WO2020063968A1 - Ar和bet双重抑制剂及其用途 - Google Patents

Ar和bet双重抑制剂及其用途 Download PDF

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WO2020063968A1
WO2020063968A1 PCT/CN2019/109077 CN2019109077W WO2020063968A1 WO 2020063968 A1 WO2020063968 A1 WO 2020063968A1 CN 2019109077 W CN2019109077 W CN 2019109077W WO 2020063968 A1 WO2020063968 A1 WO 2020063968A1
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ring
alkyl
group
bet
alkoxy
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PCT/CN2019/109077
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French (fr)
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余江
陈元伟
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四川大学
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Definitions

  • the present invention relates to polycyclic compounds and their use in dual inhibitors of AR and BET.
  • Androgen receptors belong to the nuclear receptor family and are a class of ligand-dependent transcription factors. Abnormal regulation of the AR signaling pathway plays an important role in the occurrence and development of prostate cancer. Studies have shown that castration-resistant prostate cancer (CRPC) still depends on the role of AR.
  • the androgen receptor contains 918 amino acids, and has similar structure and function to other nuclear receptors. It consists of three important domains, namely the DNA binding domain (DBD) and the ligand binding domain (ligand binding domain (LBD) and nitrogen terminal domain (NTD), DBD and LBD are connected by a hinge region (Hinge).
  • the LBD present at the carbon end of AR is the site where AR binds to the ligand, which determines the specificity of binding of the ligand to AR, and the ligand binds to LBD to activate AR.
  • Two transcriptional activation domains have been identified in AR, namely activation domain 1 (AF1) in the NTD domain and hydrophobic pocket activation domain 2 (AF2) in the LBD domain, which is highly conserved.
  • AF1 activation domain 1
  • AF2 hydrophobic pocket activation domain 2
  • the FDA has approved three inhibitors of the AR signaling pathway, namely Abiraterone Acetate and Enzalutamide (Enza) for metastatic properties, which were approved in 2011 and 2012, respectively.
  • BET bromodomain and extra-terminal domain
  • the BET protein family consists of BRD2, BRD3, BRD4 and BRDT. Except for BRDT, which is only found in the testis, the other three protein subtypes are widely expressed in various tissue cells.
  • the amino acid sequences of the bromodomains of the four BRD (bromodomain-containing protein) proteins are highly similar. Studies have shown that BRD2 ⁇ 3 ⁇ 4 directly binds to AR to regulate the expression of its downstream genes.
  • This interaction between AR and BD1 can be blocked by BET inhibitors, thereby blocking AR-mediated gene transcription and inhibiting CRPC tumors. Growth, and still has a good inhibitory effect on AR-v7 positive androgen-independent 22Rv1 tumor model.
  • BRD protein inhibitors include OTX-105, ZEN003694, and GS-5829, among which GS-5829 can also be used for lymphoma.
  • clinical trials of inhibitors such as BI894999, BMS-986158 and FT-1101 for advanced solid tumors, acute myeloid leukemia and myelodysplastic diseases are also ongoing.
  • BET inhibitors can be used to prepare drugs that prevent and / or treat diseases associated with BET proteins.
  • BET protein-related diseases include BET protein-related tumor diseases (such as prostate cancer, lung cancer, diffuse large B-cell lymphoma), benign hyperplasia, inflammatory diseases, autoimmune diseases, sepsis, viral infections, and cardiovascular diseases (such as Heart failure, myocardial infarction) and neurological diseases.
  • the purpose of the present invention is to provide the use of a compound for the preparation of dual inhibitors of AR and BET.
  • the present invention provides a compound represented by formula (I) or an optical isomer, solvate, pharmaceutically acceptable salt, prodrug, tautomer, meso, racemate,
  • Z 1 and Z 2 are each independently selected from C or N;
  • n 0, 1, or 2;
  • Ring A represents an aromatic ring, an aromatic heterocyclic ring, a benzoaromatic ring, a benzoaromatic ring, a benzocarbocyclic ring or a benzoheterocyclic ring;
  • Ring B is a heterocyclic ring, a benzene ring, an aromatic heterocyclic ring or a benzoaromatic ring, a benzoaromatic ring, a benzocarbocyclic ring or a benzoheterocyclic ring;
  • R 1 is hydrogen, halogen, CHF 2 , CF 3 , C 1 to C 6 alkyl, C 1 to C 6 alkoxy, aryl or heteroaryl, C 3 to C 6 cycloalkyl, hetero A cyclic group or a halogen-substituted C 1 to C 6 alkoxy group, alkyl group, cycloalkyl group, or heterocyclic group, wherein the alkyl group or alkoxy group is further substituted with one or more aromatic carbocyclic rings or aromatic heterocyclic rings;
  • R 2 is hydrogen, halogen, cyano, nitro or 5-12 membered aromatic carbocyclic ring, aromatic heterocyclic ring, benzoaromatic ring, benzoaromatic heterocyclic ring, benzocarbocyclic ring or benzoheterocyclic ring or C 1 ⁇ C 6 alkyl group, alkoxy group, cycloalkyl group, and heterocyclic group, wherein C 1 to C 6 alkyl group, alkoxy group, cycloalkyl group, and heterocyclic group may be each independently and optionally further one or more Are substituted with a group selected from deuterium, halogen, aromatic carbocyclic or heteroaryl;
  • R 3 represents one or none of halogen, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, cyano, nitro, or C 3 to C 6 cycloalkyl, heterocyclic group, and Halogen-substituted C 1 to C 6 alkyl, cycloalkyl, alkoxy or heterocyclic groups;
  • R 4 is deuterium, hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy , Cycloalkyl, heterocyclyl, aryl, heteroaryl are each independently optionally further selected from one or more of deuterium, halogen, cyano, amino, alkyl, haloalkyl, hydroxy, hydroxyalkyl, cyclic Substituted by alkyl, heterocyclyl, aryl, heteroaryl groups;
  • R 5 and R 6 each independently represent none, hydrogen, hydroxyl, amino, alkyl, halogen, alkoxy, cyano, nitro, cycloalkyl, alkenyl, alkynyl, or C 1 to C 6 alkyl , C 1 to C 6 alkoxy or aryl, wherein the alkyl, alkoxy or aryl are each independently optionally further selected from one or more selected from halogen, hydroxy, cyano, nitro, Substituted with a cycloalkyl group;
  • R 5 ′ and R 6 ′ each independently represent none, hydrogen, hydroxyl, amino, alkyl, halogen, or alkoxy, wherein the alkyl or alkoxy is further substituted with one or more halogens;
  • R 5 , R 5 ′, R 6 , R 6 ′ may be connected to R 4 to form a ring;
  • R 5 and R 5 ′ or R 6 and R 6 ′ may be connected to each other to form a ring;
  • R 7 represents none, hydrogen, hydroxyl, amino, cyano, halogen, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, cycloalkyl, aryl, -R 9 C (O) R 10 , -R 9 CO (O) R 10 , -R 9 (O) COR 10 , -R 9 NHC (O) R 10 or -R 9 C (O) NHR 10 , wherein C 1 to C 6 Alkyl, C 1 to C 6 alkoxy, cycloalkyl, and aryl are each independently optionally further selected from one or more of halogen, hydroxy, cyano, nitro, alkyl, cycloalkyl, and aryl Substituted by a radical;
  • R 8 represents none, hydrogen, halogen, hydroxyl, C 1 to C 6 alkyl, cycloalkyl, -R 9 C (O) R 10 , -R 9 CO (O) R 10 , -R 9 (O) COR 10 , -R 9 NHC (O) R 10 or -R 9 C (O) NHR 10 , wherein the C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group or aryl group are each independently Optionally further substituted with one or more groups selected from halogen, hydroxy, cyano, nitro, alkyl, cycloalkyl;
  • R 9 and R 10 each independently represent a linear or branched alkyl group having no or C 1 to C 6 , wherein the alkyl group is further substituted with one or more halogens.
  • Ring A, ring B, and R 1 to R 10 are as defined in claim 1.
  • R 1 is selected from the group consisting of hydrogen, halogen, CHF 2 , CF 3 , C 1 to C 6 alkyl, or C 1 to C 6 alkoxy, aryl, or heteroaryl.
  • R 1 is selected from a 5-6 membered aryl group or a 5-6 membered heteroaryl group.
  • R 2 is selected from cyano, benzoheterocyclyl, and heterocyclyl.
  • R 3 represents none.
  • R 4 is selected from C 1 to C 6 alkyl.
  • R 4 is selected from hydrogen, methyl, ethyl or deuterated methyl and ethyl.
  • R 5 and R 6 each independently represent an alkyl group without C 1 to C 6 .
  • R 5 and R 6 each independently represent no or methyl.
  • ring B represents a benzene ring, a furan ring, a pyridine ring, a benzopyridine ring, a pyrimidine ring, an imidazole ring, a benzimidazole ring, a pyrazole ring, or an isoxazole ring.
  • R 7 and R 8 each independently represent an alkyl group without C 1 to C 6 .
  • R 7 and R 8 each independently represent no or methyl group.
  • R 1 is selected from hydrogen and halogen
  • R 2 is selected from cyano, C 1 to C 2 alkyl, C 1 to C 2 alkoxy,
  • R 4 is selected from hydrogen and C 1 ⁇ C 2 alkyl;
  • R 7 and R 8 are each independently selected from C 1 to C 2 alkyl.
  • the compound is one of the following compounds:
  • the AR is mutant AR or wild-type AR
  • the BET is BRD2, BRD3 or BRD4.
  • the dual inhibitors of AR and BET can inhibit transcription of PSA and FKBP5 downstream genes of AR;
  • the dual inhibitors of AR and BET can inhibit the transcriptional activity of drug-resistant AR mutants, preferably, the drug-resistant AR mutant is an AR-F876L mutant;
  • the AR and BET dual inhibitors or BET inhibitors can down-regulate the expression of c-Myc, a downstream protein of BRD4.
  • the AR and BET dual inhibitors or BET inhibitors are drugs for preventing and / or treating diseases related to BET protein.
