Unsaturated compound and preparation method thereof

Abstract

The invention discloses an unsaturated 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.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and in particular, the present application relates to a class of unsaturated compounds and a preparation method and medical application thereof. BACKGROUND

[0002] Prostate cancer is an androgen-dependent tumor, androgens can bind to androgen receptor (AR) and stimulate the growth and progression of prostate cancer cells. Endocrine therapy is one of the conventional treatment methods, for example, the standard treatment for advanced PCa is androgen deprivation therapy (ADT), such as surgical castration (bilateral orchiectomy) or drug castration (such as injection of norethindrone). ADT therapy has a significant effect in the early stage of treatment, but as the disease progresses, AR mutations occur, 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 patients with advanced prostate cancer will eventually progress to CRPC after endocrine therapy. In addition, up to 30% of prostate cancer patients will develop into metastatic castration-resistant prostate cancer (mCRPC) within 10 years of initial treatment.

[0003] Currently, there are several oral drugs for the treatment of mCRPC, such as enzalutamide, apalutamide and darolutamide, etc., which mainly bind to the ligand binding domain (AR-LBD) of the androgen receptor, thereby blocking the interaction of AR with DNA and exerting their pharmacological effects. However, after 2-3 years of treatment with these drugs, patients are prone to drug resistance. The emergence of androgen receptor variants (AR-Vs) lacking the LBD region and mutations in the LBD region are two important drug resistance mechanisms.

[0004] Compared with normal full-length AR, AR-Vs are a kind of truncated AR, and these truncated variants lack the LBD region during formation, which leads to the inability of androgens to bind to AR-Vs. However, since AR-Vs retain the N-terminal domain and DNA-binding domain (DBD), they can still bind to genomic DNA and regulate the expression of downstream target genes, showing androgen-independent structural activity, which is one of the important mechanisms of ADT resistance and CRPC disease progression.

[0005] Developing inhibitors targeting AR receptor NTD with good physicochemical properties and drugability, by regulating the N-terminal domain of AR to inhibit the transcriptional function of androgen receptor AR and block the signaling pathway of androgen receptor, is a new direction for the treatment of prostate cancer. Inhibitors targeting AR-NTD will bring in-depth and extensive AR inhibition by acting on the N-terminal domain of AR receptor. It has important clinical value for the treatment of prostate cancer and other AR-driven cancer diseases, especially for the treatment of androgen-independent drug-resistant prostate cancer. SUMMARY

[0006] In one aspect of the present application, the present application provides a compound represented by Formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof,

[0007]

[0008] wherein,

[0009] R1is selected from H, halogen, OH, CN, NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-O-, C 1-6 alkyl-S-, C 1-6 alkyl-S(=O)2-, (C 1-6 alkyl)2-S(=O)=, C 1-6 alkyl-S(=O)2NH-, C 1-6 alkyl-S(=O)(=NH)-, 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; 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-O-, C 1-6 alkyl-S-, C 1-6 alkyl-S(=O)2-, (C 1-6 alkyl)2-S(=O)=, C 1-6 alkyl-S(=O)2NH-, C 1-6 alkyl-S(=O)(=NH)-, 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;

[0010] R2, R3, R4are each independently selected from H, CN, F, Cl, Br, 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 2-6alkyl, C 3-6 cycloalkyl-O-, C 3-6 cycloalkyl-S-, C 3-6 cycloalkyl-NH-, 4- to 6-membered heterocycloalkyl-O-, 4- to 6-membered heterocycloalkyl-S- or 4- to 6-membered heterocycloalkyl-NH-, which 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- to 6-membered heterocycloalkyl-O-, 4- to 6-membered heterocycloalkyl-S- and 4- to 6-membered heterocycloalkyl-NH- are optionally substituted by 1, 2 or 3 R;

[0011] R5, R6are independently selected from H, CN, F, CI, Br, 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- to 6-membered heterocycloalkyl-O-, 4- to 6-membered heterocycloalkyl-S-, 4- to 6-membered heterocycloalkyl-NH-, C 6-10 aryl, 5- to 10-membered heteroaryl or 3- to 10-membered heterocycloalkyl, which 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- to 6-membered heterocycloalkyl-O-, 4- to 6-membered heterocycloalkyl-S-, 4- to 6-membered heterocycloalkyl-NH-, C6-10 Aryl, 5-10-membered heteroaryl and 3-10-membered heterocyclic alkyl groups may be substituted with 1, 2 or 3 Rs;

[0012] m and n are independently selected from 0, 1, 2, 3 or 4 respectively;

[0013] L1 is selected from single bonds, -NH-, =N-, -O-, -C≡C-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, C 3-6 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein the C 3-6 Cycloalkyl and 3-10 membered heterocycloalkyl groups may be optionally substituted with 1 or 2 Rs;

[0014] Selected from or And when Selected from In this case, L1 is selected from =N- or 3-10-membered heterocyclic alkyl groups;

[0015] L2 is selected from single bonds, -CH=CH-, -C≡C-, -(CR7R8)x-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR9-, C 3-6 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 3-6 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl groups may be optionally substituted with 1, 2 or 3 Rs;

[0016] L3 is selected from -CH=CH-, -C≡C-, -(CR7R8)x-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR9;

[0017] L4 is selected from single bonds, -CH=CH-, -C≡C-, -(CR7R8)x-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR9-, C 3-6 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 3-6 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl groups may be optionally substituted with 1, 2 or 3 Rs;

[0018] L5 is selected from a single bond or -(CR7R8)x-;

[0019] L6 is selected from a single bond or -(CR7R8)x-;

[0020] selected from -CH=CH- or -C≡C-;

[0021] R7, R8are 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, said 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;

[0022] R9is selected from H or C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, said 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 1, 2 or 3;

[0023] Ring A is selected from C 4-10 cycloalkyl, 4-10 membered heterocycloalkyl, phenyl or 5-10 membered heteroaryl;

[0024] Ring B, Ring C 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;

[0025] R is independently selected from H, halogen, =0, =NR’, OH, NH2, CN, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkyl-S(=0)2-, C 1-6 alkyl-C(=0)-, C 1-6 alkyl-C(=0)0-, C 1-6 alkyl-O-C(=0)-, C 1-6 alkyl-C(=0)NH-, C 1-6alkyl-C(=O)NH-, C 1-6 alkyl-S(=O)2NH-, C 1-6 alkyl-NHS(=O)2-, 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-, said 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-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-, 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- optionally substituted with 1, 2 or 3 R’;

[0026] R’ is selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, CH2F, CHF2, CF3and C 1-6alkyl-S(=0)2-; the above heteroaryl, heteroalkyl or heterocycloalkyl comprise 1, 2 or 3 heteroatoms or groups of heteroatoms independently selected from the group consisting of -0-, -NH-, -N=, -S-, -C(=0)-, -C(=0)0-, -C(=0)NH-, -S(=0)-, -S(=0)2-, -P(=0)- and -S(=0)2NH-.

[0027] In some embodiments of the application, the above R are independently selected from H, halogen, OH, NH2, CN, =0, =NR', C 1-3 alkyl, C 3-6 cycloalkyl, C 1-3 alkyl-C(=0)-, C 1-3 alkyl-S(=0)2-, (C 1-3 alkyl)2-P(=0)-, C 1-3 alkyl-C(=0)0-, C 1-3 alkyl-O-, C 1-3 alkyl-S- or C 1-3 alkyl-NH-, said C 1-3 alkyl, C 3-6 cycloalkyl, C 1-3 alkyl-C(=0)-, C 1-3 alkyl-S(=0)2-, C 1-3 alkyl-C(=0)0-, C 1-3 alkyl-O-, C 1-3 alkyl-S- or C 1-3 alkyl-NH- optionally substituted by 1, 2 or 3 R', the remaining variables being as defined in the application.

[0028] In some embodiments of the application, the above R are independently selected from H, F, Cl, Br, I, OH, NH2, CN, =0, =NH, =N-CN, CH3, CH2F, CHF2, CF3, the remaining variables being as defined in the application.

[0029] In some embodiments of the application, the above R1is selected from H, F, Cl, Br, I, Me, CN, OH, NH2, the remaining variables being as defined in the application.

[0030] In some embodiments of the application, the above L1is selected from a single bond, -NH-, =N-, -0-, -CºC-, -S-, -C(=0)-, -S(=0)-, -S(=0)2-, the remaining variables being as defined in the application.

[0031] In some embodiments of the application, the structural unit is selected from H, F, Cl, Br, I, the remaining variables are as defined in the application.

[0032] In some embodiments of the application, the above R2, R3, R4are each independently selected from H, CN, F, Cl, Br, OH, NH2, CN, Me, 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 oxiranyl-O-, said 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 with 1, 2 or 3 R, the remaining variables being as defined in the application.

[0033] In some embodiments of the application, the above R2, R3, R4are each independently selected from H, CN, F, Cl, Br, OH, NH2, CN, Me, said Me, are optionally substituted with 1, 2 or 3 R, the remaining variables being as defined in the application.

[0034] In some embodiments of the application, the above R2, R3, R4are each independently selected from H, CN, F, Cl, Br, OH, NH2, CN, Me,

[0035] the remaining variables are as defined in the application.

[0036] In some embodiments of the present invention, R7 and R8 are independently selected from H, CN, F, Cl, Br, OH, NH2, Me, or The remaining variables are as defined in this invention.

[0037] In some embodiments of the present invention, R9 is selected from H, Me, The remaining variables are as defined in this invention.

[0038] In some embodiments of the present invention, the L2 is selected from single bonds, -CH2-, -CH(CH3)-, -C≡C-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NH-, The remaining variables are as defined in this invention.

[0039] In some embodiments of the present invention, L3 is selected from -CH2-, -CH(CH3)-, -OCH2-, -C≡C-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2- or -NH-, and the remaining variables are as defined in the present invention.

[0040] In some embodiments of the present invention, the L4 is selected from single bonds, -CH2-, -CH(CH3)-, -C≡C-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NH-, The remaining variables are as defined in this invention.

[0041] In some embodiments of the present invention, the aforementioned -L2-L3-L4- is selected from -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -C≡C-, -O-, -OCH2-, -OCH(CH3)-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NH-, -CH2NH-, The remaining variables are as defined in this invention.

[0042] In some embodiments of the present invention, L5 is selected from single bonds, -CH2-, -CH2CH2-, or... The remaining variables are as defined in this invention.

[0043] In some embodiments of the present invention, L6 is selected from single bonds, -CH2-, -CH2CH2-, or... The remaining variables are as defined in this invention.

[0044] In some embodiments of the present invention, the above-mentioned -CH2-CH=CH-, -CH2-CºC-, -CH2-CH=CH-CH2-, -CH2-CºC-CH2-, the remaining variables are as defined in the present application.

[0045] In some embodiments of the application, ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, thienyl, oxazolyl, pyridazinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, or piperidinyl, and the remaining variables are as defined in the present application.

[0046] In some embodiments of the application, the structural unit is selected from the remaining variables are as defined in the present application.

[0047] In some embodiments of the application, ring B is selected from bicyclo[l.l.l]pentanyl, cyclopentanyl, 2,6-diazaspiro[3.3]heptanyl, pyrazolyl, piperidinyl, thiazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzocyclopentanyl, benzocyclohexanyl, indolyl, isoindolinyl, spiro[cyclopropane-l,3'- dihydroindol]-2'-onyl, 3(2H)-pyridazinonyl, or 2(lH)-pyridonyl, and the remaining variables are as defined in the present application.

[0048] In some embodiments of the application, the structural unit is selected from

[0049] the remaining variables are as defined in the present application.

[0050] In some embodiments of the application, ring C is selected from phenyl, benzocyclopentanyl, benzocyclohexanyl, lH-indazolyl, 2H-indazolyl, or lH-benzo[d]imidazolyl, and the remaining variables are as defined in the present application.

[0051] In some embodiments of the application, the structural unit is selected from

[0052] the remaining variables are as defined in the present application.

[0053] The present application also provides a compound of the following formula, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from:

[0054]

[0055] the remaining variables are as defined in the present application.

[0056] In yet another aspect of the present application, the present application also provides use of the above-mentioned compounds, optical isomers thereof, or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating a disease associated with androgen receptor (AR) activity or expression.

[0057] In some embodiments of the present application, the above-mentioned disease associated with androgen receptor (AR) activity or expression is selected from the group consisting of prostate cancer, ovarian cancer, breast cancer, bladder cancer, pancreatic cancer, endometrial cancer, hepatocellular cancer, renal cell cancer, melanoma, mantle cell lymphoma, glioblastoma, salivary gland carcinoma, alopecia, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration.

[0058] Definitions and Descriptions

[0059] Unless otherwise indicated herein, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indefinite or unclear if not specifically defined, but should be interpreted in accordance with its ordinary meaning. When a trade name appears herein, it is intended to denote the corresponding product or its active ingredient.

[0060] As used herein in the specification and claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from among the individual elements in the list of one or more elements, but not necessarily including at least one of each and every element specifically listed within the list of one or more elements and not excluding any combinations of elements in the list of one or more elements. This definition also allows that the

[0061] The term "pharmaceutically acceptable," as used herein, pertains to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0062] The term "pharmaceutically acceptable salt" means a salt of a compound of this application which is found to possess the specific substituent groups discovered in this application, prepared from the compounds of this application with a relatively nontoxic acid or base. Alkali addition salts are obtained by contacting the neutral form of such compounds in solution or in a suitable inert solvent, with a sufficient amount of the base to produce the neutral form of the compound. Pharmaceutically acceptable alkali addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. Acid addition salts are obtained by contacting the neutral form of such compounds in solution or in a suitable inert solvent, with a sufficient amount of the acid to produce the neutral form of the compound. Examples of pharmaceutically acceptable acid addition salts include mineral acids, such as hydrochloric, hydrobromic, nitric, carbonic, bicarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, bisulfic, hydroiodic, phosphorous, and the like; and organic acids, such as acetic, propionic, isobutyric, trifluoroacetic, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids and the like; also salts of amino acids, such as arginine and the like, and salts of organic acids like glucuronic acid. Certain specific compounds of this application contain both basic and acidic functionalities as a result of which two salt forms can be possible. The compounds of this application can be converted into salts to form either alkali or acid addition salts.

[0063] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by contacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two.

[0064] "Pharmaceutically acceptable carrier" means a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material, formulation, formulation auxiliary or vehicle that is generally used in the art of treating agents and which together with such pharmaceutical agents, comprise a "pharmaceutical composition" for administration to a subject. The pharmaceutically acceptable carrier is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation. The pharmaceutically acceptable carrier is suitable for the formulation used.

