CN108484640A - A kind of antitumor apoptosis protein inhibitor - Google Patents
A kind of antitumor apoptosis protein inhibitor Download PDFInfo
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- CN108484640A CN108484640A CN201810492800.8A CN201810492800A CN108484640A CN 108484640 A CN108484640 A CN 108484640A CN 201810492800 A CN201810492800 A CN 201810492800A CN 108484640 A CN108484640 A CN 108484640A
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- 0 *C1CCCCC1 Chemical compound *C1CCCCC1 0.000 description 15
- XPKGUPGYTSTKSG-UHFFFAOYSA-N CC(C(NC(CSSC(C(NC(c1ccccc1)c1ccccc1)=O)NC(C(CCC1)N1C(C(C1CCCCC1)NC(CN)(C=O)N1)=O)=O)C1=O)=N)NC Chemical compound CC(C(NC(CSSC(C(NC(c1ccccc1)c1ccccc1)=O)NC(C(CCC1)N1C(C(C1CCCCC1)NC(CN)(C=O)N1)=O)=O)C1=O)=N)NC XPKGUPGYTSTKSG-UHFFFAOYSA-N 0.000 description 1
- PKVFORHFSIUDTB-UHFFFAOYSA-N CC(C1CCCCC1)NC(C(C)NC)=O Chemical compound CC(C1CCCCC1)NC(C(C)NC)=O PKVFORHFSIUDTB-UHFFFAOYSA-N 0.000 description 1
- WDALXIHTFDUFIR-UHFFFAOYSA-N CC(CCc(cc1)ccc1F)=O Chemical compound CC(CCc(cc1)ccc1F)=O WDALXIHTFDUFIR-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
Abstract
The present invention relates to formula (I) compound or its pharmaceutically acceptable salt, isomers or prodrugs, wherein R1、R2、R3、R4Definition as shown in specification.This kind of compound can be used for inhibiting IAP, so as to be used to treat and the relevant disease of IAP protein overexpressions, such as cancer.The invention further relates to the pharmaceutical composition containing this kind of compound, the method for preparing this kind of compound.The compound of the present invention activity preferably, has potential medical value and wide market-oriented foreground.
Description
Technical field
This field belongs to medicinal chemistry arts, and in particular to a kind of (apoptosis protein) IAP can be used for treating cancer
Inhibitor and preparation method thereof.
Background technology
Apoptosis or apoptosis are mechanism modulated in terms of gene and biochemistry, in no vertebra
It plays a significant role in terms of the development of animal and vertebrate and homeostasis.The Apoptosis of premature cell death will be caused
It is abnormal to be associated with polydysplasia.Cause cell death lack Apoptosis defects with cancer and slow virus sense
Dye associates.
Current cancer therapy, including chemotherapeutics, radiation and immunotherapy, the Apoptosis in indirect induction cancer cell.
Therefore, cancer cell can not be executed due to the defects of normal apoptosis mechanism apoptotic program usually with to chemotherapy, put
It penetrates or the resistance of the Apoptosis of immunotherapy induction increases correlation.This due to Apoptosis defects and to current therapy of cancer
Class primary or acquired resistance are the main problem in current cancer therapy.The central negative conditioning agent of a kind of Apoptosis is thin
The inhibitor of born of the same parents' apoptotic proteins (IAP).This classification include albumen such as XIAP, cIAP1, cIAP2, ML-IAP, HIAP,
KIAP, TSIAP, NAIP, survivin, livin, ILP-2, apollon and BRUCE.IAP albumen effectively inhibits suitable various kinds of cell
The cancer cell apoptosis of apoptotic stimulus (including chemotherapeutics, radiation and immunotherapy) induction, is the new target of Apoptosis access
Point.
Be related to IAP inhibitor application for a patent for invention have WO2011018474A1, WO2008016893A1,
WO2014047024A1, CN101484151A etc..
The IAP inhibitor of development phase has LCL161, Birinapant, BV6, GDC-0152, AZD5582, AT406 at present
Deng, wherein AT-406 is a kind of effective, orally available Smac analogies can inhibit XIAP for the antagonist of IAPs,
CIAP1 and cIAP2 albumen, structural formula are as follows：
There is IAP inhibitor extraordinary market value, the exploitation of the kind still there is more significant challenge.In order to full
Foot reaches better tumor disease therapeutic effect, we are dedicated at present clinically to the needs of apoptosis protein inhibitor
A series of research and development such as the drug design of IAP inhibitor of high-efficiency low-toxicities, this is of great significance for field of medicaments.
Invention content
The purpose of the present invention is to provide new IAP protein inhibitors or its pharmaceutically acceptable salt, isomers or preceding
Medicine, the compound have logical formula (I)：
Wherein,
R1Group is selected fromAny one；
R2And R3Group each independently arbitrarily be selected from H,
In one kind, wherein X be halogen；
R4Group represents
In a kind of scheme, X F；
In a kind of scheme, R2Group represents
In a kind of scheme, R3Group represents
The present invention also provides the preparation methods of logical formula (I) compound and its salt, isomers or its prodrug, but be not limited only to
The method of lower description.All raw materials are all the group feature for the target molecule that basis meets general formula rule, and pass through these roads
Scheme, organic chemistry filed in line method well-known to the ordinarily skilled artisan is prepared or is directly bought.It can will use following sides
In method and synthetic organic chemistry field known synthetic method or those skilled in the art will appreciate related change method combine
Together, the compounds of this invention is synthesized.Reaction route is as follows：
The preparation method of logical formula (I) compound
In above-mentioned formula (I) preparation method, R1、R2、R3、R4Definition with X group is defined above identical as specification.
The preparation method of logical formula (I) compound includes the following steps：
Step 1：Compound 1' is subjected to amidation condensation reaction under condensing agent effect with compound 2', then in alkali
Removing Fmoc protection group reactions are carried out under catalytic action, obtain compound 3'；
Step 2：By compound 3' and compound 4'(Fmoc- proline) progress amidation process obtains under condensing agent effect
To compound 5'；
Step 3：Compound 5' and compound 6' are subjected to amidation process in the case where being acted in condensing agent and obtain compound 7'；
Step 4：Compound 7' and compound 8' are subjected to amidation process in the case where being acted in condensing agent and obtain compound 9'；
Step 5：Compound 9' and compound 10' are subjected to amidation process in the case where being acted in condensing agent and obtain compound
11'；
Step 6：Compound 11' is subjected to ring-closure reaction under the catalytic action of iodine and obtains midbody compound 12'；
Step 7：By general formula compound 12', removing Boc protecting groups are anti-under the action ofs acid is, for example, trifluoroacetic acid, hydrochloric acid etc.
