CN109096219A - A kind of novel anti-PD-L1 compound, its application and the composition containing it - Google Patents
A kind of novel anti-PD-L1 compound, its application and the composition containing it Download PDFInfo
- Publication number
- CN109096219A CN109096219A CN201710470219.1A CN201710470219A CN109096219A CN 109096219 A CN109096219 A CN 109096219A CN 201710470219 A CN201710470219 A CN 201710470219A CN 109096219 A CN109096219 A CN 109096219A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- alkoxy
- compound
- butyl
- prodrug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
Abstract
The invention discloses a kind of novel anti-PD-L1 compound, its application and containing its composition.The compound is compound shown in formula I, its pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug.The compound can be used in the drug for being prepared into treatment and/or pre- preventing tumor.
Description
Technical field
The invention belongs to biomedicine fields, are related to the novel anti-PD-L1 compound of one kind, its application and the combination containing it
Object.
Background technique
PD-1/PD-L1 signal path is most popular one of the topic for the treatment of of cancer instantly and research field.Nearly 2 years granted
The immunotherapy new drug of listing leads to as the Keytruda of the Mo Shadong and Opdivo of Bristol Myers Squibb has aimed at this signal
Road prevents signal from transmitting using monoclonal antibody combination PD-1 receptor, so that the immune system of body itself be activated to attack tumour expansion
It hits.Both new drugs are granted for treating the cancers such as melanoma, while in the clinical test for being directed to some other cancer
In also show huge potentiality.In addition, Tecentriq (Atezolizumab, MPDL3280A) is the first of FDA approval
A PD-L1 inhibitor, the indication of granted bladder cancer and non-small cell lung cancer.But, monoclonal antibody class drug was up to 15-20 days
Half-life period is likely to cause side effect relevant to immune response.And PD-1/PD-L1 monoclonal antibody medicine needs vein to infuse at present
It penetrates, and bad to the therapeutic activity of solid tumor.
Thus, the novel PD-L1 inhibitor medicaments for developing safer, efficient treatment tumour have huge social valence
Value and economic benefit, and the research hotspot of major pharmaceutical manufacturer at present.
Summary of the invention
The technical problem to be solved by the present invention is in order to overcome existing PD-1/PD-L1 monoclonal antibody medicine need intravenous injection,
And the defects of bad to the therapeutic activity of solid tumor, and provide the novel anti-PD-L1 compound of one kind, its application and the group containing it
Object is closed, which is PD-L1 inhibitor, structure novel, Orally-administrable, treatment and/or prevention for tumour.
The present invention provides a kind of compound shown in formula I (its can anti-programmed death receptors ligand 1, that is, be used as PD-
L1 inhibitor), its pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer or
Prodrug；
Wherein, the R1For hydrogen, C1-6Alkyl (such as C1-4Alkyl；The C1-4Alkyl such as methyl, ethyl, positive third
Base, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl) or C1-6Alkoxy (such as C1-4Alkoxy；The C1-4Alkane
Oxygroup such as methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tertiary fourth oxygen
Base)；
The R2For hydrogen, halogen (such as fluorine, chlorine or bromine), hydroxyl, amino, by R2-1Substituted or unsubstituted C1-6Alkyl
(" the C1-6Alkyl " such as C1-4Alkyl；The C1-4Alkyl for example methyl, ethyl, n-propyl, isopropyl, normal-butyl,
Isobutyl group, sec-butyl or tert-butyl；The R2-1Number be one or more such as 2,3,4 or 5；When depositing
In multiple R2-1When, they are identical or different) or by R2-2Substituted or unsubstituted C1-6The alkoxy (" C1-6Alcoxyl
Base " such as C1-4Alkoxy；The C1-4Alkoxy for example methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy,
Isobutoxy, sec-butoxy or tert-butoxy；The R2-2Number be it is one or more < such as 2,3,4 or 5
>；When there are multiple R2-2When, they are identical or different)；
All R2-1And R2-2It independently is hydroxyl, halogen (such as fluorine, chlorine or bromine) or nitro；
The R3For hydrogen, halogen (such as fluorine, chlorine or bromine), hydroxyl, amino, by R3-1Substituted or unsubstituted C1-6Alkyl
