CN110003204A - A kind of BET protein inhibitor, preparation method and the usage - Google Patents

A kind of BET protein inhibitor, preparation method and the usage Download PDF

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CN110003204A
CN110003204A CN201910360142.1A CN201910360142A CN110003204A CN 110003204 A CN110003204 A CN 110003204A CN 201910360142 A CN201910360142 A CN 201910360142A CN 110003204 A CN110003204 A CN 110003204A
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alkyl
hydrogen
halogen
naphthenic base
cyano
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郑永勇
魏农农
金华
周峰
黄美花
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Shanghai Xunhe Pharmaceutical Technology Co Ltd
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Abstract

The invention belongs to biomedicine technical fields, and in particular to a kind of BET protein inhibitor, preparation method and the usage.Compared with prior art, present invention further progress structure on the basis of existing BET protein inhibitor is improved, obtain the BET protein inhibitor of a kind of new construction, it is expected to exploitation with preferable BET protein inhibiting activity and good pharmacokinetic property as the BET protein inhibitor of high-efficiency low-toxicity of new generation.

Description

A kind of BET protein inhibitor, preparation method and the usage
Technical field
The invention belongs to biomedicine technical fields, and in particular to a kind of BET protein inhibitor, preparation method and use On the way.
Background technique
Epigenetics (Epigenetic) is current very popular one of drug discovery theme.Acetylation of histone is The important component of epigenetic research.Bromodomain (BRD) is that one kind being capable of acetylation in specific recognition histone The conserved protein domain of lysine (KAc), by promoting protein enrichment to turn in conjunction with acetylated lysine in specific gene Record site, change the activity of rna plymerase ii, adjust gene transcriptional expression (Kuc and Allis, Bioessays, 1998,20: 615-626)。
Currently, the 61 kinds of BRD structural domains found in human body are present in 42 kinds of albumen, according to the difference of female protein function, BRD albumen is divided into 8 large families, and BET protein family is the 2nd class of BRD protein family.BET albumen include BRD2, BRD3, Tetra- members of BRD4 and BRDT (Wu and Chiang, J.Biol.chem., 2007,282:13141-13145).The extensive table of first three Up in all body cells, the latter only limits and is expressed in testis tissue.
BET albumen plays a significant role in kinds of tumors.Such as hematopoietic system cancer (acute myelocytic leukemia, lymph Tumor, Huppert's disease, B cell acute lymphatic leukaemia etc.), by interfering the combination of BRD4 and oncogene MYC, can inhibit The expression of MYC, and then cause apoptosis of tumor cells.BET albumen (BRD3 or BRD4) and NUT (are usually only expressed in testis Albumen) between fusion lead to the aggressive form of squamous cell carcinoma, be referred to as NUT center line cancer (French, Cancer Genet, Cytogenet., 2010,203:16-20).
Discovery is related to NUT (nucleoprotein in testis) and BRD3's or BRD4 in the high malignancy form that epithelioma is formed Displacement forms novel fusion oncogene BRD-NUT (French et al., Cancer Research 2003,63:304- repeatedly 307).Selectivity reduces the resilient normal cell differentiation of this oncogene and reverses tumorigenic phenotype (Fi1ippakopoulos etc. People, Nature2010,468:1068-1073).The gene knockout for having proven to BRD2, BRD3 and BRD4 can damage a variety of hematologies Growth and vigor (Zuber et al., Nature2011,478:524-528 with solid tumor cell；Delmore et al., Cell 2011,146:904-917).In addition to the effect in cancer, BET albumen also regulates and controls the inflammatory reaction to germ attack, and BRD2 hypomorph mouse model shows the inflammatory cytokine of significantly lower level and prevents the fat diabetes induced (Wang et al., Biochem J.2009,425:71-83).In addition, some viruses utilize these BET albumen by its gene system It is bolted at a part of host cell chromatin as virus replication, or promotes viral gene transcription and resistance using BET albumen Hold back (You et al., Ce11 2004,117:349-360；Zhu et al., Cell Reports 2012,2:807-816).
In conclusion targeting these albumen for developing target on cancer, the new therapeutic strategy of inflammation and virus infection can It can be beneficial.Have the micromolecular inhibitor for this receptor at present and enter clinical stage, be mainly used for cancer and from The treatment of body immunological diseases.A series of BET inhibitor class patent applications are disclosed at present, comprising: WO2013158952, WO2014165127, WO2015075665, WO2016050821, WO2018188047, WO2018130174 etc..
Abbive company discloses a kind of BET protein inhibitor in WO2013097052A, wherein compound ABBV-075 With development prospect, it is currently in the Phase I clinical trial stage.Incyte company discloses chemical combination in CN106414442A patent Object INCB-057643 is in the Phase I clinical trial stage.Bristol-Myers Squibb company is public in WO2015100282A Another kind of BET protein inhibitor is opened, representation compound BMS-986158 is in the Phase I clinical trial stage. GlaxoSmithKline company discloses compound I-BET762 in WO2011054553A, which is carrying out tumour II clinical trial phase.
Although BET protein inhibitor has a good application prospect as medicament research and development without marketed drug.Existing rank Section, it is more to be related to the novel bromine structural domain of disease and indication that bromine structure domain-functionalities include BET structure domain-functionalities for treating Inhibitor is urgently developed.The compounds of this invention also facilitates to meet such clinical needs, it is therefore desirable to be able to develop height of new generation Imitate the BET protein inhibitor of low toxicity.