  • the BET protein-related disease is selected from the group consisting of tumor diseases, benign hyperplasia, inflammatory diseases, autoimmune diseases, sepsis, viral infections, cardiovascular diseases or neurological diseases related to BET protein;
  • the tumor disease associated with BET protein is selected from the group consisting of androgen-independent prostate cancer, lung cancer, diffuse large B-cell lymphoma, Burkitt's lymphoma;
  • the cardiovascular disease is selected from the group consisting of heart failure and myocardial infarction.
  • the present invention also provides a compound represented by formula (II) or an optical isomer, solvate, pharmaceutically acceptable salt, prodrug, tautomer, meso, racemate , Enantiomers, diastereomers, mixtures, metabolites, metabolites, or isotopic substitutions:
  • R a is selected from hydrogen, Ethyl
  • R a is hydrogen
  • R b, R c are each independently selected from halogen, cyano, hydrogen, methoxy, or C 1 ⁇ C 2 alkyl group is, M being CH or N;
  • R a is R b and R c are each independently selected from halogen, cyano, Hydrogen, methoxy or C 1 -C 2 alkyl, Rd is selected from deuterium, methyl, or deuterated methyl, and M is CH or N;
  • R a is an ethyl group, M being CH or N
  • R b is hydrogen
  • R c is selected from hydrogen, methoxy or C 1 ⁇ C 2 alkyl group is.
  • the compound is one of the following compounds:
  • the C 1 to C 6 alkyl group means a C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkyl group, that is, a straight or branched chain having 1 to 6 carbon atoms.
  • Alkyl chains such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl and the like.
  • C 1 to C 6 alkoxy refers to C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy.
  • pharmaceutically acceptable means that a carrier, carrier, diluent, excipient, and / or salt formed is generally chemically or physically compatible with other ingredients constituting a pharmaceutical dosage form, and It is physiologically compatible with the receptor.
  • salt is an acidic and / or basic salt formed by a compound or a stereoisomer thereof with an inorganic and / or organic acid and a base, and also includes a zwitterionic salt (internal salt), and also includes a quaternary salt.
  • Ammonium salts such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing a compound, or a stereoisomer thereof, with an appropriate amount of an acid or a base (for example, equivalent). These salts may be precipitated in solution and collected by filtration, or recovered after evaporation of the solvent, or prepared by freeze-drying after reaction in an aqueous medium.
  • the salt described in the present invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluorate, phosphate, acetate, propionate, succinic acid of the compound Acid salt, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
  • the present invention provides a compound represented by Formula I, which can not only inhibit the transcription of PSA and FKBP5 downstream of AR, but also inhibit the transcriptional activity of AR-F876L mutants resistant to anthrazamide, and at the same time can down-regulate Expression of BRD4 downstream protein c-Myc.
  • the compounds of the present invention have good binding affinities with AR and BET proteins, indicating that the compounds of the present invention can inhibit the activity of AR and BET proteins simultaneously.
  • the deuterated form of the compound of the present invention has better metabolic stability of liver drug enzymes, helps to improve bioavailability and drug efficacy at the same dose, reduces the dosage, and thereby reduces the toxic and side effects of the drug. risk. Therefore, the compound of the present invention and its deuterated derivative, as dual inhibitors of AR and BET, have good application prospects in the preparation of a medicament for the prevention and / or treatment of diseases related to the BET protein.
  • Figure 1 Compounds inhibit transcription of PSA and FKBP5 genes in VCaP cells.
  • the raw materials and equipment used in the present invention are known products and are obtained by purchasing commercially available products.
  • Compound 001-036 is prepared in the same way as compound SKLB-C4558, SKLB-C4570, SKLB-C4561, SKLB-C4582, SKLB-C4567, SKLB-C4583, SKLB-C4579, SKLB-C4590, SKLB-C4596, SKLB-C4604 in CN107814785A.
  • the synthesis method refers to compound 038, and the reactant deuterated iodomethane is replaced with deuterated ethyl p-toluenesulfonate.
  • the synthesis method refers to compound 037, and the reactant p-toluenesulfonic acid deuterated ethyl ester is replaced with deuterated iodomethane.
  • the synthesis method refers to the synthesis of compound 042, in which the raw material 4-ethyliodobenzene is replaced with 4-methoxyiodobenzene.
  • Test Example 1 The compound of the present invention inhibits the proliferation of cancer cells
  • RIPM 1640 medium (Hyclone, SH30809.01); DMEM high sugar medium (Hyclone, SH30243.01); fetal bovine serum, FBS (BI, 04-001-1ACS); cyano-streptomycin (Hyclone, SV30010) ; Complete cell culture medium: RIPM 1640 medium / DMEM high sugar medium, 10% FBS, 1% penicillin-streptomycin (Millipore, SM-2001-C); LNCap / AR cells (LNCap with high expression of AR Cells, constructed by retroviral transfection method, donated by Sichuan Kangcheng Biotechnology Co., Ltd.); Vcap cells (Cell Bank of the Chinese Academy of Sciences Type Culture Collection Committee, TCHu220); PC-3 cells (Typical Culture Collection of the Chinese Academy of Sciences) Committee Cell Bank, SCSP-532); Cell counting reagent CCK-8 (SAB, CP002); Thermo Multiskan MK3 microplate reader.
  • LNCap / AR, VCap, PC-3 were cultured in 1640, DMEM and 1640 complete medium, respectively, and cultured in a 37 ° incubator with 5% carbon dioxide.
  • the cells were seeded in a 96-well plate, with two sub-wells, 100 microliters per well, and the number of seeded cells were LNCap / AR 2000 / well, VCap 20000 / well, and PC-3 1000 / well.
  • the drug (the compound prepared in Example 1; the positive control drug enzalutamide, that is, Enza) was formulated into a 30 mM stock solution with DMSO (dimethyl sulfoxide), and diluted to 600 ⁇ M with complete medium the next day after plating, and then used The complete medium was diluted 10-fold, with a 3-fold gradient starting at 60 ⁇ M for a total of 9 concentrations. 100 ⁇ L of the diluted compound was added to the cell culture wells, and 100 ⁇ L of medium was added to the blank control group.
  • DMSO dimethyl sulfoxide
  • the compound of the present invention has a better inhibitory effect on AR-positive prostate cancer cells LNCap / AR and VCap, especially compound 037-044, which also has significant inhibition on prostate cancer cells LNCap / AR and VCap at the same time. effect.
  • the compounds of the present invention have an inhibitory activity against VCaP of prostate cancer cells containing AR-v7 mutations even better than the marketed drug anthrazamide (50% @ 30 in Table 2 means 50% inhibition at 30 ⁇ M).
  • the compound of the present invention has generally no obvious inhibitory effect on PC-3, which is an AR-negative prostate cancer cell, indicating that the compound of the present invention can effectively inhibit the AR signaling pathway, and has good cell selectivity and good safety.
  • DMEM High Glucose Medium (Hyclone, SH30243.01), Fetal Bovine Serum FBS (BI, 04-001-1ACS), Androgen-Free Fetal Bovine Serum, CSS-FBS (Given by Sichuan Kangcheng Biotechnology Co., Ltd.) Cyano-streptomycin (Hyclone, SV30010).
  • Complete cell culture medium DMEM high glucose medium, 10% FBS or 5% CSS, 1% penicillin-streptomycin.
  • VCap was cultured in DMEM high-sugar complete medium, and cultured in a 37 ° C incubator with 5% carbon dioxide. On the first day, cells were seeded in a 6-well plate with a medium containing 5% CSS and 1% double antibody, and the number of plates was 1.2 million / well.
  • the drug was added (the compound prepared in Example 1; the positive control drug enzalutamide, that is, Enza).
  • the drug was formulated with DMSO (dimethylsulfoxide) into a 30 mM stock solution, and R1881 was prepared with DMSO into a 5 ⁇ M stock solution. , Diluted with 5% CSS complete medium, the blank group was added with complete medium containing equal concentration of DMSO.
  • RNA After dissolving RNA in 30 ⁇ l of RNase-free water, place the RNA on ice and measure the RNA concentration.
  • reverse transcription kit instructions to perform reverse transcription (25 ° C 10min, 42 ° C 15min, 85 ° C 5min) to obtain cDNA, store at -20 ° C, and store the RNA in a -80 ° C refrigerator.
  • the compound of the present invention can inhibit the transcription of the AR downstream genes PSA and FKBP5 induced by androgen R1881 in VCaP cells, especially compounds 018, 022, 041, and 014, and the inhibitory effect is even better than that of the positive control drug En Helulumine shows that the compounds of the present invention can effectively inhibit the AR signaling pathway.
  • DME / F12 medium (Hyclone, SH30023.01), fetal bovine serum, FBS (BI, 04-001-1ACS), androgen-free fetal bovine serum, CSS-FBS (donated by Sichuan Kangcheng Biotechnology Co., Ltd. ), Cyano-streptomycin (Hyclone, SV30010).
  • Complete cell culture medium DME / F12 medium, 10% FBS or 5% CSS, 1% penicillin-streptomycin
  • PC-3 cells Cell Bank of the Typical Culture Collection Committee of the Chinese Academy of Sciences, SCSP-532
  • transfection reagent EndoFectinTM-Max GeneCopoeia, EF003
  • AR-F876L plasmid constructed by Biotech Biotechnology Shanghai Co., Ltd.
  • Cignal Androgen Receptor Reporter (luc) Kit QIAGEN, CCS-1019L
  • synthetic androgen R1881 Neanjing Kangmanlin Chemical Industry Co., Ltd., CAS: 965-93-5
  • dual luciferase detection kit promega, E1910
  • Multifunctional microplate reader BioTek, Synergy H1.
  • PC-3 cells were cultured in DME / F12 complete medium and cultured in a 37 ° C incubator with 5% carbon dioxide. On the first day, cells were seeded in a 96-well plate with a medium containing 5% CSS and no double antibody, and the number of plates was 10,000 / well.
  • the compounds 041 and 014 of the present invention can inhibit the transcriptional activity of AR-F876L activated by 1nM synthetic androgen R1881, and have obvious concentration dependence.
  • the concentration of the control drug anthrazamide the transcriptional activity of AR-F876L was enhanced, showing resistance.
  • DMEM medium Gibco, 31053028
  • androgen-free fetal bovine serum Biological Industries, 04-011-1A
  • HEK293 cells provided by WuXi AppTec New Drug Development Co., Ltd.