(" the C1-6Alkyl " such as C1-4Alkyl；The C1-4Alkyl for example methyl, ethyl, n-propyl, isopropyl, normal-butyl,
Isobutyl group, sec-butyl or tert-butyl；The R3-1Number be one or more such as 2,3,4 or 5；When depositing
In multiple R3-1When, they are identical or different) or by R3-2Substituted or unsubstituted C1-6The alkoxy (" C1-6Alcoxyl
Base " such as C1-4Alkoxy；The C1-4Alkoxy for example methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy,
Isobutoxy, sec-butoxy or tert-butoxy；The R3-2Number be it is one or more < such as 2,3,4 or 5
>；When there are multiple R3-2When, they are identical or different)；
All R3-1And R3-2Independently be hydroxyl, halogen (such as fluorine, chlorine or bromine), nitro orIt is all
R3-1-1It independently is hydrogen, hydroxyl, halogen (such as fluorine, chlorine or bromine), C1-6Alkyl (such as C1-4Alkyl；The C1-4Alkyl example
Such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl) or C1-6Alkoxy (such as C1-4Alkane
Oxygroup；The C1-4Alkoxy such as methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, secondary
Butoxy or tert-butoxy)；
The R4For hydrogen or C1-6Alkyl (such as C1-4Alkyl；The C1-4Alkyl such as methyl, ethyl, n-propyl, different
Propyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl)；
The R5For hydrogen or C1-6Alkyl (such as C1-4Alkyl；The C1-4Alkyl such as methyl, ethyl, n-propyl, different
Propyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl)；
The m is 1,2 or 3；
The L is
It is describedInRefer to it for singly-bound or double bond, when it is singly-bound, X is-O- or-NH-, when it is
When double bond, X is=N-；
It is describedInRefer to it for singly-bound or double bond, when it is singly-bound, Y is-O- or-NH-, when it is
When double bond, Y is=N-.
As a result, throughout this manual, those skilled in the art can be to R described in compound shown in Formulas I1~R5And L
Group and its substituent group selected, with provide compound shown in the Formulas I described in the embodiment of the present invention, stable or its
Pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug.
It will be understood by those skilled in the art that according to convention used in the art, in the structural formula of the application,
For describing chemical bond, the chemical bond is part or the point that substituent group, core structure or skeleton structure are connected.
As a result, throughout this manual, those skilled in the art can be to the group of LIt is selected,
To provide compound shown in the Formulas I described in the embodiment of the present invention, stable or its stereoisomer, tautomer, generation
Thank product, pharmaceutically acceptable salt, hydrate, solvate or prodrug.
In the present invention, the stereoisomer include enantiomter, diastereoisomer and enantiomter or
The mixture of diastereoisomer.
It is described in a certain technical solutionFor
It is described in a certain technical solutionFor
It is described in a certain technical solutionFor
It is described in a certain technical solutionFor
In a certain technical solution, the definition of group (can not annotate as defined above as described below in the compound I
It is any described):
The R1For hydrogen.
In a certain technical solution, the definition of group (can not annotate as defined above as described below in the compound I
It is any described):
The R2For C1-6Alkyl.
In a certain technical solution, the definition of group (can not annotate as defined above as described below in the compound I
It is any described):
The R3For amino.
In a certain technical solution, the definition of group (can not annotate as defined above as described below in the compound I
It is any described):
The R4For hydrogen.
In a certain technical solution, the definition of group (can not annotate as defined above as described below in the compound I
It is any described):
The R5For hydrogen.
In a certain technical solution, the definition of group (can not annotate as defined above as described below in the compound I
It is any described):
M is 1 or 2.
In a certain technical solution, the definition of group (can not annotate as defined above as described below in the compound I
It is any described):
It is describedFor
In a certain technical solution, the compound I can be following any structure:
Compound of formula I of the present invention can be prepared according to the chemical synthesis process of this field routine, step and item
Part can refer to this field similar the step of reacting and condition.
