6 alkyl-NHS(=O)2-, C 1-6 alkyl-O-, C 1-6 alkyl-S-, or 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- to 6-membered heteroalkyl-O-, 4- to 6-membered heteroalkyl-S-, and 4- to 6-membered heteroalkyl-NH- are optionally substituted with 1, 2, or 3 R';

[0027] R' is selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, CH2F, CHF2, CF3, and C 1-6 alkyl-S(=O)2-;

[0028] The above-mentioned heteroaryl, heteroalkyl, or heteroalkyl group contains 1, 2, or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, C(=O), C(=O)O, C(=O)NH, S(=O), S(=O)2, P(=O), S(=O)2NH, and N.

[0029] In some embodiments of the present invention, the above-mentioned Rs are independently selected from H, halogen, OH, NH2, CN, =O, =NR', 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)2-P(=O)-, C 1-3 alkyl-C(=O)O-, C1-3 alkyl-O-, C 1-3 alkyl-S- or C 1-3 alkyl-NH-, 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 alkyl-O-, C 1-3 alkyl-S- and C 1-3 alkyl-NH- is optionally substituted by 1, 2 or 3 R', and the remaining variables are as defined in the present invention.

[0030] In some embodiments of the present invention, the above R are each independently selected from H, F, Cl, Br, I, OH, NH2, CN, =O, =NH, =N-CN, CH3, CH2F, CHF2, CF3, and the remaining variables are as defined in the present invention.

[0031] In some embodiments of the present invention, the above R1 is selected from H, F, Cl, Br, I, Me, CN, OH,

[0032] and the remaining variables are as defined in the present invention.

[0033] In some embodiments of the present invention, the above L1 is selected from a single bond, -NH-, =N-, -O-, -C≡C-, and the remaining variables are as defined in the present invention.

[0034] In some embodiments of the present invention, the above structural unit is selected from H, F, Cl, Br, I,

[0035] and the remaining variables are as defined in the present invention.

[0036] In some embodiments of the present invention, the above R2, R3, R4 are each independently selected from H, CN, F, Cl, Br, OH, NH2, 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 2-3alkenyl-NH-, C 3-6 cycloalkyl-O-, C 3-6 cycloalkyl-S-, C 3-6 cycloalkyl-NH- or oxiranyl-O-, wherein 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 oxiranyl-O- are optionally substituted by 1, 2 or 3 R, and the remaining variables are as defined in the present invention.

[0037] In some embodiments of the present invention, the above R2, R3, R4 are each independently selected from H, CN, F, Cl, Br, OH, NH2, CN, Me, the Me, optionally substituted by 1, 2 or 3 R, and the remaining variables are as defined in the present invention.

[0038] In some embodiments of the present invention, the above R2, R3, R4 are each independently selected from H, CN, F, Cl, Br, OH, NH2, CN, Me,

[0039] and the remaining variables are as defined in the present invention.

[0040] In some embodiments of the present invention, the above R8, R9 are each independently selected from H, CN, F, Cl, Br, OH, NH2, Me or and the remaining variables are as defined in the present invention.

[0041] In some embodiments of the present invention, the above R 10 is selected from H, Me, and the remaining variables are as defined in the present invention.

[0042] In some embodiments of the present invention, the above L2 is selected from a single bond, -CH2-, -CH(CH3)-, -CH=CH-, -C≡C-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NH-, and the remaining variables are as defined in the present invention.

[0043] In some embodiments of the present invention, the above L3 is selected from a single bond, -CH2-, -CH(CH3)-, -OCH2-, -CH=CH-, -C≡C-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2- or -NH-, and the remaining variables are as defined in the present invention.

[0044] In some embodiments of the present invention, the above L2-L3 is selected from -CH2-, -CH2CH2-, -CH(CH3)-, -CH=CH-, -C≡C-, -O-, -CH2O-, -OCH(CH3)-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NH-, and the remaining variables are as defined in the present invention.

[0045] In some embodiments of the present invention, the above ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, thienyl, oxazolyl, pyridazinyl, oxiranyl, tetrahydropyranyl or 2-oxaspiro[3.3]heptanyl, and the remaining variables are as defined in the present invention.

[0046] In some embodiments of the present invention, the above structural unit is selected from

[0047] and the remaining variables are as defined in the present invention.

[0048] In some embodiments of the present invention, the above ring B is selected from bicyclo[1.1.1]pentyl, cyclopentyl, 2,6-diazaspiro[3.3]heptanyl, cyclohexyl, piperidinyl, thiazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, 5,6-dihydro-2(1H)-pyridinone, benzocyclopentyl, benzocyclohexyl, indolyl, isoindolinyl, spiro[cyclopropane-1,3'-dihydroindol]-2'-one or naphthyl, and the remaining variables are as defined in the present invention.

[0049] In some embodiments of the present invention, the above structural unit is selected from

[0050] and the remaining variables are as defined in the present invention.

[0051] In some embodiments of the present invention, the above structural unit ring C is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, pyrazinyl, imidazolyl, indolyl, 2,5-dihydro-1H-pyrrolyl, morpholinyl, 1,2,3-triazolyl, pyrrolidinyl, azetidin-2-one, spiro[cyclopropane-1,3'-dihydroindol]-2'-one, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, octahydropyrrolo[3,4-b]pyridyl or 2-azaspiro[3.4]oct-6-enyl, and the remaining variables are as defined in the present invention.

[0052] In some embodiments of the present invention, the above structural unit is selected from

[0053] and the remaining variables are as defined in the present invention.

[0054] In some embodiments of the present invention, the above ring D is selected from phenyl, benzocyclopentyl, benzocyclohexyl, 1H-indazolyl, 2H-indazolyl or 1H-benzo[d]imidazole, and the remaining variables are as defined in the present invention.

[0055] In some embodiments of the present invention, the above structural unit is selected from

[0056] and the remaining variables are as defined in the present invention.

[0057] The present invention also provides a compound of the following formula, its optical isomers and its pharmaceutically acceptable salts, which are selected from:

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065] Definitions and Explanations

[0066] Unless otherwise indicated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered indefinite or unclear merely because it is not specifically defined, but should be construed in accordance with its ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding good or its active ingredient.

[0067] As used herein, the term "pharmaceutically acceptable" pertains to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0068] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from compounds having specific substituents found in the present invention with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds 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 compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, where the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, where the organic acids include, for example, 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, methanesulfonic acid, and similar acids; also salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can thus be converted into either base or acid addition salts.

[0069] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds containing acid or base groups by conventional chemical methods. Generally, the preparation of such salts involves reacting these compounds in the form of the free acid or base with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a mixture of both.

[0070] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereomer-enriched mixtures, all of which mixtures are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present invention.

[0071] Unless otherwise stated, the terms "tautomer" or "tautomeric form" refer to different functional group isomers that are in dynamic equilibrium at room temperature and can rapidly interconvert. If tautomers are possible (e.g., in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0072] The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms that make up the compound. For example, the compound can be labeled with a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). Alternatively, deuterium can be used to replace hydrogen to form deuterated drugs. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with the non-deuterated drug, the deuterated drug has advantages such as reducing toxic and side effects, increasing drug stability, enhancing efficacy, and prolonging the biological half-life of the drug. All isotopic compositions of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0073] "Optional" or "optionally" means that the subsequent described event or condition may but does not necessarily occur, and this description includes the case where the described event or condition occurs and the case where the described event or condition does not occur.

[0074] The term "substituted by" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and variants of hydrogen, provided that the valence state of the specific atom is normal and the resulting compound is stable. The term "optionally substituted by" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary based on what is chemically achievable.

[0075] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 1, 2, or 3 R's, the group may optionally be substituted by up to three R's, and each R has an independent option in each case. In addition, combinations of substituents and / or their variants are permitted only if such combinations result in a stable compound. For example, may be selected from etc.

[0076] When one of the variables is selected from a single bond, it means that the two groups it connects are directly linked, such as when L2 represents a single bond in it means the structure is actually 1-6 An alkylcarbonyl - refers to a C 1-6 alkyl that is connected to the rest of the molecule through a carbonyl. However, when the connection site of the substituent is obvious to those skilled in the art, for example, in the case of a halogen substituent, the "-" can be omitted.

[0077] Unless otherwise specified, when a group has a dashed line on its valence bond, such as in the dashed line represents the connection point of the group to the rest of the molecule.

[0078] When it is not specified which atom of the listed substituent is connected to the group being substituted, such a substituent can be bonded through any of its atoms. For example, a pyridyl group as a substituent can be connected to the group being substituted through any carbon atom on the pyridine ring.

[0079] When the listed linking group does not specify its connection direction, its connection direction is arbitrary. For example, in when the linking group L is it can be connected to the phenyl and cyclopentyl groups in the same direction as the reading order from left to right to form or it can be connected to the phenyl and cyclopentyl groups in the opposite direction to the reading order from left to right to form Combinations of said linking groups, substituents and / or their variants are permitted only if such combinations result in stable compounds.

[0080] Unless otherwise specified, the number of atoms in a ring refers to the number of atoms that form the ring itself in a compound obtained by bonding atoms in a ring (such as monocyclic compounds, fused-ring compounds, spiro compounds, bridged-ring compounds, cross-linked compounds, carbocyclic compounds, heterocyclic compounds). The number of atoms in a ring is usually defined as the ring member count. For example, a "4- to 6-membered ring" refers to a "ring" formed by arranging 4 to 6 atoms in a circular manner. When a ring is substituted by a substituent, the atoms contained in the substituent are not included in the ring-forming atoms. Unless otherwise specified, benzene is a 6-membered ring, naphthalene is a 10-membered ring, and thiophene is a 5-membered ring.

[0081] Unless otherwise specified, the term "alkyl" refers to a saturated hydrocarbon group containing primary (normal) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof, which can represent a straight-chain and / or branched-chain alkyl group, and which can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine). Unless otherwise specifically stated in the specification, the alkyl group can be optionally substituted.

[0082] Unless otherwise specified, the term "C 1-6 alkyl" is used to represent a straight-chain or branched-chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 alkyl includes C 1-5 、C 1-4 、C 2-6 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine). Examples of C 1-6 alkyl include, but are not limited to, methyl ("Me"), ethyl ("Et"), propyl such as n-propyl ("n-Pr") or isopropyl ("i-Pr"), butyl such as n-butyl ("n-Bu"), isobutyl ("i-Bu"), sec-butyl ("s-Bu") or tert-butyl ("t-Bu"), pentyl, hexyl, methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, etc.

[0083] Unless otherwise specified, the term "C 1-3 alkyl" is used to represent a straight-chain or branched-chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl includes C 1-2 and C 2-3 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine). C 1-3Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), methylene, 1,2-ethylene, 1,3-propylene, etc.

[0084] Unless otherwise specified, the term "alkenyl" refers to a hydrocarbon group containing at least one unsaturated site, i.e., a carbon-carbon sp 2 double bond, which can represent a straight-chain and / or branched alkenyl group. A branched chain means that one or more alkyl groups such as methyl, ethyl, or propyl are attached to the straight-chain alkenyl chain. It can be monovalent, divalent, or polyvalent. Unless otherwise specifically stated in the specification, the alkenyl group can be optionally substituted.

[0085] Unless otherwise specified, "C 2-6 alkenyl" is used to represent a straight-chain or branched hydrocarbon group composed of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond can be located at any position in the group. The C 2-6 alkenyl includes C 2-4 , C 2-3 , C4, C3, and C2 alkenyl, etc.; it can be monovalent, divalent, or polyvalent. Examples of C 2-6 alkenyl include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, vinylene, propenylene, sec-butylene, etc.

[0086] Unless otherwise specified, "C 2-3 alkenyl" is used to represent a straight-chain or branched hydrocarbon group composed of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond can be located at any position in the group. The C 2-3 alkenyl includes C3 and C2 alkenyl; the C 2-3 alkenyl can be monovalent, divalent, or polyvalent. Examples of C 2-3 alkenyl include, but are not limited to, vinyl, propenyl, vinylene, propenylene, etc.

[0087] Unless otherwise specified, the term "alkynyl" refers to a hydrocarbon group containing at least one unsaturated site, i.e., a carbon-carbon sp triple bond, which can represent a straight-chain and / or branched alkynyl group. A branched chain means that one or more alkyl groups such as methyl, ethyl, or propyl are attached to the straight-chain alkynyl chain. It can be monovalent, divalent, or polyvalent. Unless otherwise specifically stated in the specification, the alkynyl group can be optionally substituted.

[0088] Unless otherwise specified, the term "C 2-6 alkynyl" is used to represent a straight-chain or branched hydrocarbon group composed of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, and the carbon-carbon triple bond can be located at any position in the group. It can be monovalent, divalent, or polyvalent. The C 2-6 alkynyl includes C2-5 , C 2-4 , C 2-3 , C2, C 2-6 , C6 and C5 alkynyl groups, etc. C 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, ethynylene, propynylene, pentynyl, pentynylene, etc.

[0089] Unless otherwise specified, "C 2-3 alkynyl" is used to denote a straight-chain or branched-chain hydrocarbyl group consisting of 2 to 3 carbon atoms and containing at least one carbon-carbon triple bond, and the carbon-carbon triple bond can be located at any position of the group. It can be monovalent, divalent or polyvalent. The C 2-3 alkynyl group includes C3 and C2 alkynyl groups. C 2-3 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, ethynylene, propynylene, etc.

[0090] Unless otherwise specified, the term "heteroalkyl" by itself or in combination with another term denotes a stable straight-chain or branched-chain alkyl group or a combination thereof composed of a certain number of carbon atoms and at least one heteroatom or heteroatom group, wherein the "alkyl" in the "alkyl group" is defined as above in the present invention. 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)2N(H)-, and -S(=O)N(H)-. In some embodiments, the heteroalkyl is C 1-20 heteroalkyl; in some embodiments, the heteroalkyl is C 1-6 heteroalkyl; in other embodiments, the heteroalkyl is C 1-3Heteroalkyl. The heteroatom or heteroatomic group may be located at any internal position of the heteroalkyl, including the position where the alkyl is attached to the remainder of the molecule. Examples of heteroalkyl include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(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, -SCH2(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3, etc.; at most two of its heteroatoms may be consecutive, such as -CH2-NH-OCH3. Unless specifically stated otherwise in the specification, the heteroalkyl may be optionally substituted. Unless otherwise specified, the term "alkoxy" means an alkyl group attached to the remainder of the molecule through an oxygen atom, where "alkyl" in the "alkyl group" is defined as above in the present invention. Unless specifically stated otherwise in the specification, the alkoxy may be optionally substituted.

[0091] Unless otherwise specified, the term "C 1-6 alkoxy" means those alkyl groups containing 1 to 6 carbon atoms attached to the remainder of the molecule through an oxygen atom. The C 1-6 alkoxy includes C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 、C6, C5, C4, and C3 alkoxys, etc. Examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy, and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy, and neopentyloxy), hexyloxy, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentyloxy, etc.

[0092] Unless otherwise specified, the term "C 1-4 alkoxy" means those alkyl groups containing 1 to 4 carbon atoms attached to the remainder of the molecule through an oxygen atom. The C 1-4 alkoxy includes C 1-3 、C 1-2 、C 2-4 、C4, and C3 alkoxys, etc. C 1-6Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), methylenedioxy, ethylenedioxy, propylenedioxy, butylenedioxy, etc.

[0093] Unless otherwise specified, the term "C 1-3 alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through an oxygen atom. The C 1-3 alkoxy includes C 1-2 、C 2-3 、C3 and C2 alkoxy, etc. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), methylenedioxy, ethylenedioxy, propylenedioxy, etc.

[0094] Unless otherwise specified, the term "amino" can be monovalent --NH2, divalent or polyvalent

[0095] Unless otherwise specified, the term "alkylamino" refers to an alkyl group attached to the remainder of the molecule through an amino group as defined above, where "alkyl" in "alkyl group" is defined as above in the present invention. Unless otherwise specifically stated in the specification, the alkylamino can be optionally substituted.

[0096] 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 remainder of the molecule through an amino group. The C 1-6 alkylamino includes C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 、C6, C5, C4, C3 and C2 alkylamino, etc. Examples of C 1-6 alkylamino include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, etc.

[0097] Unless otherwise specified, the term "C 1-4 alkylamino" refers to those alkyl groups containing 1 to 4 carbon atoms that are attached to the remainder of the molecule through an amino group. The C 1-4 alkylamino includes C 1-3 、C 1-2 、C 2-4, C4, C3, and C2 alkylamino, etc. C 1-4 Examples of alkylamino include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, etc.

[0098] 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 remainder of the molecule through an amino group. The C 1-3 alkylamino includes C 1-2 , C3, and C2 alkylamino, etc. C 1-3 Examples of alkylamino include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, etc.

[0099] Unless otherwise specified, the term "alkylthio" refers to an alkyl group attached to the remainder of the molecule through a sulfur atom, where "alkyl" in "alkyl group" is defined as above in the present invention. Unless otherwise specifically stated in the specification, alkylthio may be optionally substituted.

[0100] 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 remainder of the molecule through a sulfur atom. The C 1-6 alkylthio includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4, C3, and C2 alkylthio, etc. C 1-6 Examples of alkylthio include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and so on.

[0101] Unless otherwise specified, the term "C 1-4 alkylthio" refers to those alkyl groups containing 1 to 4 carbon atoms that are attached to the remainder of the molecule through a sulfur atom. The C 1-4 alkylthio includes C 1-3 , C 1-2 , C 2-4 , C4, C3, and C2 alkylthio, etc. C 1-4 Examples of alkylthio include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and so on.

[0102] Unless otherwise specified, the term "C 1-3 -alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through a sulfur atom. The C 1-3 -alkylthio includes C 1-3 , C 1-2 , and C3-alkylthio, etc. Examples of C 1-3 -alkylthio include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0103] Unless otherwise specified, the term "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic saturated hydrocarbon group composed of carbon and hydrogen atoms, which may include fused rings, spiro rings, and / or bridged ring systems. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, but are not limited to, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. "C 4-6 -cycloalkyl" refers to a cycloalkyl having 4 to 6 ring carbon atoms. Similarly, "C 3-4 -cycloalkyl" refers to a cycloalkyl having 3 to 4 ring carbon atoms. Unless otherwise specifically stated in the specification, the cycloalkyl may be optionally substituted.

[0104] Unless otherwise specified, "C 3-6 -cycloalkyl" refers to a saturated monocyclic or bicyclic hydrocarbon group having 3 to 6 ring carbon atoms, such as having 3 to 5 ring carbon atoms, such as 3 to 4 ring carbon atoms; it can be monovalent, divalent, or polyvalent. Examples of C 3-6 -cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0105] Unless otherwise specified, "C 4-6 -cycloalkyl" represents a saturated cyclic hydrocarbon group composed of 4 to 6 carbon atoms, which is a monocyclic and bicyclic system. The C 4-6 -cycloalkyl includes C 4-5 , C 5-6 , C4, C5, and C6-cycloalkyl, etc.; it can be monovalent, divalent, or polyvalent. Examples of C 4-6 -cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0106] Unless otherwise specified, the term "heterocycloalkyl" represents a non-aromatic saturated cyclic group existing as a monocyclic, fused ring, spiro ring, and / or bridged ring, in which at least one of the ring atoms is a heteroatom or heteroatomic group and the rest are carbon atoms; in some embodiments, each occurrence of the heteroatom is independently selected from B, O, N, and S, where the nitrogen and sulfur atoms are optionally oxidized (i.e., NO and S(O) p, where p is 1 or 2), the heteroatom is optionally quaternized. In some other embodiments, each occurrence of the heteroatom group is independently selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. The heteroatom or heteroatom group can be located at any internal position of the heterocycloalkyl, including the position where the heterocycloalkyl is connected to the rest of the molecule. In some embodiments, the heterocycloalkyl is a 3- to 20-membered heterocycloalkyl; in some embodiments, the heterocycloalkyl is a 3- to 10-membered heterocycloalkyl; in some other embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. Unless otherwise specifically stated in the specification, the heterocycloalkyl can be optionally substituted. Unless otherwise specified, the term "3- to 6-membered heterocycloalkyl" alone or in combination with other terms separately represents a saturated cyclic group composed of 3 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from B, O, S, and N or the heteroatom groups as described above, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , where p is 1 or 2). It includes monocyclic and bicyclic systems, where the bicyclic system includes spiro, fused, and bridged rings. In addition, for this "3- to 6-membered heterocycloalkyl", the heteroatom or heteroatom group can be located at any internal position of the heterocycloalkyl, including the position that can occupy the connection position of the heterocycloalkyl to the rest of the molecule. The 3- to 6-membered heterocycloalkyl includes 5- to 6-membered, 4-membered, 5-membered, and 6-membered heterocycloalkyls, etc. Examples of the 3- to 6-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxolanyl, dithiolanyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperidinyl, etc.

[0107] Unless otherwise specified, the term "cycloalkenyl" in the present invention refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group composed of carbon and hydrogen atoms, having one or more carbon-carbon sp 2 double bonds, which can include fused, spiro, and / or bridged ring systems. Monocyclic cycloalkenyls include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc. Polycyclic cycloalkenyls include, but are not limited to, bicyclo[2.2.1]hept-2-enyl, etc. Unless otherwise specifically stated in the specification, the cycloalkenyl can be optionally substituted. "C 3-7"Cycloalkenyl" includes C3, C4, C5, C6, and C7 cycloalkenyl. Examples of cycloalkenyl include, but are not limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl.

[0108] Unless otherwise specified, the term "heterocycloalkenyl" in the present invention refers to a cyclic alkenyl group containing several heteroatoms or heteroatom groups. In some embodiments, each occurrence of a heteroatom is independently selected from B, O, N, and S, where nitrogen and sulfur atoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2), nitrogen heteroatoms are optionally quaternized. In other embodiments, each occurrence of a heteroatom group is independently selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. "5-6 membered heterocycloalkenyl" alone or in combination with other terms respectively represents an unsaturated cyclic group composed of 5 to 6 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from B, O, S, and N or heteroatom groups as described above, and the rest are carbon atoms, where nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). Examples of heterocycloalkenyl include, but are not limited to , etc. Unless otherwise specifically stated in the specification, heterocycloalkenyl can be optionally substituted.

[0109] Unless otherwise specified, when a substituent attached to ring A can be connected to ring A to form a ring, it means that the substituent can be connected to any site of ring A to form a new ring together with ring A, including fused rings, spiro rings, or bridged rings; wherein, ring A can be selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, etc. as described above. For example, when the R in can be connected to to form a 6-membered ring, examples of which include, but are not limited to

[0110] Unless otherwise specified, C n-n+m or C n -C n+m includes any specific case of n to n + m carbons. For example, C 1-12 includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 , and also includes any range from n to n + m. For example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 and so on; similarly, n - to n + m - membered rings represent rings having n to n + m atoms in the ring. For example, 3 - to 12 - membered rings include 3 - membered rings, 4 - membered rings, 5 - membered rings, 6 - membered rings, 7 - membered rings, 8 - membered rings, 9 - membered rings, 10 - membered rings, 11 - membered rings, and 12 - membered rings, and also include any range within n to n + m. For example, 3 - to 12 - membered rings include 3 - to 6 - membered rings, 3 - to 9 - membered rings, 5 - to 6 - membered rings, 5 - to 7 - membered rings, 6 - to 7 - membered rings, 6 - to 8 - membered rings, and 6 - to 10 - membered rings and so on.

[0111] Unless otherwise specified, the term "aryl" refers to a hydrocarbon ring system group containing at least one aromatic ring. In the present invention, the aryl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused rings, spiro rings and / or bridged ring systems. Aryl includes but is not limited to benzene, naphthalene, anthracene, fluoranthene, phenanthrene, benzophenanthrene, dibenzo[a,h]anthracene, tetracene, pyrene, benzopyrene, acenaphthene, fluorene and their derivative groups. Unless specifically stated otherwise in the specification, the aryl can be optionally substituted.

