NTD inhibitor and application thereof

Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to an NTD inhibitor and application thereof. The invention provides a novel NTD inhibitor, a bisphenol A structure of EPI-001 is replaced by utilizing reasonable drug design means such as skeleton transition, the aromaticity of a core skeleton of a compound is increased, and drug design is developed on the basis of the novel core skeleton. The compound prepared by the invention has proliferation inhibition activity on an enzalutamide drug-resistant cell line, has inhibition activity on transcription of a shear mutant AR-V7, and simultaneously shows a good in-vivo half-life period and certain oral bioavailability.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to an NTD inhibitor and its application. Background Technology

[0002] Prostate cancer is one of the most common malignant tumors of the genitourinary system in middle-aged and elderly men, and it has now become the second leading cause of cancer death in men. Compared with many types of cancer, prostate cancer takes longer to invade adjacent tissues and spread to distant organs. Its growth and spread rate are closely related to the degree of differentiation of prostate cancer. Poorly differentiated prostate cancer is more likely to spread rapidly from the prostate area to other parts of the body. The causes of prostate cancer are not yet clear. Common risk factors include age, genetics, race, diet, lifestyle, and medications (Noldus J, Graefen M, Haese A, Henke RP, Hammerer P, Huland H. Stage migration inclinically localized prostate cancer[J]. European urology, 2000, 38(1):74-78.). Prostate cancer generally does not have obvious symptoms in the early stages, but when the tumor grows larger and invades or obstructs the urethra and bladder neck, it may cause symptoms such as lower urinary tract obstruction. More severe cases may also present with acute urinary retention, hematuria, or urinary incontinence.

[0003] Treatment methods for prostate cancer mainly include active surveillance, radical prostatectomy, external beam radiation therapy, local therapy, and endocrine therapy. In the early stages of diagnosis, active surveillance is typically the primary treatment approach. However, prostate cancer has a long latency period, making it difficult to detect, and it is often discovered at an advanced stage. For advanced prostate cancer, castration therapy or androgen deprivation therapy (ADT) is currently the standard first-line treatment. However, castration therapy is not curative; the vast majority of patients relapse at different time points (18-48 months), exhibiting castration resistance and progressing to castration-resistant prostate cancer (CRPC). CRPC is characterized by insensitivity to surgical castration and tolerance to drug castration, and almost all patients will die within a few years due to the uncontrollable progression of the disease. Currently, treatment options for CRPC are very limited. The only drugs approved by the FDA for CRPC treatment are the conventional chemotherapy drug cabazitaxel and the second-generation AR-targeting drugs—the androgen synthesis inhibitor abiraterone and the anti-androgen MDV3100. However, as the disease progresses, patients develop resistance to these drugs, eventually leading to their death (Loriot Y, Bianchini D, Ileana E, et al. Antitumour activity of abiraterone acetate against metastaticcastration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100)[J]. Annals of oncology:officialjournal ofthe EuropeanSociety for Medical Oncology,2013,24(7):1807-1812).

[0004] The progression of prostate cancer is highly dependent on the transcriptional regulation of the androgen receptor (AR), making androgen deprivation therapy one of the first-line treatment options. Based on the effectiveness of androgen deprivation therapy, prostate cancer is clinically classified into androgen-dependent and androgen-independent types. Most early-stage prostate cancers are androgen-dependent, sensitive to castration therapy, and have better treatment prospects. However, during the progression of prostate cancer, due to mechanisms such as AR overexpression or abnormal activation, androgen-dependent prostate cancer may eventually transform into androgen-independent prostate cancer, leading to the failure of previously effective treatments, increased tumor malignancy, and worsened patient prognosis. In the disease state, increased AR expression makes prostate tissue more sensitive to androgen stimulation, promoting proliferation-related transcriptional activities, thereby driving tumor progression (REBELLO RJ, OING C, KNUDSEN KE, et al. Prostate cancer[J].Nat RevDis Primers,2021,7:9.). Most prostate cancer patients can receive androgen deprivation therapy as the primary treatment at the time of initial diagnosis. However, although most prostate cancers respond to androgen deprivation therapy in the early stages of treatment, they inevitably develop into castration-resistant prostate cancer over time. Therefore, a new treatment approach is urgently needed to address the threat of castration-resistant prostate cancer.

[0005] The androgen receptor (AR) is an androgen-activated transcription factor composed of a ligand-binding domain (LBD), a DNA-binding domain (DBD), and an N-terminal domain (NTD). The DBD segment has been crystallized and can be used for drug design and development; however, its high conservation across different receptors inevitably leads to poor specificity and numerous side effects. Most steroid receptors function through the second activation domain (AF2) at the LBD terminus, but AR is an exception; its first activation domain (AF1) at the NTD terminus plays a major role in its transcriptional activation function. The function of the LBD in AR is independent of the NTD. Even if AF-1 is deleted or mutated, it can still bind to the ligand. However, without the AF-1 domain of the NTD, AR cannot exert transcriptional activation activity (Tan MH, Li J, Xu HE, Melcher K, Yong EL. Androgen receptor: structure, role in prostate cancer and drug discovery, Actapharmacologica Sinica, 2015, 36(1):3-23.). All current treatments for AR depend on the presence of the LBD. However, the NTD of AR is the key region for its transcriptional activity. The AF-1 activation domain, located within the NTD, is essential for the transactivation of AR. Deletion of this region leads to the loss of AR transcriptional activity (Jenster G, van der Korput HA, Trapman J, et al. Identification of two transcription activation units in the N-terminal domain of the human androgen receptor[J]. The Journal of Biological Chemistry, 1995, 270(13):7341-7346.). Targeting the NTD terminus of AR can theoretically cover AR variants and other cases such as non-specific ligand activation of LBD. Therefore, in recent years, scientists have attempted to develop new drugs for the treatment of prostate cancer by targeting the NTD of AR.However, because AR-NTDs contain very few α-helices and β-sheets and have a high degree of natural disorder, it is difficult to develop targeted drugs through structure-based drug design (McEwan J. Intrinsic disorder in the androgen receptor: identification, characterisation and drugability[J]. Molecular bioSystems, 2012, 8(1): 82-90.). The most reported drug is EPI-001, discovered in 2010, which is believed to be able to bind to the NTD end of AR in a covalent manner. EPI-001 is a mixture of four isomers. The (2R,20S) isomer EPI-002 (ralaniten) and its esterified prodrug EPI-506 (ralaniten acetate) were once included in a Phase I / II clinical trial (NCT02606123) for the treatment of castration-resistant prostate cancer that has progressed after anti-androgen therapy. However, the clinical trial was eventually terminated due to the unsatisfactory efficacy of the drug molecule itself and potential pharmacokinetic problems. Therefore, targeting the NTD of the androgen receptor transcription core region to screen and develop drugs for castration-resistant prostate cancer has significant academic and clinical value. Summary of the Invention

[0006] This invention provides a novel NTD inhibitor that replaces the bisphenol A structure of EPI-001 using rational drug design techniques such as skeletal transitions, increasing the aromaticity of the core skeleton of the compound, and then conducts drug design based on the new core skeleton, thereby completing this invention.

[0007] In a first aspect, the present invention provides a compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or a prodrug thereof: the structure of said compound is shown in formula (I):

[0008]

[0009] Furthermore, in the compound shown in formula (I), A is selected from 5 to 15 aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.

[0010] Furthermore, each of the heteroaryl or heterocycloalkyl groups contains 1 to 3 heteroatoms.

[0011] Furthermore, the heteroatom is selected from N, O, or S.

[0012] Furthermore, in the compound shown in formula (I), B is selected from 5 to 15 aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.

[0013] Furthermore, each of the heteroaryl or heterocycloalkyl groups contains 1 to 3 heteroatoms.

[0014] Furthermore, the heteroatom is selected from N, O, or S.

[0015] Furthermore, in the compound shown in formula (Ⅰ), C is selected from C 1-6 Alkyl, C 2-6 Alkenyl, 3 to 10 aryl, heteroaryl, cycloalkyl or heterocycloalkyl.

[0016] Furthermore, each of the heteroaryl or heterocycloalkyl groups contains 1 to 3 heteroatoms.

[0017] Furthermore, the heteroatom is selected from N, O, or S.

[0018] Furthermore, in the compound shown in formula (Ⅰ), X is selected from compounds that do not exist, C 1-6 Alkyl, -O-, -C(=O)NH-, -SO2NH-, -NR 4 3 to 10 aryl, heteroaryl, cycloalkyl or heterocycloalkyl.

[0019] Furthermore, the -NR 4 R in 4 Selected from C 1-6 Alkyl or C 2-6 Alkenyl group.

[0020] Furthermore, the alkyl or alkenyl group is further substituted with one or more substituents.

[0021] Furthermore, the substituent is selected from hydroxyl, halogen, or -CF3.

[0022] Furthermore, each of the heteroaryl or heterocycloalkyl groups contains 1 to 3 heteroatoms.

[0023] Furthermore, the heteroatom is selected from N, O, or S.

[0024] Furthermore, the alkyl group is substituted with one or more substituents.

[0025] Furthermore, the substituents are selected from hydroxyl, halogen, and C. 1-6 Alkyl or C 3-8 Heterocyclic alkyl groups.

[0026] Furthermore, in the compound shown in formula (Ⅰ), Y is selected from -CH2-, -NH-, -O- or -C(=O)-.

[0027] Furthermore, in the compound shown in formula (Ⅰ), W is selected from -CH2-, -CH2CH2-, -NH-, -O- or -C(=O)-.

[0028] Furthermore, in the compound shown in formula (Ⅰ), Z is selected from -CH2-, -NH-, -O- or -C(=O)-.

[0029] Furthermore, in the compound shown in formula (Ⅰ), V is selected from C 1-6 Alkyl or -NH-.

[0030] Furthermore, in the compound shown in formula (Ⅰ), L is selected from C 1-6 Alkyl or C 2-6 Alkenyl group.

[0031] Furthermore, the alkyl or alkenyl group is further substituted with one or more substituents.

[0032] Furthermore, the substituents are selected from hydroxyl groups, halogens, and -C(=O)NHC. 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-OC(=O)C 1-6 Alkyl group, -OC (=O)C 1-6 alkenyl or -C(=O)OC 1-6 alkyl.

[0033] Furthermore, in the compound shown in formula (Ⅰ), the R 1 R 2 Each is independently selected from hydrogen, halogen, cyano, -CF3 or hydroxyl.

[0034] Furthermore, in the compound shown in formula (Ⅰ), the R 3 Selected from amino, hydroxyl, halogen, -C(=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 3-8 Cycloalkyl, -C(=O)C 3-8 Heterocyclic alkyl, -C(=O)C 6-10 Aryl, -C(=O)C 5-10 heteroaryl, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -SO2C 1-6Alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 Heterocyclic alkyl groups, -SO2C 6-10 Aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 Alkyl group, -SO2N(C) 1-6 Alkyl)2、-NHSO2C 1-6 Alkyl group, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 Heterocyclic alkyl groups, -NHSO2C 6-10 Aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 Alkyl group, -NHSO2N(C 1-6 alkyl)2、-CH2NHSO2C 1-6 Alkyl group, -CH2NHSO2C 3-8 cycloalkyl, -CH2NHSO2C 6-10 Aryl, -CH2NHSO2C 5-10 heteroaryl, -CH2NHSO2NHC 1-6 Alkyl or -CH2NHSO2N(C 1-6 Alkyl)2.

[0035] Furthermore, each of the heteroaryl or heterocycloalkyl groups contains 1 to 3 heteroatoms.

[0036] Furthermore, the heteroatom is selected from N, O, or S.

[0037] Furthermore, the alkyl, amino, heterocyclic alkyl, cycloalkyl, aryl, and heteroaryl groups are further substituted by one or more substituents.

[0038] Furthermore, the substituents are selected from deuterium, hydroxyl, halogen, cyano, and C. 1-6 Alkyl, C 3-8 cycloalkyl, C 5-10 heteroaryl or -SO2C 1-6 alkyl.

[0039] Furthermore, in the compound shown in formula (Ⅰ), n1, n2, and n3 are each independently selected from 0, 1, 2, or 3.

[0040] In one embodiment of the present invention, the compound structure shown in formula (Ⅰ) can be as shown in formula (Ⅱa):

[0041]

[0042] Furthermore, in the compound shown in formula (Ⅱa), X is selected from -O-, -C(=O)NH-, -SO2NH-, -NR 4 Or C 1-6 alkyl.

[0043] Furthermore, the -NR 4 R in 4 Selected from C 1-6 alkyl.

[0044] Furthermore, the alkyl group is further substituted with one or more substituents.

