NTD inhibitor and use thereof

Abstract

The present invention provides an NTD inhibitor compound of formula (I) as follows. The compound has proliferation inhibitory activity on an enzalutamide-resistant cell line, has inhibitory activity on transcription of a splice mutant AR-V7, and exhibits good half-life period in vivo and certain oral bioavailability.

Description

NTD inhibitors and uses thereof TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and particularly relates to an NTD inhibitor and uses thereof. BACKGROUND

[0002] Prostate cancer is one of the most common urogenital malignant tumors in middle-aged and elderly men, and has become the second largest malignant tumor threatening men's health. Compared with many types of cancer, prostate cancer needs a longer time to invade adjacent tissues and spread to distant organs of the body. The growth and spread rate of prostate cancer has a great relationship with the differentiation degree of prostate cancer, and the prostate cancer with low differentiation degree is more likely to rapidly spread from the prostate area and reach other parts of the body. The cause of prostate cancer is not clear at present, and its common risk factors include age, genetics, race, diet, living habits, drugs, etc. (Noldus J, Graefen M, Haese A, Henke RP, Hammerer P, Huland H. Stage migration in clinically localized prostate cancer [J]. European urology, 2000, 38(1): 74-78.). Prostate cancer generally has no obvious symptoms in the early stage, but when the tumor volume becomes large, it may cause symptoms such as lower urinary tract obstruction, and more serious patients may have acute urinary retention, hematuria or urinary incontinence.

[0003] The treatment methods of prostate cancer mainly include active monitoring, prostate radical surgery, external radiotherapy, local treatment, endocrine therapy, etc. In the early stage of diagnosis, the treatment method usually adopts the way of "active monitoring". But prostate cancer has a long incubation period, which is difficult to detect, and when found, it has often developed into advanced prostate cancer. For advanced prostate cancer, androgen deprivation therapy or androgen deprivation therapy (ADT) is the standard first-line therapy in the treatment of prostate cancer. But castration therapy is not curative, and most patients will relapse at different times (18-48 months), showing castration resistance, and progress to castration-resistant prostate cancer (CRPC), showing insensitivity to surgical castration and tolerance to drug castration, and almost all patients will die within a few years due to the uncontrolled progression of the disease. At present, the treatment method for CRPC is very limited, and the FDA-approved drugs for the treatment of CRPC are only conventional chemotherapy drugs cabazitaxel and second-generation targeted AR drugs-abiraterone and anti-androgen MDV3100, but as the patient's disease progresses, drug resistance to the above drugs will occur, eventually leading to patient death (Loriot Y, Bianchini D, Ileana E, et al. Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100) [J]. Annals of oncology: official journal of the European Society for Medical Oncology, 2013, 24(7): 1807-1812).

[0004] The progression of prostate cancer is highly dependent on the transcriptional regulation of androgen receptor (AR), and androgen deprivation therapy is one of the first-line treatments for prostate cancer. According to the effectiveness of androgen deprivation therapy, prostate cancer is also clinically divided into androgen-dependent and androgen-independent types. Most early-stage prostate cancers are androgen-dependent and sensitive to castration therapy, with better treatment prospects. However, during the progression of prostate cancer, androgen-dependent prostate cancer may eventually transform into androgen-independent prostate cancer due to mechanisms such as AR overexpression or abnormal activation, resulting in the failure of the original effective treatment, the increase in tumor malignancy, and the deterioration of patient prognosis. Under disease conditions, the increased expression of AR makes the prostate tissue more sensitive to androgen stimulation, promotes proliferation-related transcriptional activity, and thus drives tumor progression (REBELLO R J, OING C, KNUDSEN K E, et al. Prostate cancer [J]. Nat Rev Dis Primers, 2021, 7: 9.). Most prostate cancer patients can use androgen deprivation therapy as the main treatment at the time of initial diagnosis. However, although most prostate cancers are effective in androgen deprivation therapy at the beginning of treatment, over time, prostate cancer eventually develops into castration-resistant. Therefore, there is an urgent need for a new treatment method to combat the threat of castration-resistant prostate cancer.

[0005] Androgen Receptor (AR) is a kind of androgen-activated transcription factor, which is composed of three parts: Ligand binding domain (LBD), DNA binding domain (DBD) and N-terminal domain (NTD). The DBD segment has been crystallized and can be used for drug design and development, but because of its high conservation in different receptors, it will inevitably lead to poor specificity and more side effects. Most steroid receptors play a role through the 2nd activation function domain (AF2) at the end of LBD, but AR is an exception. The 1st activation function domain (AF1) at the end of its NTD plays a major role in its transcriptional activation function. The function of AR LBD is independent of NTD. Even if AF-1 is deleted or mutated, it can still bind to ligands, but without the AF-1 domain of 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, Acta pharmacologica Sinica, 2015, 36(1): 3-23.). All current treatments for AR depend on the presence of LBD. However, the NTD of AR is the key region of its transcriptional activity. The activation function domain AF-1 existing in the NTD is essential for the transactivation activity of AR. Deletion of this region will lead 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 of AR can theoretically cover the AR variants and other cases such as non-specific ligand activation of LBD. Therefore, in recent years, scientists have tried to develop new drugs for prostate cancer by targeting the NTD of AR.But because AR-NTD contains little alpha-helix and beta-sheet and has high 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 bio systems, 2012, 8(1): 82-90.). The most reported is EPI-001 discovered in 2010, which is considered to be able to bind to the NTD end of AR in a covalent manner. EPI-001 is a mixture of four isomers, (2R,20S) isomer EPI-002 (ralaniten) and its ester prodrug EPI-506 (ralaniten acetate) have entered clinical I / II phase study (NCT02606123) for the treatment of castration-resistant prostate cancer progressing after anti-androgen drug treatment. However, due to the unsatisfactory efficacy and potential pharmacokinetic problems of the drug molecule itself, the clinical trial was eventually terminated. Therefore, it has great academic significance and clinical value to screen and develop drugs targeting the transcription core segment NTD of androgen receptor for the treatment of castration-resistant prostate cancer. SUMMARY

[0006] The present application provides a new NTD inhibitor, which replaces the bisphenol A structure of EPI-001 by using reasonable drug design methods such as skeleton transition, increases the aromaticity of the compound core skeleton, and develops drug design based on the new core skeleton, thereby completing the present application.

[0007] In a first aspect, the present application 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 the compound is shown in formula (I):

[0008] Further, in the compound shown in formula (I), A is selected from 5 to 15 membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl.

[0009] Further, the heteroaryl or heterocycloalkyl each contains 1 to 3 heteroatoms.

[0010] Further, the heteroatom is selected from N, O or S.

[0011] Further, in the compound shown in formula (I), B is selected from 5 to 15 membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl.

[0012] Further, the heteroaryl or heterocycloalkyl each contains 1 to 3 heteroatoms.

[0013] Further, the heteroatoms are selected from N, O or S.

[0014] Further, in the compound of formula (I), C is selected from C 1-6 alkyl, C 2-6 alkenyl, 3 to 10 membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl.

[0015] Further, the heteroaryl or heterocycloalkyl each contains 1 to 3 heteroatoms.

[0016] Further, the heteroatoms are selected from N, O or S.

[0017] Further, in the compound of formula (I), X is selected from absent, C 1-6 alkyl, -O-, -C(=O)NH-, -SO2NH-, -NR 4 alkyl, -O-, -C(=O)NH-, -SO2NH-, -NR

[0018] Further, in the -NR 4 alkyl, -O-, -C(=O)NH-, -SO2NH-, -NR 4 alkyl, -O-, -C(=O)NH-, -SO2NH-, -NR 1-6 alkyl or C 2-6 alkenyl.

[0019] Further, the alkyl, alkenyl is further substituted with one or more substituents.

[0020] Further, the substituents are selected from hydroxy, halogen or -CF3.

[0021] Further, the heteroaryl or heterocycloalkyl each contains 1 to 3 heteroatoms.

[0022] Further, the heteroatoms are selected from N, O or S.

[0023] Further, the alkyl is substituted with one or more substituents.

[0024] Further, the substituents are selected from hydroxy, halogen, C 1-6 alkyl or C 3-8 heterocycloalkyl.

[0025] Further, in the compound of formula (I), Y is selected from -CH2-, -NH-, -O- or -C(=O)-.

[0026] Further, in the compound of formula (I), W is selected from -CH2-, -CH2CH2-, -NH-, -O- or -C(=O)-.

[0027] Further, in the compound of formula (I), Z is selected from -CH2-, -NH-, -O- or -C(=O)-.

[0028] Further, in the compound of formula (I), V is selected from C 1-6 alkyl or -NH-.

[0029] Further, in the compound of formula (I), L is selected from C 1-6 alkyl or C 2-6 alkenyl.

[0030] Still further, said alkyl, alkenyl is further substituted with one or more substituents.

[0031] Still further, said substituents are selected from hydroxy, halogen, -C(=O)NHC 1-6 alkyl, -C(=O)N(C 1-6 alkyl)2, -OC(=O)C 1-6 alkyl, -OC(=O)C 1-6 alkenyl or -C(=O)OC 1-6 alkyl.

[0032] Further, in the compound of formula (I), R 1 , R 2 are each independently selected from hydrogen, halogen, cyano, -CF3 or hydroxy.

[0033] Further, in the compound of formula (I), R 3 is selected from amino, hydroxy, halogen, -C(=O)C 1-6 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)C 3-8 cycloalkyl, -C(=O)C 3-8 heterocycloalkyl, -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, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 heterocycloalkyl, -NHC(=O)C 6-10 aryl, -NHC(=O)C 5-10 heteroaryl, -SO2C 1-6 alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 heterocycloalkyl, -SO2C6-10 aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 alkyl, -SO2N(C 1-6 alkyl)2, -NHSO2C 1-6 alkyl, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 heterocycloalkyl, -NHSO2C 6-10 aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 alkyl, -NHSO2N(C 1-6 alkyl)2, -CH2NHSO2C 1-6 alkyl, -CH2NHSO2C 3-8 cycloalkyl, -CH2NHSO2C 6-10 aryl, -CH2NHSO2C 5-10 heteroaryl, -CH2NHSO2NHC 1-6 alkyl or -CH2NHSO2N(C 1-6 alkyl)2.

[0034] Further, each of said heteroaryl or heterocycloalkyl contains 1 to 3 heteroatoms.

[0035] Further, said heteroatoms are selected from N, O or S.

[0036] Further, said alkyl, amino, heterocycloalkyl, cycloalkyl, aryl, heteroaryl are further substituted with one or more substituents.

[0037] Further, said substituents are selected from deuterium, hydroxyl, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, C 5-10 heteroaryl or -SO2C 1-6 alkyl.

[0038] Further, in the compound of formula (I), each of said n1, n2, n3 is independently selected from 0, 1, 2 or 3.