[0065] When any variable (e.g., R) occurs more than one time in a compound, its definition in each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is substituted with 0-2 R, said group can optionally be substituted with up to two R groups, and each R group is selected independently of each other R group. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. may be selected from and the like.

[0066] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for substituents. For example, -CH2- means 1-6 alkylcarbonyl- means a C 1-6 alkyl group attached to the remainder of the molecule through a carbonyl group. However, when the point of attachment of a substituent is apparent to one of ordinary skill in the art, such as a halogen substituent, the "-" can be omitted.

[0067] When a group is drawn with a dashed line as in the dashed line indicates the point of attachment of that group to the rest of the molecule.

[0068] The term "substituted" or "substitution" means that any one or more hydrogen atoms on the designated atom is replaced with a substituent group, which can include deuterium and variants of hydrogen, as long as the valency of the designated atom is not exceeded and the substituted compound is stable. The term "optionally substituted" or "optionally substitution" means that the atom can or can not be substituted and the type and number of substituents, unless otherwise specified, can be any that are chemically possible.

[0069] When any variable (e.g., R) occurs more than one time in a compound or substituent, its definition in each instance is independent of the definition of the other instances. Thus, for example, if a group is substituted with 1, 2, or 3 R', then said group can optionally be substituted with one or two or three R', and the R' at each occurrence is selected independently.

[0070] When one of the variables is selected from a single bond, it indicates that the two groups to which it is attached are directly connected, such as in which L1represents a single bond, it indicates that the structure is actually

[0071] When a substituent is recited without indicating that it is attached to the rest of the molecule by a single bond, then such substituent is attached by any of the atoms which could form such a bond, for example, a pyridine group as a substituent can be attached at any of the ring carbon atoms to the rest of the molecule.

[0072] When a linking group is recited without indicating its direction of attachment, its direction of attachment is arbitrary, for example, in which the linking group L is -CH2O-, then -CH2O- can attach the phenyl and cyclopentyl groups to form either in the same direction as the reading from left to right Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0073] The term "halogen" denotes fluorine, chlorine, bromine, iodine.

[0074] Unless otherwise specified, the number of atoms in a ring is defined as the number of members of the ring, e.g., "3-6 membered ring" means a "ring" that has 3-6 atoms arranged in a ring.

[0075] Unless otherwise specified, the term "C 1-6 "alkyl" is used to denote a straight or branched saturated carbon hydride group consisting of from 1 to 6 carbon atoms. The C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6and C5alkyl, etc.; which can be monovalent, divalent or multivalent. C Examples of C 1-6 alkyl groups include, but are not limited to, CH3, etc.

[0076] Unless otherwise specified, "C 2-6 "alkenyl" is used to denote a straight or branched carbon hydride group consisting of from 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which can be located at any position on the group. The C 2-6 alkenyl group includes C 2-4 , C 2-3 , C4, C3and C2alkenyl, etc.; which can be monovalent, divalent or multivalent. C 2-6 Examples of C 2-3 alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, etc.

[0077] Unless otherwise specified, "C 2-3 alkenyl" is used to denote a straight or branched carbon hydride group consisting of from 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which can be located at any position on the group. The C 2-3 alkenyl group includes C3and C2alkenyl; which can be monovalent, divalent or multivalent. C 2-3 Examples of C alkenyl groups include, but are not limited to,

[0078] The term "heteroalkyl" on its own or in combination with another term refers to a stable straight-chain or branched alkyl group or a combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heterogroup. In some embodiments, the heteroatom is selected from B, O, N, P, and S, wherein the nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heterogroup is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -P(=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 group is C 1-6 Heteroalkyl; in other embodiments, the heteroalkyl group is C10. 1-3 Heteroalkyl groups. Heteroatoms or heteroatomic groups can be located at any internal position of a heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule, but the term "alkoxy" is a conventional expression and refers to those alkyl groups that are attached to the rest of the molecule by an oxygen atom. Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2-S-CH3, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3, The two heteroatoms can be consecutive, for example, -CH2-NH-OCH3.

[0079] Unless otherwise specified, the term "C" 1-6 "Alkoxy" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-6 Alkoxy groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, and C3 alkoxy groups, etc. 1-6 Examples 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), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, etc.

[0080] Unless otherwise specified, the term "C 1-3 "Aryloxy" means those groups of the formula -O-Ar, where Ar is an aromatic group. The C 1-3 Aryloxy groups include C 1-3 , C 1-2 , C 2-3 , C6, C5, C4, C3, and C2 aryloxy groups. C 1-3 Examples of aryloxy groups include, but are not limited to, -O-Ph, -O-C6H4CH3,

[0081] Unless otherwise specified, the term "C 1-6 "Aryloxy" means those groups of the formula -O-Ar, where Ar is an aromatic group. The C 1-6 Aryloxy groups include C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4, C3, and C2 aryloxy groups. C 1-6 Examples of aryloxy groups include, but are not limited to, -O-Ph, -O-C6H4CH3,

[0082] Unless otherwise specified, the term "C 1-3 "Aryloxy" means those groups of the formula -O-Ar, where Ar is an aromatic group. The C 1-3 Aryloxy groups include C 1-3 , C 1-2 , C 2-3 , C6, C5, C4, C3, and C2 aryloxy groups. C 1-3 Examples of aryloxy groups include, but are not limited to, -O-Ph, -O-C6H4CH3,

[0083] Unless otherwise specified, the term "C 1-6 "Aryloxy" means those groups of the formula -O-Ar, where Ar is an aromatic group. The C 1-6 Aryloxy groups include C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4, C3, and C2 aryloxy groups. C1-6 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH(CH3)2, and the like.

[0084] The term "C 1-3 "alkylthio" denotes those alkyl groups, as defined herein, having from 1 to 3 carbon atoms, attached to the remainder of the molecule by a sulfur atom. The C 1-3 alkylthio groups include C 1-3 , C 1-2 , C 2-3 , C1, C2, and C3 alkylthio groups, and the like. The C 1-3 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH(CH3)2, and the like.

[0085] The term "C 3-6 "Cycloalkyl" denotes saturated cyclic hydrocarbon radicals consisting of three to six carbon atoms, which are monocyclic and bicyclic ring systems, the C 3-6 cycloalkyl groups include C 3-5 , C 4-5 , and C 5-6 cycloalkyl groups; which can be monovalent, divalent, or multivalent. The C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0086] The term "3-10 membered heterocycloalkyl," by itself or in combination with other terms, refers to saturated or partially unsaturated ring systems consisting of 3 to 10 ring atoms, 1, 2, 3, or 4 of which are heteroatoms independently selected from O, S, P, and N, with the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, phosphorus, and sulfur atoms can be independently optionally oxidized (i.e., C=0, P=0, NO, and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, including spiro, fused, and bridged ring systems. Further, with respect to this "3-10 membered heterocycloalkyl," a heteroatom can occupy the position of attachment of the heterocycloalkyl group to the remainder of the molecule. The 3-10 membered heterocycloalkyl groups include 3-9 membered, 3-8 membered, 3-7 membered, 3-6 membered, 3-5 membered, 3-4 membered, 4-5 membered, 4-6 membered, 4-7 membered, 4-8 membered, 4-9 membered, 5-6 membered, 5-7 membered, 5-8 membered, 5-9 membered, 6-7 membered, 6-8 membered, 6-9 membered, 7-8 membered, 3 membered, 4 membered, 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, 10 membered heterocycloalkyl groups, and the like. Examples of 3-10 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, 1,3-dioxolane, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (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.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperidinyl, etc.

[0087] Unless otherwise specified, the term "5-6 membered heteroaryl" by itself or in combination with other terms means a monocyclic radical consisting of five to six ring atoms having a conjugated pi-electron system, one, two, three, or four of which are heteroatoms independently selected from O, S, and N, with the remainder being carbon atoms. The nitrogen atoms can optionally be quaternized, and the nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., NO and S(O) p , p is 1 or 2). This includes both monocyclic and bicyclic ring systems, where the bicyclic ring systems include spiro, fused, and bridged. Further, with respect to this "5-6 membered heteroaryl," the heteroatoms can occupy any available positions of the heteroaryl radical, including the 2- and 3-positions. The 5-6 membered heteroaryl includes 5- and 6-membered heteroaryls, and the like. Examples of 5-6 membered heteroaryls include, but are not limited to, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiazinyl, and the like. pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (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.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperidinyl, etc.

[0088] Unless otherwise specified, the terms "5-6 membered heteroaryl" and "5-6 membered heteroaromatic" are used interchangeably in the present application, and the term "5-6 membered heteroaryl" means a monocyclic radical consisting of five to six ring atoms having a conjugated pi-electron system, one, two, three, or four of which are heteroatoms independently selected from O, S, and N, with the remainder being carbon atoms. The nitrogen atoms can optionally be quaternized, and the nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., NO and S(O) p, p is 1 or 2). The 5-6 membered heteroaryl groups can be attached to the rest of the molecule through a heteroatom or carbon atom. The 5-6 membered heteroaryl groups include 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thiophenyl (including 2-thiophenyl and 3-thiophenyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, etc.), pyrazinyl, or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0089] The term "C 6-10 "aryl" by itself or in combination with other terms means a monocyclic or bicyclic aromatic ring system having six to ten carbon atoms. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl.

[0090] The compounds of the present application can contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). For example, deuterium can be substituted for hydrogen to form deuterated drugs, which have advantages over non-deuterated drugs, such as reduced toxicity, increased stability, enhanced efficacy, and increased biological half-life. All isotopic variations of the compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application.

[0091] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0092] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the embodiments set forth below with other chemical synthetic methods well known in the art, and equivalents thereof as appreciated by those skilled in the art, preferred embodiments including, but not limited to, the examples of the present application.

[0093] The solvents used in the present application are commercially available.

[0094] Compounds are named according to the nomenclature rules of the chemical art or using software nomenclature, and commercially available compounds are named using the vendor catalog name.

[0095] The compounds disclosed herein can have one or more chiral centers, each of which independently has the R configuration or the S configuration, or the cis configuration or the trans configuration. Some of the compounds disclosed herein have chiral centers that are designated *R, *S, R*, S*, *cis-, or *trans-, indicating that the absolute configuration of the chiral center is not identified, but that the compound has been separated or resolved and that the chiral center is in a single configuration, the compound is a single enantiomeric monomer, or a single diastereomeric monomer, or a mixture of diastereomers in which the chiral center is in a single configuration (e.g., other chiral centers are not resolved), or a single monomer (e.g., a single cis monomer, or a single trans monomer). When the absolute configuration of a chiral center of a compound disclosed herein is not identified (R configuration, S configuration, cis configuration, or trans configuration), such a compound can be identified by the pattern of peaks in its nuclear magnetic resonance (NMR) spectrum, or by the retention time (RT or Rt) under the conditions of a chromatographic column (e.g., column type, column packing, column size, mobile phase, etc.) corresponding to that compound. 1 H-NMR, 31 P-NMR) spectrum of the compound.

[0096] The present application is more particularly described in the following examples that are intended to be illustrative only and not limiting of the scope of the application. The following examples are presented to demonstrate particular embodiments and uses of the present application. However, they should not be construed to limit the scope of this application, as such can include any and all combinations of features contained therein. Unless otherwise indicated, the methods of the experiments in the following examples were conducted in accordance with conventional methods of the art, or as otherwise described herein. Unless otherwise indicated, all percentages and parts are by weight. Unless otherwise indicated, ratios of liquids are by volume.

[0097] Unless specifically defined otherwise herein, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. DETAILED DESCRIPTION

[0098] ​The present application is described in detail below with reference to embodiments, but this does not imply any adverse limitations on the present application. The present application has been described in detail herein, and specific embodiments thereof have also been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific implementations of the present application without departing from the spirit and scope thereof.

[0099] Unless otherwise specified, all experimental materials and reagents used in the following examples are available from commercially available sources.

[0100] In all embodiments, 1 H NMR, 13 C NMR, 19 F NMR and 31 The p NMR spectra were recorded using a Bruker Ascend 400 mHz NMR spectrometer and processed using Topspin software, with a deuterated solvent acting as an internal deuterium lock. 13 C NMR, 19 F NMR and 31 p NMR 1 H-decoupling. Assignment based on a defined chemical shift / coupling mode, or according to 2D Cosy, HMBC, HSQC, or NOESY experiments. Peak multiplicity is defined as: s singlet, d doublet, t triplet, q quartet, m multiplet, br broad peak, br.s broad singlet; coupling constant (J) accurate to 0.1 Hz. Mass spectrometry was recorded using an Agilent 1260 (ESI) or Shimadzu LC-MS-2020 (ESI) or Agilent 6215 (ESI) mass spectrometer; reversed-phase preparative HPLC separation was performed using an Agilent 1290 UV-guided fully automated purification system. Prep C18OBD™ 21.2*250mm 10μm column) or a Gilson GX281 UV-guided fully automated purification system ( Prep C18OBD™ 19*250mm 10μm column or Waters QDa guided fully automated purification system ( The separation was performed using a Prep C18OBD 29*250mm 10μm column. Unless otherwise specified, separation was performed using a SepaFlash pre-packed normal-phase silica column (Sinopharm Chemical Reagent Co., Ltd.), TLC analytical plates (Yantai Jiangyou Silica Gel Development Co., Ltd., model: HSGF254, size: 2.5×5cm), and all eluent ratios were volume ratios.

[0101] The Chinese names of the reagents represented by chemical formulas or English letter abbreviations are as follows:

[0102] 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)20 represents di-tert-butyl dicarbonate; Et3SiH represents triethylsilane; HATU represents l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HOBt represents 1-hydroxybenzotriazole; TMAD represents N,N,N',N'-tetramethylazodicarbonamide; K2CO3 represents potassium carbonate; KOAc represents potassium acetate; MeONa represents sodium methoxide; LDA represents lithium diisopropylamide; LiHMDS represents bis(trimethylsilyl)amide lithium; 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 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride; Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium(0); Pd(OAc)2 represents palladium 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.Representatives toluene; SOCl2 represents dichlorosulfoxide; TFA represents trifluoroacetic acid; FA represents formic acid; TMSCN represents trimethylsilyl cyanide; H2O represents water; HC1 represents hydrogen chloride gas; HC1 aq. represents aqueous hydrochloric acid; °C represents degrees Celsius; rt or RT represents room temperature; h represents hour(s); min represents minute(s); g represents gram(s); mg represents milligram(s); mL represents milliliter(s); mmol represents millimole(s); M represents mole(s); cm represents centimeter(s); mm represents millimeter(s); pm represents micrometer(s); nm represents nanometer(s); mL / min represents milliliter per minute; Hz represents hertz; MHz represents megahertz; bar represents pressure unit bar; psi represents pressure unit pound per square inch; N2 represents nitrogen; HPLC represents high performance liquid chromatography; I.D. represents internal 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; rpm represents revolutions per minute; ATCC represents American type culture collection.