[0112] Unless otherwise specified, the term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 20 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl is preferably 5 - to 10 - membered, containing 1 to 3 heteroatoms; more preferably 5 - or 6 - membered, containing 1 to 3 heteroatoms; non - limiting examples include pyrazolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like. The heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, where the ring connected to the parent structure is the heteroaryl ring, non - limiting examples of which include: and so on. Non - limiting examples of heteroaryl also include triazine, pyridine, pyrimidine, imidazole, furan, thiophene, benzofuran, benzothiophene, indole, carbazole, pyrroloimidazole, pyrrolopyrrole, thiophenopyrrole, thiophenothiophene, furanopyrrole, furanofuran, thiophenofuran, benzisoxazole, benzisothiazole, benzimidazole, quinoline, isoquinoline, phthalazine, quinoxaline, phenanthridine, perimidine, quinazoline, quinazolinone, dibenzothiophene, dibenzofuran, carbazole and their derivatives. Unless specifically stated otherwise in the specification, the heteroaryl can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio or heterocycloalkylthio.

[0113] As used herein, the term "substituted" means that in any of the above groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl), at least one hydrogen atom is replaced by a bond to a non-hydrogen atom, and the non-hydrogen atoms include, but are not limited to, halogen atoms (such as F, Cl, Br, I), oxygen-containing groups (such as hydroxy, alkoxy, ester), sulfur-containing groups (such as mercapto, thioalkyl, sulfone, sulfonyl, sulfoxide), nitrogen-containing groups (such as amino, amide, alkylamino, dialkylamino, arylamino, aryl-alkyl-amino, diarylamino, N-oxide group, imide, enamine), silicon-containing groups (such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl), and other heteroatoms in various other groups.

[0114] The term "substituted" as used herein also means that one or more hydrogen atoms in any of the above groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl) are replaced by a higher-order bond to a heteroatom (such as a double bond or a triple bond), for example, oxygen in carbonyl, carboxyl, and ester groups, and nitrogen in imine, oxime, hydrazone, and nitrile groups. For example, "substituted" means that one or more hydrogen atoms in any of the above groups are replaced by -NR g R h 、 -NR g C(=O)R h 、 -NR g C(=O)NR g R h 、 -NR g C(=O)OR h 、 -NR g SO2R h 、 -OC(=O)NR g R h 、 -OR g 、 -SR g 、 -SOR g 、 SO2R g 、 -OSO2R g 、 -SO2OR g 、

[0115] =NSO2R g and -SO2NR g R h replace. "Substituted" may also mean that one or more hydrogen atoms in any of the above groups are replaced by -C(=O)R g 、 -C(=O)OR g 、 -C(=O)NR g R h 、 -CH2SO2Rg 、 -CH2SO2NR g R h is substituted. The R g is the same as or different from R h and is independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic group, N-heterocyclic group, heterocycloalkyl-alkyl, heteroaryl, N-heteroaryl, heteroaryl-alkyl. "Substituted" may also mean that one or more hydrogen atoms in any of the above groups are substituted by amino, cyano, hydroxy, imino, nitro, oxo, thio, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic group, N-heterocyclic group, heterocycloalkyl-alkyl, heteroaryl, N-heteroaryl, heteroaryl-alkyl. Additionally, each of the above substituents may optionally be substituted by one or more of the above substituents.

[0116] Those skilled in the art should understand that some compounds of formula (I) may contain one or more chiral centers, and thus there are two or more stereoisomers. Therefore, the compounds of the present invention may exist in the form of a single stereoisomer (e.g., enantiomer, diastereomer) and mixtures thereof in any proportion such as racemate, and, where appropriate, in the form of their tautomers and geometric isomers.

[0117] As used herein, the term "stereoisomer" refers to compounds having the same chemical constitution but different in the spatial arrangement of atoms or groups. Stereoisomers include enantiomers, diastereomers, and conformational isomers, etc.

[0118] As used herein, the term "enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.

[0119] As used herein, the term "diastereomer" refers to stereoisomers having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, or biological activity. A mixture of diastereomers can be separated by high-resolution analytical methods such as electrophoresis and chromatography such as HPLC.

[0120] As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted via a low energy barrier. For example, proton tautomers (also known as proton-transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions via the reorganization of some bonding electrons.

[0121] The compounds of the present invention can be prepared by a variety of synthetic methods well-known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and equivalent substitution methods well-known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0122] The technical and scientific terms not specifically defined herein have the meanings commonly understood by those skilled in the art to which the present invention pertains. Detailed Description of the Invention

[0123] The present application will be described in detail below by way of examples, but this does not mean any adverse limitation to the present application. The present application has been described in detail herein, and specific embodiments thereof have also been disclosed. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0124] The experimental materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.

[0125] In all examples, 1 1H NMR, 13 13C NMR, 19 19F NMR and 31 31P NMR spectra were recorded using a Bruker Ascend 400 mHz nuclear magnetic resonance spectrometer, and the spectra were processed using Topspin software, with deuterated solvents as the internal deuterium lock. Among them 13 13C NMR, 19 19F NMR and 31 31P NMR were 1H decoupling. Assignments were made according to distinct chemical shift / coupling patterns or according to 2D Cosy, HMBC, HSQC or NOESY experiments. The multiplicity of peaks was defined as: s singlet, d doublet, t triplet, q quartet, m multiplet, br broad, br.s broad singlet; coupling constants (J) were accurate to 0.1 Hz. Mass spectra were recorded using an Agilent 1260 (ESI) or a Shimadzu LC-MS-2020 (ESI) or an Agilent 6215 (ESI) mass spectrometer; reverse-phase preparative HPLC separations were performed using an Agilent 1290 UV-guided automated purification system (Xtimate C18 OBDTM 21.2 * 250 mm 10 μm column) or using a Gilson GX281 UV-guided automated purification system (xBridge C18 OBDTM 19 * 250 mm 10 μm column) or a Waters QDa-guided automated purification system (SunFire C18 OBD 29 * 250 mm 10 μm column). Unless otherwise specified, separations were performed using SepaFlash pre-packed normal-phase silica gel columns (Sinopharm Chemical Reagent Co., Ltd.), TLC analytical plates (Yantai Jiangyou Silica Gel Development Co., Ltd., model: HSGF254, specification: 2.5 × 5 cm), and the ratios of the eluents were all by volume.

[0126] Among them, the Chinese names of the reagents represented by chemical formulas or English letter abbreviations are as follows:

[0127] CD3OD represents deuterated methanol; DMSO-d6 represents deuterated dimethyl sulfoxide; Chloroform-d or CDCl3 represents deuterated chloroform; AcOH represents acetic acid; AlCl3 represents aluminum trichloride; Aq represents aqueous solution; N2 represents nitrogen; Ar represents argon; B2Pin2 represents bis(pinacolato)diboron; BBr3 represents boron tribromide; BH3 represents borane; (Boc)2O represents di-tert-butyl dicarbonate; Et3SiH represents triethylsilane; HATU represents 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HOBt represents 1-hydroxybenzotriazole; TMAD represents N,N,N',N'-tetramethylazodicarboxamide; K2CO3 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 meta-chloroperoxybenzoic 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; Oxone represents potassium peroxymonosulfate; n-BuLi represents n-butyllithium; NH4Cl represents ammonium chloride; NMP represents N-methyl-2-pyrrolidone; PBr3 represents phosphorus tribromide; Pd(dppf)Cl2 or PdCl2(dppf) represents dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II); Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium(0); Pd(OAc)2 represents palladium(II) acetate; conc. represents concentrated; (COCl)2 represents oxalyl chloride; Cs2CO3 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 CH3CN represents acetonitrile; MeOH or methanol represents methanol; EtOH or ethanol represents ethanol; DEA represents diethylamine; DIPEA or DIEA represents N,N-diisopropylethylamine; DIAD represents diisopropyl azodicarboxylate; Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; DMAP represents 4-dimethylaminopyridine; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EA or EtOAc represents ethyl acetate; PE represents petroleum ether; THF represents tetrahydrofuran; Toluene or tol.Toluene is represented by [[ID=]], SOCl2 represents thionyl chloride, TFA represents trifluoroacetic acid, FA represents formic acid, TMSCN represents trimethylsilyl cyanide, H2O represents water, HCl represents hydrogen chloride gas, HCl aq. represents aqueous hydrochloric acid, ℃ 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 milliliters per minute, Hz represents hertz, MHz represents megahertz, bar represents the pressure unit bar, psi represents the pressure unit pounds per square inch, N2 represents nitrogen, HPLC represents high performance liquid chromatography, I.D. represents inner diameter, LCMS or LC-MS represents liquid chromatography-mass spectrometry, m / z represents mass-to-charge ratio, ESI represents electrospray ionization, CO2 represents carbon dioxide, TLC represents thin layer chromatography, UV represents ultraviolet, IV represents intravenous injection, PO represents oral administration, rpm represents revolutions per minute, and ATCC represents the American Type Culture Collection.

[0128] Example 1: Preparation of Compound 1

[0129]

[0130] Preparation of Compound 1-2

[0131] Dissolve Compound 1-1 (33.0 g, 176 mmol) in acetonitrile (500 mL). Cool the solution to 0 °C in an ice-water bath, add p-toluenesulfonic acid monohydrate (30 g, 176 mmol), stir at this temperature for 30 minutes, then add NIS (43.6 g, 194 mmol). After addition, remove the ice-water bath and stir at room temperature for 16 hours. Quench the reaction by adding a sodium sulfite solution to the reaction system, add water (2 L), and extract twice with ethyl acetate (2 L). Combine the organic phases, wash three times with saturated brine (2 L), dry over anhydrous sodium sulfate, filter by suction, concentrate the filtrate, and purify by normal-phase silica gel column chromatography (EA / PE = 0 - 30%) to obtain 45 g of the title compound 1-2 with a yield of 77%. 1 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H).

[0132] Preparation of Compound 1-3

[0133] Compound 1-2 (45 g, 135 mmol) was dissolved in DMF (500 mL). Cesium carbonate (97 g, 297 mmol) and 1-bromo-2-chloroethane (28.8 g, 202 mmol) were added successively. The temperature was raised to 80 °C and the reaction was carried out for 16 hours. After the reaction was completed, the mixture was filtered. Water (3 L) was added to the filtrate, and the pH was adjusted to ~5 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (2 L) twice. The organic phases were combined, washed with saturated brine (2 L) three times, dried over anhydrous sodium sulfate, concentrated, and the resulting residue was purified by normal-phase silica gel column chromatography (EA / PE = 0 - 30%) to obtain 35 g of the title compound 1-3 with a yield of 66%. LC-MS (ESI): m / z 394.3.

[0134] Preparation of Compound 1-4

[0135] Compound 1-3 (35 g, 88.0 mmol) was dissolved in DMF (500 mL). CuCN (8.6 g, 96.8 mmol) and CuI (1.6 g, 8.8 mmol) were added. The reaction system was purged with nitrogen three times, and the temperature was raised to 100 °C and the reaction was carried out for 5 hours. The reaction was monitored by TLC. After completion, the solid was filtered off through a pad of diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrates were combined, water (2 L) was added, and the mixture was extracted with ethyl acetate (0.5 L) twice. The organic phases were combined, washed with saturated brine (1 L) three times, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated, and the resulting residue was purified by normal-phase silica gel column chromatography (EA / PE = 0 - 20%) to obtain 15 g of the title compound 1-4 with a yield of 58%. 1 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H), 4.45 (t, J = 5.2 Hz, 2H), 3.97 (t, J = 5.2 Hz, 2H).

[0136] Preparation of Compound 1-5

[0137] Under nitrogen protection, compound 1-4 (2.92 g, 10 mmol), m-hydroxybenzeneboronic acid (2.0 g, 15 mmol), K2CO3 (2.7 g, 20 mmol), Pd(dppf)Cl2 (816 mg, 1 mmol), 1,4-dioxane (100 mL) and H2O (30 mL) were added to the reaction flask. The mixture was stirred at 100 °C for 5 hours. The solvent was evaporated, and the crude product was purified by column chromatography (EA / PE = 0 - 40%) to obtain 1.8 g of compound 1-5 with a yield of 58%.

[0138] Preparation of Compound 1-7

[0139] Under nitrogen protection, compound 1-5 (1.0 g, 3.25 mmol) and compound 1-6 (1.4 g, 3.9 mmol) were dissolved in DCM (20 mL), then triethylamine (484 mg, 4.8 mmol) was added, and the reaction was carried out at room temperature for 2 hours. TLC monitoring (PE / EA = 5:1) showed that the raw materials had completely reacted. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (EA / PE = 0-20%) to obtain 800 mg of the title compound 1-7 with a yield of 56%.

[0140] Preparation of Compound 1-8

[0141] Under nitrogen protection, compound 1-7 (400 mg, 0.91 mmol), p-hydroxyphenylboronic acid (300 mg, 1.09 mmol), K2CO3 (282.6 mg, 2.04 mmol), Pd(dppf)Cl2 (100 mg, 0.13 mmol), 1,4-dioxane (10 mL) and H2O (3 mL) were added to a reaction flask, and the mixture was stirred at 100 °C for 5 hours. After evaporation to dryness, the crude product was purified by silica gel column chromatography (EA / PE = 0-40%) to obtain 280 mg of the title compound 1-8 with a yield of 80%. 1 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.29 (s, 2H), 7.93 (s, 1H), 7.70–7.59 (m, 4H), 7.51 (t, J = 7.8 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 4.50 (t, J = 5.2 Hz, 2H), 4.00 (t, J = 5.2 Hz, 2H).

[0142] Preparation of Compound 1-10

[0143] Compound 1-8 (280 mg, 0.73 mmol), compound 1-9 (54.5 mg, 1.09 mmol) and triphenylphosphine (287 mg, 1.09 mmol) were dissolved in THF (20 mL). After three replacements with nitrogen, DEAD (254 mg, 1.46 mmol) was then added. The reaction solution was stirred at 50 °C for 2 hours. The reaction solution was concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0-30%) to obtain 290 mg of the title compound 1-10 with a yield of 76%. LC-MS (ESI): m / z 522.2.

[0144] Preparation of Compound 1

[0145] Compound 1-10 (29 mg, 0.055 mmol) was dissolved in DCM (10 mL), and m-chloroperoxybenzoic acid (33.4 mg, 0.16 mmol, 85% purity) was added. The reaction was carried out at 40 °C for 2 hours. The crude product was purified by preparation to obtain 7.5 mg of the title compound 1, with a yield of 76%. LC-MS (ESI): m / z 554.2. 1 1H NMR (400 MHz, DMSO-d6) δ 9.12 (d, J = 5.1 Hz, 1H), 8.32 (q, J = 2.3 Hz, 2H), 8.03–7.99 (m, 1H), 7.96 (d, J = 5.1 Hz, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.71 (t, J = 6.1 Hz, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 8.9 Hz, 2H), 5.46 (s, 2H), 4.51 (t, J = 5.2 Hz, 2H), 4.02 (t, J = 5.2 Hz, 2H), 3.44 (s, 3H).

[0146] Example 2: Preparation of Compound 2

[0147]

[0148] Preparation of Compound 2

[0149] Compound 1 (100 mg, 0.18 mmol), dimethylphosphine oxide (76 mg, 0.98 mol), cesium carbonate (176 mg, 0.54 mmol) and acetonitrile (5 mL) were added to a reaction flask, and the reaction was carried out at 70 °C for 2 hours. After the reaction was completed, the reaction solution was filtered and evaporated to dryness. The obtained crude product was purified by preparative liquid phase (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 5%-60% acetonitrile was eluted gradiently within 30 minutes; flow rate: 30 mL / min), to obtain 12.4 mg of the title compound 2, with a yield of 12.5%. LC-MS (ESI): m / z 551.80 [M+H] + . 1HNMR(400MHz, DMSO-d6) δ 9.01 (d, J=5.2Hz, 1H), 8.31 (q, J=2.3Hz, 2H), 7.99 (s, 1H), 7.80 (d, J=8.8Hz, 2H), 7.75 (dd, J=5.3, 3.2Hz, 1H), 7.69 (t, J=7.8Hz, 2H), 7.54 (t, J=7.7Hz, 1H), 7.18 (d, J=8.8Hz, 2H), 5.37 (s, 2H), 4.50 (t, J=5.2Hz, 2H), 4.01 (t, J=5.2Hz, 2H), 1.78 (d, J=13.7Hz, 6H). 31 P NMR(162MHz, DMSO-d6) δ 34.13。

[0150] Example 3: Preparation of Compound 3

[0151]

[0152] Preparation of Compound 3

[0153] Compound 1 (100 mg, 0.18 mmol), methanesulfonamide (51.5 mg, 0.54 mol), cesium carbonate (176 mg, 0.54 mmol) and acetonitrile (5 mL) were added to a reaction flask and stirred at 80 °C overnight. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by preparative liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 5%-60% acetonitrile gradient elution within 30 minutes; flow rate: 30 mL / min), to obtain 7.7 mg of the title compound 3, with a yield of 7.5%. LC-MS (ESI): m / z 569.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6) δ 11.40 (s, 1H), 8.63 (d, J=5.1Hz, 1H), 8.31 (q, J=2.3Hz, 2H), 7.99 (t, J=1.9Hz, 1H), 7.79 (d, J=8.9Hz, 2H), 7.69 (m, 2H), 7.54 (t, J=7.7Hz, 1H), 7.22 (d, J=5.1Hz, 1H), 7.14 (d, J=8.8Hz, 2H), 5.22 (s, 2H), 4.50 (t, J=5.2Hz, 2H), 4.01 (t, J=5.2Hz, 2H), 3.36 (s, 3H).

[0154] Example 4: Preparation of Compound 4

[0155]

[0156] Preparation of Compound 4-2

[0157] Dissolve Compound 1-8 (480 mg, 1.25 mmol) in acetonitrile (10 mL). Add potassium carbonate (518 mg, 3.75 mmol) with stirring, and then After 5 minutes, add compound 4-1 (265 mg, 1.62 mmol), and react at 80 °C for 4 hours. Monitor by LCMS After the reaction is complete, Pour the reaction mixture into ice water and extract with ethyl acetate (20 mL) twice. Combine the organic phases, dry over anhydrous sodium sulfate, filter by suction, concentrate the filtrate to obtain the crude product, and purify it by normal-phase silica gel column chromatography (EA / PE = 0 - 30%) to obtain 200 mg of the title compound 4-2 with a yield of 31%. LC-MS (ESI): m / z 510.0 [M+H] + .

[0158] Preparation of Compound 4

[0159] Add Compound 4-2 (60 mg, 0.117 mmol), Compound 4-3 (70 mg, 0.58 mmol), DIEA (150 mg, 1.17 mmol), Xantphos (5.16 mg, 0.019 mmol), Pd2(dba)3 (8.2 mg, 9.92 mmol) and DMF (3 mL) into a microwave tube. Under nitrogen protection, carry out microwave reaction at 120 °C for 2 hours. Filter, and purify the obtained crude product by preparative liquid phase (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 5% - 80% acetonitrile gradient elution within 30 minutes; flow rate: 30 mL / min) to obtain 35 mg of the title compound 4 with a yield of 50.4%. LC-MS (ESI): m / z 593.3 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 5.0 Hz, 1H), 8.30 (q, J = 2.3 Hz, 2H), 7.98 (t, J = 1.8 Hz, 1H), 7.80–7.75 (m, 2H), 7.73–7.64 (m, 2H), 7.54 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 5.1 Hz, 1H), 5.13 (s, 2H), 4.50 (t, J = 5.2 Hz, 2H), 4.01 (t, J = 5.2 Hz, 2H), 3.67–3.51 (m, 2H), 3.45–3.23 (m, 2H), 2.29–2.16 (m, 2H), 2.16–2.01 (m, 2H).

[0160] Example 5: Preparation of Compound 5

[0161]

[0162] Preparation of Compound 5

[0163] Compound 4-2 (133.5 mg, 0.26 mmol) was added into a microwave tube. Then anhydrous ethanol (4 mL), 2-thia-6-azaspiro[3.3]heptane, 2,2-dioxide hydrochloride (48 mg, 0.26 mmol), and triethylamine (106 mg, 1.05 mmol) were added successively. The mixture was purged with nitrogen three times and then reacted at 90 °C under microwave irradiation for 3 hours. After the reaction was monitored by LCMS to completion, the solvent was removed under reduced pressure. The obtained crude product was recrystallized from ethyl acetate and methanol to give 120 mg of the title compound 5, with a yield of 74%. LC-MS (ESI): 621.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 5.0 Hz, 1H), 8.31 (q, J = 2.3 Hz, 2H), 7.98 (t, J = 1.9 Hz, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.69 (ddt, J = 10.8, 8.0, 1.2 Hz, 2H), 7.54 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 5.0 Hz, 1H), 5.09 (s, 2H), 4.52 (s, 4H), 4.50 (t, J = 5.2 Hz, 2H), 4.29 (s, 4H), 4.01 (t, J = 5.2 Hz, 2H).

[0164] Example 6: Preparation of Compound 6

[0165]

[0166] Preparation of Compound 6-2

[0167] Compound 6-1 (303.2 mg, 1.09 mmol), Compound 1-4 (481.5 mg, 1.63 mmol), cesium carbonate (1.06 g, 3.27 mmol), Xantphos (126 mg, 217.67 μmol), Pd2(dba)3 (99.7 mg, 108.84 μmol) and dioxane (5 mL) were added into a reaction flask. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After filtration and concentration, the obtained crude product was purified by column chromatography (EA / PE = 0 - 40%) to give 230 mg of the title compound, with a yield of 46%. LC-MS (ESI): m / z 455.0 [M+H] + .

[0168] Preparation of Compound 6-3

[0169] Compound 6-2 (430 mg, 942.65 μmol), Pd(dppf)Cl2 (68.40 mg, 94.27 μmol), bis(pinacolato)diboron (359.1 mg, 1.41 mmol), potassium acetate (277.5 mg, 2.83 mmol) and 1,4-dioxane (10 mL) were added to a reaction flask. Under nitrogen protection, the reaction was carried out at 100 °C for 4 hours. After filtration and evaporation, 1,4-dioxane (5 mL) was added to dissolve the residue, and the temperature was cooled to 0 °C. Hydrogen peroxide (1.18 g, 10.45 mmol, 30% purity) was added dropwise, and the mixture was stirred for 10 minutes. A saturated aqueous solution of sodium sulfite (10 mL) was added to quench the reaction. The mixture was extracted with DCM (10 mL) three times, and the organic phases were combined and evaporated to obtain the crude product. After silica gel column chromatography (EA / PE = 0 - 40%), 330 mg of the title compound 6-3 was obtained with a yield of 89%. LC-MS (ESI): m / z 393.2 [M+1] + 。

[0170] Preparation of Compound 6-4

[0171] Compound 6-3 (300 mg, 762.85 μmol), 2-chloro-4-(chloromethyl)pyrimidine (186.5 mg, 1.14 mmol), K2CO3 (210.9 mg, 1.53 mmol) and DMF were added to a reaction flask. The mixture was stirred at 70 °C for 3 hours. Water (10 mL) was added, and the mixture was extracted with DCM (10 mL) three times. The organic phases were combined and evaporated. The crude product was subjected to silica gel column chromatography (EA / PE = 0 - 40%) to obtain 120 mg of the title compound 6-4 with a yield of 30%. LC-MS (ESI): m / z 519.2 [M+H] + 。

[0172] Preparation of Compound 6

[0173] Compound 6-4 (80 mg, 153.90 μmol), methanesulfonamide (29.3 mg, 307.81 μmol), cesium carbonate (100.3 mg, 307.81 μmol), Xantphos (17.8 mg, 30.78 μmol), Pd2(dba)3 (14.1 mg, 15.39 μmol) and 1,4-dioxane (0.8 mL) were added to a microwave tube. Under nitrogen protection, the mixture was stirred at 100 °C for 3 hours. After filtration and concentration by rotary evaporation, the crude product was purified by preparative liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 5%-75% acetonitrile in a gradient elution within 30 minutes; flow rate: 30 mL / min), to obtain 20 mg of the title compound 6, with a yield of 22%. LC-MS (ESI): m / z 578.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.60 (d, J = 5.1 Hz, 1H), 7.34 (d, J = 3.0 Hz, 1H), 7.30 (d, J = 3.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 5.1 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 5.09 (s, 2H), 4.71 (t, J = 4.2 Hz, 1H), 4.25 (t, J = 5.8 Hz, 2H), 3.95–3.87 (m, 3H), 3.87–3.69 (m, 3H), 3.48–3.40 (m, 1H), 3.32 (s, 3H), 3.29–3.23 (m, 1H).