[0045] Furthermore, the substituent is selected from hydroxyl, halogen, or -CF3.

[0046] Furthermore, the C 1-6 The alkyl group in the alkyl group is further substituted by one or more substituents.

[0047] Furthermore, the substituent is selected from C 1-6 Alkyl or C 3-8 Heterocyclic alkyl groups.

[0048] Furthermore, in the compound shown in formula (Ⅱa), C is selected from C 1-6 Alkyl, 3 to 10 aryl, heteroaryl, cycloalkyl or heterocycloalkyl.

[0049] Furthermore, each of the heteroaryl or heterocycloalkyl groups contains 1 to 3 heteroatoms.

[0050] Furthermore, the heteroatom is selected from N, O, or S.

[0051] Furthermore, in the compound shown in formula (Ⅱa), the Y is selected from -NH-, -O-, or -C(=O)-.

[0052] Furthermore, in the compound shown in formula (Ⅱa), W is selected from -CH2-, -NH-, or -C(=O)-.

[0053] Furthermore, in the compound shown in formula (Ⅱa), Z is selected from -NH-, -O-, or -C(=O)-.

[0054] Furthermore, in the compound shown in formula (Ⅱa), V is selected from -CH2- or -NH-.

[0055] Furthermore, in the compound shown in formula (IIa), L is selected from C 1-6 alkyl.

[0056] Furthermore, the alkyl group may optionally be substituted with one or more substituents.

[0057] Furthermore, the substituent is selected from hydroxyl groups or halogens.

[0058] Furthermore, in the compound shown in formula (Ⅱa), the R 1 R 2 Each is independently selected from hydrogen, halogen, cyano, or -CF3.

[0059] Furthermore, in the compound shown in formula (Ⅱa), the R 3 Selected from amino, hydroxyl, halogen, -C(=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 3-8 Cycloalkyl, -C(=O)C 3-8 Heterocyclic alkyl, -C(=O)C 6-10 Aryl, -C(=O)C 5-10 heteroaryl, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 Heterocyclic alkyl groups, -SO2C 6-10 Aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 Alkyl group, -SO2N(C) 1-6 Alkyl)2、-NHSO2C 1-6 Alkyl group, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 Heterocyclic alkyl groups, -NHSO2C 6-10 Aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 Alkyl or NHSO2N(C 1-6 Alkyl)2.

[0060] Furthermore, each of the heterocyclic alkyl or heteroaryl groups contains 1 to 3 heteroatoms.

[0061] Furthermore, the heteroatom is selected from N, O, or S.

[0062] Furthermore, the alkyl, amino, heterocyclic alkyl, cycloalkyl, aryl, and heteroaryl groups are further substituted by one or more substituents.

[0063] Furthermore, the substituents are selected from deuterium, hydroxyl, halogen, cyano, and C. 1-6 Alkyl, C 3-8 cycloalkyl, C 5-10 heteroaryl or -SO2C 1-6 alkyl.

[0064] Furthermore, in the compound shown in formula (Ⅱa), n1, n2, and n3 are each independently selected from 0, 1, or 2.

[0065] In one embodiment of the present invention, the compound structure shown in formula (Ⅰ) can be as shown in formula (Ⅱb):

[0066]

[0067] Furthermore, in the compound shown in formula (Ⅱb), X is an aryl or aromatic heterolyl group.

[0068] Furthermore, the aryl or aromatic heterol group is selected from...

[0069] Furthermore, E1, E2, E3, and E4 are each independently selected from C or N.

[0070] Furthermore, G1, G2, G3, G4, and G5 are each independently selected from C, O, or N.

[0071] Furthermore, in the compound shown in formula (Ⅱb), the C is selected from C 1-6 Alkyl, 3 to 10 aryl, heteroaryl, cycloalkyl or heterocycloalkyl.

[0072] Furthermore, each of the heteroaryl or heterocycloalkyl groups contains 1 to 3 heteroatoms.

[0073] Furthermore, the heteroatom is selected from N, O, or S.

[0074] Furthermore, in the compound shown in formula (Ⅱb), the Y is selected from -NH-, -O-, or -C(=O)-.

[0075] Furthermore, in the compound shown in formula (Ⅱb), W is selected from -CH2-, -NH-, or -C(=O)-.

[0076] Furthermore, in the compound shown in formula (Ⅱb), Z is selected from -NH-, -O-, or -C(=O)-.

[0077] Furthermore, in the compound shown in formula (Ⅱb), V is selected from -CH2- or -NH-.

[0078] Furthermore, in the compound shown in formula (IIb), L is selected from C 1-6 Alkyl or C2-6 Alkenyl group.

[0079] Furthermore, the alkyl or alkenyl group is further substituted with one or more substituents.

[0080] Furthermore, the substituents are selected from hydroxyl groups, halogens, and -C(=O)NHC. 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-OC(=O)C 1-6 Alkyl group, -OC (=O)C 1-6 alkenyl or -C(=O)OC 1-6 alkyl.

[0081] Furthermore, in the compound shown in formula (Ⅱb), the R 1 R 2 Each is independently selected from hydrogen, halogen, cyano, -CF3 or hydroxyl.

[0082] Furthermore, in the compound shown in formula (Ⅱb), the R 3 Selected from amino, hydroxyl, halogen, -C(=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 3-8 Cycloalkyl, -C(=O)C 3-8 Heterocyclic alkyl, -C(=O)C 6-10 Aryl, -C(=O)C 5-10 heteroaryl, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 Heterocyclic alkyl groups, -SO2C 6-10 Aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 Alkyl group, -SO2N(C) 1-6 Alkyl)2、-NHSO2C 1-6 Alkyl group, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 Heterocyclic alkyl groups, -NHSO2C 6-10 Aryl, -NHSO2C 5-10heteroaryl, -NHSO2NHC 1-6 Alkyl or -NHSO2N(C 1-6 Alkyl)2.

[0083] Furthermore, each of the heterocyclic alkyl or heteroaryl groups contains 1 to 3 heteroatoms.

[0084] Furthermore, the heteroatom is selected from N, O, or S.

[0085] Furthermore, the alkyl, amino, heterocyclic alkyl, cycloalkyl, aryl, and heteroaryl groups may optionally be substituted by one or more substituents.

[0086] Furthermore, the substituents are selected from deuterium, hydroxyl, halogen, cyano, and C. 1-6 Alkyl, C 3-8 cycloalkyl, C 5-10 heteroaryl or -SO2C 1-6 alkyl.

[0087] Furthermore, in the compound shown in formula (Ⅱb), n1, n2, and n3 are each independently selected from 0, 1, or 2.

[0088] In one embodiment of the present invention, the compound structure shown in formula (Ⅰ) can also be shown in formula (Ⅱc):

[0089]

[0090] Furthermore, in the compound shown in formula (Ⅱc), A is selected from...

[0091] Furthermore, A1 is selected from aryl or aromatic heterol.

[0092] Furthermore, A2 is selected from aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.

[0093] Furthermore, E1, E2, E3, E4, and E5 are each independently selected from C or N.

[0094] Furthermore, G1, G2, G3, and G4 are each independently selected from C, O, N, or -C=O.

[0095] Furthermore, in the compound shown in formula (Ⅱc), C is selected from C 1-6 Alkyl, 3 to 10 aryl, heteroaryl, cycloalkyl or heterocycloalkyl.

[0096] Furthermore, each of the heteroaryl or heterocycloalkyl groups contains 1 to 3 heteroatoms.

[0097] Furthermore, the heteroatom is selected from N, O, or S.

[0098] Furthermore, the C 1-6 Alkyl, C 2-6 The alkenyl, 3 to 10 aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are further substituted by one or more substituents.

[0099] Furthermore, the substituents are selected from amino, hydroxyl, halogen, and -C(=O)NHC. 1-6 Alkyl, -C(=O)N(C) 1-6 alkyl)2 or -SO2C 1-6 alkyl.

[0100] Furthermore, in the compound shown in formula (Ⅱc), Y is selected from -NH-, -O-, or -C(=O)-.

[0101] Furthermore, in the compound shown in formula (Ⅱc), W is selected from -CH2-, -NH-, or -C(=O)-.

[0102] Furthermore, in the compound shown in formula (Ⅱc), Z is selected from -NH-, -O-, or -C(=O)-.

[0103] Furthermore, in the compound shown in formula (Ⅱc), V is selected from -CH2- or -NH-.

[0104] Furthermore, in the compound shown in formula (Ⅱc), L is selected from C 1-6 Alkyl or C 2-6 Alkenyl group.

[0105] Furthermore, the alkyl or alkenyl group is further substituted with one or more substituents.

[0106] Furthermore, the substituents are selected from hydroxyl groups, halogens, and -C(=O)NHC. 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-OC(=O)C 1-6 Alkyl group, -OC (=O)C 1-6 alkenyl or -C(=O)OC 1-6 alkyl.

[0107] Furthermore, in the compound shown in formula (Ⅱc), the R 1 R 2 Each is independently selected from hydrogen, halogen, cyano, -CF3 or hydroxyl.

[0108] Furthermore, in the compound shown in formula (Ⅱc), the R 3 Selected from amino, hydroxyl, halogen, -C(=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 3-8Cycloalkyl, -C(=O)C 3-8 Heterocyclic alkyl, -C(=O)C 6-10 Aryl, -C(=O)C 5-10 heteroaryl, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 Heterocyclic alkyl groups, -SO2C 6-10 Aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 Alkyl group, -SO2N(C) 1-6 Alkyl)2、-NHSO2C 1-6 Alkyl group, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 Heterocyclic alkyl groups, -NHSO2C 6-10 Aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 Alkyl group, -NHSO2N(C 1-6 alkyl)2、-CH2NHSO2C 1-6 Alkyl group, -CH2NHSO2C 3-8 cycloalkyl, -CH2NHSO2C 3-8 Heterocyclic alkyl, -CH2NHSO2C 6-10 Aryl, -CH2NHSO2C 5-10 heteroaryl, -CH2NHSO2NHC 1-6 Alkyl or -CH2NHSO2N(C 1-6 Alkyl)2.

[0109] Furthermore, each of the heterocyclic alkyl or heteroaryl groups contains 1 to 3 heteroatoms.

[0110] Furthermore, the heteroatom is selected from N, O, or S.

[0111] Furthermore, the alkyl, amino, heterocyclic alkyl, cycloalkyl, aryl, and heteroaryl groups are further substituted by one or more substituents.

[0112] Furthermore, the substituents are selected from deuterium, hydroxyl, halogen, cyano, and C.1-6 Alkyl, C 3-8 cycloalkyl, C 5-10 heteroaryl or -SO2C 1-6 alkyl.

[0113] Furthermore, in the compound shown in formula (Ⅱc), n1, n2, and n3 are each independently selected from 0, 1, or 2.

[0114] In one embodiment of the present invention, the compound structure shown in formula (Ⅰ) or (Ⅱa) can also be shown in formula (Ⅲa):

[0115]

[0116] Furthermore, in the compound shown in formula (Ⅲa), X is selected from -C(=O)NH-, -SO2NH-, or C 1-6 alkyl.

[0117] Furthermore, the alkyl group is further substituted with one or more substituents.

[0118] Furthermore, the substituent is selected from C 1-6 Alkyl or C 3-8 Heterocyclic alkyl groups.

[0119] Furthermore, in the compound shown in formula (Ⅲa), X is selected from...

[0120] Furthermore, in the compound shown in formula (Ⅲa), C is selected from C 1-6 alkyl.

[0121] Furthermore, in the compound shown in formula (Ⅲa), L is selected from C 1-6 alkyl.

[0122] Furthermore, the alkyl group is further substituted with one or more substituents.

[0123] Furthermore, the substituent is selected from hydroxyl groups or halogens.

[0124] Furthermore, in the compound shown in formula (Ⅲa), the R 1 R 2 Each is independently selected from hydrogen, halogen, cyano, or -CF3.

[0125] Furthermore, in the compound shown in formula (Ⅲa), the R 3 It is a hydroxyl group.

[0126] Furthermore, in the compound shown in formula (Ⅲa), n1, n2, and n3 are each independently selected from 0, 1, or 2.

[0127] In one embodiment of the present invention, the compound structure shown in formula (Ⅰ) or (Ⅱb) can also be shown in formula (Ⅲb):

[0128]

[0129] Furthermore, in the compound shown in formula (Ⅲb), X is selected from...

[0130] Furthermore, in the compound shown in formula (Ⅲb), C is selected from 3 to 10 aryl, heteroaryl, cycloalkyl, or heterocycloalkyl.