[0103] Example 1: Preparation of Compound 1

[0104]

[0105] Preparation of Compound 1-2

[0106] In a 100 mL single-necked flask, 2-chloro-4-bromophenol (compound 1-1, 5.0 g, 24.10 mmol) was dissolved in ammonia water (25 mL, mass fraction 25%) and water (25 mL), and then iodine (6.12 g, 24.10 mmol), potassium iodide (12.0 g, 72.31 mmol) were added in sequence. The reaction solution was stirred at 25 °C for 16 hours. After the reaction was completed, concentrated hydrochloric acid (100 mL) was added to the reaction solution, and extracted with ethyl acetate (100 mL) three times, and the organic phase was washed with aqueous sodium thiosulfate solution (100 mL) and saturated brine (100 mL) once, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 7.2 g of the title compound 1-2. 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H).

[0107] Preparation of Compound 1-3

[0108] Compound 1-2 (5.4 g, 16.20 mmol) was dissolved in N,N-dimethylformamide (30 mL) in a 100 mL single-neck flask, and cesium carbonate (10.56 g, 32.40 mmol), 1-bromo-2-chloroethane (4.65 g, 32.40 mmol) were added successively. The reaction liquid was stirred at 80°C for 16 hours. After the reaction was completed, the reaction liquid was added to water (200 mL), and extracted with ethyl acetate (100 mL) three times, and the organic phase was combined, washed with saturated brine (100 mL) once, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain 6.3 g of the title compound 1-3. LC-MS (ESI): m / z 394.3.

[0109] Preparation of compound 1-4

[0110] Compound 1-3 (3.0 g, 7.58 mmol) was dissolved in N,N-dimethylacetamide (30 mL) in a 100 mL single-neck flask, and cuprous cyanide (1.36 g, 15.16 mmol) was added. The reaction liquid was stirred at 120°C for 16 hours. After the reaction was completed, the reaction liquid was added to water (100 mL), filtered, and the filtrate was extracted with ethyl acetate (80 mL) three times, and the organic phase was combined, washed with saturated brine (100 mL) once, dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain 1.5 g of the title compound 1-4. 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 2.3 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H), 4.45 (t, J = 5.2 Hz, 2H), 3.97 (t, 2J = 5.2 Hz, 2H).

[0111] Preparation of compound 1-5

[0112] Compound 1-4 (1.5 g, 5.09 mmol) was dissolved in 1,4-dioxane (20 mL) and water (4 mL) in a 100 mL single-neck flask, and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.57 g, 10.17 mmol), potassium carbonate (2.11 g, 15.26 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (372 mg, 0.51 mmol) were added in sequence. The reaction solution was stirred at 100°C for 16 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was added to water (50 mL) and extracted with ethyl acetate (50 mL) three times. The organic phase was washed with saturated brine (50 mL) once, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain 1.3 g of the title compound 1-5. 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 2.1 Hz, 1H), 7.98 (d, J = 2.1 Hz, 1H), 6.70 (dd, J = 17.7, 11.0 Hz, 1H), 6.03 (d, J = 17.6 Hz, 1H), 5.41 (d, J = 11.1 Hz, 1H), 4.45 (t, J = 5.2 Hz, 2H), 3.97 (t, J = 5.2 Hz, 2H).

[0113] Preparation of compound 1-6

[0114] Compound 1-5 (200 mg, 0.83 mmol) was dissolved in N,N-dimethylacetamide (2 mL) in a 10 mL microwave tube, and 4-iodophenol (236 mg, 1.07 mmol), triethylamine (263 mg, 2.48 mmol), and palladium acetate (60 mg, 0.08 mmol) were added in sequence. The reaction solution was stirred at 100°C for 16 hours under a nitrogen atmosphere. After the reaction was completed, water (20 mL) was added to the reaction solution, which was filtered, and the filtrate was extracted with ethyl acetate (20 mL) three times. The organic phase was washed with saturated brine (20 mL) once, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain 110 mg of the title compound 1-6. 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.41 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 16.5 Hz, 1H), 6.99 (d, J = 16.4 Hz, 1H), 6.79 (d, J = 8.2 Hz, 2H), 4.44 (t, J = 5.1 Hz, 2H), 3.98 (t, J = 5.1 Hz, 2H). Preparation of compound 1-7

[0115] Compound 1-6 (137 mg, 0.41 mmol) was dissolved in N,N-dimethylformamide (2 mL) in a 10 mL single neck flask, 2-chloro-4-(chloromethyl)pyrimidine (134 mg, 0.82 mmol), cesium carbonate (401 mg, 1.23 mmol) were added in turn. The reaction liquid was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction liquid was added with water (10 mL), extracted with ethyl acetate (10 mL) for 3 times, the organic phase was combined, washed with saturated brine (10 mL) for 1 time, dried over anhydrous sodium sulfate, suction filtered and concentrated. The obtained crude product was purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain 95 mg of the title compound 1-7. LC-MS (ESI): m / z 460.0 [M+H] + .

[0116] Preparation of compound 1

[0117] Compound 1-7 (35 mg, 0.08 mmol) was dissolved in 1,4-dioxane (0.5 mL) in a 10 mL microwave tube, dimethyl phosphine oxide (12 mg, 0.15 mmol), tris(dibenzylideneacetone)dipalladium (7 mg, 0.007 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9 mg, 0.02 mmol), N,N-diisopropylethylamine (49 mg, 0.38 mmol) were added successively. The reaction was stirred at 120 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, the reaction was added with water (10 mL), filtered, the filtrate was extracted with ethyl acetate (10 mL) for 3 times, the combined organic phase was washed with saturated brine (10 mL) for 1 time, dried over anhydrous sodium sulfate, suction filtered, concentrated, the obtained crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1), then purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile gradient elution in 12 minutes; flow rate: 30 mL / min) to obtain 28.76 mg of the title compound 1. LC-MS (ESI): m / z 502.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 5.0 Hz, 1H), 8.07 (d, J = 2.1 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 5.2, 3.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 16.5 Hz, 1H), 7.18 - 7.05 (m, 3H), 5.34 (s, 2H), 4.45 (t, J = 5.2 Hz, 2H), 3.98 (t, J = 5.2 Hz, 2H), 1.77 (d, J = 13.7 Hz, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 34.06 (s, 1P).

[0118] Example 2: Preparation of compound 2

[0119]

[0120] Preparation of compound 2-1

[0121] Compound 1-5 (300 mg, 1.24 mmol) was dissolved in DMA (6 mL) in a 50 mL single-neck flask, and 4-(4-iodophenyl)phenol (477 mg, 1.61 mmol), palladium acetate (28 mg, 0.12 mmol), and triethylamine (376 mg, 3.72 mmol) were added in sequence. The reaction solution was stirred at 100°C under nitrogen protection for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (30 mL) was added to the reaction solution, and extraction was performed with ethyl acetate (20 mL) three times. The organic phase was combined and washed with saturated brine solution (20 mL) once, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain 160 mg of the title compound 2-1. 1 H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.12 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.67 - 7.58 (m, 4H), 7.54 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 16.5 Hz, 1H), 7.24 (d, J = 16.4 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 4.46 (t, J = 5.2 Hz, 2H), 3.99 (t, J = 5.2 Hz, 2H).

[0122] Preparation of compound 2-2

[0123] Compound 2-1 (160 mg, 0.39 mmol) was dissolved in N,N-dimethylformamide (2 mL) in a 25 mL single-neck flask, and cesium carbonate (381 mg, 1.17 mmol) and 2-chloro-4-(chloromethyl)pyrimidine (127 mg, 0.78 mmol) were added in sequence. The reaction solution was stirred at 60°C for 2 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, and extraction was performed with ethyl acetate (10 mL) three times. The organic phase was combined and washed with saturated brine (10 mL) once, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain 100 mg of the title compound 2-2.

[0124] Preparation of compound 2-3

[0125] Compound 2-2 (30 mg, 0.06 mmol), 2-thia-6-azaspiro[3.3]heptane (17 mg, 0.08 mmol), DIPEA (29 mg, 0.22 mmol) were dissolved in ethanol (1 mL). After addition, the reaction system was stirred at 100 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE / EA = 100% ~ 50%) to obtain 30 mg of the title compound 2-3. LC-MS (ESI): m / z 615.4 [M+H] + .

[0126] Preparation of compound 2

[0127] Compound 2-3 (35 mg, 0.06 mmol), diacetoxyiodobenzene (55 mg, 0.17 mmol), ammonium carbamate (18 mg, 0.23 mmol) were dissolved in methanol (1 mL), tetrahydrofuran (1 mL). The reaction system was stirred at 25 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated to obtain the crude product, which was purified by silica gel column chromatography (DCM / MeOH = 100% ~ 90%) and preparative separation (preparative method mobile phase: A: 0.1% aqueous formic acid; B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: 45% - 65% acetonitrile gradient elution in 12 minutes; flow rate: 30 mL / min) to obtain 6.2 mg of the title compound 2. LC-MS (ESI): m / z 646.6 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.35 (d, J = 5.2 Hz, 1H), 7.76 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.60 - 7.49 (m, 6H), 7.15 - 6.98 (m, 4H), 6.91 (d, J = 5.1 Hz, 1H), 5.04 (s, 2H), 4.47 (t, J = 6.0 Hz, 2H), 4.44 - 4.25 (m, 9H), 3.91 (t, J = 6.1 Hz, 2H).

[0128] Example 3: Preparation of compound 3

[0129]

[0130] Preparation of compound 3-1

[0131] (2-chloropyrimidin-5-yl)methanol (250 mg, 1.73 mmol) was dissolved in dichloromethane (3 mL), and thionyl chloride (350 mg, 2.59 mmol) was slowly added dropwise at 0 °C under nitrogen protection. After the addition was completed, the reaction system was stirred at 0 °C for 1 h. After the reaction was completed, the reaction solution was concentrated to obtain 270 mg of the title compound 3-1 crude product. Without purification, it was directly used in the next step reaction.

[0132] Preparation of compound 3-2

[0133] Compound 2-1 (140 mg, 0.85 mmol), compound 3-1 (270 mg, 0.66 mmol), cesium carbonate (429 mg, 1.32 mmol) were dissolved in DMF (4 mL). After the addition was completed, the reaction system was stirred at 70 °C for 4 h. After the reaction was completed, water (20 mL) was added, and ethyl acetate (20 mL) was extracted 3 times, the organic phase was combined, washed with saturated brine (20 mL) 2 times, 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% to 75%) to obtain 250 mg of the title compound 3-2. LC-MS (ESI): m / z 536.6 [M+H] + .

[0134] Preparation of compound 3

[0135] Compound 3-2 (50 mg, 0.09 mmol), compound 3-3 (38 mg, 0.28 mmol), cesium carbonate (61 mg, 0.18 mmol), Pd2(dba)3 (8 mg, 0.009 mmol), Xantphos (11 mg, 0.02 mmol) were dissolved in 1,4-dioxane (1 mL). The reaction system was stirred at 110 °C for 16 h under nitrogen protection, and after the reaction was completed, the reaction solution was concentrated, and the obtained crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) and preparative purification (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile was gradient eluted in 12 min; flow rate: 30 mL / min) to obtain 29.9 mg of the title compound 3. LC-MS (ESI): m / z 635.0 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 8.59 (s, 2H), 8.13 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.77 - 7.58 (m, 6H), 7.49 (d, J = 16.5 Hz, 1H), 7.27 (d, J = 16.5 Hz, 1H), 7.13 (d, J = 8.9 Hz, 2H), 5.07 (s, 2H), 4.47 (t, J = 5.2 Hz, 2H), 4.14 - 4.04 (m, 2H), 4.03 - 3.89 (m, 4H), 3.86 - 3.77 (m, 2H), 3.65 - 3.55 (m, 2H).

[0136] Example 4: Preparation of compound 4

[0137]

[0138] Preparation of compound 4

[0139] Compound 3-2 (50 mg, 0.09 mmol), dimethyl phosphine oxide (22 mg, 0.28 mmol), N,N-diisopropylethylamine (48 mg, 0.37 mmol), Pd2(dba)3(9 mg, 0.009 mmol), Xantphos (11 mg, 0.02 mmol) were dissolved in 1,4-dioxane (1 mL). The reaction system was stirred at 120 °C for 2 hours under microwave irradiation. After the reaction was completed, the reaction solution was concentrated, and the obtained crude product was purified by preparation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile was gradient eluted in 12 minutes; flow rate: 30 mL / min) to obtain 2.43 mg of the title compound 4. LC-MS (ESI): m / z 578.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.99 (s, 2H), 7.76 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.62 - 7.53 (m, 6H), 7.15 - 7.03 (m, 3H), 6.98 (d, J = 16.2 Hz, 1H), 5.20 (s, 2H), 4.47 (t, J = 6.1 Hz, 2H), 3.91 (t, J = 6.1 Hz, 2H), 1.91 (d, J = 13.5 Hz, 6H). 31 P NMR (400 MHz, Chloroform-d) δ 35.00 (s, 1P).

[0140] Example 5: Preparation of compound 5

[0141]

[0142] Preparation of compound 5-1

[0143] Compound 3-2 (60 mg, 0.11 mmol) was dissolved in ethanol (0.5 mL) and tetrahydrofuran (0.5 mL) in a 10 mL microwave tube, 2-thia-6-azaspiro[3.3]heptane (39 mg, 0.17 mmol), N,N-diisopropylethylamine (23 mg, 0.22 mmol) were added successively. The reaction was stirred at 100 °C for 2 hours. After the reaction was completed, the reaction was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain 72 mg of the title compound 5-1. LC-MS (ESI): m / z 615.1 [M+H] + .

[0144] Preparation of compound 5

[0145] Compound 5-1 (60 mg, 0.10 mmol) was dissolved in methanol (0.5 mL) and dichloromethane (0.2 mL) in a 25 mL single-neck flask, ammonium carbamate (30 mg, 0.39 mmol), iodoxybenzene diacetate (95 mg, 0.29 mmol) were added successively. The reaction was stirred at 25 °C for 16 hours. After the reaction was completed, the reaction was rotary evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM / MeOH = 100%~10%) and preparative separation purification (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250x21.2mm; column temperature: 25 °C; gradient: 45%~65% acetonitrile gradient elution in 12 minutes; flow rate: 30 mL / min) to obtain 12.74 mg of the title compound 5. LC-MS (ESI): m / z 646.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.50 (s, 2H), 8.13 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.74 - 7.60 (m, 6H), 7.49 (d, J = 16.5 Hz, 1H), 7.26 (d, J = 16.4 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 5.01 (s, 2H), 4.47 (dd, J = 10.3, 5.3 Hz, 3H), 4.31 (d, J = 12.8 Hz, 2H), 4.28 - 4.18 (m, 6H), 3.99 (t, J = 5.2 Hz, 2H).

