WO2020221006A1 - 一种bet蛋白抑制剂、其制备方法及用途 - Google Patents

一种bet蛋白抑制剂、其制备方法及用途 Download PDF

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WO2020221006A1
WO2020221006A1 PCT/CN2020/084797 CN2020084797W WO2020221006A1 WO 2020221006 A1 WO2020221006 A1 WO 2020221006A1 CN 2020084797 W CN2020084797 W CN 2020084797W WO 2020221006 A1 WO2020221006 A1 WO 2020221006A1
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alkyl
hydrogen
cycloalkyl
halogen
cyano
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French (fr)
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郑永勇
魏农农
金华
周峰
黄美花
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上海勋和医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention belongs to the technical field of biomedicine, and specifically relates to a BET protein inhibitor, a preparation method and application thereof.
  • Epigenetic is currently one of the most popular drug discovery topics. Histone acetylation is an important part of epigenetic research. Bromodomain (BRD) is a class of conserved protein domains that can specifically recognize acetylated lysine (KAc) in histones. By binding to acetylated lysine, it promotes protein enrichment at specific gene transcription sites and changes RNA The activity of polymerase II regulates the transcriptional expression of genes (Kuc and Allis, Bioessays, 1998, 20:615-626).
  • BTD Bromodomain
  • KAc acetylated lysine
  • BRD proteins are divided into 8 major families, and the BET protein family is the second type of BRD protein family.
  • BET protein includes four members of BRD2, BRD3, BRD4 and BRDT (Wu and Chiang, J. Biol. chem., 2007, 282: 13141-13145). The first three are widely expressed in all body cells, while the latter is only expressed in testicular tissues.
  • BET protein plays an important role in a variety of tumors.
  • hematopoietic tumors acute myeloid leukemia, lymphoma, multiple myeloma, B-cell acute lymphoblastic leukemia, etc.
  • BRD4 acute myeloid leukemia
  • MYC oncogene MYC
  • NUT a protein normally expressed only in the testis
  • BRD2, BRD3 and BRD4 gene knockout can damage the growth and viability of a variety of hematology and solid tumor cells (Zuber et al., Nature 2011, 478:524-528; Delmore et al., Cell 2011, 146:904-917 ).
  • BET protein also regulates the inflammatory response to bacterial attack, and the BRD2 suballelic mouse model shows significantly lower levels of inflammatory cytokines and prevents obesity-induced diabetes (Wang et al., Biochem J. 2009, 425:71-83).
  • viruses use these BET proteins to tether their genomes to host cell chromatin as part of the virus replication process, or use BET proteins to promote viral gene transcription and repression (You et al., Ce11 2004, 117:349-360; Zhu Et al., Cell Reports 2012, 2:807-816).
  • targeting these proteins may be beneficial for the development of new therapeutic strategies targeting cancer, inflammation and viral infections.
  • small molecule inhibitors targeting this receptor have entered the clinical stage and are mainly used for the treatment of cancer and autoimmune diseases.
  • BET inhibitor patent applications have been published, including: WO2013158952, WO2014165127, WO2015075665, WO2016050821, WO2018188047, WO2018130174, etc.
  • Abbive Company discloses a class of BET protein inhibitors in WO2013097052A. Among them, the compound ABBV-075 has development prospects and is currently in phase I clinical trials. Incyte company disclosed the compound INCB-057643 in the CN106414442A patent, which is in the phase I clinical trial. Bristol-Myers Squibb disclosed another type of BET protein inhibitor in WO2015100282A, representing that the compound BMS-986158 is in the phase I clinical trial. GlaxoSmithKline disclosed compound I-BET762 in WO2011054553A, which is currently undergoing tumor phase II clinical trials.
  • BET protein inhibitors Although there are no drugs on the market, BET protein inhibitors have good application prospects as drugs. At this stage, more novel bromodomain inhibitors for the treatment of diseases and indications involving the function of the bromodomain including the function of the BET domain are in urgent need of development.
  • the compounds of the present invention also help to meet such clinical needs, and we hope to develop a new generation of BET protein inhibitors with high efficiency and low toxicity.
  • the purpose of the present invention is to provide a BET protein inhibitor with high efficiency and low toxicity.
  • a BET protein inhibitor wherein the inhibitor is a compound of formula I:
  • A is selected from
  • Ring B is selected from Or a five-membered aromatic heterocyclic ring substituted by R 11 and/or R 12 ;
  • the "five-membered aromatic heterocyclic ring” refers to a monocyclic aromatic hydrocarbon of 5 atoms, and contains one or more heteroatoms (such as N , O, S), including but not limited to furan, imidazole, thiophene, pyrazole, etc. among them:
  • X is O, S or NR 13 ;
  • Z is CR 14 or N
  • U is CH or N
  • W is O or NH
  • V is CH or N
  • R 1 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, substituted C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl C 1 -C 6 alkyl, C 1 -C 6 alkyl -SO 2 -or C 3 -C 6 cycloalkyl -SO 2 -; the substituted C 1 -C 6 alkyl refers to C 1 -C 6 alkane
  • the hydrogen on the group is replaced by one or more C 3 -C 6 cycloalkyl;
  • the substituted C 3 -C 6 cycloalkyl means that the hydrogen on the C 3 -C 6 cycloalkyl group is replaced by one or more C 1 -C 6 alkyl substitution;
  • R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 3 alkoxy, halogen or cyano;
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 3 alkoxy, halogen, cyano, -S(O) 2 R 15 , -S(O) 2 NR 16 R 17 or -N( R 16 )S(O) 2 R 15 ;
  • R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 3 alkoxy, halogen or cyano;
  • R 5 and R 6 are each independently hydrogen or C 1 -C 6 alkyl
  • R 7 , R 8 , R 9 and R 10 are each independently hydrogen, halogen, cyano, C 1 -C 3 alkoxy or C 1 -C 6 alkyl;
  • R 11 is hydrogen or C 1 -C 6 alkyl
  • R 12 is hydrogen or C 1 -C 6 alkyl
  • R 13 is hydrogen or C 1 -C 6 alkyl
  • R 14 is hydrogen, C 1 -C 6 alkyl, halogen or cyano
  • R 15 is C 1 -C 6 alkyl
  • R 16 is hydrogen or C 1 -C 6 alkyl
  • R 17 is hydrogen or C 1 -C 6 alkyl
  • the aforementioned halogen is selected from fluorine, chlorine, bromine or iodine.
  • A is selected from
  • Ring B is selected from
  • X is O, S or NR 13 ;
  • Z is CR 14 or N
  • U is CH or N
  • W is O or NH
  • V is CH or N
  • R 1 is hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, substituted C 1 -C 4 alkyl, substituted C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl C 1 -C 3 alkyl, C 1 -C 4 alkyl -SO 2 -or C 3 -C 6 cycloalkyl -SO 2 -; the substituted C 1 -C 4 alkyl refers to C 1 -C 4 alkyl
  • the hydrogen on the group is replaced by one or more C 3 -C 6 cycloalkyl;
  • the substituted C 3 -C 6 cycloalkyl means that the hydrogen on the C 3 -C 6 cycloalkyl group is replaced by one or more C 1 -C 4 alkyl substitution;
  • R 2 is hydrogen, C 1 -C 4 alkyl, C 1 -C 2 alkoxy, halogen or cyano;
  • R 3 is hydrogen, C 1 -C 4 alkyl, C 1 -C 2 alkoxy, halogen, cyano, -S(O) 2 R 15 , -S(O) 2 NR 16 R 17 or -N( R 16 )S(O) 2 R 15 ;
  • R 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 3 alkoxy, halogen or cyano;
  • R 5 and R 6 are each independently hydrogen or C 1 -C 4 alkyl
  • R 7 , R 8 , R 9 and R 10 are each independently hydrogen, halogen, cyano, C 1 -C 3 alkoxy or C 1 -C 4 alkyl;
  • R 11 is hydrogen or C 1 -C 4 alkyl
  • R 12 is hydrogen or C 1 -C 4 alkyl
  • R 13 is hydrogen or C 1 -C 4 alkyl
  • R 14 is hydrogen, C 1 -C 4 alkyl, halogen or cyano
  • R 15 is a C 1 -C 4 alkyl group
  • R 16 is hydrogen or C 1 -C 4 alkyl
  • R 17 is hydrogen or C 1 -C 4 alkyl
  • the aforementioned halogen is selected from fluorine, chlorine, bromine or iodine.