Summary of the invention
In order to overcome the problems of in the prior art, the purpose of the present invention is to provide a kind of BET of high-efficiency low-toxicity Protein inhibitor.
To achieve the goals above and other related purposes, the present invention adopts the following technical scheme:
A kind of BET protein inhibitor, wherein the inhibitor is compound of formula I:
Or its pharmaceutically acceptable salt, wherein
A is selected from
B ring is selected fromOr by R11And/or R12The five yuan of heteroaromatics replaced；" five yuan of heteroaromatics " be Refer to the mononuclear aromatics of 5 atoms, and contains one or more hetero atoms (such as N, O, S), including but not limited to furans, imidazoles, Thiophene, pyrazoles etc..Wherein:
X is O, S or NR13；
Y is CH2, C=O, NR1Or Y is not present；
Z is CR14Or N；
U is CH or N；
W is O or NH；
V is CH or N；
R1For hydrogen, C1-C6Alkyl, C3-C6Naphthenic base replaces C1-C6Alkyl replaces C3-C6Naphthenic base, C3-C6Naphthenic base C1- C6Alkyl, C1-C6Alkyl-SO2Or C3-C6Naphthenic base-SO2-；The substitution C1-C6Alkyl refers to C1-C6Hydrogen on alkyl is by one A or multiple C3-C6Naphthenic base replaces；The substitution C3-C6Naphthenic base refers to C3-C6Hydrogen in naphthenic base is by one or more C1- C6Alkyl replaces；
R2For hydrogen, C1-C6Alkyl, C1-C3Alkoxy, halogen or cyano；
R3For hydrogen, C1-C6Alkyl, C1-C3Alkoxy, halogen, cyano ,-S (O)2R15、-S(O)2NR16R17Or-N (R16)S (O)2R15；
R4For hydrogen, C1-C6Alkyl, C1-C3Alkoxy, halogen or cyano；
R5And R6It is each independently hydrogen or C1-C6Alkyl；
R7、R8、R9And R10It is each independently hydrogen, halogen, cyano, C1-C3Alkoxy or C1-C6Alkyl；
R11For hydrogen or C1-C6Alkyl；
R12For hydrogen or C1-C6Alkyl；
R13For hydrogen or C1-C6Alkyl；
R14For hydrogen, C1-C6Alkyl, halogen or cyano；
R15For C1-C6Alkyl；
R16For hydrogen or C1-C6Alkyl；
R17For hydrogen or C1-C6Alkyl；
Above-mentioned halogen is selected from fluorine, chlorine, bromine or iodine.
Preferably, in the compound of formula I:
A is selected from
B ring is selected from
Wherein:
X is O, S or NR13；
Y is CH2, C=O, NR1Or Y is not present；
Z is CR14Or N；
U is CH or N；
W is O or NH；
V is CH or N；
R1For hydrogen, C1-C4Alkyl, C3-C6Naphthenic base replaces C1-C4Alkyl replaces C3-C6Naphthenic base, C3-C6Naphthenic base C1- C3Alkyl, C1-C4Alkyl-SO2Or C3-C6Naphthenic base-SO2-；The substitution C1-C4Alkyl refers to C1-C4Hydrogen on alkyl is by one A or multiple C3-C6Naphthenic base replaces；The substitution C3-C6Naphthenic base refers to C3-C6Hydrogen in naphthenic base is by one or more C1- C4Alkyl replaces；
R2For hydrogen, C1-C4Alkyl, C1-C2Alkoxy, halogen or cyano；
R3For hydrogen, C1-C4Alkyl, C1-C2Alkoxy, halogen, cyano ,-S (O)2R15、-S(O)2NR16R17Or-N (R16)S (O)2R15；
R4For hydrogen, C1-C4Alkyl, C1-C3Alkoxy, halogen or cyano；
R5And R6It is each independently hydrogen or C1-C4Alkyl；
R7、R8、R9And R10It is each independently hydrogen, halogen, cyano, C1-C3Alkoxy or C1-C4Alkyl；
R11For hydrogen or C1-C4Alkyl；
R12For hydrogen or C1-C4Alkyl；
R13For hydrogen or C1-C4Alkyl；
R14For hydrogen, C1-C4Alkyl, halogen or cyano；
R15For C1-C4Alkyl；
R16For hydrogen or C1-C4Alkyl；
R17For hydrogen or C1-C4Alkyl；
Above-mentioned halogen is selected from fluorine, chlorine, bromine or iodine.