[0146] Example 6: Preparation of compound 6

[0147]

[0148] Preparation of compound 6-2

[0149] Compound 1-5 (800 mg, 3.30 mmol), compound 6-1 (1.14 g, 4.96 mmol), Hoveyda-Grubbs catalyst (207 mg, 330.44 μmol) and DCE (5 mL) were added to a reaction flask under nitrogen protection, the gas was replaced for three times, stirred at 90 °C overnight. After the reaction was completed, it was cooled to room temperature, rotary evaporation under reduced pressure, the obtained crude product was purified by silica gel column chromatography (PE / EA = 100%) to obtain 500 mg of the title compound 6-2. LC-MS (ESI): m / z 444.2 [M+H] + .

[0150] Preparation of compound 6-3

[0151] (4-Bromophenyl)ethyne (1 g, 5.52 mmol), 2-chloro-5-iodopyrimidine (1.46 g, 6.08 mmol), bis(triphenylphosphine)palladium dichloride (776 mg, 1.10 mmol), cuprous iodide (105 mg, 552.40 μmol), triethylamine (2.79 g, 27.62 mmol, 3.85 mL) and THF (10 mL) were added to a reaction flask under nitrogen protection, stirred at 25 °C for 16 hours. Filtration, rotary evaporation, the crude product was purified by silica gel column chromatography (PE / EA = 100%~80%) to obtain 1.2 g of the title compound 6-3.

[0152] Preparation of compound 6-4

[0153] Compound 6-3 (500 mg, 1.70 mmol) was dissolved in DMF (5 mL), dimethyl phosphine oxide (160 mg, 2.04 mmol), DIEA (660 mg, 5.11 mmol), tris(dibenzylideneacetone)dipalladium (156 mg, 170.33 μmol) and Xantphos (197 mg, 340.66 μmol) were added successively. After three times of nitrogen replacement, the reaction was carried out at 100 °C for 1 h by microwave. After the reaction was completed, it was cooled to room temperature, spun dry, and purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile gradient elution in 12 min; flow rate: 30 mL / min) to give 100 mg of the title compound 6-4. LC-MS (ESI): m / z 335.0 [M+H] + .

[0154] Preparation of compound 6

[0155] Compound 6-4 (60 mg, 180.12 μmol), 6-2 (89 mg, 200 μmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (13 mg, 18.01 μmol) and K2CO3 (75 mg, 540.35 μmol) were dissolved in 1,4 dioxane (1 mL), three times of nitrogen replacement, stirred at 100 °C for 6 h. Add water (5 mL), extract with ethyl acetate (5 mL) three times, combine the organic phase, dry over anhydrous sodium sulfate, filter, spin dry, the obtained crude product was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: 15%-65% acetonitrile gradient elution in 12 min; flow rate: 30 mL / min) to give 20 mg of the title compound 6. LC-MS (ESI): m / z 572.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 2H), 8.15 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.87 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 16.5 Hz, 1H), 7.33 (d, J = 16.4 Hz, 1H), 4.48 (t, J = 5.2 Hz, 2H), 3.99 (t, J = 5.2 Hz, 2H), 1.79 (d, J = 13.8 Hz, 6H).

[0156] Example 7: Preparation of compound 7

[0157]

[0158] Preparation of compounds 1-5

[0159] Compound 6-2 (238 mg, 535.85 μmol), 2-chloro-4-(((5-iodopyridin-2-yl)oxy)methyl)pyrimidine (195.5 mg, 562.64 μmol), Pd(dppf)Cl2(39.2 mg, 53.58 μmol) and potassium carbonate (148.1 mg, 1.07 mmol) were added into a 50 mL round-bottom flask in turn, and finally 1,4-dioxane (5.6 mL) and water (1.4 mL) were added. The reaction mixture was replaced with nitrogen for 3 times, and stirred at 72 °C for 3 hours. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate, filtered with celite, and the filtrate was concentrated and dried by rotary evaporation. Purification was performed on a silica gel column (PE / EA = 7 / 3) to obtain 124.1 mg of the title compound 7-1. LC-MS (ESI): m / z 537.1 [M+H] + .

[0160] Preparation of compound 7

[0161] Compound 7-1 (45 mg, 83.67 μmol) and 2-thia-6-azaspiro[3.3]heptane-2,2-dioxide hydrochloride (23.1 mg, 125.51 μmol) were added into a sealed tube, followed by the addition of anhydrous ethanol (1.0 mL) and DIPEA (54.1 mg, 418.35 μmol, 73 μL), and the reaction mixture was stirred in the sealed tube at 90 °C overnight. After the reaction was completed, it was cooled to room temperature, diluted with dichloromethane, concentrated and dried, dissolved in 1,4-dioxane, filtered, and the filtrate was purified by preparative chromatography (preparative method: mobile phase: A: 0.1% formic acid in water, B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: B%: 60-80% for 4 min, 80-95% for 8 min; flow rate: 30 mL / min) to give 32 mg of the title compound 7. LC-MS (ESI): m / z 648.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.36 (d, J = 2.4 Hz, 1H), 8.31 (d, J = 5.2 Hz, 1H), 7.89 (dd, J = 8.6, 2.3 Hz, 1H), 7.77 (d, J = 2.1 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.60 - 7.52 (m, 4H), 7.11 (d, J = 16.3 Hz, 1H), 7.04 - 6.94 (m, 2H), 6.84 (d, J = 4.8 Hz, 1H), 5.40 (s, 2H), 4.55 - 4.43 (m, 6H), 4.40 (s, 4H), 3.91 (t, J = 6.0 Hz, 2H).

[0162] Example 8: Preparation of compound 8

[0163]

[0164] Preparation of compound 8-2

[0165] In a 25 mL single neck flask, (2-thiaspiro[3.3]hept-6-yl)methyl 4-methylbenzenesulfonate (36 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (0.5 mL), compound 2-1 (50 mg, 0.12 mmol), cesium carbonate (79 mg, 0.24 mmol) were added successively. The reaction was stirred at 60 °C for 2 hours. After the reaction was completed, the reaction was added with water (5 mL), extracted with ethyl acetate (5 mL) three times, the organic phase was combined and washed with saturated brine (5 mL) once, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 40 mg of the title compound 8-2. LC-MS (ESI): m / z 535.9 [M+H] + . Preparation of compound 8

[0166] In a 25 mL single neck flask, compound 8-2 (30 mg, 0.06 mmol) was dissolved in methanol (0.5 mL) and dichloromethane (0.2 mL), ammonium carbamate (17 mg, 0.22 mmol), and iodoxybenzene diacetate (54 mg, 0.17 mmol) were added successively. The reaction was stirred at 25 °C for 16 hours. After the reaction was completed, the reaction was rotary evaporated under reduced pressure, and the obtained crude product was purified 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; column: Welch Ultimate AQ-C18 250x21.2mm; column temperature: 25 °C; gradient: 45%~65% acetonitrile was gradient eluted in 12 minutes; flow rate: 30 mL / min) to obtain 20.75 mg of the title compound 8. LC-MS (ESI): m / z 567.2 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.75-7.57 (m, 6H), 7.49 (d, J = 16.5 Hz, 1H), 7.26 (d, J = 16.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 4.47 (t, J = 5.2 Hz, 2H), 4.33 (s, 1H), 4.15-3.88 (m, 8H), 2.73-2.66 (m, 1H), 2.45-2.36 (m, 2H), 2.23-2.12 (m, 2H).

[0167] Example 9: Preparation of compound 9

[0168]

[0169] Preparation of compound 9-1

[0170] Compound 7-1 (68.4 mg, 127.18 pmol) and 2-thia-6-azaspiro[3.3]heptane oxalate (40.8 mg, 254.36 pmol) were added into a sealed tube, anhydrous ethanol (2 mL) and DIPEA (164.4 mg, 1.27 mmol, 222 pL) were added, and the reaction mixture was stirred at 90 °C overnight. After the reaction was completed, it was cooled to room temperature, diluted with dichloromethane, concentrated and dried, and purified by silica gel column chromatography (PE / EA = 1.5 / 1 first, DCM / MeOH = 24 / 1 later) to give 70.7 mg of the title compound 9-1. LC-MS (ESI): m / z 616.2 [M+H] + .

[0171] Preparation of compound 9

[0172] Compound 9-1 (70.7 mg, 114.67 pmol) was dissolved in DCM (1.5 mL) and MeOH (1.5 mL), cooled to 0 °C in an ice water bath, and iodobenzene diacetate (110.8 mg, 344.01 pmol) and ammonium carbamate (35.8 mg, 458.67 pmol) were added respectively, and the reaction mixture was allowed to naturally rise to room temperature and stirred for 1.5 hours. It was concentrated and dried, a small amount of 1,4-dioxane was added, filtered, and purified by preparative chromatography (preparative method: mobile phase: A: 0.1% formic acid in water, B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: B%: 60-80% 8 min; flow rate: 30 mL / min) to give 26.2 mg of the title compound 9. LC-MS (ESI): m / z 647.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) d 8.36 (d, J = 1.9 Hz, 1H), 8.30 (d, J = 5.2 Hz, 1H), 7.88 (dd, J = 8.6, 2.5 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.61 - 7.51 (m, 4H), 7.10 (d, J = 16.3 Hz, 1H), 7.02 - 6.94 (m, 2H), 6.80 (d, J = 5.2 Hz, 1H), 5.38 (s, 2H), 4.50 - 4.40 (m, 6H), 4.33 (q, J = 13.0 Hz, 4H), 3.91 (t, J = 6.0 Hz, 2H).

[0173] Example 10: Preparation of compound 10

[0174]

[0175] Preparation of compound 10-1

[0176] Dissolve 2-bromo-5-hydroxypyridine (800 mg, 4.60 mmol), 4,4,5,5-tetramethyl-2- (4-vinylphenyl)-1,3,2-dioxaborolane (compound 6-1, 1.38 g, 5.98 mmol), Pd(dppf)Cl2 (336 mg, 0.460 mmol) and potassium carbonate (1.91 g, 13.79 mmol) in 1,4-dioxane (16 mL) and water (4 mL). After addition, replace with nitrogen for three times, then stir the reaction system at 100 °C for 15 hours. After the reaction is completed, add water (50 mL), extract with ethyl acetate (50 mL) for three times, wash the combined organic phase with saturated brine (30 mL) for two times, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to obtain the crude product, purify by silica gel column chromatography (PE / EA = 70%~30%) to obtain 720 mg of compound 10-1. LC-MS (ESI): m / z 198.2 [M+H] + .

[0177] Preparation of compound 10-2

[0178] Dissolve compound 10-1 (580 mg, 2.94 mmol), compound 1-5 (783 mg, 3.23 mmol), Hoveyda-Grubbs catalyst (368 mg, 0.588 mmol) in 1,2-dichloroethane (15 mL). After addition, replace with nitrogen for three times, then stir the reaction system at 90 °C for 15 hours. After the reaction is completed, concentrate to obtain the crude product, purify by silica gel column chromatography (PE / EA = 70%~30%) to obtain 325 mg of compound 10-2. LC-MS (ESI): m / z 411.0 [M+H] + .

[0179] Preparation of compound 10

[0180] Compound 10-2 (50 mg, 0.122 mmol) was dissolved in DMF (2 mL), (2- thiaspiro[3.3]heptan-6-yl-2,2-dioxide)methyl-4-methylbenzenesulfonate (44.1 mg, 0.134 mmol) was added, stirred at room temperature for 5 minutes, cesium carbonate (79.3 mg, 0.244 mmol) was added, and the reaction system was stirred at 60 °C for 2 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; column: Welch Ultimate AQ-C18 250x21.2mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile gradient elution in 12 minutes; flow rate: 30 mL / min) to obtain 34 mg of the title compound 10. LC-MS (ESI): m / z 569.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 3.0 Hz, 1H), 8.14 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 8.6 Hz, 2H), 7.96 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.54 - 7.44 (m, 2H), 7.30 (d, J = 16.4 Hz, 1H), 4.47 (t, J = 5.2 Hz, 2H), 4.29 (s, 1H), 4.21 (s, 1H), 4.09 (d, J = 6.4 Hz, 2H), 3.99 (t, J = 5.2 Hz, 2H), 2.76 - 2.66 (m, 1H), 2.55 - 2.50 (m, 2H), 2.49 - 2.40 (m, 2H), 2.28 - 2.18 (m, 2H).

[0181] Example 11: Preparation of compound 11

[0182]

[0183] Preparation of compound 11-1

[0184] (2-Thiaspiro[3.3]heptan-6-yl-2,2-dioxide)methyl-4-methylbenzenesulfonate (61 mg, 0.204 mmol), diacetyiodobenzene (198.8 mg, 0.613 mmol) and ammonium carbamate (63.8 mg, 0.818 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, it was concentrated to obtain 65 mg of the crude product of the title compound 11-1. LC-MS (ESI): m / z 330.2 [M+H]+ .

[0185] Preparation of compound 11

[0186] Compound 11-1 (44 mg, 0.134 mmol) was dissolved in DMF (2 mL), compound 10-2 (50 mg, 0.122 mmol) was added, stirred for 5 minutes at room temperature, cesium carbonate (79.3 mg, 0.244 mmol) was added, and the reaction system was stirred at 60 °C for 2 hours. After the reaction was completed, the solvent was spun dry, dissolved with acetonitrile and dioxane, filtered, and the filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250x21.2mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile gradient elution in 12 minutes; flow rate: 30 mL / min) to obtain 2.6 mg of the title compound 11. LC-MS (ESI): m / z 568.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 3.0 Hz, 1H), 8.14 (d, J = 2.1 Hz, 1H), 8.12 - 8.05 (m, 3H), 7.96 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.54 - 7.45 (m, 2H), 7.30 (d, J = 16.4 Hz, 1H), 4.47 (t, J = 5.2 Hz, 2H), 4.34 (s, 1H), 4.13 - 3.93 (m, 8H), 2.76 - 2.66 (m, 1H), 2.44 - 2.37 (m, 2H), 2.22 - 2.14 (m, 2H).