[0039] In one embodiment of the present application, the compound of formula (I) can have the structure of formula (IIa):

[0040] Further, in the compound of formula (IIa), said X is selected from -O-, -C(=O)NH-, -SO2NH-, -NR 4 or C 1-6 alkyl.

[0041] Further, said -NR 4R in R 4 selected from C 1-6 alkyl.

[0042] Still further, said alkyl is further substituted with one or more substituents.

[0043] Still further, said substituents are selected from hydroxy, halogen or -CF3.

[0044] Further, said C 1-6 alkyl in R is further substituted with one or more substituents.

[0045] Still further, said substituents are selected from C 1-6 alkyl or C 3-8 heterocycloalkyl.

[0046] Further, in the compound of formula (IIa), said C is selected from C 1-6 alkyl, 3 to 10 membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl.

[0047] Still further, said heteroaryl or heterocycloalkyl each contain 1 to 3 heteroatoms.

[0048] Still further, said heteroatoms are selected from N, O or S.

[0049] Further, in the compound of formula (IIa), said Y is selected from -NH-, -O- or -C(=O)-.

[0050] Further, in the compound of formula (IIa), said W is selected from -CH2-, -NH- or -C(=O)-.

[0051] Further, in the compound of formula (IIa), said Z is selected from -NH-, -O- or -C(=O)-.

[0052] Further, in the compound of formula (IIa), said V is selected from -CH2- or -NH-.

[0053] Further, in the compound of formula (IIa), said L is selected from C 1-6 alkyl.

[0054] Still further, said alkyl is optionally further substituted with one or more substituents.

[0055] Still further, said substituents are selected from hydroxy or halogen.

[0056] Further, in the compound of formula (IIa), said R 1 , R 2 are each independently selected from hydrogen, halogen, cyano or -CF3.

[0057] Further, in the compound of formula (IIa), the R 3 is selected from the group consisting of amino, hydroxy, halogen, -C(=O)C 1-6 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)C 3-8 cycloalkyl, -C(=O)C 3-8 heterocycloalkyl, -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, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 heterocycloalkyl, -NHC(=O)C 6-10 aryl, -NHC(=O)C 5-10 heteroaryl, -SO2C 1-6 alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 heterocycloalkyl, -SO2C 6-10 aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 alkyl, -SO2N(C 1-6 alkyl)2, -NHSO2C 1-6 alkyl, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 heterocycloalkyl, -NHSO2C 6-10 aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 alkyl or NHSO2N(C 1-6 alkyl)2.

[0058] Further, the heterocycloalkyl or heteroaryl each contains 1 to 3 heteroatoms.

[0059] Further, the heteroatoms are selected from N, O or S.

[0060] Further, the alkyl, amino, heterocycloalkyl, cycloalkyl, aryl, heteroaryl are each further substituted with one or more substituents.

[0061] Further, the substituents are selected from the group consisting of deuterium, hydroxy, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, C 5-10 heteroaryl or -SO2C 1-6 alkyl.

[0062] Further, in the compound of formula (IIa), each of n1, n2, n3 is independently selected from 0, 1 or 2.

[0063] In one embodiment of the present application, the compound of formula (I) can be of formula (IIb):

[0064] Further, in the compound of formula (IIb), X is aryl or heteroaryl.

[0065] Further, the aryl or heteroaryl is selected from

[0066] Further, each of E1, E2, E3, E4 is independently selected from C or N.

[0067] Further, each of G1, G2, G3, G4, G5 is independently selected from C, O or N.

[0068] Further, in the compound of formula (IIb), C is selected from C 1-6 alkyl, 3 to 10 membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl.

[0069] Further, each of the heteroaryl or heterocycloalkyl contains 1 to 3 heteroatoms.

[0070] Further, the heteroatom is selected from N, O or S.

[0071] Further, in the compound of formula (IIb), Y is selected from -NH-, -O- or -C(=O)-.

[0072] Further, in the compound of formula (IIb), W is selected from -CH2-, -NH- or -C(=O)-.

[0073] Further, in the compound of formula (IIb), Z is selected from -NH-, -O- or -C(=O)-.

[0074] Further, in the compound of formula (IIb), V is selected from -CH2- or -NH-.

[0075] Further, in the compound of formula (IIb), L is selected from C 1-6 alkyl or C 2-6 alkenyl.

[0076] Further, the alkyl, alkenyl is further substituted with 1 or more substituents.

[0077] Further, the substituents are selected from hydroxyl, halogen, -C(=O)NHC 1-6 alkyl, -C(=O)N(C1-6 alkyl, -OC(=O)C 1-6 alkyl, -OC(=O)C 1-6 alkenyl, or -C(=O)OC 1-6 alkyl.

[0078] Further, in the compound of formula (lib), said R 1 , R 2 each independently is selected from hydrogen, halogen, cyano, -CF3, or hydroxy.

[0079] Further, in the compound of formula (lib), said R 3 is selected from amino, hydroxy, halogen, -C(=O)C 1-6 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)C 3-8 cycloalkyl, -C(=O)C 3-8 heterocycloalkyl, -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, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 heterocycloalkyl, -NHC(=O)C 6-10 aryl, -NHC(=O)C 5-10 heteroaryl, -SO2C 1-6 alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 heterocycloalkyl, -SO2C 6-10 aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 alkyl, -SO2N(C 1-6 alkyl)2, -NHSO2C 1-6 alkyl, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 heterocycloalkyl, -NHSO2C 6-10 aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 alkyl, or -NHSO2N(C 1-6 alkyl)2.

[0080] Still further, said heterocycloalkyl or heteroaryl each contains from 1 to 3 heteroatoms.

[0081] Further, the heteroatom is selected from N, O or S.

[0082] Further, the alkyl, amino, heterocycloalkyl, cycloalkyl, aryl, heteroaryl is optionally further substituted with 1 or more substituents.

[0083] Further, the substituents are selected from deuterium, hydroxyl, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, C 5-10 heteroaryl or -SO2C 1-6 alkyl.

[0084] Further, in the compound of formula (IIb), each of n1, n2, n3 is independently selected from 0, 1 or 2.

[0085] In one embodiment of the present application, the compound of formula (I) can also have the structure of formula (IIc):

[0086] Further, in the compound of formula (IIc), A is selected from

[0087] Further, A1 is selected from aryl or heteroaryl.

[0088] Further, A2 is selected from aryl, heteroaryl, cycloalkyl or heterocycloalkyl.

[0089] Further, each of E1, E2, E3, E4, E5 is independently selected from C or N.

[0090] Further, each of G1, G2, G3, G4 is independently selected from C, O, N or -C=O.

[0091] Further, in the compound of formula (IIc), C is selected from C 1-6 alkyl, 3 to 10 membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl.

[0092] Further, each of the heteroaryl or heterocycloalkyl contains 1 to 3 heteroatoms.

[0093] Further, the heteroatom is selected from N, O or S.

[0094] Further, C 1-6 alkyl, C 2-6 alkenyl, 3 to 10 membered aryl, heteroaryl, cycloalkyl, heterocycloalkyl is further substituted with 1 or more substituents.

[0095] Further, the substituents are selected from amino, hydroxyl, halogen, -C(=O)NHC 1-6alkyl, -C(=O)NHC(=O)C 1-6 alkyl, -C(=O)NHC(=O)C 1-6 alkyl.

[0096] Further, in the compound of formula (IIc), Y is selected from -NH-, -O- or -C(=O)-.

[0097] Further, in the compound of formula (IIc), W is selected from -CH2-, -NH- or -C(=O)-.

[0098] Further, in the compound of formula (IIc), Z is selected from -NH-, -O- or -C(=O)-.

[0099] Further, in the compound of formula (IIc), V is selected from -CH2- or -NH-.

[0100] Further, in the compound of formula (IIc), L is selected from C 1-6 alkyl or C 2-6 alkenyl.

[0101] Still further, said alkyl, alkenyl is further substituted with one or more substituents.

[0102] Still further, said substituents are selected from hydroxy, halogen, -C(=O)NHC(=O)C 1-6 alkyl, -C(=O)NHC(=O)C 1-6 alkyl, -C(=O)NHC(=O)C 1-6 alkyl, -C(=O)NHC(=O)C 1-6 alkenyl or -C(=O)OC 1-6 alkyl.

[0103] Further, in the compound of formula (IIc), R 1 , R 2 are each independently selected from hydrogen, halogen, cyano, -CF3or hydroxy.

[0104] Further, in the compound of formula (IIc), R 3 is selected from amino, hydroxy, halogen, -C(=O)C 1-6 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)C 3-8 cycloalkyl, -C(=O)C 3-8 heterocycloalkyl, -C(=O)C 6-10 aryl, -C(=O)C 5-10 heteroaryl, -C(=O)NHC 1-6 alkyl, -C(=O)NHC(=O)C 1-6 alkyl, -C(=O)NHC(=O)C 1-6 alkyl, -C(=O)NHC(=O)C3-8 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.

[0105] Furthermore, each of the heterocyclic alkyl or heteroaryl groups contains 1 to 3 heteroatoms.

[0106] Furthermore, the heteroatom is selected from N, O, or S.

[0107] Furthermore, the alkyl, amino, heterocyclic alkyl, cycloalkyl, aryl, and heteroaryl groups are further substituted by one or more substituents.

[0108] 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.

[0109] Furthermore, in the compound shown in formula (Ⅱc), n1, n2, and n3 are each independently selected from 0, 1, or 2.

[0110] In one embodiment of the present application, the compound of formula (I) or (IIa) can also be of formula (IIIa):

[0111] Further, in the compound of formula (IIIa), X is selected from -C(=O)NH-, -SO2NH- or C 1-6 alkyl.

[0112] Further, the alkyl is further substituted with one or more substituents.

[0113] Further, the substituents are selected from hydroxyl or halogen. 1-6 alkyl or C 3-8 heterocycloalkyl.

[0114] Further, in the compound of formula (IIIa), X is selected from

[0115] Further, in the compound of formula (IIIa), C is selected from 3 to 10 membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl. 1-6 alkyl.

[0116] Further, in the compound of formula (IIIa), L is selected from C 1-6 alkyl.

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

[0118] Further, the substituents are selected from hydroxyl or halogen.

[0119] Further, in the compound of formula (IIIa), R 1 , R 2 are each independently selected from hydrogen, halogen, cyano or -CF3.

[0120] Further, in the compound of formula (IIIa), R 3 is hydroxyl.

[0121] Further, in the compound of formula (IIIa), n1, n2, n3 are each independently selected from 0, 1 or 2.

[0122] In one embodiment of the present application, the compound of formula (I) or (IIb) can also be of formula (IIIb):

[0123] Further, in the compound of formula (IIIb), X is selected from

[0124] Further, in the compound of formula (IIIb), C is selected from 3 to 10 membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl.

[0125] Further, each of said heteroaryl or heterocycloalkyl contains 1 to 3 heteroatoms.