[0174] Example 7: Preparation of Compound 7

[0175]

[0176] Preparation of Compound 7

[0177] Compound 6-4 (40 mg, 76.95 μmol), compound 4-3 (13.8 mg, 115.43 μmol), cesium carbonate (50.1 mg, 153.90 μmol), Xantphos (8.9 mg, 15.39 μmol), Pd2(dba)3 (7.1 mg, 7.70 μmol) and 1,4-dioxane (0.4 mL) were added to a microwave tube. Under nitrogen protection, the mixture was stirred at 100 °C for 2 hours. After filtration and concentration in vacuo, the crude product was purified by preparative liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 10%-80% acetonitrile gradient elution within 30 minutes; flow rate: 30 mL / min), and 10 mg of the title compound 7 was obtained with a yield of 21%. LC-MS (ESI): m / z 602.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 5.1 Hz, 1H), 7.34 (d, J = 3.0 Hz, 1H), 7.29 (d, J = 2.9 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.97–6.87 (m, 3H), 5.00 (s, 2H), 4.70 (t, J = 4.2 Hz, 1H), 4.25 (t, J = 5.2 Hz, 2H), 3.96–3.87 (m, 3H), 3.87–3.67 (m, 3H), 3.63–3.51 (m, 2H), 3.48–3.39 (m, 1H), 3.33–3.18 (m, 3H), 2.26–2.15 (m, 2H), 2.15–2.02 (m, 2H).

[0178] Example 8: Preparation of Compound 8

[0179]

[0180] Preparation of Compound 8-2

[0181] Under nitrogen protection, compound 8-1 (153.7 mg, 817.77 μmol), compound 1-7 (300 mg, 681.48 μmol), K2CO3 (282.6 mg, 2.04 mmol), Pd(dppf)Cl2 (99.7 mg, 136.30 μmol), 1,4-dioxane (5 mL) and H2O (1 mL) were added to a reaction flask and stirred at 110 °C for 16 hours. After concentration in vacuo, the crude product was purified by silica gel column chromatography (EA / PE = 0-100%), and 230 mg of the title compound 8-2 was obtained with a yield of 77%. LC-MS (ESI): m / z 434.3 [M+H]+ .

[0182] Preparation of Compound 8-3

[0183] Dissolve Compound 8-2 (100 mg, 230.25 μmol) and Compound 4-1 (45 mg, 276.30 μmol) in acetonitrile (2 mL), and add K2CO3 (95.5 mg, 690.75 μmol). Stir the reaction mixture at 85 °C for 2 hours. Pour the reaction mixture into water (10 mL), and extract twice with ethyl acetate (5 mL). Combine the organic phases, wash with water (5 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 80 mg of the crude title compound 8-3 with a yield of 61%. LC-MS (ESI): m / z 560.2 [M+H] + .

[0184] Preparation of Compound 8

[0185] Add Compound 8-3 (50 mg, 89.15 μmol), Compound 2-oxo-6-heterospiro[3.3]heptane (19.6 mg, 106.98 μmol), triethylamine (90.2 mg, 891.49 μmol, 124.3 μL) and DMF (1 mL) to a reaction flask, and react at 90 °C under microwave irradiation for 3 hours. Filter and concentrate under reduced pressure. The obtained crude product is purified by preparative liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 5%-60% acetonitrile gradient elution within 30 minutes; flow rate: 30 mL / min) to obtain 40 mg of the title compound 8 with a yield of 66%. LC-MS (ESI): m / z 671.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 5.0 Hz, 1H), 8.38–8.26 (m, 3H), 8.15 (s, 1H), 7.98 (d, J = 8.9 Hz, 2H), 7.91 (d, J = 8.6 Hz, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.34 (dd, J = 8.8, 2.6 Hz, 1H), 6.90 (d, J = 5.0 Hz, 1H), 5.17 (s, 2H), 4.60–4.41 (m, 6H), 4.30 (s, 4H), 4.02 (t, J = 5.0 Hz, 2H).

[0186] Example 9: Preparation of Compound 9

[0187]

[0188] Preparation of Compound 9

[0189] Compound 8-3 (25 mg, 44.57 μmol), dimethylphosphine oxide (5.2 mg, 66.86 μmol), DIEA (17.3 mg, 133.72 μmol, 23.3 μL), Xantphos (5.16 mg, 8.91 μmol), Pd2(dba)3 (4.08 mg, 4.46 μmol) and DMF (1 mL) were added to a microwave tube. Under nitrogen protection, it was stirred at 130 °C for 2 hours. After filtration, the obtained crude product was purified by preparative liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 5%-80% acetonitrile was eluted gradiently within 30 minutes; flow rate: 30 mL / min), and 10 mg of the title compound 9 was obtained, yield: 37%. LC-MS (ESI): m / z 602.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 5.3 Hz, 1H), 8.48–8.31 (m, 3H), 8.19 (s, 1H), 8.09–7.93 (m, 2H), 7.93–7.77 (m, 3H), 7.64 (t, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.54–7.39 (m, 2H), 5.49 (s, 2H), 4.54 (t, J = 5.0 Hz, 2H), 4.05 (t, J = 5.0 Hz, 2H), 1.82 (d, J = 13.7 Hz, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 34.31 (s, 1P).

[0190] Example 10: Preparation of Compound 10

[0191]

[0192] Preparation of Compound 10-1

[0193] Compound 1-7 (1.3 g, 3.4 mmol), N-phenylbis(trifluoromethanesulfonyl)imide (1.3 g, 3.7 mmol), and triethylamine (686 mg, 6.8 mmol) were dissolved in dichloromethane (50 mL). The reaction system was stirred at 25 °C for 2 hours. After the reaction, water (50 mL) was added, and the mixture was extracted with dichloromethane (30 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. Purification by column chromatography (EA / PE = 0 - 20%) gave 1.3 g of the title compound 10-1. LC-MS (ESI): m / z 532.8 [M + 18] + 。

[0194] Preparation of Compound 10-2

[0195] Compound 10-1 (1.3 g, 2.4 mmol), copper(I) iodide (137 mg, 0.72 mmol), bis(triphenylphosphine)palladium(II) dichloride (168 mg, 0.24 mmol), and triethylamine (727 mg, 7.2 mmol) were dissolved in acetonitrile (50 mL), and trimethylsilylacetylene (705 mg, 7.2 mmol) was added thereto. The reaction system was stirred at 80 °C for 16 hours. After the reaction, water (50 mL) was added, 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. Purification by column chromatography (EA / PE = 0 - 5%) gave 800 mg of the title compound 10-2. LC-MS (ESI): m / z 464.0 [M + H] + 。

[0196] Preparation of Compound 10-3

[0197] Compound 10-2 (800 mg, 1.7 mmol) and potassium carbonate (703 mg, 5.1 mmol) were dissolved in acetonitrile (50 mL). The reaction system was stirred at 25 °C for 1 hour. After the reaction, water (50 mL) was added, 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. Purification by column chromatography (EA / PE = 0 - 3%) gave 500 mg of the title compound 10-3.

[0198] Preparation of Compound 10-4

[0199] Compound 10-3 (250 mg, 0.64 mmol), copper(I) iodide (36 mg, 0.19 mmol), bis(triphenylphosphine)palladium(II) dichloride (42 mg, 0.06 mmol), and triethylamine (193 mg, 1.92 mmol) were dissolved in tetrahydrofuran (20 mL), and 2-chloro-5-iodopyrimidine (169 mg, 0.70 mmol) was added thereto. The reaction system was stirred at 25 °C for 1 hour. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE = 0 - 25%) to obtain 200 mg of the title compound 10-4. LC-MS (ESI): m / z 504.0 [M+H] + .

[0200] Preparation of Compound 10

[0201] Compound 10-4 (100 mg, 0.20 mmol) was dissolved in DMF (5 mL) solution. Dimethylphosphine oxide (46 mg, 0.60 mmol), DIPEA (77 mg, 0.60 mmol), tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.02 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (27 mg, 0.05 mmol) were added successively. The reaction system was stirred at 120 °C for 2 hours. After the reaction was completed, the insoluble solids were filtered off. Water (10 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (20 mL) three times. 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 preparative separation (preparation method: mobile phase: A: 0.1% aqueous formic acid solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 45% - 65% acetonitrile gradient elution within 12 minutes; flow rate: 30 mL / min) to obtain 1.5 mg of the title compound 10. LC-MS (ESI): m / z 546.6 [M+H] + . 31P NMR (162 MHz, Chloroform-d) δ 35.20 (s, 1P).

[0202] Example 11: Preparation of Compound 11

[0203]

[0204] Preparation of Compound 11

[0205] Compound 10-4 (100 mg, 0.20 mmol) was dissolved in DMF (5 mL) solution. 1-Imino-1-oxothiolane (71 mg, 0.60 mmol), DIPEA (77 mg, 0.60 mmol), tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.02 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (27 mg, 0.05 mmol) were added successively. The reaction system was stirred at 120 °C for 2 hours. After the reaction was completed, the insoluble solid was filtered off. The filtrate was added with water (10 mL), and extracted with dichloromethane (20 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. After preparative separation and purification (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 gradient elution within 12 minutes; flow rate: 30 mL / min), 53 mg of the title compound 11 was obtained. LC-MS (ESI): m / z 587.3 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.65 (s, 2H), 7.89 (d, J = 2.2 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.73–7.60 (m, 6H), 7.60–7.47 (m, 2H), 4.52 (t, J = 6.1 Hz, 2H), 3.93 (t, J = 6.0 Hz, 2H), 3.71 (dt, J = 13.5, 6.9 Hz, 2H), 3.44 (dt, J = 13.5, 6.8 Hz, 2H), 2.57–2.22 (m, 4H).

[0206] Example 12: Preparation of Compound 12

[0207]

[0208] Preparation of Compound 12

[0209] Compound 10-4 (100 mg, 0.20 mmol) was dissolved in DMF (5 mL) solution. 1-Imino-1-oxothiolane (71 mg, 0.60 mmol), DIPEA (77 mg, 0.60 mmol), tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.02 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (27 mg, 0.05 mmol) were added successively. The reaction system was stirred at 120 °C for 2 h. After the reaction was completed, the insoluble solid was filtered off. The filtrate was added with water (10 mL), and extracted with dichloromethane (20 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain the crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch UltimateAQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile gradient elution within 12 min; flow rate: 30 mL / min) to obtain 2.1 mg of the title compound 12. LC-MS (ESI): m / z 589.3 [M+H] + . 1 HNMR (400 MHz, Chloroform-d) δ 8.65 (s, 1H), 8.43 (s, 1H), 8.01 (s, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.69 (s, 1H), 7.63 (d, J = 7.1 Hz, 1H), 7.54 (t, J = 8.4 Hz, 2H), 7.48 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.1 Hz, 2H), 6.77 (d, J = 12.0 Hz, 1H), 6.42 (d, J = 12.0 Hz, 1H), 4.51 (t, J = 6.1 Hz, 2H), 3.93 (t, J = 6.1 Hz, 2H), 3.77–3.64 (m, 2H), 3.48–3.38 (m, 2H), 2.47–2.20 (m, 4H).

[0210] Example 13: Preparation of Compound 13

[0211]

[0212] Preparation of Compound 13-1

[0213] Compound 10-3 (250 mg, 0.64 mmol), copper(I) iodide (36 mg, 0.19 mmol), bis(triphenylphosphine)palladium(II) dichloride (42 mg, 0.06 mmol), and triethylamine (193 mg, 1.92 mmol) were dissolved in acetonitrile (20 mL). To this was added compound 2-chloro-5-bromopyrimidine (135 mg, 0.70 mmol). The reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction, water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic layers were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product. Purification by column chromatography (EA / PE = 0 - 25%) afforded 180 mg of the title compound 13-1. LC-MS (ESI): m / z 504.0 [M+H] + .

[0214] Preparation of Compound 13

[0215] Compound 13-1 (100 mg, 0.20 mmol) was dissolved in DMF (5 mL). Dimethylphosphine oxide (46 mg, 0.60 mmol), DIPEA (77 mg, 0.60 mmol), tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.02 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (27 mg, 0.05 mmol) were successively added. The reaction mixture was stirred at 100 °C for 2 h. After completion of the reaction, the insoluble solids were filtered off. Water (10 mL) was added to the filtrate, and the mixture was extracted three times with dichloromethane (20 mL). The organic layers were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product. Purification by preparative separation (preparation method: mobile phase: A: 0.1% aqueous formic acid; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 40% - 60% acetonitrile gradient elution in 12 min; flow rate: 30 mL / min) afforded 22.2 mg of the title compound 13. LC-MS (ESI): m / z 546.0 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.87 (dd, J = 5.1, 0.7 Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.77–7.66 (m, 7H), 7.61–7.56 (m, 1H), 7.55–7.52 (m, 2H), 4.52 (t, J = 6.0 Hz, 2H), 3.93 (t, J = 6.0 Hz, 2H), 1.92 (d, J = 13.6 Hz, 6H). 31P NMR (162 MHz, Chloroform-d) δ 35.08 (s, 1P).

[0216] Example 14: Preparation of Compound 14

[0217]

[0218] Preparation of Compound 14-1

[0219] Dissolve 4-bromophenol (500 mg, 2.89 mmol), Compound 1-9 (541.7 mg, 3.47 mmol) and TMAD (1.49 g, 8.67 mmol) in DCM (5 mL). Cool the system to 0 °C and add n-Bu3P (1.75 g, 8.67 mmol, 2.17 mL). The reaction solution is slowly warmed to room temperature and stirred overnight. TLC shows no remaining raw materials. Rotate to dryness and purify by silica gel column chromatography (EA / PE = 0 - 20%) to obtain 500 mg of the title compound 14-1 with a yield of 55%.

[0220] Preparation of Compound 14-2

[0221] Add Compound 14-1 (300 mg, 964.02 μmol), potassium acetate (283.8 mg, 2.89 mmol), bis(pinacolato)diboron (293.76 mg, 1.16 mmol), Pd(dppf)Cl2 (69.9 mg, 96.40 μmol) and 1,4-dioxane (3 mL) to a reaction flask. Stir at 100 °C for 16 hours under nitrogen protection. Rotate to dryness and purify the crude product by silica gel column chromatography (EA / PE = 0 - 50%) to obtain 200 mg of the title compound 14-2 with a yield of 57%. LC-MS (ESI): m / z 359.2 [M+H] + .

[0222] Preparation of Compound 14-3

[0223] Under nitrogen protection, add bis(pinacolato)diboron (4.13 g, 16.27 mmol), Compound 1-4 (4 g, 13.56 mmol), Pd(dppf)Cl2, KOAc, 1,4-dioxane (40 mL) and react at 100 °C for 16 hours. After TLC detection shows complete reaction, add water (40 mL), extract with ethyl acetate, rotate to dryness, and purify the crude product by silica gel column chromatography (EA / PE = 0 - 50%) to obtain 3.1 g of the title compound 14-3 with a yield of 66%.

[0224] Preparation of Compound 14-5

[0225] Under nitrogen protection, compound 14-4 (568.3 mg, 3.51 mmol), compound 14-3 (1 g, 2.92 mmol), Pd(dppf)Cl2 (211 mg, 0.29 mmol), K2CO3 (1.2 g, 8.76 mmol), 1,4-dioxane (10 mL) and water (3 mL) were added to a reaction flask and stirred at 100 °C for 16 hours. After evaporation to dryness, the crude product was purified by silica gel column chromatography (EA / PE = 0 - 50%) to obtain 430 mg of the title compound 14-5 with a yield of 49%. 1 H NMR (400 MHz, Chloroform-d) δ 8.13 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.78 (s, 1H), 4.49 (t, J = 6.0 Hz, 2H), 4.18 (s, 3H), 3.91 (t, J = 6.2 Hz, 2H).

[0226] Preparation of Compound 14-6

[0227] Under nitrogen protection, compound 14-5 (100 mg, 336.54 μmol) was dissolved in THF (1 mL), cooled to -78 °C, and n-BuLi (0.14 mL, 336.54 μmol, 2.5 M THF solution) was slowly added dropwise. After stirring for 1 hour, I2 (170.8 mg, 673.08 μmol) was slowly added. The system was stirred for 1 hour, and the reaction was quenched with saturated NH4Cl solution (3 mL). The mixture was extracted three times with ethyl acetate (3 mL), and the combined organic phases were evaporated to dryness. The crude product was purified by column chromatography (EA / PE = 0 - 20%) to obtain 20 mg of the title compound with a yield of 14%. LC-MS (ESI): m / z 422.9 [M+H] + 。

[0228] Preparation of Compound 14-7

[0229] Under nitrogen protection, compound 14-6 (100 mg, 236.39 μmol), compound 14-2 (101.6 mg, 283.66 μmol), potassium carbonate (98 mg, 709.16 μmol), Pd(dppf)Cl2 (17.3 mg, 23.64 μmol), water (0.5 mL) and 1,4-dioxane (1 mL) were added to a reaction flask and reacted at 100 °C for 16 hours. After evaporation to dryness, the crude product was purified by column chromatography (EA / PE = 0 - 50%) to obtain 50 mg of the title compound 14-7 with a yield of 40%. LC-MS (ESI): m / z 527.0 [M+H] + 。

[0230] Preparation of Compound 14-8

[0231] Compound 14-7 (50 mg, 94.80 μmol), potassium peroxymonosulfate (131.3 mg, 379.20 μmol), water (1 mL) and THF (1 mL) were added to a reaction flask and stirred at room temperature for 16 hours. Water (5 mL) was added, and the mixture was extracted with DCM (5 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated by rotary evaporation to obtain 50 mg of the crude title compound 14-8 with a yield of 80%. LC-MS (ESI): m / z 559.0 [M+H] + .

[0232] Preparation of Compound 14

[0233] Compound 14-8 (50 mg, 89.38 μmol), methanesulfonamide (17 mg, 178.76 μmol), potassium carbonate (24.7 mg, 178.76 μmol) and acetonitrile (1 mL) were added to a reaction flask and reacted at 85 °C for 3 hours. The mixture was filtered and concentrated by rotary evaporation. The crude product was purified by preparative liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 5%-75% acetonitrile was eluted with a gradient within 30 minutes; flow rate: 30 mL / min) to obtain 5 mg of the title compound 14 with a yield of 10%. LC-MS (ESI): m / z 574.0 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 8.61 (d, J = 5.1 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.72 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 8.7 Hz, 2H), 7.19 (m, 1H), 5.24 (s, 2H), 4.45 (t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.2 Hz, 2H), 3.88 (s, 3H), 3.40 (s, 3H).

[0234] Example 15: Preparation of Compound 15

[0235]

[0236] Preparation of Compound 15-1

[0237] Under nitrogen protection, compound 14-6 (200 mg, 472.77 μmol), 4-hydroxyphenylboronic acid (65.2 mg, 472.77 μmol), K2CO3 (196 mg, 1.42 mmol), Pd(dppf)Cl2 (34.6 mg, 47.28 μmol), water (1 mL) and 1,4-dioxane (2 mL) were added to a reaction flask, and the reaction was carried out at 100 °C for 16 hours. The reaction was monitored by TLC and was found to be complete. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA / PE = 0 - 50%) to obtain 150 mg of the title compound 15-1 with a yield of 81%.

[0238] Preparation of Compound 15-2

[0239] Compound 15-1 (760 mg, 1.95 mmol), 2-chloro-4-(chloromethyl)pyrimidine (477.4 mg, 2.93 mmol), potassium carbonate (539.7 mg, 3.91 mmol) and DMF (10 mL) were added to a reaction flask, and the mixture was stirred at 70 °C for 4 hours. Water (20 mL) was added, and the mixture was extracted twice with DCM (10 mL). The organic phases were combined, the solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA / PE = 0 - 50%) to obtain 870 mg of the title compound 15-2 with a yield of 86%. LC-MS (ESI): m / z 515.5 [M+H] + 。

[0240] Preparation of Compound 15

[0241] Compound 4-3 (34.66 mg, 290.82 μmol), compound 15-2 (100 mg, 193.88 μmol), cesium carbonate (126.3 mg, 387.76 μmol), Xantphos (22.4 mg, 38.78 μmol), Pd2(dba)3 (17.7 mg, 19.39 μmol) and 1,4-dioxane (1 mL) were added to a microwave tube. Under nitrogen protection, the mixture was stirred at 100 °C for 2 hours. The mixture was filtered, the solvent was evaporated under reduced pressure, and the crude product was purified by preparative liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 10% - 80% acetonitrile gradient elution within 30 minutes; flow rate: 30 mL / min) to obtain 40 mg of the title compound 15 with a yield of 34%. LC-MS (ESI): m / z 598.0 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 5.0 Hz, 1H), 7.76 (d, J = 2.1 Hz, 1H), 7.72 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 5.1 Hz, 1H), 5.18 (s, 2H), 4.45 (t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.2 Hz, 2H), 3.89 (s, 3H), 3.67–3.47 (m, 2H), 3.44–3.34 (m, 2H), 2.30–2.16 (m, 2H), 2.16–2.04 (m, 2H).

[0242] Example 16: Preparation of Compound 16

[0243]

[0244] Preparation of Compound 16

[0245] Compound 15-2 (100 mg, 193.88 μmol), dimethylphosphine oxide (45.4 mg, 581.6 μmol), DIEA (75.2 mg, 581.65 μmol, 101.31 μL), Xantphos (22.4 mg, 38.78 μmol), Pd2(dba)3 (17.8 mg, 19.39 μmol) and DMF (1 mL) were added to a microwave tube. Under nitrogen protection, the mixture was stirred at 120 °C for 3 hours. After filtration and evaporation to dryness, the crude product was purified by preparative liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 10%-70% acetonitrile gradient elution within 30 minutes; flow rate: 30 mL / min), to obtain 40 mg of the title compound 16, with a yield of 34%. LC-MS (ESI): m / z 557.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 5.1 Hz, 1H), 7.82–7.74 (m, 2H), 7.72 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 5.43 (s, 2H), 4.45 (t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.2 Hz, 2H), 3.89 (s, 3H), 1.76 (d, J = 13.8 Hz, 6H). 31 31P NMR (162 MHz, DMSO-d6) δ 34.12 (s, 1P).

[0246] Example 17: Preparation of Compound 17

[0247]

[0248] Preparation of Compound 17-2

[0249] Under nitrogen protection, Compound 17-1 (300 mg, 1.33 mmol), Compound 1-4 (469.6 mg, 1.59 mmol), cesium carbonate (864.6 mg, 2.65 mmol), Xantphos (153.5 mg, 265.35 μmol), Pd2(dba)3 (121.5 mg, 132.68 μmol) and 1,4-dioxane (3 mL) were added to a reaction flask and stirred at 100 °C for 16 hours. After filtration and concentration in vacuo, the crude product was purified by silica gel column chromatography (EA / PE = 0 - 40%) to obtain 440 mg of the title compound 17-2 with a yield of 75%. LC-MS (ESI): m / z 457.8 [M + 18 + H] + 。

[0250] Preparation of Compound 17-3

[0251] Compound 17-2 (460 mg, 1.05 mmol), Pd(dppf)Cl2 (75.8 mg, 104.51 μmol), bis(pinacolato)diboron (398.1 mg, 1.57 mmol), potassium acetate (307.7 mg, 3.14 mmol) and 1,4-dioxane (5 mL) were added to a reaction flask. Under nitrogen protection, the reaction was carried out at 100 °C for 4 hours. After filtration, the filtrate was concentrated in vacuo, and the residue was dissolved in 1,4-dioxane (5 mL) and cooled to 0 °C. Hydrogen peroxide (1.18 g, 10.45 mmol, 30% purity) was added dropwise, and the mixture was stirred for 10 minutes. The reaction was quenched by adding a saturated aqueous solution of sodium sulfite (10 mL), and the mixture was extracted with DCM (10 mL) three times. The organic phases were combined and concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography (EA / PE = 0 - 40%) to obtain 250 mg of the title compound 17-3 with a yield of 63%. LC-MS (ESI): m / z 376.6 [M + H] + 。

[0252] Preparation of Compound 17-4

[0253] Under nitrogen protection, compound 17-3 (150 mg, 397.60 μmol), (2-methylthio-pyrimidin-4-yl) methanol (93.2 mg, 596.40 μmol), TMAD (205.4 mg, 1.19 mmol) and DCM (2 mL) were added to a reaction flask. At 0 °C, tributylphosphine (241.3 mg, 1.19 mmol) was added dropwise, and the temperature was slowly raised to room temperature and stirred for 1 hour. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA / PE = 0 - 40%), to obtain 150 mg of the title compound 17-4, with a yield of 73%. LC-MS (ESI): m / z 515.0 [M+H] + .