If wanting to obtain the chiral purity compound of compound of formula I of the present invention, method commonly used in the art, example can be used
It is normal using this field as used chiral induction in the synthesis process, or after obtained target compound stereoisomer mixture
The chiral resolution column or chemical resolution method of rule are split, to obtain the compound of formula I of the invention of chiral purity.
Reaction dissolvent used in each reaction step of the present invention is not particularly limited, any to a certain extent
It dissolves starting material and the solvent of reaction is not inhibited to be included in the present invention.In addition, many similar changes of this field, etc.
With replacement, or it is equal to solvent described in the invention, the different proportion of solvent combination and solvent combination is accordingly to be regarded as the present invention
Scope.
The present invention also provides a kind of pharmaceutical compositions comprising the compound of formula I, its pharmaceutically acceptable salt,
Hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug and pharmaceutic adjuvant.
In the pharmaceutical composition, the compound of formula I, its pharmaceutically acceptable salt, hydrate, solvation
The dosage of object, metabolite, stereoisomer, tautomer or prodrug can be therapeutically effective amount.
The pharmaceutic adjuvant can be for auxiliary material those of be widely used in drug production field.Auxiliary material is mainly used for offer one
A safe and stable and functional pharmaceutical composition, can be with providing method, and active constituent is after so that subject is received administration with institute
Expected rate dissolution, or promote subject to receive active constituent after composition is administered and effectively absorbed.The pharmaceutic adjuvant
Can be inert filler, or certain function be provided, for example, stable the composition whole pH value or prevent composition active
The degradation of ingredient.The pharmaceutic adjuvant may include one of following auxiliary material or a variety of: adhesive, suspending agent, emulsifier,
Diluent, filler, granulating agent, adhesive, disintegrating agent, lubricant, antitack agent, glidant, wetting agent, gelling agent, absorption
Delayed-action activator, dissolution inhibitor, reinforcing agent, adsorbent, buffer, chelating agent, preservative, colorant, corrigent and sweetener.
Pharmaceutical composition of the invention can according to disclosure using any method well known by persons skilled in the art come
Preparation.For example, conventional mixing, dissolution, granulation, emulsification, levigate, encapsulating, embedding or lyophilized technique.
Pharmaceutical composition of the present invention can be administered in any form, including injection (intravenous), mucous membrane, it is oral (Gu
Body and liquid preparation), sucking, eye, rectum, part or it is parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial,
It is intramuscular) administration.Pharmaceutical composition of the invention can also be controlled release or delayed release dosage forms (such as liposome or microballoon).Solid
The example of oral preparation includes but is not limited to powder, capsule, caplet, soft capsule and tablet.Oral or mucosa delivery liquid
Formulation examples include but is not limited to suspension, lotion, elixir and solution.The example of topical preparation include but is not limited to emulsion,
Gelling agent, ointment, cream, patch, paste, foaming agent, lotion, drops or serum preparation.The preparation of parenteral is real
Example including but not limited to injection solution, the dry preparation that can be dissolved or suspended in pharmaceutically acceptable carrier, injection is outstanding
Supernatant liquid and emulsion for injection.The example of other appropriate formulations of the pharmaceutical composition includes but is not limited to eye drops and other
Ophthalmic preparation；Aerosol: such as nasal mist or inhalant；Liquid dosage form suitable for parenteral；Suppository and pastille.
The present invention also provides the compound of formula I, its pharmaceutically acceptable salt, hydrate, solvate, metabolism to produce
Object, stereoisomer, tautomer or prodrug are preparing the application in PD-L1 inhibitor.
The PD-L1 inhibitor can be used in organism；It can also be used in vitro, mainly as experimental use, example
Such as: providing comparison as standard sample or control sample, or kit is made according to conventional method in that art, the inhibition for being PD-L1 is imitated
Fruit provides quickly detection.
The present invention also provides the compound of formula I, its pharmaceutically acceptable salt, hydrate, solvate, metabolism to produce
Object, stereoisomer, tautomer or prodrug, the application in the drug of preparation treatment and/or pre- preventing tumor.