Answer, then again with contain R2The carboxylic acid compound of group or with contain R2The acyl chloride compound of group is obtained by the reaction
Compound 13'；
Step 8：By compound 13' under the action of the alkali such as piperidines, remove Fmoc protecting groups, then again with contain R3Group
Carboxylic acid compound or with contain R3The acyl chloride compound of group carries out that target molecule compound (I) is obtained by the reaction；
Further, R2Group and R3The sequencing that group introduces can be selected according to the concrete condition of reaction, i.e.,
Compound 12' can also first carry out removing Fmoc protecting groups, and reaction introduces R3Group, then Boc protecting groups are removed, it is re-introduced into R2Base
Group, finally obtains target molecule；
The condensing agent of amidation process described in above-mentioned reaction arbitrarily selected from 1,3- dicyclohexylcarbodiimides (DCC),
N, N'- diisopropylcarbodiimide (DIC), 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides (EDC) and its hydrochloride,
1- (3- dimethyl aminopropyls) -3- ethylcarbonyl group diamines methiodide, n,N-diisopropylethylamine (DIEA), I-hydroxybenzotriazole
(HoBt), 2- (7- azos benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (HATU), benzotriazole-N,
N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HBTU), 6- Chloro-Benzotriazoles -1,1,3,3- tetramethylurea hexafluorophosphoric acid esters
(HCTU), 2- (1H- benzo trisazo- L-1- yls) -1,1,3,3- tetramethylurea tetrafluoro boric acid ester (TBTU), 2- succinimides
Base -1,1,3,3- tetramethylurea tetrafluoro boric acid esters (TSTU), 5- norbornene -2,3- dicarbapentaborane-N, N, N', N'- tetramethylureas
One or more of tetrafluoro boric acid ester (TNTU) combines.
In the above preparation method, it when the stability of the preparation process of each intermediate needs and carries out radical protection, needs
Corresponding intermediate is first subjected to deprotection reaction, finally obtains target molecule compound.The method of prepare compound such as relates to
And various chemical groups are protected and are deprotected, those skilled in the art can easily determine protection and deprotection needs and
Select suitable blocking group.
The feature that the features described above or embodiment that the present invention mentions are mentioned can be arbitrary group on meeting pharmacy regular basis
It closes, each feature disclosed in specification, can be taken by any alternative characteristics for providing identical, impartial or similar purpose
Generation.It is only identical or the general example of likeness in form feature except having special instruction, the feature of announcement.
The particular compound of the present invention include but not limited to the compound of structure being listed herein below or its pharmaceutically may be used
Salt, isomers or the prodrug of receiving.
Another aspect of the present invention provides a kind of pharmaceutical composition, wherein formula (I) compound containing therapeutically effective amount or
Its pharmaceutically acceptable salt, isomers or prodrug as active constituent and one or more pharmaceutically acceptable carriers,
Diluent or excipients.
The pharmaceutical composition preferably comprises pharmaceutically acceptable salt, the isomers for the formula (I) that weight ratio is 1%-80%
Or prodrug, as active constituent, further preferably weight ratio is the active constituent of 10%-70%.
Unless otherwise indicated, the following term in claims and specification has following meaning or feature：
Term " pharmaceutically acceptable salt " indicates to retain those of biological effectiveness and the property of parent compound salt.It is
Including the salt that the compound of formula (I) is formed with organic acid or inorganic acid.This kind of salt includes：With acid at salt, pass through parent compound
Free alkali obtained, inorganic acid with inorganic acid or reacting for organic acid such as (but not limited to) hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid,
Metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., organic acids such as (but not limited to) acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or
(L) malic acid, fumaric acid, citric acid, lactic acid, maleic acid, hydroxybenzoic acid, gamma-hydroxybutyric acid, methoxy benzoic acid, adjacent benzene
Dioctyl phthalate, tartaric acid, methanesulfonic acid, ethanesulfonic acid, naphthalene -1- sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, naphthalene-2-sulfonic acid, mandelic acid, the third two
Acid or succinic acid etc..
When the compound for meeting logical formula (I) feature that " isomers " refers to the present invention has optically-active, with formula (I) molecular structure in real
The substance of object and mirror.The present invention includes both racemic compound and optical isomer.When the change for wishing structure formula (I)
When to close object be single enantiomter, it can be by the fractionation of final product or by from the pure starting material of isomerism
Or the stereotaxis carried out using chiral auxiliary is synthesized and is obtained.
" Pharmaceutical composition " refers to one or more compounds described here or theirs is pharmaceutically acceptable
Salt, isomers and prodrug etc. and other chemical compositions, such as the mixture of pharmaceutically acceptable carrier and excipient.It is medicinal
The purpose of composition is to promote the administration of compound on organism body.
" pharmaceutically acceptable carrier " refers to not causing apparent irritation to organism and does not interfere giving
Close the carrier or diluent of the bioactivity and property of object.
" excipient " refers to being added in Pharmaceutical composition with the further convenient inert substance for giving compound.It assigns
The example of shape agent is including (without limitation) microcrystalline cellulose, cellulose, lactose, glucose, sucrose, sorb potassium alcoholate, polyethylene pyrrole
Pyrrolidone and methylcellulose etc..
Pharmaceutical composition can also contain：Pharmaceutically acceptable lubricant is such as talcum powder, magnesium stearate；Wetting agent；
Emulsifier and suspending agent；Preservative such as methyl benzoate and benzoic acid hydroxy propyl ester；Sweetener and corrigent.It can be by using
Method as known in the art prepares the present composition, lives to provide quick-release, sustained release or sustained release after giving patient
The effect of property ingredient.
The present invention " prodrug " refer to need in desired physiological system occur bioconversion (such as spontaneous or enzymatic) with
By parent " drug " molecule of prodrug release or conversion (such as passing through enzymatic, physiology, machinery, electromagnetic mode) active drugs
Pharmaceutically inactive derivative.Design prodrug is to overcome and stability, toxicity, shortage specificity or limited bioavilability
Related problem.Exemplary prodrug includes that active drug molecule itself and chemistry masking group (such as reversibly inhibit the medicine
The active group of object).Some preferred prodrugs are that have the modification of the compound of the group of cleavable under metabolic conditions or spread out
Biology.Exemplary prodrug is when they undergo solvolysis in physiological conditions or carry out enzymatic degradation or other biological chemical conversion
Become in vivo or in vitro with pharmaceutical active when (such as phosphorylation, hydrogenation, dehydrogenation, glycosylation).Common prodrug includes acid
Derivative, such as the esters that are prepared by making parent acid react with suitable alcohol (such as low-level chain triacontanol), by making parent acid
Compound reacts the amides prepared, or reaction with amine to form basic group (such as the low alkyl group of acylated alkali derivant
Amide).
