WO2020156017A1 - 靶向泛素化降解brd4蛋白化合物及其制备方法和应用 - Google Patents

靶向泛素化降解brd4蛋白化合物及其制备方法和应用 Download PDF

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WO2020156017A1
WO2020156017A1 PCT/CN2020/000027 CN2020000027W WO2020156017A1 WO 2020156017 A1 WO2020156017 A1 WO 2020156017A1 CN 2020000027 W CN2020000027 W CN 2020000027W WO 2020156017 A1 WO2020156017 A1 WO 2020156017A1
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membered
amino
compound
saturated
substituted
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PCT/CN2020/000027
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French (fr)
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赵传武
蒋春华
张颜
张雪娇
杨金路
康杰琼
赵培培
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石药集团中奇制药技术（石家庄）有限公司
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Priority to JP2021544770A priority Critical patent/JP7394140B2/ja
Priority to US17/427,845 priority patent/US20220135589A1/en
Priority to CN202080012258.7A priority patent/CN113365699A/zh
Priority to EP20747854.6A priority patent/EP3919127A4/en
Publication of WO2020156017A1 publication Critical patent/WO2020156017A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • 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
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the technical field of medicine, in particular, to a new type of targeted ubiquitination degradation BRD4 protein compound and a preparation method thereof, a pharmaceutical composition containing the same, and the use of the compound or the pharmaceutical composition in the preparation of medicines .
  • the bromodomain and extra-terminal domain (BET) protein contains 4 members, namely BRD2, BRD3, BRD4 and BRDT.
  • BET family proteins recognize acetylated chromatin through its bromodomain (BD) and participate in regulating gene expression.
  • BRD4 contains two bromo domains, BD1 and BD2.
  • BDs are chromatin "readers”: by interacting with the acetylated lysine at the tail of histones, chromatin regulatory proteins are recruited in the promoter region to regulate gene expression and suppression.
  • Bromodomain-containing protein 4 is a chromatin reading protein that can recognize and bind acetylated lysine residues in histones, and is involved in epigenetics across cell division and transcriptional regulation. Play a key role in memory transmission.
  • the mammalian BET family also includes three other members: BRD2, BRD3 and BRDT, which may regulate many cellular processes through the interaction between the bromine constructing domains (CN106905347).
  • BRD4 has become a potential therapeutic target for a variety of human malignancies, including a variety of solid tumors and hematological malignancies.
  • PLX-2853 and AZD5153 as chemical molecular inhibitors of BRD4, are currently undergoing clinical trials for the treatment of related malignancies (NCT03297424, NCT03205176).
  • Ubiquitin-proteasome In mammalian cells, protein degradation is mainly carried out through the ubiquitin-proteasome system to deal with damaged or excessive proteins.
  • Ubiquitin can attach to a substrate protein through a series of enzymatic reactions, resulting in a covalent bond between the C-terminal glycine of ubiquitin and the lysine residue of the substrate.
  • Ubiquitin-labeled proteins are eventually recognized and destroyed by the proteasome.
  • some components or processes in the system can provide promising therapeutic targets for the treatment of various diseases, including cancer and neurodegeneration.
  • PROTACs Proteolysis Targeted Chimeras
  • PROTACs can simultaneously bind the target protein and E3 in the cell, so that the target protein that cannot bind to E3 is ubiquitinated, and then recognized and degraded by the proteasome (Angew Chem Int Ed Engl., 2016, 55: 1966) .
  • ARV-825 a kind of cerebellar protein (CRBN) that uses the PROTACs technology to link the BRD4 inhibitor OTX015 with the phthalimide family
  • the phthalimide family can be combined with the E3 ubiquitin ligase as a component of cerebellar protein (CRBN)
  • the combination has successfully achieved the goal of targeting the cancer protein BRD4 and degrading BRD4.
  • the phthalimide family including thalidomide and its derivatives, lenalidomide and pomalidomide, can bind to cerebellar protein (CRBN) and theoretically bind E3 ligase to the target protein, and then To achieve the purpose of degrading the target protein.
  • BRD4-targeted PROTACs structures such as dBET1, ARV-771 and BETd-246 have also been reported, which indicates that the BRD4-targeted PROTACs technology may be used as a research approach for its preparation.
  • the present invention provides a class of compounds with novel structures based on PROTAC targeted protein degradation technology that target ubiquitination to degrade BRD4 protein, which can be used to treat various tumor diseases, including various solid tumors and hematological malignancies.
  • the present invention relates to a compound having the structure of formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and the use of the compound or the pharmaceutical composition in the preparation of medicines.
  • the present invention relates to a compound of formula (I) or a tautomer, optical isomer, deuterated product, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof:
  • X is selected from amino or substituted amino, and the substituent is selected from C 1-6 alkyl and C 1-6 alkoxy;
  • Y is selected from amino, substituted or unsubstituted saturated 5-7 membered heterocycloalkyl, saturated heteromonospirocycloalkyl, saturated heterofused cycloalkyl or heteroaryl;
  • the saturated 5-7 membered heterocycloalkyl has heteroatoms selected from O, N and S, wherein the number of N heteroatoms is 1, 2, or 3, and the number of O or S heteroatoms is 0, 1, or 2, so
  • the substituted saturated 5-7 membered heterocycloalkyl refers to a saturated 5-7 membered heterocycloalkyl group independently selected from halogen, hydroxyl, cyano, nitro, amino, carbonyl, C 1-6 Alkoxy, C 1-6 alkyl, C 3-8 cycloalkyl, aryl or C 5-7 heteroaryl substituents;
  • the saturated heteromonospirocycloalkyl has heteroatoms selected from O, N and S, wherein the number of N heteroatoms is 1, 2, or 3, the number of O or S heteroatoms is 0, 1, or 2, and the saturated heteromonospiro Cycloalkyl is selected from the group consisting of 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, and 5-membered/6-membered ring, the substituted saturated heteromonospiro Cycloalkyl refers to a saturated heteromonospirocycloalkyl group independently selected from halogen, hydroxyl, cyano, nitro, amino, carbonyl, C 1-6 alkoxy, C 1-6 alkyl, C 3-8 cycloalkyl, aryl or C 5-7 heteroaryl substituents;
  • the saturated heterofused cycloalkyl group also includes 1 or 2 heteroatoms independently selected from O, N and S, and the saturated heterofused cycloalkyl group is selected from 5-membered/5-membered and 5-membered/6-membered bicyclic fused heterocyclic group
  • the substituted saturated heterocyclic fused cycloalkyl refers to a saturated heterocyclic fused cycloalkyl group independently selected from halogen, hydroxyl, cyano, nitro, amino, Substituted by substituents of carbonyl, C 1-4 alkoxy, C 1-4 alkyl, C 3-8 cycloalkyl, aryl or C 5-7 heteroaryl;
  • the heteroaryl group also includes one or two heteroatoms independently selected from O, N and S.
  • the substituted heteroaryl group means that the heteroaryl group is independently replaced by one or Multiple selected from halogen, hydroxyl, cyano, nitro, amino, carbonyl, C 1-6 alkoxy, C 1-6 alkyl, C 3-8 cycloalkyl, aryl or C 5-7 heteroaryl Substitution of cyclic group;
  • L is selected from -(CH 2 ) n -, -CH 2 CH 2 (OCH 2 CH 2 ) m -or -CH 2 R 1 -;
  • n is selected from 1, 2, 3, 4, 5 or 6;
  • n is selected from 1, 2, 3 or 4;
  • R 1 is selected from optionally substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, aryl or heteroaryl; the substituent is independently selected from one or more halogen, hydroxyl, cyano , Nitro, C 1-6 alkyl, C 1-6 alkoxy, haloheterocycloalkyl, aryl or heteroaryl;
  • W is selected from -CH 2 -, -NH-, -O-, -CONH- or -COO-;
  • Z is selected from -CH 2 -or -CO-.
