Tetrahydroquinoline NTD inhibitor and use thereof

Abstract

The present invention belongs to the technical field of biopharmaceuticals, and specifically relates to a tetrahydroquinoline NTD inhibitor and a use thereof. The present invention provides a novel NTD inhibitor, in which a bisphenol A moiety in EPI-002 is replaced with a tetrahydroquinoline structure, and rational drug design is carried out using this as a core scaffold, thereby enhancing the inhibitory activity of the compound against full-length AR and AR splice variants, while improving pharmacokinetic properties. The compound prepared in the present invention exhibits inhibitory effects toward the proliferation of castration-resistant prostate cancer cells and PSA luciferase activity, the effects thereof are superior to those of clinical drugs; it also possesses good oral bioavailability and plasma exposure.

Description

A tetrahydroquinoline ntd inhibitor and application thereof TECHNICAL FIELD

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

[0002] Prostate cancer is a very important tumor of the male reproductive system, ranking second in the world's common male malignancies and the fifth largest cause of cancer death (Bay F, Ferlay J, Soerjomatamam I, et al. Global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin. 2018, 68:394-424.). Prostate cancer is histologically manifested as adenocarcinoma, mainly of the luminal phenotype, accompanied by basal cell loss (Zhang DX, Tang D. "Splice" a way toward neuroendocrine prostate cancer[J]. EBioMedicine, 2018, 35:12-13.). The incidence of prostate cancer is increasing year by year, and the latest US cancer statistics show that the incidence of prostate cancer in American men is 20%, which has surpassed lung cancer and ranked first; the mortality rate of prostate cancer is 10%, second only to lung cancer, ranking second (Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024[J]. CA Cancer J Clin, 2024, 74(1):12-49.). Prostate cancer is characterized by a long natural history of the disease, during which different treatments are needed according to tumor stage and invasiveness. The treatment of early prostate cancer includes surgical resection, chemotherapy and castration therapy, while for patients with advanced metastatic prostate cancer, there is currently no radical treatment, and only conservative treatment can be taken (Achan V, Putora PM, Omlin A, et al. Metastatic prostate cancer: treatment options[J]. Oncotarget, 2022, 100):48-59.). Even though most prostate cancers are discovered at an early stage, a portion of patients are diagnosed with locally advanced or even distant metastasis. The common methods for treating non-metastatic prostate cancer are radical prostatectomy and androgen deprivation therapy (ADT), and radical prostatectomy is only suitable for prostate cancer patients who are younger and can tolerate surgery.But after ADT treatment with a median time of 18-24 months, almost all patients inevitably develop castration-resistant prostate cancer (CRPC), and more than 80% of CRPC eventually turn into metastatic castration-resistant prostate cancer (mCRPC) (Oudard S, Progress in emerging therapies for advanced prostate cancer [J]. Cancer Treat Rev, 2013, 39(3): 275-289; Labriola Mk, Atig S, Hirshman N, et al. Management of men with metastatie casration-resistant prastate cancer following potent androgen receptor inhibition: a review of novel investigation-al therapies [J]. Prstate Cancer Prastatie Dis, 2021. 24(2); 301-309.) with a median survival of less than 3 years. In addition, endocrine therapy is also the first-line treatment for these patients. Although the treatment regimen dominated by endocrine therapy has achieved good results in clinical practice, after 2 years of treatment, prostate cancer cells will develop resistance to androgen deprivation, leading to disease progression to castration-resistant prostate cancer (CRPC) (Leiblich A, Hellberg I E E U, Sekar A, er al. Mating induces switch from horone-dependent to hormone-independent steroid receptor-mediated growth in Drosophila secondary cells [J]. PLoS Biol, 2019, 17(10): e3000145.). So far, little is known about the potential mechanisms of the development and maintenance of castration-resistant prostate cancer, leading to a lack of new therapeutic drugs for such a deadly disease. Therefore, finding new therapeutic targets is crucial to improve the prognosis of prostate cancer patients.

[0003] Androgen Receptor (AR) is an important target for prostate cancer drugs, and its structure plays an important guiding role in drug development. Androgen receptor is composed of four domains, including N-terminal binding domain (NTD), DNA binding domain (DBD), hinge region (HR), and C-terminal binding domain (LBD). NTD is the transcription activation region, which is the most non-conserved sequence region, encoded by exon 1, and contains two independent transcription activation function regions AF1 and AF5. AF1 region also contains two transcription units Tau-1 and Tau-5 (Duan M, Liu N, Zhou w, er al. Structural diversity of ligang-binging androgen recertors revealed by microsecond long molecular dynamics simulations and enhanced sampling[J]. J Chem Theony Compu, 2016, 12(9): 4611-4619; Helsen C, Claessens F. Looking at nuclear receptors from a new angle[J]. Mol Cell Endocrinol, 2014, 382(1): 97-106.). In recent years, small molecule androgen receptor inhibitors targeting NTD domain have emerged. The NTD domain of androgen receptor is essential for androgen receptor activity and exists in all forms of androgen receptor. Targeting this key region is expected to inhibit the activity of resistance-related androgen receptor splice variants and overcome the shortcomings of current drug therapy. EPI-001 is a new type of small molecule isolated from marine sponge extract, which can bind to AR NTD and prevent the interaction between protein and ligand. Although EPI-001 does not reduce the level of AR in serum, it can directly inhibit the activity of AR splice mutant and prevent its interaction with full-length AR (Sadar, M. D. Small molecule inhibitors targeting the "achilles' heel" of androgen receptor activity[J]. Cancer Res, (2011), 71(4): 1208-1213.). EPI-002 has entered the phase II clinical study stage (NCT02606123).Myung et al. found that EPI analogs covalently bind to the NTD to block the transcriptional activity of the androgen receptor and its splice variants and reduce the growth of CRPC xenografts (Myung IK, Banuelos CA, Fernandez JG eral. An androgen receptor N-terminal domain antagonist for treating prostate cancer [J]. J Clin invest, 2013, 123(7): 2948-2960). In addition, Banuelos et al. found that the binding site of EPI-001 is Tau-5 in AF1 (Banuelos C A, Tavakoli l, Tien A H, er al. Sintokamide A is novel antagonist of androgen receptor that uniquely binds activation function-1 in its amino-terminal domain [J]. J Biol Chem, 2016, 291(42): 22231-22243.).

[0004] The main drugs for treating prostate cancer in clinical practice are androgen receptor inhibitors, which can be divided into two categories: steroidal inhibitors and non-steroidal inhibitors. Steroidal inhibitors include cyproterone acetate. Steroidal inhibitors can bind to the receptor due to their structural similarity to androgens, and were initially used in clinical practice to treat prostate cancer. However, they were found to have adverse reactions such as liver toxicity and loss of sexual desire, which limited their clinical application (Sakkiah S, Ng H W, Tong W, et al. Structures of androgen receptor bound with ligands: advancing understanding of biological functions and drug discovery [J]. Expert Opin Ther Pat, 2016, 20(10): 1267-1282.). The first generation of non-steroidal inhibitors includes flutamide, nilutamide, and bicalutamide. They initially showed anti-androgen activity without agonistic effects, and were therefore used in clinical practice to treat prostate cancer. However, their use eventually led to an increase in serum testosterone levels, similar to steroidal inhibitors (Denmeade S R, Isaacs JT. A history of prostate cancer treatment [J]. Nat Rev Cancer, 2002, 2(5): 389-396.). The second generation of non-steroidal inhibitors includes enzalutamide, ARN-509, and ODM-201, all of which have been marketed. Non-steroidal inhibitors are more widely used in clinical practice due to their high selectivity and good tolerance, and the absence of side effects associated with steroidal drugs (Wirth M P, Hakenberg O W, Froehner M. Antiandrogens in the treatment of prostate cancer [J]. Eur Urol, 2007, 51(2): 306-313.). Therefore, non-steroidal inhibitors are the main direction of research in recent years. The non-steroidal androgen receptor inhibitors currently used in clinical practice all act on the LBD binding domain, which is a single target, making it difficult to treat prostate cancer patients. With the extension of the medication time, patients will inevitably develop drug resistance, and will eventually face the situation of having no available drugs. Through the understanding of the structure of the androgen receptor, the NTD binding domain and the DBD binding domain in the androgen receptor can also be used as targets for anti-prostate cancer drugs, making the selection of drugs for treating prostate cancer more diverse. In clinical practice, a multi-target combination drug strategy can be used to increase the efficacy and improve the quality of life of prostate cancer patients. SUMMARY

[0005] The application provides a new NTD inhibitor, which replaces bisphenol A fragments with tetrahydroquinoline structures on the basis of EPI-002, and performs reasonable drug design based on the core skeleton, so that the inhibitory activity of the compound on full-length AR and AR splicing mutants is improved, and the pharmacokinetic properties are improved. Based on this, the application is completed.

[0006] In a first aspect, the 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):

[0007] Further, in the compound shown in formula (I), A is selected from 5 to 15 membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl.

[0008] Further, the heteroaryl or heterocycloalkyl each contains 1 to 3 heteroatoms.

[0009] Further, the heteroatom is selected from one of N, O or S.

[0010] Further, in the compound shown in formula (I), B is selected from 5 to 15 membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl.

[0011] Further, the heteroaryl or heterocycloalkyl each contains 1 to 3 heteroatoms.

[0012] Further, the heteroatom is selected from one of N, O or S.

[0013] Further, in the compound shown in formula (I), C is selected from 3 to 10 membered aryl, heteroaryl, cycloalkyl, heterocycloalkyl, 4 to 12 membered bicyclic heteroaryl, spiro[m.n]cyclyl or heterospiro[m.n]cyclyl, wherein m and n are each independently selected from 3, 4, 5, 6 or 7.

[0014] Further, the heteroaryl, bicyclic heteroaryl, heterocycloalkyl or heterospiro[m.n]cyclyl each contains 1 to 3 heteroatoms.

[0015] Further, the heteroatom is selected from one of N, O or S.

[0016] Further, in the compound shown in formula (I), Y is selected from nothing, -CH2-, -NH-, -O- or -C(=O)-.

[0017] Further, in the compound shown in formula (I), W is selected from nothing, -CH2-, -NH-, -O- or -C(=O)-.