The present invention also provides the formula (I) compound and its pharmaceutically acceptable salt, isomers or its prodrugs
Purposes is used for：
It prepares and the drug with the relevant disease of IAP protein overexpressions in mammal；
Further, the compound of the present invention can be used for preparing the drug of tumor disease.
Practicability：
The compound of the present invention can be used for the inducing cell apoptosis in cell, or make cell, particularly cancer cell to cell
Apoptotic signal is sensitive.
The compound of the present invention can be used for being overexpressed IAP albumen (for example, c-IAP1, c-IAP2, X-IAP or ML-IAP)
Cell in inducing cell apoptosis.Alternatively, the compound of the present invention can be used for the inducing cell apoptosis in such cell, in institute
Grain wire body apoptotic pathways in cell are stated to be destroyed so that the release of Smac ML-IAP albumen is for example by the upper of Bcl-2
It adjusts or the downward of Bax/Bak is suppressed.Broadly, the compound can be used for treating cancer.It is used especially for treatment not
All cancer types of Apoptosis can be undergone.The example of such cancer types includes neuroblastoma, intestinal cancer such as rectum
Cancer, colon cancer, familial adenomatosis polyposis cancer and hereditary nonpolyposis colorectal cancer, cancer of the esophagus, lip cancer, laryngocarcinoma, hypopharynx
Cancer, tongue cancer, salivary-gland carcinoma, gastric cancer, gland cancer, medullary carcinoma of thyroid gland, papillary thyroid carcinoma, kidney, carcinoma of renal parenchyma, oophoroma,
Cervix cancer, carcinoma of uterine body, carcinoma of endometrium, choriocarcinoma, cancer of pancreas, prostate cancer, testicular cancers, breast cancer, urinary system
Cancer, melanoma, brain tumor such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral nerve ectoderm
Tumor, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic
Leukaemia (CLL), acute myeloid leukaemia (AML), chronic myelogenous leukemia (CML), Adult T-cell leukemia's lymthoma, liver
Cell cancer, gallbladder cancer, bronchiolar carcinoma, Small Cell Lung Cancer, non-small cell lung cancer, Huppert's disease, basal cell tumor, monster
Tumor, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, cranium pharynx tumor, osteosarcoma, chondrosarcoma,
Muscle tumor, embryonal-cell lipoma, fibrosarcoma, Ewing's sarcoma and plasmacytoma.
The compounds of this invention can be used for making cell by cell apoptotic signal sensitive.Therefore, the compound can be controlled in radiation
It is administered prior to, concurrently with, or after treatment or cell proliferation inhibiting chemotherapy or anti-tumor chemotherapeutic.
Specific implementation mode
Following embodiment further describes the present invention, and still, these embodiments are only for illustrating the present invention, rather than right
The limitation of the scope of the invention.
Embodiment 1
Step 1：12.73g benzhydrylamines are dissolved in 200ml DMF, sequentially add 40.69g Fmoc-Cys (Trt)-OH,
39.49g HBTU and 13.47g DIEA are stirred at room temperature reaction 2h, TLC and detect (PE:EA=2:1) to raw material, the reaction was complete.To
20ml piperidines is added in reaction solution, reaction is stirred at room temperature, TLC detects (PE:EA=2:1) to raw material, the reaction was complete.By reaction solution
It pours into 1L water, is extracted with ethyl acetate 2 times (500ml*2), merge organic phase, saturated sodium-chloride is used in combination to washed once, it is anhydrous
Sodium sulphate is dried, and is concentrated under reduced pressure dry.Residue column chromatography (eluant, eluent DCM:MeOH it) purifies, obtaining compound I-1-1, (30.02g is yellow
Color oily liquids, [M+H]+=529.7)；
Step 2：30.00g compounds I-1-1 is dissolved in 150ml DMF, sequentially adds 19.15g Fmoc- proline,
32.26g HBTU and 11.00g DIEA are stirred at room temperature reaction 3h, TLC and detect (PE:EA=2:1) to raw material, the reaction was complete.To
20ml piperidines is added in reaction solution, reaction 0.5h, TLC is stirred at room temperature and detects (PE:EA=2:1) the reaction was complete for raw material.It will reaction
Liquid pours into 1L water, is extracted with ethyl acetate 2 times (500ml*2), merges organic phase, is used in combination saturated sodium-chloride washed once, nothing
Aqueous sodium persulfate is dried, and is concentrated under reduced pressure dry.Residue column chromatography (eluant, eluent DCM：MeOH it) purifies, obtains compound I-1-2
(29.48g, yellow solid, [M+H] +=626.3)；
Step 3：29.40g compounds I-1-2 is dissolved in 150ml DMF, sequentially adds the sweet ammonia of 17.87g Fmoc- cyclohexyl
Acid, 26.77g HBTU and 9.13g DIEA react at room temperature 2h, and TLC detects (PE:EA=1:1) the reaction was complete for raw material, then to
20ml piperidines is added in reaction solution, reaction half an hour is stirred at room temperature, TLC detects (solvent PE:EA, 1:1), raw material has reacted
Entirely.Reaction solution is poured into 1L water, is extracted with ethyl acetate 2 times (500ml*2), merges organic phase, saturated sodium-chloride is used in combination to wash
Primary, anhydrous sodium sulfate drying is washed, reduced pressure is dry.Residue is through column chromatography (eluant, eluent DCM：MeOH it) purifies, obtains compound
I-1-3 (29.19g, yellow solid, [M+H]+=766.1)；
Step 4：29.10g compounds I-1-3 is dissolved in 200ml DMF, sequentially adds 16.27g N2-Fmoc-N3-Boc-
D-2.3- diaminopropionic acids, 21.70g HBTU and 7.40g DIEA are stirred at room temperature reaction 2h, TLC and detect (PE:EA=1:1) extremely
The reaction was complete for raw material, and 30ml piperidines is added into reaction solution, and reaction 0.5h, TLC is stirred at room temperature and detects (PE:EA=1:1) to former
The reaction was complete for material, and reaction solution is poured into 1L water, is extracted with ethyl acetate 2 times (500ml*2), merges organic phase, saturation is used in combination
NaCl is primary, and anhydrous sodium sulfate drying is concentrated under reduced pressure dry.Residue column chromatography (eluant, eluent DCM：MeOH it) purifies, obtains
Compound I-1-4 (33.62g yellow oily liquids, ([M+H] +=952.4)；