  • A is selected from
  • Ring B is selected from
  • X is O, S or NR 13 ;
  • Z is CR 14 or N
  • U is CH or N
  • W is O or NH
  • V is CH or N
  • R 1 is hydrogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, substituted C 1 -C 3 alkyl, substituted C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl C 1- C 3 alkyl, C 1 -C 3 alkyl-SO 2 -or C 3 -C 6 cycloalkyl-SO 2 -; the substituted C 1 -C 3 alkyl refers to C 1 -C 3 alkyl
  • the hydrogen on the group is replaced by one or more C 3 -C 6 cycloalkyl;
  • the substituted C 3 -C 6 cycloalkyl means that the hydrogen on the C 3 -C 6 cycloalkyl group is replaced by one or more C 1 -C 3 alkyl substitution;
  • R 2 is hydrogen, C 1 -C 3 alkyl, C 1 -C 2 alkoxy, halogen or cyano;
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 2 alkoxy, halogen, cyano, -S(O) 2 R 15 , -S(O) 2 NR 16 R 17 or -N( R 16 )S(O) 2 R 15 ;
  • R 4 is hydrogen, C 1 -C 3 alkyl, C 1 -C 2 alkoxy, halogen or cyano;
  • R 5 and R 6 are each independently hydrogen or C 1 -C 3 alkyl
  • R 7 , R 8 , R 9 and R 10 are each independently hydrogen, halogen, cyano, C 1 -C 2 alkoxy or C 1 -C 3 alkyl;
  • R 11 is hydrogen or C 1 -C 3 alkyl
  • R 12 is hydrogen or C 1 -C 3 alkyl
  • R 13 is hydrogen or C 1 -C 3 alkyl
  • R 14 is hydrogen, C 1 -C 3 alkyl, halogen or cyano
  • R 15 is C 1 -C 3 alkyl
  • R 16 is hydrogen or C 1 -C 3 alkyl
  • R 17 is hydrogen or C 1 -C 3 alkyl
  • the aforementioned halogen is selected from fluorine, chlorine, bromine or iodine.
  • halogen in this application refers to F, Cl, Br or I;
  • C 1 -C 3 alkyl refers to methyl, ethyl, n-propyl or isopropyl;
  • C 1 -C 2 alkoxy means methoxy or ethoxy;
  • the "cycloalkyl”, unless otherwise specified, means saturated or partially unsaturated containing 3-6 carbon atoms Cyclic hydrocarbon.
  • Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.
  • the compounds of the present invention can be prepared in the form of pharmaceutical salts according to conventional methods; including their organic acid salts and inorganic acid salts: inorganic acids include (but are not limited to) hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, nitric acid, etc., Organic acids include, but are not limited to, acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, lactic acid, p-toluenesulfonic acid, salicylic acid, oxalic acid and the like.
  • inorganic acids include (but are not limited to) hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, nitric acid, etc.
  • Organic acids include, but are not limited to, acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, lactic acid, p-toluenesulfonic acid, salicylic acid,
  • Typical compounds of the present invention include, but are not limited to the following compounds in Table 1:
  • the second objective of the present invention is to provide a synthetic method of the above compound:
  • the compound of the general formula IA and the compound of the general formula IB are catalyzed and coupled to produce the compound I of the general formula, and the definition of each group is as described above.
  • the third object of the present invention is to provide the use of the above compound as a novel BET protein inhibitor in the preparation of drugs for preventing or treating diseases related to BET protein.
  • the diseases related to the BET protein refer to tumor diseases, benign hyperplasia, inflammatory diseases, autoimmune diseases, sepsis, viral infections, vascular diseases and neurological diseases.
  • the tumor diseases include, but are not limited to, acute myeloid leukemia, lymphoma, multiple myeloma, B-cell acute lymphoid leukemia, midline cancer, glioma, solid tumor, breast cancer, colorectal cancer, prostate cancer , Cervical cancer, non-small cell lung cancer, melanoma, etc.
  • the derivatives of the present invention can be formed into a composition by oral, injection, etc., to treat related cancers and other diseases.
  • oral administration it can be prepared into conventional solid preparations such as tablets, powders or capsules; when used for injection, it can be prepared into injections.
  • the fourth object of the present invention is to provide a composition comprising a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof and a medically acceptable carrier.
  • the carrier mentioned refers to the conventional carriers in the pharmaceutical field, such as diluents, excipients such as water, etc.; binders such as cellulose derivatives, gelatin, polyvinylpyrrolidone, etc.; fillers such as starch, etc.; disintegrating agents such as carbonic acid Calcium, sodium bicarbonate; in addition, other auxiliary agents such as flavoring and sweetening agents can also be added to the composition.
  • diluents such as water, etc.
  • binders such as cellulose derivatives, gelatin, polyvinylpyrrolidone, etc.
  • fillers such as starch, etc.
  • disintegrating agents such as carbonic acid Calcium, sodium bicarbonate
  • other auxiliary agents such as flavoring and sweetening agents can also be added to the composition.
  • composition of the present invention can be prepared by conventional methods in the medical field, and the content of the active ingredient is 0.1%-99.5% (weight ratio).
  • the dosage of the present invention can be changed according to the route of administration, the age, weight of the patient, the type and severity of the disease to be treated, etc.
  • the daily dosage is 0.005-30mg/kg body weight (oral) or 0.005-30mg/kg body weight ( injection).
  • the present invention further improves the structure on the basis of the existing BET protein inhibitor, and obtains a new structure of BET protein inhibitor, which has better BET protein inhibitory activity and good pharmacokinetics It is expected to be developed into a new generation of high-efficiency and low-toxicity BET protein inhibitor.
  • Reference example 1 Synthetic route of fragment A1.
  • Reference example 2-7 Fragments A2 ⁇ A7.
  • Reference example 13-53 Fragment C2 ⁇ C42.
  • Reference Example 54 Synthetic route of fragments C43 and C44.
  • Reference example 55-56 Fragment C45 ⁇ C46.
  • Reference example 58-60 Fragment C48-C50.
  • the final concentration of the test compound and the positive control compound AbbV-075 and I-BET762 are all starting at 1000 nM, and the concentration is 3 times diluted to 10 concentrations, and each concentration is set for two multiple well tests.