[0126] Further, said heteroatom is selected from N, O or S.

[0127] Further, in said compound of formula (IIIb), said L is selected from C 1-6 alkyl or C 2-6 alkenyl.

[0128] Further, said alkyl or alkenyl is further substituted by one or more substituents.

[0129] Further, said substituents are selected from hydroxy, halogen, -C(=O)NHC 1-6 alkyl, -C(=O)N(C 1-6 alkyl)2, -OC(=O)C 1-6 alkyl, -OC(=O)C 1-6 alkenyl or -C(=O)OC 1-6 alkyl.

[0130] Further, in said compound of formula (IIIb), said R 1 , R 2 are each independently selected from hydrogen, halogen, cyano or -CF3.

[0131] Further, in said compound of formula (IIIb), said R 3 is selected from -SO2C 1-6 alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 heterocycloalkyl, -SO2C 6-10 aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 alkyl, -SO2N(C 1-6 alkyl)2, -NHSO2C 1-6 alkyl, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 heterocycloalkyl, -NHSO2C 6-10 aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 alkyl or -NHSO2N(C 1-6 alkyl)2.

[0132] Further, each of said heterocycloalkyl or heteroaryl contains 1 to 3 heteroatoms.

[0133] Further, said heteroatom is selected from N, O or S.

[0134] Further, the alkyl, amino, heterocycloalkyl, cycloalkyl, aryl, heteroaryl are further substituted with one or more substituents.

[0135] Further, the substituents are selected from the group consisting of deuterium, hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C

[0136] Further, in the compound of formula (IIIb), each of n1, n2, n3 is independently selected from 0, 1 or 2.

[0137] In one embodiment of the present application, the compound of formula (I) or (IIc) can also be of formula (IIIc):

[0138] Further, in the compound of formula (IIIc), A is selected from

[0139] Further, in the compound of formula (IIIc), C is selected from 3 to 10 membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl.

[0140] Further, the heteroaryl or heterocycloalkyl each contains 1 to 3 heteroatoms.

[0141] Further, the heteroatoms are selected from N, O or S.

[0142] Further, in the compound of formula (IIIc), Y is selected from -NH-, -O- or -C(=O)-.

[0143] Further, in the compound of formula (IIIc), W is selected from -CH2-, -NH- or -C(=O)-.

[0144] Further, in the compound of formula (IIIc), Z is selected from -NH-, -O- or -C(=O)-.

[0145] Further, in the compound of formula (IIIc), V is selected from -CH2- or -NH-.

[0146] Further, in the compound of formula (IIIc), L is selected from C 1-6 alkyl or C 2-6 alkenyl.

[0147] Further, the alkyl, alkenyl are further substituted with one or more substituents.

[0148] Further, the substituents are selected from the group consisting of hydroxyl, halogen, -C(=O)NHC 1-6 alkyl, -C(=O)N(C 1-6alkyl)2, -OC(=O)C 1-6 alkyl, -OC(=O)C 1-6 alkenyl or -C(=O)OC 1-6 alkyl.

[0149] Further, in the compound of formula (IIIc), said R 1 , R 2 are each independently selected from hydrogen, halogen or cyano.

[0150] Further, in the compound of formula (IIIc), said R 3 are selected from amino, hydroxy, halogen, -C(=O)C 1-6 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)C 3-8 cycloalkyl, -C(=O)C 3-8 heterocycloalkyl, -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, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 heterocycloalkyl, -NHC(=O)C 6-10 aryl, -NHC(=O)C 5-10 heteroaryl, -SO2C 1-6 alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 heterocycloalkyl, -SO2C 6-10 aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 alkyl, -SO2N(C 1-6 alkyl)2, -NHSO2C 1-6 alkyl, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 heterocycloalkyl, -NHSO2C 6-10 aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 alkyl, -NHSO2N(C 1-6 alkyl)2, -CH2NHSO2C 1-6 alkyl, -CH2NHSO2C 3-8 cycloalkyl, -CH2NHSO2C 3-8 heterocycloalkyl, -CH2NHSO2C 6-10aryl, -CH2NHSO2C 5-10 heteroaryl, -CH2NHSO2NHC 1-6 alkyl or -CH2NHSO2N(C 1-6 alkyl)2.

[0151] Further, each of the heterocycloalkyl or heteroaryl contains 1 to 3 heteroatoms.

[0152] Further, the heteroatom is selected from N, O or S.

[0153] Further, the alkyl, amino, heterocycloalkyl, cycloalkyl, aryl, heteroaryl is further substituted with one or more substituents.

[0154] Further, the substituent is selected from deuterium, hydroxyl, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, C 5-10 heteroaryl or -SO2C 1-6 alkyl.

[0155] Further, in the compound of formula (IIIc), each of n1, n2, n3 is independently selected from 0, 1 or 2.

[0156] In an embodiment of the present application, the compound of formula (I), (IIa), (IIIa) is preferably a compound having the following structure:

[0157] In an embodiment of the present application, the compound of formula (I), (IIb), (IIIb) is preferably a compound having the following structure:

[0158] In an embodiment of the present application, the compound of formula (I), (IIc), (IIIc) is preferably a compound having the following structure:

[0159] In a second aspect, the present application 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.

[0160] Further, the pharmaceutical composition can be prepared in various dosage forms, including but not limited to one or more of tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal preparations, buccal tablets, suppositories and / or freeze-dried powder injections.

[0161] Further, the various preparations, if necessary, can also add colorants, preservatives, flavors, flavoring agents, sweeteners or other materials to the pharmaceutical preparations.

[0162] Further, the pharmaceutical composition can be administered by injection, cavity administration, respiratory tract administration or mucosal administration.

[0163] Further, the injection administration includes subcutaneous injection, intravenous injection, intramuscular injection and intracavity injection, etc.; the cavity administration includes rectal or vaginal administration; the respiratory tract administration is nasal cavity administration.

[0164] In a third aspect, the present application provides a use of 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 in the preparation of a medicament for treating prostate cancer.

[0165] Further, the prostate cancer includes androgen-dependent prostate cancer and androgen-independent prostate cancer.

[0166] Further, the prostate cancer includes acinar adenocarcinoma, intraductal carcinoma, ductal adenocarcinoma, urothelial carcinoma, squamous cell carcinoma, basal cell carcinoma and neuroendocrine tumor, etc.

[0167] Further, the prostate cancer includes stage I, stage II, stage III and stage IV prostate cancer. Advantages

[0168] 1. The compound prepared by the present application has an inhibitory effect on the proliferation of enzalutamide-resistant cell line 22Rv1.

[0169] 2. The compound prepared by the present application has an inhibitory effect on the transcription of the splicing mutant AR-V7.

[0170] 3. The compound prepared by the present application has a good in vivo half-life and certain oral bioavailability. DETAILED DESCRIPTION

[0171] The specific embodiments of the present application will be further described below. It should be noted that the description of these embodiments is intended for the purpose of aiding in the understanding of the present application and is not intended to be limiting of the present application. Moreover, the technical features involved in the embodiments described below can be combined with each other as long as there is no conflict.

[0172] The experimental methods in the following examples are all conventional methods unless otherwise specified. The experimental materials used in the following examples are all commercially available unless otherwise specified.

[0173] Table 1 Structure of exemplary compounds of the present application

[0174] Synthesis of key intermediate A-2

[0175] Synthesis of 4-methylbenzenesulfonic acid-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl ester (A-2)

[0176] Compound (R)-(-)-glycerol acetonide (1.00 g, 7.57 mmol, 1.0 equiv.), p-toluenesulfonyl chloride (1.73 g, 9.09 mmol, 1.2 equiv.), 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 detection showed that the raw material was completely reacted. After drying, water was added for dissolution, and extraction was performed with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography to obtain the target compound A-2, white solid 1.98 g, yield 92%.

[0177] UPLC-MS m / z: calcd for C 13 H 17 O5S[M+H] + 287.35; found: 288.10.

[0178] Synthesis of Example 1

[0179] Step 1:

[0180] Compound 4-bromo-2,6-dichlorophenol (1-1) (1.00 g, 4.16 mml, 1.0 equiv.), benzyl bromide (850 mg, 5.00 mmol, 1.2 equiv.), K2CO3(1.15 g, 8.32 mmol, 2.0 equiv.) were dissolved in DMF (10 mL), the reaction was stirred at 65 °C for 5 h. TLC detection, the raw material reaction was complete, after spin dry, add water to dissolve, extract with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated to get the crude product, column chromatography to get the target compound 1-2, white solid 1.23 g, yield 90%.

[0181] Step 2:

[0182] Compound 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 (dibenzylideneacetone) dipalladium (275 mg, 0.30 mmol, 0.1 equiv.), 2-dicyclohexylphospho-2',4',6'-triisopropylbiphenyl (143 mg, 0.30 mmol, 0.1 equiv.), potassium carbonate (1.25 g, 9.09 mmol, 3.0 equiv.) were added to toluene (50 mL), the reaction system was stirred at 85 °C for 8 h under argon protection. TLC detection, the raw material reaction was complete, the reaction mixture was diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated to get the crude product, column chromatography to get the target compound 1-3, yellow solid 640 mg, yield 53%. UPLC-MS m / z: calcd for C 22 H 18 Cl2NO2[M+H] + 400.08; found: 400.08.

[0183] Step 3:

[0184] Compound 1-3 (600 mg, 1.50 mmol, 1.0 equiv.), compound A-2 (512 mg, 1.80 mmol, 1.2 equiv.) as raw material, K2CO3(414 mg, 3.0 mmol, 2.0 equiv.) were added to DMF (15 mL), the reaction was stirred at 65 °C for 5 h. TLC detection, the raw material reaction was complete, after spin dry, add water to dissolve, extract with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated to get the crude product, column chromatography to get the target compound 1-4, yellow solid 632 mg, yield 82%. UPLC-MS m / z: calcd for C28 H 28 Cl2NO4[M+H] + 514.15; found: 514.40.

[0185] Step 4:

[0186] Compound 1-4 (600 mg, 1.17 mmol, 1.0 equiv.) and cerium chloride heptahydrate (870 mg. 2.34 mmol, 2.0 equiv.) were dissolved in 15 mL of acetonitrile, and the temperature was raised to 80 °C for 8 h. After TLC detection of the reaction, the reaction was extracted with ethyl acetate (3 x 25 mL), and the organic phase was combined and washed with saturated brine, then dried over anhydrous sodium sulfate, and the mixture was distilled under reduced pressure to obtain the crude product, which was separated by Prep-HPLC to obtain the target compound 1-5, yellow solid 388 mg, yield 70%. UPLC-MS m / z: calcd for C 25 H 25 Cl2NO4[M+H] + 474.12; found: 474.16.