Step 5：30.00g compounds I-1-4 is dissolved in 300ml DMF, sequentially adds 18.48g Fmoc-S- triphen first
Base-L-cysteine, 17.94g HBTU and 6.12g DIEA are stirred at room temperature reaction 2h, TLC and detect (PE:EA=2:1) to former
The reaction was complete for material.40ml piperidines is added into reaction solution, reaction 0.5h, TLC is stirred at room temperature and detects (PE:EA=1:1) to raw material
The reaction was complete, and reaction solution is poured into 1.5L water, is extracted with ethyl acetate 2 times (500ml*2), merges organic phase, saturation is used in combination
NaCl is primary, and anhydrous sodium sulfate drying is concentrated under reduced pressure dry.Residue column chromatography (eluant, eluent PE：EA it) purifies, obtains chemical combination
Object I-1-5 (37.87g white solids, [M+H]+=1520.1)；
Step 6：3.40g compounds I-1-5 is dissolved in 200ml DCM, 5.69g iodines/1L (DCM are added dropwise in room temperature:
MeOH=10:1) mixed solvent, the reaction was continued 0.5h after being added dropwise, TLC detect (PE:EA=1:1) it has been reacted to raw material
Entirely.It is added dropwise to saturated aqueous sodium sulfite into reaction solution to be quenched, 500ml water, liquid separation, water phase back extraction are added into reaction solution
It takes once, merges organic phase, organic phase washed once with saturated sodium-chloride, and anhydrous sodium sulfate drying is concentrated under reduced pressure dry.Residue
Column chromatography (eluant, eluent PE：EA it) purifies, obtains compound I-1-6 (1.92g white solids, [M+H]+=1033.6)；
Step 7：1.0g compounds I-1-6 is dissolved in 20ml DMF, 4ml piperidines is added into reaction solution, is stirred at room temperature anti-
0.5h is answered, after reaction, reaction solution is poured into 150ml water, is extracted with ethyl acetate 2 times (50ml*2), organic phase is merged,
It is used in combination saturated sodium-chloride washed once, anhydrous sodium sulfate drying is concentrated under reduced pressure dry.Residue column chromatography (eluant, eluent PE：EA) pure
Change, obtains compound I-1-7 (0.61g white solids, [M+H]+=810.0)；
Step 8：0.61g compounds I-1-7 is dissolved in 40ml DCM, 8ml trifluoroacetic acids are added, reacts at room temperature 1.5h, instead
After answering, pH=7-8 is adjusted with saturated sodium bicarbonate aqueous solution, liquid separation, water phase is primary with 40ml DCM back extraction, merges organic
Phase, organic phase washed once with saturated sodium-chloride, and anhydrous sodium sulfate drying is concentrated under reduced pressure dry.Residue column chromatography (eluant, eluent
PE：EA it) purifies, obtains compound I-1 (52mg white solids, [M+H]+=710.31)
Embodiment 2
Step 1：1.40g compounds I-1-6 is dissolved in 40mlDCM, 8ml trifluoroacetic acids are added, reacts at room temperature 2.5h, reaction
After, pH=7-8 is adjusted with saturated sodium bicarbonate aqueous solution, liquid separation, water phase is primary with 40ml DCM back extraction, merges organic
Phase, organic phase washed once with saturated sodium-chloride, and anhydrous sodium sulfate drying is concentrated under reduced pressure dry.The tertiary ether room temperature of 30ml first is added to beat
0.5h is starched, compound I-2-1 (2.41g, white solid) is filtered to obtain；
Step 2：1.0g compounds I-2-1 is dissolved in 40ml DMF, sequentially adds 0.44gN-Boc-2- methylalanines,
1.22g HBTU and 0.55g DIEA, react at room temperature 1.0h, and TLC detects (DCM：MeOH=15:1), until raw material the reaction was complete.To
8ml piperidines is added in reaction solution, reacts at room temperature 0.5h, TLC detects (DCM：MeOH=15:1) to raw material, the reaction was complete.It will reaction
Liquid pours into 400ml water, and 80ml*2 is extracted with ethyl acetate, and merges organic phase, and organic phase washed once with saturated sodium-chloride, nothing
Aqueous sodium persulfate is dried, and is concentrated under reduced pressure dry.Residue column chromatography (eluant, eluent DCM：MeOH) purify, obtain compound I-2-2 (0.81g,
White solid)；
Step 3：0.5g compounds I-2-2 is dissolved in 40ml DMF, sequentially adds 0.13g compounds 2,0.32g HBTU and
0.12g DIEA react at room temperature 1.0h, after reaction.Reaction solution is poured into 400ml water, has a small amount of white solid to be precipitated,
80ml*2 is extracted with ethyl acetate, merges organic phase, organic phase washed once with saturated sodium-chloride, and anhydrous sodium sulfate drying subtracts
Pressure concentration is dry.Compound I-2-3 (0.63g, white solid) is obtained, is directly thrown in next step；
Step 4：0.63g compounds I-2-3 is dissolved in 20ml DCM, 4ml trifluoroacetic acids are added, 30 DEG C are reacted 1.0h, instead
After answering.Reaction solution is poured into 200ml water, pH=7-8, liquid separation, water phase DCM are adjusted with saturated sodium bicarbonate aqueous solution
It is stripped 40ml*2, merges organic phase, organic phase washed once with saturated sodium-chloride, and dry, column is concentrated under reduced pressure in anhydrous sodium sulfate drying
Chromatograph (eluant, eluent DCM：MeOH it) purifies, obtains compound I-2 (0.44g, white solid, [M+H]+=1018.8).
Embodiment 3
Step 1：0.21g compounds I-2-2 is dissolved in 10ml DMF, 0.2g compounds 2 are added, reacts at room temperature 1.5h, instead
After answering.Reaction solution is poured into 100ml water, 40ml*2 is extracted with ethyl acetate, merges organic phase, organic phase saturation chlorine
Change sodium washed once, dry, column chromatography (eluant, eluent DCM is concentrated under reduced pressure in anhydrous sodium sulfate drying：MeOH it) purifies, obtains compound I-3
(0.15g, white solid, [M+H]+=1021.7).
Embodiment 4
Step 1：0.5g compounds I-2-2 is dissolved in 20ml methanol, sequentially adds tri- second of 0.14g compounds 4 and 0.85g
Amine is warming up to 50 DEG C of reactions overnight, after reaction.Decompression rotation removes solvent, and ethyl acetate and water, liquid separation is added, and water phase is used
The back extraction of 40ml ethyl acetate is primary, merges organic phase, and organic phase washed once with saturated sodium-chloride, and anhydrous sodium sulfate drying subtracts
Pressure concentration is dry, obtains compound I-4-1 (0.63g, white solid).