  • X is selected from amino or substituted amino, and the substituent is selected from C 1-6 alkyl and C 1-6 alkoxy;
  • Y is selected from amino, substituted or unsubstituted saturated 5-7 membered heterocycloalkyl, saturated heteromonospirocycloalkyl, saturated heterofused cycloalkyl or heteroaryl;
  • the heteroatom is selected from the group consisting of O, N and S, wherein the number of N heteroatoms is 1, 2 or 3, and O or S heteroatoms The number is 1 or 2, and the substituted saturated 5-7 membered heterocycloalkyl group is independently substituted by one or more selected from halogen, hydroxyl, cyano, nitro, amino, carbonyl, C 1-6 alkoxy, C 1- 6 substituted by substituents of alkyl, C 3-8 cycloalkyl, aryl, or C 5-7 heteroaryl;
  • the heteroatom is selected from O, N and S, wherein the number of N heteroatoms is 1, 2 or 3, and the number of O or S heteroatoms is 1 or 2, saturated heteromonospirocycloalkyl is selected from 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered and 5-membered/6-membered ring and Independently by one or more selected from halogen, hydroxyl, cyano, nitro, amino, carbonyl, C 1-6 alkoxy, C 1-6 alkyl, C 3-8 cycloalkyl, aryl or C Substitution of 5-7 heteroaryl ring group;
  • the substituted or unsubstituted saturated heterocyclic alkyl group also includes 1 or 2 heteroatoms independently selected from O, N and S, and the saturated heteromonospirocycloalkyl group is selected from 5
  • Five-membered 5-membered and 5-membered/6-membered bicyclic fused heterocyclic groups are independently substituted by one or more selected from halogen, hydroxy, cyano, nitro, amino, carbonyl, C 1-4 alkoxy, C 1- 4 substituted by substituents of alkyl, C 3-8 cycloalkyl, aryl or C 5-7 heteroaryl ring;
  • the heteroaryl group also includes 1 or 2 heteroatoms independently selected from O, N and S, and the heteroaryl group is independently selected from halogen, hydroxyl , Cyano, nitro, amino, carbonyl, C 1-6 alkoxy, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, or C 5-7 heteroaryl substituent substituted ;
  • L is selected from -(CH 2 ) n -, -CH 2 CH 2 (OCH 2 CH 2 ) m -or -CH 2 R 1 -;
  • n is selected from 1, 2, 3, 4, 5 or 6;
  • n is selected from 1, 2, 3 or 4;
  • R 1 is selected from optionally substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, aryl or heteroaryl; the substituent is independently selected from one or more halogen, hydroxyl, cyano , Nitro, C 1-6 alkyl, C 1-6 alkoxy, haloheterocycloalkyl, aryl or heteroaryl;
  • W is selected from CH 2 , amino, oxygen, -CONH- or -COO-;
  • Z is selected from CH 2 or CO.
  • X is selected from amino; Y is amino or substituted or unsubstituted saturated 5-7 membered heterocycloalkyl. In some embodiments, X is selected from amino; Y is amino or piperazinyl.
  • L is selected from -(CH 2 ) n -, -CH 2 (OCH 2 CH 2 ) m -, n is selected from 1, 2 , 3, 4, 5, or 6,
  • n is selected from 1, 2, 3, or 4.
  • the compound of the present invention may be further selected from compounds represented by the following formula (II) or tautomers, deuterated compounds, nitrogen oxides, solvates, pharmaceutically acceptable salts or prodrugs thereof : Wherein, R, L, W and Z are as defined above.
  • the compounds of the present invention include the following specific compounds or tautomers, optical isomers, deuterated compounds, nitrogen oxides, solvates, pharmaceutically acceptable salts or prodrugs thereof:
  • the present invention provides a pharmaceutical composition, which includes the above-mentioned compound of formula (I) or its tautomers, optical isomers, deuterated compounds, nitrogen oxides, solvates, pharmaceutically acceptable Salt or prodrug.
  • the present invention provides a compound of formula (I) or its tautomer, optical isomer, deuterated product, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug for preparing Use in medicines for the prevention and/or treatment of cancer, tumors, viral infections, depression, neurological disorders, trauma, age-related cataracts, organ transplant rejection or autoimmune diseases:
  • the cancer or tumor is selected From lung cancer, bone cancer, stomach cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vagina cancer, pancreatic cancer, brain cancer, pituitary adenoma , Melanoma, epidermoid carcinoma, T-cell lymphoma, chronic and acute leukemia.
  • the present invention provides a method for preparing the compound of formula (I) or its tautomers, optical isomers, deuterated compounds, nitrogen oxides, solvates, pharmaceutically acceptable salts or prodrugs, including
  • the compound of formula (M) and the compound of formula (C) are subjected to condensation reaction to obtain the compound of formula (I),
  • R, L, W, and Z are as defined above.
  • the reaction is carried out in an organic solvent selected from the group consisting of tetrahydrofuran, acetonitrile, N,N-dimethylformamide, halogenated hydrocarbons, ethylene glycol dimethyl ether, dichloroethane, methanol, One or more of ethanol, petroleum ether, n-hexane, diethyl ether and ethyl acetate; preferably, the halogenated hydrocarbon is dichloromethane, dichloroethane, chloroform or tetrachloromethane.
  • an organic solvent selected from the group consisting of tetrahydrofuran, acetonitrile, N,N-dimethylformamide, halogenated hydrocarbons, ethylene glycol dimethyl ether, dichloroethane, methanol, One or more of ethanol, petroleum ether, n-hexane, diethyl ether and ethyl acetate; preferably, the halogenated hydrocarbon
  • the compound of formula M can be obtained by the following preparation method:
  • the preparation method includes the following steps:
  • JQ1 compound is subjected to ester hydrolysis to obtain the core compound
  • R, L, W, Z are as defined above;
  • P is an amino protecting group, selected from N-benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc ), phthaloyl (Pht), trifluoroacetyl (Tfa), p-toluenesulfonyl (Tos), trityl (Trt), 2,4-dimethoxybenzyl (DMb) and p Methoxybenzyl (PMB), preferably tert-butoxycarbonyl (Boc);
  • the reactions are all carried out in an organic solvent selected from the group consisting of tetrahydrofuran, acetonitrile, N,N-dimethylformamide, halogenated hydrocarbons, and ethyl acetate.
  • organic solvent selected from the group consisting of tetrahydrofuran, acetonitrile, N,N-dimethylformamide, halogenated hydrocarbons, and ethyl acetate.
  • an organic solvent selected from the group consisting of tetrahydrofuran, acetonitrile, N,N-dimethylformamide, halogenated hydrocarbons, and ethyl acetate.
  • an organic solvent selected from the group consisting of tetrahydrofuran, acetonitrile, N,N-dimethylformamide, halogenated hydrocarbons, and ethyl acetate.
  • the halogenated hydrocarbon is dichloromethane, dichloroethane Alkane,
  • the reaction is carried out under acidic conditions, and the acid is not limited to trifluoroacetic acid, formic acid, methanesulfonic acid, acetic acid, sulfuric acid or hydrochloric acid.
  • the The acid is trifluoroacetic acid.
  • the reaction is carried out under alkaline conditions, and the base is selected from triethylamine, diisopropylethylamine, piperidine, pyrrole, pyridine, dimethyl One or more of pyridine and dimethylaminopyridine.
  • alkyl includes C 1 -C 6 alkyl, preferably C 1 -C 4 alkyl, which may be linear, branched, or cycloalkyl, and further includes but It is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • the term also includes all alkyl groups involved in alkyl groups such as alkoxy, halogen-substituted alkyl, etc.
  • aryl refers to after removing a hydrogen atom, a monovalent group remaining on the aromatic nuclear carbon of the aromatic molecules, including C 6 -C 14 aromatic ring, further including but not limited to, phenyl, naphthyl.
  • heteroaryl refers to a monovalent group after removing a hydrogen atom from the aromatic nucleus carbon of a heteroaryl compound molecule, where the heteroatom is selected from N, O or S, including 5-14 membered aromatic heterocycles
  • the aromatic heterocyclic ring may be a single ring or a condensed ring, and may be partially unsaturated.
  • the aromatic heterocyclic ring also includes a five-membered or six-membered nitrogen-containing aromatic heterocyclic ring.
  • the aromatic heterocycle includes but is not limited to pyridine, pyrazine, pyridazine, pyrrole, imidazole, thiophene, furan.
  • the aromatic ring and aromatic heterocyclic group may be further substituted with a substituent.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • substituted by one or more substituents includes, but is not limited to, substitution by one, two, three or four substituents.
  • the compounds of the present invention include compounds or tautomers, optical isomers, deuterated compounds, nitrogen oxides, solvates, pharmaceutically acceptable salts or prodrugs thereof.
  • the salt of the compound of the present invention preferably includes a pharmaceutically acceptable salt of the compound.
  • the salt can be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and nitric acid.
  • organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranonic acid such as glucuronic acid And galacturonic acid; ⁇ -hydroxy acids, such as citric acid and tartaric acid; amino acids, such as aspartic acid and glutamic acid; aromatic acids, such as benzoic acid and cinnamic acid; sulfonic acids, such as p-toluenesulfonic acid, ethyl Sulfonic acid.
  • organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid
  • pyranonic acid such as glucuronic acid And galacturonic acid
  • ⁇ -hydroxy acids such as citric acid and tartaric acid
  • amino acids such
  • solvates are those forms of the compounds of the present invention, which form a complex through coordination with solvent molecules in a solid or liquid state. Hydrates are a specific form of solvates in which the coordination is carried out with water. In the present invention, the preferred solvate is a hydrate.
  • prodrug represents the conversion of a compound into a compound represented by the aforementioned general formula or specific compound in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the maternal structure in the blood or tissue.
  • the prodrugs of the present invention can be esters. In the existing invention, esters can be used as prodrugs including phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, and carbamates. Classes and amino acid esters.
  • a compound in the present invention contains a hydroxyl/carboxyl group, that is, it can be acylated to obtain a compound in the form of a prodrug.
  • Other prodrug forms include phosphate esters, such as these phosphate ester compounds are obtained by phosphorylation of the hydroxyl group on the parent.