Preferably, in the compound of formula I:
A is selected from
B ring is selected from
Wherein:
X is O, S or NR13；
Y is CH2, C=O, NR1Or Y is not present；
Z is CR14Or N；
U is CH or N；
W is O or NH；
V is CH or N；
R1For hydrogen, C1-C3Alkyl, C3-C6Naphthenic base replaces C1-C3Alkyl replaces C3-C6Naphthenic base, C3-C6Naphthenic base C1- C3Alkyl, C1-C3Alkyl-SO2Or C3-C6Naphthenic base-SO2-；The substitution C1-C3Alkyl refers to C1-C3Hydrogen on alkyl is by one A or multiple C3-C6Naphthenic base replaces；The substitution C3-C6Naphthenic base refers to C3-C6Hydrogen in naphthenic base is by one or more C1- C3Alkyl replaces；
R2For hydrogen, C1-C3Alkyl, C1-C2Alkoxy, halogen or cyano；
R3For hydrogen, C1-C3Alkyl, C1-C2Alkoxy, halogen, cyano ,-S (O)2R15、-S(O)2NR16R17Or-N (R16)S (O)2R15；
R4For hydrogen, C1-C3Alkyl, C1-C2Alkoxy, halogen or cyano；
R5And R6It is each independently hydrogen or C1-C3Alkyl；
R7、R8、R9And R10It is each independently hydrogen, halogen, cyano, C1-C2Alkoxy or C1-C3Alkyl；
R11For hydrogen or C1-C3Alkyl；
R12For hydrogen or C1-C3Alkyl；
R13For hydrogen or C1-C3Alkyl；
R14For hydrogen, C1-C3Alkyl, halogen or cyano；
R15For C1-C3Alkyl；
R16For hydrogen or C1-C3Alkyl；
R17For hydrogen or C1-C3Alkyl；
Above-mentioned halogen is selected from fluorine, chlorine, bromine or iodine.
" halogen " described herein refers to F, Cl, Br or I；" the C1-C3Alkyl " refer to methyl, ethyl, positive third Base or isopropyl；" the C1-C2Alkoxy " refer to methoxy or ethoxy；" naphthenic base ", unless otherwise saying It is bright, refer to the unsaturated cyclic hydrocarbon of saturation or part containing 3-6 carbon atom.Naphthenic base includes but is not limited to cyclopropyl, Cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group.
The compound of the present invention can conventionally be prepared as the form of pharmaceutical salts；Including its acylate and inorganic acid Salt: inorganic acid includes but is not limited to hydrochloric acid, sulfuric acid, phosphoric acid, diphosphonic acid, hydrobromic acid, nitric acid etc., and organic acid includes (but unlimited In) acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, lactic acid, p-methyl benzenesulfonic acid, salicylic acid, oxalic acid etc..
Typical compound of the invention includes, but are not limited to following table 1 compound:
The second object of the present invention is the provision of the synthetic method of above compound:
General formula compound I is made through catalyzed coupling reaction in general formula IA compound and general formula IB compound, and each group definition is such as It is described previously.
The third object of the present invention is that providing above compound as novel B ET protein inhibitor prevents or control in preparation Treat the purposes in the drug with BET protein related diseases.
Specifically, described refer to tumor disease, hyperplasia of prostate, inflammatory disease, autoimmunity disease with BET protein related diseases Disease, septicemia, virus infection, vascular diseases and neurogenic disease.Further, the tumor disease is including but not limited to acute Myelogenous leukemia, lymthoma, Huppert's disease, B cell acute lymphatic leukaemia, center line cancer, glioma, solid tumor, Breast cancer, colorectal cancer, prostate cancer, cervical carcinoma, non-small cell lung cancer, melanoma etc..
Derivative of the invention can pass through the sides such as oral, injection in implementing treatment of diseases with the formation of composition Formula, for treating associated cancer and other diseases.When for taking orally, conventional solid pharmaceutical preparation such as tablet, powder can be prepared into Agent or capsule etc.；When for injecting, injection can be prepared into.
The fourth object of the present invention is to provide a kind of composition, and the composition includes the above-mentioned chemical combination of therapeutically effective amount Object or its pharmaceutical salt and medically acceptable carrier.
The carrier addressed refers to the carrier of pharmaceutical field routine, such as: diluent, excipient such as water；Adhesive is such as fine Tie up plain derivative, gelatin, polyvinylpyrrolidone etc.；Filler such as starch etc.；Burst apart agent such as calcium carbonate, sodium bicarbonate；In addition, Other adjuvants such as flavouring agent and sweetener can also be added in the composition.
The various dosage forms of composition of the invention can be prepared using the method for medical domain routine, wherein it is active at The content divided is 0.1%~99.5% (weight ratio).
Amount of application of the invention can be according to route of administration, the age of patient, weight, the type for the disease treated and serious Degree etc. is changed, and daily dose is 0.005-30mg/kg weight (oral) or 0.005-30mg/kg weight (injection).
Compared with prior art, present invention further progress structure on the basis of existing BET protein inhibitor is improved, and is obtained The BET protein inhibitor of a kind of new construction, with preferable BET protein inhibiting activity and good pharmacokinetic property, Exploitation is expected to as the BET protein inhibitor of high-efficiency low-toxicity of new generation.
Specific embodiment
The technical scheme in the embodiments of the invention will be clearly and completely described below, it is clear that described implementation Example is only a part of the embodiments of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, this field is common Technical staff's all other embodiment obtained without making creative work belongs to the model that the present invention protects It encloses.
Reference example 1: the synthetic route of segment A1.
Step 1: the synthesis of compound A1-2.
At 0 DEG C, into DMF (20mL) solution of compound A1-1 (400mg, 1.76mmol) be added NaH (141mg, 3.52mmol).Mixture is stirred 10 minutes at such a temperature and TsCl (671mg, 3.52mmol) is added at 0 DEG C.Then Reaction 2 hours is stirred at room temperature in mixture.Reaction mixture H2O (20mL) dilution, and extracted with EA (30mL x 2). Merge organic layer, and washed with salt water (20mL × 2), anhydrous sodium sulfate is dried, filtered and concentrated.Residue is through silica gel column chromatography (PE/EA=2/1), compound A1-2 (800mg, 95% yield) is obtained, is yellow solid.MS:382.0[M+H]+。
Step 2: the synthesis of compound A1-3.