[0254] Preparation of compound 17-5

[0255] Compound 17-4 (150 mg, 291.01 μmol), potassium peroxymonosulfate (503.9 mg, 1.46 mmol), H2O (2 mL) and THF (2 mL) were added to a reaction flask, and the reaction was carried out at 30 °C for 16 hours. Water (5 mL) was added, and the mixture was extracted with DCM (5 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was evaporated under reduced pressure to obtain 150 mg of the crude title compound 17-5, with a yield of 94%. LC-MS (ESI): m / z 547.0 [M+H] + .

[0256] Preparation of compound 17

[0257] Compound 17-5 (150 mg, 274.00 μmol), K2CO3 (113.6 mg, 821.99 μmol), methanesulfonamide (78.2 mg, 821.99 μmol) and acetonitrile (2 mL) were added to a reaction flask, and the reaction was carried out at 80 °C for 5 hours. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The crude product was purified by preparative liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent10Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 5% - 75% acetonitrile gradient elution within 30 minutes; flow rate: 30 mL / min), to obtain 80 mg of the title compound 17, with a yield of 51%. LC-MS (ESI): m / z 562.0 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.61 (d, J = 5.1 Hz, 1H), 7.19 (d, J = 5.1 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 6.73 (d, J = 2.9 Hz, 1H), 6.69 (d, J = 2.9 Hz, 1H), 5.11 (s, 2H), 4.79 (dd, J = 8.1, 2.4 Hz, 1H), 4.19 (t, J = 5.2 Hz, 2H), 3.89 (t, J = 5.2 Hz, 2H), 3.75–3.60 (m, 1H), 3.36–3.30 (s, 4H), 2.40–2.23 (m, 1H), 2.02–1.85 (m, 2H), 1.82–1.69 (m, 1H).

[0258] Example 18: Preparation of Compound 18

[0259]

[0260] Preparation of Compound 18-2

[0261] Compound 18-1 (3 g, 12.8 mmol), 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 h. After the reaction was monitored by LCMS until completion, water (20 mL) was added, and the mixture was extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried, filtered by suction, and the filtrate was concentrated. The resulting residue was separated and purified by a normal-phase silica gel column (EA / PE = 0 - 20%), and 1.8 g of the title compound 18-2 was obtained with a yield of 47.5%. 1 1H NMR (400 MHz, DMSO-d6) 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).

[0262] Preparation of Compound 18-4

[0263] Compound 18-2 (1.8 g, 5.06 mmol) was added to a three-necked flask, followed by anhydrous THF (20 mL). LiHMDS (6 mL, 6 mmol) was added, and the mixture was stirred at room temperature for 0.5 h. Then, 18-3 (1 g, 6.0 mmol) was added, and the reaction was carried out at 50 °C for 2 h. TLC showed that the raw materials had completely reacted. The reaction was quenched with ammonium chloride (50 mL), and the mixture was extracted with EA (50 mL). The organic phases were combined, dried, filtered by suction, and the filtrate was concentrated. The residue obtained was separated and purified by a normal-phase silica gel column (EA / PE = 0 - 50%) to give 620 mg of the title compound 18-4, with a yield of 33.5%. LC-MS (ESI): m / z 366.9 [M+H] + 。

[0264] Preparation of Compound 18-5

[0265] Compound 18-4 (620 mg, 1.7 mmol) was dissolved in anhydrous DMF (10 mL), and zinc cyanide (994 mg, 8.5 mmol) and tetrakis(triphenylphosphine)palladium (346 mg, 0.3 mmol) were added. After purging with nitrogen three times, the reaction was carried out at 150 °C under microwave irradiation for 3 h. After cooling to room temperature, the reaction mixture was poured into water, and the mixture was extracted with EA (50 mL). The organic phases were combined, dried and concentrated. The residue obtained was separated and purified by a normal-phase silica gel column (EA / PE = 20 - 50%) to give 330 mg of the title compound 18-5, with a yield of 62%. LC-MS (ESI): m / z 313.0 [M+H] + 。

[0266] Preparation of Compound 18-7

[0267] Dissolve compound 18-5 (330 mg, 1.05 mmol) in anhydrous 1,4-dioxane (10 mL), and add 18-6 (335 mg, 1.26 mmol), and then CuI (19 mg, 0.1 mmol) and 1,2-cyclohexanediamine (19 mg, 0.2 mmol) were added. After purging with nitrogen three times, the reaction was carried out at 150 °C under microwave irradiation for 2 h. After the reaction was completed, the reaction mixture was cooled to room temperature and poured into water. The mixture was extracted twice with EA (30 mL). The organic phases were combined, dried, filtered by suction, and the filtrate was concentrated. The residue obtained was separated and purified by a normal-phase silica gel column (EA / PE = 20 - 40%) to give 210 mg of the title compound 18-7, with a yield of 44%. LC-MS (ESI): m / z 449.2 [M+H] + 。

[0268] Preparation of Compound 18-8

[0269] Compound 18-7 (210 mg, 0.46 mmol) was dissolved in THF (10 mL), concentrated hydrochloric acid (5 mL) was added, and the reaction was carried out at room temperature for 2 hours. After detecting by TLC plate, when the raw material was completely reacted, the reaction solution was poured into water, and then extracted twice with EA (20 mL). The organic phases were combined, dried and concentrated to obtain 180 mg of the crude title compound 18-8, which was directly used in the next step of the reaction.

[0270] Preparation of Compound 18-9

[0271] Compound 18-8 (180 mg, crude product) was dissolved in DMF (10 mL), cesium carbonate (218 mg, 0.66 mmol) was added, and then 2-chloro-4-(chloromethyl)pyrimidine (91 mg, 0.5 mmol) was added. The reaction was carried out at 50 °C for 2 hours. After the reaction was completed, the reaction solution was poured into water, and then extracted twice with EA (20 mL). The organic phases were combined, dried, filtered by suction, and the filtrate was concentrated. The product was separated and purified by normal-phase silica gel column (EA / PE = 10 - 40%) to obtain 110 mg of the title compound 18-9, and the overall yield of the two steps was 44%. LC-MS (ESI): m / z 531.2 [M+H] + 。

[0272] Preparation of Compound 18

[0273] Compound 18-9 (110 mg, 0.20 mmol) was dissolved in DMF (10 mL), and dimethylphosphine oxide (78 mg, 1 mmol), DIEA (129 mg, 1 mmol), Pd2(dba)3 (27 mg, 0.03 mmol) and Xantphos (35 mg, 0.06 mmol) were added in sequence. After purging with nitrogen three times, the reaction was carried out by microwave at 120 °C for 2 hours. After tracking the reaction by LCMS until completion, the reaction solution was filtered. The crude filtrate was separated and purified by preparative method (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25 °C; mobile phase: water (10 mM / L NH4HCO3)-acetonitrile; the proportion of acetonitrile in the mobile phase was gradient eluted from 45% to 65% in 12 minutes; flow rate: 30 mL / min) to obtain 45 mg of the title compound 18, and the yield was 33%. LC-MS (ESI): m / z 573.0 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 5.2 Hz, 1H), 7.80–7.61 (m, 3H), 7.21 (d, J = 9.0 Hz, 2H), 7.06 (d, J = 9.0 Hz, 2H), 5.25 (s, 2H), 5.07 (s, 1H), 4.46 (t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.2 Hz, 2H), 1.74 (d, J = 13.7 Hz, 6H), 1.44 (s, 3H), 0.78 (s, 3H). 31 31P NMR (162 MHz, DMSO-d6) δ 34.04 (s, 1P).

[0274] Example 19: Preparation of Compound 19

[0275]

[0276] Preparation of Compound 19

[0277] Dissolve Compound 18-9 (80 mg, 0.15 mmol) in DMF (10 mL), and successively add Compound 4-3 (119 mg, 1 mmol), DIEA (129 mg, 1 mmol), Pd2(dba)3 (27 mg, 0.03 mmol) and Xantphos (40 mg, 0.07 mmol). After purging with nitrogen three times, react at 120 °C under microwave for 2 hours. After monitoring the reaction by LCMS until completion, cool to room temperature, filter the reaction solution, and purify the filtrate by preparative separation (preparation method: column: Welch Xtimate C18 250x21.2 mm; column temperature: 25 °C; mobile phase: water (10 mM / L NH4HCO3)-acetonitrile; gradient elution of acetonitrile proportion in the mobile phase from 45% to 65% within 12 minutes; flow rate 30 mL / min) to obtain 13.6 mg of the title compound 19, with a yield of 14.7%. LC-MS (ESI): m / z 615.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 5.0 Hz, 1H), 7.72 (d, J = 7.1 Hz, 2H), 7.19 (d, J = 9.0 Hz, 2H), 6.99 (d, J = 9.1 Hz, 2H), 6.94 (d, J = 5.0 Hz, 1H), 5.06 (s, 1H), 5.01 (s, 2H), 4.46 (t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.2 Hz, 2H), 3.67–3.51 (m, 2H), 3.43–3.23 (m, 2H), 2.28–2.14 (m, 2H), 2.14–2.02 (m, 2H), 1.43 (s, 3H), 0.78 (s, 3H).

[0278] Example 20: Preparation of Compound 20

[0279]

[0280] Preparation of Compound 20

[0281] Dissolve Compound 18-9 (200 mg, 0.37 mmol) in DMF (10 mL), and successively add Compound methanesulfonamide (175 mg, 1.85 mmol), DIEA (129 mg, 1 mmol), Pd2(dba)3 (54 mg, 0.06 mmol) and Xantphos (70 mg, 0.12 mmol). After purging with nitrogen three times, react at 120 °C under microwave for 2 hours. Monitor the reaction by LCMS until completion, then filter the reaction solution. The crude product of the filtrate is purified by preparative separation (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25 °C; mobile phase: water (10 mM / L NH4HCO3) - acetonitrile; acetonitrile ratio in the mobile phase is 45% - 65% in 12 min; flow rate: 30 mL / min) to obtain 45 mg of the title compound 20, with a yield of 20.6%. LC-MS (ESI): m / z 590.2 [M+H] + 。 1 1H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 8.62 (d, J = 5.1 Hz, 1H), 7.72 (d, J = 6 Hz, 2H), 7.19 (d, J = 9.0 Hz, 3H), 7.02 (d, J = 9.1 Hz, 2H), 5.10 (s, 2H), 5.06 (s, 1H), 4.46 (t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.2 Hz, 2H), 3.35 (s, 3H), 1.43 (s, 3H), 0.78 (s, 3H).

[0282] Example 21: Preparation of Compound 21

[0283]

[0284] Preparation of Compound 21-2

[0285] Dissolve Compound 21-1 (1 g, 4.22 mmol) in a solution of 1,4-dioxane (10 mL) and water (3 mL). Sequentially add Pd(dppf)Cl2 (326 mg, 0.45 mmol), 4-hydroxybenzeneboronic acid (815 mg, 5.91 mmol), and potassium carbonate (1.17 g, 8.44 mmol). Stir the reaction system at 90 °C for 5 hours. After the reaction is completed, cool to room temperature, filter by suction. Add water (20 mL) to the filtrate and extract with dichloromethane (30 mL) three times. Combine the organic phases, wash twice with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter by suction, and concentrate the filtrate to obtain the crude product. Purify by silica gel column chromatography (EA / PE = 0 - 30%) to obtain 350 mg of the title compound 21-2. LC-MS (ESI): m / z 250.0 [M+H] + 。

[0286] Preparation of Compound 21-3

[0287] Dissolve Compound 21-2 (350 mg, 1.41 mmol) in a solution of 1,4-dioxane (10 mL) and water (3 mL). Sequentially add Pd(dppf)Cl2 (103 mg, 0.14 mmol), potassium carbonate (389 mg, 2.82 mmol), and Compound 14-3 (720 mg, 2.11 mmol). Stir the reaction system at 90 °C for 5 hours. After the reaction is completed, cool to room temperature, filter by suction. Add water (20 mL) to the filtrate and extract with dichloromethane (30 mL) three times. Combine the organic phases, wash twice with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter by suction, and concentrate the filtrate to obtain the crude product. Purify by silica gel column chromatography (EA / PE = 0 - 30%) to obtain 200 mg of the title compound 21-3. LC-MS (ESI): m / z 385.0 [M+H] + 。

[0288] Preparation of Compound 21-4

[0289] Compound 21-3 (200 mg, 0.52 mmol), cesium carbonate (339 mg, 1.04 mmol) and 2-chloro-4-(chloromethyl)pyrimidine (127 mg, 0.78 mmol) were dissolved in acetonitrile (2 mL). The reaction system was stirred at 80 °C for 3 hours. After the reaction, it was cooled to room temperature, filtered by suction, and water (20 mL) was added to the filtrate, and it was extracted 3 times with dichloromethane (30 mL). The organic phases were combined, washed 2 times with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (EA / PE = 0 - 30%) to obtain 160 mg of the title compound 21-4. LC-MS (ESI): m / z 511.0 [M+H] + .

[0290] Preparation of Compound 21

[0291] Compound 21-4 (80 mg, 0.16 mmol) was dissolved in acetonitrile (3 mL). 2-Oxa-6-azaspiro[3.3]heptane (24 mg, 0.24 mmol) and cesium carbonate (104 mg, 0.32 mmol) were added successively. The reaction system was stirred at 80 °C for 2 hours. After the reaction, water (10 mL) was added, and it was extracted 3 times with dichloromethane (20 mL). The organic phases were combined, washed 2 times with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, 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: 45% - 65% acetonitrile gradient elution within 12 minutes; flow rate: 30 mL / min) to obtain 32 mg of the title compound 21. LC-MS (ESI): m / z 574.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 2.2 Hz, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 5.0 Hz, 1H), 8.18 (d, J = 8.9 Hz, 2H), 8.07–7.90 (m, 3H), 7.15 (d, J = 8.9 Hz, 2H), 6.78 (d, J = 5.0 Hz, 1H), 5.09 (s, 2H), 4.73 (s, 4H), 4.54 (t, J = 5.2 Hz, 2H), 4.22 (s, 4H), 4.02 (t, J = 5.2 Hz, 2H).

[0292] Example 22: Preparation of Compound 22

[0293]

[0294] Preparation of Compound 22

[0295] Dissolve Compound 21-4 (80 mg, 0.16 mmol) in 1,4-dioxane (2 mL). Then, successively add dimethylphosphine oxide (19 mg, 0.24 mmol), Xantphos (19 mg, 0.03 mmol), Pd2(dba)3 (29 mg, 0.03 mmol) and DIPEA (41 mg, 0.32 mmol). Stir the reaction system at 100 °C for 3 hours. After the reaction is completed, cool it to room temperature, add water (5 mL), and extract with dichloromethane (10 mL) three times. Combine the organic phases, wash them twice with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter by suction, and concentrate the filtrate to obtain the crude product. After purification 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 with gradient elution within 12 minutes; flow rate: 30 mL / min), 11 mg of the title compound 22 is obtained. LC-MS (ESI): m / z 553.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 5.2 Hz, 1H), 8.65 (d, J = 2.2 Hz, 1H), 8.62 (d, J = 2.2 Hz, 1H), 8.22 (d, J = 8.9 Hz, 2H), 8.04 (dd, J = 7.1, 1.8 Hz, 1H), 8.04–7.91 (m, 2H), 7.76 (dd, J = 5.2, 3.2 Hz, 1H), 7.23 (d, J = 8.9 Hz, 2H), 5.40 (s, 2H), 4.54 (t, J = 5.2 Hz, 2H), 4.02 (t, J = 5.2 Hz, 2H), 1.77 (d, J = 13.7 Hz, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 34.05 (s, 1H).

[0296] Example 23: Preparation of Compound 23

[0297]

[0298] Preparation of Compound 23-2

[0299] Compound 23-1 (513 mg, 2.45 mmol) was dissolved in DMF (5.0 mL). 2-Chloro-4-(chloromethyl)pyrimidine (400 mg, 2.455 mmol) and potassium carbonate (1.02 g, 7.36 mmol) were added successively. The reaction system was purged with nitrogen three times and stirred at 60 °C for 2 hours. After the reaction was completed, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE = 0 - 20%) to obtain 426 mg of the title compound 23-2. LC-MS (ESI): m / z 336.2 [M+H] + 。

[0300] Preparation of Compound 23-3

[0301] Compound 23-2 (426 mg, 1.27 mmol) was dissolved in DCM (5 mL). At 0 °C, a 1,4-dioxane solution of hydrogen chloride (4 N, 3 mL, 12.0 mmol) was added dropwise. The reaction system was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated to obtain 300 mg of the title compound 23-3 as a crude product. LC-MS (ESI): m / z 236.2 [M+H] + 。

[0302] Preparation of Compound 23-5

[0303] Compound 23-4 (120.0 g, 643.1 mmol) was dissolved in MeCN (1.2 L). The temperature was lowered to 0 °C in an ice-water bath, p-toluenesulfonic acid monohydrate (122.2 g, 643.1 mmol) was added, and the mixture was stirred at this temperature for 30 minutes. Subsequently, NIS (173.6 g, 771.1 mmol) was added. After the addition was complete, the ice-water bath was removed, and the reaction system was stirred at room temperature for 16 h. Sodium sulfite was added to quench the reaction in the reaction system. Water (3 L) was added, and the mixture was extracted with ethyl acetate (2 L × 2). The organic phase was washed with saturated brine (2 L × 3), dried over anhydrous sodium sulfate, the organic phase was concentrated, and purified by normal-phase silica gel column chromatography (EA / PE = 0 - 30%) to obtain 168.0 g of the title compound 23-5 as a white solid, with a yield of 84%.

[0304] Preparation of Compound 23-6

[0305] Compound 23-5 (163.0 g, 0.52 mol) was dissolved in DMF (800 mL). Cesium carbonate (338.9 g, 1.04 mol), 1-bromo-2-chloroethane (149.1 g, 1.04 mol) and H2O (12 mL) were added successively. The temperature was raised to 65 °C and the reaction was carried out for 16 h. After the reaction was completed, the mixture was filtered. Water (3 L) was added to the filtrate, and the mixture was extracted with ethyl acetate (2 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 column chromatography (EA / PE = 0 - 30%) to obtain 136.9 g of the white solid title compound 23-6 with a yield of 70%.

[0306] Preparation of Compound 23-7

[0307] Compound 23-6 (168.0 g, 448.0 mmol) was dissolved in DMF (1 L). 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 reaction for 4 h. The reaction was monitored by TLC (PE / EA = 5 / 1, product Rf≈0.5). After the reaction was completed, it was filtered through thin-layer diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was collected and water (4 L) was added. The mixture was 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 column chromatography (EA / PE = 0 - 20%) to obtain 66.7 g of the white solid title compound 23-7 with a yield of 54%. 1 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 5.2 Hz, 1H), 6.93 (d, J = 5.2 Hz, 1H), 5.32 (s, 2H), 2.51 (s, 3H), 2.05 (s, 2H).

[0308] Preparation of Compound 23-8

[0309] Compound 23-7 (500 mg, 1.82 mmol) was dissolved in THF / water (5.0 mL / 5.0 mL), and sodium hydroxide (438 mg, 10.92 mmol) was added dropwise. The reaction system was stirred at room temperature for 2 h. After the reaction was completed, the organic solvent was evaporated, the pH was adjusted to 4 - 5 with dilute hydrochloric acid, and the product was freeze-dried to obtain 470 mg of the crude title compound 23-8. LC-MS (ESI): m / z 260.0 [M+H] + 。

[0310] Preparation of Compound 23-9

[0311] Compound 23-8 (308 mg, 1.18 mmol) was dissolved in DMF (5 mL). At 0 °C, compound 23-3 (345 mg, 1.42 mmol), HATU (675 mg, 1.78 mmol) and diisopropylethylamine (612 mg, 4.74 mmol) were added successively. The reaction system was stirred at room temperature for 4 hours. After the reaction was completed, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (EA / PE = 0 - 25%) to obtain 550 mg of the title compound 23-9. LC-MS (ESI): m / z 477.2 [M+H] + 。

[0312] Preparation of Compound 23-11

[0313] Compound 23-9 (520 mg, 1.09 mmol) was added to anhydrous toluene (10 mL). At 0 °C, triphenylphosphine (334 mg, 2.18 mmol) was added. The reaction system was purged with nitrogen three times and then stirred at 110 °C for 3 hours. After the reaction was completed, the mixture was concentrated to obtain a crude oily product. The crude oily product (540 mg, 1.09 mmol) was dissolved in anhydrous THF (10 mL). At 0 °C, aminoacetaldehyde diethyl acetal (188 mg, 1.41 mmol) was added, and the mixture was stirred at room temperature for 14 hours. After the reaction was completed, the brown oily product obtained by rotary evaporation was added to anhydrous toluene (10 mL), and p-toluenesulfonic acid (349 mg, 2.02 mmol) was added. Under nitrogen protection, the reaction system was stirred at 110 °C for 2.5 hours. After the reaction was completed, water (10 mL) was added, and the mixture was extracted with dichloromethane (30 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (EA / PE = 0 - 35%) to obtain 46 mg of the title compound 23-11. LC-MS (ESI): m / z 500.2 [M+H] + 。

[0314] Preparation of Compound 23

[0315] Compound 23-11 (41 mg, 0.082 mmol) was dissolved in ethanol (3 mL) solution. 2-Thia-6-azaspiro[3.3]heptane-2,2-dioxide (12 mg, 0.085 mmol) and DIEA (42 mg, 0.33 mmol) were added successively. The reaction system was stirred at room temperature for 16 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) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain the 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: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile gradient elution within 12 minutes; flow rate: 30 mL / min) to obtain 6 mg of the title compound 23. LC-MS (ESI): m / z 611.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 5.0 Hz, 1H), 7.65 (d, J = 2.1 Hz, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.50 (d, J=1.3 Hz, 1H), 7.32 (d, J=8.9 Hz, 2H), 7.21 (d, J=1.2 Hz, 1H), 7.14 (d, J=8.9 Hz, 2H), 6.79 (d, J = 5.0 Hz, 1H), 5.11 (s, 2H), 4.51 (s, 4H), 4.46 (t, J = 5.2 Hz, 2H), 4.27 (s, 4H), 3.95 (t, J = 5.2 Hz, 2H).

[0316] Example 24: Preparation of Compound 24

[0317]

[0318] Preparation of Compound 24-2

[0319] Compound 1-4 (450 mg, 1.46 mmol) was dissolved in 1,4-dioxane / water (8 mL / 2 mL). 4-Hydroxyphenylboronic acid pinacol ester (482 mg, 2.19 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (110 mg, 0.15 mmol) and potassium carbonate (605 mg, 4.38 mmol) were added successively. After purging with nitrogen three times, the reaction system was stirred at 100 °C for 14 hours. After the reaction was completed, it was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL) three times. The combined organic phases were washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (EA / PE = 0 - 5%) to obtain 300 mg of the title compound 24-2. LC-MS (ESI): m / z 308.0 [M+H] + 。

[0320] Preparation of Compound 24-3

[0321] Compound 24-2 (300 mg, 0.97 mmol) was dissolved in DCM (10 mL). At 0 °C, triethylamine (493 mg, 4.87 mmol) and trifluoromethanesulfonic anhydride (550 mg, 1.94 mmol) were added dropwise successively. The reaction system was stirred at 0 °C for 1 hour. After the reaction was completed, water (30 mL) was added, and the mixture was extracted with dichloromethane (50 mL) three times. The combined organic phases were washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (EA / PE = 0 - 5%) to obtain 300 mg of the title compound 24-3. LC-MS (ESI): m / z 440.0 [M+H] + 。

[0322] Preparation of Compound 24-5

[0323] Compound 24-3 (300 mg, 0.68 mmol) was dissolved in 1,4-dioxane / water (8 mL / 2 mL). 4-Hydroxyphenylboronic acid pinacol ester (225 mg, 1.02 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (50 mg, 0.07 mmol) and potassium carbonate (282 mg, 2.04 mmol) were added successively. After purging with nitrogen three times, the reaction system was stirred at 100 °C for 14 hours. After the reaction was completed, it was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL) three times. The combined organic phases were washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (EA / PE = 0–10%) to obtain 122 mg of the title compound 24-5. LC-MS (ESI): m / z 384.0 [M+H]+ .