[0018] Further, in the compound of formula (I), Z is selected from the group consisting of absent, -CH2-, -NH-, -O-, or -C(=O)-.

[0019] Further, in the compound of formula (I), V is selected from the group consisting of absent, -CH2-, -NH-, or -C(=O)-.

[0020] Further, in the compound of formula (I), L is selected from the group consisting of C 1-6 alkyl or 3 to 10 membered heterocycloalkyl.

[0021] Still further, the heterocycloalkyl contains 1 to 2 heteroatoms.

[0022] Still further, the heteroatoms are selected from the group consisting of N, O, or S.

[0023] Further, the alkyl, heterocycloalkyl is further substituted with 1 or more substituents.

[0024] Still further, the substituents are selected from the group consisting of hydroxyl, halogen, or cyano.

[0025] Further, in the compound of formula (I), R 1 , R 2 are each independently selected from the group consisting of hydrogen, halogen, cyano, -CH3, -CF3, or hydroxyl.

[0026] Further, in the compound of formula (I), R 3 is selected from the group consisting of amino, methylamino, dimethylamino, hydroxyl, methoxyl, halogen, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, -C(=O)C 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 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 5-10heteroaryl, -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 6-10 aryl, -CH2NHSO2C 5-10 heteroaryl, -CH2NHSO2NHC 1-6 alkyl or -CH2NHSO2N(C 1-6 alkyl)2.

[0027] Further, each of the heterocycloalkyl or heteroaryl contains 1 to 3 heteroatoms.

[0028] Further, the heteroatoms are selected from N, O or S.

[0029] Further, the alkyl, heterocycloalkyl, cycloalkyl, aryl, heteroaryl are further substituted with one or more substituents.

[0030] Further, the substituents are selected from deuterium, hydroxyl, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, C 5-10 heteroaryl or -NHSO2C 1-6 alkyl.

[0031] Further, in the compound of formula (I), each of n1, n2, n3 is independently selected from 0, 1, 2 or 3.

[0032] In one embodiment of the present application, the compound of formula (I) has the structure of formula (II):

[0033] Further, in the compound of formula (II), A is selected from

[0034] Further, A1 is selected from aryl or heteroaryl.

[0035] Further, said A2 is selected from aryl, heteroaryl, cycloalkyl or heterocycloalkyl.

[0036] Further, said E1, E2, E3, E4, E5 are each independently selected from C or N.

[0037] Further, said G1, G2, G3, G4 are each independently selected from C, O, N or -C=0.

[0038] Further, in the compound of formula (II), said C is selected from 3 to 10 membered aryl, heteroaryl, 4 to 12 membered bicyclic heteroaryl or heterospiro[m.n]cyclyl, wherein m and n are each independently selected from 3, 4, 5, 6 or 7.

[0039] Further, said heteroaryl, bicyclic heteroaryl or heterospiro[m.n]cyclyl each contain 1 to 3 heteroatoms.

[0040] Further, said heteroatoms are selected from N, O or S.

[0041] Further, in the compound of formula (II), said Y is selected from absent, -NH- or -C(=0)-.

[0042] Further, in the compound of formula (II), said W is selected from absent, -NH- or -C(=0)-.

[0043] Further, in the compound of formula (II), said Z is absent or -0-.

[0044] Further, in the compound of formula (II), said V is absent or -CH2-.

[0045] Further, in the compound of formula (II), said L is selected from C 1-6 alkyl or 3 to 10 membered heterocycloalkyl.

[0046] Further, said heterocycloalkyl contains 1 to 2 heteroatoms.

[0047] Further, said heteroatoms are selected from N, O or S.

[0048] Further, said alkyl or heterocycloalkyl is further substituted with 1 or more substituents.

[0049] Further, said substituents are selected from hydroxyl or halogen.

[0050] Further, in the compound of formula (II), said R 1 , R 2 are each independently selected from hydrogen, halogen, cyano, -CH3 or -CF3.

[0051] Further, in the compound of formula (II), said R 3selected from the group consisting of amino, methylamino, dimethylamino, hydroxy, methoxy, halogen, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, -NHC(=O)C 1-6 alkyl, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 6-10 aryl, -NHC(=O)C 5-10 heteroaryl, -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 6-10 aryl, -CH2NHSO2C 5-10 heteroaryl, -CH2NHSO2NHC 1-6 alkyl or -CH2NHSO2N(C 1-6 alkyl)2.

[0052] Further, each of the heterocycloalkyl or heteroaryl contains 1 to 3 heteroatoms.

[0053] Still further, the heteroatoms are selected from N, O or S.

[0054] Further, the alkyl, heterocycloalkyl, cycloalkyl, aryl, heteroaryl are optionally further substituted with 1 or more substituents.

[0055] Still further, the substituents selected from the group consisting of deuterium, hydroxy, halogen, cyano, C 1-6 alkyl or -NHSO2C 1-6 alkyl.

[0056] Further, in the compound of formula (II), each of n1, n2, n3 is independently selected from 0, 1 or 2.

[0057] In one embodiment of the present application, the compound of formula (I) or (II) can be of formula (III):

[0058] Further, in the compound of formula (III), C is selected from a 3 to 10 membered aryl, heteroaryl, 4 to 12 membered bicyclic heteroaryl, or heterospiro[m.n] ring group, wherein m and n are each independently selected from 3, 4, 5, 6, or 7.

[0059] Further, each of the heteroaryl, bicyclic heteroaryl, or heterospiro[m.n] ring group contains 1 to 3 heteroatoms.

[0060] Further, the heteroatoms are selected from N, O, or S.

[0061] Further, in the compound of formula (III), Y is selected from absent, -NH-, or -C(=O)-.

[0062] Further, in the compound of formula (III), W is selected from absent, -NH-, or -C(=O)-.

[0063] Further, in the compound of formula (III), Z is absent or -O-.

[0064] Further, in the compound of formula (III), V is absent or -CH2-.

[0065] Further, in the compound of formula (III), L is selected from C 1-6 alkyl or 3 to 6 membered heterocycloalkyl.

[0066] Further, the heterocycloalkyl contains 1 to 2 heteroatoms.

[0067] Further, the heteroatoms are selected from N, O, or S.

[0068] Further, the alkyl, heterocycloalkyl is further substituted with 1 or more substituents.

[0069] Further, the substituents are selected from hydroxyl or halogen.

[0070] Further, in the compound of formula (III), R 1 is selected from hydrogen or -CH3.

[0071] Further, in the compound of formula (III), R 2 is selected from halogen or cyano.

[0072] Further, in the compound of formula (III), R 3 is selected from amino, methylamino, dimethylamino, hydroxyl, methoxy, halogen, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, -NHC(=O)C 1-6 alkyl, -NHSO2C 1-6 alkyl, -NHSO2C3-8 cycloalkyl, -NHSO2C 3-8 heterocycloalkyl, -NHSO2C 6-10 aryl, -NHSO2C 5-10 heteroaryl, -NHSO2NHC 1-6 alkyl, -NHSO2N(C 1-6 alkyl)2or -CH2NHSO2C 1-6 alkyl.

[0073] Further, each of the heterocycloalkyl or heteroaryl contains 1 to 3 heteroatoms.

[0074] Still further, the heteroatoms are selected from N, O or S.

[0075] Further, the alkyl, heterocycloalkyl, cycloalkyl, aryl, heteroaryl are further substituted with one or more substituents.

[0076] Still further, the substituents are selected from deuterium, hydroxyl, halogen, cyano, C 1-6 alkyl or -NHSO2C 1-6 alkyl.

[0077] Further, in the compound of formula (III), n2 is selected from 0, 1 or 2.

[0078] Further, in the compound of formula (III), n3 is selected from 1 or 2.

[0079] In one embodiment of the present application, the compound of formula (I), (II), (III) has a structure selected from any one of the following:

[0080] In a second aspect, the present application provides a pharmaceutical composition comprising a compound of formula (I), (II) or (III), 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 excipient or carrier.

[0081] Further, the pharmaceutical composition can be prepared in various dosage forms, including but not limited to one or more of tablets, capsules, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal preparations and / or suppositories.

[0082] Further, if necessary, various preparations can also add colorants, preservatives, fragrances, flavoring agents, sweeteners or other materials to the pharmaceutical preparation.

[0083] Further, the pharmaceutical composition can be administered by injection, by rectal or vaginal administration, by respiratory tract administration or by mucosal administration.

[0084] Further, the injection includes subcutaneous injection, intravenous injection, intramuscular injection and intracavity injection; the rectal or vaginal administration includes transrectal or transvaginal administration.

[0085] In a third aspect, the present application provides a use of a compound of formula (I), (II) or (III) 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 an androgen receptor modulator.

[0086] In a fourth aspect, the present application provides a use of a compound of formula (I), (II) or (III) 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 a disease related to androgen receptor.

[0087] Further, the disease is cancer, metabolic disorder, cardiovascular and cerebrovascular disease, hyperlipidemia or obesity.

[0088] Further, the cancer is prostate cancer, breast cancer or bladder cancer.

[0089] Preferably, the cancer is prostate cancer.

[0090] Further, the prostate cancer includes androgen-dependent prostate cancer and androgen-independent prostate cancer.

[0091] Further, the prostate cancer includes acinar adenocarcinoma, intraductal carcinoma, ductal adenocarcinoma, urothelial carcinoma, squamous cell carcinoma, basal cell carcinoma and neuroendocrine tumor.

[0092] Further, the prostate cancer includes stage I, stage II, stage III and stage IV prostate cancer. Beneficial effects

[0093] 1. The compound prepared by the present application has inhibitory effect on the proliferation of castration-resistant prostate cancer cells, and the effect is better than that of the marketed AR-LBD antagonist enzalutamide and the AR-NTD inhibitor EPI-7170 reported in the literature.

[0094] 2、The prepared compound has inhibitory effect on PSA luciferase activity, and the blocking ability on AR pathway is better than that of the marketed AR-LBD antagonist enzalutamide and the AR-NTD inhibitor EPI-7170 reported in the literature.

[0095] 3、The prepared compound has good oral bioavailability and plasma exposure. DETAILED DESCRIPTION

[0096] The specific embodiments of the present application are 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 following described embodiments can be combined with each other as long as there is no conflict.