The dioxane of 4M HCl is added into dioxane (10mL) solution of compound A1-2 (800mg, 2.1mmol) Solution (5mL) reaction mixture stirs 2 hours at 50 DEG C.Reaction mixture is cooled to room temperature and is concentrated, residue H2O (20mL) dilution, and extracted through EA (30mL x 2).Merge organic layer, organic layer is washed through salt water (20mL × 2), anhydrous slufuric acid Sodium is dried, filtered and concentrated, and obtains compound A1-3 (600mg, 100% yield), is yellow solid.MS:368.0[M+H]+。
Step 3: the synthesis of compound A1-4.
At 0 DEG C, into DMF (10mL) solution of compound A1-3 (600mg, 1.63mmol) be added NaH (131mg, 3.26mmol).The mixture stirs 10 minutes at this temperature and CH is added in ice bath3I (671mg, 3.52mmol).Mixing Object is stirred at room temperature 3 hours.Reaction mixture is through H2O (20mL) dilution, and extracted through EA (30mL x 2).What is merged is organic Layer is washed with salt water (20mL × 2), and anhydrous sodium sulfate is dried, filtered and concentrated.Residue is through silica gel column chromatography (PE/EA=2/ 1) compound A1-4 (450mg, 72% yield), is obtained, is yellow solid.MS:382.0[M+H]+。
Step 4: the synthesis of compound A1.
Compound A1-4 (300mg, 0.788mmol), Pin are sequentially added in reaction flask2B2(400mg, 1.57mmol), KOAc (232mg, 2.36mmol), X-phos (38mg, 0.08mmol), Pd2(dba)3(73mg, 0.08mmol) and dioxane (20mL).Under N2 protection, mixture stirs 3 hours at 85 DEG C.Reaction mixture is through H2O (20mL) dilution, and with DCM (30mL X 2) extraction.Combined organic layer is washed with salt water (20mL), anhydrous sodium sulfate is dried, filtered and concentrated, and obtains compound A1-5 crude product (500mg, 100% yield) is yellow solid.MS:429.0[M+H]+,1H NMR(400MHz,DMSO-d6)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).
Reference example 2-7: segment A2~A7.
Referring to the synthetic method of step 1-4 in reference example 1, each reference example in the following table 2 is synthesized:
Reference example 8: the synthetic route of segment A8.
Compound A-28-1 (150mg, 0.95mmol), Pin are sequentially added in reaction flask2B2(1.2g, 4.73mmol), KOAc (186mg, 1.9mmol), X-phos (91mg, 0.19mmol), Pd2(dba)3(87mg, 0.095mmol) and dioxane (10mL).Mixture is stirred to react 1 hour at 85 DEG C.Reaction solution is cooled to room temperature, adds H2O (20mL) dilution, and use DCM (30mL × 2) extraction.Merge organic layer, and washed through saline solution (20mL), anhydrous sodium sulfate dries, filters, and is concentrated, and obtains thick Product A8-1 (200mg, 94% yield) is yellow solid.MS:251.1[M+H]+。
Reference example 9-11: segment A9~A11.
Referring to the synthetic method of reference example 8, each reference example in the following table 3 is synthesized:
Reference example 12: the synthetic route of segment C1.
Step 1: the synthesis of compound C1-2.
To the dense H of compound C1-1 (11g, 0.05mol)2SO4Br is added dropwise in (60mL) solution2(8g, 0.05mol), so HNO is added in ice-water bath afterwards3(2.5mL).Reaction solution is heated to 90 DEG C, insulation reaction 5 hours.Reaction is cooled to room temperature, adds H2O (50mL) dilution, and extracted with DCM (50mL × 2).Merge 2 extract liquors, then through being saturated Na2S2O3(50mL × 2) washing, nothing Aqueous sodium persulfate dries, filters, concentration.Residue purifies residue by silica gel column chromatography (PE/EA=2/1), obtains compound C1-2 (4.3g, 29% yield) is white solid.MS:297.1[M-H]-。
Step 2: the synthesis of compound C1-4.
The fluoro- 3- iodophenol (3.45g, 14.5mmol) of compound C1-2 (4.1g, 13.8mmol), 4- and K2CO3(2g, It 14.5mmol) is added in DMSO (120mL), which heats reaction 3 hours at 120 DEG C.Reaction solution is cooled to room temperature, adds H2O (30mL) is quenched, and is extracted with EA (50mL x 2).Combined organic layer is washed with saline solution (50mL × 2), anhydrous sulphur Sour sodium dries, filters, concentration.Residue by silica gel column chromatography (PE/EA=2/1) purify, obtain compound C1-4 (5.4g, 76% yield), it is yellow solid.MS:515.1[M-H]-。
Step 3: the synthesis of compound C1-5.
Compound C1-4 (5.4g, 10.5mmol), Fe (2.0g, 37mmol) and NH4Cl (334mg, 6.3mmol) is added EtOH (100mL) and H2In O (20mL), which is stirred to react 3 hours at 90 DEG C.Reaction solution is cooled to room temperature, adds H2O (50mL) dilution is simultaneously extracted with EA (80mL).Liquid separation, concentration of organic layers, gained residue is through silica gel column chromatography (PE/EA=2/1) Purifying, obtains compound C1-5 (3.3g, 64.7% yield), is yellow solid.MS:485.1[M-H]-。
Step 4: the synthesis of compound C1-6.