  • the pharmaceutical composition can be used to achieve the desired pharmacological effects by administering to patients in need thereof.
  • patients are mammals including humans who need to treat a specific condition or disease.
  • the pharmaceutically acceptable carrier may be a carrier that is relatively non-toxic and harmless to the patient at a concentration consistent with the effective activity of the active ingredient, so that any side effects caused by the carrier will not be destroyed
  • the beneficial effects of the active ingredients are preferably an amount that produces results or effects on the specific condition being treated.
  • Any effective conventional dosage unit form including immediate-release, sustained-release and time-release formulations can be used, and the compound of the present invention can be administered together with a pharmaceutically acceptable carrier known in the art in the following manner: oral, parenteral , Topical, nasal cavity, eye, sublingual, rectal, vaginal administration, etc.
  • the compound of the present invention can be administered as a single agent or in combination with one or more other agents, wherein the combination does not cause unacceptable adverse reactions.
  • the present invention designs and synthesizes a series of aminopiperazine or hydrazine linker structure targeting BRD4 protein degradation PROTAC molecules, which have good anti-tumor activity, and exhibit excellent BRD4 inhibitory effects, which are better than JQ1 Inhibitory activity, anti-proliferation and ability to induce apoptosis.
  • FIG 1 shows the basic principle of PROTAC technology.
  • FIG. 2 shows the BRD4-PROTAC protein degradation mechanism of the compounds of the present invention.
  • Step 1 (s)-4-(2-(4-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1, 2,4]Triazolo[4,3-a][1,4]diaza-6-yl)acetamido)piperazine-1-carboxylic acid tert-butyl ester
  • Step 2 (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazole And [4,3-a][1,4]diaza-6-yl)-N-(piperazin-1-yl)acetamide
  • the synthesis method is the same as Preparation Example 2, except that tert-butyl piperazine-1-carbamate is substituted for tert-butyl 4-aminopiperazine-1-carboxylate to obtain (S)-1-(4-aminopiperazine-1- Yl)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazole[4,3 -a] [1,4]diaza-6-yl)ethanone (compound (M-2)) 0.40 g.
  • the synthesis method is the same as that of Preparation Example 3, except that tert-butyl 4-aminopiperazine-1-carboxylate is replaced with tert-butyl carbazate to obtain (S)-2-(4-(4-chlorophenyl)-2, 3,9-Trimethyl-6H-thiophene[3,2-f][1,2,4]triazole[4,3-a][1,4]diazepine-6-yl)acethydrazine ( Compound (M-3)) 0.35g.
  • Step 1 Preparation of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindolin-4-yl)amino)acetate
  • the synthesis method is the same as Preparation Example 8, except that tert-butyl 3-[2-(2-aminoethoxy)ethoxy] propionate is substituted for tert-butyl glycine to obtain 3-(2-(2-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propionic acid (compound (C-8 )) 0.30g.
  • Step 1 Preparation of tert-Butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)amino)acetate
  • Nalidomide (259mg, 1.0mmol) is dissolved in 20ml N,N-dimethylformamide, and tert-butyl bromoacetate (234mg, 1.2mmol), potassium carbonate (276mg, 2.0mmol), potassium iodide (8mg , 0.05mmol) stirred at 80°C, after the reaction was completed, ethyl acetate and water were added, the organic phase was washed twice with water, the organic phase was separated and purified by column chromatography to obtain 2-((2-(2,6-dioxopiperidine- 3-yl)-1-oxoisoindol-4-yl)amino)tert-butyl acetate 150 mg.
  • Step 2 Preparation of 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)amino)acetic acid (compound (C-11))
  • Step 1 Preparation of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetate
  • Example 1 4-(4-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1 ,2,4]Triazolo[4,3-a][1,4]diaza-6-yl)acetamido)piperazin-1-yl)-N-(2-(2,6- Preparation of dioxpiperazin-3-yl)-1-oxoisoindolin-4-yl)-4-oxobutanamide
  • Example 2-45 Preparation of the compound of Example 2-45
  • Test cell lines acute leukemia cell line RS4; 11 and multiple myeloma cell line MM.1S.
  • Test method MTT (thiazole blue) method. Also known as MTT colorimetry, it is a method to detect cell survival and growth.