[0097] The experimental methods in the following examples are all conventional methods unless otherwise specified, and the experimental materials used in the following examples are all commercially available unless otherwise specified.

[0098] Enzalutamide is an androgen receptor (AR) antagonist that competitively inhibits androgen receptor and androgen receptor nuclear translocation and interaction with DNA, and the chemical name is: 4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]-2-fluoro-N-methylbenzamide. The approved indications are advanced castration-resistant prostate cancer that has spread or relapsed.

[0099] EPI-7170, a ralaniten analog, is an effective androgen receptor N-terminal structural domain antagonist that can block the transcriptional activity of full-length AR (FL-AR) and AR splice variants (AR-Vs). EPI-7170 has an anti-tumor effect on enzalutamide-resistant castration-resistant prostate cancer (CRPC).

[0100] Table 1 Structure of exemplary compounds of the present application

[0101] Synthesis of Example Key Intermediate A-6

[0102] Step 1:

[0103] A-1 (10.00 g, 65.12 mml, 1.0 equiv.) was dissolved in acetonitrile (200 mL), NIS (15.38 g, 68.37 mml, 1.05 equiv.) was added, and the reaction was allowed to proceed at room temperature for 2 h. TLC detection showed that the starting material was completely consumed. Water was added, and the reaction mixture was 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 A-2, which was used directly in the next step.

[0104] Step 2:

[0105] A-2 was dissolved in dimethylformamide (200 mL), and potassium carbonate (10.80 g, 78.14 mmol, 1.2 equiv.) and 1-bromo-2-chloroethane were added successively. The reaction was allowed to proceed at 60 °C for 4 h. TLC detection showed that the starting material was completely consumed. After cooling to room temperature, water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by column chromatography to give the target compound A-3 as a white solid, 18.50 g, 83% yield for two steps. UPLC-MS m / z: calcd for C9H7Cl2INO [M+H] 341.89; found: 341.91. +

[0106] Step 3:

[0107] ​A-3 (18.50 g, 54.10 mmol, 1.0 equiv.) and 6-hydroxy-1,2,3,4-tetrahydroquinoline (8.07 g, 54.10 mmol, 1.0 equiv.) were suspended in toluene (300 ml), sodium tert-butoxide (13.00 g, 135.25 mmol, 2.5 equiv.) was added portionwise, after stirring uniformly, Pd2(dba)3(0.99 g, 1.08 mmol, 0.02 equiv.) and Xphos (0.77 g, 1.6 mmol, 0.03 equiv.) were added, replaced with argon for 5 times, reacted at 80 °C for 5 h. LCMS detected that the reaction was complete, after cooling to room temperature, water was added, 1M dilute hydrochloric acid was used to adjust the pH to neutral, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then purified by column chromatography to obtain the target compound A-4, yellow solid 12.75 g, yield 64%. UPLC-MS m / z: calcd for C 18 H 17 Cl2N2O2[M+H] + 363.06; found: 363.07.

[0108] Step 4:

[0109] A-4 (12.75 g, 35.10 mmol, 1.0 equiv.) and pyridine (3.05 g, 38.61 mmol, 1.1 equiv.) were dissolved in anhydrous dichloromethane (150 ml), and a solution of triflic anhydride (10.89 g, 38.61 mmol, 1.1 equiv.) in anhydrous dichloromethane (50 ml) was added dropwise under ice bath conditions, and the reaction was carried out under ice bath conditions for 1 h. LCMS detected that the reaction was complete, saturated brine was added for washing, dried over anhydrous sodium sulfate, and then purified by column chromatography to obtain the target compound A-5, yellow oil 14.96 g, yield 86%. UPLC-MS m / z: calcd for C 19 H 16 Cl2F3N2O4S[M+H] + 495.01; found: 495.08.

[0110] Step 5:

[0111] A-5 (14.96 g, 30.20 mmol, 1.0 equiv.), bis(pinacolato)diboron (15.34 g, 60.41 mmol, 2.0 equiv.), potassium acetate (8.89 g, 90.61 mmol, 3.0 equiv.) were dissolved in anhydrous dioxane (300 mL), after stirring well, Pd(dppf)Cl2(0.44 g, 1.81 mmol, 0.02 equiv.) was added, replaced by argon for 5 times, reacted at 100 °C for 4 h. LCMS detected that the reaction was complete, after cooling to room temperature, filtered, added water to the filtrate, extracted with ethyl acetate, washed the organic phase with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then purified by column chromatography to obtain the target compound A-6, yellowish solid 8.64 g, yield 60%. UPLC-MS m / z: calcd for C 24 H 28 BCl2N2O3[M+H] + 473.15; found: 473.22.

[0112] Synthesis of Example 1

[0113] Step 1:

[0114] 1-1 (500.00 mg, 1.96 mml, 1.0 equiv.) was dissolved in dichloromethane (20 mL), m-CPBA (85%, 875.30 mg, 4.31 mml, 2.2 equiv.) was added, and the reaction was carried out at room temperature for 8 h. LCMS detected that the raw material was completely reacted, water was added, the organic phase was washed with saturated sodium thiosulfate solution, 5M sodium hydroxide solution, and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, and then concentrated to obtain 1-2 crude product, which was directly used in the next step reaction.

[0115] Step 2:

[0116] 1-2 crude product was dissolved in dimethyl sulfoxide (20 mL), potassium carbonate (205.00 mg, 2.35 mml, 1.2 equiv.) and methyl sulfonamide (205.05 mg, 2.16 mmol, 1.1 equiv.) were added, and the reaction was carried out at 50 °C for 12 h. LCMS detected that the raw material was completely reacted, water was added, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then purified by column chromatography to obtain the target compound 1-3, white solid 370 mg, two-step yield 62%. UPLC-MS m / z: calcd for C9H8BrN3O2S [M+H] + 301.95; found: 303.02.

[0117] Step 3:

[0118] To a solution of 1-3 (100 mg, 330.97 pmol, 1.0 equiv.), A-6 (157 mg, 330.97 pmol, 1.0 equiv.), potassium carbonate (161 mg, 1.16 mmol, 3.5 equiv.) in dioxane (10 mL) and water (2 mL) was added Pd(PPh3)2Cl2(4.6 mg, 6.62 pmol, 0.02 equiv.) and the reaction mixture was purged with argon for 5 times. The reaction mixture was heated at 80 °C for 1 h. LCMS showed the reaction was completed. After cooling to room temperature, water was added and the pH value was adjusted to neutral with 1 M hydrogen chloride solution. The reaction mixture was extracted with ethyl acetate and the organic phase was washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography and reverse phase HPLC to give the target compound Example 1 as a yellow solid 78 mg in 41% yield.

[0119] Synthesis of Example 2

[0120] Step 1:

[0121] To a solution of 2-1 (200.00 mg, 821.40 pmol, 1.0 equiv.) in dimethyl sulfoxide (10 mL) was added potassium carbonate (136 mg, 985.67 pmol, 1.2 equiv.) and methyl sulfonamide (85.94 mg, 903.54 pmol, 1.1 equiv.) and the reaction mixture was heated at 120 °C for 1 h. LCMS showed the starting material was consumed completely. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and purified by column chromatography to give the target compound 2-2 as a white solid 180 mg in 72% yield. UPLC-MS m / z: calcd for C9H8BrN3O2S [M+H] 301.95; found: 303.02. + 301.95; found: 303.02.

[0122] Step 2:

[0123] Reference to Example 1, step 3, the target compound Example 2 was obtained as a yellow solid 74 mg in 39% yield.

[0124] Synthesis of Example 3

[0125] Reference to the synthesis of Example 2, the target compound Example 3 was obtained as a yellow solid 86 mg in 45% yield using 7-bromo-2-chloroquinoxaline as the starting material.

[0126] Synthesis of Example 4

[0127] Step 1:

[0128] Dissolve 4-1 (300.00 mg, 1.26 mmol, 1.0 equiv.) in dimethyl sulfoxide (10 mL), add potassium carbonate (383.45 mg, 2.77 mmol, 2.2 equiv.) and tert-butyl azetidin-3-ylcarbamate (238.92 mg, 1.39 mmol, 1.1 equiv.), and warm to 80 °C for 1 h. LCMS detection shows that the starting material is completely reacted. Add water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate to give the target compound 4-2 crude product, which is directly used in the next step.

[0129] Step 2:

[0130] Dissolve 4-2 crude product in dioxane (5 ml), add 4M hydrogen chloride dioxane solution (10 ml), and react at room temperature for 2 h. LCMS detection shows that the starting material is completely reacted. Remove the solvent by rotary evaporation, dissolve the residue in dichloromethane, wash with saturated sodium bicarbonate solution and saturated sodium chloride solution successively, dry over anhydrous sodium sulfate, and concentrate to give the target compound 4-3 crude product, which is directly used in the next step.

[0131] Step 3:

[0132] Dissolve 4-3 crude product in dichloromethane (10 ml), add triethylamine (191.43 mg, 1.89 mmol, 1.5 equiv.) and methane sulfonic anhydride (241.64 mg, 1.39 mmol, 1.1 equiv.) successively, and react at room temperature for 2 h. LCMS detection shows that the starting material is completely reacted. Add water, extract with dichloromethane, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and purify by column chromatography to give the target compound 4-4, white solid 123 mg, 31% yield for three steps. UPLC-MS m / z: Calcd for C8H 12 BrN4O2S[M+H] + : 306.98, Found 307.11.

[0133] Step 4:

[0134] Reference to Step 3 of Reference Example 1, the target compound Example 4 is obtained, yellow solid 21 mg, yield 46%.

[0135] Synthesis of Example 5

[0136] Reference to the synthesis of Example 4, Example 5 is obtained, yellow solid 29 mg, yield 45%, using 5-bromo-2-fluoropyrimidine as the starting material.

[0137] Synthesis of Example 6

[0138] Example 6 was obtained as a yellow solid 22 mg in 41% yield by the procedure described in Example 2, using 6-hydroxy-1,2,3,4-tetrahydroquinoline as the starting material.