[0187] Example 12: Preparation of compound 12

[0188]

[0189] Preparation of compound 12-1

[0190] Compound 1-4 (5 g, 16.95 mmol), trimethyl ethynylsilane (16.65 g, 169.5 mmol), Pd(PPh3)2Cl2(2.14 g, 3.03 mmol), cuprous iodide (1.74 g, 9.15 mmol), triethylamine (30.88 g, 305.13 mmol) were dissolved in dioxane (200 mL). After addition, replace with argon for three times, the reaction system was stirred at 80 °C for 12 hours. After the reaction was completed, the insoluble solid was filtered off, the filtrate was added with water (10 mL) and dichloromethane (20 mL) was extracted for three times. The combined organic phase was washed with saturated brine (20 mL) for two times, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain the crude product. Purification was performed by silica gel column chromatography (DCM / PE = 0-90%) to obtain 5 g of the title compound 12-1.

[0191] Preparation of compound 12-2

[0192] Compound 12-1 (5 g, 16.00 mmol) was dissolved in DMF (50 mL) solution, and cesium fluoride (5.84 g, 38.34 mmol) was added. After addition, it was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated, and the obtained crude product was purified by silica gel column chromatography (DCM / PE = 0-90%) to obtain 3 g of the title compound 12-2. LC-MS (ESI): m / z 240.3 [M+H] + .

[0193] Preparation of compound 12-3

[0194] Compound 12-2 (2.8 g, 11.66 mmol), 4'-iodo-[1,1'-biphenyl]-4-ol (4.14 g, 14.00 mmol), Pd(PPh3)2Cl2(1.47 g, 2.10 mmol), cuprous iodide (1.20 g, 6.30 mmol), triethylamine (5.90 g, 58.31 mmol) were dissolved in acetonitrile (100 mL). After addition, replace with argon for three times, the reaction system was stirred at 80 °C for 16 hours. After the reaction was completed, the insoluble solid was filtered off, the filtrate was added with water (10 mL) and dichloromethane (20 mL) was extracted for three times. The combined organic phase was washed with saturated brine (20 mL) for two times, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain the crude product. Purification was performed by preparative separation (DCM / PE = 0-90%) to obtain 1.56 g of the title compound 12-3. LC-MS (ESI): m / z 408.4 [M+H] + .

[0195] Preparation of compound 12

[0196] Compound 12-3 (30 mg, 0.073 mmol) was dissolved in N,N-dimethylformamide (3 mL) solution, (2-thiaspiro[3.3]heptane-6-yl-2,2-dioxide)methyl-4-methylbenzenesulfonate (36 mg, 0.11 mmol), cesium carbonate (72 mg, 0.22 mmol) were added successively. The reaction system was stirred at room temperature for 16 hours after nitrogen replacement for three times. 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) for three times. The organic phase was combined, washed with saturated brine (20 mL) for two times, dried over anhydrous sodium sulfate, and concentrated under filtration to obtain the crude product. Purification was performed by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile was gradient eluted in 12 minutes; flow rate: 30 mL / min) to obtain 21 mg of the title compound 12. LC-MS (ESI): m / z 566.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 4.52 (t, J = 5.2 Hz, 2H), 4.28 (s, 2H), 4.20 (s, 2H), 4.05 - 3.96 (m, 4H), 2.75 - 2.68 (m, 1H), 2.46 - 2.41 (m, 2H), 2.26 - 2.17 (m, 2H).

[0197] Example 13: Preparation of compound 13

[0198]

[0199] Preparation of compound 13-1

[0200] Into a 50 mL round-bottom flask were added 2-hydroxy-5-iodopyridine (250 mg, 1.13 mmol), (2-thiaspiro[3.3]hept-6-yl)methyl 4-methylbenzenesulfonate (371.4 mg, 1.24 mmol), cesium carbonate (737.2 mg, 2.26 mmol), and silver carbonate (312 mg, 1.13 mmol), followed by DMF (5 mL), and the reaction mixture was stirred at 95 °C for 8 h. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through celite. The filtrate was diluted with water and saturated aqueous ammonium chloride solution, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification on a silica gel column (PE / EA = 23 / 2) gave 187.4 mg of the title compound 13-1. LC-MS (ESI): m / z 348.0 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.29 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 8.7, 2.4 Hz, 1H), 6.57 (d, J = 8.5 Hz, 1H), 4.17 (d, J = 6.5 Hz, 2H), 3.26 (s, 2H), 3.18 (s, 2H), 2.66–2.47 (m, 1H), 2.40–2.29 (m, 2H), 1.99–1.89 (m, 2H).

[0201] Preparation of compound 13-2

[0202] Into a 50 mL round-bottom flask were added compound 6-2 (120 mg, 270.17 µmol), compound 13-1 (98.5 mg, 283.68 µmol), Pd(dppf)Cl2 (19.8 mg, 27.02 µmol), and potassium carbonate (74.7 mg, 540.35 µmol), followed by 1,4-dioxane (2.8 mL) and water (0.7 mL), and the reaction mixture was replaced with nitrogen three times. The reaction mixture was stirred at 72 °C for 3 h. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through celite. The filtrate was mixed with silica gel, concentrated, and dried by rotary evaporation. Purification on a silica gel column (PE / EA = 4 / 1) gave 135.8 mg of the title compound 13-2. LC-MS (ESI): m / z 537.0 [M+H] + .

[0203] Preparation of compound 13

[0204] Compound 13-2 (135.8 mg, 252.65 μmol) was dissolved in DCM (2 mL) and MeOH (3 mL), cooled to 0 °C in ice water bath, iodobenzene diacetate (244.1 mg, 757.96 μmol) and ammonium carbamate (78.9 mg, 1.01 mmol) were added, the reaction mixture was allowed to warm to room temperature and stirred for 1.5 h. After the reaction was completed, concentrated and dried by rotary evaporation, a small amount of 1,4-dioxane was added, the filtrate was purified by preparative chromatography (Preparation method: mobile phase: A: 0.1% formic acid in water, B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: B%: 60-80% 8 min, 80-88% 2 min; flow rate: 30 mL / min) to give a crude product, which was further purified by silica gel preparative plate (DCM / MeOH = 18 / 1) to give 29.4 mg of the title compound 13. LC-MS (ESI): m / z 568.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 2.6, 0.8 Hz, 1H), 8.14 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 8.06 (dd, J = 8.7, 2.6 Hz, 1H), 7.76 - 7.64 (m, 4H), 7.50 (d, J = 16.5 Hz, 1H), 7.29 (d, J = 16.4 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 4.47 (t, J = 5.2 Hz, 2H), 4.33 (s, 1H), 4.29 (d, J = 6.5 Hz, 2H), 4.12 - 4.03 (m, 2H), 4.02 - 3.93 (m, 4H), 3.13 - 3.06 (m, 2H), 2.74 - 2.66 (m, 1H), 2.43 - 2.36 (m, 2H).

[0205] Example 14: Preparation of compound 14

[0206]

[0207] Preparation of compound 14-2

[0208] Into a 50 mL round-bottom flask were added 2-hydroxy-5-iodopyridine (130 mg, 588.25 µmol), compound 14-1 (213.8 mg, 647.07 µmol), cesium carbonate (383.3 mg, 1.18 mmol) and silver carbonate (162.2 mg, 588.25 µmol) sequentially, and finally DMF (3.5 mL) was added. The reaction mixture was stirred at 95 °C for 8 hours. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate, filtered through celite, and the filtrate was added to water and saturated aqueous ammonium chloride solution. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained concentrate was purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain 129.5 mg of the title compound 14-2. LC-MS (ESI): m / z 379.8 [M+H] + .

[0209] Preparation of compound 14

[0210] Into a 50 mL round-bottom flask were added compound 6-2 (80 mg, 180.12 µmol), compound 14-2 (71.7 mg, 189.12 µmol), Pd(dppf)Cl2 (13.2 mg, 18.01 µmol) and potassium carbonate (49.8 mg, 360.23 µmol) sequentially, and finally 1,4-dioxane (2.4 mL) and water (0.6 mL) were added. The flask was replaced with nitrogen three times, and the reaction was stirred at 72 °C for 3 hours. After the reaction was completed, it was cooled to room temperature, diluted with a small amount of 1,4-dioxane, filtered, and the filtrate was purified by preparative chromatography (preparative method: mobile phase: A: 0.1% formic acid in water, B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 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 65 mg of the title compound 14. LC-MS (ESI): m / z 569.2 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.42 (s, 1H), 7.94 (d, J = 4.4 Hz, 1H), 7.77 (d, J = 2.1 Hz, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.63 - 7.48 (m, 4H), 7.11 (d, J = 16.2 Hz, 1H), 7.00 (d, J = 16.3 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 4.48 (t, J = 6.0 Hz, 2H), 4.42 (s, 2H), 4.20 (s, 2H), 4.16 (s, 2H), 3.91 (t, J = 6.0 Hz, 2H), 2.90 - 2.79 (m, 1H), 2.59 - 2.50 (m, 2H), 2.44 - 2.33 (m, 2H).

[0211] Example 15: Preparation of compound 15

[0212]

[0213] Preparation of compound 15

[0214] Compound 1-7 (44 mg, 0.096 mmol), 2-thia-6-azaspiro[3.3]heptane-2,2-dioxide (14 mg, 0.096 mmol), DIPEA (49 mg, 0.38 mmol) were added into ethanol (2 mL). The reaction system was stirred at room temperature for 15 hours. After the reaction was completed, the solvent was rotary evaporated, dissolved in acetonitrile, and purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250x21.2mm; column temperature: 25°C; gradient: 45%-65% acetonitrile gradient elution in 12 minutes; flow rate: 30 mL / min) to obtain 5.2 mg of compound 15. LC-MS (ESI): m / z 571.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 5.0 Hz, 1H), 8.06 (d, J = 2.2 Hz, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 16.4 Hz, 1H), 7.13 - 7.01 (m, 3H), 6.81 (d, J = 5.0 Hz, 1H), 5.05 (s, 2H), 4.51 (s, 4H), 4.45 (t, J = 5.2 Hz, 2H), 4.28 (s, 4H), 3.98 (t, J = 5.2 Hz, 2H).

[0215] Example 16: Preparation of compound 16

[0216]

[0217] Preparation of compound 16

[0218] Compound 3-2 (40 mg, 0.07 mmol), 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide (16 mg, 0.11 mmol), DIPEA (29 mg, 0.22 mmol) were dissolved in ethanol (0.5 mL) and 1,4-dioxane (0.2 mL). The reaction system was subjected to microwave stirring at 100 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was slurried with methanol, filtered, and the filter cake was dried under reduced pressure to obtain 18.74 mg of the title compound 16. LC-MS (ESI): m / z 647.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 2H), 8.13 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.73 - 7.60 (m, 6H), 7.49 (d, J = 16.5 Hz, 1H), 7.27 (d, J = 16.4 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 5.02 (s, 2H), 4.51 (s, 4H), 4.47 (t, J = 5.2 Hz, 2H), 4.28 (s, 4H), 3.99 (t, J = 5.2 Hz, 2H).

[0219] Example 17: Preparation of compound 17

[0220]

[0221] Preparation of compound 17

[0222] Compound 1-7 (40 mg, 0.09 mmol) was dissolved in 1,4-dioxane (0.5 mL) in a 25 mL single neck flask, compound 3-3 (23 mg, 0.17 mmol), tris(dibenzylideneacetone)dipalladium (8 mg, 0.009 mmol), Xantphos (10 mg, 0.02 mmol), potassium carbonate (36 mg, 0.26 mmol) were added successively. The reaction was stirred at 110 °C under nitrogen atmosphere for 16 hours. After the reaction was completed, the reaction was filtered, the filtrate was concentrated, the crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain the crude product, which was further purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile gradient elution in 12 minutes; flow rate: 30 mL / min) to obtain 7.09 mg of the title compound 17. LC-MS (ESI): m / z 559.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.46 (d, J = 5.0 Hz, 1H), 8.07 (d, J = 2.1 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 16.4 Hz, 1H), 7.14 - 7.02 (m, 3H), 6.98 (d, J = 5.0 Hz, 1H), 5.11 (s, 2H), 4.45 (t, J = 5.2 Hz, 2H), 4.11 - 4.03 (m, 2H), 3.98 (t, J = 5.2 Hz, 2H), 3.96 - 3.87 (m, 2H), 3.85 - 3.73 (m, 2H), 3.63 - 3.51 (m, 2H).

[0223] Example 18: Preparation of compound 18

[0224]

[0225] Preparation of compound 18

[0226] Compound 2-2 (30 mg, 0.06 mmol) was dissolved in 1,4-dioxane (0.5 mL) in a 10 mL microwave tube, compound 3-3 (15 mg, 0.11 mmol), tris(dibenzylideneacetone)dipalladium (5 mg, 0.006 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6 mg, 0.01 mmol), potassium carbonate (23 mg, 0.17 mmol) were added successively. The reaction was stirred at 110 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, the reaction was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1), and then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile gradient elution in 12 minutes; flow rate: 30 mL / min) to obtain 12.73 mg of the title compound 18. LC-MS (ESI): m / z 635.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.47 (d, J = 5.0 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.76 - 7.60 (m, 6H), 7.49 (d, J = 16.4 Hz, 1H), 7.27 (d, J = 16.4 Hz, 1H), 7.10 (d, J = 8.9 Hz, 2H), 7.00 (d, J = 5.0 Hz, 1H), 5.14 (s, 2H), 4.47 (t, J = 5.2 Hz, 2H), 4.11 - 4.03 (m, 2H), 3.99 (t, J = 5.2 Hz, 2H), 3.96 - 3.88 (m, 2H), 3.84 - 3.73 (m, 2H), 3.62 - 3.53 (m, 2H).

[0227] Example 19: Preparation of compound 19

[0228]

[0229] Preparation of compound 19

[0230] Compound 2-2 (30 mg, 0.06 mmol) was dissolved in 1,4-dioxane (0.5 mL) in a 10 mL microwave tube, dimethyl phosphine oxide (13 mg, 0.17 mmol), tris(dibenzylideneacetone)dipalladium (5 mg, 0.006 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6 mg, 0.01 mmol), cesium carbonate (73 mg, 0.22 mmol) were added successively. The reaction was stirred at 110 °C under nitrogen atmosphere for 16 hours. After the reaction was completed, the reaction was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain a crude product, which was further purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile gradient elution in 12 minutes; flow rate: 30 mL / min) to obtain 12.92 mg of the title compound 19. LC-MS (ESI): m / z 578.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (dd, J = 5.2, 0.6 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.74 (dd, J = 5.2, 3.2 Hz, 1H), 7.72 - 7.67 (m, 4H), 7.64 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 16.5 Hz, 1H), 7.27 (d, J = 16.4 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 5.37 (s, 2H), 4.47 (t, J = 5.2 Hz, 2H), 3.99 (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, 1P).