[0187] Step 5:

[0188] Compound 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 detection showed that the raw material was completely reacted, and after drying, water was added for dissolution, 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, which was purified by column chromatography to obtain the target compound 1-6, yellow solid 402 mg, yield 61%. UPLC-MS m / z: calcd for C 32 H 31 Cl2NO6S[M+H] + 628.12; found: 628.65.

[0189] Step 6:

[0190] Compound 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 stirred at 40 °C for 5 h. TLC detection, the raw material reaction was complete, after the solvent was dried and dissolved in water, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography to give the target compound 1-7, white solid 151 mg, yield 63%. UPLC-MS m / z: calcd for C 25 H 26 Cl2N4O3[M+H] + 499.12; found: 500.99.

[0191] Step 7:

[0192] Compound 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 stirred at 60 °C overnight. TLC detection, the raw material reaction was complete, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography to give the target compound 1-8, yellow solid 112 mg, yield 60%. UPLC-MS m / z: calcd for C 25 H 26 Cl2N2O3[M+H] + 473.13; found: 473.30.

[0193] Step 8:

[0194] Compound 1-8 (100 mg, 0.22 mmol, 1.0 equiv.) and methanesulfonyl chloride (30 mg, 0.26 mmol, 1.2 equiv.), Et3N (44 mg, 0.44 mmol, 2 equiv.) were dissolved in DCM (30 mL) and reacted at room temperature for 1 h. TLC detection, the raw material reaction was complete, after drying, water was added to dissolve, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography to give the target compound 1-9, white solid 75 mg, yield 62%. UPLC-MS m / z: calcd for C 26 H 28 Cl2N2O5S[M+H] + 551.11; found: 552.01.

[0195] Step 9:

[0196] Compound 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), stirred at room temperature under hydrogen for 1 h, TLC detection of complete consumption of raw materials, remove the solid by filtration with diatomite, remove the solvent under reduced pressure. The crude product was purified by column chromatography to obtain the target compound 1-10, white oily liquid 55 mg, yield 80%. UPLC-MS m / z: calcd for C 19 H 20 Cl2N2O5S[M+H] + 461.11; found: 461.22.

[0197] Step 10:

[0198] With compound 1-10 (50 mg, 0.15 mmol, 1.0 equiv.) and (R)-glycidyl p-toluenesulfonate (40 mg, 0.17 mmol, 1.2 equiv.) as raw materials, referring to the synthesis method of step 3, the target compound 1-11 was obtained, colorless oily liquid 55 mg, yield 71%. UPLC-MS m / z: calcd for C 22 H 26 Cl2N2O6S[M+H] + 517.09; found: 517.69.

[0199] Step 11:

[0200] With compound 1-11 (20 mg, 0.04 mmol, 1.0 equiv.) and cerium chloride heptahydrate (96 mg, 0.26 mmol, 2.0 equiv.) as raw materials, referring to the synthesis method of step 4, the target compound Example 1 was obtained, white solid 9 mg, yield 42%.

[0201] Synthesis of Example 2

[0202] Step 1:

[0203] With compound 1-3 (500 mg, 1.25 mmol, 1.0 equiv.) and 1-N-Boc-4-(4-methylphenylsulfonyloxymethyl)piperidine (554 mg, 1.50 mmol, 1.2 equiv.) as raw materials, referring to the synthesis method of compound 1-4, the target compound 2-2 was obtained, white solid 529 mg, yield 71%. UPLC-MS m / z: calcd for C 33 H 39Cl2N2O4[M+H] + 597.22; found: 597.28.

[0204] Step 2:

[0205] Compound 2-2 (500 mg, 0.83 mmol, 1.0 equiv.) was dissolved in dichloromethane (10 mL), hydrochloric acid dioxane solution (4 M, 3 mL) was added, and stirring was performed at room temperature for 1 h. TLC detection showed that the raw material was completely reacted. After filtration, the solid was dissolved with water, the pH was adjusted to 8-9 by ammonia water, and then extracted with dichloromethane, washed with saturated sodium chloride solution, and finally dried with anhydrous magnesium sulfate, and concentrated to obtain the target compound 2-3, white solid 330 mg, yield 81%. UPLC-MS m / z: calcd for C 28 H 31 Cl2N2O4[M+H] + 497.17; found: 497.17.

[0206] Step 3:

[0207] With compound 2-3 (400 mg, 0.80 mmol, 1.0 equiv.) and methanesulfonyl chloride (115 mg, 0.97 mmol, 1.2 equiv.) as raw materials, the synthesis method of compound 1-9 was referred to, and the target compound 2-4 was obtained, white solid 323 mg, yield 70%. UPLC-MS m / z: calcd for C 29 H 33 Cl2N2O4S[M+H] + 576.15; found: 577.08.

[0208] Step 4:

[0209] With compound 2-4 (300 mg, 0.52 mmol, 1.0 equiv.) as raw material, the synthesis method of compound 1-10 was referred to, and the target compound 2-5 was obtained without purification and directly used in the next step reaction.

[0210] Step 5:

[0211] With compound 2-5 (300 mg, 0.60 mmol, 1.0 equiv.) as raw material and (R)-glycidyl p-toluenesulfonate (169 mg, 0.74 mmol, 1.2 equiv.) as raw material, the synthesis method of compound 1-11 was referred to, and the target compound 2-6 was obtained, white solid 334 mg, yield 71%. UPLC-MS m / z: calcd for C 25 H 31Cl2N2O5S [M+H] + 541.48; found: 541.29.

[0212] Step 6:

[0213] The target compound was obtained by replacing compound A-53 (20 mg, 0.13 mmol, 1.0 equiv.) and cerium chloride heptahydrate (96 mg, 0.26 mmol, 2.0 equiv.) with compound 1-12 in the synthetic method of compound 1-12, white solid 10 mg, yield 42%.

[0214] Synthesis of Example 3

[0215] Example 3 was obtained by replacing 1-Boc-3-(methylsulfonyloxy)azetidine with 1-N-Boc-4-(4-methylbenzenesulfonyloxymethyl)piperidine in Example 2, yellow solid 30 mg, yield 12%.

[0216] Synthesis of Example 4

[0217] The target compound Example 4 was obtained by replacing 1-Boc-3-(methylsulfonyloxy)azetidine with tert-butyl 4-(bromomethyl)benzylcarbamate in Example 2, brown solid 20 mg, yield 21%.

[0218] Synthesis of Example 5

[0219] Step 1:

[0220] The synthetic method was based on the preparation of compound 1-4, and 4-chloromethyl-2-methylsulfanylpyrimidine was replaced with 1-N-Boc-4-(4-methylbenzenesulfonyloxymethyl)piperidine to obtain the target compound 5-2, yellow solid 500 mg, yield 73%. UPLC-MS m / z: calcd for C 28 H 25 Cl2N3O2S [M+H] + 538.10; found: 538.10.

[0221] Step 2:

[0222] Compound 5-2 (500 mg, 0.93 mmol, 1.0 equiv.), 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 detection showed that the raw material was completely reacted. Water was added to the reaction solution, which 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, which was purified by column chromatography to obtain the target compound 5-3, a light yellow solid 266 mg, in a yield of 61%. UPLC-MS m / z: calcd for C 28 H 26 Cl2N3O4S[M+H] + 570.09; found: 570.23.

[0223] Step 3:

[0224] Compound 5-3 (100 mg, 0.17 mmol, 1.0 equiv.), 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 detection showed that the raw material was completely reacted. Water was added to the reaction solution, which 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, which was purified by column chromatography to obtain the target compound 5-4, a light yellow solid 41 mg, in a yield of 42%. UPLC-MS m / z: calcd for C 28 H 27 Cl2N2O4S[M+H] + 585.32; found: 585.26.

[0225] Step 4:

[0226] The target compound 5-5 was obtained by referring to the synthesis method of 1-10, using compound 5-4 (60 mg, 0.10 mmol, 1.0 equiv.) as the raw material, without purification, and directly used in the next step reaction.

[0227] Step 5:

[0228] The target compound 5-6 was obtained by referring to the synthesis method of 1-11, using compound 5-5 (30 mg, 0.05 mmol, 1.0 equiv.) as the raw material, in a yield of 71% of white solid 26 mg. UPLC-MS m / z: calcd for C 28 H 27 Cl2N2O4S[M+H] +551.08; found: 551.23.

[0229] Step 6:

[0230] The target compound was obtained by referring to the synthetic method of Example 1, using compound 5-6 (20 mg, 0.03 mmol, 1.0 equiv.) as a raw material, and was a white solid 9 mg in yield of 42%.

[0231] Synthesis of Example 6

[0232] Step 1:

[0233] Compound 6-1 (1.00 g, 4.87 mmol, 1.0 equiv.), I2 (1234 mg, 4.87 mmol, 1.0 equiv.), Ag2SO4 (1514 mg, 4.87 mmol, 1.0 equiv.) were added to an ethanol solution (50 ml) and reacted at room temperature for 3 h. TLC detection showed that the raw material was completely reacted. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The target compound 6-2 was obtained by column chromatography purification and was a light yellow solid 1450 mg in yield of 92%.

[0234] Step 2:

[0235] The target compound 6-3 was obtained by referring to the synthetic method of 1-2, using compound 6-2 (1.00 g, 3.01 mmol, 1.0 equiv.), benzyl bromide (623 mg, 3.60 mmol, 1.2 equiv.) as a raw material, and was a yellow solid 1140 mg in yield of 90%.

[0236] Step 3:

[0237] Compound 6-3 (1.00 g, 2.36 mmol, 1.0 equiv.), cuprous cyanide (252 mg, 2.80 mmol, 1.2 equiv.) were added to an N-methylpyrrolidone solution (50 ml) and reacted at 150°C for 3 h. TLC detection showed that the raw material was completely reacted. Ammonia was added to the reaction solution to quench, extraction was performed with ethyl acetate, the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The target compound 6-4 was obtained by column chromatography purification and was a white solid 226 mg in yield of 30%.

[0238] Step 4:

[0239] The target compound 6-5 was obtained by using compound 6-4 (500 mg, 1.56 mmol, 1.0 equiv.), 6-hydroxy-1,2,3,4-tetrahydroquinoline (234 mg, 1.56 mmol, 1.0 equiv.) as raw material, according to the synthetic method of 1-3, yellow solid 323 mg, yield 53%. UPLC-MS m / z: calcd for C 23 H 20 ClN2O2[M+H] + 391.11; found: 391.19.

[0240] Step 5:

[0241] The target compound 6-6 was obtained by using compound 6-5 (500 mg, 1.27 mmol, 1.0 equiv.) as raw material, according to the synthetic method of 1-4, yellow solid 750 mg, yield 70%. UPLC-MS m / z: calcd for C 34 H 39 ClN3O4[M+H] + 588.26; found: 588.65.