[0139] Synthesis of Example 7

[0140] Step 1:

[0141] Dissolve 7-1 (500.00 mg) in acetonitrile (10 ml), add pyridine (354.60 mg, 4.48 mmol, 2.0 equiv.) and methanesulfonyl chloride (385.11 mg, 3.36 mmol, 1.5 equiv.), and warm to 50 °C for 8 h. LCMS detection shows that the starting material is completely consumed. Add water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and purify by column chromatography to obtain the target compound 7-2, a gray solid 425 mg in 63% yield. UPLC-MS m / z: Calcd for C 10 H 10 BrN2O2S[M+H] + : 301.08.

[0142] Step 2:

[0143] Refer to Step 3 in Reference Example 1 to obtain the target compound Example 7, a yellow solid 35 mg in 37% yield.

[0144] Synthesis of Example 8

[0145] Step 1:

[0146] Dissolve 2-1 (500.00 mg) in dimethylformamide (10 ml), add potassium carbonate (624.36 mg, 4.52 mmol, 2.2 equiv.) and p-methoxybenzylamine (309.87 mg, 2.26 mmol, 1.1 equiv.), and warm to 80 °C for 1 h. LCMS detection shows that the starting material is completely consumed. Add water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and purify by column chromatography to obtain the target compound 8-2, a gray solid 620 mg in 87% yield. UPLC-MS m / z: Calcd for C 16 H 15 BrN3O[M+H] + : 344.14.

[0147] Step 2:

[0148] Dissolve 8-2 (620.00 mg) in dichloromethane (10 ml), add trifluoroacetic acid (10 ml), and warm to 60 °C for 4 h. LCMS detection shows that the reaction is complete. Remove the solvent and excess trifluoroacetic acid by rotary evaporation, dissolve in dichloromethane, wash the organic phase with saturated sodium bicarbonate solution and saturated sodium chloride solution, dry over anhydrous sodium sulfate, and purify by column chromatography to obtain the target compound 013-3, 240 mg of brown oil, in a yield of 59%. UPLC-MS m / z: Calcd for C8H7BrN3[M+H] + : 223.97, Found 224.08.

[0149] Step 3:

[0150] Dissolve 8-3 (240.00 mg) in dichloromethane (10 ml), add pyridine (101.67 mg, 1.29 mmol, 1.2 equiv.) and acetyl chloride (92.49 mg, 1.18 mmol, 1.1 equiv.), and react at room temperature for 8 h. LCMS detection shows that the reaction is complete. Add water, extract with dichloromethane, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and purify by column chromatography to obtain the target compound 8-4, 180 mg of brown solid, in a yield of 63%. UPLC-MS m / z: Calcd for C 10 H9BrN3O [M+H] + : 265.98, Found 266.09.

[0151] Step 4:

[0152] Reference Example 1, Step 3, to obtain the target compound Example 8, 21 mg of yellow solid, in a yield of 48%.

[0153] Synthesis of Example 9

[0154] Reference Example 2, using 6-bromo-2-chloroquinoline as the starting material, to obtain Example 9, 18 mg of yellow solid, in a yield of 27%.

[0155] Synthesis of Example 10

[0156] Step 1:

[0157] Dissolve 10-1 (500.00 mg, 2.25 mmol, 1.0 equiv.) in dimethyl sulfoxide (10 ml), add iodine (857.13 mg, 3.38 mmol, 1.5 equiv.) and trifluoroacetic acid (385.07 mg, 3.38 mmol, 1.5 equiv.), heat to 120 °C for 30 min under air atmosphere. LCMS detection shows the starting material is consumed completely, add water after cooling to room temperature, extract with ethyl acetate, wash the organic phase with saturated sodium bicarbonate solution, saturated sodium thiosulfate solution and saturated sodium chloride solution in turn, dry over anhydrous sodium sulfate and purify by column chromatography to give the target compound 10-2, white solid 450 mg, 84% yield for three steps. UPLC-MS m / z: Calcd for C 10 H7BrNO[M+H] + : 235.96, Found 236.11.

[0158] Step 2:

[0159] Dissolve 10-2 (450 mg, 1.91 mmol, 1.0 equiv.) and tert-butyl carbamate (446.62 mg, 3.81 mmol, 2.0 equiv.) in acetonitrile (50 ml), add trifluoroacetic acid (652.06 mg, 5.72 mmol, 3.0 equiv.) and triethylsilane (2.22 g, 19.06 mmol, 10.0 equiv.) under ice bath condition, react at room temperature for 48 h. LCMS detection shows the starting material is consumed completely, quench the reaction by slow addition of saturated sodium bicarbonate solution, extract with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate and purify by column chromatography to give the target compound 10-3, white solid 420 mg, 65% yield for three steps. UPLC-MS m / z: Calcd for C 15 H 18 BrN2O2[M+H] + : 337.05, Found 337.00.

[0160] Subsequent steps refer to the synthesis of Example 4, give yellow solid 53 mg.

[0161] Synthesis of Example 11

[0162] Take 2,6-dichlorophenol as raw material, refer to the synthesis of key intermediate A-6 and Example 2, give Example 11 yellow solid 53 mg.

[0163] Synthesis of Example 12

[0164] Example 12 was obtained as a yellow solid 18 mg in 41% yield by following the procedure of Example 2 using cyclopropyl sulfonamide as starting material.

[0165] Synthesis of Example 13

[0166] Example 13 was obtained as a yellow solid 31 mg in 38% yield by following the procedure of Example 2 using isopropyl sulfonamide as starting material.

[0167] Synthesis of Example 14

[0168] Example 14 was obtained as a yellow solid 10 mg in 14% yield by following the procedure of Example 2 using 2,5-dibromopyrazine as starting material.

[0169] Synthesis of Example 15

[0170] Example 15 was obtained as a yellow solid 21 mg in 22% yield by following the procedure of Example 2 using 2,6-dibromopyrazine as starting material.

[0171] Synthesis of Example 16

[0172] Example 16 was obtained as a yellow solid 18 mg in 39% yield by following the procedure of Example 1 using N-(4-bromophenyl)methanesulfonamide as starting material.

[0173] Synthesis of Example 17

[0174] Step 1:

[0175] Step 1: 17-1 (500 mg, 2.18 mmol, 1.0 equiv.) was dissolved in pyridine (10 ml), methane sulfonyl chloride (375 mg, 3.27 mmol, 1.5 equiv.) was added, and the reaction was heated to 50 °C for 8 h. LCMS showed the starting material was consumed completely. The solvent was removed by rotary evaporation, and the residue was dissolved in dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate, and purified by column chromatography to give the target compound 17-2 as a brown solid 270 mg in 40% yield. UPLC-MS m / z: Calcd for C8H8BrN2O2S2[M+H]: 306.91, Found 306.99. +

[0176] Step 2:

[0177] Step 3 of Example 1 was followed to give the target compound Example 17 as a yellow solid 28 mg in 30% yield. UPLC-MS m / z: Calcd for C 26 H​23 Cl2N4O3S2[M+H] + : 573.05, Found 573.10.

[0178] Synthesis of Example 18

[0179] Step 1:

[0180] Dissolve 18-1 (500 mg, 3.26 mmol, 1.0 equiv.) in DMF (10 ml), add NaH (60%, 143.24 mg, 3.58 mmol, 1.1 equiv.) under ice-bath condition, after 10 min at 0 °C, slowly drop iodomethane (415.92 mg, 2.93 mmol, 0.9 equiv.), continue to react at 0 °C for 1 h. Add saturated ammonium chloride solution to quench the reaction, add ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, then purify by column chromatography to obtain the target compound 18-2, white solid 230 mg, yield 42%. UPLC-MS m / z: Calcd for C7H7ClN3[M+H] + : 168.03, Found 168.07.

[0181] Step 2:

[0182] Dissolve 18-2 (230 mg, 1.37 mmol, 1.0 equiv.) in dioxane (5 ml), add methanesulfonamide (144 mg, 1.51 mmol, 1.1 equiv.), Pd-175 (54 mg, 0.07 mmol, 0.05 equiv.) and cesium carbonate (536.56 mg, 1.65 mmol, 1.2 equiv.), replace with argon for 5 times, warm up to 90 °C and react for 2 h. LCMS detects that the raw material is completely reacted, cool to room temperature, add ethyl acetate and water, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, then purify by column chromatography to obtain the target compound 18-3, white solid 140 mg, yield 45%. UPLC-MS m / z: Calcd for C8H 11 N4O2S[M+H] + : 227.05, Found 228.06.

[0183] Step 3:

[0184] Dissolve 18-3 (140 mg, 618.77 μmol, 1.0 equiv.) in DMF (5 ml), add NBS (88.11 mg, 495.02 μmol, 0.8 equiv.) in batches under ice bath condition, react for 1 h under ice bath. Add ethyl acetate and water, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate and purify by column chromatography to obtain the target compound 18-4, white solid 80 mg, yield 42%. UPLC-MS m / z: Calcd for C8H 10 BrN4O2S [M+H] + : 304.96, Found 306.00.

[0185] Step 4:

[0186] Dissolve 18-4 (30 mg, 98.31 μmol, 1.0 equiv.), A-6 (46.52 mg, 98.31 μmol, 1.0 equiv.), cesium carbonate (112.11 mg, 344.09 μmol, 3.5 equiv.) in toluene (2 ml) and ethanol (1 ml), add Pd(OAc)2(1.10 mg, 4.92 μmol, 0.05 equiv.) and Xphos (2.34 mg, 4.92 μmol, 0.05 equiv.), replace with argon for 5 times, react for 1 h at 80 °C. LCMS shows that the reaction is complete, after cooling to room temperature, add water, adjust pH value to neutral with 1 M hydrogen chloride solution, extract with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate and purify by column chromatography and reverse phase HPLC to obtain the target compound Example 18, yellow solid 18 mg, yield 32%.

[0187] Synthesis of Example 19

[0188] Take 6-bromo-4-chloroquinazoline as raw material, refer to the synthesis of Example 2 to obtain the target compound Example 19, yellow solid 15 mg. UPLC-MS m / z: Calcd for C 27 H 24 Cl2N5O3S [M+H] + : 568.09, Found 568.10.