Compound C1-5 (500mg, 1.03mmol), Cs2CO3(1g, 3.09mmol), BINAP (128mg, 0.2mmol) and Pd2(dba)3(192mg, 0.2mmol) is added in dioxane (40mL), which is stirred to react overnight at 80 DEG C.Reaction Liquid cooling adds H to room temperature2O (50mL) dilution, and extracted with EA (50mL × 2).Organic layer is washed through saline solution (30mL × 2), nothing Aqueous sodium persulfate dries, filters, concentration.Residue is purified through silica gel column chromatography (PE/EA=2/1), obtains compound C1-6 (290mg, 37.6% yield) is yellow solid.MS:357.2[M-H]-。
Step 5: the synthesis of compound C1.
Under ice bath, to the mixed of compound 5 (660mg, 0.02mol), polyformaldehyde (166mg, 5.53mmol) and DCM (20mL) It closes and TFA (1.3mL) and Et is added in solution3Reaction 2 hours is stirred at room temperature in SiH (2.6mL).Reaction solution adds H2O (30mL) dilution, And it is extracted with EA (50mL × 2).Merge organic layer, and washed with saline solution (50mL), anhydrous sodium sulfate dries, filters, concentration. Residue is purified through silica gel column chromatography (PE/EA=2/1), is made compound C1 (300mg, 41% yield), is yellow solid. MS:373.2[M+H]+,1H NMR(400MHz,CDCl3)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)。
Reference example 13-53: segment C2~C42.
Referring to the synthetic method of step 1-5 in reference example 12, each reference example in the following table 4 is synthesized:
Reference example 54: the synthetic route of segment C43 and C44.
Step 1: the synthesis of compound C43-3.
Compound C43-1 (2.51g, 10.0mmol), C43-2 (1.65g, 10.5mmol) and K2CO3(2.1g, 15mmol) It is added in DMF (20mL), which heats reaction 3 hours at 100 DEG C.Reaction solution is cooled to room temperature, adds H2O (30mL) quenches It goes out, and is extracted with EA (50mL x 2).Combined organic layer is washed with saline solution (50mL × 2), anhydrous sodium sulfate is dry, mistake Filter, concentration.Residue is purified by silica gel column chromatography (PE/EA=2/1), obtains compound C43-3 (2.4g, 62% yield), For white solid.MS:390.2[M+H]+。
Step 2: the synthesis of compound C43.
Compound C43-3 (2.0g, 5.1mmol) is added in polyphosphoric acids (10mL), and 120 DEG C of reactions 3 are heated under stirring Hour, reaction solution is cooled to room temperature, is added with stirring ice water (30mL) stirring 30min, filtering, gained crude product is through methanol (10mL) weight Crystallization, 50 DEG C of vacuum drying 4h obtain C43 (1.54g, 81% yield), are off-white powder.MS:358.2[M+H]+,1H NMR (400MHz,CDCl3)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)。
Step 3: the synthesis of compound C44.
1N borine tetrahydrofuran solution is added dropwise under ice salt bath into the THF solution (10mL) of C43 (1.0g, 2.7mmol) (2mL) is added dropwise to complete rear room temperature and is stirred to react 1h, then be warming up to back flow reaction 2h.It is cooled to room temperature, anhydrous second is added dropwise under stirring Alcohol (2mL), is concentrated to dryness after being added dropwise to complete, and residue is through methylene chloride (10mL)/H2O (5mL) extraction, liquid separation, it is organic Layer is washed through saturated salt solution (5mL) again, is separated, is dried, being concentrated to give C42 crude product, which recrystallizes through dehydrated alcohol (5mL), 50 DEG C of vacuum drying 4h obtain C44 (0.82g, 85% yield), are off-white powder.MS:372.2[M+H]+,1H NMR (400MHz,CDCl3)δ:8.21(s,1H),8.05(s,1H),7.15-7.22(m,3H),3.34(s,3H)。
Reference example 55-56: segment C45~C46.
Referring to the synthetic method of step 1-3 in reference example 54, each reference example in the following table 5 is synthesized:
Reference example 57: the synthetic route of segment C47.
Step 1: the synthesis of compound C47-2.
Compound C47-1 (2.51g, 10.0mmol), fluorobenzoic boric acid (1.53g, 11.0mmol) and K2CO3(3.45g, It 25.0mmol) is added in DMF (20mL), reaction solution N2Under gas shielded, it is heated to heating reaction 3 hours at 100 DEG C.Reaction solution It is cooled to room temperature, adds H2O (30mL)/EtOAc (60mL) extraction, organic layer are washed with saline solution (50mL × 2), and anhydrous sodium sulfate is dry It is dry, it filters, concentration.Residue by silica gel column chromatography (PE/EA=1/1) purify, obtain compound C47-2 (2.13g, 80% Yield), it is off-white powder.MS:267.3[M+H]+。
Step 2: the synthesis of compound C47.
C47-2 (2.1g, 7.9mmol), CuI (2.2g, 11.8mmol), pivalic acid are sequentially added in open reaction flask (0.8g, 7.9mmol) and DMSO (10mL) is heated to 130 DEG C of reaction 12h of interior temperature under stirring.After the reaction was completed, by EtOAc (30mL) is added in cooling reaction mixture.Sequentially add ammonium hydroxide (15mL) and saline solution (15mL) washing, liquid separation.It is organic Layer is dry with anhydrous sodium sulfate, filters, and is concentrated in vacuo to dry.Gained residue passes through silica gel column chromatography (PE/EA=10/1) Purifying, obtains compound C47 (1.78g, 58% yield), is off-white powder.MS:391.2[M+H]+,1H NMR(400MHz, CDCl3)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)。
Reference example 58-60: segment C48-C50.