[0242] Step 6, Step 7:

[0243] The target compound 6-8 was obtained by using compound 6-6 (500 mg, 1.21 mmol, 1.0 equiv.) as raw material, according to the synthetic method of 2-3, 2-4, yellow solid 683 mg, yield 70% for two steps. UPLC-MS m / z: calcd for C 30 H 33 ClN3O4[M+H] + 566.18; found: 566.30.

[0244] Step 8:

[0245] The target compound 6-9 was obtained by using compound 6-8 (300 mg, 0.53 mmol, 1.0 equiv.) as raw material, according to the synthetic method of 1-10, yellow solid 209 mg, yield 83%. UPLC-MS m / z: calcd for C 30 H 33 ClN3O4[M+H] + 476.13; found: 476.12.

[0246] Step 9:

[0247] The target compound 6-10 was obtained as a white solid 264 mg, yield 79% by following the synthetic method of 1-11, using compound 6-9 (300 mg, 0.60 mmol, 1.0 equiv.) and (R)-glycidyl p-toluenesulfonate (169 mg, 0.74 mmol, 1.2 equiv.) as starting materials. UPLC-MS m / z: calcd for C 26 H 31 ClN3O5S [M+H] + 532.13; found: 532.63.

[0248] Step 10:

[0249] The target compound was obtained as a yellow solid 22 mg, yield 42% by following the synthetic method of Example 2, using compound 6-10 (50 mg, 0.09 mmol, 1.0 equiv.) and (R)-glycidyl p-toluenesulfonate (31 mg, 0.11 mmol, 1.2 equiv.) as starting materials.

[0250] Synthesis of Example 7

[0251] The target compound was obtained as a yellow solid 6 mg, yield 12% by following the synthetic method of Example 6, using 1-Boc-3-(methylsulfonyloxy)azetidine instead of 1-N-Boc-4-(4-methylphenylsulfonyloxymethyl)piperidine.

[0252] Synthesis of Example 8

[0253] The target compound was obtained as a yellow solid 44 mg, yield 66% by using compound 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.

[0254] Synthesis of Example 9

[0255] The target compound was obtained as a yellow solid 38 mg, yield 61% by 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.

[0256] Synthesis of Example 10

[0257] The compound 6-9 (50 mg, 0.12 mmol, 1.0 equiv.) and 1-bromo-2-chloroethane (34 mg, 0.24 mmol, 2 equiv.) as raw material, the target compound yellow solid 41 mg, yield 65%.

[0258] Synthesis of Example 11

[0259] The compound 7-5 (54 mg, 0.12 mmol, 1.0 equiv.) and 1-bromo-2-chloroethane (34 mg, 0.24 mmol, 2 equiv.) as raw material, the target compound yellow solid 23 mg, yield 38% was obtained according to the synthesis method of 1-11.

[0260] Synthesis of Example 12

[0261] The synthesis method is based on the preparation of Example 5, and intermediate 6-5 is used as raw material, and (R)-glycidyl p-toluenesulfonate is replaced with 1-bromo-2-chloroethane to obtain the target compound yellow solid 500 mg, yield 73%.

[0262] Synthesis of Example 13

[0263] The synthesis method is based on the synthesis of Example 6, and 1-bromo-2-chloroethane is used instead of bromobenzyl in step 2, and methanesulfonyl chloride is replaced with morpholine sulfonyl chloride in step 7 to obtain the target compound yellow solid 20 mg, yield 76%.

[0264] Synthesis of Example 14

[0265] The compound 13-7 (50 mg, 0.11 mmol, 1.0 equiv.) and N-acetylglycine (14 mg, 0.12 mmol, 1.1 equiv.) as raw material, EDCI (32 mg, 0.16 mmol, 1.5 equiv), HOAt (23 mg, 0.16 mmol, 1.5 equiv), DIPEA (56 mg, 0.44 mmol, 4 equiv) were added and dissolved in DMF (6 mL) and reacted at room temperature for 8 h. After the reaction was detected by TLC, it was extracted with ethyl acetate (3 x 10 mL), the organic phase was combined and washed with saturated brine, then dried with anhydrous sodium sulfate, and the mixture was distilled under reduced pressure to obtain the crude product, which was separated by Prep-HPLC to obtain the target compound yellow solid 37 mg, yield 60%.

[0266] Synthesis of Example 15

[0267] The synthetic method was referred to the synthesis of compound 14-5, N-acetylglycine was replaced by N,N-dimethylglycine, the target compound was obtained as yellow solid 33 mg by Prep-HPLC separation, the yield was 53%.

[0268] Synthesis of Example 16

[0269] The synthetic method was referred to the synthesis of compound 14-5, N-acetylglycine was replaced by 1-methylimidazole-4-carboxylic acid, the target compound was obtained as yellow solid 33 mg by Prep-HPLC separation, the yield was 53%.

[0270] Synthesis of Example 17

[0271] The synthetic method was referred to the synthesis of compound 14-5, N-acetylglycine was replaced by (3-methylisoxazol-5-yl)acetic acid, the target compound was obtained as yellow solid 27 mg by Prep-HPLC separation, the yield was 42%.

[0272] Synthesis of Example 18

[0273] The synthetic method was referred to the synthesis of compound 14-5, N-acetylglycine was replaced by 2-methylcyclopropane-1-carboxylic acid, the target compound was obtained as yellow solid 19 mg by Prep-HPLC separation, the yield was 32%.

[0274] Synthesis of Example 19

[0275] The synthetic method was referred to the synthesis of compound 14-5, N-acetylglycine was replaced by 2-cyclopentane-1-carboxylic acid, the target compound was obtained as yellow solid 21 mg by Prep-HPLC separation, the yield was 34%.

[0276] Synthesis of Example 20

[0277] The synthetic method was referred to the synthesis of compound 14-5, N-acetylglycine was replaced by 2-methylcyclopropane-1-carboxylic acid, the target compound was obtained as yellow solid 19 mg by Prep-HPLC separation, the yield was 32%.

[0278] Synthesis of Example 21

[0279] The synthesis method refers to the synthesis of compound Example 20, and 2-chloromethyl-5-methyl-1,3,4-thiadiazole is replaced with 5-tert-butyl-2-(chloromethyl)oxazole. The target compound is obtained by Prep-HPLC separation as a yellow solid 27 mg, with a yield of 39%.

[0280] Synthesis of Example 22

[0281] The synthesis method refers to the synthesis of compound Example 20, and 2-chloromethyl-5-methyl-1,3,4-thiadiazole is replaced with 2-chloromethyl-5-methyl-1,3,4-thiadiazole. The target compound is obtained by Prep-HPLC separation as a yellow solid 39 mg, with a yield of 62%.

[0282] Synthesis of Example 23

[0283] Replace 1-N-Boc-4-(4-methylbenzenesulfonyloxymethyl)piperidine in Example 10 with tert-butyl 4-(bromomethyl)benzylcarbamate to obtain the target compound as a brown solid 26 mg, with a yield of 39%.

[0284] Synthesis of Example 24

[0285] Replace 1-N-Boc-4-(4-methylbenzenesulfonyloxymethyl)piperidine in Example 13 with tert-butyl 4-(bromomethyl)benzylcarbamate to obtain the target compound as a yellow solid 30 mg, with a yield of 40%.

[0286] Synthesis of Example 25

[0287] With compound 1-10 (20 mg, 0.04 mmol, 1.0 equiv.) and methyl 2-(bromomethyl) acrylate (30 mg, 0.17 mmol, 1.2 equiv.) as raw materials, the synthesis method refers to that of 1-11 to obtain the target compound as a white solid 14 mg, with a yield of 65%.

[0288] Synthesis of Example 26

[0289] With compound 1-10 (20 mg, 0.04 mmol, 1.0 equiv.) and ethyl 4-bromocrotonate (33 mg, 0.17 mmol, 1.2 equiv.) as raw materials, the synthesis method refers to that of 1-11 to obtain the target compound as a white solid 15 mg, with a yield of 65%.

[0290] Synthesis of Example 27:

[0291] The target compound was obtained as a white solid 17 mg in 65% yield by using compound 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 according to the synthetic method of 1-11.

[0292] Synthesis of Example 28

[0293] Example 25 (40 mg, 0.07 mmol, 1.0 equiv.) was dissolved in methanol solution (5 ml), LiOH H2O (5 mg, 0.21 mmol, 3.0 equiv.) aqueous solution (1 ml) was added, and the reaction was carried out at room temperature for 1 h. TLC detection showed that the raw material was completely reacted. After drying, water was added for dissolution, and extraction was carried out with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The concentrate and dimethylamine (5 mg, 0.07 mmol, 1.0 equiv.), EDCI (27 mg, 0.14 mml, 2.0 equiv), HOAt (20 mg, 0.14 mml, 2.0 equiv), DIPEA (27 mg, 0.21 mml, 3.0 equiv) were dissolved in DMF (5 mL), and the reaction was carried out at room temperature for 5 h under an argon atmosphere. TLC detection showed that the raw material was completely reacted. Water was added to the reaction solution, and extraction was carried out 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. The target compound was obtained as a white solid 25 mg in 63% yield by separation with Prep-HPLC.

[0294] Synthesis of Example 29

[0295] The target compound was obtained as a white solid 17 mg in 65% yield by using compound 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 according to the synthetic method of 1-11.

[0296] Synthesis of Example 30

[0297] The target compound was obtained as a white solid 16 mg in 64% yield by using compound 2-5 (20 mg, 0.04 mmol, 1.0 equiv.) and 4-bromoethyl crotonate (10 mg, 0.05 mmol, 1.2 equiv.) as starting materials according to the synthetic method of 1-11.

[0298] Synthesis of Example 31

[0299] The synthesis method is according to the preparation of Example 32, with 1-Boc-3- (methylsulfonyloxy)azetidine replacing 1-N-Boc-4-(4-methylbenzenesulfonyloxymethyl) piperidine, to obtain the target compound Example 32, yellow solid 23 mg, yield 65%.

[0300] Synthesis of Example 32

[0301] The synthesis method is according to the preparation of Example 32, with 1-Boc-3- (methylsulfonyloxy)azetidine replacing 1-N-Boc-4-(4-methylbenzenesulfonyloxymethyl) piperidine, to obtain the target compound Example 32, yellow solid 23 mg, yield 65%.

[0302] Synthesis of Example 33

[0303] The synthesis method is according to the preparation of Example 32, with 1-Boc-3- (methylsulfonyloxy)azetidine replacing 1-N-Boc-4-(4-methylbenzenesulfonyloxymethyl) piperidine, to obtain the target compound Example 32, yellow solid 23 mg, yield 65%.

[0304] Synthesis of Example 34

[0305] The synthesis method is according to the preparation of Example 32, with 1-Boc-3- (methylsulfonyloxy)azetidine replacing 1-N-Boc-4-(4-methylbenzenesulfonyloxymethyl) piperidine, to obtain the target compound Example 32, yellow solid 23 mg, yield 65%.