[0131] Furthermore, each of the heteroaryl or heterocycloalkyl groups contains 1 to 3 heteroatoms.

[0132] Furthermore, the heteroatom is selected from N, O, or S.

[0133] Furthermore, in the compound shown in formula (Ⅲb), L is selected from C 1-6 Alkyl or C 2-6 Alkenyl group.

[0134] Furthermore, the alkyl or alkenyl group is further substituted with one or more substituents.

[0135] Furthermore, the substituents are selected from hydroxyl groups, halogens, and -C(=O)NHC. 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-OC(=O)C 1-6 Alkyl group, -OC (=O)C 1-6 alkenyl or -C(=O)OC 1-6 alkyl.

[0136] Furthermore, in the compound shown in formula (Ⅲb), the R 1 R 2 Each is independently selected from hydrogen, halogen, cyano, or -CF3.

[0137] Furthermore, in the compound shown in formula (Ⅲb), the R 3 Selected from -SO2C 1-6 Alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 Heterocyclic alkyl groups, -SO2C 6-10 Aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 Alkyl group, -SO2N(C) 1-6 Alkyl)2、-NHSO2C 1-6 Alkyl group, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 Heterocyclic alkyl groups, -NHSO2C6-10 Aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 Alkyl or -NHSO2N(C 1-6 Alkyl)2.

[0138] Furthermore, each of the heterocyclic alkyl or heteroaryl groups contains 1 to 3 heteroatoms.

[0139] Furthermore, the heteroatom is selected from N, O, or S.

[0140] Furthermore, the alkyl, amino, heterocyclic alkyl, cycloalkyl, aryl, and heteroaryl groups are further substituted by one or more substituents.

[0141] Furthermore, the substituents are selected from deuterium, hydroxyl, halogen, cyano, and C. 1-6 Alkyl, C 1-6 Alkyl groups or -SO2C 1-6 alkyl.

[0142] Furthermore, in the compound shown in formula (Ⅲb), n1, n2, and n3 are each independently selected from 0, 1, or 2.

[0143] In one embodiment of the present invention, the compound structure shown in formula (Ⅰ) or (Ⅱc) can also be shown in formula (Ⅲc):

[0144]

[0145] Furthermore, in the compound shown in formula (Ⅲc), A is selected from...

[0146] Furthermore, in the compound shown in formula (Ⅲc), C is selected from 3 to 10 aryl, heteroaryl, cycloalkyl, or heterocycloalkyl.

[0147] Furthermore, each of the heteroaryl or heterocycloalkyl groups contains 1 to 3 heteroatoms.

[0148] Furthermore, the heteroatom is selected from N, O, or S.

[0149] Furthermore, in the compound shown in formula (Ⅲc), Y is selected from -NH-, -O-, or -C(=O)-.

[0150] Furthermore, in the compound shown in formula (Ⅲc), W is selected from -CH2-, -NH-, or -C(=O)-.

[0151] Furthermore, in the compound shown in formula (Ⅲc), Z is selected from -NH-, -O-, or -C(=O)-.

[0152] Furthermore, in the compound shown in formula (Ⅲc), V is selected from -CH2- or -NH-.

[0153] Furthermore, in the compound shown in formula (Ⅲc), L is selected from C 1-6 Alkyl or C 2-6 Alkenyl group.

[0154] Furthermore, the alkyl or alkenyl group is further substituted with one or more substituents.

[0155] Furthermore, the substituents are selected from hydroxyl groups, halogens, and -C(=O)NHC. 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-OC(=O)C 1-6 Alkyl group, -OC (=O)C 1-6 alkenyl or -C(=O)OC 1-6 alkyl.

[0156] Furthermore, in the compound shown in formula (Ⅲc), the R 1 R 2 Each is independently selected from hydrogen, halogen, or cyano groups.

[0157] Furthermore, in the compound shown in formula (Ⅲc), the R 3 Selected from amino, hydroxyl, halogen, -C(=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 3-8 Cycloalkyl, -C(=O)C 3-8 Heterocyclic alkyl, -C(=O)C 6-10 Aryl, -C(=O)C 5-10 heteroaryl, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 Heterocyclic alkyl groups, -SO2C 6-10 Aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 Alkyl group, -SO2N(C) 1-6 Alkyl)2、-NHSO2C 1-6Alkyl group, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 Heterocyclic alkyl groups, -NHSO2C 6-10 Aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 Alkyl group, -NHSO2N(C 1-6 alkyl)2、-CH2NHSO2C 1-6 Alkyl group, -CH2NHSO2C 3-8 cycloalkyl, -CH2NHSO2C 3-8 Heterocyclic alkyl, -CH2NHSO2C 6-10 Aryl, -CH2NHSO2C 5-10 heteroaryl, -CH2NHSO2NHC 1-6 Alkyl or -CH2NHSO2N(C 1-6 Alkyl)2.

[0158] Furthermore, each of the heterocyclic alkyl or heteroaryl groups contains 1 to 3 heteroatoms.

[0159] Furthermore, the heteroatom is selected from N, O, or S.

[0160] Furthermore, the alkyl, amino, heterocyclic alkyl, cycloalkyl, aryl, and heteroaryl groups are further substituted by one or more substituents.

[0161] Furthermore, the substituents are selected from deuterium, hydroxyl, halogen, cyano, and C. 1-6 Alkyl, C 3-8 cycloalkyl, C 5-10 heteroaryl or -SO2C 1-6 alkyl.

[0162] Furthermore, in the compound shown in formula (Ⅲc), n1, n2, and n3 are each independently selected from 0, 1, or 2.

[0163] In one embodiment of the present invention, the compounds of formulas (Ⅰ), (Ⅱa), and (Ⅲa) preferably have the following structures:

[0164]

[0165] In one embodiment of the present invention, the compounds of formulas (Ⅰ), (Ⅱb), and (Ⅲb) preferably have the following structures:

[0166]

[0167] In one embodiment of the present invention, the compounds of formulas (Ⅰ), (Ⅱc), and (Ⅲc) preferably have the following structures:

[0168]

[0169]

[0170]

[0171] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), (IIa), (IIIa), (IIb), (IIIb), (IIc) or (IIIc), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or a prodrug thereof, and a pharmaceutically acceptable diluent or carrier thereof.

[0172] Furthermore, the pharmaceutical composition can be formulated into various dosage forms, including but not limited to one or more of the following: tablets, capsules, drops, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal preparations, lozenges, suppositories, and / or lyophilized powder injections.

[0173] Furthermore, colorants, preservatives, flavorings, tasters, sweeteners, or other materials may be added to the pharmaceutical preparations if necessary.

[0174] Furthermore, the pharmaceutical composition can be administered by injection, cavity administration, respiratory administration, or mucosal administration.

[0175] Furthermore, the injection administration includes subcutaneous injection, intravenous injection, intramuscular injection, and intracavitary injection; the cavity administration includes rectal or vaginal administration; and the respiratory administration is nasal administration.

[0176] Thirdly, the present invention provides the use of a compound of formula (I), (IIa), (IIIa), (IIb), (IIIb), (IIc) or (IIIc) or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug in the preparation of a medicament for treating prostate cancer.

[0177] Furthermore, the prostate cancer includes androgen-dependent prostate cancer and androgen-independent prostate cancer.

[0178] Furthermore, the prostate cancer includes acinar carcinoma, ductal carcinoma in situ, ductal adenocarcinoma, urothelial carcinoma, squamous cell carcinoma, basal cell carcinoma, and neuroendocrine tumors, etc.

[0179] Furthermore, the prostate cancer includes stage I, stage II, stage III, and stage IV prostate cancer.

[0180] Beneficial effects

[0181] 1. The compound prepared in this invention has an inhibitory effect on the proliferation of enzalutamide-resistant cell line 22Rv1.

[0182] 2. The compound prepared in this invention has an inhibitory effect on transcription of the splicing mutant AR-V7.

[0183] 3. The compounds prepared in this invention have a good in vivo half-life and a certain oral bioavailability. Detailed Implementation

[0184] The specific embodiments of the present invention will be further described below. It should be noted that these descriptions are for the purpose of aiding understanding the present invention, but do not constitute a limitation thereof. Furthermore, the technical features involved in the embodiments described below can be combined with each other as long as they do not conflict with each other.

[0185] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods, and the experimental materials used in the following embodiments are all available through conventional commercial channels.

[0186] Table 1. Exemplary compound structures of the present invention

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198] Synthesis of key intermediate A-2 in the example

[0199]

[0200] Synthesis of 4-methylbenzenesulfonic acid-[(4R)-2,2-dimethyl-1,3-dioxanepent-4-yl]methyl ester (A-2)

[0201] Compound (R)-(-)-glycerol acetal (1.00 g, 7.57 mmol, 1.0 equiv.), p-toluenesulfonyl chloride (1.73 g, 9.09 mmol, 1.2 equiv.), and Et3N (1.53 g, 15.15 mmol, 2.0 equiv.) were dissolved in DCM (30 mL) and reacted at room temperature for 3 h. TLC analysis showed that the reaction proceeded completely. After rotary evaporation to dryness, the product was dissolved in water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography purification yielded the target compound A-2, 1.98 g of white solid, with a yield of 92%.

[0202] UPLC-MS m / z:calcd for C 13 H 17 O5S[M+H] + 287.35; found: 288.10.

[0203] Synthesis of Example 1

[0204]

[0205] Step 1:

[0206] Compound 4-bromo-2,6-dichlorophenol (1-1) (1.00 g, 4.16 mmol, 1.0 equiv.), benzyl bromide (850 mg, 5.00 mmol, 1.2 equiv.), and K₂CO₃ (1.15 g, 8.32 mmol, 2.0 equiv.) were dissolved in DMF (10 mL) and reacted at 65 °C for 5 h with stirring. TLC analysis showed that the reaction proceeded completely. After rotary evaporation to dryness, the product was dissolved in water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography purification yielded the target compound 1-2, a white solid of 1.23 g, with a yield of 90%.

[0207] Step 2:

[0208] Compounds 1-2 (1.00 g, 3.03 mmol, 1.0 equiv.), 6-hydroxy-1,2,3,4-tetrahydroquinoline (455 mg, 3.03 mmol, 1.0 equiv.), tetrakis(dibenzylacetone)dipalladium (275 mg, 0.30 mmol, 0.1 equiv.), 2-dicyclohexylphospho-2′,4′,6′-triisopropylbiphenyl (143 mg, 0.30 mmol, 0.1 equiv.), and potassium carbonate (1.25 g, 9.09 mmol, 3.0 equiv.) were added to a toluene (50 mL) solution. The reaction system was stirred at 85 °C for 8 h under argon protection. TLC analysis showed that the reactants reacted completely. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography purification yielded target compounds 1-3, 640 mg of a yellow solid, in 53% yield. UPLC-MS m / z:calcd for C 22 H 18 Cl2NO2[M+H] + 400.08; found: 400.08.

[0209] Step 3:

[0210] Compounds 1-3 (600 mg, 1.50 mmol, 1.0 equiv.), compound A-2 (512 mg, 1.80 mmol, 1.2 equiv.) as starting materials, and K2CO3 (414 mg, 3.0 mmol, 2.0 equiv.) were added to DMF (15 mL) and reacted at 65 °C for 5 h with stirring. TLC analysis showed that the reaction proceeded completely. After rotary evaporation, the reactants were dissolved in water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the crude product was concentrated and purified by column chromatography to obtain the target compound 1-4 as a yellow solid (632 mg, yield 82%). UPLC-MS m / z: calcd for C 28 H 28 Cl2NO4[M+H] + 514.15; found: 514.40.

[0211] Step 4:

[0212] Compounds 1-4 (600 mg, 1.17 mmol, 1.0 equiv.) and cerium trichloride heptahydrate (870 mg, 2.34 mmol, 2.0 equiv.) were dissolved in 15 mL of acetonitrile and reacted at 80 °C for 8 h. After the reaction was completed by TLC, the mixture was extracted with ethyl acetate (3 × 25 mL), the organic phases were combined and washed with saturated brine, and then dried over anhydrous sodium sulfate. The mixture was distilled under reduced pressure to obtain the crude product, which was separated by Prep-HPLC to obtain the target compounds 1-5 as a yellow solid (388 mg, yield 70%). UPLC-MS m / z: calcd for C 25 H 25 Cl2NO4[M+H] + 474.12; found: 474.16.