[0324] Preparation of Compound 24-6

[0325] Compound 24-5 (122 mg, 0.32 mmol) was dissolved in DMF (5 mL), and 2-chloro-4-(chloromethyl)pyrimidine (78 mg, 0.48 mmol) and cesium carbonate (209 mg, 0.64 mmol) were added in sequence at 0°C. The reaction system was stirred at room temperature for 2 hours. After the reaction was completed, water (20 mL) was added, and ethyl acetate (50 mL) was extracted 3 times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by chromatography (EA / PE: = 10-50%) to obtain 70 mg of the title compound 24-6. LC-MS (ESI): m / z 510.2 [M+H] + .

[0326] Preparation of compound 24

[0327] Compound 24-6 (32 mg, 0.063 mmol) was dissolved in a dioxane (3 mL) solution, and 1-aminotetrahydrothiophene-1-oxide (9 mg, 0.075 mmol), DIEA (25 mg, 0.19 mmol), tris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (6 mg, 0.01 mmol) were added in sequence, and nitrogen was replaced three times. The reaction system was stirred at 100°C for 14 hours. After the reaction was completed, the mixture was cooled to room temperature, the insoluble solid was filtered off, 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, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by preparative separation (preparative 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 6.6 mg of the title compound 24. LC-MS (ESI): m / z 593.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 5.1 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 5.1 Hz, 1H), 5.13 (s, 2H), 4.49 (t, J = 5.2 Hz, 2H), 4.01 (t, J = 5.2 Hz, 2H), 3.63–3.53 (m, 2H), 3.41–3.35 (m, 2H), 2.28–2.16 (m, 2H), 2.16–2.03 (m, 2H).

[0328] Example 25: Preparation of Compound 25

[0329]

[0330] Preparation of Compound 25-2

[0331] Compound 1-4 (800 mg, 2.71 mmol) was dissolved in 1,4-dioxane / water (12 mL / 3 mL). Then, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (894 mg, 4.07 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (197 mg, 0.27 mmol) and potassium carbonate (1.12 g, 8.13 mmol) were added successively. The reaction system was purged with nitrogen three times and stirred at 100 °C for 14 h. After the reaction was completed, it was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL) three times. The organic phases were combined, washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (EA / PE = 0 - 5%) to give 736 mg of the title compound 25-2. LC-MS (ESI): m / z 308.0 [M+H] + .

[0332] Preparation of Compound 25-3

[0333] Compound 25-2 (570 mg, 1.85 mmol) was dissolved in DCM (15 mL). At 0 °C, triethylamine (936 mg, 9.25 mmol) and trifluoromethanesulfonic anhydride (1.04 g, 3.70 mmol) were added dropwise successively. The reaction system was stirred at 0 °C for 1 hour. After the reaction was completed, water (30 mL) was added, and the mixture was extracted with dichloromethane (50 mL) three times. The organic phases were combined, washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (EA / PE = 0 - 5%) to obtain 610 mg of the title compound 25-3. LC-MS (ESI): m / z 440.0 [M+H] + 。

[0334] Preparation of Compound 25-4

[0335] Compound 25-3 (610 mg, 1.39 mmol) was dissolved in 1,4-dioxane / water (8 mL / 2 mL). 4-Hydroxyphenylboronic acid pinacol ester (396 mg, 1.80 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (100 mg, 0.14 mmol) and potassium carbonate (575 mg, 4.17 mmol) were added successively. The reaction system was purged with nitrogen three times and stirred at 100 °C for 14 hours. After the reaction was completed, it was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL) three times. The organic phases were combined, washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (EA / PE = 0 - 10%) to obtain 170 mg of the title compound 25-4. LC-MS (ESI): m / z 384.0 [M+H] + 。

[0336] Preparation of Compound 25-5

[0337] Compound 25-4 (170 mg, 0.44 mmol) was dissolved in DMF (5 mL). At 0 °C, 2-chloro-4-(chloromethyl)pyrimidine (144 mg, 0.88 mmol) and cesium carbonate (288 mg, 0.88 mmol) were added successively. The reaction system was stirred at room temperature for 2 hours. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (EA / PE = 10 - 50%) to obtain 120 mg of the title compound 25-5. LC-MS (ESI): m / z 510.2 [M+H] + 。

[0338] Preparation of Compound 25

[0339] Compound 25-5 (50 mg, 0.098 mmol) was dissolved in 1,4-dioxane (3 mL). 1-Aminothioxane-1-oxide (15 mg, 0.127 mmol), DIEA (38 mg, 0.294 mmol), tris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6 mg, 0.01 mmol) were added successively, and the reaction system was purged with nitrogen three times. The reaction system was stirred at 100 °C for 14 hours. After the reaction was completed, it was cooled to room temperature, the insoluble solids were filtered off, water (10 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (20 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, 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: 45%-65% acetonitrile gradient elution within 12 minutes; flow rate: 30 mL / min) to obtain 8.5 mg of the title compound 25. LC-MS (ESI): m / z 593.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 5.0 Hz, 1H), 7.53–7.45 (m, 5H), 7.44–7.40 (m, 1H), 7.05 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 5.1 Hz, 1H), 5.06 (s, 2H), 4.42 (t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.2 Hz, 2H), 3.62–3.52 (m, 2H), 3.40–3.34 (m, 2H), 2.26–2.15 (m, 2H), 2.15–2.04 (m, 2H).

[0340] Example 26: Preparation of Compound 26

[0341]

[0342] Preparation of Compound 26

[0343] Compound 25-5 (50 mg, 0.098 mmol) was dissolved in dioxane (3 mL). Dimethylphosphine oxide (15 mg, 0.196 mmol), DIEA (38 mg, 0.294 mmol), tris(dibenzylideneacetone)dipalladium(0) (9 mg, 0.01 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6 mg, 0.01 mmol) were added successively, and the reaction system was purged with nitrogen three times. The reaction system was stirred at 100 °C for 14 h. After the reaction was completed, it was cooled to room temperature, the insoluble solids were filtered off, water (10 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (20 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% aqueous formic acid solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile gradient elution in 12 min; flow rate: 30 mL / min) to obtain 14.2 mg of the title compound 26. LC-MS (ESI): m / z 552.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 5.2, 0.6 Hz, 1H), 7.67 (dd, J = 5.2, 3.2 Hz, 1H), 7.54–7.45 (m, 5H), 7.42 (dt, J = 7.0, 1.3 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 5.31 (s, 2H), 4.42 (t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.2 Hz, 2H), 1.76 (d, J = 13.7 Hz, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 34.02.

[0344] Example 27: Preparation of Compound 27

[0345]

[0346] Preparation of Compound 27

[0347] Compound 24-6 (80 mg, 0.157 mmol) was dissolved in 1,4-dioxane (5 mL). Dimethylphosphine oxide (25 mg, 0.314 mmol), DIEA (101 mg, 0.785 mmol), tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.016 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (14 mg, 0.024 mmol) were added successively, and the reaction system was purged with nitrogen three times. The reaction system was stirred at 110 °C for 14 hours. After the reaction was completed, it was cooled to room temperature, and the insoluble solids were filtered off. The filtrate was added with water (10 mL), and extracted with dichloromethane (20 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% aqueous formic acid solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile was eluted gradiently within 12 minutes; flow rate: 30 mL / min) to obtain 21 mg of the title compound 27. LC-MS (ESI): m / z 552.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (dd, J = 5.2, 0.6 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.76 (m, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 5.38 (s, 2H), 4.50 (t, J = 5.2 Hz, 2H), 4.01 (t, J = 5.2 Hz, 2H), 1.77 (d, J = 13.7 Hz, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 34.07.

[0348] Example 28: Preparation of Compound 28

[0349]

[0350] Preparation of Compound 28

[0351] Compound 24-6 (80 mg, 0.157 mmol) was dissolved in ethanol (3 mL) solution. 2-Thia-6-azaspiro[3.3]heptane-2,2-dioxide (37 mg, 0.251 mmol) and triethylamine (79 mg, 0.785 mmol) were added successively, and the reaction system was purged with nitrogen three times. The reaction system was stirred at 90 °C under microwave for 3 hours. After the reaction was completed, it was cooled to room temperature, the insoluble solid was filtered off, water (10 mL) was added to the filtrate, and it was extracted with dichloromethane (20 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain the crude product. After purification 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 gradient elution within 12 minutes; flow rate: 30 mL / min), 38 mg of the title compound 28 was obtained. LC-MS (ESI): m / z 621.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 5.0 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 5.0 Hz, 1H), 5.09 (s, 2H), 4.52 (s, 4H), 4.49 (t, J = 5.2 Hz, 2H), 4.29 (s, 4H), 4.01 (t, J = 5.2 Hz, 2H).

[0352] Example 29: Preparation of Compound 29

[0353]

[0354] Preparation of Compound 29

[0355] Compound 25-5 (80 mg, 0.157 mmol) was dissolved in ethanol (3 mL) solution. 2-Thia-6-azaspiro[3.3]heptane-2,2-dioxide (37 mg, 0.251 mmol) and triethylamine (79 mg, 0.785 mmol) were added successively, and the reaction system was purged with nitrogen three times. The reaction system was stirred at 90 °C under microwave for 3 hours. After the reaction, it was cooled to room temperature, the insoluble solid was filtered off, water (10 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (20 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain the crude product. After purification 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 gradient elution within 12 minutes; flow rate: 30 mL / min), 55 mg of the title compound 29 was obtained. LC-MS (ESI): m / z 621.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 5.0 Hz, 1H), 7.52–7.45 (m, 5H), 7.43–7.39 (m, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 5.0 Hz, 1H), 5.02 (s, 2H), 4.51 (s, 4H), 4.42 (t, J = 5.2 Hz, 2H), 4.27 (s, 4H), 3.96 (t, J = 5.2 Hz, 2H).

[0356] Example 30: Preparation of Compound 30

[0357]

[0358] Preparation of Compound 30

[0359] Dissolve compound 24-6 (30 mg, 0.059 mmol), 2-oxa-6-aza-spiro[3.3]heptane (15 mg, 0.089 mmol), and DIPEA (44 mg, 0.34 mmol) in ethanol (3 mL). Stir the reaction system at 90 °C for 15 hours. After the reaction is completed, evaporate the ethanol under reduced pressure, dissolve it with acetonitrile and dioxane, and purify it 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 gradient elution within 12 minutes; flow rate: 30 mL / min) to obtain 19.5 mg of compound 30. LC-MS (ESI): m / z 573.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 5.0 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.21 (d, J = 2.3 Hz, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 5.0 Hz, 1H), 5.07 (s, 2H), 4.73 (s, 4H), 4.49 (t, J = 5.2 Hz, 2H), 4.22 (s, 4H), 4.00 (t, J = 5.2 Hz, 2H).

[0360] Example 31: Preparation of Compound 31

[0361]

[0362] Preparation of Compound 31-1

[0363] Dissolve compound 24-5 (120 mg, 0.312 mmol) in DMF (5 mL), add 4-(4-(bromomethyl)phenyl)-2-chloropyrimidine (116 mg, 0.409 mmol) thereto, add potassium carbonate (86 mg, 0.624 mmol), and stir the reaction system at 60 °C for 2 hours. After the reaction is completed, add water (50 mL), extract with ethyl acetate (50 mL) 3 times, combine the organic phases, wash with saturated brine (30 mL) 2 times, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product, which is purified by silica gel column chromatography (PE / EA = 100% - 90%) to obtain 122 mg of compound 31-1. LC-MS (ESI): m / z 586.1 [M+H] + .

[0364] Preparation of Compound 31

[0365] Compound 31-1 (40 mg, 0.068 mmol), dimethylphosphine oxide (16 mg, 0.204 mmol), DIPEA (44 mg, 0.34 mmol), tris(dibenzylideneacetone)dipalladium(0) (6 mg, 0.007 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6 mg, 0.010 mmol) were added to 1,4-dioxane (2 mL), and the nitrogen was replaced three times. Then the reaction system was stirred at 110 °C for 15 hours. After the reaction was completed, the solvent was evaporated to dryness, dissolved in acetonitrile, and 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 was eluted gradiently within 12 minutes; flow rate: 30 mL / min) to obtain 35 mg of compound 31. LC-MS (ESI): m / z 628.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (dd, J = 5.4, 0.8 Hz, 1H), 8.32 (d, J = 8.4 Hz, 2H), 8.26–8.18 (m, 3H), 7.85 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.5 Hz, 2H), 7.73–7.65 (m, 4H), 7.15 (d, J = 8.8 Hz, 2H), 5.31 (s, 2H), 4.49 (t, J = 5.2 Hz, 2H), 4.01 (t, J = 5.2 Hz, 2H), 1.83 (d, J = 13.7 Hz, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 34.37 (s, 1P).

[0366] Example 32: Preparation of Compound 32

[0367]

[0368] Preparation of Compound 32

[0369] Compound 31-1 (38 mg, 0.065 mmol), 2-thia-6-azaspiro[3.3]heptane-2,2-dioxide (19 mg, 0.130 mmol), and DIPEA (44 mg, 0.34 mmol) were added to ethanol (2 mL). Then the reaction system was stirred at 90 °C for 15 h. After the reaction was completed, the solvent was evaporated, dissolved in acetonitrile, and 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 gradient elution within 12 min; flow rate: 30 mL / min) to obtain 5.2 mg of compound 32. LC-MS (ESI): m / z 697.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 5.2 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.16 (d, J = 8.2 Hz, 2H), 7.85 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 5.3 Hz, 1H), 7.14 (d, J = 8.9 Hz, 2H), 5.27 (s, 2H), 4.53 (s, 4H), 4.49 (t, J = 5.2 Hz, 2H), 4.34 (s, 4H), 4.01 (t, J = 5.2 Hz, 2H).

[0370] Example 33: Preparation of Compound 33

[0371]

[0372] Preparation of Compound 33

[0373] Compound 31-1 (39 mg, 0.066 mmol), compound 33-1 (27 mg, 0.198 mmol), DIPEA (44 mg, 0.34 mmol), tris(dibenzylideneacetone)dipalladium(0) (6 mg, 0.007 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6 mg, 0.010 mmol) were added to 1,4-dioxane (2 mL). The nitrogen was displaced three times. The reaction system was stirred at 110 °C for 15 h. After the reaction was completed, the solvent was evaporated under reduced pressure and dissolved in acetonitrile. It 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 gradient elution within 12 min; flow rate: 30 mL / min) to obtain 8.6 mg of compound 33. LC-MS (ESI): m / z 685.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 5.3 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.15 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 5.3 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 5.27 (s, 2H), 4.49 (t, J = 5.2 Hz, 2H), 4.16–4.08 (m, 2H), 4.04–3.93 (m, 4H), 3.86 (d, J = 15.0 Hz, 2H), 3.67–3.58 (m, 2H).

[0374] Example 34: Preparation of Compound 34

[0375]

[0376] Preparation of Compound 34-1

[0377] Compound 1-4 (3 g, 10.17 mmol), 1,4-benzenediboronic acid bis(pinacol) ester (5.03 g, 15.25 mmol), and sodium carbonate (3.23 g, 30.51 mmol) were dissolved in 1,4-dioxane (20 mL) and water (5 mL), and Pd(dppf)Cl2 (744 mg, 1.017 mmol) was added thereto. After completion of the addition, the reaction system was purged with nitrogen three times and stirred at 75 °C for 2 hours. After completion of the reaction, water (50 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL). 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, which was purified by silica gel column chromatography (PE / EA = 100% - 75%) to obtain 2.2 g of compound 34-1.

[0378] Preparation of Compound 34-2

[0379] Compound 34-1 (1.26 g, 3.02 mmol), 2-bromo-5-hydroxypyridine (0.35 g, 2.01 mmol), and potassium carbonate (833 mg, 6.03 mmol) were dissolved in 1,4-dioxane (20 mL) and water (5 mL), and Pd(dppf)Cl2 (147 mg, 0.201 mmol) was added thereto. After completion of the addition, the reaction system was purged with nitrogen three times and stirred at 95 °C for 3 hours. After completion of the reaction, water (50 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL). 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, which was purified by silica gel column chromatography (PE / EA = 100% - 50%) to obtain 450 mg of compound 34-2. LC-MS (ESI): m / z 385.4 [M+H] + .

[0380] Preparation of Compound 34-3

[0381] Compound 34-2 (85 mg, 0.22 mmol) was dissolved in DMF (3 mL), 2-chloro-4-(chloromethyl)pyrimidine (72 mg, 0.44 mmol) was added thereto, and the mixture was stirred at room temperature for 15 minutes. Cesium carbonate (143 mg, 0.44 mmol) was added, and the reaction system was stirred at 60 °C for 2 hours. After completion of the reaction, water (50 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE / EA = 100% - 90%) to obtain 72 mg of compound 34-3. LC-MS (ESI): m / z 511.2 [M+H] + .

[0382] Preparation of Compound 34

[0383] Dissolve Compound 34-3 (35 mg, 0.068 mmol), 2-thia-6-azaspiro[3.3]heptane, 2,2-dioxide (15 mg, 0.103 mmol), and DIPEA (44 mg, 0.34 mmol) in ethanol (5 mL). Stir the reaction system at 90 °C for 15 hours. After the reaction is completed, evaporate the ethanol to dryness, dissolve it with acetonitrile and dioxane, and purify it 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 gradient elution within 12 minutes; flow rate: 30 mL / min) to obtain 7.5 mg of Compound 34. LC-MS (ESI): m / z 622.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 3.0 Hz, 1H), 8.42 (d, J = 4.8 Hz, 1H), 8.27 (d, J = 2.3 Hz, 1H), 8.25 (d, J = 2.3 Hz, 1H), 8.14 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.56 (dd, J = 8.8, 3.0 Hz, 1H), 6.87 (d, J = 5.0 Hz, 1H), 5.18 (s, 2H), 4.56–4.46 (m, 6H), 4.28 (s, 4H), 4.01 (t, J = 5.1 Hz, 2H).

[0384] Example 35: Preparation of Compound 35

[0385]

[0386] Preparation of Compound 35-1

[0387] Compound 1-4 (1 g, 3.39 mmol), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (1.22 g, 5.09 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (248 mg, 0.34 mmol), and potassium carbonate (937 mg, 6.78 mmol) were dissolved in dioxane (10 mL) and water (2 mL). After addition, the reaction system was stirred at 105 °C for 16 h. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE / EA = 100% - 66%) to obtain 570 mg of compound 35-1. LC-MS (ESI): m / z 328.0 [M+H] + .

[0388] Preparation of compound 35-2

[0389] Compound 35-1 (150 mg, 0.46 mmol), 4-hydroxyphenylboronic acid (94 mg, 0.68 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (33 mg, 0.05 mmol), and potassium carbonate (126 mg, 0.91 mmol) were dissolved in dioxane (0.5 mL) and water (0.1 mL). After addition, the reaction system was stirred at 90 °C for 16 h. After completion of the reaction, it was cooled to room temperature, the reaction solution was filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE / EA = 100% - 66%) to obtain 100 mg of compound 35-2. LC-MS (ESI): m / z 386.2 [M+H] + .

[0390] Preparation of compound 35-3

[0391] Compound 35-2 (80 mg, 0.21 mmol) was dissolved in DMF (1 mL), and 2-chloro-4-(chloromethyl)pyrimidine (67 mg, 0.41 mmol) and potassium carbonate (72 mg, 0.52 mmol) were added thereto. After addition, the reaction system was stirred at 60 °C for 2 h. After completion of the reaction, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL) three times. The organic phases were combined, washed twice with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (DCM / MeOH = 100% - 90%) to obtain 80 mg of compound 35-3. LC-MS (ESI): m / z 512.2 [M+H] + .

[0392] Preparation of compound 35

[0393] Compound 35-3 (65 mg, 0.13 mmol), 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide (28 mg, 0.19 mmol), and DIPEA (49 mg, 0.38 mmol) were dissolved in tetrahydrofuran (0.5 mL) and ethanol (0.5 mL). The reaction system was stirred by microwave at 100 °C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, and the reaction solution was concentrated to obtain a crude product, which was purified by trituration with methanol to obtain 22.14 mg of compound 35. LC-MS (ESI): m / z 623.3 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 2H), 8.44 (d, J = 2.3 Hz, 1H), 8.43–8.37 (m, 4H), 7.18 (d, J = 9.0 Hz, 2H), 6.84 (d, J = 5.0 Hz, 1H), 5.13 (s, 2H), 4.57–4.46 (m, 6H), 4.29 (s, 4H), 4.01 (t, J = 5.2 Hz, 2H).

[0394] Example 36: Preparation of Compound 36

[0395]

[0396] Preparation of Compound 36-1

[0397] Under nitrogen protection, 2,6-dibromopyridine (1.77 g, 7.46 mmol), compound 14-3 (1.7 g, 4.97 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (364 mg, 497.04 μmol), K2CO3 (2.06 g, 14.91 mmol), dioxane (20 mL), and H2O (5 mL) were added to a reaction flask. After being purged with nitrogen three times, the reaction was carried out at 90 °C for 5 h. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (PE / EA = 100% - 90%) to obtain 600 mg of the title compound 36-1. LC-MS (ESI): m / z 373.0 [M+H] + . Preparation of Compound 36-2

[0398] Under nitrogen protection, compound 36-1 (600 mg, 1.61 mmol), 4-[(trimethylsilyl)ethynyl]phenylboronic acid pinacol ester (581 mg, 1.94 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (118 mg, 161.27 μmol), K2CO3 (669 mg, 4.84 mmol), dioxane (10 mL) and H2O (2 mL) were added to a reaction flask. After replacing the nitrogen three times, the reaction was carried out at 90 °C for 5 hours. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 100% - 50%) to obtain 420 mg of the title compound 36-2. LC-MS (ESI): m / z 465.2 [M+H] + .

[0399] Preparation of compound 36-3

[0400] Compound 36-2 (420 mg, 902.36 μmol), KF (262 mg, 4.51 mmol) and methanol (20 mL) were added to a reaction flask, and the reaction was carried out at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA / PE = 0 - 40%) to obtain 300 mg of the title compound 36-3. LC-MS (ESI): m / z 393.0 [M+H] + .

[0401] Preparation of compound 36-4

[0402] Compound 36-3 (200 mg, 508.56 μmol), 2-chloro-5-iodopyridine (146 mg, 610.28 μmol), bis(triphenylphosphine)palladium dichloride (71 mg, 101.71 μmol), CuI (80 mg, 101.71 μmol), TEA (257 mg, 2.54 mmol) and THF (2 mL) were added to a reaction flask. After replacing the nitrogen three times, the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 100% - 50%) to obtain 200 mg of the title compound 36-4. LC-MS (ESI): m / z 505.0 [M+H] + .

[0403] Preparation of compound 36

[0404] Compound 36-4 (100 mg, 197.71 μmol) was dissolved in DMF (1 mL). Dimethylphosphine oxide (46 mg, 593.14 μmol), DIEA (77 mg, 593.14 μmol), tris(dibenzylideneacetone)dipalladium (20 mg, 21.90 μmol) and Xantphos (25 mg, 43.81 μmol) were added successively. After the reaction system was purged with nitrogen three times, it was reacted at 120 °C for 1 hour using microwave. After filtration, the crude product 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: 25%-85% acetonitrile gradient elution within 12 minutes; flow rate: 30 mL / min) to obtain 30 mg of the title compound 36. LC-MS (ESI): m / z 547.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 2H), 8.70–8.63 (m, 2H), 8.37 (d, J = 8.4 Hz, 2H), 8.19–8.03 (m, 3H), 7.81 (d, J = 8.2 Hz, 2H), 4.55 (t, J = 5.2 Hz, 2H), 4.02 (t, J = 5.2 Hz, 2H), 1.80 (d, J = 13.7 Hz, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 34.58 (s, 1P).