  • the compound was diluted with DMSO as the solvent to a solution of 1000 times the final concentration, and then the DMSO solution of the corresponding concentration was diluted 100 times with a 1 ⁇ Assay buffer (the DMSO concentration was 1% at this time), and 2 ⁇ L of the compound was transferred with a discharge gun. Transfer the DMSO solution to a 384-well reaction plate to be tested. Transfer 2 ⁇ L of 1% DMSO solution into the Max well, and transfer 2 ⁇ L of the AbbV-075 highest concentration 1% DMSO solution into the Min well.
  • MV4-11 cells acute myeloid leukemia
  • 100 ⁇ L growth medium RPMI1640, 10% FCS
  • C1 value the fluorescence value
  • C0 value the fluorescence value
  • the compound of the present invention has significantly better BRD4 binding activity than ABBV-075 and INCB-057643; the compound of the present invention has obvious inhibitory activity on the proliferation of leukemia cells MV4-11, and the inhibitory activity is better than ABBV-075 and INCB-057643.
  • the LC/MS/MS method was used to determine that the rats were intragastrically administered ABBV-075 and the preferred embodiment compounds of the present invention, and then the drug concentration in the plasma at different times was measured to study the compounds of the present invention in Pharmacokinetic characteristics in rats.
  • Administration method single intragastric administration
  • Standard curve and quality control sample preparation and processing Take an appropriate amount of stock solution and dilute with 50% acetonitrile water into a standard working solution of 0.04, 0.10, 0.20, 0.40, 1.00, 2.00, 4.00 ⁇ g/mL, 0.10, 1.00, 3.00 ⁇ g/mL Quality control working fluid.
  • the compounds of the examples of the present invention show good pharmacokinetic properties. Compared with ABBV-075, the blood concentration and curve area are higher, the half-life is longer, and the residence time is shorter.
  • mice were inoculated subcutaneously with MV4-11 cells to establish a MV4-11 nude mouse xenograft model. 13 days after inoculation (d13), the average tumor volume is about 215mm3. According to the tumor volume, the tumor-bearing mice are divided into groups by random block method, including solvent control group, control sample INCB-057643 group, and test sample group, each with 6 only. Each group was given intragastric administration with a dose of 30mg/kg and a volume of 10ml/kg, once a day for 14 consecutive days. The solvent control group was given a blank solvent (50mM sodium lactate aqueous solution, PH4.0). Tumors were measured and weighed twice a week after the test drug was started. After the experiment, the animals were euthanized.
  • solvent control group was given a blank solvent (50mM sodium lactate aqueous solution, PH4.0).
  • Table 12 shows the efficacy results of the preferred compounds of the present invention in animals.
  • the compounds of the examples of the present invention show good anti-tumor activity. Compared with the control group INCB-057643, the anti-tumor activity is more significant.

Abstract

本发明属于生物医药技术领域，具体涉及一种BET蛋白抑制剂、其制备方法及用途。与现有技术相比，本发明在现有BET蛋白抑制剂基础上进一步进行结构改进，得到一类新结构的BET蛋白抑制剂，其具有较好的BET蛋白抑制活性及良好的药代动力学性质，有望开发为新一代高效低毒的BET蛋白抑制剂。

Description

一种BET蛋白抑制剂、其制备方法及用途 技术领域
本发明属于生物医药技术领域，具体涉及一种BET蛋白抑制剂、其制备方法及用途。
背景技术
表观遗传学(Epigenetic)是当前非常热门的药物发现主题之一。组蛋白乙酰化是表观遗传研究的重要组成部分。Bromodomain(BRD)是一类能够特异性识别组蛋白中乙酰化赖氨酸(KAc)的保守蛋白结构域，通过与乙酰化赖氨酸结合促使蛋白富集于特定的基因转录位点，改变RNA聚合酶II的活性，调节基因的转录表达(Kuc和Allis，Bioessays,1998,20:615-626)。
目前，人体内发现的61种BRD结构域存在于42种蛋白中，根据母蛋白功能的不同，BRD蛋白划分为8大家族，BET蛋白家族是BRD蛋白家族的第2类。BET蛋白包括BRD2、BRD3、BRD4和BRDT四个成员(Wu和Chiang,J.Biol.chem.,2007,282:13141-13145)。前三种广泛表达于所有机体细胞，后者仅限表达于睾丸组织。
BET蛋白在多种肿瘤中发挥重要作用。如造血***肿瘤(急性髓细胞白血病、淋巴瘤、多发性骨髓瘤、B细胞急性淋巴白血病等)，通过干扰BRD4与癌基因MYC的结合，可以抑制MYC的表达，进而引起肿瘤细胞凋亡。BET蛋白(BRD3或BRD4)和NUT(通常仅在睾丸中表达的蛋白)之间的融合导致鳞状细胞癌的攻击性形式，其被称作NUT中线癌(French，Cancer Genet，Cytogenet.,2010，203:16-20)。