  • transfection reagents Promega, E2311
  • wt-AR expression plasmid Origene, RC235415
  • reporter gene plasmid Promega, E1360
  • Steady-Glo detection reagent Promega, E2550
  • HEK293 cells were seeded in a 96-well plate with a complete medium containing 89% DMEM medium, 1% GlutaMax, and 10% fetal calf serum to remove androgens by dialysis.
  • 5 ng wt-AR plasmid was transfected using transfection reagent according to the instructions. Cotransfect into cells with 100ng reporter gene plasmid. After 24 hours, cells were treated with compound or DMSO and testosterone. The final concentrations of compound and testosterone were 5 ⁇ M and 2 nM, respectively. After 24 hours of incubation, the luminescence signal was measured on an Envision instrument using Steady-Glo reagent.
  • RIPM 1640 medium (Hyclone, SH30809.01), DMEM high sugar medium (Hyclone, SH30243.01), FBS (BI, 04-001-1ACS), penicillin-streptomycin (Hyclone, SV30010).
  • Complete cell culture medium RIPM 1640 / DMEM high sugar medium, 10% FBS, 1% penicillin-streptomycin.
  • LNCap, 22RV1 was cultured in 1640 complete medium, VCap was cultured in DMEM high-sugar complete medium, and cultured in a 37 ° C incubator with 5% carbon dioxide. On the first day, cells were seeded in 6-well plates, and the number of LNCap and 22RV1 plates was 700,000 / well, and the VCap was 1 million / well.
  • the drug was added (the compound prepared in Example 1; the positive control drug 1: enzalutamide, that is, Enza; the positive control drug 2: Galeterone, that is, Gal), and the drug was configured with DMSO (dimethylsulfoxide) to 30 mM.
  • the stock solution was diluted with complete medium, and the blank group was added with complete medium containing the same concentration of DMSO.
  • the medium was aspirated, washed with pre-chilled PBS once, blotted dry, 60 ⁇ l of RIPA lysate per well, lysed on ice for 5 min, collected by cell scraping and transferred to a centrifuge tube. Centrifuge at 4 ° C for 10 min, 13000 rpm. Transfer the supernatant to a new centrifuge tube, use the BCA protein quantification kit for protein quantification, then add 1/4 volume of 5X loading buffer, boil it in boiling water for 5 minutes, cool on ice, and then transfer to -20 ° C for storage.
  • a 10% polyacrylamide gel kit was used to make the gel, and 30 ⁇ g of protein was loaded. The volume was filled with 1X loading buffer. The gel was concentrated with 80V and the gel was separated with 100V. Wet transfer film, 300mA, 1h, and then block with 5% skim milk for 2h at room temperature. Primary antibody Tublin was diluted 1: 5000, AR and PSA were diluted 1: 2000 and 1: 1000, respectively, and incubated at 4 ° C with shaking overnight.
  • FIG. 3 show that the compound 014 of the present invention can significantly inhibit the expression of c-Myc protein in a variety of cells, and has a concentration dependence. But the marketed drugs enzalutamide and Galeteron cannot down-regulate the protein levels of c-Myc.
  • Liquid phase system Shiadzu
  • mass spectrometry system API 4000 instrument from AB Inc (Canada) with an ESI interface
  • chromatography column ACE Excel 3 AQ 30 ⁇ 2.1mm Column
  • human liver drug enzyme Corning, Cat. # 452117
  • Phosphate buffer Ultrapure water, MgCl 2 solution, NADPH
  • the third compound 039 of the present invention is a deuterated derivative of 014. It can be seen from the results in Table 3 that the deuterated form of the present compound (039) has a lower elimination rate in vitro than the non-deuterated compound (014) and has a longer half-life.
  • LNCaP cell lysate 3H-R1881 (PerkinElmer, Cat: NET590250UC, Lot: 2133648), glycerol (Sigma, Cat: G9012, Lot: BCBG6624V), 0.5M EDTA (Invitrogen-15575-038), DTT (Sigma, Cat: 43815, Lot: BCBD7009V), dextran (Sigma, Cat: D1662, Lot: SLBK5258V), activated carbon (Sigma, Cat: 05105, Lot: BCBF9839V), Tris base (Sigma, Cat: T1503-1KG), Protease inhibitor (PerkinElmer, Cat: 6013329, Lot: 77-16371), Scint-tube, 6ml (PerkinElmer, Cat: 6000192), 96-well plate (Agilent, Cat # 5042-1385), TopSeal plated membrane (Perkin Elmer (Cat # 6050185), Tri-Carb liquid scintillation analyzer (PerkinElmer, 29
  • test compound (the compound prepared in Example 1 of the present invention; the positive control Enzalutamide) was diluted with DMSO four-fold gradient, a total of 8 concentration points, 1 ⁇ l of each concentration was transferred to the detection plate. Transfer 1 ⁇ l of DMSO as a blank control well. Add 100 ⁇ l of cell lysate and 100 ⁇ l of radioligand (final concentration of 1 nM) to each well. Incubate at 4 ° C for 24h, then add 100 ⁇ l of buffer for radioligand adsorption and shake at 4 ° C for 15min. After centrifugation, 100 ⁇ l of the supernatant was added to the scint-tube, and 2 ml of the proteasome inhibitor was added, followed by counting with a liquid scintillation analyzer.
  • IC 50 represents the concentration of the compound corresponding to AR at a binding rate of 50%, and the lower the IC 50 value, the stronger the affinity of the compound for binding to AR.
  • BRD4 (1,2) (Cat.No.31044); BRD2 (1,2) (Cat.No.31024); BRD3 (1,2) (Cat.No.31035); BRD9 (Cat.No.B1048) ; CREBBP (Cat.No.31873); EP300 (Cat.No.31801);
  • the inhibitory effect of the compound (the compound prepared in Example 1 of the present invention; the positive control enzalutamide) on the bromodomain-containing proteins BRD4 and BRD9 was evaluated by homogeneous time-resolved fluorescence (HTRF) technology.
  • the test compound was serially diluted by 10 concentrations, and (+)-JQ1 (BPS, Cat. No. 27402) was used as a reference compound (Ref).
  • the final concentration of DMSO was 0.1%.
  • the compound or DMSO was transferred to a 384-well assay plate, and then 2x Protein and PeptideMix and 2x DetectionMix were added in this order.
  • the HTRF signal was read on Envision, with excitation light at 340 nm and emitted light at 615 nm and 665 nm.
  • the test concentration of compounds 041, 018, 014, 013, 042, and 044 is 10 ⁇ M.
  • BetaScreen technology was used to evaluate the inhibitory effects of compounds on bromodomain proteins BRD2, BRD3, CREBBP, EP300, SMARCA2, FALZ, TAF1 (D2).
  • the test compound was serially diluted at 10 concentrations, and (+)-JQ1 (BPS, Cat. No. 27402) was used as a reference compound, and the final concentration of DMSO was 0.1%.
  • the compound or DMSO was transferred to a 384-well assay plate (PerkinElmer, USA).
  • BRD2 (BPS, Cat. No. 31024) and BRD3 (BPS, Cat. No. 31035) were added to the 1x HEPES buffer respectively as protein solutions.
  • the substrate solution is added to the peptide in 1x buffer.
  • the compound of the present invention can effectively inhibit the activity of a variety of BET proteins, but has a poor inhibitory activity against other bromodomain-containing proteins. Therefore, it is demonstrated that the compounds of the present invention can not only specifically target AR ligands, but also specifically target BET proteins, and have good selectivity.
  • the present invention provides a compound represented by Formula I, which not only inhibits the transcription of PSA and FKBP5 downstream of AR, but also inhibits the transcriptional activity of AR-F876L mutants resistant to anthrazelamine, and It can also down-regulate the expression of c-Myc, a downstream protein of BRD4.
  • the compounds of the present invention have good binding affinities with AR and BET proteins, indicating that the compounds of the present invention can inhibit the activity of AR and BET proteins simultaneously.
  • the deuterated form of the compound of the present invention has better metabolic stability of liver drug enzymes, helps to improve bioavailability and drug efficacy at the same dose, reduces the dosage, and thereby reduces the toxic and side effects of the drug. risk. Therefore, the compounds of the present invention and their deuterated derivatives have good application prospects in the preparation of AR and BET dual inhibitors.