[0231] Example 20: Preparation of compound 20

[0232]

[0233] Preparation of compound 20

[0234] In a 10 mL microwave tube was added compound 2-2 (30 mg, 0.06 mmol), ethanol (0.5 mL), 2-thia-6-azaspiro[3.3]heptane-2,2-dioxide (21 mg, 0.11 mmol), triethylamine (28 mg, 0.28 mmol). The reaction was stirred at 90 °C for 3 hours in a microwave reactor. After the reaction was completed, the reaction was concentrated to dryness, and the crude product was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile gradient eluted in 12 minutes; flow rate: 30 mL / min) to give 21.68 mg of the title compound 20. LC-MS (ESI): m / z 647.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 5.0 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.73 - 7.60 (m, 6H), 7.49 (d, J = 16.4 Hz, 1H), 7.27 (d, J = 16.5 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 5.0 Hz, 1H), 5.08 (s, 2H), 4.52 (s, 4H), 4.47 (t, J = 5.2 Hz, 2H), 4.29 (s, 4H), 3.99 (t, J = 5.2 Hz, 2H).

[0235] Example 21: Preparation of compound 21

[0236]

[0237] Preparation of compound 21

[0238] In a 50 mL single-necked flask, compound 2-1 (55 mg, 0.13 mmol) was dissolved in DMF (0.5 mL), and 4-methylbenzenesulfonic acid tetrahydropyran-4-ylmethyl ester (30 mg, 0.11 mmol), cesium carbonate (108 mg, 0.33 mmol) were added successively. The reaction was stirred at 70 °C for 16 hours under a nitrogen atmosphere. After the reaction was completed, the reaction was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile gradient eluted in 12 minutes; flow rate: 30 mL / min) to give 10.09 mg of the title compound 21. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.71 - 7.61 (m, 6H), 7.49 (d, J = 16.5 Hz, 1H), 7.26 (d, J = 16.4 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 4.47 (t, J = 5.2 Hz, 2H), 3.99 (t, J = 5.2 Hz, 2H), 3.91 - 3.86 (m, 4H), 3.39 - 3.28 (m, 2H), 2.08 - 1.96 (m, 1H), 1.73 - 1.66 (m, 2H), 1.34 (qd, J = 12.2, 4.5 Hz, 2H).

[0239] Example 22: Preparation of compound 22

[0240]

[0241] Preparation of compound 22

[0242] Compound 2-1 (30 mg, 0.07 mmol) was dissolved in DMF (0.5 mL) in a 25 mL single neck flask, compound 14-1 (20 mg, 0.06 mmol), cesium carbonate (39 mg, 0.12 mmol) were added in turn. The reaction liquid was stirred at 80 °C for 2 hours. After the reaction was completed, the reaction liquid was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile gradient elution in 12 minutes; flow rate: 30 mL / min) to obtain 7.07 mg of the title compound 22. 1 H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.71 - 7.63 (m, 6H), 7.49 (d, J = 16.4 Hz, 1H), 7.26 (d, J = 16.5 Hz, 1H), 7.03 (d, J = 8.6 Hz, 2H), 4.52 - 4.42 (m, 2H), 4.28 (s, 2H), 4.20 (s, 2H), 4.06 - 3.93 (m, 4H), 2.76 - 2.67 (m, 1H), 2.45 - 2.41 (m, 2H), 2.24 - 2.19 (m, 2H).

[0243] Example 23: Preparation of compound 23

[0244]

[0245] Preparation of compound 23-1

[0246] Dissolve 2-(4-hydroxyphenyl)acetonitrile (5.0 g, 37.6 mmol) in tetrahydrofuran (50 mL), replace with nitrogen for three times, then add sodium hydride (1.8 g, 45.1 mmol, 60% purity) under ice bath, stir the reaction for 30 minutes under ice bath, then add bromomethyl methyl ether (5.6 g, 45.1 mmol) dropwise, stir the reaction for 3 hours under ice bath. After the reaction is completed, add water (50 mL) dropwise under ice bath, extract with ethyl acetate (30 mL) for three times, combine the organic phase, wash with saturated brine (50 mL) for two times, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to get the crude product, purify it by silica gel column chromatography (EA / PE = 15%) to get 5.2 g of the title compound 23-1. 1 HNMR (400 MHz, DMSO-d6) δ 7.28 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 8.9 Hz, 2H), 5.19 (s, 2H), 3.95 (s, 2H), 3.37 (s, 3H).

[0247] Preparation of compound 23-2

[0248] Dissolve compound 23-1 (5.2 g, 29.3 mmol) in tetrahydrofuran (60 mL), replace with nitrogen for three times, then add sodium hydride (3.5 g, 87.9 mmol, 60% purity) in batches under ice bath, stir the reaction for 30 minutes under ice bath, then add iodomethane (12.5 g, 87.9 mmol) dropwise, stir the reaction at 35 °C for 12 hours. After the reaction is completed, add water (50 mL) dropwise under ice bath, extract with ethyl acetate (30 mL) for three times, combine the organic phase, wash with saturated brine (50 mL) for two times, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to get the crude product, purify it by silica gel column chromatography (EA / PE = 0-5%) to get 4.9 g of the title compound 23-2. 1 HNMR (400 MHz, DMSO-d6) δ 7.48 - 7.38 (m, 2H), 7.12 - 7.00 (m, 2H), 5.19 (s, 2H), 3.37 (s, 3H), 1.65 (s, 6H).

[0249] Preparation of compound 23-3

[0250] Compound 23-2 (3 g, 14.61 mmol) was dissolved in toluene (30 mL), replaced with nitrogen for three times, diisobutylaluminum hydride (21.9 mL, 21.9 mmol, 1 mol / L) was added dropwise at -60 ℃, and the reaction was stirred at -60 ℃ for 2 h. After the reaction was completed, it was restored to room temperature, saturated aqueous ammonium chloride solution (50 mL) was added dropwise, and the reaction was stirred for 12 h. The organic phase was extracted with ethyl acetate (30 mL) three times, washed with saturated brine (50 mL) twice, dried over anhydrous sodium sulfate, and concentrated under suction to obtain a crude product. Purification by silica gel column chromatography (EA / PE = 0-8%) gave 2.7 g of the title compound 23-3. 1 H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H) 7.44 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 5.23 (s, 2H), 3.41 (s, 3H), 1.41 (s, 6H).

[0251] Preparation of compound 23-4

[0252] Compound 23-3 (2.7 g, 13.0 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (3.0 g, 15.6 mmol) were dissolved in methanol (35 mL), replaced with nitrogen for three times, and cesium carbonate (8.45 g, 26 mol) was added under ice bath. The reaction system was restored to room temperature, and the reaction was stirred for 3 h. After the reaction was completed, water (30 mL) was added, and the organic phase was extracted with ethyl acetate (30 mL) three times. The combined organic phase was washed with saturated brine (50 mL) twice, dried over anhydrous sodium sulfate, and concentrated under suction to obtain a crude product. Purification by silica gel column chromatography (EA / PE = 0-7%) gave 2.3 g of the title compound 23-4. 1 H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H) 7.44 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 5.23 (s, 2H), 3.41 (s, 3H), 1.41 (s, 6H).

[0253] Preparation of compound 23-5

[0254] Compound 23-4 (1 g, 4.90 mmol), 2-(2-chloroethoxy)-3-chloro-5- bromobenzonitrile (1.59 g, 5.39 mmol), triethylamine (1.1 g, 9.8 mmol), cuprous iodide (94 mg, 490 µmol), bis(triphenylphosphine)palladium dichloride (344 mg, 490 µmol) were added into acetonitrile (10 mL). The reaction was stirred at 80 °C for 5 h. After the reaction was completed, the insoluble solid was filtered off, the filtrate was added with water (20 mL) and extracted with ethyl acetate (10 mL) for 3 times. The organic phase was combined, washed with saturated brine (30 mL) for 2 times, dried over anhydrous sodium sulfate, and concentrated by suction filtration. The crude product was purified by silica gel column chromatography (EA / PE = 0-15%) to give 1.6 g of the title compound 23-5. LC-MS (ESI): m / z 418.2 [M+H] + .

[0255] Preparation of compound 23-6

[0256] Compound 23-5 (1.6 g, 3.82 mmol) was dissolved in dichloromethane (20 mL), and hydrogen chloride solution in 1,4-dioxane (5 mL, 4 mol / L) was added under ice bath. The reaction system was stirred at room temperature for 4 h. After the reaction was completed, water (30 mL) was added, and dichloromethane (20 mL) was extracted for 3 times. The organic phase was combined, washed with saturated brine (20 mL) for 2 times, dried over anhydrous sodium sulfate, and concentrated by suction filtration. The crude product was purified by silica gel column chromatography (PE / EA = 0-30%) to give 1.1 g of the title compound 23-6. LC-MS (ESI): m / z 374.3 [M+H] + . Preparation of compound 23-7

[0257] Compound 23-6 (300 mg, 0.80 mmol), 2-chloro-4-(chloromethyl)pyrimidine (136 mg, 0.83 mmol), and cesium carbonate (487 mg, 1.50 mol) were added into acetonitrile (5 mL). The reaction was replaced with nitrogen for 3 times, and stirred at 60 °C for 3 h. After the reaction was completed, water (15 mL) was added, and ethyl acetate (10 mL) was extracted for 3 times. The organic phase was combined, washed with saturated brine (20 mL) for 2 times, dried over anhydrous sodium sulfate, and concentrated by suction filtration. The crude product was purified by silica gel column chromatography (PE / EA = 0-25%) to give 365 mg of the title compound 23-7. LC-MS (ESI): m / z 500.1 [M+H] + .

[0258] Preparation of compound 23

[0259] To a reaction vial was added compound 23-7 (100 mg, 239 μmol), tris(dibenzylideneacetone)dipalladium (4 mg, 5.5 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3 mg, 5.2 μmol), DIEA (52 mg, 400 μmol), compound 23-8 (56 mg, 717 μmol). The reaction was stirred at 120 °C for 2 h. After completion of the reaction, insoluble solid was filtered off, the filtrate was diluted with water (10 mL) and extracted with dichloromethane (20 mL) for 3 times. The combined organic phase was washed with saturated brine (20 mL) for 2 times, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by preparative HPLC (Preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: 10% to 40% acetonitrile in 12 min; flow rate: 30 mL / min) to give 19 mg of the title compound 23. LC-MS (ESI): m / z 583.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.46 (d, J = 5.1 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.01 - 6.96 (m, 2H), 6.95 (d, J = 5.1 Hz, 1H), 5.06 (s, 2H), 4.47 (t, J = 5.2 Hz, 2H), 3.97 (t, J = 5.2 Hz, 2H), 3.66 - 3.50 (m, 2H), 3.42 - 3.29 (m, 2H), 2.28 - 2.15 (m, 2H), 2.15 - 2.00 (m, 2H), 1.59 (s, 6H).

[0260] Example 24: Preparation of compound 24

[0261]

[0262] Preparation of compound 24

[0263] Compound 23-7 (100 mg, 200 µmol) was dissolved in DMF (1 mL), and tris(dibenzylideneacetone)dipalladium (4 mg, 5.5 µmol), 4,5-bis(diphenyl)phosphin-9,9-dimethylxanthene (3 mg, 5.2 µmol), DIEA (52 mg, 400 µmol), dimethyl phosphine oxide (47 mg, 600 µmol) 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 (10 mL) for 3 times, the combined organic phase was washed with saturated brine (20 mL) for 2 times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 10%-60% acetonitrile was gradient eluted in 12 minutes; flow rate: 30 mL / min) to obtain 21 mg of the title compound 24. LC-MS (ESI): m / z 542.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 5.2 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 5.2, 3.2 Hz, 1H), 7.55 (d, J = 8.9 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 5.30 (s, 2H), 4.47 (t, J = 5.2 Hz, 2H), 3.97 (t, J = 5.2 Hz, 2H), 1.76 (d, J = 13.7 Hz, 6H), 1.60 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 34.04 (s, 1P).

[0264] Example 25: Preparation of compound 25

[0265]

[0266] Preparation of compound 25

[0267] Compound 23-7 (70 mg, 140 μmol), 2-thia-6-azaspiro[3.3]heptane-2,2-dioxide (41 mg, 280 μmol), N,N-diisopropylethylamine (36 mg, 280 μmol) were added into acetonitrile (2 mL), purged with nitrogen for three times, the reaction was stirred at 90 °C for 2 hours. After the reaction was completed, the insoluble solid was filtered off, the filtrate was added with water (10 mL), extracted with dichloromethane (20 mL) for three times, the combined organic phase was washed with saturated brine (20 mL) for two times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile was gradient eluted in 12 minutes; flow rate: 30 mL / min) to give 32 mg of the title compound 25. 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), 7.97 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 5.0 Hz, 1H), 5.01 (s, 2H), 4.51 (s, 4H), 4.47 (t, J = 5.2 Hz, 2H), 4.27 (s, 4H), 3.97 (t, J = 5.2 Hz, 2H), 1.59 (s, 6H).

[0268] Example 26: Preparation of compound 26

[0269]

[0270] Preparation of compound 26-1

[0271] Compound 23-6 (1 g, 2.67 mmol) and triethylamine (540 mg, 5.34 mmol) were weighed into dichloromethane (15 mL), purged with nitrogen for three times, then N-phenyl bis(trifluoromethylsulfonyl)imide (1.14 g, 3.2 mmol) was added dropwise at 0 °C. The reaction was stirred at room temperature for 1 hour. LCMS showed that the starting material disappeared and the product was generated. The reaction was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (EtOAc / PE = 0-10%) to give 1.2 g of the title compound 26-1.

[0272] Preparation of compound 26-2

[0273] Compound 26-1 (1 g, 1.98 mmol) was dissolved in 1,4-dioxane (15 mL), 4- hydroxybenzeneboronic acid (358 mg, 2.6 mmol), potassium carbonate (546 mg, 3.96 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (228 mg, 0.31 mmol), water (2 ml). Nitrogen was replaced for three times, the reaction system was stirred at 100 °C for 5 hours. After the reaction was completed, water (10 mL) was added, dichloromethane (20 mL) was extracted three times, the combined organic phase was washed with saturated brine (20 mL) for 2 times, dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (EA / PE = 0-25%) to obtain 730 mg of the title compound 26-2. LC-MS (ESI): m / z 450.2 [M+H] + Preparation of compound 26-3

[0274] Compound 26-2 (400 mg, 1.06 mmol), 2-chloro-4-(chloromethyl)pyrimidine (181 mg, 1.11 mmol), cesium carbonate (691 mg, 2.12 mol) were dissolved in acetonitrile (5 mL). Nitrogen was replaced for three times, the reaction was stirred at 60 °C for 3 hours. After the reaction was completed, water (15 mL) was added, ethyl acetate (10 mL) was extracted three times, the combined organic phase was washed with saturated brine (20 mL) for 2 times, dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE / EA = 100%-25%) to obtain 385 mg of the title compound 26-3. LC-MS (ESI): m / z 576.1 [M+H] + .