The tumour can be cancer.The cancer include but is not limited to non-small cell lung cancer, melanoma, advanced stage suddenly
Odd gold lymthoma, liver cancer, oophoroma or breast cancer.
The tumour can be tumour related with PD-L1 activity.The described tumour related with PD-L1 activity can for
The related cancer of PD-L1 activity.The related cancer with PD-L1 activity includes but is not limited to non-small cell lung cancer, black
Plain tumor, advanced stage Hodgkin lymphoma, liver cancer, oophoroma or breast cancer.
Unless otherwise prescribed, all technical terms and scientific terms used herein have claimed theme fields
Standard meaning.If to Mr. Yu's term, there are multiple definition, then to be defined herein as standard.When Referral URL or other identifier or
Address, it should be appreciated that such identifier can change, and the specific information on internet can change, but mutual by search
Networking can find same information.Reference this type of information can get and open propagate.
It should be understood that above-mentioned general explanation and following detailed description are merely illustrative of, to the present invention not by
This limitation.The singular being used in the present invention, as "an" or "one", including plural, unless otherwise prescribed.This
Outside, term " includes " is open limits and non-enclosed.
Unless otherwise indicated, the present invention using mass spectrum, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology or
The conventional method of pharmacology detection, each step and condition can refer to the operating procedure and condition of this field routine.Unless otherwise specified,
The present invention is using the standard name of analytical chemistry, Synthetic Organic Chemistry and medical chemistry and standard laboratory step and technology.?
In some cases, standard technique is used for chemical synthesis, chemical analysis, medicine preparation, formula and drug delivery and patient
Treatment.
Term " pharmaceutically acceptable " as used in the present invention is for those compounds, material, composition
And/or for dosage form, within the scope of reliable medical judgment, contacting suitable for the tissue with human and animal makes for they
With without excessive toxicity, irritation, allergic reaction or other problems or complication, with reasonable interests/Hazard ratio phase
Claim.
Term " pharmaceutically acceptable salt " refers to the salt of the compounds of this invention, by present invention discover that have specific substitution
It is prepared by the compound of base and the acid of relative nontoxic or alkali.It, can when in the compound of the present invention containing relatively acid functional group
To pass through the side for using the alkali of sufficient amount to contact with the neutral form of this kind of compound in pure solution or suitable atent solvent
Formula obtains base addition salts.Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salt.
It, can be by pure solution or suitable atent solvent when in the compound of the present invention containing relatively alkaline functional group
Acid-addition salts are obtained with the mode that the acid of sufficient amount is contacted with the neutral form of this kind of compound.Pharmaceutically acceptable acid addition
The example of salt includes inorganic acid salt, and the inorganic acid includes such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, phosphorus
A sour hydrogen radical, dihydrogen phosphate, sulfuric acid, bisulfate ion, hydroiodic acid, phosphorous acid etc.；And acylate, the organic acid include
As acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid,
Phthalic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, citric acid, the tartaric acid acid similar with methanesulfonic acid etc.；Further include amino acid (such as
Arginine etc.) salt, and such as glucuronic acid organic acid salt (referring to Berge et al., " Pharmaceutical
Salts",Journal of Pharmaceutical Science 66:1-19(1977)).Certain specificization of the invention
It closes object and contains alkalinity and acid functional group, so as to be converted into any alkali or acid-addition salts.Preferably, in a usual manner
It contacts salt with alkali or acid, then separates parent compound, thus the neutral form of raw compounds again.The parent fo of compound with
The form of its various salt is the difference is that certain physical properties, such as the different solubility in polar solvent.
" pharmaceutically acceptable salt " used in the present invention belongs to the derivative of the compounds of this invention, wherein by with acid
The parent compound is modified at the mode of salt at salt or with alkali.The example of pharmaceutically acceptable salt includes but is not limited to: alkali
The inorganic acid of base such as amine or the alkali metal of acylate, acid group such as carboxylic acid or organic salt etc..Pharmaceutically acceptable salt
Quaternary ammonium salt including conventional avirulent salt or parent compound, such as nontoxic inorganic acid or organic acid are formed by salt.