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Abstract

提供一种式（I）所示的多元环化合物及其在AR和BET双重抑制剂中的用途，具体地，提供式（I）所示化合物或其光学异构体、溶剂合物、药学上可接受的盐、前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、混合物形式、代谢产物、代谢前体或其同位素替代形式在制备AR和BET双重抑制剂中的用途。实验结果表明，所述化合物不仅能够抑制AR下游PSA和FKBP5的转录，还能抑制对蒽杂鲁胺耐药的AR-F876L突变体转录活性，同时还能下调BRD4下游蛋白c-Myc的表达，并且化合物对AR和BET蛋白均有较好的结合亲和力，说明所述化合物能够同时抑制AR和BET蛋白的活性，在制备预防和/或治疗与BET蛋白相关疾病的药物上具有良好的应用前景。

Description

AR和BET双重抑制剂及其用途 技术领域
本发明涉及多元环化合物及其在AR和BET双重抑制剂中的用途。
背景技术
雄激素受体(androgen receptor,AR)属于核受体家族，是一类配体依赖的转录因子。AR信号通路的异常调节对前列腺癌的发生、发展有重要作用，研究表明去势抵抗型前列腺癌(castration-resistant prostate cancer,CRPC)仍然依赖AR的作用。雄激素受体包含918个氨基酸，与其他核受体具有相似的结构和功能，它由三个重要的结构域组成，分别是DNA结合域(DNA binding domain,DBD)、配体结合域(ligand binding domain,LBD)和氮端结合域(N-terminal domain,NTD),DBD和LBD之间通过一个铰链区(Hinge)相连。存在于AR碳端的LBD是AR与配体结合的位点，决定了配体与AR结合的特异性，配体与LBD结合从而激活AR。在AR中已确定了两个转录激活功能区，即NTD结构域中的激活功能区1(activation function 1,AF1)和LBD结构域中高度保守的疏水口袋激活功能区2(AF2)。2010年以前，以多西紫杉醇为基础的化疗是唯一能延长转移性CRPC患者生存期的治疗方法。从2011年起，FDA陆续批准了三个AR信号通路的抑制剂，分别是于2011和2012批准的醋酸阿比特龙(Abiraterone Acetate)和恩杂鲁胺(Enzalutamide，简写为Enza)用于转移性去势抵抗型前列腺癌的治疗以及2018年刚刚批准用于非转移性CRPC的阿帕鲁胺(Apalutamide)。尽管第二代抗雄激素阿比特龙和恩杂鲁胺在临床治疗中取得了一些成功，但是临床上已经出现了耐药性。配体结合区F876L突变是对恩杂鲁胺产生耐药，使其从拮抗剂转变为激动剂的一种错义突变。此外，AR剪接突变体，尤其是缺少配体结合区的AR-v7突变是介导第二代耐药性产生的重要原因。因此，目前临床上迫切需要新型AR信号通路的抑制剂来治疗CRPC。
BET(bromodomain and extra-terminal domain)是一类表观遗传调节因子，通过BD1和BD2结构域识别DNA上乙酰化的组蛋白来调控基因的表达。BET蛋白家族由BRD2,BRD3,BRD4和BRDT组成，其中除了BRDT只存在于睾丸中，其他三种蛋白亚型在各种组织细胞中广泛表达。四种BRD(bromodomain-containing protein)蛋白的溴结构域氨基酸序列有着高度的相似性。研究表明BRD2\3\4直接与AR结合可调控其下游基因的表达， AR和BD1的这种相互作用能被BET抑制剂所阻断，从而阻断AR介导的基因转录并抑制CRPC肿瘤的生长,并且对AR-v7阳性且雄激素非依赖的22Rv1肿瘤模型仍有很好的抑制作用。近年来多个BRD蛋白的抑制剂已进入临床研究用于CRPC的治疗，这些抑制剂包括OTX-105,ZEN003694和GS-5829等，其中GS-5829还可以用于淋巴瘤。以及BI894999,BMS-986158和FT-1101等抑制剂用于晚期实体瘤、急性髓性白血病以及骨髓增生异常等疾病的临床试验也正在进行中。在晚期前列腺癌中，AR的上调增强了溴结构域介导的染色质开放，而且AR过表达的细胞对BET抑制剂更加敏感。此外，有研究表明对恩杂鲁胺耐药的CRPC细胞依然对BET抑制剂(如JQ1)敏感。与单独使用抗雄激素类药物相比，抗雄激素和BET抑制剂联用能够更好的抑制前列腺癌肿瘤生长。有研究表明对BET耐药的CRPC细胞的基因转录不依赖BRD蛋白，但对于AR的阻断更加敏感。这些研究结果表明AR和BET的双重抑制剂有希望成为治疗CRPC和其他相关疾病的新策略。
此外，研究表明，BET抑制剂能够用于制备预防和/或治疗与BET蛋白相关疾病的药物。与BET蛋白相关疾病包括与BET蛋白相关的肿瘤疾病(如前列腺癌、肺癌、弥漫性大B细胞淋巴瘤)、良性增生、炎性疾病、自身免疫疾病、败血症、病毒感染、心血管疾病(如心脏衰竭、心肌梗塞)和神经性疾病等。
因此，研制出能够同时有效抑制AR和BET的双重抑制剂具有非常重要的意义。
发明内容
本发明的目的在于提供一种化合物在制备AR和BET双重抑制剂上的用途。
本发明提供了式(Ⅰ)所示化合物或其光学异构体、溶剂合物、药学上可接受的盐、前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、混合物形式、代谢产物、代谢前体或其同位素替代形式在制备AR和BET双重抑制剂、或制备BET抑制剂中的用途，
Figure PCTCN2019109077-appb-000001
其中，Z 1、Z 2分别独立地选自C或者N；
m＝0、1或者2；
环A表示芳环、芳杂环、苯并芳环、苯并芳杂环、苯并碳环或苯并杂环；
环B为杂环、苯环、芳杂环或苯并芳环、苯并芳杂环、苯并碳环或苯并杂环；
R 1为氢、卤素、CHF 2、CF 3、C 1～C 6的烷基、C 1～C 6的烷氧基、芳基或杂芳基、C 3～C 6的环烷基、杂环基或卤素取代的C 1～C 6的烷氧基、烷基、环烷基、杂环基，其中的烷基、烷氧基进一步被一个或者多个芳香碳环或者芳杂环取代；
R 2为氢、卤素、氰基、硝基或5-12元的芳香碳环、芳香杂环、苯并芳环、苯并芳杂环、苯并碳环或苯并杂环或者C 1～C 6的烷基、烷氧基、环烷基、杂环基，其中C 1～C 6的烷基、烷氧基、环烷基、杂环基可各自独立的任选进一步被一个或多个被选自氘、卤素、芳香碳环或杂芳基的基团所取代；
R 3表示无或环上的一个卤素、C 1～C 6的烷基、C 1～C 6的烷氧基、氰基、硝基或C 3～C 6的环烷基、杂环基以及卤素取代的C 1～C 6的烷基、环烷基、烷氧基或杂环基；
R 4为氘、氢、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基、杂芳基各自独立的任选进一步被一个或多个选自氘、卤素、氰基、氨基、烷基、卤代烷基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基的基团所取代；
R 5、R 6各自独立的表示无、氢、羟基、氨基、烷基、卤素、烷氧基，氰基、硝基、环烷基、烯基、炔基、C 1～C 6的烷基、C 1～C 6的烷氧基或芳基，其中所述的烷基、烷氧基或芳基各自独立的任选进一步被一个或者多个选自卤素、羟基、氰基、硝基、环烷基的基团所取代；
R 5’、R 6’各自独立的表示无、氢、羟基、氨基、烷基、卤素、烷氧基，其中的烷基、烷氧基进一步被一个或者多个卤素取代；
R 5、R 5’、R 6、R 6’可以分别与R 4连接成环；
R 5和R 5’或者R 6和R 6’可以相互连接成环；
R 7表示无、氢、羟基、氨基、氰基、卤素、C 1～C 6的烷基、C 1～C 6的烷氧基、环烷基、芳基、-R 9C(O)R 10、-R 9CO(O)R 10、-R 9(O)COR 10、-R 9NHC(O)R 10或者-R 9C(O)NHR 10，其中所述C 1～C 6的烷基、C 1～C 6的烷氧基、环烷基、芳基各自独立的任选进一步被一个或者多个选自卤素、羟基、氰基、硝基、烷基、环烷基、芳基的基团所取代；
R 8表示无、氢、卤素、羟基、C 1～C 6的烷基、环烷基、-R 9C(O)R 10、-R 9CO(O)R 10、-R 9(O)COR 10、-R 9NHC(O)R 10或者-R 9C(O)NHR 10，其中所述C 1～C 6的烷基、C 1～C 6的烷氧基或芳基各自独立的任选进一步被一个或者多个选自卤素、羟基、氰基、硝基、烷基、环 烷基的基团所取代；
R 9、R 10各自独立的表示无、C 1～C 6的直链或者支链烷基，其中的烷基进一步被一个或者多个卤素取代。
进一步地，所述化合物具有如式(Ⅰa)或式(Ⅰb)所示的结构：
Figure PCTCN2019109077-appb-000002
其中，n＝0、1或2；m＝0、1或2；
环A、环B、R 1～R 10如权利要求1中所定义。
进一步地，R 1选自氢、卤素、CHF 2、CF 3、C 1～C 6的烷基或C 1～C 6的烷氧基、芳基或杂芳基。
进一步地，R 1选自5-6元的芳基或5-6元的杂芳基。
进一步地，R 2选自氰基、苯并杂环基、杂环基。
进一步地，R 3表示无。
进一步地，R 4选自C 1～C 6的烷基。
进一步地，R 4选自氢、甲基、乙基或者氘代的甲基、乙基。
进一步地，R 5、R 6各自独立地表示无或C 1～C 6的烷基。
进一步地，R 5、R 6各自独立地表示无或甲基。
进一步地，环B表示苯环、呋喃环、吡啶环、苯并吡啶环、嘧啶环、咪唑环、苯并咪唑环、吡唑环或异噁唑环。
进一步地，R 7、R 8各自独立地表示无或C 1～C 6的烷基。
进一步地，R 7、R 8各自独立地表示无或甲基。
进一步地，所述化合物具有如式(Ⅰc)或式(Ⅰd)所示的结构：
Figure PCTCN2019109077-appb-000003
其中，R 1选自氢、卤素；R 2选自氰基、C 1～C 2的烷基、C 1～C 2的烷氧基、
Figure PCTCN2019109077-appb-000004
R 4选自氢、C 1～C 2的烷基；
R 7、R 8各自独立地选自C 1～C 2的烷基。