Referring to the synthetic method of step 1-2 in reference example 57, each reference example in the following table 6 is synthesized:
Embodiment 1
Synthetic route:
Step 1: the synthesis of compound I-1-1
Compound A1 (473mg, 0.97mmol), C1 (180mg, 0.485mmol), CsF (221mg, 1.45mmol), Pd (dppf)Cl2(35mg, 0.05mmol), dioxane (10mL), H2O (2mL) is sequentially added in reaction flask, the lower heating of N2 protection It is warming up to 85 DEG C of reaction 12h.Reaction solution is cooled to room temperature, adds H2O (20mL) dilution is merged organic with DCM (30mL x 2) extraction Phase.Organic phase washes through saturated salt solution (20mL), liquid separation.Organic layer is dry with anhydrous sodium sulfate, filters, and is concentrated in vacuo to It is dry.Gained residue is purified by silica gel column chromatography (PE/EA=1/2), obtains compound I-1-1 (178mg, 62% yield), For faint yellow solid.MS:594.6[M+H]+。
Step 2: the synthesis of compound I-1
6M NaOH aqueous solution (5mL) is added in the methanol solution (10mL) of I-1-1 (160mg, 0.27mmol), reaction is mixed It closes liquid and is heated to 80 DEG C of reaction 1h.Reaction solution is cooled to room temperature, adds H2O (20mL) dilution is merged with DCM (30mL x 2) extraction Organic phase.Organic phase washes through saturated salt solution (20mL), liquid separation.Organic layer is dry with anhydrous sodium sulfate, filters, and is concentrated in vacuo It is extremely dry.Gained residue is purified by silica gel column chromatography (PE/EA=1/2), is obtained compound I-1 (52mg, 44% yield), is White solid.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).
Referring to the synthetic method of step 1~2 in embodiment 1, each embodiment compound in the following table 7 is synthesized:
Embodiment 56:I-56
Synthetic route:
Compound A12 (200mg, 2.06mmol), C1 (1533mg, 4.12mmol), K2CO3(568mg,4.12mmol)、Pd (OAc)2(46mg, 0.2mmol), dioxane (20mL), H2O (2mL) is sequentially added in reaction flask, N2Protect lower heat temperature raising To 85 DEG C of reaction 12h.Reaction solution is cooled to room temperature, adds H2O (20mL) dilution merges organic phase with DCM (30mL x 2) extraction. Organic phase washes through saturated salt solution (20mL), liquid separation.Organic layer is dry with anhydrous sodium sulfate, filters, and is concentrated in vacuo to dry.Institute It obtains residue to purify by silica gel column chromatography (PE/EA=1/1), obtains compound I-56 (400mg, 50% yield), be yellowish Color solid.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).
Referring to synthetic method in embodiment 56, each embodiment compound in the following table 8 is synthesized:
NMR the and MS data summarization of each embodiment see the table below shown in 9:
Test case 1, BRD4 active testing
Association reaction process:
(1) 1 × Assay buffer is prepared.
(2) preparation of compound concentration gradient: test-compound and positive reference compound AbbV-075, I-BET762 are surveyed Examination final concentration is 1000nM starting, 3 times of dilutions, 10 concentration, each concentration setting two multiple holes test.First by compound with DMSO is that Solvent Gradient is diluted to the solution of corresponding 1000 times of final concentrations, then with 1 × Assay buffer by respective concentration DMSO solution dilutes 100 times (DMSO concentration is 1% at this time), and it is anti-to 384 holes to shift 2 μ L compound 1%DMSO solution with the volley of rifle fire It answers to be measured in plate.The 1%DMSO solution of 2 μ L is shifted in the hole Max, and the AbbV-075 maximum concentration 1% of 2 μ L is shifted in the hole Min DMSO solution.
(3) 5 × protein solution is prepared with 1 × reaction solution.
(4) 5 × polypeptide solution is prepared with 1 × reaction solution.
(5) in 5 × protein solution of each 4 μ L of Kong Zhongjia, 1000rpm is centrifuged 1min, is incubated at room temperature 15 minutes.
(6) 5 × polypeptide solution of 4 μ L is added in each hole of reaction plate, 1000rpm is centrifuged 1min.
(7) 10 μ L are added and detect liquid, 1000rpm is centrifuged 60 seconds, after gently oscillation mixes, is incubated at room temperature 60 minutes.
(8) it is read with EnVision.
Data analysis:
Calculation formula
It is fitted amount effect curve
Using the log value of concentration as X-axis, percent inhibition is Y-axis, using analysis software GraphPad Prism's 5 Log (inhibitor) vs.response-Variable slope is fitted amount effect curve, to show that compound for protein combines The IC of inhibition50Value.
Test case 2, MV4-11 cell proliferation experiment
Pass throughReagent (Invitrogen) measures cell viability.