在上皮瘤形成的高度恶性形式中发现涉及NUT(睾丸中的核蛋白)与BRD3或BRD4的反复移位形成新颖融合致癌基因BRD-NUT(French等人，Cancer Research 2003，63:304-307)。选择性减少此致癌基因可复原正常细胞分化且逆转致瘤表型(Fi1ippakopoulos等人，Nature2010，468:1068-1073)。已证实BRD2、BRD3和BRD4的基因剔除会损害多种血液学和实体肿瘤细胞的生长和活力(Zuber等人，Nature 2011，478:524-528；Delmore等人，Cell 2011，146:904-917)。除在癌症中的作用以外，BET蛋白还调控对细菌攻击的炎性反应，且BRD2亚等位基因小鼠模型显示显著较低水平的炎性细胞因子和防止肥胖诱导的糖尿病(Wang等人，Biochem J.2009，425:71-83)。另外，一些病毒利用这些BET蛋白将其基因组系栓于宿主细胞染色质作为病毒复制过程的一部分，或使用BET蛋白促进病毒基因转录和阻遏(You等人，Ce11 2004，117:349-360；Zhu等人，Cell Reports 2012，2:807-816)。
综上所述，靶向这些蛋白对于发展靶向癌症，炎症和病毒感染的新的治疗策略可能是有益的。目前已有针对这一受体的小分子抑制剂进入临床阶段，其主要用于癌症及自身免疫疾病的治疗。目前公开了一系列BET抑制剂类专利申请，包括：WO2013158952、WO2014165127、WO2015075665、WO2016050821、WO2018188047、WO2018130174等。
Abbive公司在WO2013097052A中公开了一类BET蛋白抑制剂，其中化合物ABBV-075具有开发前景，目前处于Ⅰ期临床试验阶段。Incyte公司在CN106414442A专利中公开了化合物INCB-057643，处于Ⅰ期临床试验阶段。Bristol-Myers Squibb公司在WO2015100282A中公开了另一类BET蛋白抑制剂，代表化合物BMS-986158处于Ⅰ期临床试验阶段。GlaxoSmithKline公司在WO2011054553A中公开了化合物I-BET762，该化合物正在开展肿瘤Ⅱ期临床试验。
Figure PCTCN2020084797-appb-000001
虽然没有上市药物，但BET蛋白抑制剂作为药物研发具有良好的应用前景。现阶段，更多用于治疗涉及溴结构域功能包括BET结构域功能的疾病和适应症的新型溴结构域抑制剂亟待开发。本发明化合物亦有助于满足此类临床需要，我们希望能开发出新一代高效低毒的BET蛋白抑制剂。
发明内容
为了克服现有技术中所存在的问题，本发明的目的在于提供一种高效低毒的BET蛋白抑制剂。
为了实现上述目的以及其他相关目的，本发明采用如下技术方案：
一种BET蛋白抑制剂，其中所述抑制剂为式I化合物：
Figure PCTCN2020084797-appb-000002
或其药学上可接受的盐，其中，
A选自
Figure PCTCN2020084797-appb-000003
B环选自
Figure PCTCN2020084797-appb-000004
或被R 11和/或R 12取代的五元芳杂环；所述的“五元芳杂环”，是指5个原子的单环芳烃，并且含有1个或多个杂原子(例如N，O，S)，包括但不限于呋喃，咪唑，噻吩，吡唑等。其中：
X为O、S或NR 13；
Y为CH 2、C＝O、NR 1或Y不存在；
Z为CR 14或N；
U为CH或N；
W为O或NH；
V为CH或N；
R 1为氢、C 1-C 6烷基、C 3-C 6环烷基、取代C 1-C 6烷基、取代C 3-C 6环烷基、C 3-C 6环烷基C 1-C 6烷基、C 1-C 6烷基-SO 2-或C 3-C 6环烷基-SO 2-；所述取代C 1-C 6烷基是指C 1-C 6烷基上的氢被一个或多个C 3-C 6环烷基取代；所述取代C 3-C 6环烷基是指C 3-C 6环烷基上的氢被一个或多个C 1-C 6烷基取代；
R 2为氢、C 1-C 6烷基、C 1-C 3烷氧基、卤素或氰基；
R 3为氢、C 1-C 6烷基、C 1-C 3烷氧基、卤素、氰基、-S(O) 2R 15、-S(O) 2NR 16R 17或-N(R 16)S(O) 2R 15；
R 4为氢、C 1-C 6烷基、C 1-C 3烷氧基、卤素或氰基；
R 5和R 6各自独立地为氢或C 1-C 6烷基；
R 7、R 8、R 9和R 10各自独立地为氢、卤素、氰基、C 1-C 3烷氧基或C 1-C 6烷基；
R 11为氢或C 1-C 6烷基；
R 12为氢或C 1-C 6烷基；
R 13为氢或C 1-C 6烷基；
R 14为氢、C 1-C 6烷基、卤素或氰基；
R 15为C 1-C 6烷基；
R 16为氢或C 1-C 6烷基；
R 17为氢或C 1-C 6烷基；
上述卤素选自氟、氯、溴或碘。
优选的，所述式I化合物中：
A选自
Figure PCTCN2020084797-appb-000005
B环选自
Figure PCTCN2020084797-appb-000006
其中：
X为O、S或NR 13；
Y为CH 2、C＝O、NR 1或Y不存在；
Z为CR 14或N；
U为CH或N；
W为O或NH；
V为CH或N；
R 1为氢、C 1-C 4烷基、C 3-C 6环烷基、取代C 1-C 4烷基、取代C 3-C 6环烷基、C 3-C 6环烷基C 1-C 3烷基、C 1-C 4烷基-SO 2-或C 3-C 6环烷基-SO 2-；所述取代C 1-C 4烷基是指C 1-C 4烷基上的氢被一个或多个C 3-C 6环烷基取代；所述取代C 3-C 6环烷基是指C 3-C 6环烷基上的氢被一个或多个C 1-C 4烷基取代；
R 2为氢、C 1-C 4烷基、C 1-C 2烷氧基、卤素或氰基；
R 3为氢、C 1-C 4烷基、C 1-C 2烷氧基、卤素、氰基、-S(O) 2R 15、-S(O) 2NR 16R 17或-N(R 16)S(O) 2R 15；
R 4为氢、C 1-C 4烷基、C 1-C 3烷氧基、卤素或氰基；
R 5和R 6各自独立地为氢或C 1-C 4烷基；
R 7、R 8、R 9和R 10各自独立地为氢、卤素、氰基、C 1-C 3烷氧基或C 1-C 4烷基；
R 11为氢或C 1-C 4烷基；
R 12为氢或C 1-C 4烷基；
R 13为氢或C 1-C 4烷基；
R 14为氢、C 1-C 4烷基、卤素或氰基；
R 15为C 1-C 4烷基；
R 16为氢或C 1-C 4烷基；
R 17为氢或C 1-C 4烷基；
上述卤素选自氟、氯、溴或碘。
优选的，所述式I化合物中：
A选自
Figure PCTCN2020084797-appb-000007
B环选自
Figure PCTCN2020084797-appb-000008
其中：
X为O、S或NR 13；
Y为CH 2、C＝O、NR 1或Y不存在；
Z为CR 14或N；
U为CH或N；
W为O或NH；
V为CH或N；
R 1为氢、C 1-C 3烷基、C 3-C 6环烷基、取代C 1-C 3烷基、取代C 3-C 6环烷基、C 3-C 6环烷基C 1-C 3烷基、C 1-C 3烷基-SO 2-或C 3-C 6环烷基-SO 2-；所述取代C 1-C 3烷基是指C 1-C 3烷基上的氢被一个或多个C 3-C 6环烷基取代；所述取代C 3-C 6环烷基是指C 3-C 6环烷基上的氢被一个或多个C 1-C 3烷基取代；
R 2为氢、C 1-C 3烷基、C 1-C 2烷氧基、卤素或氰基；
R 3为氢、C 1-C 3烷基、C 1-C 2烷氧基、卤素、氰基、-S(O) 2R 15、-S(O) 2NR 16R 17或-N(R 16)S(O) 2R 15；
R 4为氢、C 1-C 3烷基、C 1-C 2烷氧基、卤素或氰基；
R 5和R 6各自独立地为氢或C 1-C 3烷基；
R 7、R 8、R 9和R 10各自独立地为氢、卤素、氰基、C 1-C 2烷氧基或C 1-C 3烷基；
R 11为氢或C 1-C 3烷基；
R 12为氢或C 1-C 3烷基；
R 13为氢或C 1-C 3烷基；
R 14为氢、C 1-C 3烷基、卤素或氰基；
R 15为C 1-C 3烷基；
R 16为氢或C 1-C 3烷基；
R 17为氢或C 1-C 3烷基；
上述卤素选自氟、氯、溴或碘。
本申请所述的“卤素”是指F、Cl、Br或I；所述的“C 1-C 3的烷基”是指甲基、乙基、正丙基或异丙基；所述的“C 1-C 2的烷氧基”是指甲氧基或乙氧基；所述的“环烷基”，除非另有说明，是指含有3-6个碳原子的饱和或者部分不饱和的环状烃。环烷基包括但不限于环丙基，环丁基，环戊基，环戊烯基，环己基，环己烯基。