[0189] Synthesis of Example 20

[0190] Step 1:

[0191] A-3 (1.00 g, 2.92 mmol, 1.0 equiv.) and 6-bromo-1,2,3,4-tetrahydroquinoline (620.22 mg, 2.92 mmol, 1.0 equiv.) were suspended in toluene (30 ml), sodium tert-butoxide (702.70 mg, 7.31 mmol, 2.5 equiv.) was added portionwise, after stirring uniformly, Pd2(dba)3(53.51 mg, 58.37 μmol, 0.02 equiv.) and Xphos (41.62 mg, 86.49 μmol, 0.03 equiv.) were added, replaced with argon for 5 times, reacted at 80 °C for 3 h. LCMS detected that the reaction was complete, after cooling to room temperature, water was added, 1M dilute hydrochloric acid was used to adjust the pH to neutral, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then column chromatography to purify the target compound 20-1, yellow solid 520 mg, yield 42%. UPLC-MS m / z: calcd for C 18 H 16 BrCl2N2O [M+H] + : 424.97; found: 424.99.

[0192] Step 2:

[0193] 21-1 (520 mg, 1.22 mmol, 1.0 equiv.) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (312.81 mg, 1.22 mmol, 1.0 equiv.) were suspended in toluene (30 ml), cesium carbonate (596.38 mg, 1.83 mmol, 1.5 equiv.) was added, after stirring uniformly, Pd(OAc)2(10.10 mg, 61.01 μmol, 0.05 equiv.) and Xphos (29.09 mg, 61.01 μmol, 0.05 equiv.) were added, replaced with argon for 5 times, reacted at 100 °C for 2 h. LCMS detected that the reaction was complete, after cooling to room temperature, water was added, 1M dilute hydrochloric acid was used to adjust the pH to neutral, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then column chromatography to purify the target compound 20-2, yellow solid 480 mg, yield 65%. UPLC-MS m / z: calcd for C 31 H 39 Cl2N4O4 [M+H] + : 601.23; found: 601.25.

[0194] Step 3:

[0195] Dissolve 21-2 (100 mg, 166.23 μmol, 1.0 equiv.) in dichloromethane (5 ml), add trifluoroacetic acid (5 ml), react at room temperature for 1 h. LCMS detection shows the reaction is complete, spin to remove the solvent and trifluoroacetic acid, dissolve the residue in dichloromethane, wash the organic phase with saturated sodium bicarbonate solution and saturated sodium chloride solution in turn, dry over anhydrous sodium sulfate, spin dry to obtain the crude product 20-3, which is used directly in the next step. UPLC-MS m / z: calcd for C 31 H 39 Cl2N4O4[M+H] + :501.17; found: 501.15.

[0196] Step 4:

[0197] Dissolve the crude product 21-3 in dichloromethane (5 ml), add DMAP (24.37 mg, 199.48 μmol, 1.2 equiv.) and methanesulfonyl chloride (20.94 mg, 182.86 μmol, 1.1 equiv.), react at room temperature for 1 h. LCMS detection shows the reaction is complete, wash the reaction solution with saturated sodium chloride solution, dry over anhydrous sodium sulfate, then purify by column chromatography and reverse phase HPLC to obtain the target compound Example 20, yellow solid 58 mg, two-step yield 60%.

[0198] Synthesis of Example 21

[0199] Take 2-Boc-2,8-diaza-spiro[4.5]decane as the raw material, refer to the synthesis of Example 20 to obtain Example 21, yellow solid 19 mg.

[0200] Synthesis of Example 22

[0201] Step 1:

[0202] Dissolve 22-1 (500 mg, 2.29 mmol, 1.0 equiv.) in NMP (10 ml), add urea (688.64 mg, 11.47 mmol, 5.0 equiv.), heat to 160°C and react for 1 h. LCMS detection shows the reaction is complete, cool to room temperature, then filter, and purify the filtrate by reverse phase HPLC to obtain 22-2, white solid 120 mg, yield 22%. UPLC-MS m / z: Calcd for C8H5BrFN2O [M+H] + :242.95, Found 242.98.

[0203] Step 2:

[0204] Dissolve 22-2 (120 mg, 493.76 μmol, 1.0 equiv.) in phosphorus oxychloride (5 ml), warm to 100 °C for 1 h. LCMS shows the reaction is complete, after cooling to room temperature, slowly drop the reaction into ice water, filter, collect the filter cake, purify by column chromatography to get the target compound 22-3, white solid 80 mg, yield 62%. UPLC-MS m / z: calcd for C8H4BrClFN2[M+H] 260.92; found: 260.90. + :260.92; found: 260.90.

[0205] Step 3:

[0206] Dissolve 22-3 (80 mg, 305.95 μmol, 1.0 equiv.), A-6 (144.78 mg, 305.95 μmol, 1.0 equiv.), potassium carbonate (147.99 mg, 1.07 mmol, 3.5 equiv.) in dioxane (10 ml) and water (2 ml), add Pd(PPh3)2Cl2 (4.3 mg, 6.11 μmol, 0.02 equiv.), replace with argon for 5 times, react at 80 °C for 1 h. LCMS shows the reaction is complete, after cooling to room temperature, add water, adjust pH to neutral with 1 M hydrogen chloride solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, purify by column chromatography to get the target compound 22-4, yellow solid 86 mg, yield 53%. UPLC-MS m / z: calcd for C 26 H 19 Cl3FN4O[M+H] + :527.05; found: 527.04.

[0207] Step 4:

[0208] Dissolve 22-4 (20 mg, 37.89 μmol, 1.0 equiv.) and methyl sulfonamide (3.96 mg, 41.68 μmol, 1.1 equiv.) in dioxane (5 ml), add Pd2(dba)3 (0.69 mg, 0.76 μmol, 0.02 equiv.), Xantphos (1.10 mg, 1.89 μmol, 0.05 equiv.), cesium carbonate (18.52 mg, 56.84 μmol, 1.5 equiv.), replace with argon for 5 times, react at 100 °C for 2 h. LCMS shows the reaction is complete, after cooling to room temperature, add water, adjust pH to neutral with 1 M dilute hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, purify by column chromatography to get the target compound Example 22, yellow solid 12 mg, yield 54%.

[0209] Synthesis of Example 23

[0210] Step 1:

[0211] Dissolve 23-1 (500 mg, 2.10 mmol, 1.0 equiv.) in dichloromethane (10 ml), add 85% mCPBA (398.64 mg, 2.31 mmol, 1.2 equiv.) under ice bath condition, react for 2 h at room temperature. LCMS test shows the reaction is complete, wash the reaction solution with saturated sodium thiosulfate and saturated brine solution in turn, dry over anhydrous sodium sulfate to get the crude target compound 23-2, white solid 510 mg. UPLC-MS m / z: calcd for C 10 H9BrNO2[M+H] + : 253.97; found: 253.99. Step 2:

[0212] Dissolve 23-2 (510 mg) in dichloromethane (10 ml), add phosphorus tribromide (662.27 mg, 2.31 mmol, 1.1 equiv.), react for 1 h at room temperature. LCMS test shows the reaction is complete, wash the reaction solution with saturated sodium bicarbonate and saturated brine solution in turn, dry over anhydrous sodium sulfate, then purify by column chromatography to get the target compound 23-3, white solid 480 mg, two-step yield 72%. UPLC-MS m / z: calcd for C 10 H8Br2NO[M+H] + : 315.89; found: 315.87.

[0213] Step 3:

[0214] Dissolve 23-3 (480 mg, 1.51 mmol, 1.0 equiv.) and methyl sulfonamide (144.03 mg, 1.51 mmol, 1.0 equiv.) in dioxane (10 ml), add Pd(OAc)2(6.80 mg, 30.29 μmol, 0.02 equiv.), Xantphos (17.52 mg, 30.29 μmol, 0.02 equiv.), cesium carbonate (740.08 mg, 2.27 mmol, 1.5 equiv.), replace argon for 5 times, react for 2 h at 100 °C. LCMS test shows the reaction is complete, after cooling to room temperature, add water, adjust pH to neutral with 1M dilute hydrochloric acid, extract with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, then purify by column chromatography to get the target compound 23-4, yellow solid 260 mg, yield 52%. UPLC-MS m / z: calcd for C 11 H 12BrN2O3S[M+H] + : 330.97; found: 330.99.

[0215] Step 4:

[0216] Dissolve 23-4 (50 mg, 150.97 μmol, 1.0 equiv.), A-6 (71.44 mg, 150.97 μmol, 1.0 equiv.), potassium carbonate (73.03 mg, 528.41 μmol, 3.5 equiv.) in dioxane (3 ml) and water (1 ml), add Pd(PPh3)2Cl2(2.1 mg, 3.02 μmol, 0.02 equiv.), replace with argon for 5 times, react at 80 °C for 1 h. LCMS shows the reaction is complete, after cooling to room temperature, add water, adjust pH value to neutral with 1 M hydrogen chloride solution, extract with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate and purify by column chromatography to obtain the target compound Example 23, yellow solid 33 mg, yield 37%.

[0217] Synthesis of Example 24

[0218] Take 6-bromo-4-chloroquinoline as raw material, refer to the synthesis of Example 23 to obtain Example 24, yellow solid 18 mg.

[0219] Synthesis of Example 25

[0220] Step 1:

[0221] Dissolve 25-1 (1 g, 5.79 mmol, 1.0 equiv.) in DMF (10 ml), add methyl sulfonamide (661.42 mg, 6.95 mmol, 1.2 equiv.), K2CO3(1.6 g, 11.58 mmol, 2 equiv.), react at 120 °C for 2 h. LCMS shows that the reaction is complete, wash the reaction liquid with saturated sodium thiosulfate and saturated brine successively, dry over anhydrous sodium sulfate to obtain the crude target compound 25-2, white solid 1 g, yield 72%. UPLC-MS m / z: calcd for C7H9N3O4S [M+H] + : 231.23; found: 231.39.