Conventional avirulent salt includes but is not limited to the salt that those are derived from inorganic acid and organic acid, the inorganic acid or organic acid
Selected from Aspirin, 2- ethylenehydrinsulfonic acid, acetic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, bicarbonate radical, carbonic acid,
Citric acid, edetic acid(EDTA), ethane disulfonic acid, ethane sulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic, hydrobromic acid,
Hydrochloric acid, hydriodate, hydroxyl naphthalene, isethionic acid, lactic acid, lactose, dodecyl sodium sulfonate, maleic acid, malic acid, mandelic acid, methane
Sulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, sub- acetic acid, succinic acid, ammonia
Base sulfonic acid, p-aminobenzene sulfonic acid, sulfuric acid, tannin, tartaric acid and p-methyl benzenesulfonic acid.
" pharmaceutically acceptable salt " of the invention can pass through conventional chemical by the parent compound containing acid group or base
Method synthesis.Under normal circumstances, the preparation method of such salt is: in the mixture of water or organic solvent or both, via
Free acid or these compounds of alkali form are reacted with the alkali appropriate of stoichiometry or acid to prepare.It is generally preferable that ether, second
The non-aqueous medias such as acetoacetic ester, ethyl alcohol, isopropanol or acetonitrile.
In addition to the form of salt, there is also prodrug forms for compound provided by the present invention.Compounds described herein
Chemical change easily occurs in physiological conditions for prodrug to be converted to the compound of the present invention.It can convert in vivo to provide
Any compound of bioactive substance (i.e. compound shown in Formulas I) is the prodrug in the scope and spirit of the present invention.For example,
Compound containing carboxyl can hydrolyzable ester on physiology, by being hydrolyzed in vivo to obtain compound sheet shown in Formulas I
Body and serve as prodrug.The prodrug is preferably administered orally, this is because hydrolysis is in many cases mainly in the influence of digestive ferment
Lower generation.When ester itself is active or hydrolysis occurs in blood, parenteral administration can be used.In addition, pro-drug can
To be switched to the compound of the present invention by chemistry or biochemical method in environment in vivo.
Certain compounds of the invention can exist with nonsolvated forms or solvation form, including hydrate form.
In general, solvation form is suitable with non-solvated form, it is intended to be included within the scope.Of the invention is certain
Compound can exist with polycrystalline or amorphous form.
The compound of the present invention can include the original of unnatural proportions on one or more atoms for constituting the compound
Daughter isotope.For example, radioisotope labeled compound, such as tritium (3H), iodine-125 (125I) or C-14 (14C) can be used.
The transformation of all isotopics of the compound of the present invention, no matter radioactivity whether, be included within the scope of the present invention.
In some embodiments, compound described in the invention exists as stereoisomer, wherein in the presence of not right
Title or chiral centre.Stereoisomer is named as according to the substituent group configuration around asymmetric carbon atomOr (S).It uses herein
Term(S) is IUPAC 1974Recommendations for Section E, Fundamental
Stereochemistry, Pure Appl.Chem, (1976), configuration defined in 45:13-30, by reference to by its content simultaneously
Enter herein.The embodiments described herein particularly including various stereoisomers and its mixture.Stereoisomer includes mapping
The mixture of isomers, diastereoisomer and enantiomer or diastereomer.In some embodiments, chemical combination
Each stereoisomer of object is synthetically prepared from the commercial materials containing asymmetric or chiral centre, or passes through preparation racemic mixing
Then object splits and prepares.Method for splitting is for example: (1) by the mixture of enantiomter in conjunction with chiral auxiliary, by tying again
The non-enantiomer mixture that brilliant or chromatographic isolation obtains, discharges optically pure product from auxiliary agent；Or (2) in chiral chromatogram
The mixture of optical enantiomorphs is directly separated on column.