[0213] Step 5:

[0214] Compounds 1-5 (500 mg, 1.05 mmol, 1.0 equiv.) and p-toluenesulfonyl chloride (241 mg, 1.29 mmol, 1.2 equiv.) and Et3N (212 mg, 2.10 mmol, 2.0 equiv.) were dissolved in DCM (30 mL) and reacted at room temperature for 3 h. TLC analysis showed that the reaction proceeded completely. After rotary evaporation, the reactants were dissolved in water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the crude product was concentrated and purified by column chromatography to give the target compounds 1-6 as a yellow solid (402 mg, yield 61%). UPLC-MS m / z: calcd for C 32 H 31 Cl2NO6S[M+H] + 628.12; found: 628.65.

[0215] Step 6:

[0216] Compounds 1-6 (300 mg, 0.48 mmol, 1.0 equiv.) and sodium azide (37 mg, 0.57 mmol, 1.2 equiv.) were dissolved in dimethyl sulfoxide solution (5 mL) and reacted at 40 °C with stirring for 5 h. TLC analysis showed the reaction proceeded completely. The solvent was evaporated to dryness, dissolved in water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the crude product was concentrated and purified by column chromatography to give target compounds 1-7 as 151 mg of white solid, with a yield of 63%. UPLC-MS m / z: calcd for C 25 H 26 Cl2N4O3[M+H] + 499.12; found: 500.99.

[0217] Step 7:

[0218] Compounds 1-7 (200 mg, 0.40 mmol, 1.0 equiv.) and triphenylphosphine (126 mg, 0.48 mmol, 1.2 equiv.) were dissolved in dimethyl sulfoxide solution and reacted overnight at 60 °C with stirring. TLC analysis showed the reactants reacted completely. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography purification yielded target compounds 1-8 as a yellow solid, 112 mg, in 60% yield. UPLC-MS m / z: calcd for C 25 H 26 Cl2N2O3[M+H] + 473.13; found: 473.30.

[0219] Step 8:

[0220] Compounds 1-8 (100 mg, 0.22 mmol, 1.0 equiv.) and methanesulfonyl chloride (30 mg, 0.26 mmol, 1.2 equiv.) and Et3N (44 mg, 0.44 mmol, 2 equiv.) were dissolved in DCM (30 mL) and reacted at room temperature for 1 h. TLC analysis showed that the reaction proceeded completely. After rotary evaporation, the reactants were dissolved in water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography purification yielded target compounds 1-9 as 75 mg of white solid, in a yield of 62%. UPLC-MS m / z: calcd for C 26 H 28 Cl2N2O5S[M+H] + 551.11; found: 552.01.

[0221] Step 9:

[0222] Compounds 1-9 (80 mg, 0.15 mmol, 1.0 equiv.) and 10% Pd / C (30.0 mg, 0.07 mmol, 0.1 equiv.) were added to MeOH (10 mL) and stirred at room temperature under hydrogen atmosphere for 1 h. TLC analysis confirmed complete consumption of the starting material. The solid was removed by filtration with diatomaceous earth, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to give target compounds 1-10, a white oily liquid, 55 mg, in 80% yield. UPLC-MS m / z: calcd for C 19 H 20 Cl2N2O5S[M+H] + 461.11; found: 461.22.

[0223] Step 10:

[0224] Using compounds 1-10 (50 mg, 0.15 mmol, 1.0 equiv.) and (R)-p-toluenesulfonic acid glycidyl ester (40 mg, 0.17 mmol, 1.2 equiv.) as starting materials, the target compound 1-11 was synthesized according to the method in step 3, yielding 55 mg of a colorless oily liquid in 71% yield. UPLC-MS m / z: calcd for C 22 H 26 Cl2N2O6S[M+H] + 517.09; found: 517.69.

[0225] Step 11:

[0226] Using compound 1-11 (20 mg, 0.04 mmol, 1.0 equiv.) and cerium trichloride heptahydrate (96 mg, 0.26 mmol, 2.0 equiv.) as raw materials, the target compound of Example 1 was obtained by following the synthesis method in step 4, yielding 9 mg of white solid with a yield of 42%.

[0227] Synthesis of Example 2

[0228]

[0229] Step 1:

[0230] Using compounds 1-3 (500 mg, 1.25 mmol, 1.0 equiv.) and 1-N-Boc-4-(4-methylbenzenesulfonyloxymethyl)piperidine (554 mg, 1.50 mmol, 1.2 equiv.) as starting materials, and following the synthetic method for compounds 1-4, target compound 2-2 was obtained, a white solid of 529 mg, in 71% yield. UPLC-MS m / z: calcd for C 33 H 39 Cl2N2O4[M+H] + 597.22; found: 597.28.

[0231] Step 2:

[0232] Compound 2-2 (500 mg, 0.83 mmol, 1.0 equiv.) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride (4 M, 3 mL) solution was added. The mixture was stirred at room temperature for 1 h. TLC analysis showed complete reaction of the starting material. After filtration, the solid was dissolved in water, and the pH was adjusted to 8-9 with ammonia. The solution was then extracted with dichloromethane, washed with saturated sodium chloride solution, and finally dried over anhydrous magnesium sulfate. The concentrate yielded the target compound 2-3 as a white solid (330 mg), with a yield of 81%. UPLC-MS m / z: calcd for C 28 H 31 Cl2N2O4[M+H] + 497.17; found: 497.17.

[0233] Step 3:

[0234] Using compounds 2-3 (400 mg, 0.80 mmol, 1.0 equiv.) and methanesulfonyl chloride (115 mg, 0.97 mmol, 1.2 equiv.) as starting materials, and following the synthetic method for compounds 1-9, target compound 2-4 was obtained as a white solid (323 mg, yield 70%). UPLC-MS m / z: calcd for C 29 H 33 Cl2N2O4S[M+H] + 576.15; found: 577.08.

[0235] Step 4:

[0236] Using compound 2-4 (300 mg, 0.52 mmol, 1.0 equiv.) as the starting material, and following the synthetic method of compound 1-10, target compound 2-5 was obtained. No purification was required, and it was directly used in the next reaction.

[0237] Step 5:

[0238] Using compounds 2-5 (300 mg, 0.60 mmol, 1.0 equiv.) and (R)-p-toluenesulfonic acid glycidyl ester (169 mg, 0.74 mmol, 1.2 equiv.) as starting materials, and following the synthetic method for compounds 1-11, target compound 2-6 was obtained as a white solid, 334 mg, in 71% yield. UPLC-MS m / z: calcd for C 25 H 31 Cl2N2O5S[M+H] + 541.48; found: 541.29.

[0239] Step 6:

[0240] Using compound A-53 (20 mg, 0.13 mmol, 1.0 equiv.) and cerium trichloride heptahydrate (96 mg, 0.26 mmol, 2.0 equiv.) as starting materials, the target compound was obtained by following the synthetic method of compounds 1-12. The result was 10 mg of white solid, with a yield of 42%.

[0241] Synthesis of Example 3

[0242] Replacing 1-N-Boc-4-(4-methylbenzenesulfonyloxymethyl)piperidine with 1-Boc-3-(methanesulfonyloxymethyl)azonylbutane in Example 2 yielded Example 3, 30 mg of yellow solid, 12% yield.

[0243] Synthesis of Example 4

[0244] In Example 2, 1-Boc-3-(methanesulfonyloxy)azacyclobutane was replaced with tert-butyl 4-(bromomethyl)benzylcarbamate to obtain the target compound in Example 4, 20 mg of brown solid, yield 21%.

[0245] Synthesis of Example 5

[0246]

[0247] Step 1:

[0248] The synthetic method followed the preparation of compounds 1-4, replacing 1-N-Boc-4-(4-methylbenzenesulfonyloxymethyl)piperidine with 4-chloromethyl-2-methylthiopyrimidine to obtain target compounds 5-2, 500 mg of yellow solid, in 73% yield. UPLC-MS m / z: calcd for C 28 H 25 Cl2N3O2S[M+H] + 538.10; found: 538.10.

[0249] Step 2:

[0250] Compound 5-2 (500 mg, 0.93 mmol, 1.0 equiv.) and m-CPBA (201 mg, 1.12 mmol, 1.2 equiv.) were dissolved in anhydrous DCM (15 mL) and reacted at room temperature for 3 h under argon protection. TLC analysis showed the reaction proceeded to completion. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography purification yielded the target compound 5-3 as a pale yellow solid (266 mg), with a yield of 61%. UPLC-MS m / z: calcd for C 28 H 26 Cl2N3O4S[M+H] +570.09; found: 570.23.

[0251] Step 3:

[0252] Compound 5-3 (100 mg, 0.17 mmol, 1.0 equiv.) and methanesulfonamide (30 mg, 0.26 mmol, 1.5 equiv.) were dissolved in anhydrous DMF (10 mL), and potassium carbonate (276 mg, 0.34 mmol, 2 equiv.) was added. The reaction was carried out at 65 °C for 5 h under argon protection. TLC analysis showed that the reaction proceeds were complete. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography purification yielded the target compound 5-4 as a pale yellow solid (41 mg, yield 42%). UPLC-MS m / z: calcd for C 28 H 27 Cl2N2O4S[M+H] + 585.32; found: 585.26.

[0253] Step 4:

[0254] Using compound 5-4 (60 mg, 0.10 mmol, 1.0 equiv.) as the starting material, the target compound 5-5 was obtained by following the synthetic method described in 1-10. No purification was required, and it was directly used in the next reaction.

[0255] Step 5:

[0256] Using compound 5-5 (30 mg, 0.05 mmol, 1.0 equiv.) as the starting material, and following the synthetic method described in 1-11, the target compound 5-6 was obtained as a white solid, 26 mg, in 71% yield. UPLC-MS m / z: calcd for C 28 H 27 Cl2N2O4S[M+H] + 551.08; found: 551.23.

[0257] Step 6:

[0258] Using compounds 5-6 (20 mg, 0.03 mmol, 1.0 equiv.) as starting material, the target compound was obtained by following the synthetic method in Example 1, yielding 9 mg of white solid in 42% yield.

[0259] Synthesis of Example 6

[0260]

[0261] Step 1:

[0262] Compound 6-1 (1.00 g, 4.87 mmol, 1.0 equiv.), I2 (1234 mg, 4.87 mmol, 1.0 equiv.), and Ag2SO4 (1514 mg, 4.87 mmol, 1.0 equiv.) were added to an ethanol solution (50 mL), and the mixture was reacted at room temperature for 3 h. TLC analysis showed that the reaction proceeded completely. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography purification yielded the target compound 6-2, a pale yellow solid, 1450 mg, with a yield of 92%.

[0263] Step 2:

[0264] Using compound 6-2 (1.00 g, 3.01 mmol, 1.0 equiv.) and benzyl bromide (623 mg, 3.60 mmol, 1.2 equiv.) as starting materials, the target compound 6-3 was obtained by following the synthetic method described in 1-2, yielding 1140 mg of yellow solid in 90% yield.

[0265] Step 3:

[0266] Compound 6-3 (1.00 g, 2.36 mmol, 1.0 equiv.) and cuprous cyanide (252 mg, 2.80 mmol, 1.2 equiv.) were added to an N-methylpyrrolidone solution (50 mL), and the reaction was carried out at 150 °C for 3 h. TLC analysis showed that the reaction proceeds were completely reacted. The reaction solution was quenched with ammonia, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography purification yielded the target compound 6-4, 226 mg of a white solid, in a yield of 30%.

[0267] Step 4:

[0268] Using compounds 6-4 (500 mg, 1.56 mmol, 1.0 equiv.) and 6-hydroxy-1,2,3,4-tetrahydroquinoline (234 mg, 1.56 mmol, 1.0 equiv.) as starting materials, and following the synthetic method described in 1-3, the target compound 6-5 was obtained as a yellow solid (323 mg), with a yield of 53%. UPLC-MS m / z: calcd for C 23 H 20 ClN2O2[M+H] + 391.11; found: 391.19.

[0269] Step 5:

[0270] Using compound 6-5 (500 mg, 1.27 mmol, 1.0 equiv.) as the starting material, the target compound 6-6 was synthesized according to the method described in 1-4, yielding 750 mg of a yellow solid in 70% yield. UPLC-MS m / z: calcd for C 34 H 39 ClN3O4[M+H] + 588.26; found: 588.65.

[0271] Steps 6 and 7:

[0272] Starting with compound 6-6 (500 mg, 1.21 mmol, 1.0 equiv.), and following the synthetic methods described in steps 2-3 and 2-4, the target compound 6-8 was obtained as a yellow solid (683 mg), with a two-step yield of 70%. UPLC-MS m / z: calcd for C 30 H 33 ClN3O4[M+H] + 566.18; found: 566.30.