[0405] Example 37: Preparation of Compound 37

[0406]

[0407] Preparation of Compound 37-1

[0408] 2-Chloro-5-iodopyrimidine (100 mg, 415.92 μmol), 2-oxa-6-azaspiro[3.3]heptane hydrochloride (85 mg, 623.88 μmol), DIPA (538 mg, 4.16 mmol) and acetonitrile (1 mL) were added to a reaction flask and heated to 90 °C with stirring for 2 hours. Subsequently, ethyl acetate (10 mL) was added, and the organic phase was washed three times with saturated ammonium chloride aqueous solution (10 mL). The organic phase was evaporated to dryness, and the crude product was purified by silica gel column chromatography (EA / PE = 0-50%) to obtain 39 mg of Compound 37-1. LC-MS (ESI): m / z 304.0 [M+H] + .

[0409] Preparation of Compound 37

[0410] Compound 36-3 (39 mg, 127.14 μmol), compound 37-1 (50 mg, 127.14 μmol), bis(triphenylphosphine)palladium dichloride (18 mg, 25.43 μmol), CuI (20 mg, 25.43 μmol), triethylamine (64 mg, 635.70 μmol) and tetrahydrofuran (1 mL) were charged, purged with nitrogen three times, and stirred at room temperature for 16 hours. The reaction mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL) three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative separation (preparation method: mobile phase: A: 0.1% aqueous formic acid solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 20%-85% acetonitrile with gradient elution within 20 minutes; flow rate: 30 mL / min) to obtain 20 mg of the title compound 37. LC-MS (ESI): m / z 568.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 2.2 Hz, 1H), 8.64 (d, J = 2.2 Hz, 1H), 8.57 (s, 2H), 8.29 (d, J = 8.5 Hz, 2H), 8.12 (dd, J = 7.0, 1.7 Hz, 1H), 8.10–7.99 (m, 2H), 7.68 (d, J = 8.5 Hz, 2H), 4.73 (s, 4H), 4.55 (t, J = 5.2 Hz, 2H), 4.28 (s, 4H), 4.02 (t, J = 5.2 Hz, 2H).

[0411] Example 38: Preparation of Compound 38

[0412]

[0413] Preparation of Compound 38-1

[0414] Dissolve 2-hydroxy-5-iodopyridine (4.90 g, 22.17 mmol) in DMAc (20 mL). At room temperature, sequentially add 2-chloro-4-(chloromethyl)pyrimidine (4.34 g, 26.61 mmol), potassium carbonate (6.13 g, 44.34 mmol) and silver carbonate (3.72 g, 22.17 mmol). After addition, stir the reaction system at 95 °C for 3 hours. After the reaction is completed, add water (50 mL), and extract with ethyl acetate (100 mL) three times. Combine the organic phases, wash twice with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter by suction, and concentrate the filtrate to obtain the crude product. Purify by silica gel column chromatography (PE / EA = 100% - 30%) to obtain 1.05 g of the title compound 38-1. LC-MS (ESI): m / z 348.0 [M+H] + .

[0415] Preparation of Compound 38-2

[0416] Dissolve compound 38-1 (600 mg, 1.73 mmol), compound 34-1 (1.08 g, 2.59 mmol), potassium carbonate (595.6 mg, 4.32 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (126.3 mg, 0.173 mmol) in 1,4-dioxane (12 mL) and water (3 mL). Replace the gas with nitrogen three times, and stir the reaction system at 65 °C for 2 hours. After the reaction is completed, add water (30 mL), and extract with dichloromethane (50 mL) three times. Combine the organic phases, wash twice with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the crude product. Purify by silica gel column chromatography (PE / EA = 80% - 50%) to obtain 224 mg of the title compound 38-2. LC-MS (ESI): m / z 511.2 [M+H] + .

[0417] Preparation of Compound 38

[0418] Compound 38-2 (50 mg, 0.098 mmol) was dissolved in ethanol (3 mL). To this, 2-thia-6-azaspiro[3.3]heptane-2,2-dioxide (17.3 mg, 0.117 mmol) and DIEA (63.1 mg, 0.488 mmol) were added, and the reaction system was stirred at 90 °C for 15 hours. After the reaction was completed, the ethanol was evaporated, and the residue was dissolved in acetonitrile and dioxane. It 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 gradient elution in 12 minutes; flow rate: 30 mL / min) to obtain 48.2 mg of the title compound 38. LC-MS (ESI): m / z 622.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 2.5 Hz, 1H), 8.34 (d, J = 5.0 Hz, 1H), 8.26 (d, J = 2.3 Hz, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.17 (dd, J = 8.6, 2.6 Hz, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.7 Hz, 1H), 6.71 (d, J = 5.0 Hz, 1H), 5.32 (s, 2H), 4.54–4.45 (m, 6H), 4.27 (s, 4H), 4.01 (t, J = 5.2 Hz, 2H).

[0419] Example 39: Preparation of Compound 39

[0420]

[0421] Preparation of Compound 39-1

[0422] Compound 38-2 (20 mg, 0.039 mmol), 2-thia-6-azaspiro[3.3]heptane (4.5 mg, 0.039 mmol) and DIEA (25.3 mg, 1.42 mmol) were dissolved in ethanol (1 mL). After addition, the reaction system was stirred at 90 °C for 15 hours. After the reaction was completed, the reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE / EA = 70% - 30%) to obtain 23 mg of the title compound 39-1. LC-MS (ESI): m / z 590.2 [M+H] + .

[0423] Preparation of Compound 39

[0424] Compound 39-1 (23 mg, 0.039 mmol), iodobenzene diacetate (47.8 mg, 0.147 mmol) and ammonium carbamate (15.3 mg, 0.196 mmol) were dissolved in tetrahydrofuran (1 mL) and methanol (1 mL). After addition, the reaction system was stirred at room temperature for 15 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, dissolved in acetonitrile and dioxane, and purified by preparative separation (preparation method: mobile phase: A: 0.1% aqueous formic acid solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile was eluted with a gradient within 12 minutes; flow rate: 30 mL / min) to obtain 11.4 mg of the title compound 39. LC-MS (ESI): m / z 621.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 3.0 Hz, 1H), 8.41 (d, J = 4.9 Hz, 2H), 8.27 (d, J = 2.3 Hz, 1H), 8.25 (d, J = 2.3 Hz, 1H), 8.14 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.6 Hz, 2H), 7.56 (dd, J = 8.9, 3.0 Hz, 1H), 6.85 (d, J = 5.0 Hz, 1H), 5.17 (s, 2H), 4.50 (t, J = 5.2 Hz, 2H), 4.36–4.17 (m, 8H), 4.01 (t, J = 5.2 Hz, 2H).

[0425] Example 40: Preparation of Compound 40

[0426]

[0427] Preparation of Compound 40-1

[0428] Compound 24-6 (70 mg, 0.137 mmol), 2-thia-6-azaspiro[3.3]heptane (15.8 mg, 0.137 mmol) and DIEA (88.6 mg, 0.685 mmol) were dissolved in ethanol (1 mL). After addition, the reaction system was stirred at 90 °C for 15 hours. After the reaction was completed, the crude product was concentrated and purified by silica gel column chromatography (PE / EA = 70% - 30%) to obtain 70 mg of Compound 40-1. LC-MS (ESI): m / z 589.2 [M+H] + .

[0429] Preparation of Compound 40

[0430] Compound 40-1 (52 mg, 0.088 mmol), iodobenzene diacetate (85.8 mg, 0.265 mmol) and ammonium carbamate (27.5 mg, 0.353 mmol) were dissolved in tetrahydrofuran (1 mL) and methanol (1 mL). After addition, the reaction system was stirred at room temperature for 15 hours. After the reaction was completed, the solvent was evaporated, dissolved with acetonitrile and dioxane, and 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 gradient elution in 12 minutes; flow rate: 30 mL / min) to obtain 17.6 mg of the title compound 40. LC-MS (ESI): m / z 620.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 5.0 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 5.0 Hz, 1H), 5.08 (s, 2H), 4.54–4.47 (m, 3H), 4.37–4.18 (m, 8H), 4.01 (t, J = 5.2 Hz, 2H).

[0431] Example 41: Preparation of Compound 41

[0432]

[0433] Preparation of Compound 41-1

[0434] Compound 38-2 (145 mg, 0.283 mmol), 2-thia-6-azaspiro[3.3]heptane (39.2 mg, 0.340 mmol) and DIEA (183.1 mg, 1.42 mmol) were dissolved in ethanol (3 mL). After addition, the reaction system was stirred at 90 °C for 15 hours. After the reaction was completed, the crude product was concentrated and purified by silica gel column chromatography (PE / EA = 70% - 30%) to obtain 70 mg of the title compound 41-1. LC-MS (ESI): m / z 590.2 [M+H] + .

[0435] Preparation of Compound 41

[0436] Compound 41-1 (100 mg, 0.169 mmol), iodobenzene diacetate (164.7 mg, 0.508 mmol) and ammonium carbamate (52.9 mg, 0.677 mmol) were dissolved in tetrahydrofuran (2 mL) and methanol (2 mL). After addition, the reaction system was stirred at room temperature for 15 hours. After the reaction was completed, it was concentrated by rotary evaporation, dissolved in acetonitrile and dioxane, and 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 was eluted with a gradient within 12 minutes; flow rate: 30 mL / min) to obtain 28.9 mg of the title compound 41. LC-MS (ESI): m / z 621.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 2.6 Hz, 1H), 8.33 (d, J = 5.0 Hz, 1H), 8.25 (d, J = 2.3 Hz, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.17 (dd, J = 8.6, 2.6 Hz, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.6 Hz, 1H), 6.70 (d, J = 5.0 Hz, 1H), 5.32 (s, 2H), 4.52–4.47 (m, 3H), 4.36–4.15 (m, 8H), 4.00 (t, J = 5.2 Hz, 2H).

[0437] Example 42: Preparation of Compound 42

[0438]

[0439] Preparation of Compound 42-1

[0440] Compound 35-3 (100 mg, 0.20 mmol) was dissolved in ethanol (1 mL) and tetrahydrofuran (0.5 mL) in a 10 mL microwave tube. 2-Thia-6-azaspiro[3.3]heptane (34 mg, 0.29 mmol) and N,N-diisopropylethylamine (50 mg, 0.39 mmol) were added successively. The reaction solution was stirred under microwave at 100 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain 70 mg of the title compound 42-1. LC-MS (ESI): m / z 591.2 [M+H] + .

[0441] Preparation of Compound 42

[0442] Dissolve compound 42-1 (30 mg, 0.06 mmol) in methanol (0.5 mL) and dichloromethane (0.2 mL) in a 25 mL single-necked flask. Add ammonium carbamate (42 mg, 0.54 mmol) and iodobenzene diacetate (132 mg, 0.41 mmol) successively. Stir the reaction mixture at 25 °C for 16 hours. After the reaction is completed, rotary evaporate the reaction mixture under reduced pressure. Purify the crude product by silica gel column chromatography (DCM / MeOH = 100% - 10%) and preparative separation and purification (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 gradient elution in 12 minutes; flow rate: 30 mL / min) to obtain 44.43 mg of the title compound 42. LC-MS (ESI): m / z 622.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 2H), 8.49–8.31 (m, 5H), 7.18 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 5.0 Hz, 1H), 5.12 (s, 2H), 4.56–4.47 (m, 3H), 4.37–4.16 (m, 8H), 4.01 (t, J = 5.0 Hz, 2H).

[0443] Example 43: Preparation of Compound 43

[0444]

[0445] Preparation of Compound 43-1

[0446] Weigh compound 24-5 (580 mg, 1.51 mmol) and 2-chloro-5-(chloromethyl)pyrimidine (270.7 mg, 1.66 mmol) and dissolve them in [solvent not specified in the original]. Add K2CO3 (417.2 mg, 3.02 mmol). Heat the reaction mixture at 80 °C for 12 hours. LCMS shows that the raw materials disappear and the product is formed. Pour the reaction mixture into water (30 mL), extract with ethyl acetate three times (30 mL), combine the organic phases, wash twice with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, rotary evaporate the filtrate, and purify the obtained residue by trituration with methanol to obtain 500 mg of the title compound 43-1. LC-MS (ESI): m / z 509.9 [M+H] + .

[0447] Preparation of Compound 43

[0448] Compound 43-1 (100 mg, 195.77 μmol) was dissolved in DMF (2 mL). Pd2(dba)3 (17.9 mg, 19.58 μmol), Xantphos (22.7 mg, 39.15 μmol), DIPEA (50.6 mg, 391.54 μmol, 68.20 μL), and dimethylphosphine oxide (76.40 mg, 978.86 μmol) were added successively. The reaction was stirred at 120 °C for 16 hours. After the reaction was completed, the insoluble solids were filtered off. The filtrate was added with water (10 mL), and extracted with dichloromethane (20 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative separation (preparation method: mobile phase: A: 0.1% aqueous formic acid solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile gradient elution within 12 minutes; flow rate: 30 mL / min) to obtain 16.72 mg of the title compound 43. LC-MS (ESI): m / z 552.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 2H), 8.24 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.78–7.71 (m, 4H), 7.18 (d, J = 8.8 Hz, 2H), 5.33 (s, 2H), 4.49 (t, J = 5.2 Hz, 2H), 4.01 (t, J = 5.2 Hz, 2H), 1.78 (d, J = 13.8 Hz, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 34.15 (s, 1P).

[0449] Example 44: Preparation of Compound 44

[0450]

[0451] Preparation of Compound 44

[0452] Compound 43-1 (100 mg, 195.77 μmol) and 3-(methylsulfonyl)azetidine (50.4 mg, 293.66 μmol, HCl) were dissolved in acetonitrile (2 mL), and TEA (39.6 mg, 391.54 μmol, 54.61 μL) was added. The reaction mixture was heated and stirred at 80 °C for 16 h. LCMS showed that the starting materials disappeared and the product was formed. The reaction mixture was filtered and purified by preparative chromatography (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: 50%-70% acetonitrile gradient elution in 12 min; flow rate: 30 mL / min) to obtain 46.28 mg of the title compound 44. LC-MS (ESI): m / z 609.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 2H), 8.27–8.19 (m, 2H), 7.89–7.82 (m, 2H), 7.79–7.73 (m, 2H), 7.73–7.66 (m, 2H), 7.18–7.08 (m, 2H), 5.04 (s, 2H), 4.54–4.47 (m, 2H), 4.44–4.31 (m, 3H), 4.29–4.20 (m, 2H), 4.04–3.99 (m, 2H), 3.07 (s, 3H).

[0453] Example 45: Preparation of Compound 45

[0454]

[0455] Preparation of Compound 45-1

[0456] Compound 25-4 (200.0 mg, 20.49 μmol) and 2-chloro-5-(chloromethyl)pyrimidine (93.3 mg, 572.54 μmol) were dissolved in acetonitrile (4 mL), and K2CO3 (143.87 mg, 1.04 mmol) was added. The reaction mixture was heated at 80 °C for 12 h. LCMS showed that the starting materials disappeared and the product was formed. The reaction mixture was poured into water (30 mL), and extracted with ethyl acetate three times (30 mL). The combined organic phases were washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (EA / PE = 0-30%) to obtain 260 mg of the title compound 45-1. LC-MS (ESI): m / z 510.4 [M+H] + .

[0457] Preparation of Compound 45

[0458] Compound 45-1 (130.0 mg, 254.50 μmol) and 3-(methylsulfonyl)azetidine hydrochloride (65.5 mg, 381.76 μmol) were dissolved in acetonitrile (2 mL), and TEA (51.5 mg, 509.01 μmol, 70.99 μL) was added. The reaction mixture was heated by microwave at 90 °C for 4 h. LCMS showed that the raw materials disappeared and the product was formed. The reaction mixture was filtered, and the filtrate was purified by preparative liquid chromatography (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 was eluted gradiently within 12 min; flow rate: 30 mL / min) to obtain 91.49 mg of the title compound 45. LC-MS (ESI): m / z 609.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 2H), 7.55 (d, J = 2.1 Hz, 1H), 7.53–7.48 (m, 2H), 7.48–7.44 (m, 2H), 7.41 (d, J = 7.1 Hz, 1H), 7.06 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 4.96 (s, 2H), 4.44 (t, J = 5.2 Hz, 2H), 4.41–4.30 (m, 3H), 4.26–4.20 (m, 2H), 3.96 (t, J = 5.2 Hz, 2H), 3.06 (s, 3H).

[0459] Example 46: Preparation of Compound 46

[0460]

[0461] Preparation of Compound 46

[0462] Compound 45-1 (130.0 mg, 254.50 μmol) was dissolved in DMF (2 mL). Pd2(dba)3 (23.3 mg, 25.45 μmol), Xantphos (29.5 mg, 50.90 μmol), DIPEA (65.8 mg, 509.01 μmol, 88.66 μL), and dimethylphosphine oxide (99.3 mg, 1.27 mmol) were added successively, and the mixture was microwave-heated at 120 °C for 3 hours. After the reaction was completed, the insoluble solid was filtered off. The filtrate was added with water (10 mL), and extracted with dichloromethane (20 mL) three times. The combined organic phases were washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative separation (preparation method: mobile phase: A: 0.1% aqueous formic acid solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile gradient elution in 12 minutes; flow rate: 30 mL / min) to obtain 14.13 mg of the title compound 46. LC-MS (ESI): m / z 552.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 2H), 7.55 (d, J = 2.2 Hz, 1H), 7.53–7.45 (m, 4H), 7.42 (d, J = 7.0 Hz, 1H), 7.08 (d, J = 8.7 Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 5.26 (s, 2H), 4.43 (t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.2 Hz, 2H), 1.77 (d, J = 13.7 Hz, 6H). 31 31P NMR (162 MHz, DMSO-d6) δ 34.01 (s, 1P).

[0463] Example 47: Preparation of Compound 47

[0464]

[0465] Preparation of Compound 47

[0466] Compound 47-1 (50 mg, 0.083 mmol), palladium on calcium carbonate (10%, 89 mg, 0.043 mmol), and ethyl acetate (5 mL) were added to an autoclave. After replacing the hydrogen, the mixture was stirred overnight at 2 Mpa and 50 °C. The reaction was monitored by LCMS and found to be complete. The reaction was stopped, cooled to room temperature, and the solid was filtered off. The filtrate was concentrated and purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Column: Sunfire C18, 19*250 mm, 10 um; column temperature: 25 °C; gradient: 78%-83% acetonitrile gradient elution in 16 minutes; flow rate: 20 mL / min) to obtain 16.66 mg of the title compound 47. LC-MS (ESI): m / z 607.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (q, J = 2.3 Hz, 2H), 8.27 (s, 2H), 8.02 (t, J = 1.9 Hz, 1H), 7.76–7.69 (m, 4H), 7.56 (t, J = 7.8 Hz, 1H), 7.32 (d, J = 8.2 Hz, 2H), 4.50 (t, J = 5.2 Hz, 2H), 4.41–4.34 (m, 1H), 4.28 (t, J = 8.7 Hz, 2H), 4.20–4.14 (m, 2H), 4.01 (t, J = 5.2 Hz, 2H), 3.04 (s, 3H), 2.90 (t, J = 7.2 Hz, 2H), 2.80 (t, J = 7.5 Hz, 2H).

[0467] Example 48: Preparation of Compound 48

[0468]

[0469] Preparation of Compound 48

[0470] Compound 47-1 (250 mg, 0.41 mmol), palladium on calcium carbonate (5%, 44 mg, 0.021 mmol), and ethyl acetate (15 mL) were added to an autoclave. After replacing the hydrogen, the mixture was stirred overnight at 1 MPa and 50 °C. The next day, a small amount of product was detected by LCMS. The reaction was stopped, cooled to room temperature, and the solid was filtered off. The filtrate was concentrated and purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Column: Sunfire C18, 19*250 mm, 10 um; column temperature: 25 °C; gradient: 74%-74% acetonitrile gradient elution in 16 minutes; flow rate: 20 mL / min) to obtain 1.38 mg of the target product 48. LC-MS (ESI): m / z 605.3 [M+H] + .1 1H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 8.25 (s, 2H), 8.08 (d, J = 2.1 Hz, 1H), 7.99 (d, J = 2.2 Hz, 1H), 7.85 (s, 1H), 7.67 (d, J = 7.9 Hz, 3H), 7.57 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 8.1 Hz, 2H), 6.76 (d, J = 12.0 Hz, 1H), 6.48 (d, J = 12.0 Hz, 1H), 4.51 (t, J = 5.5 Hz, 2H), 4.45–4.34 (m, 5H), 3.95 (t, J = 5.6 Hz, 2H), 3.00 (s, 3H).

[0471] Example 49: Preparation of Compound 49

[0472]

[0473] Preparation of Compound 49-2

[0474] Under nitrogen protection, dimethylphosphine oxide (966 mg, 12.38 mmol) was dissolved in THF (20 mL), and NaHMDS (2 M, 12.38 mmol, 6.2 mL) was added dropwise at 0 °C. The temperature was slowly raised to room temperature and stirred for 1 hour. After the system was cooled to 0 °C, a THF (5 mL) solution of 49-1 (2 g, 6.19 mmol) was added dropwise, and the temperature was slowly raised to room temperature and stirred for 48 hours. The system was directly evaporated to dryness, ethyl acetate (20 mL) was added and stirred for 1 hour, filtered, and the filtrate was evaporated to dryness. The crude product was purified by column chromatography (EA / PE = 0 - 10%) to obtain 580 mg of the target compound 49-2 with a yield of 34%. LC-MS (ESI): m / z 218.2 [M - 56 + H] + 。

[0475] Preparation of Compound 49-3

[0476] At 0 °C, Compound 49-2 (200 mg, 731.78 μmol) was dissolved in DCM (4 mL), and a 1,4-dioxane (1 mL, 4 M) solution of HCl was added dropwise slowly. Stir for 2 hours. Discard the supernatant and evaporate to dryness to obtain 100 mg of the target compound 49-3 with a yield of 78%. Without purification, it was directly used for the next reaction.

[0477] Preparation of Compound 49

[0478] Compound 21-4 (80 mg, 156.32 μmol), compound 49-3 (40.6 mg, 234.47 μmol), DIPEA (202 mg, 1.56 mmol, 272.27 μL), and acetonitrile (759.23 μL) were added to a reaction flask and stirred at 80 °C under microwave irradiation for 2 hours. After evaporation to dryness, the crude product was purified by preparative liquid chromatography (preparation method: mobile phase: A: 0.1% aqueous formic acid solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 10%-80% acetonitrile in a gradient elution within 20 minutes; flow rate: 25 mL / min), and 50 mg of the title compound 49 was obtained with a yield of 49%. LC-MS (ESI): m / z 648.4 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 2.2 Hz, 1H), 8.62 (d, J = 2.2 Hz, 1H), 8.34 (d, J = 5.0 Hz, 1H), 8.21–8.15 (m, 2H), 8.03 (dd, J = 7.4, 1.4 Hz, 1H), 7.98 (t, J = 7.6 Hz, 1H), 7.94 (dd, J = 7.8, 1.4 Hz, 1H), 7.19–7.10 (m, 2H), 6.76 (d, J = 5.0 Hz, 1H), 5.08 (s, 2H), 4.54 (t, J = 5.2 Hz, 2H), 4.09 (s, 2H), 4.02 (t, J = 5.2 Hz, 2H), 3.96 (s, 2H), 2.48–2.40 (m, 1H), 2.40–2.28 (m, 4H), 1.29 (d, J = 12.6 Hz, 6H). 31 31P NMR (162 MHz, DMSO-d6) δ 40.76 (s, 1P).

[0479] Example 50: Preparation of Compound 50

[0480]

[0481] Preparation of Compound 50

[0482] Compound 21-4 (60 mg, 0.12 mmol) was added into a microwave tube, followed by anhydrous acetonitrile (3 mL), 3-(methylsulfonyl)azetidine hydrochloride (30 mg, 0.18 mmol), and cesium carbonate (115 mg, 0.35 mmol). The mixture was purged with nitrogen three times and then reacted at 75 °C under microwave irradiation for 2 hours. After the reaction was monitored by LCMS until completion, the reaction mixture was filtered. The crude product in the filtrate was separated and purified by preparative chromatography (Preparative 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 with gradient elution within 12 minutes; Flow rate: 30 mL / min) to obtain 13 mg of the title compound 50 with a yield of 18%. LC-MS (ESI): m / z 610.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 2.2 Hz, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.43 (d, J = 5.0 Hz, 1H), 8.22–8.15 (m, 2H), 8.04 (dd, J = 7.3, 1.4 Hz, 1H), 7.98 (t, J = 7.6 Hz, 1H), 7.94 (dd, J = 7.8, 1.5 Hz, 1H), 7.20–7.13 (m, 2H), 6.88 (d, J = 5.0 Hz, 1H), 5.14 (s, 2H), 4.54 (t, J = 5.2 Hz, 2H), 4.46–4.39 (m, 1H), 4.35 (t, J = 8.7 Hz, 2H), 4.28–4.21 (m, 2H), 4.02 (t, J = 5.2 Hz, 2H), 3.07 (s, 3H).