Step 2：0.63g compounds I-4-1 is dissolved in 20mlDCM, 3.5ml trifluoroacetic acids are added, 30 DEG C are reacted 1.0h, instead
After answering.PH=7-8, liquid separation will be adjusted with saturated sodium bicarbonate aqueous solution, water phase is stripped 20ml*2 with DCM, merges organic
Phase, organic phase washed once with saturated sodium-chloride, and dry, column chromatography (eluant, eluent DCM is concentrated under reduced pressure in anhydrous sodium sulfate drying：
MeOH it) purifies, obtains compound I-4 (0.22g, white solid, [M+H]+=987.4).
Embodiment 5
Step 1：100mg compounds I-4 is dissolved in 10ml DCM, 200mg triethylamines are added, is cooled to -10 DEG C, is added dropwise
The dichloromethane solution of 132mg/2ml DCM acryloyl chlorides instills in reaction solution, 0.5h is reacted after being added dropwise, reaction terminates
Afterwards.20ml water, liquid separation are added into reaction solution, water phase is stripped 20ml*2 with DCM, merges organic phase, organic phase saturation chlorination
Sodium washed once, and dry, column chromatography (eluant, eluent DCM is concentrated under reduced pressure in anhydrous sodium sulfate drying：MeOH it) purifies, obtains compound I-5
(25mg, white solid).
Embodiment 6
Step 1：150mg compounds I-2-2 is dissolved in 10ml DMF, sequentially adds 58mg compounds 5,95mg HBTU and
32mg DIEA react at room temperature 1.0h, after reaction.Reaction solution is poured into 100ml water, is extracted with ethyl acetate
(40ml*2) merges organic phase, and organic phase washed once with saturated sodium-chloride, and anhydrous sodium sulfate drying is concentrated under reduced pressure and does, must change
Object I-6-1 (200mg, yellow oil) is closed, is directly thrown in next step；
Step 2：200mg compounds I-6-1 is dissolved in 20ml DCM, 4ml trifluoroacetic acids are added, react 1.0h at 30 DEG C,
After reaction.PH=7-8, liquid separation are adjusted with saturated sodium bicarbonate aqueous solution, water phase is stripped (20ml*2) with DCM, is associated with
Machine phase, organic phase washed once with saturated sodium-chloride, and dry, column chromatography (DCM is concentrated under reduced pressure in anhydrous sodium sulfate drying：MeOH) pure
Change, obtains compound I-6 (80mg, white solid, [M+H]+=1009.7).
Embodiment 7
Step 1：500mg compounds I-2-2 is dissolved in 15ml DMF, sequentially adds 330mg compounds 6,320mg HBTU
And 110mg DIEA, 2.0h is reacted at room temperature, after reaction.Reaction solution is poured into 150ml water, is extracted with ethyl acetate
(50ml*2) merges organic phase, and organic phase washed once with saturated sodium-chloride, and dry, column layer is concentrated under reduced pressure in anhydrous sodium sulfate drying
Analyse (eluant, eluent DCM：MeOH it) purifies, obtains compound I-7-1 (210mg, off-white powder)；
Step 2：210mg compounds I-7-1 is dissolved in 20ml DCM, 4ml trifluoroacetic acids are added, react 1.0h at 30 DEG C,
After reaction.PH=7-8, liquid separation are adjusted with saturated sodium bicarbonate aqueous solution, water phase is stripped (20mlX2) with DCM, is associated with
Machine phase, organic phase washed once with saturated sodium-chloride, and dry, column chromatography (DCM is concentrated under reduced pressure in anhydrous sodium sulfate drying：MeOH) pure
Change, obtains compound I-7 (60mg, white solid, [M+H]+=933.6).
Embodiment 8
Step 1：1.29g compounds I-2-1 is dissolved in 45ml DMF, sequentially adds 240mg compounds 7,840mg HBTU
And 286mg DIEA, 2.5h is reacted at room temperature, after reaction.9ml piperidines is added into reaction solution, reacts at room temperature 0.5h, reaction
After.Reaction solution is poured into 500ml water, is extracted with ethyl acetate (50ml*2), organic phase, organic phase saturation are merged
NaCl is primary, and anhydrous sodium sulfate drying is concentrated under reduced pressure and does, obtains compound I-8-1 (680mg, off-white powder)；
Step 2：680mg compounds I-8-1 is dissolved in 15ml DMF, sequentially adds 330mg Boc-N- the-the third ammonia of methyl DL
Acid, 403mg HBTU and 136mg DIEA react at room temperature 2.0h, after reaction.Reaction solution is poured into 150ml water, is used
Ethyl acetate extracts (50ml*2), merges organic phase, and organic phase washed once with saturated sodium-chloride, and anhydrous sodium sulfate drying subtracts
Pressure concentration is dry, obtains compound I-8-2 (800mg, off-white powder), directly throws in next step；
Step 3：800mg compounds I-8-2 is dissolved in 30ml DCM, 6ml trifluoroacetic acids are added, react 1.0h at 30 DEG C,
After reaction.PH=7-8, liquid separation are adjusted with saturated sodium bicarbonate aqueous solution, water phase is stripped (20mlX2) with DCM, is associated with
Machine phase, organic phase washed once with saturated sodium-chloride, and dry, column chromatography (DCM is concentrated under reduced pressure in anhydrous sodium sulfate drying：MeOH) pure
Change, obtains compound I-8 (30mg, white solid, [M+H]+=923.3).
Embodiment 9
Step 1：1.29g compounds I-2-1 is dissolved in 45ml DMF, sequentially adds 605mg compounds 8,840mg HBTU
And 286mg DIEA, 2.5h is reacted at room temperature, after reaction.9ml piperidines is added into reaction solution, reacts at room temperature 0.5h, reaction
After.Reaction solution is poured into 500ml water, is extracted with ethyl acetate (50ml*2), organic phase, organic phase saturation are merged
NaCl is primary, and anhydrous sodium sulfate drying is concentrated under reduced pressure and does, obtains compound I-9-1 (1.6g, off-white powder)；
Step 2：1.6g compounds I-9-1 is dissolved in 25ml DMF, sequentially adds 330mg Boc-N- the-the third ammonia of methyl DL
Acid, 403mg HBTU and 136mg DIEA react at room temperature 2.0h, after reaction.Reaction solution is poured into 250ml water, is used
Ethyl acetate extracts (80ml*2), merges organic phase, and organic phase washed once with saturated sodium-chloride, and anhydrous sodium sulfate drying subtracts
Pressure concentration is dry, obtains compound I-9-2 (750mg, off-white powder), directly throws in next step；
Step 3：750mg compounds I-9-2 is dissolved in 30ml DCM, 6ml trifluoroacetic acids are added, react 1.0h at 30 DEG C,
After reaction.PH=7-8, liquid separation are adjusted with saturated sodium bicarbonate aqueous solution, water phase is stripped (20mlX2) with DCM, is associated with
Machine phase, organic phase washed once with saturated sodium-chloride, and dry, column chromatography (DCM is concentrated under reduced pressure in anhydrous sodium sulfate drying：MeOH) pure
Change, obtains compound I-9 (45mg, white solid, [M+H]+=1116.5).