  • the detection principle is that the succinate dehydrogenase in the mitochondria of living cells can reduce the exogenous MTT to water-insoluble blue-purple crystal formazan (Formazan) and deposit it in the cells, while dead cells have no such function.
  • Dimethyl sulfoxide (DMSO) can dissolve formazan in cells, and its light absorption value is measured at 550nm wavelength with an enzyme-linked immunoassay, which can indirectly reflect the number of living cells. Within a certain range of cell numbers, the amount of MTT crystal formation is proportional to the number of cells.
  • This method has been widely used in the activity detection of some biologically active factors, large-scale anti-tumor drug screening, cytotoxicity test, and tumor radiosensitivity determination.
  • the compound concentration gradient is set to: 0-25.6pM-128pM-640pM-3.2Nm-16nM-80nM-400nM-2 ⁇ M-10 ⁇ M;
  • MTT working solution 5mg/ml
  • 20 ⁇ l per well 20 ⁇ l per well; at 37°C for 4 hours, centrifuge at 1000rpm/min for 5min in a plate centrifuge, RS4; 11 groups aspirate 180 ⁇ l of medium and add 150 ⁇ l DMSO; MM In the .1S group, 200 ⁇ l of medium was aspirated and 150 ⁇ l DMSO was added; the microwell shaker was shaken and mixed, the bottom of the plate was wiped clean, and the optical density (OD) was measured at 550nm by the microplate reader.
  • IC 50 ⁇ 100nM is C
  • 20nM ⁇ IC 50 ⁇ 100nM is B
  • IC 50 ⁇ 20nM is A.
  • the experimental results show that the compound of the present invention has good anti-tumor activity. Compared with JQ1, dBET1 and ARV-825, it exhibits better inhibitory activity, anti-proliferation and apoptosis-inducing ability.
  • the purpose of the experiment to observe the effect of BRD4-PROTAC on the degradation of the target protein through MG132 pretreatment, and to study whether the test compound degrades the target protein through the protease degradation pathway.

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Abstract

本发明涉及一种式(I)所示的化合物或其互变异构体、光学异构体、氘代物、氮氧化物、溶剂化物、药学上可接受的盐或前药，所述化合物的制备方法，包含其的药物组合物及所述化合物或药物组合物在制备在制备用于预防和/或治疗癌症、肿瘤、病毒感染、抑郁症、神经性病症、创伤、年龄相关的白内障、器官移植排斥或自身免疫疾病的药物中的用途。

Description

靶向泛素化降解BRD4蛋白化合物及其制备方法和应用 技术领域
本发明涉及医药技术领域，具体而言，涉及一类新的靶向泛素化降解BRD4蛋白化合物及其制备方法，包含其的药物组合物及所述化合物或药物组合物在制备药物中的用途。
背景技术
溴结构域家族蛋白(bromodomain and extra-terminal domain，BET)含4个成员，分别是BRD2、BRD3、BRD4和BRDT。BET家族蛋白通过其溴结构域(bromodomain，BD)识别乙酰化染色质，并参与调节基因表达。作为BET家族成员之一，BRD4含有两个溴结构域，分别是BD1和BD2。BDs是染色质“读者(readers)”：通过与组蛋白尾部的乙酰化赖氨酸相互作用，在启动子区域募集染色质调节蛋白以调节基因的表达和抑制。(Balasundaram Padmanabhan等，Journal of Biosciences；2016，41(2)：295)。溴结构域蛋白4(bromodomain-containing protein 4，BRD4)是一种染色质阅读蛋白，可识别和结合组蛋白中的乙酰化赖氨酸残基，并在跨细胞分裂和转录调节的表观遗传记忆传递中起关键作用。除BRD4之外，哺乳动物BET家族还包括其他三个成员：BRD2、BRD3和BRDT，它们可能通过溴建构域间的相互作用调控许多细胞过程(CN106905347)。BRD4已成为多种人类恶性肿瘤的潜在治疗靶点，包括多种实体瘤和血液恶性肿瘤，PLX-2853和AZD5153作为BRD4的化学分子抑制剂，目前正在进行相关恶性肿瘤治疗的临床试验(NCT03297424、NCT03205176)。
在哺乳动物细胞中，蛋白质降解主要通过遍在蛋白-蛋白酶体系统进行，以处理受损或过量的蛋白质。遍在蛋白可以通过一系列酶促反应附着于底物蛋白，导致遍在蛋白的C末端甘氨酸和底物的赖氨酸残基之间的共价键合。遍在蛋白标记的蛋白质最终被蛋白酶体识别和破坏。尽管泛素系统的高度复杂性，但是该系统中的一些组分或过程可以提供治疗多种疾病(包括癌症和神经变性)的有希望的治疗靶标。最近，一项基于E3连接酶的靶蛋白降解技术策略，Proteolysis Targeted Chimeras(PROTACs)便是通过将目标蛋白质置于E3连接酶附近，原则上来选择性降解任何蛋白质。PROTACs正在成为一种有前途的策略，可以实现靶向所谓的“不可摧毁”蛋白质，如雌激素相关受体α、细胞维甲酸结合蛋白和BRD4。PROTACs的关键技术是构建双功能小分子，实现两个连接策略：一个与目标蛋白结合，另一个招募E3连接酶。因 此，在细胞内PROTACs可以实现同时将靶蛋白和E3结合，使本来不能与E3结合的靶蛋白泛素化，进而被蛋白酶体识别并降解(Angew Chem Int Ed Engl.，2016，55：1966)。
临床研究表明药物长期维持较高浓度抑制靶蛋白，有可能产生耐药，药效降低等情况，甚至伴随严重的副作用，而PROTAC分子降解靶蛋白时，类似于催化过程，PROTAC与目标蛋白结合足够长的时间完成泛素标记即可，药物又可以重复利用，并不需要等摩尔量的药物，所以设计具有双功能小分子药物有利于降低药物剂量和减轻副作用。
ARV-825，一种采用PROTACs技术，将BRD4抑制剂OTX015与邻苯二甲酰亚胺家族连接，利用邻苯二甲酰亚胺家族可与E3泛素连接酶复合成分小脑蛋白(CRBN)的结合作用，成功实现靶向癌蛋白BRD4并降解BRD4的目的。邻苯二甲酰亚胺家族，包括沙利度胺及其衍生物来那度胺和泊马度胺，均可以与小脑蛋白(CRBN)结合，理论上可以将E3连接酶与靶蛋白结合，进而实现降解靶蛋白的目的。其他靶向BRD4的PROTACs结构，如dBET1、ARV-771和BETd-246也有报道，这说明靶向BRD4的PROTACs技术有可能作为其成药的研究途径。
Figure PCTCN2020000027-appb-000001
发明内容
本发明提供了一类结构新颖的基于PROTAC靶向蛋白降解技术的靶向泛素化降解BRD4蛋白的化合物，可用于治疗多种肿瘤疾病，包括多种实体瘤和血液恶性肿瘤等。具体而言，本发明涉及一种具有式(I)结构的化合物，及其制备方法，包含其的药物组合物及所述化合物或药物组合物在制备药物中的用途。
一方面，本发明涉及一种式(I)的化合物或其互变异构体、光学异构体、氘代物、氮氧化物、溶剂化物、药学上可接受的盐或前药：
Figure PCTCN2020000027-appb-000002
其中：
R为
Figure PCTCN2020000027-appb-000003
X选自氨基、或取代氨基，所述取代基选自C 1-6烷基、C 1-6烷氧基；
Y选自氨基、取代或未取代的饱和5-7元杂环烷基、饱和杂单螺环烷基、饱和杂稠环烷基或杂芳基；
所述的饱和5-7元杂环烷基，其杂原子选自O、N和S，其中N杂原子数目为1、2或3，O或S杂原子数目为0、1或2，所述取代的饱和5-7元杂环烷基是指饱和5-7元杂环烷基独立地被一个或多个选自卤素、羟基、氰基、硝基、氨基、羰基、C 1-6烷氧基、C 1-6烷基、C 3-8环烷基、芳基或C 5-7杂芳基的取代基所取代；