[0483] Example 51: Preparation of Compound 51

[0484]

[0485] Preparation of Compound 51

[0486] Compound 4-2 (100 mg, 0.20 mmol) was added to a microwave tube, followed by anhydrous ethanol (3 mL), 2-oxa-6-azaspiro[3.3]heptane (26 mg, 0.26 mmol), and DIPEA (78 mg, 0.6 mmol). The mixture was purged with nitrogen three times and reacted at 90 °C under microwave irradiation for 2 h. After the reaction was monitored by LCMS until completion, the reaction mixture was filtered, and the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% aqueous formic acid solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile gradient elution within 12 min; flow rate: 30 mL / min) to obtain 50 mg of the title compound 51 with a yield of 43%. LC-MS (ESI): m / z 573.8 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 5.0 Hz, 1H), 8.32 (q, J = 2.3 Hz, 2H), 7.98 (t, J = 1.9 Hz, 1H), 7.81–7.74 (m, 2H), 7.73–7.64 (m, 2H), 7.54 (t, J = 7.7 Hz, 1H), 7.14–7.07 (m, 2H), 6.78 (d, J = 5.0 Hz, 1H), 5.07 (s, 2H), 4.73 (s, 4H), 4.50 (t, J = 5.2 Hz, 2H), 4.22 (s, 4H), 4.01 (t, J = 5.2 Hz, 2H).

[0487] Example 52: Preparation of Compound 52

[0488]

[0489] Preparation of Compound 52-1

[0490] Compound 1-7 (500 mg, 1.14 mmol) and potassium vinyltrifluoroborate (201.00 mg, 1.5 mmol) were weighed into a 100 mL three-necked flask, and potassium carbonate (207 mg, 1.5 mmol) and Pd(dppf)Cl2 (100.7 mg, 0.11 mmol) were added. The mixture was purged with nitrogen three times. The reaction mixture was heated at 100 °C for 12 h. TLC showed that the starting materials disappeared and the product was formed. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (EtOAc / PE = 0-20%) to obtain 280 mg of the title compound 52-1 with a yield of 62.5%.

[0491] Preparation of Compound 52-2

[0492] Compound 52-1 (280 mg, 0.71 mmol) was dissolved in DCE (50 mL), and 2-chloro-5-vinylpyrimidine (99.4 mg, 0.71 mmol) and Grubbs Catalyst 2nd (84.9 mg, 0.1 mmol) were added. The mixture was stirred at 90 °C for 12 h. LCMS showed the disappearance of the starting material and the formation of the product. The reaction solution was concentrated in vacuo and purified by silica gel column chromatography (EtOAc / PE = 0 - 30%) to obtain 190 mg of the title compound 52-2 in a yield of 62.5%. LC-MS (ESI): m / z 506.0 [M+H] + .

[0493] Preparation of Compound 52

[0494] Compound 52-2 (70 mg, 0.14 mmol) and 3-(methylsulfonyl)azetidine (24.6 mg, 0.18 mmol) were dissolved in EtOH (10 mL), and DIPEA (87 mg, 0.68 mmol) was added. The reaction mixture was stirred at 80 °C for 2 h. The reaction solution was filtered and purified by preparative purification (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: 55% - 75% acetonitrile gradient elution within 12 min; flow rate: 30 mL / min) to obtain 6.20 mg of the title compound 52 in a yield of 7.3%. LC-MS (ESI): m / z 605.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 2H), 8.34 (t, J = 1.9 Hz, 2H), 8.08 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.76 (t, J = 7.8 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 7.58 (t, J = 7.7 Hz, 1H), 7.29 (d, J = 16.6 Hz, 1H), 7.20 (d, J = 16.7 Hz, 1H), 4.51 (t, J = 5.2 Hz, 2H), 4.45–4.34 (m, 3H), 4.29–4.23 (m, 2H), 4.01 (t, J = 5.2 Hz, 2H), 3.08 (s, 3H).

[0495] Example 53: Preparation of Compound 53

[0496]

[0497] Preparation of Compound 53

[0498] Compound 52-2 (100 mg, 0.20 mmol) was dissolved in DMF (10 mL). Compound 4-3 (119 mg, 1 mmol), DIEA (129 mg, 1 mmol), Pd2(dba)3 (27 mg, 0.03 mmol), and Xantphos (40 mg, 0.07 mmol) were added successively. After purging with nitrogen three times, the reaction was carried out at 120 °C under microwave irradiation for 2 hours. After monitoring the reaction by LCMS until completion, the reaction solution was filtered. The crude product of the 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 NH4HCO3)-acetonitrile; mobile phase: gradient elution with 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL / min), to obtain 18.7 mg of the title compound 53, with a yield of 15.9%. LC-MS (ESI): m / z 588.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 2H), 8.38–8.32 (m, 2H), 8.08 (t, J = 1.9 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.80–7.74 (m, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.59 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 16.6 Hz, 1H), 7.23 (d, J = 16.6 Hz, 1H), 4.51 (t, J = 5.2 Hz, 2H), 4.02 (d, J = 5.2 Hz, 2H), 3.66–3.56 (m, 2H), 3.44–3.38 (m, 2H), 2.29–2.18 (m, 2H), 2.18–2.06 (m, 2H).

[0499] Example 54: Preparation of Compound 54

[0500]

[0501] Preparation of Compound 54

[0502] Compound 52-2 (100 mg, 0.20 mmol) was dissolved in DMF (10 mL). Dimethylphosphine oxide (78 mg, 1 mmol), DIEA (129 mg, 1 mmol), Pd2(dba)3 (27 mg, 0.03 mmol) and Xantphos (40 mg, 0.07 mmol) were added successively. After three nitrogen replacements, the reaction was carried out under microwave at 120 °C for 2 hours. After the reaction was monitored by LCMS until completion, the reaction solution was filtered, and the 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 NH4HCO3)-acetonitrile; mobile phase: 45%-65% acetonitrile gradient elution within 12 minutes; flow rate: 30 mL / min), to obtain 17.8 mg of the title compound 54, with a yield of 16.27%. LC-MS (ESI): m / z 548.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 2H), 8.39–8.30 (m, 2H), 8.10 (d, J = 1.9 Hz, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.85–7.76 (m, 4H), 7.73 (d, J = 16.6 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 16.6 Hz, 1H), 4.51 (t, J = 5.2 Hz, 2H), 4.02 (t, J = 5.2 Hz, 2H), 1.78 (d, J = 13.7 Hz, 6H). 31 31P NMR (162 MHz, DMSO-d6) δ 33.61 (s, 1P).

[0503] Example 55: Preparation of Compound 55

[0504]

[0505] Preparation of Compound 55-1

[0506] 4-(Hydroxymethyl)phenylboronic acid (1.3 g, 8.56 mmol) and 2-chloro-5-iodopyrimidine (1.87 g, 7.78 mmol) were dissolved in 1,4-dioxane (16 mL) and water (4 mL). K2CO3 (3.2 g, 22.3 mmol) and Pd(dppf)Cl2 (284 mg, 0.38 mmol) were added successively. The reaction system was purged with nitrogen three times and stirred at 60 °C for 2 hours. After the reaction was completed, it was cooled to room temperature. The reaction solution was filtered through diatomaceous earth, and the filter cake was rinsed with ethyl acetate (30 mL). The filtrate was added with water (50 mL), and extracted with ethyl acetate (150 mL) three times. The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography to obtain 1.6 g of the title compound 55-1. LC-MS (ESI): m / z 221.0 [M+H] + .

[0507] Preparation of Compound 55-2

[0508] Compound 55-1 (300 mg, 1.36 mmol), 3-(methylsulfonyl)azetidine hydrochloride (467 mg, 2.72 mmol), DIEA (530 mg, 4.10 μmol) and acetonitrile (3 mL) were added to a three-necked flask, and the reaction was stirred at 85 °C for 3 hours. After the reaction was completed, saturated sodium chloride aqueous solution (10 mL) was added to the reaction system, and extracted with DCM (10 mL) three times. The combined organic phases were dried, filtered by suction and concentrated. The obtained crude product was purified by silica gel chromatography column (EA / PE = 0-60%) to obtain 110 mg of the title compound 55-2. LC-MS (ESI): m / z 320.3 [M+H] + .

[0509] Preparation of Compound 55

[0510] Compound 25-4 (200 mg, 0.52 mmol) was dissolved in acetonitrile (8 mL), potassium carbonate (11.4 mg, 0.8 mmol), compound 55-3 (227 mg, 0.57 mmol) were added, and the reaction was carried out at 70 °C for 2 hours. After the reaction was tracked by LCMS to completion, the reaction solution was concentrated, and the crude product 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 NH4HCO3)-acetonitrile; mobile phase: 45%-65% acetonitrile gradient elution within 12 minutes; flow rate: 30 mL / min) to obtain 151.9 mg of the title compound 55, with a yield of 42.7%. LC-MS (ESI): m / z 685.0 [M+H] + . 1HNMR(400MHz, DMSO-d6) δ 8.76 (s, 2H), 7.67 (d, J = 8.3 Hz, 2H), 7.58–7.36 (m, 8H), 7.05 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 5.15 (s, 2H), 4.48–4.32 (m, 5H), 4.32–4.23 (m, 2H), 3.95 (t, J = 5.2 Hz, 2H), 3.08 (s, 3H).

[0511] Example 56: Preparation of Compound 56

[0512]

[0513] Preparation of Compound 56

[0514] Dissolve Compound 45-1 (109 mg, 0.213 mmol) in DMF (3 mL), and sequentially add Compound 56-1 (62.4 mg, 0.427 mmol) and cesium carbonate (208.6 mg, 0.639 mmol) thereto. After addition, stir the reaction system at room temperature for 4 hours. After the reaction is completed, evaporate the solvent under reduced pressure, dissolve it with acetonitrile and 1,4-dioxane, filter, and purify the filtrate 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 gradient elution in 12 minutes; flow rate: 30 mL / min) to obtain 20.1 mg of the title compound 56. LC-MS (ESI): m / z 620.2 [M+H] + . 1 HNMR(400MHz, DMSO-d6) δ 8.36 (d, J = 5.0 Hz, 1H), 7.55–7.37 (m, 6H), 7.05 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 5.0 Hz, 1H), 5.01 (s, 2H), 4.50 (s, 1H), 4.42 (t, J = 5.2 Hz, 2H), 4.31 (d, J = 13.1 Hz, 2H), 4.26–4.19 (m, 5H), 3.96 (t, J = 5.2 Hz, 2H).

[0515] Example 57: Preparation of Compound 57

[0516]

[0517] Preparation of Compound 57-2

[0518] Compound 57-1 (557 mg, 2.0 mmol), 2-chloro-4-(chloromethyl)pyrimidine (489.9 mg, 3.0 mmol) were dissolved in acetonitrile (10 mL), and cesium carbonate (1.3 g, 4.0 mmol) was added. After the addition, the reaction system was stirred at 25 °C for 12 h. After the reaction was completed, the mixture was concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE / EA = 100% - 80%) to obtain 705 mg of the title compound 57-2. LC-MS (ESI): m / z 405.2 [M+H] + . Preparation of Compound 57-3

[0519] Compound 57-2 (100 mg, 0.25 mmol) and compound 5-1 (45.4 mg, 0.25 mmol) were dissolved in ethanol (10 mL), and triethylamine (50.2 mg, 0.5 mmol) was added. After the addition, the reaction system was stirred at 100 °C for 12 h. After the reaction was completed, the mixture was concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE / EA = 100% - 80%) to obtain 100 mg of the title compound 57-3.

[0520] . Preparation of Compound 57-4

[0521] Compound 57-3 (100 mg, 0.19 mmol) was dissolved in dichloromethane (3 mL), and a 1,4-dioxane solution of hydrogen chloride (354 mg, 9.7 mmol) was added. After the addition, the reaction system was stirred at 25 °C for 2 h. After the reaction was completed, the mixture was concentrated to obtain the crude product of the title compound 57-4. Without purification, it was directly used in the next reaction.

[0522] . Preparation of Compound 57

[0523] Compound 57-4 (67.8 mg, 0.15 mmol), compound 1-4 (88.5 mg, 0.30 mmol), Pd2(dba)3 (13.7 mg, 0.015 mmol), Xantphos (17.3 mg, 0.03 mmol), and cesium carbonate (98 mg, 0.3 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction system was stirred in a microwave reactor at 100 °C for 8 hours. After the reaction was completed, the insoluble solids were filtered off. The filtrate was added with water (10 mL), and extracted with dichloromethane (20 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain the 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: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile was eluted with a gradient within 12 minutes; flow rate: 30 mL / min) to obtain 7 mg of the title compound 57. LC-MS (ESI): m / z 629.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 5.0 Hz, 1H), 7.45 (d, J = 3.1 Hz, 1H), 7.39 (d, J = 3.0 Hz, 1H), 6.96 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 9.0 Hz, 2H), 6.79 (d, J = 5.0 Hz, 1H), 4.95 (s, 2H), 4.51 (s, 4H), 4.37–4.20 (m, 6H), 3.94 (t, J = 5.1 Hz, 2H), 3.54–3.22 (m, 4H), 3.18–3.07 (m, 4H).

[0524] Example 58: Preparation of Compound 58

[0525]

[0526] Preparation of Compound 58-1

[0527] Dissolve (4-(2-chloropyrimidin-5-yl)phenyl)methanol (400 mg, 1.81 mmol) in 1,4-dioxane (10 mL). Sequentially add dimethylphosphine oxide (707 mg, 9.06 mmol), Xantphos (210 mg, 0.36 mmol), DIPEA (702 mg, 5.44 mmol). Replace the gas with nitrogen three times, then add Pd2(dba)3 (166 mg, 0.18 mmol). The reaction system is stirred by microwave at 130 °C for 2 hours. After the reaction is completed, add water (25 mL), and extract with dichloromethane (25 mL) three times. Concentrate the aqueous phase to obtain 262 mg of the crude product of the title compound 58-1. LC-MS (ESI): m / z 263.1 [M+H] + .

[0528] Preparation of Compound 58

[0529] Dissolve Compound 25-4 (100 mg, 0.26 mmol) in acetonitrile (8 mL), add potassium carbonate (11.4 mg, 0.8 mmol), Compound 58-2 (102 mg, 0.30 mmol), and react at 70 °C for 2 hours. After tracking the reaction by LCMS until completion, filter the reaction solution. The filtrate is purified by preparative separation (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25 °C; mobile phase: water (10 mM / L NH4HCO3)-acetonitrile; mobile phase: 45%-65% acetonitrile with gradient elution within 12 minutes; flow rate: 30 mL / min) to obtain 16.1 mg of the title compound 58, with a yield of 9.9%. LC-MS (ESI): m / z 628.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 2H), 7.89 (d, J = 7.9 Hz, 2H), 7.61 (d, J = 7.9 Hz, 2H), 7.56–7.36 (m, 6H), 7.06 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.5 Hz, 2H), 5.21 (s, 2H), 4.41 (t, J = 5.1 Hz, 2H), 3.94 (t, J = 5.0 Hz, 2H), 1.80 (d, J = 13.7 Hz, 6H).

[0530] Example 59: Preparation of Compound 59

[0531]

[0532] Preparation of Compound 59-1

[0533] Compound 38-1 (30 mg, 86.32 μmol) and 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide hydrochloride (19.0 mg, 103.59 μmol) were added into a sealed tube, followed by the addition of anhydrous ethanol (1 mL) and DIPEA (55.8 mg, 431.61 μmol, 75 μL). The reaction mixture was stirred overnight at 90 °C in the sealed tube. After the reaction was completed, it was cooled to room temperature, diluted with ethanol, filtered, and the filter cake was washed with ethanol. Then it was concentrated to dryness under reduced pressure to obtain 35.8 mg of the title compound 59-1. LC-MS (ESI): m / z 459.0 [M+H] + .

[0534] Preparation of Compound 59-2

[0535] 2-Iodo-5-bromopyrimidine (549.7 mg, 1.93 mmol), compound 14-3 (550 mg, 1.61 mmol), sodium carbonate (340.9 mg, 3.22 mmol) and Pd(dppf)Cl2 (117.7 mg, 160.81 μmol) were successively added into a 100 mL round-bottom flask. Then 1,4-dioxane (12 mL) and water (3 mL) were added. The reaction system was purged with nitrogen three times, and then stirred at 60 °C for 2 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate, filtered through diatomaceous earth, and the filtrate was concentrated to dryness. It was purified by silica gel column chromatography (PE / EA = 24 / 1) to obtain 369.1 mg of the title compound 59-2. LC-MS (ESI): m / z 371.9 [M+H] + .

[0536] Preparation of Compound 59-4

[0537] Compound 59-2 (30 mg, 80.42 μmol), compound 59-3 (36.3 mg, 160.84 μmol), Pd(dppf)Cl2 (6.0 mg, 8.04 μmol) and potassium acetate (23.7 mg, 241.27 μmol) were successively added into a 50 mL round-bottom flask. Then 1,4-dioxane (1 mL) was added. The reaction mixture was purged with nitrogen three times, and then stirred at 95 °C for 16 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate, filtered through diatomaceous earth, and the filtrate was concentrated to dryness to obtain the crude product of the title compound 59-4. Without purification, it was directly used for the next step of the reaction.

[0538] Preparation of Compound 59

[0539] Compound 59-1 (26 mg, 56.73 μmol), compound 59-4 (32.7 mg, 80.53 μmol), sodium carbonate (12.0 mg, 113.47 μmol) and Pd(dppf)Cl2 (4.2 mg, 5.67 μmol) were successively added into a 50 mL round-bottom flask. 1,4-Dioxane (1.2 mL) and water (0.3 mL) were added. The reaction system was purged with nitrogen three times, and the reaction was stirred at 70 °C for 2.5 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, diluted with 1,4-dioxane (1.5 mL), filtered, and the filtrate was purified by preparative chromatography (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: B%: 60 - 80% for 8 min, 80 - 95% for 4 min; flow rate: 30 mL / min) to obtain 6.1 mg of the title compound 59. LC-MS (ESI): m / z 624.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.97 (s, 2H), 8.77 (d, J = 2.1 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 6.79 (s, 1H), 5.40 (s, 2H), 4.56 (t, J = 6.0 Hz, 2H), 4.40 (s, 8H), 3.93 (t, J = 6.0 Hz, 2H).

[0540] Example 60: Preparation of Compound 60

[0541]

[0542] Preparation of Compound 60-1

[0543] 1,3 - Dibromo - 5 - fluoro - 2 - (methoxy)benzene (4 g, 14.18 mmol) was dissolved in a solution of 1,4 - dioxane (20 mL) and water (6 mL). [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.1 g, 1.42 mmol), potassium carbonate (3.8 g, 28.36 mmol) and 4 - hydroxyphenylboronic acid (2.9 g, 21.27 mmol) were added successively. The reaction system was stirred at 90 °C for 3 hours. After the reaction, water (30 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (50 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 100% - 30%) to obtain 4.1 g of the title compound 60 - 1. LC - MS (ESI): m / z 297.3 [M + H] + .

[0544] Preparation of Compound 60 - 2

[0545] Compound 60 - 1 (4.1 g, 13.82 mmol) was dissolved in a solution of 1,4 - dioxane (30 mL) and water (10 mL). [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.1 g, 1.38 mmol), potassium carbonate (3.8 g, 27.64 mmol) and bis(pinacolato)diboron (5.3 g, 20.77 mmol) were added successively. The reaction system was stirred at 90 °C for 2 hours. After the reaction solution was cooled to room temperature, compound 14 - 3 (6.1 g, 20.77 mmol) was added to the reaction solution. The reaction system was stirred at 90 °C for another 2 hours. After the reaction, water (30 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (50 mL) three times. 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 column chromatography (PE / EA = 100% - 30%) to obtain 900 mg of the title compound 60 - 2. LC - MS (ESI): m / z 432.3 [M + H] + .

[0546] Preparation of Compound 60 - 3

[0547] Compound 60-2 (900 mg, 2.09 mmol) was dissolved in acetonitrile (5 mL). (2-(Methylthio)pyrimidin-4-yl)methyl methanesulfonate (733 mg, 3.13 mmol) and DIPEA (540 mg, 4.18 mmol) were added successively. The reaction system was stirred at 80 °C for 2 h. After the reaction, water (5 mL) was added, and the mixture was extracted with dichloromethane (10 mL) three times. The organic phases were combined, washed twice with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain 800 mg of the crude product of the title compound 60-3. Without purification, it was directly used for the next reaction. LC-MS (ESI): m / z 570.2 [M+H] + .

[0548] Preparation of Compound 60-4

[0549] Compound 60-3 (800 mg, 1.41 mmol) was dissolved in dichloromethane (10 mL). m-CPBA (730 mg, 4.22 mmol) was added under an ice bath. The reaction system was stirred at 25 °C for 1 h. After the reaction, water (20 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (30 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE / EA = 100% - 30%) to obtain 500 mg of the title compound 60-4. LC-MS (ESI): m / z 603.2 [M+H] + .

[0550] Preparation of Compound 60

[0551] Compound 60-4 (150 mg, 0.24 mmol) was dissolved in acetonitrile (3 mL). 2-Thia-6-azaspiro[3.3]heptane 2,2-dioxide hydrochloride (70 mg, 0.48 mmol) and DIPEA (93 mg, 0.72 mmol) were added successively. The reaction system was stirred at 80 °C for 2 h. After the reaction, water (3 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (5 mL) three times. The organic phases were combined, washed twice with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered by suction, 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: 45% - 65% acetonitrile was eluted gradiently within 12 min; flow rate: 30 mL / min) to obtain 10 mg of the title compound 60. LC-MS (ESI): m / z 669.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 5.0 Hz, 1H), 8.10 (d, J = 2.2 Hz, 1H), 8.04 (d, J = 2.2 Hz, 1H), 7.62–7.54 (m, 2H), 7.33 (dd, J = 8.9, 3.2 Hz, 1H), 7.27 (dd, J = 9.1, 3.2 Hz, 1H), 7.15–7.07 (m, 2H), 6.83 (d, J = 5.0 Hz, 1H), 5.07 (s, 2H), 4.52 (t, J = 5.2 Hz, 2H), 4.36–4.17 (m, 8H), 4.01 (t, J = 5.2 Hz, 1H), 3.06 (s, 3H). 19 19F NMR (376 MHz, DMSO-d6) δ -117.89 (s, 1F).

[0552] Example 61: Preparation of Compound 61

[0553]

[0554] Preparation of Compound 61

[0555] Dissolve Compound 60-4 (150 mg, 0.24 mmol) in acetonitrile (3 mL). Subsequently, add 3-(methylsulfonyl)azetidine (65 mg, 0.48 mmol) and DIPEA (93 mg, 0.72 mmol). The reaction system was stirred at 80 °C for 2 hours. After the reaction, water (20 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (20 mL) three times. The combined organic phases were washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain a crude product. The crude product was purified by preparative separation (preparation method: mobile phase: A: 0.1% aqueous formic acid solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile with gradient elution within 12 min; flow rate: 30 mL / min) to obtain 7 mg of the title compound 61. LC-MS (ESI): m / z 657.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 5.0 Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.64–7.52 (m, 2H), 7.33 (dd, J = 8.9, 3.2 Hz, 1H), 7.27 (dd, J = 9.1, 3.2 Hz, 1H), 7.19–7.07 (m, 2H), 6.89 (d, J = 5.0 Hz, 1H), 5.11 (s, 2H), 4.52 (t, J = 5.2 Hz, 2H), 4.46–4.38 (m, 1H), 4.34 (t, J = 8.7 Hz, 2H), 4.28–4.20 (m, 2H), 4.01 (t, J = 5.2 Hz, 2H), 3.07 (d, J = 1.3 Hz, 6H). 19 19F NMR (376 MHz, DMSO-d6) δ -117.90.