本发明的化合物可按照常规方法制备为药用盐的形式；包括其有机酸盐及无机酸盐：无机酸包括(但不限于)盐酸、硫酸、磷酸、二磷酸、氢溴酸、硝酸等，有机酸包括(但不限于)乙酸、马来酸、富马酸、酒石酸、琥珀酸、乳酸、对甲苯磺酸、水杨酸、草酸等。
本发明的典型化合物包括，但不限于以下表1化合物：
Figure PCTCN2020084797-appb-000009
Figure PCTCN2020084797-appb-000010
Figure PCTCN2020084797-appb-000011
Figure PCTCN2020084797-appb-000012
Figure PCTCN2020084797-appb-000013
本发明的第二目的在于提供了上述化合物的合成方法：
Figure PCTCN2020084797-appb-000014
通式IA化合物和通式IB化合物经催化偶联反应制得通式化合物I，各基团定义如前文所述。
本发明的第三目的在于提供上述化合物作为新型BET蛋白抑制剂在制备预防或治疗与BET蛋白相关疾病的药物中的用途。
具体的，所述与BET蛋白相关疾病指肿瘤疾病、良性增生、炎性疾病、自身免疫疾病、败血症、病毒感染、血管疾病和神经性疾病。进一步的，所述肿瘤疾病包括但不限于急性髓性白血病、淋巴瘤、多发性骨髓瘤、B细胞急性淋巴白血病、中线癌、神经胶质瘤、实体瘤、乳腺癌、结直肠癌、***癌、***、非小细胞肺癌、黑色素瘤等。
本发明的衍生物在实施疾病治疗过程中，可以组合物的形成通过口服、注射等方式，用于治疗相关癌症及其他疾病。用于口服时，可将其制备成常规的固体制剂如片剂、粉剂或胶囊等；用于注射时，可将其制备成注射液。
本发明的第四目的在于提供一种组合物，所述组合物包括治疗有效量的上述化合物或其可药用的盐和医学上可接受的载体。
所述及的载体是指药学领域常规的载体，如：稀释剂、赋形剂如水等；粘合剂如纤维素衍生物、明胶、聚乙烯吡咯烷酮等；填充剂如淀粉等；崩裂剂如碳酸钙、碳酸氢钠；另外，还可以在组合物中加入其他辅助剂如香味剂和甜味剂。
本发明的组合物的各种剂型可以采用医学领域常规的方法进行制备，其中活性成分的含量为0.1％～99.5％(重量比)。
本发明的施用量可根据用药途径、患者的年龄、体重、所治疗的疾病的类型和严重程度等进行变化，其日剂量为0.005-30mg/kg体重(口服)或0.005-30mg/kg体重(注射)。
与现有技术相比，本发明在现有BET蛋白抑制剂基础上进一步进行结构改进，得到一类新结构的BET蛋白抑制剂，其具有较好的BET蛋白抑制活性及良好的药代动力学性质，有望开发为新一代高效低毒的BET蛋白抑制剂。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明的一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其它实施例，都属于本发明保护的范围。
参考例1：片段A1的合成路线。
Figure PCTCN2020084797-appb-000015
步骤1：化合物A1-2的合成。
0℃下，向化合物A1-1(400mg，1.76mmol)的DMF(20mL)溶液中加入NaH(141mg，3.52mmol)。将混合物在该温度下搅拌10分钟并在0℃下加入TsCl(671mg，3.52mmol)。然后将混合物在室温下搅拌反应2小时。反应混合物用H 2O(20mL)稀释，并用EA(30mL x 2)萃取。合并有机层，并用盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤并浓缩。残留物经硅胶柱层析(PE/EA＝2/1)，得到化合物A1-2(800mg， 95％产率)，为黄色固体。MS:382.0[M+H] +。
步骤2：化合物A1-3的合成。
向化合物A1-2(800mg，2.1mmol)的二氧六环(10mL)溶液中加入4M HCl的二氧六环溶液(5mL)反应混合物在50℃下搅拌2小时。将反应混合物冷却至室温并浓缩，剩余物用H 2O(20mL)稀释，并经EA(30mL x 2)萃取。合并有机层，有机层经盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤并浓缩，得到化合物A1-3(600mg，100％收率)，为黄色固体。MS:368.0[M+H] +。
步骤3：化合物A1-4的合成。
0℃下，向化合物A1-3(600mg，1.63mmol)的DMF(10mL)溶液中加入NaH(131mg，3.26mmol)。该混合物在此温度下搅拌10分钟并于冰浴中加入CH 3I(671mg，3.52mmol)。混合物在室温下搅拌3小时。反应混合物经H 2O(20mL)稀释，并经EA(30mL x 2)萃取。合并的有机层用盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤并浓缩。残留物经硅胶柱层析(PE/EA＝2/1)，得到化合物A1-4(450mg，72％产率)，为黄色固体。MS:382.0[M+H] +。
步骤4：化合物A1的合成。
反应瓶中依次加入化合物A1-4(300mg，0.788mmol)，Pin 2B 2(400mg，1.57mmol)，KOAc(232mg，2.36mmol)，X-phos(38mg，0.08mmol)、Pd 2(dba) 3(73mg，0.08mmol)和二氧六环(20mL)。N2保护下，混合物在85℃搅拌3小时。反应混合物经H 2O(20mL)稀释，并用DCM(30mL x 2)萃取。将合并的有机层用盐水(20mL)洗涤，无水硫酸钠干燥，过滤并浓缩，得到化合物A1-5粗品(500mg，100％产率)，为黄色固体。MS:429.0[M+H] +， 1H NMR(400MHz,DMSO-d 6)δ:8.11(s,1H),7.99-8.01(m,2H),7.92-7.93(d,J＝4.0Hz,1H),7.30-7.32(m,2H),6.50-6.51(d,J＝4.0Hz,1H),3.50(s,3H),2.40(s,3H),1.25(s,12H)。
参考例2-7：片段A2～A7。
参照参考例1中步骤1-4的合成方法，合成下表2中各参考例：
Figure PCTCN2020084797-appb-000016
Figure PCTCN2020084797-appb-000017
参考例8：片段A8的合成路线。
Figure PCTCN2020084797-appb-000018
反应瓶中依次加入化合物A8-1(150mg，0.95mmol)，Pin 2B 2(1.2g，4.73mmol)，KOAc(186mg，1.9mmol)，X-phos(91mg，0.19mmol)、Pd 2(dba) 3(87mg，0.095mmol)和二氧六环(10mL)。混合物在85℃下搅拌反应1小时。反应液冷至室温，加H 2O(20mL)稀释，并用DCM(30mL×2)萃取。合并有机层，并经食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，得到粗产物A8-1(200mg，94％产率)，为黄色固体。MS:251.1[M+H] +。
参考例9-11：片段A9～A11。
参照参考例8的合成方法，合成下表3中各参考例:
Figure PCTCN2020084797-appb-000019
Figure PCTCN2020084797-appb-000020
参考例12：片段C1的合成路线。
Figure PCTCN2020084797-appb-000021
步骤1：化合物C1-2的合成。
向化合物C1-1(11g，0.05mol)的浓H 2SO 4(60mL)溶液中滴加入Br 2(8g，0.05mol)，然后在冰水浴中加入HNO 3(2.5mL)。反应液加热至90℃，保温反应5小时。反应冷至室温，加H 2O(50mL)稀释，并用DCM(50mL×2)萃取。合并2次萃取液，再经饱和Na 2S 2O 3(50mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。剩余物通过硅胶柱层析(PE/EA＝2/1)纯化残余物，得到化合物C1-2(4.3g，29％收率)，为白色固体。MS:297.1[M-H] -。
步骤2：化合物C1-4的合成。
化合物C1-2(4.1g，13.8mmol)，4-氟-3-碘苯酚(3.45g，14.5mmol)和K 2CO 3(2g，14.5mmol)加入DMSO(120mL)中，该反应液在120℃下加热反应3小时。反应液冷至室温，加H 2O(30mL)淬灭，并用EA(50mL x 2)萃取。将合并的有机层用食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。剩余物通过硅胶柱层析(PE/EA＝2/1)纯化，得到化合物C1-4(5.4g，76％产率)，为黄色固体。MS:515.1[M-H] -。