[0306] Synthesis of Example 35

[0307] The synthesis method is according to the preparation of Example 32, with 1-Boc-3- (methylsulfonyloxy)azetidine replacing 1-N-Boc-4-(4-methylbenzenesulfonyloxymethyl) piperidine, to obtain the target compound Example 32, yellow solid 23 mg, yield 65%.

[0308] Synthesis of Example 36

[0309] The synthesis method is according to the preparation of Example 32, with 1-Boc-3- (methylsulfonyloxy)azetidine replacing 1-N-Boc-4-(4-methylbenzenesulfonyloxymethyl) piperidine, to obtain the target compound Example 32, yellow solid 23 mg, yield 65%.

[0310] Synthesis of Example 37

[0311] Step 1:

[0312] Compound 4-(boc-amino)phenol (1.00 g, 4.78 mmol, 1.0 equiv.), benzyl bromide (981 mg, 5.74 mmol, 1.2 equiv.), K2CO3(1.32 mg, 9.56 mmol, 2.0 equiv.) were dissolved in DMF (10 mL), and the reaction was stirred at 65 °C for 5 h. TLC detection showed that the starting material was completely reacted. After drying, water was added for dissolution, and extraction was performed with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography to obtain the target compound 37-2, white solid, 1.29 g, yield 90%. UPLC-MS m / z: calcd for C 18 H 20 NO3[M+H] + 300.38; found: 300.10.

[0313] Step 2:

[0314] Compound 37-2 (500 mg, 1.67 mml, 1.0 equiv.) was dissolved in dichloromethane (10 mL), and a hydrochloric acid dioxane (4 M, 3 mL) solution was added. The reaction was stirred at room temperature for 1 h. TLC detection showed that the starting material was completely reacted. After filtration, the solid was dissolved in water, and the pH was adjusted to 8-9 by ammonia water. Extraction was then performed with dichloromethane, the organic phase was washed with saturated sodium chloride solution, and finally dried over anhydrous magnesium sulfate. Concentration obtained the target compound 37-3, white solid, 319 mg, yield 95%. UPLC-MS m / z: calcd for C 13 H 12 NO[M+H] + 200.11; found: 200.09.

[0315] Step 3:

[0316] Compound 37-3 (300 mg, 1.51 mml, 1.0 equiv.), p-hydroxybenzoic acid (208 mg, 1.51 mml, 1.0 equiv.), EDCI (576 mg, 3.02 mml, 2.0 equiv.), HOAt (652 mg, 3.02 mml, 2.0 equiv.), DIPEA (589 mg, 4.53 mml, 3.0 equiv.) were dissolved in DMF (10 mL), and the reaction was stirred at room temperature for 8 h under an argon atmosphere. After TLC detection showed that the starting material was completely reacted, a certain amount of water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography to obtain the target compound 37-4, white solid, 347 mg, yield 76%. UPLC-MS m / z: calcd for C 20H 16 NO3[M+H] + 320.13; found: 320.09.

[0317] Step 4:

[0318] Compound 37-4 (300 mg, 0.94 mmol, 1.0 equiv.), compound A-2 (321 mg, 1.13 mmol, 1.2 equiv.), K2CO3 (259 mg, 1.88 mmol, 2.0 equiv.) were dissolved in DMF (10 mL), stirred at 65 °C for 5 h. TLC detection, the raw material reaction was complete, after spin dry, dissolved with water, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to get the crude product, purified by column chromatography to get the target compound 37-5, 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.

[0319] Step 5:

[0320] 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), stirred at room temperature under hydrogen for 1 h, TLC detection, the raw material was completely consumed, added diatomite to remove the solid by filtration, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain the target compound 37-6, colorless oily liquid 195 mg, yield 82%. UPLC-MS m / z: calcd for C 19 H 21 NO5[M+H] + 344.15; found: 344.08.

[0321] The subsequent synthesis refers to the relevant steps in Example 1, and the target compound Example 37 is obtained by Prep-HPLC separation, colorless transparent liquid 50 mg.

[0322] Synthesis of Example 38

[0323] Step 1:

[0324] Compound 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.), 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 detection, the raw material was completely reacted, after spin dry, add water to dissolve, extract with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to get the crude product, column chromatography to get the target compound 38-2, white solid 1.64 g, yield 80%. UPLC-MS m / z: calcd for C 12 H 21 NOSi[M+H] + 224.15; found: 224.15.

[0325] Step 2:

[0326] 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.), triethylamine (678 mg, 6.72 mmol, 3.0 equiv.) were dissolved in DCM (30 mL) and reacted at room temperature for 3 h. TLC detection, the raw material was completely reacted, after spin dry, add water to dissolve, extract with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to get the crude product, column chromatography to get the target compound 38-3, white solid 839 mg, yield 80%. UPLC-MS m / z: calcd for C 25 H 31 NO4SSi[M+H] + 470.68; found: 470.22.

[0327] Step 3:

[0328] Compound 38-3 (500 mg, 1.07 mmol, 1.0 equiv.) was dissolved in THF (10 mL), and TBAF tetrahydrofuran solution (0.8 ml, 4 mmol / ml) was slowly added at room temperature and reacted for 0.5 h. TLC detection, the raw material was completely reacted, after spin dry, add water to dissolve, extract with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to get the crude product 38-4, yellowish oil liquid 265 mg, yield 70%. UPLC-MS m / z: calcd for C 19H 17 NO4S[M+H] + 356.10; found: 356.12.

[0329] The target compound Example 38 was obtained as a colorless oily liquid 51 mg by following the procedures described in Example 1 and isolation by Prep-HPLC.

[0330] Synthesis of Example 39

[0331] Step 1:

[0332] Phenol (500 mg, 5.32 mmol, 2.0 equiv.), cyclohexanone (260 mg, 2.65 mmol, 1.0 equiv.) were dissolved in the mixture of HCl and glacial acetic acid (1:1, 10 mL), 1 drop of 3-mercaptopropionic acid was added, and the reaction was refluxed at 70 °C for 5 h. TLC detection showed that the starting material was completely consumed. The reaction was slowly neutralized with NaOH aqueous solution at 0 °C, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was purified by column chromatography to give the target compound 39-2 as a white solid 1.11 g in 78% yield. UPLC-MS m / z: calcd for C 18 H 20 O2[M+H] + 269.36; found: 175.01.

[0333] The target compound Example 39 was obtained as a colorless oily liquid 34 mg by following the procedures described in Example 1 and isolation by Prep-HPLC.

[0334] Synthesis of Example 40

[0335] The target compound Example 40 was obtained as a colorless oily liquid 20 mg by following the procedures described in Example 39, replacing cyclohexanone with cyclopentanone (223 mg, 2.65 mmol, 1.0 equiv.) and isolation by Prep-HPLC.

[0336] Synthesis of Example 41

[0337] The target compound Example 41 was obtained as a colorless oily liquid 15 mg by following the procedures described in Example 39, replacing cyclohexanone with piperidone (220 mg, 2.65 mmol, 1.0 equiv.) and isolation by Prep-HPLC.

[0338] Synthesis of Example 42

[0339] Example compound 41 (20 mg, 0.04 mml, 1.0 equiv.) was dissolved in dichloromethane (10 mL), hydrochloric acid dioxane (4 M, 0.5 mL) solution was added, and the reaction was stirred at room temperature for 1 h. TLC detection showed that the starting material was completely reacted, and compound example 42 was obtained by Prep-HPLC separation as a colorless oily liquid 15 mg, with a yield of 95%.

[0340] Synthesis of example 43

[0341] Referring to the synthesis of example 39, cyclohexanone was replaced by 1- isopropyl-4-piperidinone. The target compound example 43 was obtained by Prep-HPLC separation as a white solid 16 mg.

[0342] Synthesis of example 44

[0343] Referring to the synthesis of example 39, cyclohexanone was replaced by N- methyl-4-piperidinone. The target compound example 44 was obtained by Prep-HPLC separation as a colorless oily liquid 23 mg.

[0344] Synthesis of example 45

[0345] Step 1:

[0346] 2,6-dibromopyridine (1.00 g, 4.27 mmol, 1.0 equiv.), p-hydroxybenzene boronic acid (1.78 g, 12.81 mmol, 3.0 equiv.), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (936 mg, 1.28 mmol, 0.1 equiv.), cesium carbonate (10.41 g, 30.02 mmol, 2.5 equiv.) were added to a solution of tetrahydrofuran (50 mL), and the reaction system was stirred at 75 °C under argon protection overnight. TLC detection showed that the starting material was completely reacted, the reaction mixture was diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give a crude product, which was purified by column chromatography to give the target compound 45-2 as a light yellow solid 468 mg with a yield of 43%. UPLC-MS m / z: calcd for C 17 H 13 NO2[M+H] + 264.10; found: 264.11.

[0347] Step 2:

[0348] With compound 45-2 (1.00 g, 3.80 mmol, 1.0 equiv.), 4-chloromethyl-2- methylthiopyrimidine (793 mg, 4.56 mmol, 1.2 equiv.) as raw materials, the target compound 45-3 was obtained by referring to the synthetic method of 5-2, yellow solid 1173 mg, yield 78%. UPLC-MS m / z: calcd for C 23 H 20 N3O2S[M+H] + 402.12; found: 402.23.

[0349] The subsequent synthesis refers to the relevant steps of Example 5, and the target compound Example 45 is obtained by Prep-HPLC separation, yellow solid 13 mg, yield 70%.

[0350] Synthesis of Example 46

[0351] The target compound Example 46 is obtained by referring to the relevant synthesis steps in Example 2 and Example 45, and Prep-HPLC separation, white solid 86 mg, yield 85%.

[0352] Synthesis of Example 47

[0353] Step 1:

[0354] With compound 45-1 (1.00 g, 4.27 mmol, 1.0 equiv.), p-hydroxyphenylboronic acid (884 g, 6.40 mmol, 1.5 equiv.) as raw materials, the target compound 47-1 was obtained by referring to the synthetic method of 45-2, yellow solid 428 mg, yield 40%. UPLC-MS m / z: calcd for C 11 H9BrNO[M+H] + 251.10; found: 251.32.

[0355] Step 2:

[0356] With compound 47-2 (1.00 g, 3.02 mmol, 1.0 equiv.), 1-bromo-2-chloroethane (511 mg, 3.63 mmol, 1.2 equiv.) as raw materials, the target compound 47-3 was obtained by referring to the synthetic method of Example 10, yellow solid 1.07 g, yield 90%.

[0357] Step 3:

[0358] With compound 47-3 (1.00 g, 2.52 mmol, 1.0 equiv.), cuprous cyanide (271 mg, 3.05 mmol, 1.2 equiv.) as raw materials, referring to the synthetic method of 5-4, the target compound 47-4 was obtained, white solid 219 mg, yield 30%.