[0273] Step 8:

[0274] Using compounds 6-8 (300 mg, 0.53 mmol, 1.0 equiv.) as starting material, and following the synthetic method described in 1-10, target compounds 6-9 were obtained as a yellow solid, 209 mg, in 83% yield. UPLC-MS m / z: calcd for C 30 H 33 ClN3O4[M+H] + 476.13; found: 476.12.

[0275] Step 9:

[0276] Using compounds 6-9 (300 mg, 0.60 mmol, 1.0 equiv.) as starting materials and (R)-p-toluenesulfonic acid glycidyl ester (169 mg, 0.74 mmol, 1.2 equiv.) as starting materials, the target compound 6-10 was obtained by following the synthetic method described in 1-11, yielding 264 mg of a white solid in 79% yield. UPLC-MS m / z: calcd for C 26 H 31 ClN3O5S[M+H] + 532.13; found: 532.63.

[0277] Step 10:

[0278] Using compounds 6-10 (50 mg, 0.09 mmol, 1.0 equiv.) and (R)-p-toluenesulfonic acid glycidyl ester (31 mg, 0.11 mmol, 1.2 equiv.) as starting materials, 22 mg of the target compound as a yellow solid was obtained by following the synthesis method in Example 2, with a yield of 42%.

[0279] Synthesis of Example 7

[0280]

[0281] Replacing 1-N-Boc-4-(4-methylbenzenesulfonyloxymethyl)piperidine with 1-Boc-3-(methanesulfonyloxymethyl)azacyclobutane in Example 6 yielded 6 mg of the target compound as a yellow solid, with a yield of 12%.

[0282] Synthesis of Example 8

[0283]

[0284] Using compounds 6-9 (50 mg, 0.12 mmol, 1.0 equiv.) and 1-bromo-3-chloropropane (37 mg, 0.24 mmol, 2 equiv.) as starting materials, 44 mg of the target compound as a yellow solid was obtained, with a yield of 66%.

[0285] Synthesis of Example 9

[0286]

[0287] Using compound 7-5 (54 mg, 0.12 mmol, 1.0 equiv.) and 1-bromo-3-chloropropane (37 mg, 0.24 mmol, 2 equiv.) as starting materials, 38 mg of the target compound as a yellow solid was obtained, with a yield of 61%.

[0288] Synthesis of Example 10

[0289]

[0290] Using compounds 6-9 (50 mg, 0.12 mmol, 1.0 equiv.) and 1-bromo-2-chloroethane (34 mg, 0.24 mmol, 2 equiv.) as starting materials, 41 mg of the target compound as a yellow solid was obtained, with a yield of 65%.

[0291] Synthesis of Example 11

[0292]

[0293] Using compound 7-5 (54 mg, 0.12 mmol, 1.0 equiv.) and 1-bromo-2-chloroethane (34 mg, 0.24 mmol, 2 equiv.) as starting materials, and following the synthetic method described in 1-11, 23 mg of the target compound as a yellow solid was obtained, with a yield of 38%.

[0294] Synthesis of Example 12

[0295] The synthesis method was based on the preparation in Example 5, using intermediate 6-5 as the starting material, replacing (R)-p-toluenesulfonic acid glycidyl ester with 1-bromo-2-chloroethane, to obtain 500 mg of the target compound as a yellow solid, with a yield of 73%.

[0296] Synthesis of Example 13

[0297]

[0298] The synthesis method was the same as in Example 6, except that benzyl bromo was replaced with 1-bromo-2-chloroethane in step 2 and methanesulfonyl chloride was replaced with morpholinesulfonyl chloride in step 7, yielding 20 mg of the target compound as a yellow solid with a yield of 76%.

[0299] Synthesis of Example 14

[0300]

[0301] Using compound 13-7 (50 mg, 0.11 mmol, 1.0 equiv.) and N-acetylglycine (14 mg, 0.12 mmol, 1.1 equiv.) as starting materials, EDCI (32 mg, 0.16 mmol, 1.5 equiv.), HOAt (23 mg, 0.16 mmol, 1.5 equiv.), and DIPEA (56 mg, 0.44 mmol, 4 equiv.) were added and dissolved in DMF (6 mL). The reaction was carried out at room temperature for 8 h. After the reaction was completed by TLC, the mixture was extracted with ethyl acetate (3 × 10 mL), the organic phases were combined and washed with saturated brine, and then dried over anhydrous sodium sulfate. The mixture was distilled under reduced pressure to obtain the crude product, which was separated by Prep-HPLC to obtain 37 mg of the target compound as a yellow solid, with a yield of 60%.

[0302] Synthesis of Example 15

[0303]

[0304] The synthesis method was the same as in Example 14, except that N-acetylglycine was replaced with N,N-dimethylglycine. The target compound was separated by Prep-HPLC and 32 mg of yellow solid was obtained, with a yield of 53%.

[0305] Synthesis of Example 16

[0306]

[0307] The synthesis method was the same as that in Example 14, except that N-acetylglycine was replaced with 1-methylimidazol-4-carboxylic acid. The target compound was separated by Prep-HPLC and 33 mg of yellow solid was obtained, with a yield of 53%.

[0308] Synthesis of Example 17

[0309]

[0310] The synthesis method was the same as that in Example 14, except that N-acetylglycine was replaced with (3-methylisoxazole-5-yl)acetic acid. The target compound was separated by Prep-HPLC and 27 mg of yellow solid was obtained, with a yield of 42%.

[0311] Synthesis of Example 18

[0312]

[0313] The synthesis method was the same as that in Example 14, except that N-acetylglycine was replaced with 2-methylcyclopropane-1-carboxylic acid. The target compound was separated by Prep-HPLC and 19 mg of yellow solid was obtained, with a yield of 32%.

[0314] Synthesis of Example 19

[0315]

[0316] The synthesis method was the same as that in Example 14, except that N-acetylglycine was replaced with 2-cyclopentane-1-carboxylic acid. The target compound was separated by Prep-HPLC and 21 mg of yellow solid was obtained, with a yield of 34%.

[0317] Synthesis of Example 20

[0318]

[0319] Compound 13-5 (50 mg, 0.14 mmol, 1.0 equiv.) and 2-chloromethyl-5-methyl-1,3,4-thiadiazole (31 mg, 0.21 mmol, 1.5 equiv.) were dissolved in DMF (6 mL), and cesium carbonate (90 mg, 0.28 mmol, 2 equiv.) was added. The reaction was carried out at 50 °C for 8 h. After the reaction was completed by TLC, the mixture was extracted with ethyl acetate (3 × 10 mL), the organic phases were combined and washed with saturated brine, and then dried over anhydrous sodium sulfate. The mixture was distilled under reduced pressure to obtain the crude product, which was separated by Prep-HPLC to obtain 37 mg of the target compound as a yellow solid, with a yield of 56%.

[0320] Synthesis of Example 21

[0321]

[0322] The synthesis method was the same as that in Example 20, except that 2-chloromethyl-5-methyl-1,3,4-thiadiazole was replaced with 5-tert-butyl-2-(chloromethyl)oxazole. The target compound was separated by Prep-HPLC to obtain 27 mg of yellow solid, with a yield of 39%.

[0323] Synthesis of Example 22

[0324]

[0325] The synthesis method was the same as that in Example 20, except that 2-chloromethyl-5-methyl-1,3,4-thiadiazole was replaced with 2-chloromethyl-5-methyl-1,3,4-thiadiazole. The target compound was separated by Prep-HPLC and 39 mg of yellow solid was obtained, with a yield of 62%.

[0326] Synthesis of Example 23

[0327] In Example 10, 1-N-Boc-4-(4-methylbenzenesulfonyloxymethyl)piperidine was replaced with tert-butyl 4-(bromomethyl)benzylcarbamate, yielding 26 mg of the target compound as a brown solid, with a yield of 39%.

[0328] Synthesis of Example 24

[0329] In Example 13, 1-N-Boc-4-(4-methylbenzenesulfonyloxymethyl)piperidine was replaced with tert-butyl 4-(bromomethyl)benzylcarbamate to obtain 30 mg of the target compound as a yellow solid, with a yield of 40%.

[0330] Synthesis of Example 25

[0331] Using compounds 1-10 (20 mg, 0.04 mmol, 1.0 equiv.) and methyl 2-(bromomethyl)acrylate (30 mg, 0.17 mmol, 1.2 equiv.) as starting materials, and following the synthetic method described in 1-11, 14 mg of the target compound as a white solid was obtained, with a yield of 65%.

[0332] Synthesis of Example 26

[0333] Using compounds 1-10 (20 mg, 0.04 mmol, 1.0 equiv.) and ethyl 4-bromocrotonate (33 mg, 0.17 mmol, 1.2 equiv.) as starting materials, and following the synthetic method described in 1-11, 15 mg of the target compound as a white solid was obtained, with a yield of 65%.

[0334] Synthesis of Example 27:

[0335] Using compounds 1-10 (20 mg, 0.04 mmol, 1.0 equiv.) and 2-bromoethyl methacrylate (33 mg, 0.17 mmol, 1.2 equiv.) as starting materials, and following the synthetic method described in 1-11, 15 mg of the target compound as a white solid was obtained, with a yield of 65%.

[0336] Synthesis of Example 28

[0337]

[0338] Example 25 (40 mg, 0.07 mmol, 1.0 equiv.) was dissolved in methanol (5 mL), and an aqueous solution of LiOH·H2O (5 mg, 0.21 mmol, 3.0 equiv.) (1 mL) was added. The reaction was carried out at room temperature for 1 h. TLC analysis showed that the starting material reacted completely. After evaporation to dryness, water was added to dissolve the product, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The concentrate, along with dimethylamine (5 mg, 0.07 mmol, 1.0 equiv.), EDCI (27 mg, 0.14 mmol, 2.0 equiv.), HOAt (20 mg, 0.14 mmol, 2.0 equiv.), and DIPEA (27 mg, 0.21 mmol, 3.0 equiv.), was dissolved in DMF (5 mL). The reaction was carried out at room temperature for 5 h under an argon atmosphere. TLC analysis showed that the reaction proceeded to completion. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Prep-HPLC separation yielded 25 mg of the target compound as a white solid, with a two-step yield of 63%.

[0339] Synthesis of Example 29

[0340] Using compounds 2-5 (20 mg, 0.04 mmol, 1.0 equiv.) and 2-bromoethyl methacrylate (10 mg, 0.05 mmol, 1.2 equiv.) as starting materials, and following the synthetic method described in 1-11, 17 mg of the target compound as a white solid was obtained, with a yield of 65%.

[0341] Synthesis of Example 30

[0342] Using compounds 2-5 (20 mg, 0.04 mmol, 1.0 equiv.) and ethyl 4-bromocrotonate (10 mg, 0.05 mmol, 1.2 equiv.) as starting materials, and following the synthetic method described in 1-11, 16 mg of the target compound as a white solid was obtained, with a yield of 64%.

[0343] Synthesis of Example 31

[0344] Using compounds 2-5 (20 mg, 0.04 mmol, 1.0 equiv.) and methyl 2-bromomethacrylate (10 mg, 0.05 mmol, 1.2 equiv.) as starting materials, and following the synthetic method described in 1-11, 17 mg of the target compound as a white solid was obtained, with a yield of 65%.

[0345] Synthesis of Example 32

[0346] The synthesis method was based on the preparation of Example 32, except that 1-N-Boc-4-(4-methylbenzenesulfonyloxymethyl)piperidine was replaced with 1-Boc-3-(methanesulfonyloxy)azacyclobutane to obtain the target compound of Example 32, 23 mg of yellow solid, yield 65%.

[0347] Synthesis of Example 33

[0348] The synthesis method was based on the preparation of compound in Example 30, replacing 1-N-Boc-4-(4-methylbenzenesulfonyloxymethyl)piperidine with 1-Boc-3-(methanesulfonyloxy)azacyclobutane to obtain 20 mg of the target compound as a yellow solid, with a yield of 65%.

[0349] Synthesis of Example 34

[0350] Using compounds 7-5 (20 mg, 0.04 mmol, 1.0 equiv.) and methyl 2-bromomethacrylate (9 mg, 0.05 mmol, 1.2 equiv.) as starting materials, and following the synthetic method described in 1-11, 13 mg of the target compound as a white solid was obtained, with a yield of 53%.

[0351] Synthesis of Example 35

[0352] Using compounds 7-5 (20 mg, 0.04 mmol, 1.0 equiv.) and ethyl 4-bromocrotonate (9 mg, 0.05 mmol, 1.2 equiv.) as starting materials, and following the synthetic method described in 1-11, 14 mg of the target compound as a white solid was obtained, with a yield of 56%.