For drug or pharmacologically active agents, term " effective quantity " or " therapeutically effective amount " refer to nontoxic but can reach
To the drug of desired effect or enough dosages of medicament.For the peroral dosage form in the present invention, a kind of active material in composition
" effective quantity " refer to when being combined with active material another in the composition for the required dosage that achieves the desired results.Have
The determination of effect amount varies with each individual, and age and ordinary circumstance depending on receptor also depend on specific active material, close in case
Suitable effective quantity can be determined by those skilled in the art according to routine test.
Term " active constituent ", " therapeutic agent ", " active material " or " activating agent " refers to a kind of chemical entities, it can have
The therapeutic purpose disorder of effect ground, disease or illness.
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise
Content.
Small molecule PD-L1 inhibitor of the present invention may be used as single dose, or be combined with other therapeutic agents, to enhance this
The effect of a little therapeutic agents.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that: small molecule PD-L1 inhibitor of the present invention, structure novel,
Orally-administrable treatment will not cause strong exempt from other positions of body while keeping immune system to attack cancer
Epidemic disease reaction, and prepare convenient, lower production costs.
Specific embodiment
The solution of the present invention is explained below in conjunction with embodiment.It will be understood to those of skill in the art that following
Embodiment is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Particular technique or item are not specified in embodiment
Part, it described technology or conditions or is carried out according to the literature in the art according to product description.Agents useful for same or instrument
Production firm person is not specified in device, and being can be with conventional products that are commercially available.
The embodiment provides compound shown in Formulas I or its pharmaceutically acceptable salt, hydrate, solvations
Object, metabolite, stereoisomer, tautomer or prodrug, compound shown in preparation formula Ι or its is pharmaceutically acceptable
The method and intermediate of salt, hydrate, solvate, stereoisomer, tautomer or prodrug, pharmaceutical composition, and
The purposes of the compound of the present invention in medicine preparation.
The preparation of 1 compound I-1 (number PD-11-C) of embodiment
(1) synthesis of compound 2c
Compound 1c (2.0g, 1eq) and thionyl chloride (10mL) are added in the single port bottle of 25mL, at 80 DEG C, instead
It should stay overnight, next day is spin-dried for, and obtains product 1.6g with distillation under vacuum, number is compound 2c.
(2) synthesis of compound 3c
Compound 3a (740mg, 1eq) and compound 2c (590mg, 1.1eq) are added in the single port bottle of 25mL, are added
13mL THF is slowly instilling TEA (1.35mL, 2.3eq), and overnight, next day TLC detects fully reacting for room temperature reaction, is spin-dried for, obtains
Compound 3c, directly progress the next step.
(3) synthesis of compound PD-10-C
By compound PD-9 (100mg, 1eq), compound 3c (166mg, 3eq), (1- ethyl -3 (3- dimethyl propylamine) carbon
Diimine) (EDCI) (41mg, 1.3eq), I-hydroxybenzotriazole (HOBT) (29mg, 1.3eq), n,N-diisopropylethylamine
(DIPEA) (0.067mg, 2.5eq) is added in the single port bottle of 25mL, DMF 3mL is added, overnight, next day TLC supervises for room temperature reaction
Control, fully reacting are spin-dried for, and are crossed column and are obtained compound PD-10-C, yield 60mg.
1H NMR(CDCl3, 500MHz): δ=7.13-7.29 (m, 15H), 6.83 (m, 1H), 5.57 (m, 1H), 4.32-
4.38 (m, 2H), 4.15-4.18 (m, 2H), 3.67-3.70 (m, 2H), 3.01-3.16 (m, 2H), 1.45 (d, J=5Hz,
18H), 1.25-1.27 (m, 4H), 1.20 (d, J=5Hz, 3H), 1.16 (s, 9H), 1.08 (s, 9H)
(4) synthesis of compound shown in Formulas I -1
Compound PD-10-C (60mg, 1eq) is added in the single port bottle of 10mL, TFA 1mL is added, DCM 2mL adds
Enter 1 drop tri isopropyl silane, overnight, next day TLC monitoring, fully reacting is spin-dried for for room temperature reaction.By the substance being spin-dried on oil pump
Draw it is dry after, 1mL n-hexane, ultrasonic vibration are added thereto, supernatant is removed, is repeated 2 times by standing, oil pump draw it is dry after, to
1mL ethyl acetate is wherein added, repeats aforesaid operations, oil pump draws dry target product compound I-1 (number PD-11-C) 18mg.