Embodiment 10
Step 1：2.55g benzhydrylamines are dissolved in 25ml DMF, sequentially add 10.20g Fmoc-Cys (Trt)-OH,
9.65g HBTU and 3.38g DIEA are stirred at room temperature reaction 2h, TLC and detect (PE:EA=2:1) to raw material, the reaction was complete.To anti-
Addition 5ml piperidines in liquid is answered, reaction is stirred at room temperature, TLC detects (PE:EA=2:1) to raw material, the reaction was complete.Reaction solution is poured into
It in 250ml water, is extracted with ethyl acetate 2 times (50ml*2), merges organic phase, be used in combination saturated sodium-chloride washed once, anhydrous sulphur
Sour sodium drying, is concentrated under reduced pressure dry.Residue column chromatography (eluant, eluent DCM:MeOH) purify, obtain compound I-10-1 (7.76g, it is light
Yellow solid)；
Step 2：7.75g compounds I-10-1 is dissolved in 25ml DMF, sequentially adds 5.32g Fmoc- proline, 8.13g
HBTU and 2.75g DIEA are stirred at room temperature reaction 3h, TLC and detect (PE:EA=2:1) to raw material, the reaction was complete.Into reaction solution
5ml piperidines is added, reaction 0.5h, TLC is stirred at room temperature and detects (PE:EA=2:1) the reaction was complete for raw material.Reaction solution is poured into
It in 250ml water, is extracted with ethyl acetate 2 times (50ml*2), merges organic phase, be used in combination saturated sodium-chloride washed once, anhydrous sulphur
Sour sodium drying, is concentrated under reduced pressure dry.Residue column chromatography (eluant, eluent DCM：MeOH) purify, obtain compound I-10-2 (7.4g, it is yellowish
Color solid)；
Step 3：6.9g compounds I-10-2 is dissolved in 25ml DMF, sequentially adds 4.47g Fmoc- Cyclohexylglycines,
6.73g HBTU and 2.27g DIEA, react at room temperature 2h, and TLC detects (PE:EA=1:1) the reaction was complete for raw material, then to reaction
5ml piperidines is added in liquid, reacts at room temperature 0.5h, TLC detects (solvent PE:EA=1:1), the reaction was complete for raw material.By reaction solution
It pours into 500ml water, is extracted with ethyl acetate 2 times (100ml*2), merge organic phase, be used in combination saturated sodium-chloride washed once, nothing
Aqueous sodium persulfate is dried, and is concentrated under reduced pressure dry.Residue is through column chromatography (eluant, eluent DCM：MeOH it) purifies, obtains compound I-10-3
(6.85g, yellow solid)；
Step 4：6.85g compounds I-10-3 is dissolved in 20ml DMF, sequentially adds 4.10g N2-Fmoc-N3-Boc-D-
2.3- diaminopropionic acids, 5.4g HBTU and 1.85g DIEA react at room temperature 2h, and TLC detects (PE:EA=1:1) it is reacted to raw material
Completely, 4ml piperidines is added into reaction solution, reaction 0.5h, TLC is stirred at room temperature and detects (PE:EA=1:1) it has been reacted to raw material
Entirely, reaction solution is poured into 200ml water, is extracted with ethyl acetate 2 times (50ml*2), merged organic phase, saturated sodium-chloride is used in combination
It washed once, anhydrous sodium sulfate drying is concentrated under reduced pressure dry.Residue column chromatography (eluant, eluent DCM：MeOH it) purifies, obtains compound
I-10-4 (7.21g, off-white powder)；
Step 5：7.21g compounds I-10-4 is dissolved in 30ml DMF, sequentially adds 4.62g Fmoc-S- trityls-
L-cysteine, 4.48g HBTU and 1.53g DIEA are stirred at room temperature reaction 2h, TLC and detect (PE:EA=2:1) anti-to raw material
It should be complete.Reaction solution is poured into 300ml water, is extracted with ethyl acetate 2 times (50ml*2), organic phase is merged, saturation chlorine is used in combination
Change sodium washed once, anhydrous sodium sulfate drying is concentrated under reduced pressure dry.Residue column chromatography (eluant, eluent PE：EA it) purifies, obtains compound
I-10-5 (8.46g white solids)；
Step 6：2.8g compounds I-10-5 is dissolved in 200ml DCM, 4.80g iodines/1L (DCM are added dropwise in room temperature:
MeOH=10:1) mixed solvent, the reaction was continued 0.5h after being added dropwise, TLC detect (PE:EA=1:1) it has been reacted to raw material
Entirely.It is added dropwise to saturated aqueous sodium sulfite into reaction solution to be quenched, 500ml water, liquid separation, water phase back extraction are added into reaction solution
It takes once, merges organic phase, organic phase washed once with saturated sodium-chloride, and anhydrous sodium sulfate drying is concentrated under reduced pressure dry.Residue
Column chromatography (eluant, eluent PE：EA it) purifies, obtains compound I-10-6 (1.52g, white solid)；
Step 7：1.0g compounds I-10-6 is dissolved in 40ml DCM, 8ml trifluoroacetic acids are added, reacts at room temperature 1.5h, instead
After answering, pH=7-8 is adjusted with saturated sodium bicarbonate aqueous solution, liquid separation, water phase is primary with 40ml DCM back extraction, merges organic
Phase, organic phase washed once with saturated sodium-chloride, and anhydrous sodium sulfate drying is concentrated under reduced pressure and does, obtains compound I-10-7 (800mg
White solid), it directly throws in next step；
Step 8：800mg compounds I-10-7 is dissolved in 20ml DMF, sequentially adds 588mg compounds 8,507mg HBTU
And 172mg DIEA, reaction 2h is stirred at room temperature, after reaction, 4ml piperidines is added into reaction solution, reaction is stirred at room temperature
0.5h after reaction pours into reaction solution in 150ml water, is extracted with ethyl acetate (50ml*2), merges organic phase, is used in combination
Saturated sodium-chloride washed once, and anhydrous sodium sulfate drying is concentrated under reduced pressure dry.Residue column chromatography (eluant, eluent PE：EA it) purifies, obtains
Compound I-10-8 (778mg white solids)；
Step 8：778mg compounds I-10-8 is dissolved in 20ml DMF, sequentially adds 173mg Boc-N- methyl DLs-the third
Propylhomoserin, 403mg HBTU and 137mg DIEA are stirred at room temperature reaction 2h and after reaction pour into reaction solution in 200ml water,
It is extracted with ethyl acetate (50ml*2), merges organic phase, saturated sodium-chloride is used in combination to washed once, anhydrous sodium sulfate drying, decompression
Concentration is dry.Residue column chromatography (eluant, eluent PE：EA it) purifies, obtains compound I-10-9 (726mg, white solid)；
Step 9：726mg compounds I-10-9 is dissolved in 40ml DCM, 8ml trifluoroacetic acids are added, reacts at room temperature 1.5h, instead
After answering, pH=7-8 is adjusted with saturated sodium bicarbonate aqueous solution, liquid separation, water phase is primary with 40ml DCM back extraction, merges organic
Phase, organic phase washed once with saturated sodium-chloride, and anhydrous sodium sulfate drying is concentrated under reduced pressure and does, and obtain compound I-10 (28mg whites
Solid).