[0275] Preparation of compound 26

[0276] Compound 26-3 (100 mg, 174 μmol) was dissolved in DMF (1 mL) solution, tris(dibenzylideneacetone)dipalladium (2.0 mg, 2.74 μmol), 4,5-bis(diphenyl)phosphin-9,9-dimethylxanthene (1.59 mg, 2.74 μmol), DIEA (45 mg, 348 μmol), dimethyl phosphine oxide (41 mg, 522 μmol) 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) for 3 times, the combined organic phase was washed with saturated brine (20 mL) for 2 times, dried over anhydrous sodium sulfate and suction filtered, the filtrate was concentrated to give the crude product, which was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: 15%-50% acetonitrile gradient elution in 12 minutes; flow rate: 30 mL / min) to give 21 mg of the title compound 26. LC-MS (ESI): m / z 618.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 5.2 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.74 (dd, J = 5.2, 3.2 Hz, 1H), 7.70 - 7.53 (m, 6H), 7.16 (d, J = 8.8 Hz, 2H), 5.36 (s, 2H), 4.48 (t, J = 5.2 Hz, 2H), 3.98 (t, J = 5.2 Hz, 2H), 1.77 (d, J = 13.8 Hz, 6H), 1.66 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 34.05 (s, 1P).

[0277] Example 27: Preparation of compound 27

[0278]

[0279] Preparation of compound 27-2

[0280] Compound 26-3 (80 mg, 139 µmol) was dissolved in DMF (1 mL), and tris(dibenzylideneacetone)dipalladium (2.01 mg, 2.74 µmol), 4,5-bis(diphenyl)phosphin-9,9-dimethylxanthene (1.59 mg, 2.74 µmol), DIEA (36 mg, 278 µmol), compound 27-1 (98 mg, 418 µmol) 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 extracted with water (10 mL) and dichloromethane (20 mL) for 3 times, the organic phase was combined, washed with saturated brine (20 mL) for 2 times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (MeOH / DCM = 10%) to give 42 mg of the title compound 27-2. LC-MS (ESI): m / z 774.2 [M+H] + .

[0281] Preparation of compound 27

[0282] Compound 27-2 (42 mg, 54 µmol) was dissolved in dichloromethane (4 mL), and hydrogen chloride solution in 1,4-dioxane (0.5 mL, 4 mol / L) was added under ice bath, and the reaction system was stirred at room temperature for 4 h. After the reaction was completed, the crude product was concentrated, and purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 15%-45% acetonitrile was gradient eluted in 12 min; flow rate: 30 mL / min) to give 11 mg of the title compound 27. LC-MS (ESI): m / z 674.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 5.1 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.66 (d, J = 8.5 Hz, 2H), 7.63-7.52 (m, 4H), 7.09 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 5.0 Hz, 1H), 5.11 (s, 2H), 4.48 (t, J = 5.2 Hz, 2H), 3.98 (t, J = 5.2 Hz, 2H), 3.65-3.56 (m, 2H), 3.33-3.24 (m, 2H), 3.19-3.11 (m, 2H), 3.03-2.95 (m, 2H), 1.66 (s, 6H).

[0283] Example 28: Preparation of compound 28

[0284]

[0285] Preparation of compound 28-2

[0286] Compound 28-1 (120.0 g, 643.1 mmol) was dissolved in MeCN (1.2 L), cooled to 0 °C with ice water bath, added p-toluenesulfonic acid monohydrate (122.2 g, 643.1 mmol) and stirred at this temperature for 30 min; then added NIS (173.6 g, 771.1 mmol), after addition, removed the ice water bath, the reaction system was stirred at room temperature for 16 h. Added sodium sulfite to quench the reaction, added water (3 L), extracted with ethyl acetate (2 L x 2), washed the organic phase with saturated brine (2 L x 3), dried over anhydrous sodium sulfate, concentrated the organic phase and purified by normal phase silica gel column chromatography (EA / PE = 0-30%) to obtain 168 g of the title compound 28-2 (white solid, yield 84%).

[0287] Preparation of compound 28-3

[0288] Compound 28-2 (163.0 g, 0.52 mol) was dissolved in DMF (800 mL), added cesium carbonate (338.9 g, 1.04 mol), compound 1-bromo-2-chloroethane (149.1 g, 1.04 mol) and H2O (12 mL) in turn, and warmed to 65 °C for 16 h. After the reaction was completed, filtered, added water (3 L) to the filtrate, extracted with ethyl acetate (2 L x 2), washed the organic phase with saturated brine (2 L x 3), dried over anhydrous sodium sulfate, suction filtered, concentrated the filtrate, and the obtained residue was purified by normal phase silica gel column chromatography (EA / PE = 0-30%) to obtain 136.9 g of the title compound 28-3 (white solid, yield 70%).

[0289] Preparation of compound 28-4

[0290] Compound 28-3 (168.0 g, 448.0 mmol) was dissolved in DMF (1 L), added CuCN (100.3 g, 1120.0 mmol) and CuI (73.1 g, 385.4 mmol) and warmed to 140 °C for 4 h. TLC (PE / EA = 5 / 1, product Rf≈0.5) was used to monitor the completion of the reaction, filtered through thin layer diatomite, and the filter cake was eluted with ethyl acetate. The filtrate was collected and added water (4 L), extracted with ethyl acetate (3 L x 2), the organic phase was washed with saturated brine (2 L x 3), dried over anhydrous sodium sulfate, suction filtered, concentrated the organic phase and purified by normal phase silica gel column chromatography (EA / PE = 0-20%) to obtain 66.7 g of the title compound 28-4 (white solid, yield 54%). 1H NMR (400 MHz, CDC13) 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).

[0291] Preparation of compound 28-5

[0292] Compound 28-4 (5 g, 18 mmol) was added to a three-necked flask, replaced with nitrogen three times, added anhydrous tetrahydrofuran (20 mL), and added methyl magnesium bromide (3.0 mol / L, 18 mL, 54 mmol) dropwise at -10°C. The reaction system was stirred at 0°C for 2 hours, and the reaction was completed. The reaction system was slowly added with saturated aqueous ammonium chloride solution (50 mL) under ice bath, and extracted with EtOAc (50 mL x 3). The organic phase was combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to obtain the crude product, which was separated and purified by silica gel column chromatography (EtOAc / PE = 0-20%) to obtain 3 g of the title compound 28-5 (light yellow liquid, yield 60%). 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 2.2 Hz, 1H), 7.83 (d, J = 2.2 Hz, 1H), 5.37 (s, 1H), 4.43 (t, J = 4.0 Hz, 2H), 3.97 (t, J = 4.0 Hz, 2H), 1.43 (s, 6H).

[0293] Preparation of compound 28-6

[0294] Compound 28-5 (4.5 g, 16.48 mmol) and indium bromide (875 mg, 2.47 mmol) were added to dichloromethane (50 mL), and trimethylsilyl cyanide (3.2 g, 32.96 mmol) was added thereto at 0°C. After addition, the reaction system was stirred at 25°C for 1 hour. After the reaction was completed, saturated brine solution (50 mL) was added, and dichloromethane (50 mL) was extracted three times, and the combined organic phase was washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE / EA = 100% to 85%) to obtain 4.2 g of the title compound 28-6. LC-MS (ESI): m / z 283.0 [M+H] + .

[0295] Preparation of compound 28-7

[0296] Compound 28-6 (4.2 g, 14.89 mmol) was dissolved in toluene (50 mL), diisobutylaluminum hydride (14.5 ml, 1 mol / L in n-hexane) was added at -78 °C. After addition, the reaction system was stirred at 0 °C for 1 h. After the reaction was completed, water (50 mL) was added, and ethyl acetate (50 mL) was extracted three times, the organic phase was combined, washed with saturated brine (50 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 4 g of the title compound 28-7 as a crude product. Without purification, it was directly used in the next step reaction. LC-MS (ESI): m / z 285.9 [M+H] + Preparation of compound 28-8

[0297] Compound 28-7 (4 g, 13.99 mmol) and cesium carbonate (9 g, 27.98 mmol) were dissolved in methanol (50 mL), and dimethyl (1-diazo-2-oxopropyl)phosphonate (3.2 g, 16.78 mmol) was added. After addition, the reaction system was stirred at 25 °C for 1 h. After the reaction was completed, water (50 mL) was added, and ethyl acetate (50 mL) was extracted three times, the organic phase was combined, washed with saturated brine (50 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (PE / EA = 100% to 95%) to give 960 mg of the title compound 28-8. LC-MS (ESI): m / z 282.0 [M+H] + .

[0298] Preparation of compound 28-9

[0299] P-phenylphenol iodide (370 mg, 1.68 mmol), bis(triphenyl)phosphine palladium dichloride (105 mg, 0.15 mmol), cuprous iodide (57 mg, 0.30 mmol), and triethylamine (463 mg, 4.59 mmol) were dissolved in tetrahydrofuran (50 mL), and 28-8 (430 mg, 1.53 mmol) was added at 0 °C. After addition, the reaction system was stirred at 25 °C for 1 h. After the reaction was completed, water (50 mL) was added, and ethyl acetate (50 mL) was extracted three times, the organic phase was combined, washed with saturated brine (50 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (PE / EA = 100% to 80%) to give 500 mg of the title compound 28-9. LC-MS (ESI): m / z 374.0 [M+H] + .

[0300] Preparation of compound 28-10

[0301] Compound 28-9 (350 mg, 0.94 mmol), 2-chloro-4-(l-chloromethyl)pyrimidine (229 mg, 1.40 mmol) were dissolved in acetonitrile (50 mL), and cesium carbonate (611 mg, 1.88 mmol) was added. After addition, the reaction system was stirred at 80 °C for 16 hours. After the reaction was completed, water (50 mL) was added, and ethyl acetate (50 mL) was extracted three times. The organic phase was combined, washed with saturated brine (50 mL) twice, 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% to 70%) to obtain 330 mg of the title compound 28-10. LC-MS (ESI): m / z 500.0 [M+H] + .

[0302] Preparation of compound 28

[0303] Compound 28-10 (100 mg, 0.20 mmol), dimethyl phosphine oxide (47 mg, 0.60 mmol), Pd2(dba)3(18 mg, 0.02 mmol), Xantphos (27 mg, 0.05 mmol), DIPEA (78 mg, 0.60 mmol) were dissolved in DMF (5 mL). The reaction system was stirred at 100 °C for 16 hours. After the reaction was completed, the insoluble solid was filtered off, water (10 mL) was added to the filtrate, and dichloromethane (20 mL) was extracted three times. The organic phase was combined, washed with saturated brine (20 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: 45% to 65% acetonitrile gradient elution in 12 minutes; flow rate: 30 mL / min) to obtain 12.77 mg of the title compound 28. LC-MS (ESI): m / z 542.0 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.87 (d, J = 5.1 Hz, 1H), 7.83 (d, J = 2.3 Hz, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.64 (t, J = 4.0 Hz, 1H), 7.45 - 7.38 (m, 2H), 6.97 - 6.88 (m, 2H), 5.27 (s, 2H), 4.44 (t, J = 6.1 Hz, 2H), 3.89 (t, J = 6.1 Hz, 2H), 1.90 (d, J = 13.6 Hz, 6H), 1.65 (s, 6H). 31P NMR (162 MHz, Chloroform-d) δ 35.24 (s, 1P).

[0304] Example 29: Preparation of compound 29

[0305]

[0306] Preparation of compound 29

[0307] Compound 28-10 (100 mg, 0.20 mmol), 2-oxa-6-azaspiro[3.3]heptane (60 mg, 0.60 mmol), DIPEA (78 mg, 0.60 mmol) were dissolved in DMF (5 mL). The reaction system was stirred at 100 °C for 16 hours. After the reaction was completed, the insoluble solid was removed by filtration, the filtrate was added with water (10 mL) and extracted with dichloromethane (20 mL) for 3 times. The combined organic phase was washed with saturated brine (20 mL) for 2 times, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The product was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: 40%-60% acetonitrile was gradient eluted in 12 minutes; flow rate: 30 mL / min) to give 12.77 mg of the title compound 29. LC-MS (ESI): m / z 563.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J = 5.1 Hz, 1H), 7.83 (d, J = 2.3 Hz, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.42 - 7.34 (m, 2H), 6.93 - 6.87 (m, 2H), 6.78 (d, J = 5.1 Hz, 1H), 4.99 (s, 2H), 4.87 (s, 4H), 4.44 (t, J = 6.1 Hz, 2H), 4.32 (s, 4H), 3.89 (t, J = 6.1 Hz, 2H), 1.64 (s, 6H).

[0308] Example 30: Preparation of compound 30

[0309]

[0310] Preparation of compound 30

[0311] Compound 28-10 (100 mg, 0.20 mmol), compound 30-1 (71 mg, 0.60 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), Xantphos (27 mg, 0.05 mmol), DIPEA (78 mg, 0.60 mmol) were dissolved in DMF (5 mL). The reaction was stirred at 100 °C for 16 hours. After the reaction was completed, the insoluble solid was removed by filtration, the filtrate was added with water (10 mL) and extracted with dichloromethane (20 mL) for 3 times. The combined organic phase was washed with saturated brine (20 mL) for 2 times, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The product was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 x 21.2 mm; column temperature: 25 °C; gradient: 45%-65% acetonitrile gradient elution in 12 minutes; flow rate: 30 mL / min) to give 5.94 mg of the title compound 30. LC-MS (ESI): m / z 583.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.46 (d, J = 5.1 Hz, 1H), 7.83 (d, J = 2.3 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.40 - 7.36 (m, 2H), 7.01 (d, J = 5.2 Hz, 1H), 6.91 - 6.86 (m, 2H), 5.08 (s, 2H), 4.43 (t, J = 6.1 Hz, 2H), 3.88 (t, J = 6.1 Hz, 2H), 3.77 - 3.63 (m, 2H), 3.48 - 3.36 (m, 2H), 2.43 - 2.22 (m, 4H), 1.64 (s, 6H).