[0222] Step 2:

[0223] Dissolve 25-2 (1 g, 4.32 mmol) in THF / MeOH (6 / 6 ml), dissolve lithium hydroxide (207.13 mg, 8.65 mmol, 2 equiv.) in water, add to the reaction system under ice bath, react at room temperature for 1 h. LCMS detects that the reaction is complete, the reaction liquid is washed with saturated sodium bicarbonate and saturated brine in turn, dried over anhydrous sodium sulfate and purified by column chromatography to obtain the target compound 25-3, white solid 900 mg. UPLC-MS m / z: calcd for C6H7N3O4S [M+H] + : 217.20; found: 217.11. Step 3:

[0224] Dissolve A-3 (600 mg, 1.75 mmol, 1.0 equiv.) and tert-butyl (1,2,3,4-tetrahydroquinolin-6- yl)carbamate (522.86 mg, 2.11 mmol, 1.2 equiv.) in toluene (10 ml), add Pd2(dba)3 (32.06 mg, 30 μmol, 0.02 equiv.), Xphos (16.6 mg, 30 μmol μmol, 0.02 equiv.), t BuON (557.35 mg, 6.13 mmol, 3.5 equiv.), replace argon 5 times, react at 80°C for 2 h. LCMS detects that the reaction is complete, add water after cooling to room temperature, adjust pH to neutral with 1M dilute hydrochloric acid, extract with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate and purify by column chromatography to obtain the target compound 25-4, yellow solid 60 mg, yield 7.4%. UPLC-MS m / z: calcd for C 23 H 25 Cl2N3O3[M+H] + : 462.37; found: 462.33.

[0225] Step 4:

[0226] Dissolve 25-4 in dioxane (1 ml), add 4M hydrogen chloride dioxane solution (1 ml), react at room temperature for 2 h. LCMS detects that the starting material is completely reacted, spin evaporation to remove the solvent, dissolve the residue in dichloromethane, wash with saturated sodium bicarbonate solution and saturated sodium chloride solution in turn, dry over anhydrous sodium sulfate and concentrate to obtain the target compound 25-5 crude product, which is directly used in the next step reaction.

[0227] Step 5:

[0228] To a solution of 25-5 (60 mg, 165.63 μmol, 1.0 equiv.) and 26-3 (39.57 mg, 182.19 μmol, 1.1 equiv.) in DMF (3 ml) was added HATU (50.16 mg, 132.1 μmol, 0.8 equiv.) and DIEA (74.49 mg, 579.70 μmol, 3.5 equiv.) and the reaction was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and purified by column chromatography and reverse phase HPLC to give the title compound Example 25 as a yellow solid 30 mg in 32% yield.

[0229] Synthesis of Example 26

[0230] Using 6-bromo-2-chloroquinoxaline as starting material, the synthesis was performed according to Example 2 to give Example 26 as a yellow solid 40 mg in 38.9% yield.

[0231] Synthesis of Example 27

[0232] Using 6-bromo-2-chloroquinoxaline as starting material, the synthesis was performed according to Example 2 to give Example 27 as a yellow solid 24.5 mg in 22.6% yield.

[0233] Synthesis of Example 28

[0234] Using 4-morpholine sulfonamide as starting material, the synthesis was performed according to Example 25 to give Example 28 as a yellow solid 39 mg in 55.84% yield.

[0235] Synthesis of Example 29

[0236] Using 6-bromo-2-chloroquinoxaline and ethyl sulfonamide as starting material, the synthesis was performed according to Example 2 to give Example 29 as a yellow solid 41 mg in 37.09% yield.

[0237] Synthesis of Example 30

[0238] Step 1:

[0239] Dissolve 3-chloro-2-fluorobenzonitrile (500 mg, 3.21 mmol, 1.0 equiv.) in DMSO (10 mL), add azetidin-3-ol (258.44 mg, 3.54 mmol, 1.1 equiv.), K2CO3(885.96 mg, 6.42 mmol, 2 equiv.) and warm to 110 °C for 4 h. TLC shows the reaction is complete. After cooling to room temperature, add water and extract with ethyl acetate. Wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate and purify by column chromatography to give the target compound 30-2 as a white solid 500 mg, 74.5% yield. UPLC-MS m / z: calcd for C 10 H9ClN2O [M+H] + 208.04; found: 208.65.

[0240] Step 2:

[0241] Add 30-2 (500 mg, 2.4 mmol, 1.0 equiv.) to NBS (136.3 mg, 2.4 mmol, 1.0 equiv.) and react at room temperature for 2 h. TLC shows the reaction is complete. Add water and extract with ethyl acetate. Wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate and purify by column chromatography to give the target compound 30-3 as a yellow solid 500 mg, 72.5% yield. UPLC-MS m / z: calcd for C 10 H8BrClN2O [M+H] + 285.95; found: 287.54.

[0242] Step 3:

[0243] Dissolve 30-3 (62.3 mg, 1.74 mmol, 1.0 equiv.) in dichloromethane (10 ml), add imidazole (177.6 mg, 2.61 mmol, 1.5 equiv.) and tert-butyldimethylsilyl chloride (262.3 mg, 1.74 mmol, 1.0 equiv.) and react at room temperature for 4 h. TLC shows the reaction is complete. After cooling to room temperature, add water and extract with dichloromethane. Wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate and purify by column chromatography to give the target compound 30-4 as a yellow solid 600 mg, 85% yield. UPLC-MS m / z: calcd for C 16 H 22 BrClN2OSi [M+H] + 400.04; found: 401.80.

[0244] Step 4:

[0245] To a solution of 30-4 (590 mg, 1.47 mmol, 1.0 equiv.) and 6-hydroxy-1,2,3,4- tetrahydroquinoline (219.07 mg, 1.47 mmol, 1.0 equiv.) in THF (10 ml) was added sodium tert-butoxide (353.1 mg, 3.67 mmol, 2.5 equiv.) portionwise, after stirring well trifurylphosphine (23.35 mg, 0.029 mmol, 0.02 equiv.) and tBuxphos (18.73 mg, 0.044 mmol, 0.03 equiv.) were added, replaced with argon for 5 times, reacted at 60 °C for 2 h. LCMS detected that the reaction was completed, after cooling to room temperature, water was added, 1M dilute hydrochloric acid was used to adjust the pH to neutral, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then purified by column chromatography to obtain the target compound 30-5, yellow solid 12.75 g, yield 64%. UPLC-MS m / z: calcd for C 25 H 32 ClN3O2Si[M+H] + 469.20; found: 470.09.

[0246] Step 5:

[0247] To a solution of 30-5 (590 mg, 1.26 mmol, 1.0 equiv.) and pyridine (110.3 mg, 1.38 mmol, 1.1 equiv.) in anhydrous dichloromethane (10 ml), a solution of trifluoromethanesulfonic anhydride (391.04 mg, 1.38 mmol, 1.1 equiv.) in anhydrous dichloromethane (5 ml) was added dropwise under ice bath conditions, and the reaction was carried out under ice bath conditions for 1 h. LCMS detected that the reaction was completed, saturated brine was added for washing, dried over anhydrous sodium sulfate, and then purified by column chromatography to obtain the target compound 30-6, yellow oil 560 mg, yield 74.1%. UPLC-MS m / z: calcd for: C 26 H 31 ClF3N3O4SSi[M+H] + 601.14; found: 602.14.

[0248] Step 6:

[0249] Dissolve 30-6 (550 mg, 913.41 μmol, 1.0 equiv.), bis(pinacolato)diboron (464.01 mg, 1.83 mmol, 2.0 equiv.), potassium acetate (268.92 mg, 2.7 mmol, 3.0 equiv.) in anhydrous dioxane (10 ml), after stirring well, add Pd(dppf)Cl2(13.37 mg, 18.26 μmol, 0.02 equiv.), replace with argon for 5 times, react at 100 °C for 4 h. LCMS shows that the reaction is complete, after cooling to room temperature, filter, add water to the filtrate, extract with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, then purify by column chromatography to obtain the target compound 30-7, yellowish solid 430 mg, yield 81%. UPLC-MS m / z: calcd for C 31 H 43 BClN3O3Si[M+H] + 579.29; found: 580.02.

[0250] Step 7:

[0251] Dissolve 30-7 (100 mg, 172.40 μmol, 1.0 equiv.), 32-8 (52.09 mg, 172.40 μmol, 1.0 equiv.), potassium carbonate (83.2 mg, 603.4 μmol, 3.5 equiv.) in dioxane (5 ml) and water (1 ml), add Pd(PPh3)2Cl2(2.4 mg, 3.44 μmol, 0.02 equiv.), replace with argon for 5 times, react at 80 °C for 1 h. LCMS shows that the reaction is complete, after cooling to room temperature, add water, adjust pH to neutral with 1 M hydrogen chloride solution, extract with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, then purify by column chromatography to obtain the target compound 30-9, yellowish solid 60 mg, yield 51.5%. UPLC-MS m / z: calcd for C 34 H 39 ClN6O3SSi[M+H]+674.23; found: 675.32.

[0252] Step 8:

[0253] To a solution of 30-9 (60 mg, 88.85 μmol, 1.0 equiv.) in THF (2 mL) was added TBAF 1.0 M in THF 2.0 equiv. at 0 °C and stirred for 1 h at room temperature. LCMS showed the reaction was complete. After cooling to room temperature, water was added, the pH value was adjusted to neutral with aqueous sodium bicarbonate solution, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by column chromatography and reverse phase HPLC to give the target compound Example 30 as a yellow solid 10 mg in 20.6% yield.

[0254] Synthesis of Example 31

[0255] Step 1:

[0256] To a solution of 31-1 (300 mg, 0.86 mmol, 1.0 equiv.) in THF (5 ml) was added triethylamine (126.7 mg, 1.25 mmol, 1.5 equiv.), Boc anhydride (187.69 mg, 0.86 mmol, 1 equiv.), and stirred for 2 h at room temperature. LCMS showed the reaction was complete. The reaction mixture was washed with saturated sodium thiosulfate and saturated brine successively, dried over anhydrous sodium sulfate, and purified by column chromatography to give the target compound 31-2 as a white solid 225 mg in 73% yield. UPLC-MS m / z: calcd for C 13 H 13 BrClN3O2[M+H] + :358.62; found: 358.33.

[0257] Step 2:

[0258] To a solution of A-6 (300 mg, 633.98 μmol) and 33-2 (225 mg, 633.98 μmol, 1.0 equiv.) in dioxane (10 ml) and water (2 ml) was added cesium carbonate (732.34 mg, 2.21 mmol, 3.5 equiv.) and Pd(dppf)Cl2(23.2 mg, 3.17 μmol, 0.05 equiv.), and stirred for 4 h at 80 °C. LCMS showed the reaction was complete. After cooling to room temperature, water was added, the pH value was adjusted to neutral with 1 M hydrogen chloride solution, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by column chromatography to give the target compound 31-3 as a yellow solid 200 mg in 43.51% yield. UPLC-MS m / z: calcd for C 36 H 36 Cl3N5O5[M+H] +: 725.06; found: 725.13.