MV4-11 cell (acute myeloid leukaemia) is seeded in 96 hole microtiter plates with the concentration of 5000 cells/wells On 100 μ L growth mediums (RPMI1640,10%FCS) in.After being incubated overnight at 37 DEG C, measure fluorescent value (C1 value). Then many kinds of substance dilution processing board is used, and is incubated for 72h at 37 DEG C, then measures fluorescent value (C0 value).For data Analysis, from C0 value deduct C1 value, and by it is handle with many kinds of substance dilution or only with buffer solution processing cell results It is compared.To calculate IC50Value.Above-mentioned experimental result is as shown in table 10.
10. test result of table:
Conclusion: the compounds of this invention is substantially better than ABBV-075, INCB-057643 to BRD4 combination activity；Of the present inventionization Closing object has apparent inhibitory activity to leukaemia cell MV4-11 proliferation, and inhibitory activity is better than ABBV-075, INCB- 057643。
Test case 3, the test of the compounds of this invention pharmacokinetics
Using SD rat as animal subject, ABBV-075 is given using LC/MS/MS method measurement rat oral gavage and the present invention is preferred After embodiment compound, the drug concentration in its different moments blood plasma is measured, studies the compounds of this invention medicine generation in rat body Dynamic characteristic.
SD rat source: Beijing Vital River Experimental Animals Technology Co., Ltd.
Administration mode: single oral gavage administration
Dosage and concentration: 10mg/kg；1mg/mL
Preparation prescription: 0.5%methylcellulose
Sample point: 5min, 15min, 30min, 1h, 2h, 4h, 8h, for 24 hours
Standard curve and Quality Control sample preparation processing: take appropriate stock solution to be diluted to 0.04 with 50% acetonitrile water, 0.10, 0.20, the standard working solution of 0.40,1.00,2.00,4.00 μ g/mL, the Quality Control working solution of 0.10,1.00,3.00 μ g/mL.Point The standard curve working solution and Quality Control working solution that 2.50 μ L are added in 47.5 μ L blank rat plasmas are not taken, are configured to containing determinand Concentration is 2.00,5.00,10.00,20.00,50.00,100.00, the mark of 200.00ng/mL is bent and concentration is 5.00,50.00 With the Quality Control sample of 150.00ng/mL, it is separately added into the acetonitrile (containing the internal standard Loratadine 5ng/mL) of 200 μ L, vortex oscillation After 3min, 15000rpm, 4 DEG C of centrifugation 15min take supernatant 100L to carry out LC-MS/MS analysis.Using8.0 meter Calculate experimental result.
Preferred compound pharmacokinetic parameter of the present invention is as shown in table 11.
Table 11: preferred compound pharmacokinetic parameter
Conclusion: compound of the embodiment of the present invention shows good pharmacokinetic property, compared with ABBV-075, blood medicine Concentration, area under the curve are higher, long half time, and the residence time is short.
Pharmacodynamic test is tested in test case 4, the compounds of this invention body
Purpose: inhibiting effect of the test test-compound to MV4-11 leukaemia transplanted tumor in nude mice tumor growth.
Method: BALB/c nude mouse inoculates MV4-11 cell, establishes MV4-11 Nude Mouse Model.Inoculation 13 days (d13) afterwards, mean tumour volume are about 215mm3, are grouped mice with tumor using randomized blocks according to gross tumor volume size, wrap Include solvent control group, control sample INCB-057643 group, test sample group, every group 6.Each group is all made of gastric infusion, administration Dosage is 30mg/kg, and administered volume is 10ml/kg, is administered once a day, and successive administration 14 days, solvent control group stomach-filling was given Give blank solvent (50mM sodium lactate aqueous solution, PH4.0).Start to give after testing drug secondary amounts tumor, weighing on every Tuesdays.Experiment knot Be euthanized animal after beam.
Pharmacodynamic results are as shown in table 12 in preferred compound animal body of the present invention.
Table 12: drug effect in preferred compound animal body
Conclusion: compound of the embodiment of the present invention shows good antitumor activity.The tumor suppression compared with control group INCB-057643 Activity is more significant.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention Within mind and principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.

Claims (9)

1. a kind of BET protein inhibitor, which is characterized in that its structure is shown in formula I:
Or its pharmaceutically acceptable salt, wherein
A is selected from
B ring is selected fromOr by R11And/or R12The five yuan of heteroaromatics replaced；
Wherein:
X is O, S or NR13；
Y is CH2, C=O, NR1Or Y is not present；
Z is CR14Or N；
U is CH or N；
W is O or NH；
V is CH or N；
R1For hydrogen, C1-C6Alkyl, C3-C6Naphthenic base replaces C1-C6Alkyl replaces C3-C6Naphthenic base, C3-C6Naphthenic base C1-C6Alkane Base, C1-C6Alkyl-SO2Or C3-C6Naphthenic base-SO2-；
R2For hydrogen, C1-C6Alkyl, C1-C3Alkoxy, halogen or cyano；
R3For hydrogen, C1-C6Alkyl, C1-C3Alkoxy, halogen, cyano ,-S (O)2R15、-S(O)2NR16R17Or-N (R16)S(O)2R15；
R4For hydrogen, C1-C6Alkyl, C1-C3Alkoxy, halogen or cyano；
R5And R6It is each independently hydrogen or C1-C6Alkyl；
R7、R8、R9And R10It is each independently hydrogen, halogen, cyano, C1-C3Alkoxy or C1-C6Alkyl；
R11For hydrogen or C1-C6Alkyl；
R12For hydrogen or C1-C6Alkyl；
R13For hydrogen or C1-C6Alkyl；
R14For hydrogen, C1-C6Alkyl, halogen or cyano；
R15For C1-C6Alkyl；
R16For hydrogen or C1-C6Alkyl；
R17For hydrogen or C1-C6Alkyl；
Above-mentioned halogen is selected from fluorine, chlorine, bromine or iodine.