步骤3：化合物C1-5的合成。
化合物C1-4(5.4g，10.5mmol)，Fe(2.0g，37mmol)和NH 4Cl(334mg，6.3mmol)加入EtOH(100mL)和H 2O(20mL)中，该混合液在90℃下搅拌反应3小时。反应液冷至室温，加H 2O(50mL)稀释并用EA(80mL)萃取。分液，浓缩有机层，所得剩余物经硅胶柱层析(PE/EA＝2/1)纯化，得化合物C1-5(3.3g，64.7％产率)，为黄色固体。MS:485.1[M-H] -。
步骤4：化合物C1-6的合成。
化合物C1-5(500mg，1.03mmol)，Cs 2CO 3(1g，3.09mmol)，BINAP(128mg，0.2mmol)和Pd 2(dba) 3(192mg，0.2mmol)加入二氧六环(40mL)中，该反应液在80℃下搅拌反应过夜。反应液冷至室温，加H 2O(50mL)稀释，并用EA(50mL×2)萃取。有机层经食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。剩余物经硅胶柱层析(PE/EA＝2/1)纯化，得到化合物C1-6(290mg，37.6％产率)，为黄色固体。MS:357.2[M-H] -。
步骤5：化合物C1的合成。
冰浴下，向化合物5(660mg，0.02mol)、聚甲醛(166mg，5.53mmol)和DCM(20mL)的混合溶液中加入TFA(1.3mL)和Et 3SiH(2.6mL)室温搅拌反应2小时。反应液加H 2O(30mL)稀释，并用EA(50mL×2)萃取。合并有机层，并用食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩。剩余物经硅胶柱层析(PE/EA＝2/1)纯化，制得化合物C1(300mg，41％收率)，为黄色固体。MS:373.2[M+H] +， 1H NMR(400MHz, CDCl 3)δ:7.35(s,1H),7.00(s,1H),6.52-6.55(m,1H),6.38-6.42(m,1H),6.36(s,1H),3.35(s,3H),3.19(s,3H)。
参考例13-53：片段C2～C42。
参照参考例12中步骤1-5的合成方法，合成下表4中各参考例：
Figure PCTCN2020084797-appb-000022
Figure PCTCN2020084797-appb-000023
Figure PCTCN2020084797-appb-000024
Figure PCTCN2020084797-appb-000025
参考例54：片段C43和C44的合成路线。
Figure PCTCN2020084797-appb-000026
步骤1：化合物C43-3的合成。
化合物C43-1(2.51g，10.0mmol)，C43-2(1.65g，10.5mmol)和K 2CO 3(2.1g，15mmol)加入DMF(20mL)中，该反应液在100℃下加热反应3小时。反应液冷至室温，加H 2O(30mL)淬灭，并用EA(50mL x 2)萃取。将合并的有机层用食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。剩余物通过硅胶柱层析(PE/EA＝2/1)纯化，得到化合物C43-3(2.4g，62％产率)，为白色固体。MS:390.2[M+H] +。
步骤2：化合物C43的合成。
化合物C43-3(2.0g，5.1mmol)加入多聚磷酸(10mL)中，搅拌下加热至120℃反应3小时，反应液冷至室温，搅拌下加入冰水(30mL)搅拌30min，过滤，所得粗品经甲醇(10mL)重结晶，50℃真空干燥4h，得C43(1.54g，81％收率)，为类白色固体。MS:358.2[M+H] +， 1H NMR(400MHz,CDCl 3)δ:7.41(s,1H),7.05(s,1H),6.67(m,2H),6.58(m,1H),3.86(s,1H),3.35(s,3H)。
步骤3：化合物C44的合成。
冰盐浴下向C43(1.0g，2.7mmol)的THF溶液(10mL)中滴加1N硼烷四氢呋喃溶液(2mL)，滴加完成后室温搅拌反应1h，再升温至回流反应2h。冷至室温，搅拌下滴加入无水乙醇(2mL)，滴加完成后减压浓缩至干，剩余物经二氯甲烷(10mL)/H 2O(5mL)萃取、分液，有机层再经饱和食盐水(5mL)洗，分离、干燥、浓缩得C42粗品，该粗品经无水乙醇(5mL)重结晶，50℃真空干燥4h，得C44(0.82g，85％收率)，为类白色固体。MS:372.2[M+H] +， 1H NMR(400MHz,CDCl 3)δ:8.21(s,1H),8.05(s,1H),7.15-7.22(m,3H),3.34(s,3H)。
参考例55-56：片段C45～C46。
参照参考例54中步骤1-3的合成方法，合成下表5中各参考例：
Figure PCTCN2020084797-appb-000027
参考例57：片段C47的合成路线。
Figure PCTCN2020084797-appb-000028
步骤1：化合物C47-2的合成。
化合物C47-1(2.51g，10.0mmol)，间氟苯硼酸(1.53g，11.0mmol)和K 2CO 3(3.45g，25.0mmol)加入DMF(20mL)中，该反应液N 2气保护下，加热至100℃下加热反应3小时。反应液冷至室温，加H 2O(30mL)/EtOAc(60mL)萃取，有机层用食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。剩余物通过硅胶柱层析(PE/EA＝1/1)纯化，得到化合物C47-2(2.13g，80％产率)，为类白色固体。MS:267.3[M+H] +。
步骤2：化合物C47的合成。
敞口反应瓶中依次加入C47-2(2.1g，7.9mmol)、CuI(2.2g，11.8mmol)、特戊酸(0.8g，7.9mmol)和DMSO(10mL)，搅拌下加热至内温130℃反应12h。反应完成后，将EtOAc(30mL)加入到冷却的反应混合物中。依次加入氨水(15mL)和食盐水(15mL)洗涤、分液。有机层用无水硫酸钠干燥、过滤，并真空浓缩至干。所得剩余物通过硅胶柱层析(PE/EA＝10/1)纯化，得到化合物C47(1.78g，58％产率)，为类白色固体。MS:391.2[M+H] +， 1H NMR(400MHz,CDCl 3)δ:8.24(s,1H),8.15(s,1H),7.88(m,1H),7.13(m,1H),6.84(m,1H),3.32(s,1H)。
参考例58-60：片段C48-C50。
参照参考例57中步骤1-2的合成方法，合成下表6中各参考例：
Figure PCTCN2020084797-appb-000029
实施例1
合成路线：
Figure PCTCN2020084797-appb-000030
步骤1：化合物I-1-1的合成
化合物A1(473mg,0.97mmol)、C1(180mg,0.485mmol)、CsF(221mg,1.45mmol)、Pd(dppf)Cl 2(35mg,0.05mmol)、二氧六环(10mL)、H 2O(2mL)依次加入反应瓶中，N2保护下加热升温至85℃反应12h。反应液冷至室温，加H 2O(20mL)稀释，以DCM(30mL x 2)萃取，合并有机相。有机相经饱和食盐水(20mL)洗、分液。有机层用无水硫酸钠干燥、过滤，并真空浓缩至干。所得剩余物通过硅胶柱层析(PE/EA＝1/2)纯化，得到化合物I-1-1(178mg,62％产率)，为淡黄色固体。MS:594.6[M+H] +。
步骤2：化合物I-1的合成
I-1-1(160mg,0.27mmol)的甲醇溶液(10mL)中加入6M NaOH水溶液(5mL)，反应混合液加热至 80℃反应1h。反应液冷至室温，加H 2O(20mL)稀释，以DCM(30mL x 2)萃取，合并有机相。有机相经饱和食盐水(20mL)洗、分液。有机层用无水硫酸钠干燥、过滤，并真空浓缩至干。所得剩余物通过硅胶柱层析(PE/EA＝1/2)纯化，得到化合物I-1(52mg,44％产率)，为白色固体。MS:440.5[M+H] +。 1H NMR(400MHz,DMSO-d6)δ:12.11(s,1H),7.31-7.37(m,3H),7.14(s,1H),6.74-6.77(m,1H),6.44-6.52(m,2H),6.16(s,1H),3.59(s,3H),3.25(s,3H),3.17(s,3H).