Embodiment 11
Step 1：1.2g compounds I-1-2 is dissolved in 25ml DMF, sequentially adds 1.0g Fmoc- valines, 1.10g
HBTU and 0.38g DIEA, react at room temperature 2h, and TLC detects (PE:EA=1:1) the reaction was complete for raw material, then adds into reaction solution
Enter 5ml piperidines, react at room temperature 0.5h, TLC detects (solvent PE:EA=1:1), the reaction was complete for raw material.Reaction solution is poured into
It in 500ml water, is extracted with ethyl acetate 2 times (100ml*2), merges organic phase, be used in combination saturated sodium-chloride washed once, anhydrous sulphur
Sour sodium drying, is concentrated under reduced pressure dry.Residue is through column chromatography (eluant, eluent DCM：MeOH) purify, obtain compound I-11-1 (1.15g,
White solid)；
Step 2：1.15g compounds I-11-1 is dissolved in 20ml DMF, sequentially adds 1.0g N2-Fmoc-N3-Boc-D-
2.3- diaminopropionic acids, 0.9g HBTU and 0.3g DIEA react at room temperature 2h, and TLC detects (PE:EA=1:1) it is reacted to raw material
Completely, 4ml piperidines is added into reaction solution, reaction 0.5h, TLC is stirred at room temperature and detects (PE:EA=1:1) it has been reacted to raw material
Entirely, reaction solution is poured into 200ml water, is extracted with ethyl acetate 2 times (50ml*2), merged organic phase, saturated sodium-chloride is used in combination
It washed once, anhydrous sodium sulfate drying is concentrated under reduced pressure dry.Residue column chromatography (eluant, eluent DCM：MeOH it) purifies, obtains compound
I-11-2 (1.15g, off-white powder)；
Step 3：1.15g compounds I-11-2 is dissolved in 30ml DMF, sequentially adds 1.1g Fmoc-S- trityls-L-
Cysteine, 0.72g HBTU and 0.24g DIEA are stirred at room temperature reaction 2h, TLC and detect (PE:EA=2:1) it is reacted to raw material
Completely.Reaction solution is poured into 300ml water, is extracted with ethyl acetate 2 times (50ml*2), organic phase is merged, saturation chlorination is used in combination
Sodium washed once, and anhydrous sodium sulfate drying is concentrated under reduced pressure dry.Residue column chromatography (eluant, eluent PE：EA it) purifies, obtains compound I-
11-3 (1.56g white solids)；
Step 4：1.56g compounds I-11-3 is dissolved in 200ml DCM, 2.70g iodines/500ml is added dropwise in room temperature
(DCM:MeOH=10:1) mixed solvent, the reaction was continued 0.5h after being added dropwise, TLC detect (PE:EA=1:1) anti-to raw material
It should be complete.It is added dropwise to saturated aqueous sodium sulfite into reaction solution to be quenched, 500ml water, liquid separation, water phase are added into reaction solution
Back extraction is primary, merges organic phase, and organic phase washed once with saturated sodium-chloride, and anhydrous sodium sulfate drying is concentrated under reduced pressure dry.It is residual
Stay object column chromatography (eluant, eluent PE：EA it) purifies, obtains compound I-11-4 (0.52g, white solid)；
Step 5：520mg compounds I-11-4 is dissolved in 20ml DCM, 4ml trifluoroacetic acids are added, reacts at room temperature 1.5h, instead
After answering, pH=7-8 is adjusted with saturated sodium bicarbonate aqueous solution, liquid separation, water phase is primary with 40ml DCM back extraction, merges organic
Phase, organic phase washed once with saturated sodium-chloride, anhydrous sodium sulfate drying, be concentrated under reduced pressure it is dry, obtain compound I-11-5 (420mg,
White solid)；
Step 6：420mg compounds I-11-5 is dissolved in 10ml DMF, sequentially adds 143mg N-Boc-2- methyl-prop ammonia
Acid, 267mg HBTU and 91mg DIEA react at room temperature 1.0h, and TLC detects (DCM：MeOH=15:1) to raw material, the reaction was complete.
2ml piperidines is added into reaction solution, reaction 0.5h, TLC is stirred at room temperature and detects (PE:EA=1:1) to raw material, the reaction was complete, will be anti-
It answers liquid to pour into 400ml water, 80ml*2 is extracted with ethyl acetate, merge organic phase, organic phase washed once with saturated sodium-chloride,
Anhydrous sodium sulfate is dried, and is concentrated under reduced pressure dry.Residue column chromatography (eluant, eluent DCM：MeOH it) purifies, obtains compound I-11-6
(322mg, white solid)；
Step 7：322mg compounds I-11-6 is dissolved in 10ml DCM, 100mg triethylamines are added, is cooled to -10 DEG C, drop
Add the dichloromethane solution of 70mg/2ml DCM acryloyl chlorides, instills in reaction solution, 0.5h is reacted after being added dropwise, reaction terminates
Afterwards.20ml water, liquid separation are added into reaction solution, water phase is stripped 20ml*2 with DCM, merges organic phase, organic phase saturation chlorination
Sodium washed once, and dry, column chromatography (eluant, eluent DCM is concentrated under reduced pressure in anhydrous sodium sulfate drying：MeOH it) purifies, obtains compound I-11-
7 (250mg, white solids)；
Step 8：250mg compounds I-11-7 is dissolved in 10ml DCM, 2ml trifluoroacetic acids are added, reacts at room temperature 1.5h, instead
After answering, pH=7-8 is adjusted with saturated sodium bicarbonate aqueous solution, liquid separation, water phase is primary with 20ml DCM back extraction, merges organic
Phase, organic phase washed once with saturated sodium-chloride, and anhydrous sodium sulfate drying is concentrated under reduced pressure and does, and obtain compound I-11 (35mg whites
Solid).