2. BET protein inhibitor as described in claim 1, which is characterized in that A is selected from
B ring is selected from
Wherein:
X is O, S or NR13；
Y is CH2, C=O, NR1Or Y is not present；
Z is CR14Or N；
U is CH or N；
W is O or NH；
V is CH or N；
R1For hydrogen, C1-C4Alkyl, C3-C6Naphthenic base replaces C1-C4Alkyl replaces C3-C6Naphthenic base, C3-C6Naphthenic base C1-C3Alkane Base, C1-C4Alkyl-SO2Or C3-C6Naphthenic base-SO2-；The substitution C1-C4Alkyl refers to C1-C4Hydrogen on alkyl by one or Multiple C3-C6Naphthenic base replaces；The substitution C3-C6Naphthenic base refers to C3-C6Hydrogen in naphthenic base is by one or more C1-C4Alkane Base replaces；
R2For hydrogen, C1-C4Alkyl, C1-C2Alkoxy, halogen or cyano；
R3For hydrogen, C1-C4Alkyl, C1-C2Alkoxy, halogen, cyano ,-S (O)2R15、-S(O)2NR16R17Or-N (R16)S(O)2R15；
R4For hydrogen, C1-C4Alkyl, C1-C3Alkoxy, halogen or cyano；
R5And R6It is each independently hydrogen or C1-C4Alkyl；
R7、R8、R9And R10It is each independently hydrogen, halogen, cyano, C1-C3Alkoxy or C1-C4Alkyl；
R11For hydrogen or C1-C4Alkyl；
R12For hydrogen or C1-C4Alkyl；
R13For hydrogen or C1-C4Alkyl；
R14For hydrogen, C1-C4Alkyl, halogen or cyano；
R15For C1-C4Alkyl；
R16 is hydrogen or C1-C4Alkyl；
R17 is hydrogen or C1-C4Alkyl；
Above-mentioned halogen is selected from fluorine, chlorine, bromine or iodine.
3. BET protein inhibitor as described in claim 1, which is characterized in that A is selected from
B ring is selected from
Wherein:
X is O, S or NR13；
Y is CH2, C=O, NR1Or Y is not present；
Z is CR14Or N；
U is CH or N；
W is O or NH；
V is CH or N；
R1For hydrogen, C1-C3Alkyl, C3-C6Naphthenic base replaces C1-C3Alkyl replaces C3-C6Naphthenic base, C3-C6Naphthenic base C1-C3Alkane Base, C1-C3Alkyl-SO2Or C3-C6Naphthenic base-SO2-；The substitution C1-C3Alkyl refers to C1-C3Hydrogen on alkyl by one or Multiple C3-C6Naphthenic base replaces；The substitution C3-C6Naphthenic base refers to C3-C6Hydrogen in naphthenic base is by one or more C1-C3Alkane Base replaces；
R2For hydrogen, C1-C3Alkyl, C1-C2Alkoxy, halogen or cyano；
R3For hydrogen, C1-C3Alkyl, C1-C2Alkoxy, halogen, cyano ,-S (O)2R15、-S(O)2NR16R17Or-N (R16)S(O)2R15；
R4For hydrogen, C1-C3Alkyl, C1-C2Alkoxy, halogen or cyano；
R5And R6It is each independently hydrogen or C1-C3Alkyl；
R7、R8、R9And R10It is each independently hydrogen, halogen, cyano, C1-C2Alkoxy or C1-C3Alkyl；
R11For hydrogen or C1-C3Alkyl；
R12For hydrogen or C1-C3Alkyl；
R13For hydrogen or C1-C3Alkyl；
R14For hydrogen, C1-C3Alkyl, halogen or cyano；
R15For C1-C3Alkyl；
R16For hydrogen or C1-C3Alkyl；
R17For hydrogen or C1-C3Alkyl；
Above-mentioned halogen is selected from fluorine, chlorine, bromine or iodine.
4. BET protein inhibitor as described in claim 1, which is characterized in that be selected from following compound:
Or its pharmaceutical salt.
5. a kind of method for synthesizing the described in any item compounds of Claims 1 to 4, it is characterised in that reaction equation is as follows:
General formula compound I, each group definition such as right is made through catalyzed coupling reaction in general formula IA compound and general formula IB compound It is required that described in 1~4 any one.
6. if the described in any item compounds of Claims 1 to 4 are in the drug of preparation prevention or treatment and BET protein related diseases In purposes.
7. purposes as claimed in claim 6, which is characterized in that described to refer to tumor disease, benign increasing with BET protein related diseases Life, inflammatory disease, autoimmune disease, septicemia, virus infection, vascular diseases or neurogenic disease.
8. purposes as claimed in claim 7, which is characterized in that the tumor disease includes but is not limited to acute myelogenous white blood Disease, lymthoma, Huppert's disease, B cell acute lymphatic leukaemia, center line cancer, glioma, solid tumor, breast cancer, knot The carcinoma of the rectum, prostate cancer, cervical carcinoma, non-small cell lung cancer or melanoma.
9. a kind of composition, the composition include therapeutically effective amount the described in any item compounds of Claims 1 to 4 or its Pharmaceutical salt and medically acceptable carrier.
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