参照实施例1中步骤1～2的合成方法，合成下表7中各实施例化合物：
Figure PCTCN2020084797-appb-000031
Figure PCTCN2020084797-appb-000032
Figure PCTCN2020084797-appb-000033
Figure PCTCN2020084797-appb-000034
Figure PCTCN2020084797-appb-000035
Figure PCTCN2020084797-appb-000036
Figure PCTCN2020084797-appb-000037
Figure PCTCN2020084797-appb-000038
Figure PCTCN2020084797-appb-000039
实施例56:I-56
合成路线：
Figure PCTCN2020084797-appb-000040
化合物A12(200mg,2.06mmol)、C1(1533mg,4.12mmol)、K 2CO 3(568mg,4.12mmol)、Pd(OAc) 2(46mg,0.2mmol)、二氧六环(20mL)、H 2O(2mL)依次加入反应瓶中，N 2保护下加热升温至85℃反应12h。反应液冷至室温，加H 2O(20mL)稀释，以DCM(30mL x 2)萃取，合并有机相。有机相经饱和食盐水(20mL)洗、分液。有机层用无水硫酸钠干燥、过滤，并真空浓缩至干。所得剩余物通过硅胶柱层析(PE/EA＝1/1)纯化，得到化合物I-56(400mg,50％产率)，为淡黄色固体。MS:389.4[M+H] +。 1H NMR(400MHz,DMSO-d6)δ:7.41(s,1H),7.05(s,1H),6.91(m,1H),6.50(m,2H),3.35(s,3H),3.20(s,3H),2.25(s,6H).
参照实施例56中合成方法，合成下表8中各实施例化合物：
Figure PCTCN2020084797-appb-000041
各实施例的NMR和MS数据汇总见下表9所示：
Figure PCTCN2020084797-appb-000042
Figure PCTCN2020084797-appb-000043
Figure PCTCN2020084797-appb-000044
Figure PCTCN2020084797-appb-000045
Figure PCTCN2020084797-appb-000046
测试例1、BRD4活性测试
结合反应过程:
(1)配制1×Assay buffer。
(2)化合物浓度梯度的配制：受试化合物与阳性对照化合物AbbV-075、I-BET762测试终浓度均为1000nM起始，3倍稀释10个浓度，每个浓度设置二复孔测试。先将化合物以DMSO为溶剂梯度稀释成相应1000倍终浓度的溶液，然后用1×Assay buffer将相应浓度的DMSO溶液稀释100倍(此时DMSO浓度为1％)，用排枪转移2μL化合物1％DMSO溶液到384孔反应板中待测。Max孔中转移2μL的1％DMSO溶液，Min孔中转移2μL的AbbV-075最高浓度1％DMSO溶液。
(3)用1×反应溶液配制5×蛋白溶液。
(4)用1×反应溶液配制5×多肽溶液。
(5)在各孔中加4μL的5×蛋白溶液，1000rpm离心1min，室温孵育15分钟。
(6)反应板各孔中加入4μL的5×多肽溶液，1000rpm离心1min。
(7)加入10μL检测液，1000rpm离心60秒，轻轻振荡混匀后，室温孵育60分钟。
(8)用EnVision读数。
数据分析:
计算公式
Figure PCTCN2020084797-appb-000047
拟合量效曲线
以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出化合物对蛋白结合抑制的IC 50值。
测试例2、MV4-11细胞增殖实验
通过
Figure PCTCN2020084797-appb-000048
试剂(Invitrogen)测定细胞活力。
将MV4-11细胞(急性髓性白血病)以5000个细胞/孔的浓度接种在96孔微量滴定板上的100μL生长培养基(RPMI1640，10％FCS)中。在37℃下孵育过夜后，测定荧光值(C1值)。然后用多种物质稀释物处理板，并且在37℃下孵育72h，然后测定荧光值(C0值)。对于数据分析，从C0值扣除C1值，并且将用多种物质稀释物处理的或仅用缓冲溶液处理的细胞结果进行比较。从而计算IC 50值。
上述实验结果如表10所示。
表10.测试结果：
Figure PCTCN2020084797-appb-000049
结论：本发明化合物对BRD4结合活性明显优于ABBV-075、INCB-057643；本发明化合物对白血病 细胞MV4-11增殖具有明显的抑制活性，抑制活性优于ABBV-075、INCB-057643。
测试例3、本发明化合物药代动力学测试
以SD大鼠为受试动物，采用LC/MS/MS法测定大鼠灌胃给予ABBV-075和本发明优选实施例化合物后，测定其不同时刻血浆中的药物浓度，研究本发明化合物在大鼠体内药代动力学特征。
SD大鼠来源：北京维通利华实验动物技术有限公司
给药方式:单次灌胃给药
给药剂量及浓度：10mg/kg；1mg/mL
制剂处方：0.5％methylcellulose
取样点：5min，15min，30min，1h，2h，4h，8h，24h.