所述饱和杂单螺环烷基，其杂原子选自O、N和S，其中N杂原子数目为1、2或3，O或S杂原子数目为0、1或2，饱和杂单螺环烷基选自3元/5元、4元/4元、4元/5元、4元/6元、5元/5元和5元/6元环，所述取代的饱和杂单螺环烷基是指饱和杂单螺环烷基独立地被一个或多个选自卤素、羟基、氰基、硝基、氨基、羰基、C 1-6烷氧基、C 1-6烷基、C 3-8环烷基、芳基或C 5-7杂芳基的取代基所取代；
所述饱和杂稠环烷基除了含有碳原子外，还包括选自1或2个独立地选自O、N和S的杂原子，饱和杂稠环环烷基选自5元/5元和5元/6元双环稠杂环基，所述取代的饱和杂稠环烷基是指饱和杂稠环烷基独立地被一个或多个选自卤素、羟基、氰基、硝基、氨基、羰基、C 1-4烷氧基、C 1-4烷基、C 3-8环烷基、芳基或C 5-7杂芳基的取代基所取代；
所述的杂芳基除了含有碳原子外，还包括选自1或2个独立地选自O、N和S的杂原子，所述取代的杂芳基是指杂芳基独立地被一个或多个选自卤素、羟基、氰基、硝基、氨基、羰基、C 1-6烷氧基、C 1-6烷基、C 3-8环烷基、芳基或C 5-7杂芳环基的取代基所取代；
L选自-(CH 2) n-、-CH 2CH 2(OCH 2CH 2) m-或-CH 2R 1-；
n选自1、2、3、4、5或6；
m选自1、2、3或4；
R 1选自任选被取代的环烷基、杂环烷基，卤代杂环烷基，芳基或杂芳基；所述取代基独立的选自一个或多个卤素、羟基、氰基、硝基、C 1-6烷基、C 1-6烷氧基、卤代杂环烷基、芳基或杂芳基；
W选自-CH 2-、-NH-、-O-、-CONH-或-COO-；
Z选自-CH 2-或-CO-。
在一些实施方案中：
R为
Figure PCTCN2020000027-appb-000004
X选自氨基、或取代氨基，所述取代基选自C 1-6烷基、C 1-6烷氧基；
Y选自氨基、取代或未取代的饱和5-7元杂环烷基、饱和杂单螺环烷基、饱和杂稠环烷基或杂芳基；
所述的取代或未取代饱和5-7元杂环烷基，所述杂原子选自还包括选自O、N和S，其中N杂原子数目为1、2或3，O或S杂原子数目为1或2，取代饱和5-7元杂环烷基独立地被一个或多个选自卤素、羟基、氰基、硝基、氨基、羰基、C 1-6烷氧基、C 1-6烷基、C 3-8环烷基、芳基或C 5-7杂芳环基的取代基所取代；
所述的取代或未取代饱和杂单螺环烷基，所述杂原子选自还包括选自O、N和S，其中N杂原子数目为1、2或3，O或S杂原子数目为1或2，饱和杂单螺环烷基选自3元/5元、4元/4元、4元/5元、4元/6元、5元/5元和5元/6元环并且独立地被一个或多个选自卤素、羟基、氰基、硝基、氨基、羰基、C 1-6烷氧基、C 1-6烷基、C 3-8环烷基、芳基或C 5-7杂芳环基的取代基所取代；
所述的取代或未取代饱和杂稠环烷基除了含有碳原子外，还包括选自1或2个独立地选自O、N和S的杂原子，饱和杂单螺环烷基选自5元/5元和5元/6元双环稠杂环基并且独立地被一个或多个选自卤素、羟基、氰基、硝基、氨基、羰基、C 1-4烷氧基、C 1-4烷基、C 3-8环烷基、芳基或C 5-7杂芳环基的取代基所取代；
所述的杂芳基除了含有碳原子外，还包括选自1或2个独立地选自O、N和S的杂原子，所述杂芳基独立地被一个或多个选自卤素、羟基、氰基、硝基、氨基、羰基、C 1-6烷氧基、C 1-6烷基、C 3-8环烷基、芳基或C 5-7杂芳环基的取代基所取代；
L选自-(CH 2) n-、-CH 2CH 2(OCH 2CH 2) m-或-CH 2R 1-；
n选自1、2、3、4、5或6；
m选自1、2、3或4；
R 1选自任选被取代的环烷基、杂环烷基，卤代杂环烷基，芳基或杂芳基；所述取代基独立的选自一个或多个卤素、羟基、氰基、硝基、C 1-6烷基、C 1-6烷氧基、卤代杂环烷基、芳基或杂芳基；
W选自CH 2、氨基、氧、-CONH-或-COO-；
Z选自CH 2或CO。
在一些实施方案中，X选自氨基；Y为氨基或取代或未取代的饱和5-7元杂环烷基。在一些实施方案中，X选自氨基；Y为氨基或哌嗪基。
在一些实施方案中，L选自-(CH 2) n-、-CH 2(OCH 2CH 2) m-，n选自1、2、3、4、5或6，
m选自1、2、3或4。
在一些实施方案中，本发明的化合物可进一步选自如下式(II)所示的化合物或其互变异构体、氘代物、氮氧化物、溶剂化物、药学上可接受的盐或前药：
Figure PCTCN2020000027-appb-000005
其中，R、L、W和Z如前述所定义。
在一些实施方案中，本发明的化合物包括如下具体化合物或其互变异构体、光学异构体、氘代物、氮氧化物、溶剂化物、药学上可接受的盐或前药：
Figure PCTCN2020000027-appb-000006
Figure PCTCN2020000027-appb-000007
Figure PCTCN2020000027-appb-000008
Figure PCTCN2020000027-appb-000009
Figure PCTCN2020000027-appb-000010
Figure PCTCN2020000027-appb-000011
另一方面，本发明提供一种药物组合物，其包括上述的式(I)化合物或其互变异构体、光学异构体、氘代物、氮氧化物、溶剂化物、药学上可接受的盐或前药。
另一方面，本发明提供一种式(I)化合物或其互变异构体、光学异构体、氘代物、氮氧化物、溶剂化物、药学上可接受的盐或前药在制备用于预防和/或治疗癌症、肿瘤、病毒感染、抑郁症、神经性病症、创伤、年龄相关的白内障、器官移植排斥或自身免疫疾病的药物中的用途：其中，优选地，所述癌症或肿瘤选自肺癌、骨癌、胃癌、胰腺癌、皮肤癌、头颈癌、子宫癌、卵巢癌、睾丸癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、胰腺癌、脑癌、垂体腺瘤，黑素瘤、表皮样癌、T细胞淋巴瘤、慢性和急性白血病。
另一方面，本发明提供上述式(I)化合物或其互变异构体、光学异构体、氘代物、氮氧化物、溶剂化物、药学上可接受的盐或前药的制备方法，包括将式(M)化合物与式(C)化合物进行缩合反应得到式(I)化合物，
Figure PCTCN2020000027-appb-000012
其中，R、L、W、Z如前述所定义。
优选地，所述反应在有机溶剂中进行，所述有机溶剂选自四氢呋喃、乙腈、N，N-二甲基甲酰胺、卤代烃、乙二醇二甲醚、二氯乙烷、甲醇、乙醇、石油醚、正己烷、乙醚和乙酸乙酯中的一种或多种；优选地，所述卤代烃为二氯甲烷，二氯乙烷，氯仿或四氯甲烷。
式M化合物可通过以下制备方法得到：
Figure PCTCN2020000027-appb-000013
所述制备方法包括以下步骤：
(1)将JQ1化合物进行酯水解反应得到母核化合物；
(2)将母核化合物与R-P化合物进行酰化反应得到式JYS-1所示的化合物；
(3)将式JYS-1化合物脱保护得到式(M)化合物。
其中，R、L、W、Z如前述所定义；
P为氨基保护基，选自N-苄氧羰基(Cbz)、叔丁氧羰基(Boc)、笏甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、邻苯二甲酰基(Pht)、三氟乙酰基(Tfa)、对甲苯磺酰基(Tos)、三苯甲基(Trt)、2，4-二甲氧基苄基(DMb)和对甲氧基苄基(PMB)，优选为叔丁氧羰基(Boc)；
优选地，在上述步骤(1)-(3)中，所述反应均在有机溶剂中进行，所述有机溶剂选自四氢呋喃、乙腈、N，N-二甲基甲酰胺、卤代烃、乙二醇二甲醚、二氯乙烷、甲醇、乙醇、石油醚、正己烷、乙醚和乙酸乙酯中的一种或多种；优选地，所述卤代烃为二氯甲烷，二氯乙烷，氯仿或四氯甲烷；
优选地，在上述步骤(1)和(3)中，所述反应在酸性条件下进行，所述酸不限于三氟乙酸、甲酸、甲磺酸、乙酸、硫酸或盐酸，优选地，所述酸为三氟乙酸。
优选地，在上述步骤(2)和(3)中，所述反应在碱性条件下进行，所述碱选自三乙胺，二异丙基乙胺，哌啶、吡咯、吡啶、二甲基吡啶和二甲氨基吡啶中的一种或多种。
本发明术语解释和详细说明
术语“任选”或“任选地”是指随后描述的事件或情形可以但不一定出现，并且该描述包括其中所述事件或情形出现的情况以及其中它不出现的情况。
术语“烷基”包括C 1-C 6烷基，优选为C 1-C 4烷基，其可以是直链烷基，也可以是支链烷基，还可以是环烷基，进一步包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基。该术语还包括诸如烷氧基，卤素取代的烷基等所有涉及烷基基团中的烷基。
术语“芳基”是指芳烃分子的芳核碳上去掉一个氢原子后，剩下一价基团，包括C 6-C 14芳香环，进一步包括但不限于苯基、萘基。
术语“杂芳基”是指杂芳基化合物分子的芳核碳上去掉一个氢原子后，剩下一价基团，其中杂原子选自N，O或S，包括5-14元芳杂环，所述芳杂环可以是单环，也可以是稠环，并且可以是部分不饱和的。所述芳杂环还包括五元或六元含氮芳杂环。所述芳杂环包括但不限于吡啶、吡嗪、哒嗪、吡咯、咪唑、噻吩、呋喃。所述芳香环、芳杂环基团上进一步可被取代基取代。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“被一个或多个取代基取代”包括但不限于被一个、二个、三个或四个取代基取代。
本发明所述化合物包含化合物或其互变异构体、光学异构体、氘代物、氮氧化物、溶剂化物、药学上可接受的盐或前药。
本发明中化合物的盐，优选包括化合物的药学上可接受的盐，所述盐可以通过文献上提供的任何合适的方法制备得到，例如，使用无机酸，如盐酸，氢溴酸，硫酸，硝酸和磷酸；或者使用有机酸，如乙酸，马来酸，琥珀酸，扁桃酸，富马酸，丙二酸，丙酮酸，草酸，羟乙酸和水杨酸；吡喃糖酸，如葡萄糖醛酸和半乳糖醛酸；α-羟酸，如柠檬酸和酒石酸；氨基酸，如天门冬氨酸和谷氨酸；芳香族酸，如苯甲酸和肉桂酸；磺酸，如对甲苯磺酸，乙磺酸。
本发明中，溶剂化物是本发明的化合物的那些形式，其以固体或液体的状态通过与溶剂分子的配位作用形成配合物。水合物是溶剂化物的特定形式，其中配位作用是与水进行。在本发明中，优选的溶剂化物是水合物。
术语“前药”或称为“药物前体”，代表一个化合物在体内转化为前述通式或具体化合物所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前药可以是酯，在现有的发明中酯可以作为前药的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基/羧基，即可以将其酰化得到前体药物形式的化合物。其他的前药形式包括磷酸酯，如这些 磷酸酯类化合物是经母体上的羟基磷酸化得到的。