[0353] Synthesis of Example 36

[0354] Using compound 7-5 (20 mg, 0.04 mmol, 1.0 equiv.) and 2-bromoethyl methacrylate (9 mg, 0.05 mmol, 1.2 equiv.) as starting materials, and following the synthetic method described in 1-11, 15 mg of the target compound as a white solid was obtained, with a yield of 60%.

[0355] Synthesis of Example 37

[0356]

[0357] Step 1:

[0358] Compound 4-(boc-amino)phenol (1.00 g, 4.78 mmol, 1.0 equiv.), benzyl bromide (981 mg, 5.74 mmol, 1.2 equiv.), and K₂CO₃ (1.32 mg, 9.56 mmol, 2.0 equiv.) were dissolved in DMF (10 mL) and reacted at 65 °C for 5 h with stirring. TLC analysis showed that the reaction proceeded completely. After rotary evaporation to dryness, the product was dissolved in water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography purification yielded the target compound 37-2 as a white solid, 1.29 g, with a yield of 90%. UPLC-MS m / z: calcd for C 18 H 20 NO3[M+H] + 300.38; found: 300.10.

[0359] Step 2:

[0360] Compound 37-2 (500 mg, 1.67 mL, 1.0 equiv.) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride (4 M, 3 mL) solution was added. The mixture was stirred at room temperature for 1 h. TLC analysis showed complete reaction of the starting material. After filtration, the solid was dissolved in water, and the pH was adjusted to 8-9 with ammonia. The solution was then extracted with dichloromethane, washed with saturated sodium chloride solution, and finally dried over anhydrous magnesium sulfate. The concentrate yielded the target compound 37-3 as a white solid (319 mg), with a yield of 95%. UPLC-MS m / z: calcd for C 13 H 12 NO[M+H] + 200.11; found: 200.09.

[0361] Step 3:

[0362] Compound 37-3 (300 mg, 1.51 mmol, 1.0 equiv.), p-hydroxybenzoic acid (208 mg, 1.51 mmol, 1.0 equiv.), EDCI (576 mg, 3.02 mmol, 2.0 equiv.), HOAt (652 mg, 3.02 mmol, 2.0 equiv.), and DIPEA (589 mg, 4.53 mmol, 3.0 equiv.) were dissolved in DMF (10 mL) and reacted at room temperature for 8 h under an argon atmosphere. After the reaction proceeded to completion as determined by TLC, a certain amount of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography purification yielded the target compound 37-4, a white solid of 347 mg, with a yield of 76%. UPLC-MS m / z: calcd for C 20 H 16 NO3[M+H] + 320.13; found: 320.09.

[0363] Step 4:

[0364] Compound 37-4 (300 mg, 0.94 mmol, 1.0 equiv.), compound A-2 (321 mg, 1.13 mmol, 1.2 equiv.), and K₂CO₃ (259 mg, 1.88 mmol, 2.0 equiv.) were dissolved in DMF (10 mL) and reacted at 65 °C for 5 h with stirring. TLC analysis showed that the reaction proceeded completely. After rotary evaporation, the reactants were dissolved in water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the crude product was concentrated and purified by column chromatography to give the target compound 37-5 as a colorless oily liquid (333 mg, yield 82%). UPLC-MS m / z: calcd for C 26 H 27 NO5[M+H] + 434.20; found: 434.28.

[0365] Step 5:

[0366] Compound 37-5 (300 mg, 0.69 mmol, 1.0 equiv.) and 10% Pd / C (30.0 mg, 0.07 mmol, 0.1 equiv.) were added to MeOH (10 mL), and stirred at room temperature for 1 h under hydrogen atmosphere. TLC analysis showed complete consumption of the starting material. The solid was removed by filtration with diatomaceous earth, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to give the target compound 37-6, a colorless oily liquid (195 mg), with a yield of 82%. UPLC-MS m / z: calcd for C 19 H21 NO5[M+H] + 344.15; found: 344.08.

[0367] The subsequent synthesis followed the steps in Example 1, and the target compound Example 37 was obtained by Prep-HPLC separation, yielding 50 mg of a colorless and transparent liquid.

[0368] Synthesis of Example 38

[0369]

[0370] Step 1:

[0371] Compounds 4-aminophenol (1.00 g, 9.17 mmol, 1.0 equiv.), DMAP (112 mg, 0.92 mmol, 0.10 equiv.), TBSCl (2.06 g, 13.76 mmol, 1.5 equiv.), and imidazole (1.25 g, 18.35 mmol, 2.0 equiv.) were dissolved in DCM (30 mL) and reacted at room temperature for 1 h. TLC analysis showed the reaction proceeded completely. After rotary evaporation, the product was dissolved in water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography purification yielded the target compound 38-2 as a white solid, 1.64 g, in 80% yield. UPLC-MS m / z: calcd for C 12 H 21 NOSi[M+H] + 224.15; found: 224.15.

[0372] Step 2:

[0373] Compound 38-2 (500 mg, 2.24 mmol, 1.0 equiv.), 4-(benzyloxy)benzene-1-sulfonyl chloride (632 mg, 2.24 mmol, 1.0 equiv.), DMAP (26 mg, 0.22 mmol, 0.10 equiv.), and triethylamine (678 mg, 6.72 mmol, 3.0 equiv.) were dissolved in DCM (30 mL) and reacted at room temperature for 3 h. TLC analysis showed that the reaction proceeded completely. After rotary evaporation to dryness, the product was dissolved in water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography purification yielded the target compound 38-3 as a white solid (839 mg), with a yield of 80%. UPLC-MS m / z: calcd for C 25 H 31 NO4SSi[M+H] + 470.68; found: 470.22.

[0374] Step 3:

[0375] Compound 38-3 (500 mg, 1.07 mmol, 1.0 equiv.) was dissolved in THF (10 mL), and a tetrahydrofuran solution of TBAF (0.8 mL, 4 mmol / mL) was slowly added at room temperature. The reaction proceeded for 0.5 h. TLC analysis showed that the reaction proceeded completely. After rotary evaporation, the product was dissolved in water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give crude product 38-4, a pale yellow oily liquid, 265 mg, yield 70%. UPLC-MS m / z: calcd for C 19 H 17 NO4S[M+H] + 356.10; found: 356.12.

[0376] The subsequent synthesis followed the relevant steps in Example 1, and the target compound Example 38 was obtained by Prep-HPLC separation, 51 mg of colorless oily liquid.

[0377] Synthesis of Example 39

[0378]

[0379] Step 1:

[0380] Phenol (500 mg, 5.32 mmol, 2.0 equiv.) and cyclohexanone (260 mg, 2.65 mmol, 1.0 equiv.) were dissolved in a mixed solution of HCl and glacial acetic acid (1:1, 10 mL). One drop of 3-mercaptopropionic acid was added, and the mixture was refluxed at 70 °C for 5 h. TLC analysis showed that the reaction proceeded completely. The mixture was slowly neutralized with NaOH at 0 °C, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography purification yielded the target compound 39-2 as a white solid (1.11 g), with a yield of 78%. UPLC-MS m / z: calcd for C 18 H 20 O2[M+H] + 269.36; found: 175.01.

[0381] The subsequent synthesis followed the relevant steps in Example 1, and the target compound Example 39 was obtained by Prep-HPLC separation, 34 mg of colorless oily liquid.

[0382] Synthesis of Example 40

[0383] Following the synthesis described in Example 39, cyclohexanone was replaced with cyclopentanone (223 mg, 2.65 mmol, 1.0 equiv.). The target compound, Example 40, was obtained by Prep-HPLC separation as 20 mg of a colorless oily liquid.

[0384] Synthesis of Example 41

[0385] Following the synthesis described in Example 39, cyclohexanone was replaced with piperidinone (220 mg, 2.65 mmol, 1.0 equiv.). The target compound, Example 41, was obtained by Prep-HPLC separation as 15 mg of a colorless oily liquid.

[0386] Synthesis of Example 42

[0387]

[0388] Compound 41 (20 mg, 0.04 mL, 1.0 equiv.) from Example 41 was dissolved in dichloromethane (10 mL), and dioxane hydrochloride (4 M, 0.5 mL) solution was added. The mixture was stirred at room temperature for 1 h. TLC analysis showed that the reaction proceeded completely. Compound 42 (Example 42) was obtained by Prep-HPLC separation, yielding 15 mg of a colorless oily liquid, with a yield of 95%.

[0389] Synthesis of Example 43

[0390] Following the synthesis described in Example 39, cyclohexanone was replaced with 1-isopropyl-4-piperidinone. The target compound, Example 43, was obtained by Prep-HPLC separation, yielding 16 mg of a white solid.

[0391] Synthesis of Example 44

[0392] Following the synthesis described in Example 39, cyclohexanone was replaced with N-methyl-4-piperidinone. The target compound, Example 44, was obtained by Prep-HPLC separation, yielding 23 mg of a colorless oily liquid.

[0393] Synthesis of Example 45

[0394]

[0395] Step 1:

[0396] 2,6-Dibromopyridine (1.00 g, 4.27 mmol, 1.0 equiv.), p-hydroxyphenylboronic acid (1.78 g, 12.81 mmol, 3.0 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (936 mg, 1.28 mmol, 0.1 equiv.), and cesium carbonate (10.41 g, 30.02 mmol, 2.5 equiv.) were added to a tetrahydrofuran (50 mL) solution. The reaction mixture was stirred overnight at 75 °C under argon protection. TLC analysis showed that the reactants reacted completely. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the crude product was concentrated and purified by column chromatography to give the target compound 45-2 as a pale yellow solid (468 mg, yield 43%). UPLC-MS m / z: calcd for C 17 H 13 NO2[M+H] + 264.10; found: 264.11.

[0397] Step 2:

[0398] Using compound 45-2 (1.00 g, 3.80 mmol, 1.0 equiv.) and 4-chloromethyl-2-methylthiopyrimidine (793 mg, 4.56 mmol, 1.2 equiv.) as starting materials, the target compound 45-3 was obtained by following the synthetic method of 5-2, yielding 1173 mg of a yellow solid in 78% yield. UPLC-MS m / z: calcd for C 23 H 20 N3O2S[M+H] + 402.12; found: 402.23.

[0399] The subsequent synthesis followed the steps in Example 5, and the target compound Example 45 was obtained by Prep-HPLC separation, yielding 13 mg of yellow solid, with a yield of 70%.

[0400] Synthesis of Example 46

[0401]

[0402] Following the relevant synthesis steps in Examples 2 and 45, the target compound of Example 46 was obtained by Prep-HPLC separation, yielding 86 mg of white solid and a yield of 85%.

[0403] Synthesis of Example 47

[0404]

[0405] Step 1:

[0406] Using compound 45-1 (1.00 g, 4.27 mmol, 1.0 equiv.) and p-hydroxyphenylboronic acid (884 g, 6.40 mmol, 1.5 equiv.) as starting materials, and following the synthetic method for 45-2, the target compound 47-1 was obtained as a yellow solid (428 mg), with a yield of 40%. UPLC-MS m / z: calcd for C 11 H9BrNO[M+H] + 251.10; found: 251.32.

[0407] Step 2:

[0408] Using compound 47-2 (1.00 g, 3.02 mmol, 1.0 equiv.) and 1-bromo-2-chloroethane (511 mg, 3.63 mmol, 1.2 equiv.) as starting materials, the target compound 47-3 was obtained by following the synthetic method of Example 10, yielding 1.07 g of a yellow solid in 90% yield.

[0409] Step 3:

[0410] Using compound 47-3 (1.00 g, 2.52 mmol, 1.0 equiv.) and cuprous cyanide (271 mg, 3.05 mmol, 1.2 equiv.) as starting materials, the target compound 47-4 was obtained by following the synthetic method described in 5-4, yielding 219 mg of white solid in 30% yield.

[0411] Step 4:

[0412] Compound 47-4 (500 mg, 1.46 mmol, 1.0 equiv.), bis(pinacol)diboron (557 g, 2.20 mmol, 1.5 equiv.), potassium acetate (1.16 g, 5.84 mmol, 4.0 equiv.), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (109 mg, 0.15 mmol, 0.1 equiv.) were added to a tetrahydrofuran (150 mL) solution. The reaction mixture was stirred overnight at 75 °C under argon protection. TLC analysis showed that the reactants reacted completely. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography purification yielded the target compound 47-5, 154 mg of white solid, in a yield of 33%.

[0413] Step 5:

[0414] Using compounds 47-5 (800 mg, 2.34 mmol, 1.0 equiv.) and 47-1 (585 mg, 2.34 mmol, 1.0 equiv.) as starting materials, and following the synthetic method of 48-2, the target compound 47-6 was obtained, yielding 490 mg of a yellow solid in a yield of 42%.