进一步地，所述化合物为如下化合物之一：
Figure PCTCN2019109077-appb-000005
Figure PCTCN2019109077-appb-000006
进一步地，所述AR为突变型AR或野生型AR；所述BET为BRD2,BRD3或BRD4。
进一步地，所述AR和BET双重抑制剂能够抑制AR下游基因PSA和FKBP5的转录；
和/或，所述AR和BET双重抑制剂能抑制耐药性AR突变体的转录活性，优选地，所述耐药性AR突变体为AR-F876L突变体；
和/或，所述AR和BET双重抑制剂或BET抑制剂能下调BRD4下游蛋白c-Myc的表达。
进一步地，所述AR和BET双重抑制剂或BET抑制剂为预防和/或治疗与BET蛋白相关疾病的药物。
进一步地，所述与BET蛋白相关疾病选自与BET蛋白相关的肿瘤疾病、良性增生、炎性疾病、自身免疫疾病、败血症、病毒感染、心血管疾病或神经性疾病；
优选地，所述与BET蛋白相关的肿瘤疾病选自雄激素非依赖性前列腺癌、肺癌、弥漫性大B细胞淋巴瘤、伯基特氏淋巴瘤；
所述心血管疾病选自心脏衰竭、心肌梗塞。
本发明还提供了式(II)所示的化合物或其光学异构体、溶剂合物、药学上可接受的盐、前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、混合物形式、代谢产物、代谢前体或其同位素替代形式：
Figure PCTCN2019109077-appb-000007
其中，R a选自氢、
Figure PCTCN2019109077-appb-000008
乙基；
当R a为氢时，R b、R c各自独立地选自卤素、氰基、氢、甲氧基或C 1～C 2的烷基，M为CH或N；
当R a为
Figure PCTCN2019109077-appb-000009
时，R b、R c各自独立地选自卤素、氰基、
Figure PCTCN2019109077-appb-000010
氢、甲氧基或C 1～C 2 的烷基，R d选自氘、甲基、或氘代甲基，M为CH或N；
当R a为乙基时，M为CH或N，R b为氢，R c选自氢、甲氧基或C 1～C 2的烷基。
进一步地，所述化合物为如下化合物之一：
Figure PCTCN2019109077-appb-000011
本发明中，所述C 1～C 6的烷基是指C 1、C 2、C 3、C 4、C 5、C 6的烷基，即具有1～6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、己基等等。类似的，C 1～C 6的烷氧基是指C 1、C 2、C 3、C 4、C 5、C 6的烷氧基。
本发明中，“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
本发明中，“盐”是将化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明提供了一种式I所示的化合物，该化合物不仅能够抑制AR下游PSA和FKBP5的转录，还能抑制对蒽杂鲁胺耐药的AR-F876L突变体的转录活性，同时还能下调BRD4下游蛋白c-Myc的表达。而且，本发明的化合物与AR和BET蛋白均有很好的结合亲和力，说明本发明化合物能够同时抑制AR和BET蛋白的活性。此外，实验证明，本发明化合物的氘代形式具有更好的肝药酶代谢稳定性，有助于提高生物利用度以及同等剂量下 的药效，降低给药剂量，从而降低药物产生毒副作用的风险。因此，本发明的化合物及其氘代衍生物作为AR和BET双重抑制剂，在制备预防和/或治疗与BET蛋白相关疾病的药物上具有良好的应用前景。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1.化合物抑制VCaP细胞中PSA和FKBP5基因的转录。
图2.化合物对AR-F876L突变体转录活性的影响。
图3.化合物对多种细胞中c-Myc蛋白水平的影响。
图4.化合物与多种BET蛋白的结合亲和力实验。
图5.化合物对BRD4的抑制活性。
图6.化合物对野生型AR转录活性的影响。
具体实施方式
本发明所用原料与设备均为已知产品，通过购买市售产品所得。
实施例1、本发明中化合物的合成
表1本发明各化合物的结构
Figure PCTCN2019109077-appb-000012
Figure PCTCN2019109077-appb-000013
Figure PCTCN2019109077-appb-000014
(1)化合物001-036的合成：
化合物001-036的制备方法同CN107814785A中化合物SKLB-C4558、SKLB-C4570、SKLB-C4561、SKLB-C4582、SKLB-C4567、SKLB-C4583、SKLB-C4579、SKLB-C4590、SKLB-C4596、SKLB-C4604、SKLB-C4613、SKLB-C4612、SKLB-C4614、SKLB-C4615、SKLB-C2602、SKLB-C4573、SKLB-C4578、SKLB-C4577、SKLB-C4574、SKLB-C4575、SKLB-C4576、SKLB-C4608、SKLB-C4609、SKLB-C4569、SKLB-C4572、SKLB-C2603、SKLB-C2601、SKLB-C4568、SKLB-C2604、SKLB-C4599、SKLB-C4602、SKLB-C4601、SKLB-C4565、SKLB-C4562、SKLB-C4563、SKLB-C4560的制备方法。
(2)化合物037的合成：
a.氘代乙醇-d6(500mg,10.8mmol)溶于THF(2.7ml)冷至0℃，NaOH(1.3g,2.4ml)溶于水预冷后加入，搅拌10min后加入对甲苯磺酰氯(2.27g,12mmol)，温度不超过5℃，加完后移至室温搅拌过夜。加水淬灭，DCM萃取2次，有机层合并用饱和氯化铵洗，然后水洗，无水硫酸钠干燥，浓缩得无色透明液体1g,即对甲苯磺酸氘代乙酯，收率46.3％。
b.参照CN107814785A中化合物SKLB-C4573的合成方法，将反应物1H-吡唑-4-硼酸换成3,5-二甲基异恶唑-4-硼酸频哪醇酯，5-溴-2甲基苯胺换成3-溴-2甲基苯胺，溴乙烷换成步骤a制得的对甲苯磺酸氘代乙酯。 1H NMR(400MHz,DMSO)δ7.60(d,J＝8.9Hz,1H),7.45(t,J＝7.7Hz,1H),7.35–7.23(m,2H),6.63(s,1H),6.44(s,1H),2.25(s,3H),2.06(s,3H),1.82(s,3H)；MS(ESI):371.1685[M+H +]。
(3)化合物038的合成：
参照CN107814785A中化合物SKLB-C4613的合成方法，将反应物苯并咪唑换成咪唑，(1-甲基-1H-吡唑-3)-硼酸换成3,5-二甲基-异恶唑硼酸频哪酯，溴乙烷换成氘代碘甲烷。
1H NMR(400MHz,DMSO)δ8.02(s,1H),7.53(s,1H),7.45(d,J＝7.9Hz,1H),7.41–7.35(m,2H),7.27(dd,J＝7.8,1.8Hz,1H),7.19(d,J＝1.7Hz,1H),7.04(s,1H),6.65–6.57(m,2H),2.40(s,3H),2.22(s,3H),2.13(s,3H)；MS(ESI):362.2058[M+H +]。
(4)化合物实039的合成：
合成方法参照化合物038，将反应物氘代碘甲烷换成对甲苯磺酸氘代乙酯。
1H NMR(400MHz,DMSO)δ8.00(s,1H),7.51(t,J＝1.2Hz,1H),7.48(d,J＝7.9Hz,1H),7.39–7.32(m,2H),7.29(dd,J＝7.8,1.8Hz,1H),7.17(d,J＝1.7Hz,1H),7.04(s,1H),6.60–6.53(m,2H),2.41(s,3H),2.23(s,3H),2.12(s,3H)；MS(ESI):378.2360[M+H]+。
(5)化合物040的合成：
合成方法参照化合物037，将反应物对甲苯磺酸氘代乙酯换成氘代碘甲烷。
1H NMR(400MHz,DMSO)δ7.62(d,J＝8.7Hz,1H),7.44(t,J＝7.7Hz,1H),7.29(dd,J＝20.1,7.5Hz,2H),6.68(s,1H),6.43(s,1H),2.25(s,3H),2.03(d,J＝28.0Hz,3H),1.83(s,3H)；MS(ESI):355.1403[M+H]+。
(6)化合物041的合成：
合成方法参照化合物039。将反应物1H-吡唑-4-硼酸改为1-甲基-1H-吡唑-5-硼酸频哪醇酯，同时不用溴乙烷上乙基。得60mg白色固体,即化合物041，产率：44.9％。
1H NMR(400MHz,DMSO)δ8.73(s,1H),7.63(d,J＝8.6Hz,1H),7.41(d,J＝7.6Hz, 1H),7.22(s,1H),7.17(d,J＝7.5Hz,1H),6.89(s,1H),6.77(d,J＝8.3Hz,1H),2.40(s,3H),2.23(s,6H)；MS(ESI):360.0854[M+Na]+。
(7)化合物043的合成：
Pd(pph 3) 4(900mg,0.8mmol),3,5-二甲基异恶唑-4-硼酸频哪酯(5g,22.5mmol)，Na 2CO 3(4.74g,45mmol)和5-溴-2-甲基苯胺(2.79g,15mmol)一并加入烧瓶中，然后加入H 2O(20ml)和1,4-二氧六环(37ml)抽换氮气3次，加热至90℃搅拌过夜。冷却至室温，加水稀释，乙酸乙酯萃取2次，饱和食盐水洗，无水硫酸钠干燥后浓缩，硅胶柱纯化(PE:EA＝2:1)得2g淡黄色固体，即中间体5-(3,5-二甲基异恶唑-4-)-2-甲基苯胺,产率：66.0％。
2-溴吡啶(173.8mg,1.1mmol),5-(3,5-二甲基异恶唑-4-)-2-甲基苯胺(202mg,1mmol),Cs 2CO 3(585.0mg,2.5mmol)，Pd(OAc) 2(22.4mg,0.1mmol)和Xantphos(86.8mg,0.15mmol)一并加入反应管中，再加入2.5ml乙腈作溶剂。抽换N 2三次后加热至90℃，搅拌过夜。冷至室温后硅藻土过滤后浓缩，粗产品用硅胶柱纯化(PE:EA＝3:1)得200mg淡黄色粘稠状物，即中间体N-吡啶-2-(5-(3,5-二甲基异恶唑-4-)-2-甲基苯胺,产率：71.6％。