[0312] Example 31: Preparation of compound 31

[0313]

[0314] Preparation of compound 31-1

[0315] Compound 12-2 (520 mg, 1.12 mmol) was dissolved in THF (10 mL), triethylamine (505 mg, 5.00 mmol), 1-iodo-4-(methoxymethoxy)benzene (792 mg, 3.00 mmol), CuI (48 mg, 0.25 mmol), Pd(PPh3)Cl2 (88 mg, 0.13 mmol) were added, and the mixture was stirred at 70 °C for 12 h after purging with nitrogen for 3 times. After TLC tracking the reaction to completion, the reaction solution was filtered, and the filtrate was concentrated. The crude product was purified by silica gel column separation (PE / EA = 10 / 1) to obtain 420 mg of the title compound 31-1 with a yield of 51.6%. 1 H NMR (400 MHz, Chloroform-d) δ 7.74 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.48 - 7.39 (m, 2H), 7.08 - 6.98 (m, 2H), 5.20 (s, 2H), 4.48 (t, J = 6.0 Hz, 2H), 3.90 (t, J = 6.0 Hz, 2H), 3.49 (s, 3H).

[0316] Preparation of compound 31-2

[0317] Compound 31-1 (420 mg, 1.12 mmol) was dissolved in THF (10 mL), and hydrochloric acid (10 mL, 6 mol / L) was added. The mixture was stirred at room temperature for 1 h. After TLC tracking the reaction to completion, water (50 mL) was added, followed by EA (50 mL) extraction. The organic phase was concentrated, and the crude product was purified by silica gel column separation (PE / EA = 5 / 1) to obtain 300 mg of the title compound 31-2 with a yield of 80.9%.

[0318] Preparation of compound 31

[0319] Compound 31-2 (100 mg, 0.30 mmol) was dissolved in acetonitrile (10 mL), potassium carbonate (82.8 mg, 0.6 mmol), (2-(dimethylphosphoryl)pyrimidin-4-yl)methyl methanesulfonate (95.7 mg, 0.36 mmol) were added, and the mixture was stirred at 70 °C for 2 h after purging with nitrogen for 3 times. After LCMS tracking the reaction to completion, the reaction solution was concentrated, and the obtained crude product was purified by preparative separation (preparation method: column: Welch Xtimate C18 250x21.2mm; column temperature: 25 °C; mobile phase: water (10 mM / L NH4HCO3)-acetonitrile; mobile phase: 45%-65% acetonitrile gradient elution in 12 min; flow rate: 30 mL / min) to obtain 18 mg of the title compound 31 with a yield of 12%. LC-MS (ESI): m / z 500.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 5.2 Hz, 1H), 8.06 (d, J = 2.1 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 5.2, 3.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.9 Hz, 2H), 5.37 (s, 2H), 4.50 (t, J = 5.2 Hz, 2H), 3.98 (t, J = 5.2 Hz, 2H), 1.76 (d, J = 13.7 Hz, 6H).

[0320] Test Example 1: Cell proliferation inhibition test of 22RV1 and LNCaP cells:

[0321] 1. Human prostate cancer cell lines 22RV1 and LNCaP were purchased from ATCC, and the cell culture medium was RPMI-1640 + 10% FBS, and the cells were cultured in a 37°C, 100% relative humidity, 5% CO2 incubator.

[0322] 2. On the first day, collect cells in the logarithmic growth phase, count, and resuspend the cells in phenol red-free RPMI-1640 medium containing 10% CD-FBS, adjust the cell concentration to the appropriate concentration (determined according to the cell density optimization test results), inoculate a 96-well plate, and add 100 μl of cell suspension to make the cell number 3000 per well. Incubate the cells in a 37°C, 5% CO2 incubator for 24 hours.

[0323] 3. On the second day, for 22Rv1 cells, add different concentrations of the test compound, and incubate the cells in a 37°C, 5% CO2 incubator for 7 days; for LNCaP cells, first add different concentrations of the test compound, then add 0.2 nM of DHT after 1 hour, and incubate the cells in a 37°C, 5% CO2 incubator for 7 days.

[0324] 4. After the end of the culture, add an equal volume of CellTiter-Glo detection reagent to each well, shake well for 5 minutes, then incubate at room temperature for 10 minutes, and then use a PerkinElmer EnVision enzyme reader to read the results.

[0325] 5. Calculate the inhibition rate of the drug on cell growth according to the following formula: Cell growth inhibition rate % = [(Ac-As) / (Ac-Ab)] x 100%

[0326] As: OA of the sample (cells + test compound)

[0327] Ac: OA of normal growth cell control (cells + DMSO)

[0328] Ab: OA of the blank control (medium + DMSO)

[0329] IC50values were calculated using Graphpad Prism 8 with the formula XY-analysis / Nonlinear regression (curve fit) / Dose response-Inhibition / log (inhibitor) vs. response-Variable slope (four parameters) 50 curve fitting and calculation of IC 50 values.

[0330] Table 1: Results of cell proliferation inhibition experiment of the compounds of the present application in 22RV1 cells

[0331] Compound No. IC 50 (μM) Compound No. IC 50 (μM) 2 D 20 A 4 D 21 C 7 A 22 B 9 D 25 D 10 B 27 A 11 C 28 D 13 C 29 C 14 A 30 D 17 D 18 D

[0332] wherein "A" means ≤ 0.1 μM, "B" means 0.1 μM < IC50≤ 0.5 μM, "C" means 0.5 μM < IC50≤ 1 μM, "D" means 1 μM < IC50≤ 2.5 μM

[0333] From the experimental data in Table 1, the compounds of the present application show excellent activity in the 22RV1 cell proliferation inhibition experiment.

[0334] Table 2: Results of cell proliferation inhibition experiment of the compounds of the present application in LnCaP cells

[0335] Compound No. Compound No. IC 50 (μM) 7 A 10 A 22 B

[0336] wherein "A" means ≤ 0.5 μM, "B" means 0.5 μM < IC 50 ≤ 1 μM, "C" means 1 μM < IC 50 ≤ 2.5 μM

[0337] From the experimental data in Table 2, the compounds of the present application show excellent activity in the LnCaP cell proliferation inhibition experiment.

[0338] In the description of the specification, the description using the terms "one embodiment", "some embodiments", "an example", "a specific example", or "some examples" etc. means that the particular feature, structure, material or characteristic being described is included in at least one embodiment or example of the present application. The illustrative appearances of the above-mentioned terms in various places in the specification are not necessarily referred to the same embodiment or example. Moreover, the particular features, structures, materials, or characteristics can be combined in any suitable manner in one or more embodiments or examples. Furthermore, the description herein of certain examples does not necessarily exclude these features, structures, materials, or characteristics from being used in other examples. Neither, should the following claims that include minimum features explain only some embodiments or examples of the present application. Other embodiments and examples of the present application that are not expressly mentioned in the description and in the following claims are possible and are contemplated.

[0339] Although the embodiments of the present application have been shown and described above, it is understood that the above-described embodiments are exemplary and are not to be interpreted as limiting the present application, and that those skilled in the art can make various changes, modifications, substitutions and variations of the above-described embodiments within the scope of the present application.

Claims

1. A compound represented by Formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein, m, n are each independently selected from 0, 1, 2, 3, or 4; L3 is selected from -CH=CH-, -C≡C-, -(CR7R8)x-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR9; L4 is selected from -CH=CH-, -C≡C-, -(CR7R8)x-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR9; L5 is selected from a single bond or -(CR7R8)x-; L6 is selected from a single bond or -(CR7R8)x-; L7 is selected from -CH2-, -CH(CH3)-, -OCH2-, -C≡C-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, or -NH-. Ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, thienyl, oxazolyl, pyridazinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, or piperidinyl. R1is selected from H, halogen, OH, CN, NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-O-, C 1-6 alkyl-S-, C 1-6 alkyl-S(=0)2-, (C 1-6 alkyl)2-S(=0)=, C 1-6 alkyl-S(=0)2NH-, C 1-6 alkyl-S(=0)(=NH)-, 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; 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-O-, C 1-6 alkyl-S-, C 1-6 alkyl-S(=0)2-, (C 1-6 alkyl)2-S(=0)=, C 1-6 alkyl-S(=0)2NH-, C 1-6 alkyl-S(=0)(=NH)-, 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, R4are each independently selected from H, CN, F, CI, Br, 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-, said 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, R6are each independently selected from H, CN, F, Cl, Br, 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, which 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; Ring B is selected from bicyclo[ L1is selected from a single bond, -NH-, =N-, -O-, -CºC-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, C 3-6 cycloalkyl or 3-10 membered heterocycloalkyl, said C 3-6 cycloalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1 or 2 R; selected from or and when selected from L1is selected from =N- or 3-10 membered heterocycloalkyl; L2is selected from a single bond, -CH=CH-, -CºC-, -(CR7R8)x-, -0-, -S-, -C(=0)-, -S(=0)-, -S(=0)2-, -NR9-, C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, said 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; 1.1.1]pentanyl, cyclopentanyl, 2,6-diazaspiro[3.3]heptanyl, pyrazolyl, piperidinyl, thiazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzocyclopentanyl, benzocyclohexanyl, indolyl, isoindolinyl, spiro[cyclopropane-l,3'-dihydroindol]-2'-onyl, 3(2H)-pyridazinonyl, or 2(lH)-pyridonyl. L4is selected from a single bond, -CH=CH-, -C≡C-, -(CR7R8)x-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR9-, C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, said 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; Ring C is selected from phenyl, benzocyclopentanyl, benzocyclohexanyl, lH-indazolyl, 2H-indazolyl, or lH-benzo[d]imidazolyl.

26. Use of a compound according to any one of claims 1-25, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease associated with androgen receptor (AR) activity or expression. is selected from -CH=CH- or -CºC-; R7, R8are each independently selected from H, CN, F, CI, 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, said 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; R9is selected from H or C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, said 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 1, 2, or 3; Ring A is selected from C 4-10 cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, or 5-10 membered heteroaryl; B, ring C is independently selected from C 4-10 cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, benzo 5-6 cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, benzo 5-6 cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, benzo R is independently selected from H, halogen, =0, =NR', OH, NH2, CN, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkyl-S(=0)2-, C 1-6 alkyl-C(=0)-, C 1-6 alkyl-C(=0)0-, C 1-6 alkyl-O-C(=0)-, C 1-6 alkyl-C(=0)NH-, C 1-6 alkyl-NH-C(=0)-, C 1-6 alkyl-S(=0)2NH-, C 1-6 alkyl-NHS(=0)2-, 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- to 6-membered heterocycloalkyl-O-, 4- to 6-membered heterocycloalkyl-S- or 4- to 6-membered heterocycloalkyl-NH-, said C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkyl-S(=0)2-, C 1-6 alkyl-C(=0)-, C 1-6 alkyl-C(=0)0-, C 1-6 alkyl-O-C(=0)-, C 1-6 alkyl-C(=0)NH-, C 1-6 alkyl-NH-C(=0)-, C 1-6 alkyl-S(=0)2NH-, C 1-6 alkyl-NHS(=0)2-, 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- 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 heteroaryl, heteroalkyl or heterocycloalkyl comprises 1, 2 or 3 heteroatoms or groups of heteroatoms independently selected from -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -C(=O)NH-, -S(=O)-, -S(=O)2-, -P(=O)- and -S(=O)2NH-.

2. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, wherein, R is independently selected from H, halogen, OH, NH2, CN, =0, =NR', C 1-3 alkyl, C 3-6 cycloalkyl, C 1-3 alkyl-C(=0)-, C 1-3 alkyl-S(=0)2-, (C 1-3 alkyl)2-P(=0)-, C 1-3 alkyl-C(=0)0-, C 1-3 alkyl-0-, C 1-3 alkyl-S-, or C 1-3 alkyl-NH-, said C 1-3 alkyl, C 3-6 cycloalkyl, C 1-3 alkyl-C(=0)-, C 1-3 alkyl-S(=0)2-, C 1-3 alkyl-C(=0)0-, C 1-3 alkyl-0-, C 1-3 alkyl-S-, or C 1-3 alkyl-NH- optionally substituted with 1, 2 or 3 R'.

3. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to claim 2, wherein, R is independently selected from H, F, CI, Br, I, OH, NH2, CN, =0, =NH, =N-CN, CH3, CH2F, CHF2, CF3, 4. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, R1is selected from H, F, Cl, Br, I, Me, CN, OH, NH2, 5. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, L1is selected from a single bond, -NH-, =N-, -0-, -CºC-, -S-, -C(=0)-, -S(=0)-, -S(=0)2-, 6. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein Structural unit selected from H, F, Cl, Br, I, 7. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R2, R3, R4are each independently selected from the group consisting of 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 oxiranyl-O-, said 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 with 1, 2 or 3 R.

8. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to claim 7, wherein, R2, R3, R4are each independently selected from H, CN, F, Cl, Br, OH, NH2, CN, Me, said Me, and optionally substituted with 1, 2 or 3 R.

9. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to claim 8, wherein, R2, R3, R4are each independently selected from H, CN, F, CI, Br, OH, NH2, CN, Me, 10. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, R7, R8are each independently selected from H, CN, F, Cl, Br, OH, NH2, Me or 11. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, R9is selected from H, Me, 12. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, L2 is selected from single bonds, -CH2-, -CH(CH3)-, -C≡C-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NH-, 13. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, 27. The disease associated with androgen receptor (AR) activity or expression according to claim 26 is selected from prostate cancer, ovarian cancer, breast cancer, bladder cancer, pancreatic cancer, endometrial cancer, hepatocellular cancer, renal cell cancer, melanoma, mantle cell lymphoma, glioblastoma, salivary gland cancer, alopecia, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration.

14. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, L4 is selected from single bonds, -CH2-, -CH(CH3)-, -C≡C-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NH-, 15. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, -L2-L3-L4-selected from -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -C≡C-, -O-, -OCH2-, -OCH(CH3)-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NH-, -CH2NH-, 16. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, L5is selected from a single bond, -CH2-, -CH2CH2- or 17. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, L6is selected from a single bond, -CH2-, -CH2CH2- or 18. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, -CH2-CH=CH-, -CH2-CºC-, -CH2-CH=CH-CH2-, -CH2-CºC-CH2-, 19. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, ​ 20. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to claim 19, wherein, Structural unit selected from 21. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein ​ ​ 22. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to claim 21, wherein, Structural unit selected from 23. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, ​ 24. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to claim 9 or 23, wherein, Structural unit selected from 25. Compounds of the following formula, their optical isomers or pharmaceutically acceptable salts thereof, selected from: ​ ​

Images