[0415] The subsequent steps were the same as those in Example 6. The target compound, Example 47, was obtained by Prep-HPLC separation, yielding 40 mg of a yellow solid.

[0416] Synthesis of Example 48

[0417]

[0418] Following the relevant synthesis steps in Example 5, the target compound Example 48 was obtained by Prep-HPLC separation, yielding 10 mg of a yellow solid.

[0419] Synthesis of Example 49

[0420]

[0421] Step 1:

[0422] 4-Amino-2,6-dichlorophenol (300 mg, 1.68 mmol, 1.0 equiv.), sodium azide (130 mg, 2.02 mmol, 1.2 equiv.), and sodium nitrite (140 mg, 2.02 mmol, 1.2 equiv.) were added to a mixed solution of hydrochloric acid and water (1:2). The mixture was stirred at room temperature for 2 h. The reaction was confirmed by TLC to be complete. The pH was adjusted to 8-9 with ammonia. The mixture was extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to give the target compound 49-2 as a white solid of 271 mg, with a yield of 80%.

[0423] Step 2:

[0424] Using compound 49-2 (200 mg, 0.99 mmol, 1.0 equiv.) and 1-bromo-2-chloroethane (169 mg, 1.18 mmol, 1.2 equiv.) as starting materials, the target compound 49-3 was obtained by the synthetic method of Example 8, yielding 235 mg of a yellow solid in 90% yield.

[0425] Steps 3-5 follow the relevant synthesis steps in Example 5, yielding 49-7, a white solid, 143 mg, after three steps of reaction. UPLC-MS m / z: calcd for C 14 H 13 N3O3S[M+H] + 304.07; found: 304.12.

[0426] Step 6:

[0427] Compound 49-7 (50 mg, 0.16 mmol, 1.0 equiv.), compound 49-3 (43 mg, 0.16 mmol, 1.0 equiv.), cuprous iodide (30 mg, 0.16 mmol, 1.0 equiv.), and DIPEA (62 mg, 0.48 mmol, 3.0 equiv.) were added to a tetrahydrofuran (10 mL) solution and reacted overnight at 70 °C. TLC analysis showed the reactants were completely reacted. The organic phase was removed, and the aqueous phase was extracted with dichloromethane. The organic phases were then combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Prep-HPLC separation yielded the target compound (Example 49), 54 mg of white solid, in a 60% yield.

[0428] Synthesis of Example 50

[0429]

[0430] Using compound 46 (50 mg, 0.11 mmol, 1.0 equiv.) and methanesulfonyl chloride (25 mg, 0.22 mmol, 2.0 equiv.) as starting materials, and following the synthesis methods described in 2-4 of Example 2, the target compound Example 50 was obtained, yielding 40 mg of a white solid in a yield of 70%.

[0431] Synthesis of Example 51

[0432] Following the synthesis of Examples 13 and 50, the target compound Example 51 was obtained by Prep-HPLC separation, yielding 12 mg of a white solid.

[0433] Synthesis of Example 52

[0434] Following the synthesis of Examples 14 and 50, the target compound of Example 52 was obtained by Prep-HPLC separation, yielding 15 mg of a white solid.

[0435] Synthesis of Example 53

[0436] Following the synthesis of Examples 15 and 50, the target compound of Example 53 was obtained by Prep-HPLC separation, yielding 20 mg of a white solid.

[0437] Synthesis of Example 54

[0438] Referring to the synthesis of compound Example 1, 6-hydroxy-1,2,3,4-tetrahydroisoquinoline was substituted for 6-hydroxy-1,2,3,4-tetrahydroquinoline to obtain the target compound Example 54, 10 mg of a colorless oily liquid.

[0439] Analysis of the inhibitory activity of the compound in Example 1 against prostate tumor cell proliferation

[0440] Both LNCaP and 22Rv1 prostate tumor cells were cultured in RPMI 1640 medium with 10% FBS. Cells in the exponential growth phase were collected on the day of the experiment. LNCaP cells were adjusted to the appropriate cell concentration and plated in RPMI 1640 medium containing 1% carbon-adsorbed serum (CSS). 22Rv1 cells were adjusted to the appropriate cell concentration and plated in RPMI 1640 medium containing 10% FBS. For LNCaP cells, different concentrations of the compound were added to the appropriate medium containing R1881 after 48 hours of culture. For 22Rv1 cells, different concentrations of the compound were added to the medium after overnight culture. Both cell types were cultured for another 5 days. After culture, the medium was removed, and the cells were cultured according to CellTiter-LumiGenius assay. TM Instructions for use of the chemiluminescence cell viability assay kit (Beyotime, C0065): Add culture medium and assay reagent to each well at a 1:1 ratio, shake, and incubate at room temperature until the luminescence signal stabilizes. Then, perform chemiluminescence detection using a multi-functional microplate reader with chemiluminescence detection capabilities. The results are processed according to formula (1), and the inhibition rate of each compound concentration is calculated. Using Prism 8 software, the IC50 value for a 50% inhibition rate of the compound is calculated. 50 value.

[0441] Inhibition rate (%) = (1 - Chemiluminescence value of experimental group / Chemiluminescence value of control group) × 100% Equation (1).

[0442] The results of prostate tumor cell proliferation inhibition are shown in Table 2. The compounds in the examples exhibited certain inhibitory activity against castration-resistant prostate cancer cell proliferation (ND indicates not measured).

[0443] Table 2. Inhibitory effects of the compounds of this invention on tumor cell growth.

[0444]

[0445]

[0446] Evaluation of AR-reporter inhibitory activity of compounds in Example 2

[0447] Human embryonic kidney cells (293T) were cultured in DMEM (high glucose) + 10% FBS. Cells in the exponential growth phase were collected on the day of the experiment. 293T cells were seeded in medium containing 10% FBS; transfection was performed within 24 hours of seeding, with a cell density of approximately 60-80%. Before transfection, the medium was changed to serum-free and antibiotic-free basal medium; AR plasmid or AR-V7 plasmid and Reporter plasmid were transfected using PEI transfection reagent.

[0448] ① Tube A: Add the plasmid to the serum-free culture medium;

[0449] ② Tube B: Add PEI reagent to serum-free culture medium and let stand at room temperature;

[0450] ③ Add the liquid from tube B to tube A, mix well, incubate at room temperature, and then add to the culture plate;

[0451] ④ Replace with normal complete culture medium after 4-6 hours.

[0452] 24 hours after transfection, cells were plated in DMEM (high glucose) medium containing 1% carbon-adsorbed serum (CSS). After 4-5 hours of plated culture, different concentrations of the compound were added, along with 1 nM R1881. Cells were incubated for another 24 hours, then the medium was removed. Following the instructions of the Luciferase Assay System kit, prepared lysis buffer was added to each well, and cells were lysed on a shaker. Luciferase assay reagent (LAR) was added to each well, and chemiluminescence detection was immediately performed using a multi-mode microplate reader with chemiluminescence detection capabilities.

[0453] The results were processed according to equation (2), and the PSA luciferase activity of the compound at various concentrations was calculated. Then, using Prism 8 software, the IC50 value for a luciferase activity inhibition rate of 50% was calculated. 50 value.

[0454] Inhibition rate (%) = (1 - Chemiluminescence value of experimental group / Chemiluminescence value of control group) × 100% Equation (2).

[0455] Results for 293T cell AR Reporter and AR-V7 Reporter are shown in Table 3. The compounds in the examples exhibited some PSA luciferase activity inhibitory activity (ND indicates not measured).

[0456] Table 3. Inhibitory effect of the compounds of this invention on AR-reporter

[0457]

[0458] Pharmacokinetic study of the compound in mice in Example 3.

[0459] Six male ICR mice were randomly divided into two groups. The compounds from the examples were dissolved in the appropriate solvents and administered via oral gavage (po) or intravenous injection (iv) into the tail vein, respectively. In the intravenous injection group, blood was collected from the orbital venous plexus at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. In the oral gavage group, blood was collected from the orbital venous plexus at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The blood samples were placed in tubes containing EDTA-2K, incubated on moist ice, centrifuged, and the plasma was separated and stored for analysis. The concentration of the compounds from the examples in the plasma samples at each time point was determined by LC-MS / MS, and pharmacokinetic parameters were calculated using WinNolin software. (Including T...) max (Peak time), C max (peak concentration), t 1 / 2 (Elimination half-life), AUC (area under the plasma concentration-time curve), and other parameters. Absolute bioavailability is calculated according to equation (3), where Dose i.v. The dosage for the tail vein injection group, Dose p.o. The dosage for the gavage administration group; AUC iv(0-∞) The area under the plasma concentration-time curve (AUC) for the tail vein injection group is given. oral(0-∞) The area under the blood drug concentration-time curve for the gavage administration group is denoted as 1.

[0460] F(%) = (Dose) i.v. ×AUC p.o.(0-∞) ) / (Dose p.o. ×AUC i.v.(0-∞) )×100%.

[0461] The pharmacokinetic data of some of the compounds in animals are shown in Table 4. The compounds exhibit good in vivo half-life and certain oral bioavailability.

[0462] Table 4. Pharmacokinetic parameters of the compounds of the present invention in mouse plasma.

[0463]

Claims

1. A compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or a prodrug thereof: the structure of said compound is shown in formula (I): in, The A is selected from 5 to 15 aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein each heteroaryl or heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O or S; The B is selected from 5 to 15 aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein each heteroaryl or heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O or S; The C is selected from C. 1-6 Alkyl, C 2-6 Alkenyl, 3 to 10 aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein each of the heteroaryl or heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O or S; X is selected from non-existent, C 1-6 Alkyl, -O-, -C(=O)NH-, -SO2NH-, -NR 4 3 to 10 aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein -NR 4 R in 4 Selected from C 1-6 Alkyl or C 2-6 The alkyl group is further substituted with one or more substituents selected from hydroxyl, halogen, or -CF3, and each of the heteroaryl or heterocyclic alkyl groups contains one to three heteroatoms selected from N, O, or S, and the alkyl group is substituted with one or more substituents selected from hydroxyl, halogen, or C. 1-6 Alkyl or C 3-8 Substituents of heterocyclic alkyl groups; The Y is selected from -CH2-, -NH-, -O- or -C(=O)-; The W is selected from -CH2-, -CH2CH2-, -NH-, -O- or -C(=O)-; The Z is selected from -CH2-, -NH-, -O- or -C(=O)-; The V is selected from C. 1-6 Alkyl or -NH-; The L is selected from C 1-6 Alkyl or C 2-6 Alkenyl group, wherein the alkyl group is further surrounded by one or more elements selected from hydroxyl, halogen, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-OC(=O)C 1-6 Alkyl group, -OC (=O)C 1-6 alkenyl or -C(=O)OC 1-6 Alkyl substituents; The R 1 R 2 Each is independently selected from hydrogen, halogen, cyano, -CF3, or hydroxyl; The R 3 Selected from amino, hydroxyl, halogen, -C(=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 3-8 Cycloalkyl, -C(=O)C 3-8 Heterocyclic alkyl, -C(=O)C 6-10 Aryl, -C(=O)C 5-10 heteroaryl, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 Heterocyclic alkyl groups, -SO2C 6-10 Aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 Alkyl group, -SO2N(C) 1-6 Alkyl)2、-NHSO2C 1-6 Alkyl group, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 Heterocyclic alkyl groups, -NHSO2C 6-10 Aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 Alkyl group, -NHSO2N(C 1-6 alkyl)2、-CH2NHSO2C 1-6 Alkyl group, -CH2NHSO2C 3-8 cycloalkyl, -CH2NHSO2C 6-10 Aryl, -CH2NHSO2C 5-10 heteroaryl, -CH2NHSO2NHC 1-6 Alkyl or -CH2NHSO2N(C 1-6 Alkyl group 2, wherein each of the heteroaryl or heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O or S, and the alkyl, amino, heterocycloalkyl, cycloalkyl, aryl, heteroaryl group is further surrounded by one or more atoms selected from deuterium, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 cycloalkyl, C 5-10 heteroaryl or -SO2C 1-6 Substituents of alkyl groups; The R 4 Selected from C 1-6 Alkyl or C 2-6 The alkyl group, wherein the alkyl group is further substituted by one or more substituents selected from hydroxyl, halogen or -CF3; The n1, n2, and n3 are each independently selected from 0, 1, 2, or 3.