标准曲线和质控样本配制处理：取适量储备液用50％乙腈水稀释成0.04、0.10、0.20、0.40、1.00、2.00、4.00μg/mL的标准工作液，0.10、1.00、3.00μg/mL的质控工作液。分别取47.5μL空白大鼠血浆中加入2.50μL的标准曲线工作液和质控工作液，配置成含待测物浓度为2.00、5.00、10.00、20.00、50.00、100.00、200.00ng/mL的标曲和浓度为5.00、50.00和150.00ng/mL的质控样本，分别加入200μL的乙腈(含内标氯雷他定5ng/mL)，涡旋振荡3min后，15000rpm，4℃离心15min，取上清液100L进行LC-MS/MS分析。采用
Figure PCTCN2020084797-appb-000050
8.0计算实验结果。
本发明优选化合物药代动力学参数如表11所示。
表11：优选化合物药代动力学参数
Figure PCTCN2020084797-appb-000051
结论：本发明实施例化合物表现出良好的药代动力学性质，与ABBV-075相比，血药浓度、曲线面积较高，半衰期长，滞留时间短。
测试例4、本发明化合物体内药效试验测试
目的：测试受试化合物对MV4-11白血病裸鼠移植瘤体内生长的抑制作用。
方法：BALB/c裸小鼠皮下接种MV4-11细胞，建立MV4-11裸鼠移植瘤模型。接种13天后(d13)，平均肿瘤体积约为215mm3，根据肿瘤体积大小采用随机区组法将荷瘤鼠分组，包括溶剂对照组、对照样品INCB-057643组、受试样品组，每组6只。各组均采用灌胃给药，给药剂量为30mg/kg，给药体积均为10ml/kg，每天给药一次，连续给药14天，溶剂对照组灌胃给予空白溶剂(50mM乳酸钠水溶液，PH4.0)。开始给予测试药物后每周二次量瘤、称重。实验结束后安乐死动物。
本发明优选化合物动物体内药效结果如表12所示。
表12：优选化合物动物体内药效
Figure PCTCN2020084797-appb-000052
结论：本发明实施例化合物表现出良好抑瘤活性。与对照组INCB-057643相比抑瘤活性更加显著。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (9)

  1. 一种BET蛋白抑制剂，其特征在于，其结构如式I所示：
    Figure PCTCN2020084797-appb-100001
    或其药学上可接受的盐，其中，
    A选自
    Figure PCTCN2020084797-appb-100002
    B环选自
    Figure PCTCN2020084797-appb-100003
    或被R 11和/或R 12取代的五元芳杂环；
    其中：
    X为O、S或NR 13；
    Y为CH 2、C＝O、NR 1或Y不存在；
    Z为CR 14或N；
    U为CH或N；
    W为O或NH；
    V为CH或N；
    R 1为氢、C 1-C 6烷基、C 3-C 6环烷基、取代C 1-C 6烷基、取代C 3-C 6环烷基、C 3-C 6环烷基C 1-C 6烷基、C 1-C 6烷基-SO 2-或C 3-C 6环烷基-SO 2-；
    R 2为氢、C 1-C 6烷基、C 1-C 3烷氧基、卤素或氰基；
    R 3为氢、C 1-C 6烷基、C 1-C 3烷氧基、卤素、氰基、-S(O) 2R 15、-S(O) 2NR 16R 17或-N(R 16)S(O) 2R 15；
    R 4为氢、C 1-C 6烷基、C 1-C 3烷氧基、卤素或氰基；
    R 5和R 6各自独立地为氢或C 1-C 6烷基；
    R 7、R 8、R 9和R 10各自独立地为氢、卤素、氰基、C 1-C 3烷氧基或C 1-C 6烷基；
    R 11为氢或C 1-C 6烷基；
    R 12为氢或C 1-C 6烷基；
    R 13为氢或C 1-C 6烷基；
    R 14为氢、C 1-C 6烷基、卤素或氰基；
    R 15为C 1-C 6烷基；
    R 16为氢或C 1-C 6烷基；
    R 17为氢或C 1-C 6烷基；
    上述卤素选自氟、氯、溴或碘。
  2. 如权利要求1所述的BET蛋白抑制剂，其特征在于，A选自
    Figure PCTCN2020084797-appb-100004
    Figure PCTCN2020084797-appb-100005
    B环选自
    Figure PCTCN2020084797-appb-100006
    其中：
    X为O、S或NR 13；
    Y为CH 2、C＝O、NR 1或Y不存在；
    Z为CR 14或N；
    U为CH或N；
    W为O或NH；
    V为CH或N；
    R 1为氢、C 1-C 4烷基、C 3-C 6环烷基、取代C 1-C 4烷基、取代C 3-C 6环烷基、C 3-C 6环烷基C 1-C 3烷基、C 1-C 4烷基-SO 2-或C 3-C 6环烷基-SO 2-；所述取代C 1-C 4烷基是指C 1-C 4烷基上的氢被一个或多个C 3-C 6环烷基取代；所述取代C 3-C 6环烷基是指C 3-C 6环烷基上的氢被一个或多个C 1-C 4烷基取代；
    R 2为氢、C 1-C 4烷基、C 1-C 2烷氧基、卤素或氰基；
    R 3为氢、C 1-C 4烷基、C 1-C 2烷氧基、卤素、氰基、-S(O) 2R 15、-S(O) 2NR 16R 17或-N(R 16)S(O) 2R 15；
    R 4为氢、C 1-C 4烷基、C 1-C 3烷氧基、卤素或氰基；
    R 5和R 6各自独立地为氢或C 1-C 4烷基；
    R 7、R 8、R 9和R 10各自独立地为氢、卤素、氰基、C 1-C 3烷氧基或C 1-C 4烷基；
    R 11为氢或C 1-C 4烷基；
    R 12为氢或C 1-C 4烷基；
    R 13为氢或C 1-C 4烷基；
    R 14为氢、C 1-C 4烷基、卤素或氰基；
    R 15为C 1-C 4烷基；
    R16为氢或C 1-C 4烷基；
    R17为氢或C 1-C 4烷基；
    上述卤素选自氟、氯、溴或碘。
  3. 如权利要求1所述的BET蛋白抑制剂，其特征在于，A选自
    Figure PCTCN2020084797-appb-100007
    Figure PCTCN2020084797-appb-100008
    B环选自
    Figure PCTCN2020084797-appb-100009
    其中：
    X为O、S或NR 13；
    Y为CH 2、C＝O、NR 1或Y不存在；
    Z为CR 14或N；
    U为CH或N；
    W为O或NH；
    V为CH或N；
    R 1为氢、C 1-C 3烷基、C 3-C 6环烷基、取代C 1-C 3烷基、取代C 3-C 6环烷基、C 3-C 6环烷基C 1-C 3烷基、C 1-C 3烷基-SO 2-或C 3-C 6环烷基-SO 2-；所述取代C 1-C 3烷基是指C 1-C 3烷基上的氢被一个或多个C 3-C 6环烷基取代；所述取代C 3-C 6环烷基是指C 3-C 6环烷基上的氢被一个或多个C 1-C 3烷基取代；
    R 2为氢、C 1-C 3烷基、C 1-C 2烷氧基、卤素或氰基；
    R 3为氢、C 1-C 3烷基、C 1-C 2烷氧基、卤素、氰基、-S(O) 2R 15、-S(O) 2NR 16R 17或-N(R 16)S(O) 2R 15；
    R 4为氢、C 1-C 3烷基、C 1-C 2烷氧基、卤素或氰基；
    R 5和R 6各自独立地为氢或C 1-C 3烷基；
    R 7、R 8、R 9和R 10各自独立地为氢、卤素、氰基、C 1-C 2烷氧基或C 1-C 3烷基；
    R 11为氢或C 1-C 3烷基；
    R 12为氢或C 1-C 3烷基；
    R 13为氢或C 1-C 3烷基；
    R 14为氢、C 1-C 3烷基、卤素或氰基；
    R 15为C 1-C 3烷基；
    R 16为氢或C 1-C 3烷基；
    R 17为氢或C 1-C 3烷基；
    上述卤素选自氟、氯、溴或碘。
  4. 如权利要求1所述的BET蛋白抑制剂，其特征在于，选自如下化合物：
    Figure PCTCN2020084797-appb-100010
    Figure PCTCN2020084797-appb-100011
    Figure PCTCN2020084797-appb-100012
    Figure PCTCN2020084797-appb-100013
    Figure PCTCN2020084797-appb-100014
    或其可药用的盐。
  5. 一种合成权利要求1～4任一项所述的化合物的方法，其特征在于反应式如下：
    Figure PCTCN2020084797-appb-100015
    通式IA化合物和通式IB化合物经催化偶联反应制得通式化合物I，各基团定义如权利要求1～4任一项所述。
  6. 如权利要求1～4任一项所述的化合物在制备预防或治疗与BET蛋白相关疾病的药物中的用途。
  7. 如权利要求6所述的用途，其特征在于，所述与BET蛋白相关疾病指肿瘤疾病、良性增生、炎性疾病、自身免疫疾病、败血症、病毒感染、血管疾病或神经性疾病。
  8. 如权利要求7所述的用途，其特征在于，所述肿瘤疾病包括但不限于急性髓性白血病、淋巴瘤、多发性骨髓瘤、B细胞急性淋巴白血病、中线癌、神经胶质瘤、实体瘤、乳腺癌、结直肠癌、***癌、***、非小细胞肺癌或黑色素瘤。
  9. 一种组合物，所述组合物包括治疗有效量的权利要求1～4任一项所述的化合物或其可药用的盐和医学上可接受的载体。
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