本发明中，可利用药物组合物通过向有此需要的患者给药来实现期望的药理学作用。就本发明的目的而言，患者是需要治疗具体病症或疾病的包括人在内的哺乳动物。
本发明中，药学上可接受的载体可以是这样的载体，其在与活性成分的有效活性一致的浓度下对患者相对无毒且无害，以至于由所述载体引起的任何副作用不会破坏所述活性成分的有益作用。化合物或其药学上可接受的盐的药学有效量优选是对正在治疗的具体病况产生结果或者产生影响的量。可使用包括速释、缓释和定时释放制剂在内的任意有效的常规剂量单位形式，将本发明的化合物与本领域公知的药学上可接受的载体一起以如下方式给药：口服、肠胃外、局部、鼻腔、眼部、舌下、直肠、阴道给药等。
可将本发明的化合物作为单一药剂给药或者与一种或多种其它药剂组合给药，其中所述组合不会引起不可接受的不良反应。
本发明的有益效果：
本发明设计合成了一系列氨基哌嗪或联胺类linker结构的靶向BRD4蛋白降解PROTAC分子，具有良好的抗肿瘤活性，并表现出优异的BRD4抑制作用，相比JQ1，表现出更优的抑制活性，抗增殖及诱导细胞凋亡能力。
附图说明
图1为PROTAC技术基本原理。
图2为本发明化合物的BRD4-PROTAC蛋白降解机制。
具体实施方式
下文将结合具体实施例对本发明的制备方法做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。下述实施例中如无特殊说明，所有的温度定为摄氏度。如无特殊说明，原料化合物是通过本文中所述的方法合成的或者是市售可得的，并且购自以下厂家：百灵威、北京伊诺凯科技有限公司、阿拉丁试剂、阿法埃莎、韶远化学科技有限公司等。
制备实施例、实施例及本文其他地方使用的缩写词是：
DCM        二氯甲烷
DIPEA       N，N-二异丙基乙胺
DMF         N，N-二甲基甲酰胺
EtOAc       乙酸乙酯
h           小时
HATU        2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯
MeOH        甲醇
TFA         三氟乙酸
制备例1：(6S)-4-(4-氯苯基)-2，3，9-三甲基-6H-噻吩并[3，2-f][1，2，4]噻唑并[4，3-a][1，4]二氮杂卓-6-乙酸(母核)：
Figure PCTCN2020000027-appb-000014
在500ml的反应瓶中，将(S)-2-(4-(4-氯苯基)-2，3，9-三甲基-6H-噻吩并[3，2-f][1，2，4]三唑并[4，3-a][1，4]二氮杂卓-6-基)乙酸叔丁酯((+)-JQ1)(2.30g，5.00mmol)溶于100ml二氯甲烷中，加入20ml的TFA，室温搅拌4h后，减压蒸馏得到(6S)-4-(4-氯苯基)-2，3，9-三甲基-6H-噻吩并[3，2-f][1，2，4]噻唑并[4，3-a][1，4]二氮杂卓-6-乙酸2.00g，产品不经纯化直接进行下一步反应。
制备例2：(S)-2-(4-(4-氯苯基)-2，3，9-三甲基-6H-噻吩并[3，2-f][1，2，4]三唑并[4，3-a][1，4]二氮杂-6-基)-N-(哌嗪-1-基)乙酰胺(化合物(M-1))的制备
Figure PCTCN2020000027-appb-000015
步骤1：(s)-4-(2-(4-(4-(4-氯苯基)-2，3，9-三甲基-6H-噻吩并[3，2-f][1，2，4]三唑并[4，3-a][1，4]二氮杂-6-基)乙酰胺基)哌嗪-1-甲酸叔丁酯的制备
在100ml的反应瓶中，将母核1(0.40g，1mmol)溶于DMF(20.0ml)中，依次加入DIPEA(522μl，3mmol)，HATU(86.0mg，3mmol)和4-氨基哌嗪-1-羧酸叔丁酯(0.20g，1mmol)，室温搅拌2h，反应完毕后，加入乙酸乙酯和水，分离有机相，有机相减压蒸馏得到粗品(s)-4-(2-(4-(4-(4-氯苯基)-2，3，9-三甲基-6H-噻吩并[3，2-f][1，2，4]三唑并[4，3-a][1，4]二氮杂-6-基)乙酰胺基)哌嗪-1-甲酸叔丁酯，产品不经纯化直接进行下一步反应。
步骤2：(S)-2-(4-(4-氯苯基)-2，3，9-三甲基-6H-噻吩并[3，2-f][1，2，4]三唑并[4，3-a][1，4]二氮杂-6-基)-N-(哌嗪-1-基)乙酰胺的制备
在100ml的反应瓶中，将(s)4-(2-(4-(4-(4-氯苯基)-2，3，9-三甲基-6H-噻吩并[3，2-f][1，2，4]三唑并[4，3-a][1，4]二氮杂-6-基)乙酰胺基)哌嗪-1-甲酸叔丁酯(0.50g，0.86mmol)溶于100ml二氯甲烷中，加入5ml的三氟乙酸，室温搅拌4h后，减压蒸馏得到(S)-2-(4-(4-氯苯基)-2，3，9-三甲基-6H-噻吩并[3，2-f][1，2，4]三唑并[4，3-a][1，4]二氮杂-6-基)-N-(哌嗪-1-基)乙酰胺(化合物(M-1))0.40g，产品不经纯化直接进行下一步反应。
制备例3：(S)-1-(4-氨基哌嗪-1-基)-2-(4-(4-氯苯基)-2，3，9-三甲基-6H-噻吩并[3，2-f][1，2，4]三唑[4，3-a][1，4]二氮杂-6-基)乙酮(化合物(M-2))的制备
Figure PCTCN2020000027-appb-000016
合成方法同制备例2，只是用哌嗪-1-氨基甲酸叔丁酯替换4-氨基哌嗪-1-羧酸叔丁酯，得到(S)-1-(4-氨基哌嗪-1-基)-2-(4-(4-氯苯基)-2，3，9-三甲基-6H-噻吩并[3，2-f][1，2，4]三唑[4，3-a][1，4]二氮杂-6-基)乙酮(化合物(M-2))0.40g。
制备例4：(S)-2-(4-(4-氯苯基)-2，3，9-三甲基-6H-噻吩[3，2-f][1，2，4]三唑[4，3-a][1，4]二氮平-6-基)乙酰肼(化合物(M-3))的制备
Figure PCTCN2020000027-appb-000017
合成方法同制备例3，只是用肼基甲酸叔丁酯替换4-氨基哌嗪-1-羧酸叔丁酯，得到(S)-2-(4-(4-氯苯基)-2，3，9-三甲基-6H-噻吩[3，2-f][1，2，4]三唑[4，3-a][1，4]二氮平-6-基)乙酰肼(化合物(M-3))0.35g。
制备例5：4-(2-(2，6-二氧杂哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-4-氧代丁酸(化合物(C-1))的制备
Figure PCTCN2020000027-appb-000018
在250ml的反应瓶中，将来那度胺(1.28g，4.9mmol)和丁二酸酐(0.64g，6.4mmol)依次加入到甲苯(100ml)中，升温至125℃，反应5.0h，冷却至室温，抽滤，晾干得到4-(2-(2，6-二氧杂哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-4-氧代丁酸(化合物(C-1))1.70g。
制备例6：5-(2-(2，6-二氧杂哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-5-氧代戊酸(化合物(C-2))的制备
参照制备例5，只是将丁二酸酐替换为戊二酸酐，得5-(2-(2，6-二氧杂哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-5-氧代戊酸(化合物(C-2))1.65g。
制备例7：6-(2-(2，6-二氧杂哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-6-氧代己酸(化合物(C-3))的制备
参照制备例5，只是将丁二酸酐替换为己二酸酐，得6-(2-(2，6-二氧杂哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-6-氧代己酸(化合物(C-3))1.21g。
制备例8：2-((2-(2，6-二氧杂哌嗪-3-基)-1，3-二氧杂吲哚-4-基)氨基)乙酸(化合物(C-4))的制备
Figure PCTCN2020000027-appb-000019
步骤1：2-((2-(2，6-二氧代哌啶-3-基)-1，3-二氧杂吲哚啉-4-基)氨基)乙酸叔丁酯的制备
在100ml的反应瓶中，将2-(2，6-二氧哌啶-3-基)-4-氟异吲哚啉-1，3-二酮(0.30g，1.1mmol)溶于DMF中，加入DIPEA(382μl，2.2mmol)，甘氨酸叔丁酯(0.17g，1.3mmol)，升温至90℃反应2h，冷却至室温，加入水和乙酸乙酯，分离有机相，有机相减压蒸馏得到2-((2-(2，6-二氧代哌啶-3-基)-1，3-二氧代异吲哚啉-4-基)氨基)乙酸叔丁酯0.38g，产品不经纯化直接进行下一步反应。
步骤2：2-((2-(2，6-二氧代哌啶-3-基)-1，3-二氧代异吲哚啉-4-基)氨基)乙酸(化合物(C-4))的制备
在100ml的反应瓶中，将2-((2-(2，6-二氧代哌啶-3-基)-1，3-二氧代异吲哚啉-4-基)氨基)乙酸叔丁酯(0.38g，0.98mmol)溶于100ml二氯甲烷中，加入5ml的三氟乙酸，室温磁力搅拌4h后，减压蒸馏得到2-((2-(2，6-二氧代哌啶-3-基)-1，3-二氧代异吲哚啉-4-基)氨基)乙酸(化合物(C-4))0.30g，产品不经纯化直接进行下一步反应。
制备例9：3-((2-(2，6-二氧杂哌嗪-3-基)-1，3-二氧杂吲哚-4-基)氨基)丙酸(化合物(C-5))的制备
参照制备例8制备方法，只是将甘氨酸叔丁酯替换为丙氨酸叔丁酯，得3-((2-(2，6-二氧代哌啶-3-基)-1，3-二氧代异吲哚啉-4-基)氨基)丙酸(化合物(C-5))0.42g，产品不经纯化直接进行下一步反应。
制备例10：4-((2-(2，6-二氧杂哌嗪-3-基)-1，3-二氧杂吲哚-4-基)氨基)丁酸(化合物(C-6))的制备