中间体N-吡啶-2-(5-(3,5-二甲基异恶唑-4-)-2-甲基苯胺(140mg,0.5mmol)溶于干燥的DMF(3ml),冰浴条件下加入NaH(50mg,1.25mmol)，搅拌30min后加入溴乙烷(108mg,1mmol)，加毕，移至室温，继续搅拌5h。冰浴条件下加水淬灭，乙酸乙酯萃取3次，有机相合并，饱和氯化钠洗，无水硫酸钠干燥后浓缩，硅胶柱纯化(PE:EA＝10:1)得50mg淡黄色固体，即化合物043，产率：33.3％。
1H NMR(400MHz,CDCl3)δ8.21(ddd,J＝5.0,1.9,0.8Hz,1H),7.40(d,J＝7.8Hz,1H),7.32–7.26(m,1H),7.15(dd,J＝7.8,1.8Hz,1H),7.06(d,J＝1.8Hz,1H),6.56(ddd,J＝7.0,5.0,0.8Hz,1H),6.02(d,J＝8.6Hz,1H),3.94(s,2H),2.41(s,3H),2.28(s,3H),2.18(s,3H),1.24(t,J＝7.1Hz,3H)；MS(ESI):330.1618[M+Na]+。
(8)化合物042的合成：
中间体5-(3,5-二甲基异恶唑-4-)-2-甲基苯胺的合成同实施例043。
4-乙基碘苯(348.0mg,1.5mmol),5-(3,5-二甲基异恶唑-4-)-2-甲基苯胺(202.1mg,1mmol),Cs 2CO 3(585.0mg,2.5mmol)，Pd 2(dba) 3(46.0mg,0.05mmol)和Davephos(32.0mg,0.08mmol)一并加入反应管中，再加入6ml乙腈作溶剂。抽换N 2三次后加热至80℃，搅拌过夜。冷至室温后硅藻土过滤后浓缩，粗产品用硅胶柱纯化(PE:EA＝20:1)得250mg淡黄色粘稠状物，即中间体N-吡啶-2-(5-(3,5-二甲基异恶唑-4-)-2-甲基苯胺,产率：82.2％。再经过N-乙基化反应得化合物042，操作同实施例043。
1H NMR(400MHz,CDCl 3)δ7.35(d,J＝7.8Hz,1H),7.07(dd,J＝7.8,1.8Hz,1H),7.02(d,J＝1.8Hz,1H),7.00(d,J＝8.6Hz,2H),6.54–6.44(m,2H),3.66(q,J＝7.1Hz,2H),2.54(q,J＝7.6Hz,2H),2.39(s,3H),2.26(s,3H),2.17(s,3H),1.23(t,J＝7.1Hz,3H),1.19(t,J＝7.6Hz,3H).MS(ESI):335.2123[M+H]+。
(9)化合物044的合成：
合成方法参考化合物042的合成，其中原料4-乙基碘苯换成4-甲氧基碘苯。
1H NMR(400MHz,CDCl 3)δ7.32(d,J＝7.7Hz,1H),7.03(dd,J＝7.7,1.8Hz,1H),7.01(d,J＝1.7Hz,1H),6.80–6.74(m,2H),6.58–6.52(m,2H),3.75(s,3H),3.64(q,J＝7.1Hz,2H),2.39(s,3H),2.26(s,3H),2.15(s,3H),1.22(t,J＝7.1Hz,3H)；MS(ESI):337.1899[M+H]+。
以下通过试验例来具体说明本发明的有益效果。
试验例1本发明化合物对癌细胞的增殖抑制活性
1)材料及仪器：
RIPM 1640培养基(Hyclone,SH30809.01)；DMEM高糖培养基(Hyclone,SH30243.01)；胎牛血清，FBS(BI,04-001-1ACS)；青-链霉素(Hyclone,SV30010)；细胞完全培养液：RIPM 1640培养基/DMEM高糖培养基，10％FBS，1％青-链霉素胰酶(Millipore,SM-2001-C)；LNCap/AR细胞(高表达AR的LNCap细胞，通过逆转录病毒转染方法构建，由四川康城生物科技有限公司赠予)；Vcap细胞(中国科学院典型培养物保藏委员会细胞库，TCHu220)；PC-3细胞(中国科学院典型培养物保藏委员会细胞库，SCSP-532)；细胞计数试剂CCK-8(SAB,CP002)；Thermo Multiskan MK3酶标仪。
2)方法：
将LNCap/AR,VCap,PC-3分别培养于1640，DMEM和1640完全培养基中，置于5％二氧化碳的37度培养箱中培养。将细胞接种于96孔板中，2个副孔，每孔100微升，接种细胞数分别为LNCap/AR 2000/孔、VCap 20000/孔、PC-3 1000/孔。
药物(实施例1制备的化合物；阳性对照药物恩杂鲁胺，即Enza)用DMSO(二甲亚砜)配置成30mM的储备液，铺板后第二天用完全培养基稀释成600μM,再用完全培养基稀释10倍，从60μM开始3倍梯度稀释，共9个浓度。取100μL稀释后的化合物加入细胞培养孔中，空白对照组加100μL培养基。
药物作用6天后，吸走90μL含药培养基，每孔加入10μL CCK-8，37℃避光孵育1-2h后，在酶标仪上，450Nm，测定各孔的OD值。按照CCK-8试剂盒说明书计算IC50，至少重复测试2次。
3)结果：
表2、各化合物对癌细胞的IC50值
Figure PCTCN2019109077-appb-000015
上述实验数据表明，本发明化合物对AR阳性的前列腺癌细胞LNCap/AR和VCap具有较好的抑制作用，特别是化合物037-044，其同时对前列腺癌细胞LNCap/AR和VCap 均有显著的抑制效果。此外，本发明化合物对含AR-v7突变的前列腺癌细胞VCaP的抑制活性甚至优于上市药物蒽杂鲁胺(表2中50％@30指30μM时抑制率为50％)。
此外，本发明化合物对AR阴性的前列腺癌细胞PC-3的抑制作用普遍不明显，说明本发明化合物能够有效抑制AR信号通路，并且具有良好的细胞选择性，安全性好。
试验例2降低前列腺癌细胞中PSA和FKBP5的mRNA生物活性评价
1、材料仪器
DMEM高糖培养基(Hyclone,SH30243.01)、胎牛血清FBS(BI,04-001-1ACS)、去雄激素的胎牛血清、CSS-FBS(由四川康城生物科技有限公司赠予)、青-链霉素(Hyclone,SV30010)。
细胞完全培养液：DMEM高糖培养基，10％FBS或者5％CSS，1％青-链霉素。
胰酶(Millipore,SM-2001-C)、VCap细胞(中国科学院典型培养物保藏委员会细胞库，TCHu220)人工合成雄激素R1881(南京康满林化工实业有限公司,CAS:965-93-5)、Trizol(ambion，15596026)、氯仿(CAS:67-66-3)、异丙醇(天津市致远化学试剂有限公司，CAS:67-63-0)、无水乙醇(川东化工)、RNase-free water(biosharp，BL510A)、测RNA浓度的仪器(Thermo，NANODROP 2000)、逆转录试剂盒(abm，G492)、逆转录仪(LongGene，型号：Mini1620；规格：DC 20V 160W；序号：022-00001)、QPCR试剂盒(abm，MaterMix-S)、QPCR仪(BIO-RAD，CFX96TMOptics Module)、PSA引物(GeneCopoeia，HQP009633)、FKBP5引物(GeneCopoeia，HQP057374)。
2、方法
将VCap培养于DMEM高糖完全培养基中，置于5％二氧化碳的37℃培养箱中培养。第一天用含5％CSS和1％双抗的培养基将细胞接种于6孔板中，铺板数为120万/孔。
第三天加药(实施例1制备的化合物；阳性对照药物恩杂鲁胺，即Enza)，药物用DMSO(二甲亚砜)配置成30mM的储备液，R1881用DMSO配成5μM的储备液，用5％CSS完全培养基稀释，空白组加含等量浓度DMSO的完全培养基。
药物作用24h后，吸弃培养基，加500μl Trizol，用力摇晃15秒，室温放置3分钟。然后4℃，12000g离心15分钟。吸取上层水相至新离心管中，加250μl异丙醇颠倒混匀，室温放置10分钟后4℃，12000g离心10分钟。弃上清，加500μl 75％乙醇洗涤，温和振荡。然后4℃，7500g离心5分钟，弃尽上清，室温晾干5-10min。用30μl RNase-free水溶解RNA后，放置冰上测RNA浓度。按照逆转录试剂盒说明书操作进行逆转录(25℃ 10min，42℃15min，85℃5min)得到cDNA，-20℃储存，RNA放置-80℃冰箱储存。
3、结果
由图1结果看出，本发明化合物能够抑制VCaP细胞中雄激素R1881诱导的AR下游基因PSA和FKBP5的转录，特别是化合物018、022、041、014，其抑制效果甚至优于阳性对照药物恩杂鲁胺，说明本发明化合物能够有效抑制AR信号通路。
试验例3抑制AR-F876L转录活性的生物活性评价
1、材料仪器
DME/F12培养基(Hyclone,SH30023.01)、胎牛血清，FBS(BI,04-001-1ACS)、去雄激素的胎牛血清，CSS-FBS(由四川康城生物科技有限公司赠予)、青-链霉素(Hyclone,SV30010)。
细胞完全培养液：DME/F12培养基，10％FBS或者5％CSS，1％青-链霉素
胰酶(Millipore,SM-2001-C)。
PC-3细胞(中国科学院典型培养物保藏委员会细胞库，SCSP-532)、转染试剂EndoFectinTM-Max(GeneCopoeia，EF003)、AR-F876L质粒(由生工生物工程上海股份有限公司构建)、Cignal Androgen Receptor Reporter(luc)Kit(QIAGEN,CCS-1019L)、人工合成雄激素R1881(南京康满林化工实业有限公司,CAS:965-93-5)、双荧光素酶检测试剂盒(promega，E1910)、多功能酶标仪(BioTek，Synergy H1)。
2、方法