[0359] Step 4:

[0360] Compound 47-4 (500 mg, 1.46 mmol, 1.0 equiv.), bis(pinacolato)diboron (557 g, 2.20 mmol, 1.5 equiv.), potassium acetate (1.16 g, 5.84 mmol, 4.0 equiv.) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (109 mg, 0.15 mmol, 0.1 equiv.) were added to a tetrahydrofuran (150 mL) solution, and the reaction system was stirred at 75°C under argon protection overnight. TLC detection, the raw material reaction was complete, the reaction mixture was diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography to give the target compound 47-5, white solid 154 mg, yield 33%.

[0361] Step 5:

[0362] Compound 47-5 (800 mg, 2.34 mmol, 1.0 equiv.), compound 47-1 (585 mg, 2.34 mmol, 1.0 equiv.) as raw materials, referring to the synthetic method of 48-2, the target compound 47-6 was obtained, yellow solid 490 mg, yield 42%.

[0363] The subsequent steps refer to the synthesis of Example 6, and the target compound Example 47 is obtained by Prep-HPLC separation, yellow solid 40 mg.

[0364] Synthesis of Example 48

[0365] Referring to the relevant synthetic steps of Example 5, the target compound Example 48 is obtained by Prep-HPLC separation, yellow solid 10 mg.

[0366] Synthesis of Example 49

[0367] Step 1:

[0368] To a mixture of 4-amino-2,6-dichlorophenol (300 mg, 1.68 mmol, 1.0 equiv.), sodium azide (130 mg, 2.02 mmol, 1.2 equiv.), sodium nitrite (140 mg, 2.02 mmol, 1.2 equiv.) in a mixture of hydrochloric acid and water (1:2) was stirred at room temperature for 2 h. TLC showed the starting material was consumed completely. The pH was adjusted to 8-9 with ammonia water. The mixture was extracted with dichloromethane and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and concentrated to give the target compound 49-2 as a white solid 271 mg in 80% yield.

[0369] Step 2:

[0370] The synthetic method of Example 8 was used with compound 49-2 (200 mg, 0.99 mmol, 1.0 equiv.), 1-bromo-2-chloroethane (169 mg, 1.18 mmol, 1.2 equiv.) as starting material to give the target compound 49-3 as a yellow solid 235 mg in 90% yield.

[0371] Steps 3-5 were performed according to the related synthetic steps in Example 5 to give 49-7 as a white solid 143 mg in three steps. UPLC-MS m / z: calcd for C 14 H 13 N3O3S [M+H] + 304.07; found: 304.12.

[0372] Step 6:

[0373] 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.), DIPEA (62 mg, 0.48 mmol, 3.0 equiv.) were added to a solution of tetrahydrofuran (10 mL) and stirred at 70 °C overnight. TLC showed the starting material was consumed completely. The organic phase was removed and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give the crude product. The target compound Example 49 was obtained as a white solid 54 mg in 60% yield by Prep-HPLC.

[0374] Synthesis of Example 50

[0375] Using example compound 46 (50 mg, 0.11 mmol, 1.0 equiv.), methanesulfonyl chloride (25 mg, 0.22 mmol, 2.0 equiv.) as raw materials, the target compound example 50 was obtained by referring to the synthetic method of 2-4 in example 2, white solid 40 mg, yield 70%.

[0376] Synthesis of example 51

[0377] The target compound example 51 was obtained by referring to the synthesis of examples 13 and 50, and isolated by Prep-HPLC, white solid 12 mg.

[0378] Synthesis of example 52

[0379] The target compound example 52 was obtained by referring to the synthesis of examples 14 and 50, and isolated by Prep-HPLC, white solid 15 mg.

[0380] Synthesis of example 53

[0381] The target compound example 53 was obtained by referring to the synthesis of examples 15 and 50, and isolated by Prep-HPLC, white solid 20 mg.

[0382] Synthesis of example 54

[0383] The target compound example 54 was obtained by referring to the synthesis of compound example 1, using 6-hydroxy-1,2,3,4-tetrahydroisoquinoline instead of 6-hydroxy-1,2,3,4-tetrahydroquinoline, colorless oily liquid 10 mg.

[0384] Verification example 1 analysis of the inhibitory activity of example compounds on prostate tumor cell proliferation

[0385] The culture medium of prostate tumor cells LNCaP and 22Rv1 was RPMI 1640 + 10% FBS. Cells in the exponential growth phase were collected on the test day. LNCaP cells were plated at the corresponding cell concentration using RPMI 1640 medium containing 1% carbon adsorbed serum (CSS). 22Rv1 cells were plated at the corresponding cell concentration using RPMI 1640 medium containing 10% FBS. Among them, LNCaP cells were cultured for 48 h, then different concentrations of compounds were added in the corresponding medium containing R1881, and 22Rv1 cells were cultured overnight, then different concentrations of compounds were added in the medium, and the two kinds of cells were placed in the incubator for continuous culture for 5 days. After the culture ended, the culture medium was removed, and the CellTiter-Lumi TMThe luminescence method cell viability detection kit (Beyotime, C0065) operation instruction, add culture medium and detection reagent according to 1:1 per well, shake, incubate at room temperature, and after the luminescence signal tends to be stable, use a multifunctional enzyme label instrument with detection chemiluminescence function to detect chemiluminescence. The results are processed according to formula (1), the inhibition rate of each concentration of the compound is calculated, and Prism 8 software is used to calculate the IC 50 value of the compound when the inhibition rate is 50%.

[0386] Inhibition rate (%) = (1-test group chemiluminescence value / control group chemiluminescence value) x 100% formula (1).

[0387] The prostate tumor cell proliferation inhibition results are shown in Table 2. The example compounds exhibit certain castration-resistant prostate cancer cell proliferation inhibition activity (ND represents not detected).

[0388] Table 2 Inhibition of tumor cell growth by compounds of the present application

[0389] Verification example 2 Evaluation of AR-reporter inhibition activity of example compounds

[0390] The culture medium of human embryonic kidney cells 293T is DMEM (high sugar) + 10% FBS. The cells in the exponential growth phase were collected on the test day. The 293T cells were plated using 10% FBS medium; the transfection experiment was carried out within 24 h of plating, and the cell density was about 60-80%. The cells were changed before transfection, and the basic culture medium without serum and double antibody was replaced; AR plasmid or AR-V7 plasmid and reporter plasmid were transfected using PEI transfection reagent;

[0391] ① A tube: add plasmid to serum-free medium;

[0392] ② B tube: add PEI reagent to serum-free medium and stand at room temperature;

[0393] ③ Add B tube liquid to A tube, mix well, incubate at room temperature, and add to the culture plate;

[0394] ④ Replace with normal complete culture medium after 4-6 h.

[0395] After 24h transfection, cells were plated with DMEM (high glucose) medium containing 1% charcoal-stripped serum (CSS), and 4-5h later, different concentrations of compounds were added with 1nM R1881. After 24h incubation in the incubator, the medium was removed, and according to the operation instruction of Luciferase Assay System kit, prepared lysis solution was added to each well, and lysis was performed on a shaker. Luciferase detection reagent (LAR) was added to each well, and immediately chemiluminescence detection was performed using a multifunctional enzyme label instrument with chemiluminescence detection function.

[0396] Results were processed according to formula (2), the PSA luciferase activity of each concentration of the compound was calculated, and Prism 8 software was used to calculate the IC 50 value of the compound when the luciferase activity inhibition rate was 50%.

[0397] Inhibition rate (%) = (1 - test group chemiluminescence value / control group chemiluminescence value) x 100% formula (2).

[0398] The results of 293T cell AR Reporter and AR-V7 Reporter are shown in Table 3. The example compounds showed certain PSA luciferase activity inhibition activity (ND represents not detected).

[0399] Table 3 Inhibition of AR-reporter by compounds of the present application

[0400] Example 3 Pharmacokinetic study of example compounds in mice

[0401] Six male ICR mice were randomly divided into two groups, and after the example compound was dissolved with the corresponding solvent, the example compound was administered by gavage (p.o.) and tail vein injection (i.v.), respectively. The intravenous injection group was at 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h after administration; the gavage group was at 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h after administration. The orbital plexus was taken blood and placed in a test tube containing EDTA-2K, and was placed in a wet ice environment, centrifuged, and the plasma was separated and stored for testing. Plasma sample analysis used LC-MS / MS method to determine the concentration of example compound in plasma sample at each time point, and WinNolin software was used to calculate pharmacokinetic parameters. Including T max (time to peak), C max (peak concentration), t 1 / 2 (elimination half-life), AUC(area under the plasma concentration-time curve) and other parameter values. The absolute bioavailability was calculated according to formula (3), wherein Dose i.v. is the dose of the tail vein injection administration group, and Dosep.o. Dose for intragastrically administered group; AUC iv(0-∞) Area under the blood concentration-time curve, AUC, for intravenously administered group oral(0-∞) Area under the blood concentration-time curve for intragastrically administered group.

[0402] F(%) = (Dose i.v. x AUC p.o.(0-∞) ) / (Dose p.o. x AUC i.v.(0-∞) ) x 100%.

[0403] The animal in vivo pharmacokinetic data of some of the compounds of the examples are shown in Table 4, which show good in vivo half-life and certain oral bioavailability.

[0404] Table 4 Pharmacokinetic parameters of the compounds of the present application in mouse plasma