参照制备例8制备方法，只是将甘氨酸叔丁酯替换为丁氨酸叔丁酯，得4-((2-(2，6-二氧代哌啶-3-基)-1，3-二氧代异吲哚啉-4-基)氨基)丁酸(化合物(C-6))0.25g，产品不经纯化直接进行下一步反应。
制备例11：5-((2-(2，6-二氧杂哌嗪-3-基)-1，3-二氧杂吲哚-4-基)氨基)戊酸(化合物(C-7))的制备
参照制备例8制备方法，只是将甘氨酸叔丁酯替换为戊氨酸叔丁酯，得5-((2-(2，6-二氧代哌啶-3-基)-1，3-二氧代异吲哚啉-4-基)氨基)戊酸(化合物(C-7))0.12g，产品不经纯化直接进行下一步反应。
制备例12：3-(2-(2-((2-(2，6-二氧代哌啶-3-基)-1，3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酸(化合物(C-8))的制备
Figure PCTCN2020000027-appb-000020
合成方法同制备例8，只是用3-[2-(2-氨基乙氧基)乙氧基]丙酸叔丁酯替换甘氨酸叔丁酯，得到3-(2-(2-((2-(2，6-二氧代哌啶-3-基)-1，3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酸(化合物(C-8))0.30g。
制备例13：3-(2-(2-(2-(2-(2，6-二氧代哌啶-3-基)-1，3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基丙酸(化合物(C-9))的制备
参照制备例12制备方法，只是将3-[2-(2-氨基乙氧基)乙氧基]丙酸叔丁酯替换为3-[2-[2-(2-氨基乙氧基)乙氧基]乙氧基]丙酸叔丁酯，得到3-(2-(2-(2-(2-(2，6-二氧代哌啶-3-基)-1，3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基丙酸(化合物(C-9))0.37g。
制备例14：1-((2-(2，6-二氧杂哌嗪-3-基)-1，3-二氧杂吲哚-4-基)氨基)-3，6，9，12-四氧杂十五烷-15-酸(化合物(C-10))的制备
参照制备例12制备方法，只是将3-[2-(2-氨基乙氧基)乙氧基]丙酸叔丁酯替换为2-[2-[2-[2-(2-叔丁氧羰基乙氧基)乙氧基]乙氧基]乙氧基]乙胺，得到1-((2-(2，6-二氧杂哌嗪-3-基)-1，3-二氧杂吲哚-4-基)氨基)-3，6，9，12-四氧杂十五烷-15-酸(化合物(C-10))0.26g。
制备例15：2-((2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氨基)乙酸(化合物(C-11))的制备
Figure PCTCN2020000027-appb-000021
步骤1：2-((2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氨基)乙酸叔丁酯的制备
将来那度胺(259mg，1.0mmol)溶于20ml N，N-二甲基甲酰胺中，再加入溴乙酸叔丁酯(234mg，1.2mmol)，碳酸钾(276mg，2.0mmol)，碘化钾(8mg，0.05mmol)80℃搅拌，反应完毕后加入乙酸乙酯和水，有机相水洗两次，分离有机相，柱层析纯化得到2-((2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氨基)乙酸叔丁酯150mg。
步骤2：2-((2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氨基)乙酸(化合物(C-11))的制备
将2-((2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氨基)乙酸叔丁酯(0.15g，0.40mmol)溶于20ml二氯甲烷中，再加入7ml三氟乙酸，室温搅拌，反应完毕后，减压蒸馏得到油状产物2-((2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氨基)乙酸(化合物(C-11))0.10g，产品不经纯化直接进行下一步反应。
制备例16：3-((2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氨基)丙酸(化合物(C-12))的制备
参照制备例15制备方法，只是将溴乙酸叔丁酯替换为溴丙酸叔丁酯，得到油状产物3-((2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氨基)丙酸(化合物(C-12))0.05g，产品不经纯化直接进行下一步反应。
制备例17：4-((2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氨基)丁酸(化合物(C-13))的制备
参照制备例15制备方法，只是将溴乙酸叔丁酯替换为溴丁酸叔丁酯，得到油状产物4-((2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氨基)丁酸(化合物(C-13))0.13g，产品不经纯化直接进行下一步反应。
制备例18：5-((2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氨基)戊酸(化合物(C-14))的制备
参照制备例15制备方法，只是将溴乙酸叔丁酯替换为溴戊酸叔丁酯，得到油状产物5-((2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氨基)戊酸(化合物(C-14))0.13g，产品不经纯化直接进行下一步反应。
制备例19：2-((2-(2，6-二氧代哌啶-3-基)-1，3-二氧代异吲哚啉-4-基)氧基)乙酸(化合物(C-15))的制备
Figure PCTCN2020000027-appb-000022
步骤1：2-((2-(2，6-二氧代哌啶-3-基)-1，3-二氧代异吲哚啉-4-基)氧基)乙酸叔丁酯的制备
将2-(2，6-二氧代哌啶-3-基)-4-羟基异吲哚啉-1，3-二酮(274mg，1.0mmol)溶于20ml N，N-二甲基甲酰胺中，再加入溴乙酸叔丁酯(234mg，1.2mmol)，碳酸钾(276mg，2.0mmol)，碘化钾(8mg，0.05mmol)80℃搅拌，反应完毕后加入乙酸乙酯和水，有机相水洗两次，分离有机相，柱层析纯化得到2-((2-(2，6-二氧代哌啶-3-基)-1，3-二氧代异吲哚啉-4-基)氧基)乙酸叔丁酯150mg。
步骤2：2-((2-(2，6-二氧代哌啶-3-基)-1，3-二氧代异吲哚啉-4-基)氧基)乙酸(化合物(C-6))的制备
将2-((2-(2，6-二氧代哌啶-3-基)-1，3-二氧代异吲哚啉-4-基)氧基)乙酸叔丁酯(0.15g，0.37mmol)溶于20ml二氯甲烷中，再加入7ml三氟乙酸，室温搅拌，反应完毕后，减压蒸馏得到油状产物2-((2-(2，6-二氧代哌啶-3-基)-1，3-二氧代异吲哚啉-4-基)氧基)乙酸(化合物(C-15))0.10g，产品不经纯化直接进行下一步反应。
实施例1：4-(4-(2-((S)-4-(4-氯苯基)-2，3，9-三甲基-6H-噻吩并[3，2-f][1，2，4]三唑并[4，3-a][1，4]二氮杂-6-基)乙酰胺基)哌嗪-1-基)-N-(2-(2，6-二氧哌嗪-3-基)-1-氧代异吲哚啉-4-基)-4-氧代丁酰胺的制备
Figure PCTCN2020000027-appb-000023
在100ml的反应瓶中，将M-1(53mg，0.11mmol)溶于DMF(10.0ml)中，然后依次加入HATU(40μl，0.23mmol)和C-1(39mg，0.11mmol)，室温搅拌2.0h。TLC监测发现原料反应完毕。反应液倒入水(100.0ml)中，再用DCM萃取，无水硫酸钠干燥，浓缩，采用制备液相分离纯化(二氯甲烷∶甲醇＝30∶1)，最终得到4-(4-(2-((S)-4-(4-氯苯基)-2，3，9-三甲基-6H-噻吩并[3，2-f][1，2，4]三唑并[4，3-a][1，4]二氮杂-6-基)乙酰胺基)哌嗪-1- 基)-N-(2-(2，6-二氧哌嗪-3-基)-1-氧代异吲哚啉-4-基)-4-氧代丁酰胺30mg，收率为33％。
实施例2-45：实施例2-45化合物的制备
参照实施例1制备方法，只是将M1和C1分别替换为相应的M-1～M-3和C-1～C-15，具体如下：
Figure PCTCN2020000027-appb-000024
Figure PCTCN2020000027-appb-000025
Figure PCTCN2020000027-appb-000026
Figure PCTCN2020000027-appb-000027
Figure PCTCN2020000027-appb-000028
Figure PCTCN2020000027-appb-000029
Figure PCTCN2020000027-appb-000030
Figure PCTCN2020000027-appb-000031
Figure PCTCN2020000027-appb-000032
具体化合物物理表征结果：
Figure PCTCN2020000027-appb-000033
Figure PCTCN2020000027-appb-000034
Figure PCTCN2020000027-appb-000035
生物实施例1：化合物对RS4；11和MM.1S细胞增殖的影响
试验细胞株：急性白血病细胞株RS4；11和多发性骨髓瘤细胞株MM.1S。
试验方法：MTT(噻唑蓝)法。又称MTT比色法，是一种检测细胞存活和生长的方法。其检测原理为活细胞线粒体中的琥珀酸脱氢酶能使外源性MTT还原为水不溶性的蓝紫色结晶甲臜(Formazan)并沉积在细胞中，而死细胞无此功能。二甲基亚砜(DMSO)能溶解细胞中的甲臜，用酶联免疫检测仪在550nm波长处测定其光吸收值，可间接反映活细胞数量。在一定细胞数范围内，MTT结晶形成的量与细胞数成正比。该方法已广泛用于一些生物活性因子的活性检测、大规模的抗肿瘤药物筛选、细胞毒性试验以及肿瘤放射敏感性测定等。