将PC-3细胞培养于DME/F12完全培养基中，置于5％二氧化碳的37℃培养箱中培养。第一天用含5％CSS且不含双抗的培养基将细胞接种于96孔板中，铺板数为1万/孔。
24小时内按转染试剂说明书将50ng AR-F876L和50ng AR-reporter一并转染进细胞。第三天加药(实施例1制备的化合物；阳性对照药物恩杂鲁胺，即Enza)，药物用DMSO(二甲亚砜)配置成30mM的储备液，R1881用DMSO配成3μM的储备液，用5％CSS完全培养基稀释，阴性对照组加等量的DMSO。药物作用24h后，吸弃培养基，按双荧光素酶检测试剂盒说明书操作，用多功能酶标仪检测发光信号。
3、结果
由图2结果看出，本发明化合物041和014能抑制由1nM人工合成雄激素R1881所激活的AR-F876L的转录活性，且具有明显的浓度依赖性。相反，随着对照药物蒽杂鲁胺浓度的增加，AR-F876L的转录活性反而增强，表现出抗性。
上述实验表明，本发明化合物可以很好的抑制AR-F876L的转录活性，而AR-F876L是临床上发现对恩杂鲁胺产生耐药性的一种AR突变体。说明本发明化合物对蒽杂鲁胺耐药的AR-F876L仍然有效，具有显著的抑制效果。
试验例4化合物抑制野生型AR转录活性的生物学评价
1、材料仪器
DMEM培养基(Gibco,31053028)、去除雄激素的胎牛血清(Biological Industries,04-011-1A)、HEK293细胞(由药明康德新药开发有限公司提供)、转染试剂(Promega,E2311)、wt-AR表达质粒(Origene,RC235415)、报告基因质粒(Promega,E1360)、Steady-Glo检测试剂(Promega,E2550)
2、方法
用含89％DMEM培养基、1％GlutaMax和10％经透析去除雄激素的胎牛血清的完全培养基将HEK293细胞接种在96孔板中，同时根据说明书使用转染试剂将5ng wt-AR质粒和100ng报道基因质粒共转染入细胞。24小时后，加入化合物或DMSO以及睾酮处理细胞。化合物和睾酮的终浓度分别为5μM和2nM。孵育24小时后，使用Steady-Glo试剂在Envision仪上测量发光信号。
3、结果
结果如图6所示，测试结果为平均值±SD(n＝3)。该结果说明本发明化合物能抑制雄激素激活的野生型AR的转录活性。也就是说，本发明化合物不仅可以有效抑制突变型AR的转录活性，还可以有效抑制野生型AR的转录活性，从而充分阻断前列腺癌细胞中异常激活的AR信号。
试验例5下调BRD4下游c-Myc表达的生物活性评价
1、材料仪器
RIPM 1640培养基(Hyclone,SH30809.01)、DMEM高糖培养基(Hyclone,SH30243.01)、FBS(BI,04-001-1ACS)、青-链霉素(Hyclone,SV30010)。
细胞完全培养液：RIPM 1640/DMEM高糖培养基，10％FBS，1％青-链霉素。
胰酶(Millipore,SM-2001-C)、VCap细胞(中国科学院典型培养物保藏委员会细胞库，TCHu220)、22RV1细胞(中国科学院典型培养物保藏委员会细胞库，TCHu100)、LNCap细胞(中国科学院典型培养物保藏委员会细胞库，TCHu173)、RIPA裂解液 (Beyotime,P0013B)、BCA蛋白定量试剂盒(Beyotime,P0012)、5X loading buffer(Beyotime,P0015)、10％聚丙烯酰胺凝胶试剂盒(佰和，PG112)、PVDF膜(Immobilon-PSQ,ISEQ00010)、Tublin Antibody(Zen BioScience,200608)、Androgen Receptor Antibody(CST,3202S)、PSA/KLK3(D11E1)
Figure PCTCN2019109077-appb-000016
Rabbit mAb(CST,D11E1)、敏ECL化学发光液(四正柏,4AW011-50)、学发光仪(上海勤翔,Serial NO.810060)。
2、方法
将LNCap，22RV1培养于1640完全培养基中，VCap培养于DMEM高糖完全培养基中，置于5％二氧化碳的37℃培养箱中培养。第一天将细胞接种于6孔板中，LNCap和22RV1铺板数为70万/孔，VCap为100万/孔。
第三天加药(实施例1制备的化合物；阳性对照药物1：恩杂鲁胺，即Enza；阳性对照药物2：Galeterone，即Gal)，药物用DMSO(二甲亚砜)配置成30mM的储备液，用完全培养基稀释，空白组加含等量浓度DMSO的完全培养基。
药物作用24h后，吸弃培养基，用预冷的PBS洗一次，吸干，每孔60μl RIPA裂解液，冰上裂解5min，用细胞刮收集并转移至离心管中。4℃离心10min，13000rpm。将上清液转移至新的离心管中，用BCA蛋白定量试剂盒进行蛋白定量，然后加入1/4体积的5X loading buffer，沸水煮5min后放冰上降温，再转移至-20℃保存。
用10％的聚丙烯酰胺凝胶试剂盒制胶，蛋白上样30μg，体积用1X loading buffer补齐，用80V跑浓缩胶，100V跑分离胶。湿法转膜，300mA，1h，然后用5％脱脂牛奶室温封闭2h。一抗Tublin按1:5000稀释，AR和PSA分别按1:2000和1:1000稀释，4℃摇床孵育过夜。
TBS/T洗膜10min*3次，二抗按1:5000稀释，室温孵育2h,TBS/T洗膜10min*3次,加超敏TCL化学发光液曝光。
3、结果
由图3结果表明，本发明化合物014能显著抑制多种细胞中c-Myc蛋白表达，并且具有浓度依赖性。但已上市药物恩杂鲁胺和Galeteron不能下调c-Myc的蛋白水平。
上述实验结果表明，本发明化合物能够下调BRD4调控的c-Myc蛋白的表达。因此，说明本发明化合物不仅能够抑制AR信号通路，还同时具有抑制BRD4的功能。
试验例6氘代化合物肝微粒体稳定性实验
1、材料仪器
液相系统(Shimadzu)、质谱系统(API 4000 instrument from AB Inc(Canada)with an ESI interface)、色谱柱(ACE Excel 3 AQ 30×2.1mm Column)、人肝药酶(Corning,Cat.#452117)、磷酸盐缓冲液、超纯水、MgCl 2溶液、NADPH
2、方法
10μl肝微粒体和40μl NADPH一起加到孵育管中。同时准备一组不加NADPH加等量的超纯水做对照组。然后加入4μl浓度为200μM的待测化合物(实施例1制得的014、039)。化合物的终浓度为2μM。分别于孵育0,15,30,45和60min时取出50μl反应液加冰乙腈终止反应。取出的样品离心40min(3220g)取出上清液，往清液中加等体积超纯水混匀用于LC-MS/MS检测。最后计算药代动力学参数。
表3人肝微粒体稳定性实验
化合物 014 039
In vitro T 1/2(min) 533.73 685.05
In vitro CI int(μL/min/mg protein) 2.60 2.02
Scale-up CI int(mL/min/mg) 3.26 2.54
3、结果
本发明第化合物039是014的氘代衍生物，由表3结果看出，本发明氘代形式的化合物(039)的体外消除速率低于非氘代化合物(014)，具有更长的半衰期。
上述实验结果表明，本发明氘代形式的化合物比非氘代化合物在体外有更好的肝微粒体代谢稳定性。
实施例7雄激素受体结合亲和力实验
1、材料仪器
LNCaP细胞裂解液、3H-R1881(PerkinElmer,Cat:NET590250UC,Lot:2133648)、丙三醇(Sigma,Cat:G9012,Lot:BCBG6624V)、0.5M EDTA(Invitrogen-15575-038)、DTT(Sigma,Cat:43815,Lot:BCBD7009V)、右旋糖苷(Sigma,Cat:D1662,Lot:SLBK5258V)、活性碳(Sigma,Cat:05105,Lot:BCBF9839V)、Tris base(Sigma,Cat:T1503-1KG)、蛋白酶抑制剂(PerkinElmer,Cat:6013329,Lot:77-16371)、Scint-tube,6ml(PerkinElmer,Cat:6000192)、96孔板(Agilent,Cat#5042-1385)、TopSeal封板膜(Perkin Elmer,Cat#6050185)、Tri-Carb液体闪烁分析仪(PerkinElmer,2910 TR)
2、方法
待测化合物(本发明实施例1制得的化合物；阳性对照恩杂鲁胺Enzalutamide)分别用DMSO四倍梯度稀释，共8个浓度点，每个浓度取1μl转移到检测板上。转移1μl DMSO作为空白对照孔。每个孔分别加入100μl细胞裂解液以及100μl放射性配体(终浓度为1nM)。4℃孵育24h，然后加100μl吸附放射性配体的缓冲液4℃振摇15min。离心后100μl上清液至scint-tube中再加2ml蛋白酶体抑制剂然后用液体闪烁分析仪计数。
IC 50表示与AR在结合率为50％时所对应的化合物的浓度，IC 50值越低，表示该化合物与AR结合的亲和力越强。
3、结果
表4各化合物的IC 50值
Compound IC 50(nM)
041 641.3
014 3413.0
Enzalutamide 5336.0
表4结果表明，本发明化合物能够与雄激素竞争性结合AR，且结合亲和力强于恩杂鲁胺。因此，说明本发明化合物能直接靶向AR的配体结合区。
实施例8 BET蛋白结合亲和力实验
1、材料仪器
BRD4(1,2)(Cat.No.31044)；BRD2(1,2)(Cat.No.31024)；BRD3(1,2)(Cat.No.31035)；BRD9(Cat.No.B1048)；CREBBP(Cat.No.31873)；EP300(Cat.No.31801)；
SMARCA2(Biogenie)；FALZ(Cat.No.31447)；TAF1(D2,Biogenie).(+)-JQ1(BPS,Cat.No.27402)；EnSpire仪(PerkinElmer，USA).