[0259] Step 3:

[0260] Dissolve 31-3 (200 mg, 275.84 μmol, 1.0 equiv.) and methyl sulfonamide (39.35 mg, 413.76 μmol, 1.1 equiv.) in dioxane (5 ml), add Pd2(dba)3(5.05 mg, 5.5 μmol, 0.02 equiv.), Xantphos (6.56 mg, 1.37 μmol, 0.05 equiv.), cesium carbonate (134.88 mg, 413.76 μmol, 1.5 equiv.), replace argon 5 times, react at 100 °C for 2 h. Detect complete reaction by LCMS, add water after cooling to room temperature, adjust pH to neutral with 1M dilute hydrochloric acid, extract with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and purify by column chromatography to obtain the target compound 31-4, yellow solid 100 mg, yield 46.2%. UPLC-MS m / z: calcd for C 37 H 40 Cl2N6O7S[M+H] + : 783.72; found: 783.10.

[0261] Step 4:

[0262] Dissolve 31-4 (90 mg, 114.84 μmol, 1.0 equiv.) in dichloromethane (3 ml), add trifluoroacetic acid (1 ml), react at room temperature for 1 h. Detect complete reaction by LCMS, remove the solvent and trifluoroacetic acid by rotary evaporation, dissolve the residue in dichloromethane, wash the organic phase with saturated sodium bicarbonate solution and saturated sodium chloride solution in turn, dry over anhydrous sodium sulfate, and purify by column chromatography and reverse phase HPLC to obtain the target compound Example 31, yellow solid 25 mg, yield 37%.

[0263] Synthesis of Example 32

[0264] Step 1:

[0265] Dissolve 2,6-dichloro-1,5-naphthyridine (300 mg, 1.51 mmol) and A-6 (1 g, 2.26 mmol, 1.5 equiv.), potassium carbonate (732.34 mg, 5.28 mmol, 3.5 equiv.) in dioxane (10 ml) and water (2 ml), add Pd(pph3)4(87.2 mg, 75.5 μmol, 0.05 equiv.), replace with argon for 5 times, react at 80 °C for 16 h. LCMS shows the reaction is complete, after cooling to room temperature, add water, adjust pH value to neutral with 1 M hydrogen chloride solution, extract with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and purify by column chromatography to obtain the target compound 34-1, yellow solid 160 mg, yield 20%. UPLC-MS m / z: calcd for C 26 H 19 Cl3N4O[M+H] + :509.82; found: 510.13.

[0266] Purify by column chromatography and reverse phase HPLC according to the reference of example 31 step 3 to obtain the target compound example 32, yellow solid 50 mg, yield 29.8%.

[0267] Synthesis of example 33

[0268] Take 2-amino-5-bromothiazole as raw material, refer to the synthesis of example 17 to obtain example 33, yellow solid 20 mg, yield 17.85%.

[0269] Synthesis of example 34

[0270] Take 3-bromo-8-chloro-1,7-naphthyridine as raw material, refer to the synthesis of example 32 to obtain example 34, yellow solid 18 mg, yield 16.1%.

[0271] Synthesis of example 35

[0272] Take 2,4-dichloro-7-bromoquinazoline as raw material, refer to the synthesis of example 2 and example 32 to obtain example 35, yellow solid 20 mg, yield 26%.

[0273] Synthesis of example 36

[0274] Step 1:

[0275] To a solution of 3-chloro-2-fluorobenzonitrile (900 mg, 3.79 mmol, 1.0 equiv.) in tetrahydrofuran and aqueous ammonia (20 mL and 20 mL) was added iodine (1.94 g, 7.58 mmol, 2 equiv.) and the reaction was stirred at room temperature overnight. TLC indicated that the starting material was consumed and aqueous sodium sulfite was added. The reaction mixture was extracted with ethyl acetate and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give the crude 36-2 which was used directly in the next step.

[0276] Step 2:

[0277] To a solution of 36-2 (800 mg, 3.41 mmol, 1.0 equiv.) in DMSO (10 mL) was added morpholine (327.01 mg, 3.75 mmol, 1.1 equiv.), K2CO3 (941.16 mg, 6.82 mmol, 2 equiv.) and the reaction was stirred at 100 °C for 4 h. TLC indicated that the starting material was consumed and the reaction mixture was cooled to room temperature, added water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and purified by column chromatography to give the target compound 36-3 as a yellow solid 800 mg in 77% yield. UPLC-MS m / z: calcd for C 11 H 10 BrClN2O [M+H] + 299.97; found: 301.57.

[0278] Step 3-6:

[0279] The synthesis was carried out as described in Reference Example 30 to give the target compound Example 36 as a yellow solid 37 mg in 30.8% yield.

[0280] Synthesis of Example 37

[0281] The synthesis was carried out as described in Reference Example 32 using 7-bromo-1- chloroisoquinoline as the starting material to give Example 37 as a yellow solid 45 mg in 15.9% yield.

[0282] Synthesis of Example 38

[0283] Step 1-3 synthesis was carried out as described in Reference Example 2 using 6-bromo-2,4- dichloroquinazoline as the starting material.

[0284] Step 4:

[0285] Dissolve 38-4 (50 mg, 92.79 μmol, 1.0 equiv.) in dioxane (2 ml), add methanesulfonamide (144 mg, 139.18 μmol, 1.5 equiv.), Pd-175 (5.1 mg, 6.49 μmol, 0.05 equiv.) and cesium carbonate (36.2 mg, 111.3 μmol, 1.2 equiv.), replace with argon for 5 times, warm up to 100 °C for 1 h. LCMS shows the starting material is consumed completely, cool down to room temperature, add ethyl acetate and water, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, then purify by column chromatography and reverse phase HPLC to get the target compound Example 38, yellow solid 5 mg, yield 9.2%.

[0286] Synthesis of Example 39

[0287] Use 6-bromo-2,4-dichloroquinazoline and dimethylamine as starting materials, refer to the synthesis of Example 38 to get Example 39, yellow solid 46 mg, yield 34.6%.

[0288] Synthesis of Example 40

[0289] Use 6-chloro-2-acetylpyrazine as starting material, refer to Example 25 to get Example 40, yellow solid 6 mg, yield 6.6%.

[0290] Synthesis of Example 41

[0291] Step 1-4 Use 1,2,3,4-tetrahydroquinoline-6-carboxylate as starting material, refer to Example 25 to get compound 41, yellow solid 25 mg. UPLC-MS m / z: Calcd for C 19 H 16 Cl2N2O3[M+H] + : 391.25, Found 391.56.

[0292] Step 5:

[0293] To a solution of 41-6 (25 mg, 63.90 μmol, 1.0 equiv.) and 43-3 (14.43 mg, 76.68 μmol, 1.2 equiv.) in ACN (2 ml) was added NMI (9.4 mg, 115 μmol, 1.8 equiv.) and stirred for 10 min. TCFH (19.6 mg, 70.28 μmol, 3.5 equiv.) was added under ice-bath and the reaction was stirred at room temperature for 1 h. LCMS showed the reaction was completed. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and purified by column chromatography and reverse phase HPLC to give the target compound Example 41 as a yellow solid 3.6 mg in a yield of 10.3%.

[0294] Synthesis of Example 42

[0295] Example 42 was synthesized from 6-bromo-4-fluoroquinoline as starting material according to the procedure described in Example 23 to give Example 42 as a yellow solid 32 mg.

[0296] Verification Example 1: Prostate tumor cell proliferation inhibition activity of Example compounds

[0297] Prostate tumor cells LNCaP and VCaP were purchased from Wuhan Pnnsay Life Science Co., Ltd. The culture medium of LNCaP cells was RPMI 1640 + 10% FBS, and the culture medium of VCaP cells was DMEM + 10% FBS. The cells in the exponential growth phase were collected on the test day. The LNCaP cells were adjusted to the corresponding cell concentration and plated with RPMI 1640 medium containing 1% carbon adsorbed serum (CSS). The VCaP cells were adjusted to the corresponding cell concentration and plated with DMEM medium containing 5% CSS. After 48 h of culture, different concentrations of compounds were added to the corresponding medium containing 0.1 nM R1881, and the two cells were placed in the incubator for continuous culture for 5 days. After the culture was completed, the culture medium was removed, and the CellTiter-Lumi TM Glo Cell Viability Assay Kit (Beyotime, C0065) was used according to the instructions. The medium and detection reagent were added at a ratio of 1:1 per well, shaken, incubated, and allowed to reach a stable luminescence signal. Then, a multifunctional enzyme labeler with chemiluminescence detection function was used for chemiluminescence detection. The results were processed according to formula (1), the inhibition rates of the compounds at various concentrations were calculated, and Prism 8 software was used to calculate the IC 50 values of the compounds at 50% inhibition rate.

[0298] Inhibition rate (%) = (1 - test group chemiluminescence value / control group chemiluminescence value) x 100% formula (1)

[0299] The results of prostate tumor cell proliferation inhibition are shown in Table 1. Some of the example compounds exhibit certain castration-resistant prostate cancer cell proliferation inhibition activity (ND represents not tested), which is better than the marketed AR-LBD antagonist enzalutamide and the AR-NTD inhibitor EPI-7170 reported in the literature.

[0300] Table 1 Inhibition of tumor cell growth by compounds of the application

[0301] Test Example 2: AR-reporter inhibitory activity of example compounds

[0302] The human embryonic kidney cell 293T culture medium is DMEM (high sugar) + 10% FBS. Cells in the exponential growth phase are collected on the test day. The 293T cells are plated using a culture medium containing 10% FBS; the transfection experiment is performed within 24 hours of plating, and the cell density is about 60-80%. Before transfection, the cells are changed to a serum-free and double-antibody-free basic culture medium; AR plasmid or AR-V7 plasmid and reporter plasmid are transfected using PEI transfection reagent;

[0303] ① A tube: add the plasmid to the serum-free medium;

[0304] ② B tube: add PEI reagent to serum-free medium;

[0305] ③ Slowly add the B tube liquid to the A tube using a pipette, mix well, incubate, and add to the culture plate;

[0306] ④ Replace with normal complete culture medium after 4-6 hours.