2. The compound of claim 1, in one embodiment of the present invention, has the structural formula shown in formula (IIa): in, X is selected from -O-, -C(=O)NH-, -SO2NH-, and -NR. 4 Or C 1-6 Alkyl group, the -NR 4 R in 4 Selected from C 1-6 Alkyl group, further substituted with one or more substituents selected from hydroxyl, halogen, or -CF3, wherein the C 1-6 The alkyl group is further divided by one or more C16 atoms. 1-6 Alkyl or C 3-8 Substituents of heterocyclic alkyl groups; The C is selected from C. 1-6 Alkyl, 3 to 10 aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein each of the heteroaryl or heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O or S; The Y is selected from -NH-, -O-, or -C(=O)-; The W is selected from -CH2-, -NH-, or -C(=O)-; Z is selected from -NH-, -O-, or -C(=O)-; The V is selected from -CH2- or -NH-; The L is selected from C 1-6 Alkyl group, wherein the alkyl group is optionally further substituted with one or more substituents selected from hydroxyl or halogen; The R 1 R 2 Each is independently selected from hydrogen, halogen, cyano, or -CF3; The R 3 Selected from amino, hydroxyl, halogen, -C(=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 3-8 Cycloalkyl, -C(=O)C 3-8 Heterocyclic alkyl, -C(=O)C 6-10 Aryl, -C(=O)C 5-10 heteroaryl, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 Heterocyclic alkyl groups, -SO2C 6-10 Aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 Alkyl group, -SO2N(C) 1-6 Alkyl)2、-NHSO2C 1-6 Alkyl group, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 Heterocyclic alkyl groups, -NHSO2C 6-10 Aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 Alkyl or NHSO2N(C 1-6 Alkyl group 2, wherein each of the heterocyclic alkyl or heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S, and the alkyl, amino, heterocyclic alkyl, cycloalkyl, aryl, or heteroaryl group is further surrounded by one or more atoms selected from deuterium, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 cycloalkyl, C 5-10 heteroaryl or -SO2C 1-6 Substituents of alkyl groups; The n1, n2, and n3 are each independently selected from 0, 1, or 2.

3. The compound of claim 1, in one embodiment of the present invention, has the structural formula shown in formula (IIb): in, X is an aryl or aromatic heterol group, which is selected from... E1, E2, E3, and E4 are each independently selected from C or N, and G1, G2, G3, G4, and G5 are each independently selected from C, O, or N. The C is selected from C. 1-6 Alkyl, 3 to 10 aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein each of the heteroaryl or heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O or S; The Y is selected from -NH-, -O-, or -C(=O)-; The W is selected from -CH2-, -NH-, or -C(=O)-; Z is selected from -NH-, -O-, or -C(=O)-; The V is selected from -CH2- or -NH-; The L is selected from C 1-6 Alkyl or C 2-6 Alkenyl group, wherein the alkyl group is further surrounded by one or more elements selected from hydroxyl, halogen, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-OC(=O)C 1-6 Alkyl group, -OC (=O)C 1-6 alkenyl or -C(=O)OC 1-6 Alkyl substituents; The R 1 R 2 Each is independently selected from hydrogen, halogen, cyano, -CF3, or hydroxyl; The R 3 Selected from amino, hydroxyl, halogen, -C(=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 3-8 Cycloalkyl, -C(=O)C 3-8 Heterocyclic alkyl, -C(=O)C 6-10 Aryl, -C(=O)C 5-10 heteroaryl, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 Heterocyclic alkyl groups, -SO2C 6-10 Aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 Alkyl group, -SO2N(C) 1-6 Alkyl)2、-NHSO2C 1-6 Alkyl group, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 Heterocyclic alkyl groups, -NHSO2C 6-10 Aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 Alkyl or -NHSO2N(C 1-6 Alkyl)2, wherein each of the heterocyclic alkyl or heteroaryl groups contains 1 to 3 heteroatoms selected from N, O, or S, and the alkyl, amino, heterocyclic alkyl, cycloalkyl, aryl, or heteroaryl group is optionally further surrounded by one or more atoms selected from deuterium, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 cycloalkyl, C 5-10 heteroaryl or -SO2C 1-6 Substituents of alkyl groups; The n1, n2, and n3 are each independently selected from 0, 1, or 2.

4. The compound of claim 1, in one embodiment of the present invention, has the structural formula shown in formula (IIc): in, The A is selected from A1 is selected from aryl or aryl heteroyl, A2 is selected from aryl, heteroaryl, cycloalkyl or heterocycloalkyl, E1, E2, E3, E4 and E5 are each independently selected from C or N, and G1, G2, G3 and G4 are each independently selected from C, O, N or -C=O. The C is selected from C. 1-6 Alkyl, 3 to 10 aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein each of the heteroaryl or heterocycloalkyl groups contains 1 to 3 heteroatoms selected from N, O, or S, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, 3 to 10 aryl, heteroaryl, cycloalkyl, heterocycloalkyl further being selected from one or more amino, hydroxyl, halogen, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 alkyl)2 or -SO2C 1-6 Alkyl substituents; The Y is selected from -NH-, -O-, or -C(=O)-; The W is selected from -CH2-, -NH-, or -C(=O)-; Z is selected from -NH-, -O-, or -C(=O)-; The V is selected from -CH2- or -NH-; The L is selected from C 1-6 Alkyl or C 2-6 Alkenyl group, wherein the alkyl group is further surrounded by one or more elements selected from hydroxyl, halogen, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-OC(=O)C 1-6 Alkyl group, -OC (=O)C 1-6 alkenyl or -C(=O)OC 1-6 Alkyl substituents; The R 1 R 2 Each is independently selected from hydrogen, halogen, cyano, -CF3, or hydroxyl; The R 3 Selected from amino, hydroxyl, halogen, -C(=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 3-8 Cycloalkyl, -C(=O)C 3-8 Heterocyclic alkyl, -C(=O)C 6-10 Aryl, -C(=O)C 5-10 heteroaryl, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 Heterocyclic alkyl groups, -SO2C 6-10 Aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 Alkyl group, -SO2N(C) 1-6 Alkyl)2、-NHSO2C 1-6 Alkyl group, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 Heterocyclic alkyl groups, -NHSO2C 6-10 Aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 Alkyl group, -NHSO2N(C 1-6 alkyl)2、-CH2NHSO2C 1-6 Alkyl group, -CH2NHSO2C 3-8 cycloalkyl, -CH2NHSO2C 3-8 Heterocyclic alkyl, -CH2NHSO2C 6-10 Aryl, -CH2NHSO2C 5-10 heteroaryl, -CH2NHSO2NHC 1-6 Alkyl or -CH2NHSO2N(C 1-6 Alkyl group 2, wherein each of the heterocyclic alkyl group or heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S, and the alkyl, amino, heterocyclic alkyl, cycloalkyl, aryl, or heteroaryl group is further surrounded by one or more atoms selected from deuterium, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 cycloalkyl, C 5-10 heteroaryl or -SO2C 1-6 Substituents of alkyl groups; The n1, n2, and n3 are each independently selected from 0, 1, or 2.

5. The compound according to any one of claims 1-4, in one embodiment of the present invention, the compound structure shown in formula (I) or (IIa) can also be as shown in formula (IIIa): in, X is selected from -C(=O)NH-, -SO2NH-, or C 1-6 Alkyl group, wherein the alkyl group is further composed of one or more C14 atoms. 1-6 Alkyl or C 3-8 Substituents of heterocyclic alkyl groups; X is selected from The C is selected from C. 1-6 alkyl; The L is selected from C 1-6 Alkyl group, wherein the alkyl group is further substituted with one or more substituents selected from hydroxyl or halogen; The R 1 R 2 Each is independently selected from hydrogen, halogen, cyano, or -CF3; The R 3 It is a hydroxyl group; The n1, n2, and n3 are each independently selected from 0, 1, or 2.

6. The compound according to any one of claims 1-4, in one embodiment of the present invention, the compound structure shown in formula (I) or (IIb) may also be as shown in formula (IIIb): in, X is selected from The C is selected from 3 to 10 aryl, heteroaryl, cycloalkyl or heterocycloalkyl, and each of the heteroaryl or heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O or S; The L is selected from C 1-6 Alkyl or C 2-6 Alkenyl group, wherein the alkyl group is further surrounded by one or more elements selected from hydroxyl, halogen, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-OC(=O)C 1-6 Alkyl group, -OC (=O)C 1-6 alkenyl or -C(=O)OC 1-6 Alkyl substituents; The R 1 R 2 Each is independently selected from hydrogen, halogen, cyano, or -CF3; The R 3 Selected from -SO2C 1-6 Alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 Heterocyclic alkyl groups, -SO2C 6-10 Aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 Alkyl group, -SO2N(C) 1-6 Alkyl)2、-NHSO2C 1-6 Alkyl group, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 Heterocyclic alkyl groups, -NHSO2C 6-10 Aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 Alkyl or -NHSO2N(C 1-6 Alkyl group 2, wherein each of the heterocyclic alkyl or heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S, and the alkyl, amino, heterocyclic alkyl, cycloalkyl, aryl, or heteroaryl group is further surrounded by one or more atoms selected from deuterium, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkyl groups or -SO2C 1-6 Substituents of alkyl groups; The n1, n2, and n3 are each independently selected from 0, 1, or 2.

7. The compound according to any one of claims 1-4, in one embodiment of the present invention, the compound structure shown in formula (I) or (IIc) may also be as shown in formula (IIIc): in, The A is selected from The C is selected from 3 to 10 aryl, heteroaryl, cycloalkyl or heterocycloalkyl, and each of the heteroaryl or heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O or S; The Y is selected from -NH-, -O-, or -C(=O)-; The W is selected from -CH2-, -NH-, or -C(=O)-; Z is selected from -NH-, -O-, or -C(=O)-; The V is selected from -CH2- or -NH-; The L is selected from C 1-6 Alkyl or C 2-6 Alkenyl group, wherein the alkyl group is further surrounded by one or more elements selected from hydroxyl, halogen, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-OC(=O)C 1-6 Alkyl group, -OC (=O)C 1-6 alkenyl or -C(=O)OC 1-6 Alkyl substituents; The R 1 R 2 Each is independently selected from hydrogen, halogen, and cyano groups; The R 3 Selected from amino, hydroxyl, halogen, -C(=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 3-8 Cycloalkyl, -C(=O)C 3-8 Heterocyclic alkyl, -C(=O)C 6-10 Aryl, -C(=O)C 5-10 heteroaryl, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2、-NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 Heterocyclic alkyl groups, -SO2C 6-10 Aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 Alkyl group, -SO2N(C) 1-6 Alkyl)2、-NHSO2C 1-6 Alkyl group, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 Heterocyclic alkyl groups, -NHSO2C 6-10 Aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 Alkyl group, -NHSO2N(C 1-6 alkyl)2、-CH2NHSO2C 1-6 Alkyl group, -CH2NHSO2C 3-8 cycloalkyl, -CH2NHSO2C 3-8 Heterocyclic alkyl, -CH2NHSO2C 6-10 Aryl, -CH2NHSO2C 5-10 heteroaryl, -CH2NHSO2NHC 1-6 Alkyl or -CH2NHSO2N(C 1-6 Alkyl group 2, wherein each of the heterocyclic alkyl or heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S, and the alkyl, amino, heterocyclic alkyl, cycloalkyl, aryl, or heteroaryl group is further surrounded by one or more atoms selected from deuterium, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 cycloalkyl, C 5-10 heteroaryl or -SO2C 1-6 Substituents of alkyl groups; The n1, n2, and n3 are each independently selected from 0, 1, or 2.

8. The compound according to any one of claims 1-7, in one embodiment of the present invention, the compound according to formulas (Ⅰ), (Ⅱa), and (Ⅲa) preferably has the following structure: In one embodiment of the present invention, the compounds of formulas (Ⅰ), (Ⅱb), and (Ⅲb) preferably have the following structures: In one embodiment of the present invention, the compounds of formulas (Ⅰ), (Ⅱc), and (Ⅲc) preferably have the following structures:

9. A pharmaceutical composition comprising a compound of formula (I), (IIa), (IIIa), (IIb), (IIIb), (IIc) or (IIIc), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or a prodrug thereof, and a pharmaceutically acceptable diluent or carrier thereof.

10. The use of a compound of formula (I), (IIa), (IIIa), (IIb), (IIIb), (IIc) or (IIIc) or its stereoisomer, or a pharmaceutically acceptable salt thereof, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotopically labeled compound, or its metabolite, or its prodrug in the preparation of a medicament for treating prostate cancer, wherein the prostate cancer includes acinar carcinoma, ductal carcinoma in situ, ductal adenocarcinoma, urothelial carcinoma, squamous cell carcinoma, basal cell carcinoma, and neuroendocrine tumors, etc.

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