2、方法
通过均相时间分辨荧光(HTRF)技术评估化合物(本发明实施例1制得的化合物；阳性对照恩杂鲁胺)对含溴结构域蛋白BRD4和BRD9的抑制作用。将待测化合物连续稀释10个浓度，以(+)-JQ1(BPS,Cat.No.27402)为参照化合物(Ref)，DMSO的最终浓度为0.1％。将化合物或DMSO转移到384孔测定板中，然后依次加入2x Protein and Peptide Mix和2x的Detection Mix。在室温下孵育2小时后，在Envision上读取HTRF信号，激发光波长为340nm，发射光波长为615nm和665nm。其中化合物041、018、014、013、042、044的测试浓度为10μM。
利用AlphaScreen技术评估化合物对溴结构域蛋白BRD2,BRD3,CREBBP,EP300,SMARCA2,FALZ,TAF1(D2)的抑制作用。将待测化合物连续稀释10个浓度，以(+)-JQ1(BPS,Cat.No.27402)为参照化合物，DMSO的最终浓度为0.1％。将化合物或DMSO转移到384孔测定板孔板(PerkinElmer，USA)。BRD2(BPS，Cat.No.31024)和BRD3(BPS,Cat.No.31035)分别加到1x的HEPES缓冲液中即为蛋白溶液。将肽加入1x缓冲液中即为底物溶液。然后将5μL的蛋白质溶液转移至测定板同时以5μL的1x缓冲液作孔板对照。然后将测定板在室温下孵育15分钟。向每个孔中加入5μL底物溶液以开始反应，并将得到的混合物在室温下温育60分钟。然后加入15μL受体和供体溶液，用锡箔纸密封避光并在室温下再孵育60分钟。最后在具有Alpha模式的EnSpire读板仪(PerkinElmer，USA)上读取信号。
3、结果
结果如图4、图5和表5所示。
表5化合物对BET蛋白的选择性
Figure PCTCN2019109077-appb-000017
可以看出，本发明多个化合物能够有效抑制BET蛋白的活性，特别是化合物014(图5)。而且，本发明的化合物对多种BET蛋白均有良好的抑制效果，且其抑制效果强于阳性对照恩杂鲁胺(图4)。
此外，根据表5可以看出，本发明的化合物物能够有效抑制多种BET蛋白的活性，但对其他含溴结构域蛋白的抑制活性较差。因此说明本发明化合物不仅能够特异性的靶向AR的配体，也能特异性的靶向BET蛋白，具有良好的选择性。
综上，本发明提供了一种式I所示的化合物，该化合物不仅能够抑制AR下游PSA和FKBP5的转录，还能抑制对蒽杂鲁胺耐药的AR-F876L突变体的转录活性，同时还能 下调BRD4下游蛋白c-Myc的表达。而且，本发明的化合物与AR和BET蛋白均有很好的结合亲和力，说明本发明化合物能够同时抑制AR和BET蛋白的活性。此外，实验证明，本发明化合物的氘代形式具有更好的肝药酶代谢稳定性，有助于提高生物利用度以及同等剂量下的药效，降低给药剂量，从而降低药物产生毒副作用的风险。因此，本发明的化合物及其氘代衍生物在制备AR和BET双重抑制剂上具有良好的应用前景。

Claims (21)

  1. 式(Ⅰ)所示化合物或其光学异构体、溶剂合物、药学上可接受的盐、前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、混合物形式、代谢产物、代谢前体或其同位素替代形式在制备AR和BET双重抑制剂、或制备BET抑制剂中的用途，
    Figure PCTCN2019109077-appb-100001
    其中，Z 1、Z 2分别独立地选自C或者N；
    m＝0、1或者2；
    环A表示芳环、芳杂环、苯并芳环、苯并芳杂环、苯并碳环或苯并杂环；
    环B为杂环、苯环、芳杂环或苯并芳环、苯并芳杂环、苯并碳环或苯并杂环；
    R 1为氢、卤素、CHF 2、CF 3、C 1～C 6的烷基、C 1～C 6的烷氧基、芳基或杂芳基、C 3～C 6的环烷基、杂环基或卤素取代的C 1～C 6的烷氧基、烷基、环烷基、杂环基，其中的烷基、烷氧基进一步被一个或者多个芳香碳环或者芳杂环取代；
    R 2为氢、卤素、氰基、硝基或5-12元的芳香碳环、芳香杂环、苯并芳环、苯并芳杂环、苯并碳环或苯并杂环或者C 1～C 6的烷基、烷氧基、环烷基、杂环基，其中C 1～C 6的烷基、烷氧基、环烷基、杂环基可各自独立的任选进一步被一个或多个被选自氘、卤素、芳香碳环或杂芳基的基团所取代；
    R 3表示无或环上的一个卤素、C 1～C 6的烷基、C 1～C 6的烷氧基、氰基、硝基或C 3～C 6的环烷基、杂环基以及卤素取代的C 1～C 6的烷基、环烷基、烷氧基或杂环基；
    R 4为氘、氢、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基、杂芳基各自独立的任选进一步被一个或多个选自氘、卤素、氰基、氨基、烷基、卤代烷基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基的基团所取代；
    R 5、R 6各自独立的表示无、氢、羟基、氨基、烷基、卤素、烷氧基，氰基、硝基、环烷基、烯基、炔基、C 1～C 6的烷基、C 1～C 6的烷氧基或芳基，其中所述的烷基、烷氧基 或芳基各自独立的任选进一步被一个或者多个选自卤素、羟基、氰基、硝基、环烷基的基团所取代；
    R 5’、R 6’各自独立的表示无、氢、羟基、氨基、烷基、卤素、烷氧基，其中的烷基、烷氧基进一步被一个或者多个卤素取代；
    R 5、R 5’、R 6、R 6’可以分别与R 4连接成环；
    R 5和R 5’或者R 6和R 6’可以相互连接成环；
    R 7表示无、氢、羟基、氨基、氰基、卤素、C 1～C 6的烷基、C 1～C 6的烷氧基、环烷基、芳基、-R 9C(O)R 10、-R 9CO(O)R 10、-R 9(O)COR 10、-R 9NHC(O)R 10或者-R 9C(O)NHR 10，其中所述C 1～C 6的烷基、C 1～C 6的烷氧基、环烷基、芳基各自独立的任选进一步被一个或者多个选自卤素、羟基、氰基、硝基、烷基、环烷基、芳基的基团所取代；
    R 8表示无、氢、卤素、羟基、C 1～C 6的烷基、环烷基、-R 9C(O)R 10、-R 9CO(O)R 10、-R 9(O)COR 10、-R 9NHC(O)R 10或者-R 9C(O)NHR 10，其中所述C 1～C 6的烷基、C 1～C 6的烷氧基或芳基各自独立的任选进一步被一个或者多个选自卤素、羟基、氰基、硝基、烷基、环烷基的基团所取代；
    R 9、R 10各自独立的表示无、C 1～C 6的直链或者支链烷基，其中的烷基进一步被一个或者多个卤素取代。
  2. 根据权利要求1所述的用途，其特征在于：所述化合物具有如式(Ⅰa)或式(Ⅰb)所示的结构：
    Figure PCTCN2019109077-appb-100002
    其中，n＝0、1或2；m＝0、1或2；
    环A、环B、R 1～R 10如权利要求1中所定义。
  3. 根据权利要求1或2所述的用途，其特征在于：R 1选自氢、卤素、CHF 2、CF 3、C 1～C 6的烷基或C 1～C 6的烷氧基、芳基或杂芳基。
  4. 根据权利要求3所述的用途，其特征在于：R 1选自5-6元的芳基或5-6元的杂芳基。
  5. 根据权利要求1-4任一项所述的用途，其特征在于：R 2选自氰基、苯并杂环基、杂环基。
  6. 根据权利要求1-5任一项所述的用途，其特征在于：R 3表示无。
  7. 根据权利要求1-6任一项所述的用途，其特征在于：R 4选自C 1～C 6的烷基。
  8. 根据权利要求7所述的用途，其特征在于：R 4选自氢、甲基、乙基或者氘代的甲基、乙基。
  9. 根据权利要求1-8任一项所述的用途，其特征在于：R 5、R 6各自独立地表示无或C 1～C 6的烷基。
  10. 根据权利要求9所述的用途，其特征在于：R 5、R 6各自独立地表示无或甲基。
  11. 根据权利要求1-10任一项所述的用途，其特征在于：环B表示苯环、呋喃环、吡啶环、苯并吡啶环、嘧啶环、咪唑环、苯并咪唑环、吡唑环或异噁唑环。
  12. 根据权利要求1-11任一项所述的用途，其特征在于：R 7、R 8各自独立地表示无或C 1～C 6的烷基。
  13. 根据权利要求12所述的用途，其特征在于：R 7、R 8各自独立地表示无或甲基。
  14. 根据权利要求3所述的用途，其特征在于：所述化合物具有如式(Ⅰc)或式(Ⅰd)所示的结构：
    Figure PCTCN2019109077-appb-100003
    其中，R 1选自氢、卤素；R 2选自氰基、C 1～C 2的烷基、C 1～C 2的烷氧基、
    Figure PCTCN2019109077-appb-100004
    R 4选自氢、C 1～C 2的烷基；
    R 7、R 8各自独立地选自C 1～C 2的烷基。
  15. 根据权利要求1-14任一项所述的用途，其特征在于：所述化合物为如下化合物之一：
    Figure PCTCN2019109077-appb-100005
    Figure PCTCN2019109077-appb-100006
  16. 根据权利要求1-15任一项所述的用途，其特征在于：所述AR为突变型AR或野生型AR；所述BET为BRD2,BRD3或BRD4。
  17. 根据权利要求1-15任一项所述的用途，其特征在于：所述AR和BET双重抑制剂能够抑制AR下游基因PSA和FKBP5的转录；
    和/或，所述AR和BET双重抑制剂能抑制耐药性AR突变体的转录活性，优选地，所述耐药性AR突变体为AR-F876L突变体；
    和/或，所述AR和BET双重抑制剂或BET抑制剂能下调BRD4下游蛋白c-Myc的 表达。
  18. 根据权利要求1-17任一项所述的用途，其特征在于：所述AR和BET双重抑制剂或BET抑制剂为预防和/或治疗与BET蛋白相关疾病的药物。
  19. 根据权利要求18所述的用途，其特征在于：所述与BET蛋白相关疾病选自与BET蛋白相关的肿瘤疾病、良性增生、炎性疾病、自身免疫疾病、败血症、病毒感染、心血管疾病或神经性疾病；
    优选地，所述与BET蛋白相关的肿瘤疾病选自雄激素非依赖性前列腺癌、肺癌、弥漫性大B细胞淋巴瘤、伯基特氏淋巴瘤；
    所述心血管疾病选自心脏衰竭、心肌梗塞。
  20. 式(II)所示的化合物或其光学异构体、溶剂合物、药学上可接受的盐、前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、混合物形式、代谢产物、代谢前体或其同位素替代形式：
    Figure PCTCN2019109077-appb-100007
    其中，R a选自氢、
    Figure PCTCN2019109077-appb-100008
    乙基；
    当R a为氢时，R b、R c各自独立地选自卤素、氰基、氢、甲氧基或C 1～C 2的烷基、
    Figure PCTCN2019109077-appb-100009
    M为CH或N；
    当R a为
    Figure PCTCN2019109077-appb-100010
    时，R b、R c各自独立地选自卤素、氰基、
    Figure PCTCN2019109077-appb-100011
    氢、甲氧基或C 1～C 2 的烷基，R d选自氘、甲基、或氘代甲基，M为CH或N；
    当R a为乙基时，M为CH或N，R b为氢，R c选自氢、甲氧基、
    Figure PCTCN2019109077-appb-100012
    或C 1～C 2的烷基。
  21. 根据权利要求20所述的化合物或其光学异构体、溶剂合物、药学上可接受的盐、前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、混合物形式、代谢产物、代谢前体或其同位素替代形式，其特征在于：所述化合物为如下化合物之一：
    Figure PCTCN2019109077-appb-100013
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