[0307] After 24 hours of transfection, plate the cells into white plates using DMEM (high sugar) medium containing 1% carbon adsorbed serum (CSS), and after 4-5 hours of plating, add different concentrations of compounds and R1881. After 24 hours of continued incubation in the incubator, remove the culture medium, prepare the lysis solution according to the instructions of the luciferase assay system kit, add it to the wells, lyse, add luciferase detection reagent (LAR) to each well, and use a multifunctional enzyme label instrument with chemiluminescence detection function to detect chemiluminescence.

[0308] The results are processed according to formula (2), the PSA luciferase activity of each concentration of the compound is calculated, and Prism 8 software is used to calculate the IC 50 value at which the luciferase activity of the compound is inhibited by 50%.

[0309] Inhibition rate (%) = (1 - test group chemiluminescence value / control group chemiluminescence value) x 100% formula (2)

[0310] 293T cell AR Reporter and AR-V7 Reporter results are shown in Table 2. Some of the example compounds exhibit certain PSA luciferase activity inhibitory activity (ND represents not determined), and the blocking ability of AR pathway is better than that of the marketed AR-LBD antagonist enzalutamide and the AR-NTD inhibitor EPI-7170 reported in the literature.

[0311] Table 2 Inhibition of AR-reporter by compounds of the present application

[0312] Test Example 3: Pharmacokinetic study of example compounds in mice

[0313] Six male ICR mice were randomly divided into two groups, and the example compound was dissolved in the corresponding solvent, and then administered by gavage (p.o.) and tail vein injection (i.v.) respectively. The intravenous injection group was taken blood from the orbital plexus at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration; the gavage group was taken blood from the orbital plexus at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration, and placed in EP containing EDTA-2K in a wet ice environment, centrifuged, separated the plasma 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 the pharmacokinetic parameters. Including T max (maximum time), 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, Dose p.o. is the dose of the gavage administration group; AUC iv(0-∞) is the area under the plasma concentration-time curve of the tail vein injection administration group, AUC oral(0-∞) is the area under the plasma concentration-time curve of the gavage administration group. The solvent used is 20% PEG300+5% Tween 80+75%(10% SBE-β-CD in saline).

[0314] F(%)=(Dose i.v. ×AUC p.o.(0-∞) ) / (Dose p.o. ×AUC i.v.(0-∞) )×100%.

[0315] Animal in vivo pharmacokinetic data for some of the example compounds are shown in Table 3. Example compounds 2 and 3 exhibited good oral bioavailability and plasma exposure.

[0316] Table 3 Pharmacokinetic parameters of compounds of the application in mouse plasma

Claims

1. A compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or a prodrug thereof: the structure of said compound is shown in formula (I): wherein A is selected from a 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; B is selected from a 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; C is selected from a 3- to 10-membered aryl, heteroaryl, cycloalkyl, heterocycloalkyl, 4- to 12-membered bicyclic heteroaryl, spiro[m.n]cyclyl or heterospiro[m.n]cyclyl, wherein m and n are each independently selected from 3, 4, 5, 6 or 7, each of said heteroaryl, bicyclic heteroaryl, heterocycloalkyl or heterospiro[m.n]cyclyl containing 1 to 3 heteroatoms selected from N, O or S; Y is selected from absent, -CH2-, -NH-, -O- or -C(=O)-; W is selected from absent, -CH2-, -NH-, -O- or -C(=O)-; Z is selected from absent, -CH2-, -NH-, -O- or -C(=O)-; V is selected from absent, -CH2-, -NH- or -C(=O)-; said L is selected from C 1-6 alkyl or 3- to 10-membered heterocycloalkyl, said heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O or S, said alkyl, heterocycloalkyl being further substituted by one or more substituents selected from hydroxy, halogen or cyano; said R 1 , R 2 each independently is selected from hydrogen, halogen, cyano, -CH3, -CF3, or hydroxyl; R 3 selected from amino, methylamino, dimethylamino, hydroxy, methoxy, halogen, C 3-8 alkyl, -C(=O)C 6-10 alkyl, -C(=O)C 5-10 alkyl, -C(=O)C 1-6 alkyl, -C(=O)C 3-8 alkyl, -C(=O)C 3-8 alkyl, -C(=O)C 6-10 alkyl, -C(=O)C 5-10 alkyl, -C(=O)C 1-6 alkyl, -C(=O)C 1-6 alkyl, -C(=O)C 1-6 alkyl, -C(=O)C 3-8 alkyl, -C(=O)C 6-10 alkyl, -C(=O)C 5-10 alkyl, -C(=O)C 1-6 alkyl, -C(=O)C 3-8 alkyl, -C(=O)C 3-8 alkyl, -C(=O)C 6-10 alkyl, -C(=O)C 5-10 alkyl, -C(=O)C 1-6 alkyl, -C(=O)C 1-6 alkyl, -C(=O)C 1-6 alkyl, -C(=O)C 3-8 alkyl, -C(=O)C 3-8 alkyl, -C(=O)C 6-10 alkyl, -C(=O)C 5-10 alkyl, -C(=O)C 1-6 alkyl, -C(=O)C 1-6 alkyl, -C(=O)C 1-6 alkyl, -C(=O)C 3-8 alkyl, -C(=O)C 3-8 alkyl, -C(=O)C 6-10 alkyl, -C(=O)C 5-10 alkyl, -C(=O)C 1-6 alkyl, -C(=O)C 1-6 alkyl, -C(=O)C 1-6 alkyl, -C(=O)C 3-8 alkyl, -C(=O)C 5-10 heteroaryl or -NHSO2C 1-6 substituted by one or more substituents selected from the group consisting of n1, n2, n3 are each independently selected from 0, 1, 2 or 3.

2. The compound of claim 1, which has a structural formula of formula (II): ###0002### (II) ​ wherein Said A is selected from A1 is selected from an aryl or heteroaryl, A2 is selected from an aryl, heteroaryl, cycloalkyl or heterocycloalkyl, E1, E2, E3, E4, E5 are each independently selected from C or N, G1, G2, G3, G4 are each independently selected from C, O, N or -C=O; C is selected from a 3- to 10-membered aryl, heteroaryl, 4- to 12-membered bicyclic heteroaryl or heterospiro[m.n]cyclyl, wherein m and n are each independently selected from 3, 4, 5, 6 or 7, each of said heteroaryl, bicyclic heteroaryl or heterospiro[m.n]cyclyl containing 1 to 3 heteroatoms selected from N, O or S; Y is selected from absent, -NH- or -C(=O)-; W is selected from absent, -NH- or -C(=O)-; Z is absent or -O-; V is absent or -CH2-; said L is selected from C 1-6 alkyl or 3- to 10-membered heterocycloalkyl, said heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O or S, said alkyl or heterocycloalkyl being optionally further substituted by 1 or more substituents selected from hydroxy or halogen; said R 1 , R 2 are each independently selected from hydrogen, halogen, cyano, -CH3, or -CF3; said R 3 selected from amino, methylamino, dimethylamino, hydroxy, methoxy, halogen, C 3-8 cycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, -NHC(=O)C 1-6 alkyl, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 6-10 aryl, -NHC(=O)C 5-10 heteroaryl, -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 6-10 aryl, -CH2NHSO2C 5-10 heteroaryl, -CH2NHSO2NHC 1-6 alkyl or -CH2NHSO2N(C 1-6 alkyl)2, said heterocycloalkyl or heteroaryl each containing 1 to 3 heteroatoms selected from N, O or S, said alkyl, heterocycloalkyl, cycloalkyl, aryl, heteroaryl optionally further substituted by 1 or more substituents selected from deuterium, hydroxy, halogen, cyano, C 1-6 alkyl or -NHSO2C 1-6 alkyl substituents; n1, n2, n3 are each independently selected from 0, 1 or 2.

3. The compound of any one of claims 1 or 2, having a structural formula of Formula (III): ###0002### (III) ​ wherein, C is selected from a 3- to 10-membered aryl, heteroaryl, 4- to 12-membered bicyclic heteroaryl or heterospiro[m.n]cyclyl, wherein m and n are each independently selected from 3, 4, 5, 6 or 7, each of said heteroaryl, bicyclic heteroaryl or heterospiro[m.n]cyclyl containing 1 to 3 heteroatoms selected from N, O or S; Y is selected from absent, -NH- or -C(=O)-; W is selected from absent, -NH- or -C(=O)-; Z is absent or -O-; V is absent or -CH2-; L is selected from a C1-6alkyl or a 3- to 6-membered heterocycloalkyl, said heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O or S, said alkyl, heterocycloalkyl being further substituted by one or more substituents selected from hydroxy or halogen; said R 1 selected from hydrogen or -CH3; said R 2 selected from halogen or cyano; said R 3 selected from amino, methylamino, dimethylamino, hydroxy, methoxy, halogen, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, -NHC(=O)C 1-6 alkyl, -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)2or -CH2NHSO2C 1-6 alkyl, said heterocycloalkyl or heteroaryl each containing 1 to 3 heteroatoms selected from N, O or S, said alkyl, heterocycloalkyl, cycloalkyl, aryl, heteroaryl further substituted with 1 or more substituents selected from deuterium, hydroxy, halogen, cyano, C 1-6 alkyl or -NHSO2C 1-6 alkyl substituents; n2 is selected from 0, 1 or 2; n3 is selected from 1 or 2.

4. The compound according to any one of claims 1-3, wherein the structure of the compound is selected from any one of the following:

5. A pharmaceutical composition comprising a compound of Formula (I), (II) or (III), 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 excipient or carrier thereof.

6. The pharmaceutical composition of claim 5, which can be formulated into one or more of a variety of dosage forms, including but not limited to tablets, capsules, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal patches, and / or suppositories.

7. Use of a compound of Formula (I), (II) or (III), 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 an androgen receptor modulator.

8. Use of a compound of Formula (I), (II) or (III), 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 a disease associated with androgen receptor, which is cancer, metabolic disorder, cardiovascular and cerebrovascular disease, hyperlipidemia or obesity.

9. The use of claim 8, wherein the cancer is prostate cancer, breast cancer or bladder cancer.

10. The use of claim 9, wherein the prostate cancer includes androgen-dependent prostate cancer and androgen-independent prostate cancer.

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