Claims

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 the compound is shown as formula (I): wherein said A is selected from 5 to 15 membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of said heteroaryl or heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O or S; said B is selected from 5 to 15 membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of said heteroaryl or heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O or S; said C is selected from C 1-6 alkyl, C 2-6 alkenyl, 3- to 10-membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of said heteroaryl or heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O or S; said X is selected from the absence, C 1-6 alkyl, -O-, -C(=O)NH-, -SO2NH-, -NR 4 , 3 to 10 membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl, said -NR 4 in R 4 is selected from C 1-6 alkyl or C 2-6 alkenyl, said alkyl, alkenyl further substituted with 1 or more substituents selected from hydroxy, halogen or -CF3, said heteroaryl or heterocycloalkyl each containing 1 to 3 heteroatoms selected from N, O or S, said alkyl substituted with 1 or more substituents selected from hydroxy, halogen, C 1-6 alkyl or C 3-8 heterocycloalkyl; said Y is selected from -CH2-, -NH-, -O- or -C(=O)-; said W is selected from -CH2-, -CH2CH2-, -NH-, -O- or -C(=O)-; said Z is selected from -CH2-, -NH-, -O- or -C(=O)-; V is selected from C 1-6 alkyl or -NH-; said L is selected from C 1-6 alkyl or C 2-6 alkenyl, said alkyl, alkenyl being further substituted with 1 or more substituents selected from the group consisting of hydroxy, halogen, -C(=O)NHC 1-6 alkyl, -C(=O)N(C 1-6 alkyl)2, -OC(=O)C 1-6 alkyl, -OC(=O)C 1-6 alkenyl or -C(=O)OC 1-6 alkyl; said R 1 , R 2 each independently is selected from hydrogen, halogen, cyano, -CF3, or hydroxyl; R1is selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, cyano, C 3 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-8 alkyl, -C(=O)OC 3-8 alkyl, -C(=O)OC 6-10 alkyl, -C(=O)OC 5-10 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-8 alkyl, -C(=O)OC 3-8 alkyl, -C(=O)OC 6-10 alkyl, -C(=O)OC 5-10 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-8 alkyl, -C(=O)OC 3-8 alkyl, -C(=O)OC 6-10 alkyl, -C(=O)OC 5-10 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-8 alkyl, -C(=O)OC 3-8 alkyl, -C(=O)OC 6-10 alkyl, -C(=O)OC 5-10 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-8 alkyl, -C(=O)OC 6-10 alkyl, -C(=O)OC 5-10 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-8 alkyl, -C(=O)OC 5-10 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)OCsubstituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo said R 4 selected from C 1-6 alkyl or C 2-6 alkenyl, said alkyl, alkenyl being further substituted by one or more substituents selected from the group consisting of hydroxy, halogen or -CF3; said n1, n2, n3 are each independently selected from 0, 1, 2 or 3. The compound of claim 1, in one embodiment of the present application, has a structural formula as shown in formula (IIa): wherein, 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; said C is selected from C 1-6 alkyl, 3- to 10-membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of said heteroaryl or heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O or S; said Y is selected from -NH-, -O- or -C(=O)-; said W is selected from -CH2-, -NH- or -C(=O)-; said Z is selected from -NH-, -O- or -C(=O)-; said V is selected from -CH2- or -NH-; said L is selected from C 1-6 alkyl, said alkyl is optionally further substituted with 1 or more substituents selected from hydroxy or halogen; said R 1 , R 2 each independently is selected from hydrogen, halogen, cyano or -CF3; said R 3 selected from amino, hydroxy, halogen, -C(=O)C 1-6 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)C 3-8 cycloalkyl, -C(=O)C 3-8 heterocycloalkyl, -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, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 heterocycloalkyl, -NHC(=O)C 6-10 aryl, -NHC(=O)C 5-10 heteroaryl, -SO2C 1-6 alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 heterocycloalkyl, -SO2C 6-10 aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 alkyl, -SO2N(C 1-6 alkyl)2, -NHSO2C 1-6 alkyl, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 heterocycloalkyl, -NHSO2C 6-10 aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 alkyl or NHSO2N(C 1-6 alkyl)2, said heterocycloalkyl or heteroaryl each containing 1 to 3 heteroatoms selected from N, O or S, said alkyl, amino, heterocycloalkyl, cycloalkyl, aryl, heteroaryl being further substituted with one or more substituents selected from deuterium, hydroxy, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, C 5-10 heteroaryl or -SO2C 1-6 alkyl; said n1, n2, n3 are each independently selected from 0, 1 or 2. The compound of claim 1, in one embodiment of the present application, has a structural formula as shown in formula (IIb): wherein, X is aryl or heteroaryl selected from the group consisting of said E1, E2, E3, E4 are each independently selected from C or N, said G1, G2, G3, G4, G5 are each independently selected from C, O or N; said C is selected from C 1-6 alkyl, 3- to 10-membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of said heteroaryl or heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O or S; said Y is selected from -NH-, -O- or -C(=O)-; said W is selected from -CH2-, -NH- or -C(=O)-; said Z is selected from -NH-, -O- or -C(=O)-; said V is selected from -CH2- or -NH-; said L is selected from C 1-6 alkyl or C 2-6 alkenyl, said alkyl, alkenyl being further substituted with 1 or more substituents selected from the group consisting of hydroxy, halogen, -C(=O)NHC 1-6 alkyl, -C(=O)N(C 1-6 alkyl)2, -OC(=O)C 1-6 alkyl, -OC(=O)C 1-6 alkenyl or -C(=O)OC 1-6 alkyl; said R 1 , R 2 each independently is selected from hydrogen, halogen, cyano, -CF3, or hydroxyl; said R 3 selected from amino, hydroxy, halogen, -C(=O)C 1-6 alkyl, -C(=O)OC 1-6 alkyl, -C(=O)C 3-8 cycloalkyl, -C(=O)C 3-8 heterocycloalkyl, -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, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 heterocycloalkyl, -NHC(=O)C 6-10 aryl, -NHC(=O)C 5-10 heteroaryl, -SO2C 1-6 alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 heterocycloalkyl, -SO2C 6-10 aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 alkyl, -SO2N(C 1-6 alkyl)2, -NHSO2C 1-6 alkyl, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 heterocycloalkyl, -NHSO2C 6-10 aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 alkyl or -NHSO2N(C 1-6 alkyl)2, said heterocycloalkyl or heteroaryl each containing 1 to 3 heteroatoms selected from N, O or S, said alkyl, amino, heterocycloalkyl, cycloalkyl, aryl, heteroaryl being optionally further substituted with 1 or more substituents selected from deuterium, hydroxy, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, C 5-10 heteroaryl or -SO2C 1-6 alkyl; said n1, n2, n3 are each independently selected from 0, 1 or 2. The compound of claim 1, in one embodiment of the present application, has a structural formula as shown in formula (IIc): wherein, Said A is selected from said A1 is selected from aryl or heteroaryl, said A2 is selected from aryl, heteroaryl, cycloalkyl or heterocycloalkyl, said E1, E2, E3, E4, E5 are each independently selected from C or N, said G1, G2, G3, G4 are each independently selected from C, O, N or -C=O; said C is selected from C 1-6 alkyl, 3- to 10-membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of said heteroaryl or heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O or S, said C 1-6 alkyl, C 2-6 alkenyl, 3- to 10-membered aryl, heteroaryl, cycloalkyl, heterocycloalkyl, further substituted with 1 or more substituents selected from amino, hydroxy, halogen, -C(=O)NHC 1-6 alkyl, -C(=O)N(C 1-6 alkyl)2or -SO2C 1-6 alkyl; said Y is selected from -NH-, -O- or -C(=O)-; said W is selected from -CH2-, -NH- or -C(=O)-; said Z is selected from -NH-, -O- or -C(=O)-; said V is selected from -CH2- or -NH-; said L is selected from C 1-6 alkyl or C 2-6 alkenyl, said alkyl, alkenyl being further substituted with 1 or more substituents selected from the group consisting of hydroxy, halogen, -C(=O)NHC 1-6 alkyl, -C(=O)N(C 1-6 alkyl)2, -OC(=O)C 1-6 alkyl, -OC(=O)C 1-6 alkenyl or -C(=O)OC 1-6 alkyl; said R 1 , R 2 each independently is 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 substituted by one or more substituents selected from the group consisting of said n1, n2, n3 are each independently selected from 0, 1 or 2. The compound of any one of claims 1-4, in an embodiment of the present application, the compound of formula (I) or (IIa) can also be of formula (IIIa): wherein said X is selected from -C(=O)NH-, -SO2NH- or C 1-6 alkyl, said alkyl being further substituted by one or more substituents selected from the group consisting of C 1-6 alkyl or C 3-8 heterocycloalkyl; Said X is selected from said C is selected from C 1-6 alkyl; said L is selected from C 1-6 alkyl, said alkyl is further substituted with one or more substituents selected from the group consisting of hydroxy or halogen; said R 1 , R 2 each independently is selected from hydrogen, halogen, cyano or -CF3; The R 3 It is a hydroxyl group; said n1, n2, n3 are each independently selected from 0, 1 or 2. The compound of any one of claims 1-4, in an embodiment of the application, the compound of formula (I) or (IIb) can also be of formula (IIIb): wherein, Said X is selected from said C is selected from 3 to 10 membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of said heteroaryl or heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O or S; said L is selected from C 1-6 alkyl or C 2-6 alkenyl, said alkyl, alkenyl being further substituted with 1 or more substituents selected from the group consisting of hydroxy, halogen, -C(=O)NHC 1-6 alkyl, -C(=O)N(C 1-6 alkyl)2, -OC(=O)C 1-6 alkyl, -OC(=O)C 1-6 alkenyl or -C(=O)OC 1-6 alkyl; said R 1 , R 2 each independently is selected from hydrogen, halogen, cyano or -CF3; R is selected from -SO2C 3 alkyl, -SO2C 1-6 alkyl, -SO2C 3-8 cycloalkyl, -SO2C 3-8 heterocycloalkyl, -SO2C 6-10 aryl, -SO2C 5-10 heteroaryl, -SO2NHC 1-6 alkyl, -SO2N(C 1-6 alkyl)2, -NHSO2C 1-6 alkyl, -NHSO2C 3-8 cycloalkyl, -NHSO2C 3-8 heterocycloalkyl, -NHSO2C 6-10 aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 alkyl or -NHSO2N(C 1-6 alkyl)2, each of said heterocycloalkyl or heteroaryl containing from 1 to 3 heteroatoms selected from N, O or S, said alkyl, amino, heterocycloalkyl, cycloalkyl, aryl, heteroaryl being further substituted with 1 or more substituents selected from deuterium, hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy or -SO2C 1-6 alkyl; said n1, n2, n3 are each independently selected from 0, 1 or 2. The compound of any one of claims 1-4, in an embodiment of the application, the compound of formula (I) or (IIc) can also be of formula (IIIc): wherein, Said A is selected from said C is selected from 3 to 10 membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of said heteroaryl or heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O or S; said Y is selected from -NH-, -O- or -C(=O)-; said W is selected from -CH2-, -NH- or -C(=O)-; said Z is selected from -NH-, -O- or -C(=O)-; said V is selected from -CH2- or -NH-; said L is selected from C 1-6 alkyl or C 2-6 alkenyl, said alkyl, alkenyl being further substituted with 1 or more substituents selected from the group consisting of hydroxy, halogen, -C(=O)NHC 1-6 alkyl, -C(=O)N(C 1-6 alkyl)2, -OC(=O)C 1-6 alkyl, -OC(=O)C 1-6 alkenyl or -C(=O)OC 1-6 alkyl; said R 1 , R 2 each independently is selected from hydrogen, halogen and cyano; 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 substituted by one or more substituents selected from the group consisting of said n1, n2, n3 are each independently selected from 0, 1 or 2. The compound according to any one of claims 1-7, in an embodiment of the application, the compound according to formula (I), (IIa), (IIIa) preferably has the structure of the following compounds: In one embodiment of the present application, the compound of formula (I), (IIb), (IIIb) is preferably a compound having the structure of: In one embodiment of the present application, the compound of formula (I), (IIc), (IIIc) is preferably a compound having the structure of: 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. Use of 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, in the manufacture of a medicament for treating prostate cancer, including acinar adenocarcinoma, intraductal carcinoma, ductal adenocarcinoma, urothelial carcinoma, squamous cell carcinoma, basal cell carcinoma, and neuroendocrine tumor.

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