With reference to the preparation method example of above compound, under suitable solvent and reaction temperature, by series reaction system
Standby obtained compound carries out nuclear-magnetism and mass spectrometric measurement and HPLC detections, and it is shown that test result is as follows.
Biological assessment
Embodiment 1.1 detects IC50 value of the compounds of this invention to XIAP BIR3 and cIAP1BIR3
BIR3 structural regions (10nM) are with Smac polypeptides (10nM) in assay buffer in the presence of testing compound
Incubation at room temperature 1h in (50mMTris, 120mM NaCl, 0.1%BSA, 1mM DTT, 0.05%TritonX100).Its mixture
It is transferred to the plate of Streptavidin coating, then incubation at room temperature 1h, the peptide that biotin links is allowed to be combined with BIR3 structural regions
Onto plate.After washing several times, anti-GST antibody (Perkin Elmer DELFIA the Eu-N1- anti-GST, # of Eu- labels
AD0250 it) is added in each hole and (carries out 1 with Perkin Elmer DELFIA assay buffers 2013-01:5000 dilutions), so
Incubation at room temperature 1h afterwards.After DELFIA cleaning buffer solutions (Perkin Elmer DELFIA Wash 2013-05) wash 3 times, add increasing
Strong liquid (Perkin Elmer enhancement solution 2013-02), hatches 10min, then the intensity of detection time resolved fluorometric europium, uses
5.0 softwares of GraphPad Prizm calculate the IC50 values that compound inhibits.
It is thin to Breast cancer lines MDA-MB-231 cells and prostate cancer that embodiment 1.2 detects the compounds of this invention
The cytotoxicity IC50 values of born of the same parents' strain PC-3 cells
Exponential phase cell is collected first, is counted, with complete medium again suspension cell, adjustment cell concentration to conjunction
Suitable concentration (being determined according to cell density optimization test result), is inoculated with 96 orifice plates, adds 100 μ l cell suspensions per hole.Cell is 37
DEG C, 100% relative humidity, 5%CO2It is incubated 24 hours in incubator.Untested compound is diluted to culture medium set
Cell is added by 25 holes μ l/ in respective action concentration.Compound effects final concentration is since 100 μM, 4 times of gradient dilutions, totally 10
Concentration point.Cell is placed in 37 DEG C, 100% relative humidity, 5%CO2It is incubated 72 hours in incubator.It is directly added into the CCK- of 10 μ l
8 in cell culture medium, is placed in 37 DEG C of incubators and is incubated 2-4 hours.In SpectraMax M5 after gently shaking
Absorbance is measured on Microplate Reader, calculates inhibiting rate.
Biological assessment experimental result can be seen that the compounds of this invention has very strong inhibitory activity to cIAP1 and XIAP,
Moreover, the compounds of this invention can inhibit breast cancer cell MDA-MB-231 and prostate gland cancer cell PC-3 very much by force.
Claims (9)
1. a kind of compound or its pharmaceutically acceptable salt, isomers or prodrug, it is characterised in that the compound has logical
Formula (I)：
Wherein,
R1Group is selected fromAny one；R2And R3Base
Group each independently arbitrarily selected from H,
In one kind, wherein the X represents halogen；
R4Group represents
2. compound as described in claim 1 and its pharmaceutically acceptable salt, isomers or prodrug, it is characterised in that X is
F。
3. compound as described in claim 1 and its pharmaceutically acceptable salt, isomers or prodrug, it is characterised in that R2Base
Group represents
4. compound as described in claim 1 or its pharmaceutically acceptable salt, isomers or prodrug, it is characterised in that R3Base
Group represents
5. compound as described in claim 1 or its pharmaceutically acceptable salt, isomers or prodrug, it is characterised in that the change
Object is closed to be selected from：
6. a kind of pharmaceutical composition, it is characterised in that can be connect containing Claims 1 to 5 any one of them compound or its pharmacy
Salt, isomers or the prodrug received are as active constituent and one or more pharmaceutically acceptable carriers, diluent or tax
Type agent.
7. being made according to Claims 1 to 5 any one of them compound or its pharmaceutically acceptable salt, isomers or prodrug
It is standby in mammal with the application in the drug of the relevant disease of IAP protein overexpressions.
8. application according to claim 7, wherein described be selected from cancer with the relevant diseases of IAP.
9. application according to claim 8, wherein the cancer is selected from neuroblastoma, intestinal cancer, cancer of the esophagus, lip
Cancer, laryngocarcinoma, hypopharyngeal cancer, tongue cancer, salivary-gland carcinoma, gastric cancer, gland cancer, medullary carcinoma of thyroid gland, papillary thyroid carcinoma, kidney, kidney are real
Matter cancer, oophoroma, cervix cancer, carcinoma of uterine body, carcinoma of endometrium, choriocarcinoma, cancer of pancreas, prostate cancer, testicular cancers, mammary gland
Cancer, urinary system cancer, melanoma, brain tumor such as glioblastoma, astrocytoma, meningioma, medulloblastoma and surrounding
Neuroectodermal tumor, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphatic leukemia, chronic leaching
Bar property leukaemia, acute myeloid leukaemia, chronic myelogenous leukemia, Adult T-cell leukemia's lymthoma, hepatocellular carcinoma, gall-bladder
Cancer, bronchiolar carcinoma, Small Cell Lung Cancer, non-small cell lung cancer, Huppert's disease, basal cell tumor, teratoma, retina are female thin
Born of the same parents' tumor, choroidal melanoma, seminoma, rhabdomyosarcoma, cranium pharynx tumor, osteosarcoma, chondrosarcoma, muscle tumor, fatty meat
Tumor, fibrosarcoma, Ewing's sarcoma and plasmacytoma, cancer of pancreas or chromoma.
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| CN110028508A (en) * | 2019-05-16 | 2019-07-19 | 南京华威医药科技集团有限公司 | A kind of antitumor diazo bicyclic class apoptosis protein inhibitor |
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