试验步骤：
■ 剂量设计
化合物浓度梯度设置为：0-25.6pM-128pM-640pM-3.2Nm-16nM-80nM-400nM-2μM-10μM；
(n＝3)
■ 检测与计算
药物作用72小时后，加入MTT工作液(5mg/ml)，每孔20μl；37℃作用4小时，平板离心机1000rpm/min离心5min，RS4；11组吸弃培养基180μl后加入150μl DMSO；MM.1S组吸弃培养基200μl后加入150μl DMSO，；微孔振荡器震荡混匀，将板底擦拭干净，酶标仪550nm处检测光密度值(OD)。采用LOGIT法计算半数抑制浓度IC 50。
实验结果：
Figure PCTCN2020000027-appb-000036
Figure PCTCN2020000027-appb-000037
IC 50≥100nM为C，20nM≤IC 50＜100nM为B，IC 50＜20nM为A。
实验结果表明，本发明化合物具有良好的抗肿瘤活性，相比JQ1、dBET1、ARV-825，表现出更优的抑制活性，抗增殖及诱导细胞凋亡能力。
生物实施例2：BRD4-PROTAC蛋白降解机制研究
实验目的：通过MG132预处理，观察BRD4-PROTAC对靶蛋白降解的影响，研究待测化合物是否通过蛋白酶降解途径降解靶蛋白。
试验方法：
体外培养RS4；11和MM.1S细胞，将细胞接种于6孔板内，待细胞长至80％左右时，加入MG132至终浓度50uM，2小时后，加入实施例1化合物和实施例16化合物至100nM，作用4小时后收集细胞，提取蛋白，进行Westing Bloting检测BRD4蛋白水平。
实验结果见附图2。
实验结果表明，本发明化合物能有效降解多种肿瘤细胞内靶蛋白BRD4；并且这种蛋白降解可被MG-132阻断，说明本发明化合物的蛋白降解是依赖于泛素化-蛋白酶体途径的。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (11)

  1. 式(I)的化合物或其互变异构体、光学异构体、氘代物、氮氧化物、溶剂化物、药学上可接受的盐或前药：
    Figure PCTCN2020000027-appb-100001
    其中：
    R为
    Figure PCTCN2020000027-appb-100002
    X选自氨基、或取代氨基，所述取代基选自C 1-6烷基、C 1-6烷氧基；
    Y选自氨基、取代或未取代的饱和5-7元杂环烷基、饱和杂单螺环烷基、饱和杂稠环烷基或杂芳基；
    所述的饱和5-7元杂环烷基，其杂原子选自O、N和S，其中N杂原子数目为1、2或3，O或S杂原子数目为0、1或2，所述取代的饱和5-7元杂环烷基是指饱和5-7元杂环烷基独立地被一个或多个选自卤素、羟基、氰基、硝基、氨基、羰基、C 1-6烷氧基、C 1-6烷基、C 3-8环烷基、芳基或C 5-7杂芳基的取代基所取代；
    所述饱和杂单螺环烷基，其杂原子选自O、N和S，其中N杂原子数目为1、2或3，O或S杂原子数目为0、1或2，饱和杂单螺环烷基选自3元/5元、4元/4元、4元/5元、4元/6元、5元/5元和5元/6元环，所述取代的饱和杂单螺环烷基是指饱和杂单螺环烷基独立地被一个或多个选自卤素、羟基、氰基、硝基、氨基、羰基、C 1-6烷氧基、C 1-6烷基、C 3-8环烷基、芳基或C 5-7杂芳基的取代基所取代；
    所述饱和杂稠环烷基除了含有碳原子外，还包括选自1或2个独立地选自O、N和S的杂原子，饱和杂稠环环烷基选自5元/5元和5元/6元双环稠杂环基，所述取代的饱和杂稠环烷基是指饱和杂稠环烷基独立地被一个或多个选自卤素、羟基、氰基、硝基、氨基、羰基、C 1-4烷氧基、C 1-4烷基、C 3-8环烷基、芳基或C 5-7杂芳基的取代基所取代；
    所述的杂芳基除了含有碳原子外，还包括选自1或2个独立地选自O、N和S的杂原子，所述取代的杂芳基是指杂芳基独立地被一个或多个选自卤素、羟基、氰基、硝基、氨基、羰基、C 1-6烷氧基、C 1-6烷基、C 3-8环烷基、芳基或C 5-7杂芳环基的取代基所取代；
    L选自-(CH 2) n-、-CH 2CH 2(OCH 2CH 2) m-或-CH 2R 1-；
    n选自1、2、3、4、5或6；
    m选自1、2、3或4；
    R 1选自任选被取代的环烷基、杂环烷基，卤代杂环烷基，芳基或杂芳基；所述取代基独立的选自一个或多个卤素、羟基、氰基、硝基、C 1-6烷基、C 1-6烷氧基、卤代杂环烷基、芳基或杂芳基；
    W选自-CH 2-、-NH-、-O-、-CONH-或-COO-；
    Z选自-CH 2-或-CO-。
  2. 式(I)的化合物或其互变异构体、光学异构体、氘代物、氮氧化物、溶剂化物、药学上可接受的盐或前药：
    Figure PCTCN2020000027-appb-100003
    其中：
    R为
    Figure PCTCN2020000027-appb-100004
    X选自氨基、或取代氨基，所述取代基选自C 1-6烷基、C 1-6烷氧基；
    Y选自氨基、取代或未取代的饱和5-7元杂环烷基、饱和杂单螺环烷基、饱和杂稠环烷基或杂芳基；
    所述的取代或未取代饱和5-7元杂环烷基，所述杂原子选自还包括选自O、N和S，其中N杂原子数目为1、2或3，O或S杂原子数目为1或2，取代饱和5-7元杂环烷基独立地被 一个或多个选自卤素、羟基、氰基、硝基、氨基、羰基、C 1-6烷氧基、C 1-6烷基、C 3-8环烷基、芳基或C 5-7杂芳环基的取代基所取代；
    所述的取代或未取代饱和杂单螺环烷基，所述杂原子选自还包括选自O、N和S，其中N杂原子数目为1、2或3，O或S杂原子数目为1或2，饱和杂单螺环烷基选自3元/5元、4元/4元、4元/5元、4元/6元、5元/5元和5元/6元环并且独立地被一个或多个选自卤素、羟基、氰基、硝基、氨基、羰基、C 1-6烷氧基、C 1-6烷基、C 3-8环烷基、芳基或C 5-7杂芳环基的取代基所取代；
    所述的取代或未取代饱和杂稠环烷基除了含有碳原子外，还包括选自1或2个独立地选自O、N和S的杂原子，饱和杂单螺环烷基选自5元/5元和5元/6元双环稠杂环基并且独立地被一个或多个选自卤素、羟基、氰基、硝基、氨基、羰基、C 1-4烷氧基、C 1-4烷基、C 3-8环烷基、芳基或C 5-7杂芳环基的取代基所取代；
    所述的杂芳基除了含有碳原子外，还包括选自1或2个独立地选自O、N和S的杂原子，所述杂芳基独立地被一个或多个选自卤素、羟基、氰基、硝基、氨基、羰基、C 1-6烷氧基、C 1-6烷基、C 3-8环烷基、芳基或C 5-7杂芳环基的取代基所取代；
    L选自-(CH 2) n-、-CH 2CH 2(OCH 2CH 2) m-或-CH 2R 1-；
    n选自1、2、3、4、5或6；
    m选自1、2、3或4；
    R 1选自任选被取代的环烷基、杂环烷基，卤代杂环烷基，芳基或杂芳基；所述取代基独立的选自一个或多个卤素、羟基、氰基、硝基、C 1-6烷基、C 1-6烷氧基、卤代杂环烷基、芳基或杂芳基；
    W选自CH 2、氨基、氧、-CONH-或-COO-；
    Z选自CH 2或CO。
  3. 前述权利要求中任一项所述的式(I)的化合物或其互变异构体、光学异构体、氘代物、氮氧化物、溶剂化物、药学上可接受的盐或前药，其特征在于：X选自氨基；Y为氨基或取代或未取代的5-7元杂环烷基。
  4. 前述权利要求中任一项所述的式(I)的化合物或其互变异构体、光学异构体、氘代物、氮氧化物、溶剂化物、药学上可接受的盐或前药，其特征在于：X选自氨基；Y为氨基或哌嗪基。
  5. 前述权利要求中任一项所述的式(I)的化合物或其互变异构体、光学异构体、氘代物、氮氧化物、溶剂化物、药学上可接受的盐或前药，其特征在于：
    L选自-(CH 2) n-、-CH 2(OCH 2CH 2) m-，
    n选自1、2、3、4、5或6，
    m选自1、2、3或4。
  6. 前述权利要求中任一项所述的式(I)的化合物或其互变异构体、光学异构体、氘代物、氮氧化物、溶剂化物、药学上可接受的盐或前药，其特征在于：所述式(I)化合物*位置构型为S型。
  7. 下列化合物，其互变异构体、光学异构体、氘代物、氮氧化物、溶剂化物、或其药学上可接受的盐或前药：
    Figure PCTCN2020000027-appb-100005
    Figure PCTCN2020000027-appb-100006
    Figure PCTCN2020000027-appb-100007
    Figure PCTCN2020000027-appb-100008
    Figure PCTCN2020000027-appb-100009
  8. 一种药物组合物，其包括权利要求1-7中任一项所述的式(I)化合物或其互变异构体、光学异构体、氘代物、氮氧化物、溶剂化物、药学上可接受的盐或前药。
  9. 权利要求1-7中任一项所述的式(I)化合物或其互变异构体、光学异构体、氘代物、氮氧化物、溶剂化物、药学上可接受的盐或前药，或权利要求8所述的药物组合物在制备用于预防和/或治疗癌症、肿瘤、病毒感染、抑郁症、神经性病症、创伤、年龄相关的白内障、器官移植排斥或自身免疫疾病的药物中的用途。
  10. 如权利要求9所述的用途，其特征在于：所述癌症或肿瘤选自肺癌、骨癌、胃癌、胰腺癌、皮肤癌、头颈癌、子宫癌、卵巢癌、睾丸癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、胰腺癌、脑癌、垂体腺瘤，黑素瘤、表皮样癌、T细胞淋巴瘤、慢性和急性白血病。
  11. 一种如权利要求1-2所述的式(I)化合物或其互变异构体、光学异构体、氘代物、氮氧化物、溶剂化物、药学上可接受的盐或前药的制备方法，包括将式(M)化合物与式(C)化合物进行缩合反应得到式(I)化合物，
    Figure PCTCN2020000027-appb-100010
    其中，R、L、W、Z如权利要求1或2所定义。
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