[0556] Example 62: Preparation of Compound 62

[0557]

[0558] Preparation of Compound 62-1

[0559] Dissolve (2-chloropyrimidin-4-yl)methanol (100 mg, 0.69 mmol) and 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide hydrochloride (139.8 mg, 0.76 mmol) in ethanol (10 mL), and add triethylamine (0.29 ml, 2.08 mmol). After addition, stir the reaction system at 90 °C under microwave for 2 hours. After the reaction is completed, concentrate to obtain the crude product, and purify it by silica gel column chromatography (MeOH / DCM = 0% - 10%) to obtain 125 mg of the title compound 62-1. LC-MS (ESI): m / z 256.0 [M+H] + .

[0560] Preparation of Compound 62-2

[0561] Dissolve Compound 14-3 (1.03 g, 3.0 mmol), 2,5-dibromopyrazine (475.8 mg, 2.0 mmol), and sodium carbonate (424.0 mg, 4.0 mmol) in 1,4-dioxane (40 mL) and water (10 ml), add Pd(dppf)Cl2 (146.4 mg, 0.2 mmol), protect with nitrogen, and stir the reaction system at 100 °C for 2 hours. After the reaction is completed, concentrate to obtain the crude product, and purify it by silica gel column chromatography (PE / EA = 100% - 80%) to obtain 305 mg of the title compound 62-2.

[0562] Preparation of Compound 62-3

[0563] Dissolve Compound 62-2 (112 mg, 0.3 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (100.4 mg, 0.45 mmol), and sodium carbonate (63.6 mg, 0.6 mmol) in 1,4-dioxane (3 mL) and water (1 mL). Add Pd(dppf)Cl2 (22 mg, 0.03 mmol), and under nitrogen protection, stir the reaction system at 60 °C for 2 hours. After the reaction is completed, concentrate to obtain the crude product, and purify it by silica gel column chromatography (PE / EA = 100% - 80%) to obtain 305 mg of the title compound 62-3.

[0564] Preparation of Compound 62

[0565] Dissolve Compound 62-3 (50 mg, 0.13 mmol), Compound 62-1 (36.1 mg, 0.14 mmol), and cesium carbonate (139.5 mg, 0.27 mmol) in 1,4-dioxane (2 mL). Stir the reaction system in a microwave reactor at 120 °C for 3 hours. After the reaction is completed, filter off the insoluble solids, add water (10 mL) to the filtrate, extract with dichloromethane (20 mL) 3 times, combine the organic phases, wash with saturated brine (20 mL) 2 times, dry over anhydrous sodium sulfate, filter by suction, concentrate the filtrate to obtain the crude product, and purify it 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 gradient elution within 12 minutes; flow rate: 30 mL / min) to obtain 6 mg of the title compound 62. LC-MS (ESI): m / z 624.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.53 (s, 1H), 8.96 (d, J = 2.5 Hz, 1H), 8.65–8.49 (m, 3H), 8.34 (d, J = 5.1 Hz, 1H), 7.17 (d, J = 8.7 Hz, 1H), 6.72 (d, J = 5.0 Hz, 1H), 5.36 (s, 2H), 4.56 (t, J = 5.2 Hz, 2H), 4.51 (s, 4H), 4.26 (s, 4H), 4.02 (t, J = 5.2 Hz, 2H).

[0566] Example 63: Preparation of Compound 63

[0567]

[0568] Preparation of Compound 63-1

[0569] Compound 38-1 (50 mg, 143.87 μmol) and 2-thia-6-azaspiro[3.3]heptane oxalate (30 mg, 187.03 μmol, oxalate) were added into a sealed tube, followed by anhydrous ethanol (1.5 mL) and DIPEA (111.6 mg, 863.21 μmol, 150 μL). The reaction mixture was stirred at 90 °C overnight in the sealed tube. After the reaction was completed, it was cooled to room temperature, diluted with ethanol, filtered, and the filter cake was washed with ethanol. Then it was evaporated to dryness under reduced pressure to obtain 40.8 mg of the title compound 63-1. LC-MS (ESI): m / z 427.0 [M+H] + .

[0570] Preparation of Compound 63-2

[0571] Compound 63-1 (40.8 mg, 95.71 μmol), Compound 59-4 (52.3 mg, 128.67 μmol), sodium carbonate (20.3 mg, 191.43 μmol) and Pd(dppf)Cl2 (7 mg, 9.57 μmol) were successively added into a 50 mL round-bottom flask. Finally, 1,4-dioxane (1.6 mL) and water (0.4 mL) were added. The reaction system was purged with nitrogen three times and then stirred at 70 °C for 2.5 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate, filtered through diatomaceous earth, and the filtrate was concentrated and dried by rotary evaporation. The crude product of the title compound 63-2 (50 mg) was obtained by purification on a silica gel column chromatography (DCM). LC-MS (ESI): m / z 592.2 [M+H] + .

[0572] Preparation of Compound 63

[0573] Compound 63-2 (50 mg, 84.39 μmol) was dissolved in DCM (2 mL) and MeOH (1.5 mL), cooled to 0 °C in an ice-water bath, and iodobenzenediacetic acid (81.5 mg, 253.17 μmol) and ammonium carbamate (26.4 mg, 337.55 μmol) were added respectively. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 h. After the reaction was completed, it was concentrated to dryness by rotary evaporation, dissolved in a small amount of 1,4-dioxane, filtered through a membrane, and purified by preparative chromatography (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: B%: 40 - 60% for 8 min, 60 - 80% for 4 min; flow rate: 30 mL / min) to obtain 14.5 mg of the title compound 63. LC-MS (ESI): m / z 623.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 2H), 8.71 (t, J = 1.9 Hz, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.65 (t, J = 1.9 Hz, 1H), 8.35–8.30 (m, 2H), 7.18 (d, J = 8.7 Hz, 1H), 6.69 (d, J = 5.0 Hz, 1H), 5.34 (s, 2H), 4.59 (t, J = 5.2 Hz, 2H), 4.49 (s, 1H), 4.31 (d, J = 12.9 Hz, 2H), 4.27–4.16 (m, 6H), 4.02 (t, J = 5.2 Hz, 2H).

[0574] Example 64: Preparation of Compound 64

[0575]

[0576] Preparation of Compound 64-1

[0577] Compound 62-2 (112 mg, 0.3 mmol), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (108.2 mg, 0.45 mmol), and sodium carbonate (63.6 mg, 0.6 mmol) were dissolved in 1,4-dioxane (3 mL) and water (1 mL), Pd(dppf)Cl2 (22 mg, 0.03 mmol) was added, and the reaction system was stirred at 80 °C for 2 h under nitrogen protection. After the reaction was completed, the crude product was obtained by concentration and purified by silica gel column chromatography (PE / EA = 100% - 80%) to obtain 305 mg of the title compound 64-1.

[0578] Preparation of Compound 64

[0579] Compound 64-2 (40.7 mg, 0.10 mmol), compound 62-1 (28.1 mg, 0.11 mmol), and cesium carbonate (108.6 mg, 0.2 mmol) were dissolved in 1,4-dioxane (2 mL). The reaction system was stirred in a microwave reactor at 120 °C for 3 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) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain a crude product. The crude product was purified by preparative separation (preparation method: mobile phase: A: 0.1% aqueous formic acid solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile was eluted gradiently within 12 minutes; flow rate: 30 mL / min) to obtain 6 mg of the title compound 64. LC-MS (ESI): m / z 624.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 9.47 (d, J = 1.5 Hz, 1H), 9.41 (d, J = 1.5 Hz, 1H), 9.38 (s, 2H), 8.64 (s, 2H), 8.36 (d, J = 5.0 Hz, 1H), 6.73 (d, J = 5.1 Hz, 1H), 5.42 (s, 2H), 4.57 (t, J = 5.2 Hz, 2H), 4.50 (s, 4H), 4.25 (s, 5H), 4.02 (t, J = 5.2 Hz, 2H).

[0580] Example 65: Preparation of Compound 65

[0581]

[0582] Preparation of Compound 65-1

[0583] (2-Chloropyrimidin-4-yl)methanol (100 mg, 0.69 mmol) and 2-thia-6-azaspiro[3.3]heptane oxalate (121.9 mg, 0.76 mmol) were dissolved in ethanol (10 mL), and triethylamine (0.29 mL, 2.08 mmol) was added. After addition, the reaction system was stirred in a microwave at 90 °C for 2 hours. After the reaction was completed, the mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (MeOH / DCM = 0% - 10%) to obtain 135 mg of the title compound 65-1. LC-MS (ESI): m / z 224.0 [M+H] + .

[0584] Preparation of Compound 65-2

[0585] Compound 64-1 (163 mg, 0.40 mmol), compound 65-1 (98.2 mg, 0.44 mmol), and cesium carbonate (434.4 mg, 0.8 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction system was stirred in a microwave reactor at 120 °C for 3 hours. After the reaction was completed, the insoluble solid was filtered off. The filtrate was added with water (10 mL), and extracted with dichloromethane (20 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 100% - 80%) to obtain 150 mg of the title compound 65-2. LC-MS (ESI): m / z 592.2 [M+H] + .

[0586] Preparation of Compound 65

[0587] Compound 65-2 (101 mg, 0.17 mmol), iodobenzenediacetic acid (164.3 mg, 0.51 mmol), and ammonium carbamate (53.1 mg, 0.68 mmol) were dissolved in methanol (3 mL) and dichloromethane (4 mL). The reaction system was stirred at room temperature for 2 hours. After the reaction was completed, the insoluble solid was filtered off. The filtrate was added with water (10 mL), and extracted with dichloromethane (20 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to obtain the 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: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 45% - 65% acetonitrile was eluted with a gradient within 12 minutes; flow rate: 30 mL / min) to obtain 18 mg of the title compound 65. LC-MS (ESI): m / z 623.2 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 9.45 (d, J = 1.5 Hz, 1H), 9.40 (d, J = 1.5 Hz, 1H), 9.37 (s, 2H), 8.63 (s, 2H), 8.35 (d, J = 5.0 Hz, 1H), 6.71 (d, J = 5.1 Hz, 1H), 5.41 (s, 2H), 4.57 (t, J = 5.0 Hz, 2H), 4.48 (s, 1H), 4.30 (d, J = 12.9 Hz, 2H), 4.22 (d, J = 6.4 Hz, 6H), 4.02 (t, J = 5.0 Hz, 2H).

[0588] Example 66: Preparation of Compound 66

[0589]

[0590] Preparation of Compound 66-1

[0591] Dissolve Compound 1-4 (1.0 g, 3.39 mmol), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (1.22 g, 5.09 mmol), and sodium carbonate (937 mg, 8.84 mmol) in 1,4-dioxane (12 mL) and water (3 mL). Add Pd(dppf)Cl2 (339 mg, 0.339 mmol) thereto. After addition, displace nitrogen three times, and then stir the reaction system at 90 °C for 4 hours. After the reaction is completed, add water (50 mL), extract with ethyl acetate (50 mL) three times, combine the organic phases, wash with saturated brine (30 mL) twice, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. Purify the crude product by silica gel column chromatography (PE / EA = 100% - 75%) to obtain 500 mg of Compound 66-1. LC-MS (ESI): m / z 328.0 [M+H] + .

[0592] Preparation of Compound 66-2

[0593] Dissolve Compound 66-1 (500 mg, 1.53 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (511 mg, 2.29 mmol), and potassium carbonate (633 mg, 4.59 mmol) in 1,4-dioxane (8 mL) and water (2 mL). Add Pd(dppf)Cl2 (110 mg, 0.15 mmol) thereto. After addition, displace nitrogen three times, and stir the reaction system at 80 °C for 14 hours. After the reaction is completed, add water (50 mL), extract with ethyl acetate (50 mL) three times, combine the organic phases, wash with saturated brine (30 mL) twice, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. Purify the crude product by silica gel column chromatography (PE / EA = 100% - 75%) to obtain 462 mg of Compound 66-2. LC-MS (ESI): m / z 389.0 [M+H] + .

[0594] Preparation of Compound 66

[0595] Compound 66-2 (80 mg, 0.206 mmol), compound 62-1 (51 mg, 0.200 mmol), and cesium carbonate (201 mg, 0.618 mmol) were dissolved in 1,4-dioxane (3 mL). The reaction system was stirred at 120 °C under microwave for 2 hours. After the reaction was completed, it was evaporated to dryness under reduced pressure, dissolved with acetonitrile and 1,4-dioxane, filtered, and the filtrate 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 was eluted gradiently within 12 minutes; flow rate: 30 mL / min) to obtain 10.9 mg of compound 66. LC-MS (ESI): m / z 624.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 2H), 9.14 (d, J = 2.4 Hz, 1H), 8.70 (dd, J = 8.7, 2.4 Hz, 1H), 8.45 (d, J = 2.3 Hz, 1H), 8.41 (d, J = 2.3 Hz, 1H), 8.35 (d, J = 5.0 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 6.74 (d, J = 5.0 Hz, 1H), 5.37 (s, 2H), 4.57–4.47 (m, 6H), 4.27 (s, 4H), 4.01 (t, J = 5.2 Hz, 2H).

[0596] Test Example 1: Cell proliferation inhibition test of 22RV1 and LNCaP cells:

[0597] 1. Human prostate cancer cell lines 22RV1 and LNCaP were purchased from ATCC. The cell culture medium was RPMI-1640 + 10% FBS, and they were cultured in a 37 °C, 100% relative humidity, 5% CO2 incubator.

[0598] 2. On the first day, cells in the logarithmic growth phase were collected, counted, resuspended with phenol red-free RPMI-1640 medium containing 10% CD-FBS, and the cell concentration was adjusted to an appropriate concentration (determined according to the optimized test results of cell density). They were seeded in a 96-well plate, and 100 μl of cell suspension was added to make the number of cells 3000 cells / well. The cells were incubated in a 37 °C, 5% CO2 incubator for 24 hours.

[0599] 3. On the second day, for 22Rv1 cells, different concentrations of the test compound were added, and the cells were incubated in a 37°C, 5% CO2 incubator for 7 days; for LNCaP cells, different concentrations of the test compound were first added, and after 1 hour, 0.2 nM of DHT was added, and the cells were incubated in a 37°C, 5% CO2 incubator for 7 days.

[0600] 4. After the culture was completed, CellTiter-Glo detection reagent equal in volume to the culture medium was added to each well. After shaking and mixing for 5 minutes, it was incubated at room temperature for 10 minutes, and the readings were taken using a PerkinElmer EnVision microplate reader.

[0601] 5. Calculate the inhibition rate of the drug on cell growth according to the following formula: Cell growth inhibition rate % = [(Ac - As) / (Ac - Ab)] × 100%

[0602] As: OA of the sample (cells + test compound)

[0603] Ac: OA of the normal growth cell control (cells + DMSO)

[0604] Ab: OA of the blank control (culture medium + DMSO)

[0605] Using the software Graphpad Prism 8 and the calculation formula XY - analysis / Nonlinear regression (curve fit) / Dose response - Inhibition / log(inhibitor) vs. response - Variable slope (four parameters) to perform IC 50 Curve fitting and calculate the IC 50 value.

[0606] Table 1: Results of cell proliferation inhibition experiments of some compounds in 22RV1 cells

[0607] Compound number <![CDATA[IC 50 (μM)]]> Compound number <![CDATA[IC 50 (μM)]]> Compound number <![CDATA[IC 50 (μM)]]> 1 +++ 34 ++ 52 +++ 5 +++ 35 + 56 ++ 13 +++ 36 + 57 +++ 21 ++ 38 + 59 +++ 24 +++ 39 ++ 60 +++ 28 + 43 +++ 62 ++ 29 +++ 47 +++ 63 ++ 31 +++ 51 +++ 66 +++

[0608] Among them, "+" indicates IC 50 ≤0.5 μM, "++" indicates 0.5 μM < IC 50 ≤1 μM, "+++" indicates 1 μM < IC 50 ≤2.5 mM, "++++" indicates IC 50 >2.5 μM

[0609] From the experimental data in Table 1, it can be seen that the compounds of the present invention show excellent activity in the 22RV1 cell proliferation inhibition experiment.

[0610] Table 2: Results of the cell proliferation inhibition experiment of the compounds of the present invention in LnCaP cells

[0611]

[0612]

[0613] Among them, "+" indicates IC 50 ≤0.5 μM, "++" indicates 0.5 μM < IC 50 ≤1 μM, "+++" indicates 1 μM < IC 50 ≤2.5 mM, "++++" indicates IC 50 >2.5 μM

[0614] From the experimental data in Table 2, it can be seen that the compounds of the present invention show excellent activity in the LnCaP cell proliferation inhibition experiment.

[0615] Test Example 2: Mouse pharmacokinetics test

[0616] Drug preparation: The drug solution was prepared on the day of administration. Weigh 2 mg of the compound and dissolve it with 3% DMSO + 1.5% Tween 80 + 95.5% Saline to prepare an intravenous administration solution with a concentration of 0.1 mg / mL; weigh 3 mg of the compound and dissolve it with 5% DMSO + 5% NMP + 10% Solutol + 80% PEG400 to obtain an oral administration solution with a concentration of 3.0 mg / mL.

[0617] Take 6 healthy male ICR mice, weighing 25 - 30 g, were divided into two groups (intravenous and oral groups), with three mice in each group, and a single dose was administered. After 3 days of adaptive feeding of the mice, they were fasted overnight (10 - 12 h) the night before the experiment, allowed free access to water during the experiment, and resumed feeding 4 h after administration. Timing started after intravenous and oral administration. Whole blood of the mice was collected at the planned time points (IV&PO 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 h) into 1.5 mL EP tubes containing sodium heparin. The collected whole blood was vortexed and shaken 2 times to mix evenly, placed on wet ice, centrifuged at 8000 rpm for 5 min at 4°C within 1 h, and the supernatant plasma was placed in a -80°C refrigerator for storage until analysis.

[0618] Table 3: Mouse pharmacokinetics

[0619]

[0620] From the experimental data in Table 3, it can be seen that the compounds of the present invention show good pharmacokinetic results in the mouse oral PK experiment.

[0621] In the description of this specification, the descriptions with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples", etc. mean that the specific features, structures, materials, or characteristics described in connection 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 are not necessarily 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 a suitable manner. In addition, without contradiction, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples.

[0622] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A compound represented by formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof, in, R1 is selected from H, halogen, OH, CN, NH2, 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, 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; R2, R3, and R4 are independently selected from H, CN, halogen, OH, NH2, C 1-6 Alkyl, C 3-6 Cycloalkyl, 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-, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 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 with 1, 2 or 3 R; R5, R6, and R7 are independently selected from H, CN, halogen, OH, NH2, C 1-6 Alkyl, C 3-6 Cycloalkyl, 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-, 4-6 membered heterocycloalkyl-NH-, C 6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 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-, 4-6 membered heterocycloalkyl-NH-, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R; m, n, y are independently selected from 0, 1, 2, 3 or 4; L1 is selected from a single bond, -NH-, =N-, -O-, -C≡C-, -CH2-, -CH2CH2-, -OCH2-, C 3-6 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein -NH-, -CH2-, -CH2CH2-, -OCH2-, C 3-6 Cycloalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1 or 2 R; Selected from or And when Selected from When L1 is selected from =N- or 3-10 membered heterocycloalkyl; L2 is selected from a single bond, -CH=CH-, -C≡C-, -CH=CH-, -(CR8R9)x-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR 10 -、 C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2 or 3 R; L3 is selected from a single bond, -CH=CH-, -C≡C-, -(CR8R9)x-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR 10 -or-(CR8R9)xO-; Furthermore, L2 and L3 are not simultaneously selected from single bonds; And, when L2 is selected from C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 When aryl or 5-10 membered heteroaryl, L3 is not selected from a single bond; R8 and R9 are independently selected from H, CN, F, Cl, Br, OH, NH2, 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, 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; R 10 Select 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, 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; x is selected from 0, 1, 2 or 3; Ring A is selected from C 4-10 Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl or 5-10 membered heteroaryl; Ring B, ring C, and ring D are independently selected from C 4-10 Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, benzo 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, =NR', OH, NH2, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkyl-S(=O)2-, 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)2NH-, C 1-6 Alkyl-NHS(=O)2-, C 1-6 Alkyl-O-, C 1-6 Alkyl-S- or 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-, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkyl-S(=O)2-, 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)2NH-, C 1-6 Alkyl-NHS(=O)2-, C 1-6 Alkyl-O-, C 1-6 Alkyl-S- or 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 with 1, 2 or 3 R'; R' is selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, CH2F, CHF2, CF3 and C 1-6 Alkyl-S(=O)2-; The above-mentioned heteroaryl, heteroalkyl or heterocycloalkyl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, C(═O), C(═O)O, C(═O)NH, S(═O), S(═O)2, P(═O), S(═O)2NH and N.

2. The compound according to claim 1, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R is independently selected from H, halogen, OH, NH2, CN, =O、=NR'、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)2-P(=O)-, C 1-3 Alkyl-C(=O)O-, C 1-3 Alkyl-O-, C 1-3 Alkyl-S- or C 1-3 Alkyl-NH-, 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 Alkyl-O-, C 1-3 Alkyl-S- and C 1-3 Alkyl-NH- is optionally substituted with 1, 2 or 3 R'.

3. The compound according to claim 2, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R is independently selected from H, F, Cl, Br, I, OH, NH2, CN, =O, =NH, =N-CN, CH3, CH2F, CHF2, CF3, 4. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from H, F, Cl, Br, I, Me, CN, OH, 5. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: L1 is selected from a single bond, -NH-, =N-, -O-, -C≡C-, 6. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from H, F, Cl, Br, I, 7. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R2, R3, and R4 are independently selected from H, CN, F, Cl, Br, OH, NH2, 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 oxirane-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 oxirane-O- are optionally substituted with 1, 2 or 3 R groups.

8. The compound according to claim 7, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R2, R3, and R4 are independently selected from H, CN, F, Cl, Br, OH, NH2, CN, Me, The Me, Optionally substituted with 1, 2 or 3 R.

9. The compound according to claim 8, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R2, R3, and R4 are independently selected from H, CN, F, Cl, Br, OH, NH2, CN, Me, 10. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R8 and R9 are independently selected from H, CN, F, Cl, Br, OH, NH2, Me or 11. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R 10 Selected from H, Me, 12. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: L2 is selected from a single bond, -CH2-, -CH(CH3)-, -CH=CH-, -C≡C-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NH-, 13. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: L3 is selected from a single bond, -CH2-, -CH(CH3)-, -OCH2-, -CH=CH-, -C≡C-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2- or -NH-.

14. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: L2-L3-CH2-、-CH2CH2-、-CH(CH3)-、-CH=CH-、-C≡C-、-O-、-CH2O-、-OCH(CH3)-、-S-、-C(=O)-、-S(=O)-、-S(=O)2-、-NH-、 15. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, thienyl, oxazolyl, pyridazinyl, oxiranyl, tetrahydropyranyl or 2-oxaspiro[3.3]heptanyl.

16. The compound according to claim 15, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from 17. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Ring B is selected from a bicyclic [ 1.1.1]pentyl, cyclopentyl, 2,6-diazaspiro[3.3]heptyl, cyclohexanyl, piperidinyl, thiazolyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, 5,6-dihydro-2(1H)-pyridonyl, benzocyclopentyl, benzocyclohexanyl, indolyl, isoindolyl, spiro[cyclopropane-1,3'-dihydroindole]-2'-onyl or naphthyl.

18. The compound according to claim 17, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from 19. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Ring C is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, piperazinyl, pyrazinyl, imidazolyl, indolyl, 2,5-dihydro-1H-pyrrolyl, morpholinyl, 1,2,3-triazolyl, pyrrolidinyl, azetidin-2-one, spiro[cyclopropane-1,3'-dihydroindole]-2'-one, bicyclo[2.1.1]hexanyl, bicyclo[3.1.1]heptanyl, octahydropyrrolo[3,4-b]pyridinyl or 2-azaspiro[3.4]oct-6-enyl.

20. The compound according to claim 19, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from 21. The compound according to claim 1, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Ring D is selected from phenyl, benzocyclopentyl, benzocyclohexyl, 1H-indazolyl, 2H-indazolyl or 1H-benzo[d]imidazole.

22. The compound according to claim 9 or 21, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from 23. A compound of the following formula, an optical isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:

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