1H NMR(CD3OD, 500MHz): δ=5.56-5.59 (m, 1H), 4.62-4.64 (m, 1H), 4.44 (s, 1H),
4.34-4.35(m,1H),3.96-4.06(m,2H),3.05-3.08(m,2H),1.44-1.50(m,4H),1.18-1.21(m,
3H).
The preparation of 2 compound I-2 of embodiment
The preparation method is the same as that of Example 1 by compound I-2.
ESI-MS (m/z): 431 (M+1)+。
1 biological characteristis of effect example
Using BPS science company PD-1:PD-L1 Homogeneous Assay Kit (Catalog#:72014,
384 holes) to carry out biological characteristis to the compounds of this invention, steps are as follows:
Step 1:
1) thaw PD-1-FLAG-Avi-His on ice.After defrosting, protein is divided into single use aliquot.
2) with 2 parts of distilled water dilution portion 3x PD-1 measurement buffers (i.e. 3 times dilutions), 1 × PD-1 measurement buffering is made
Liquid.
3) PD-1-FLAG-Avi-His is diluted to 25ng/ μ l in 1 × PD-1 measurement buffer.By diluted albumen
Quality guarantee is held on ice, until preparing to use.
4) prepare main mixture (master mixture): the hole N × (it is diluted that 2 μ l 3x PD-1 measure+2 μ l of buffer
PD-1-FLAG+2 μ l distilled water).6 μ l main mixtures are added into each hole.
| Blank is than control | Positive control | Testing inhibitor | |
| 3x PD-1 measures buffer | 2μl | 2μl | 2μl |
| PD-1-FLAG-Avi-His(25ng/μl) | 2μl | 2μl | 2μl |
| Distilled water | 2μl | 2μl | 2μl |
| Testing inhibitor | - | - | 2μl |
| Inhibitor buffer (no inhibitor) | 2μl | 2μl | - |
| 1x PD-1 measures buffer | 2μl | ||
| PD-L1-biotin(3ng/μl) | - | 2μl | 2μl |
| Total amount | 10μl | 10μl | 10μl |
5) 2 μ l inhibitor solutions are added into each hole for being named as " test inhibitor (test inhibitor) ".It is right
In " positive control (positive control) " and " blank (blank) ", 2 μ l are added and are free of inhibitor (inhibitor buffer)
Same solution.
6) 2 μ l 1x PD-1 measurement buffer is added in specified " Blank ".
7) defrosting PD-L1-biotin (biotin) on ice.After defrosting, protein is divided into single use etc. point examination
Sample.
8) 1 μ lPD-1 is measured into the PD-L1-biotin in buffer and is diluted to 3ng/ μ l.Diluted protein is saved
On ice until using.
9) by the addition of the diluted PD-L1- biotin for preparing 2 μ l as described above be each named as " positive control " and
In the cell of " test inhibitor ", initiation reaction.It is incubated at room temperature 60 minutes.
Step 2:
1) FLAG Acceptor beads (FLAG acceptor bead, PerkinElmer# are diluted with 1x PD-1 measurement buffer
AL112C) 250 times.Every hole adds 10 μ l, and of short duration rolling movable plate is incubated at room temperature 30 minutes.
Step 3:
1) with 125 times of the donor bead (PE#6760002S) of 1x PD-1 measurement buffer dilution Streptavidin coupling.Often
Hole adds 10 μ l, is incubated at room temperature 30 minutes.
2) Alpha is read to count.IC is calculated accordingly50。
The result shows that compound I-1, I-2 of the present invention have good activity, their IC50Respectively less than 10 μM.
So the activity of inhibitor of the compound of the present invention with the interaction as PD-1/PD-L1, and because
This can be used for treating disease relevant to the interaction of PD-1/PD-L1.By inhibiting the interaction of PD-1/PD-L1, this
Invention compound can be used for treating and/or preventing tumor disease.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means particular features, structures, materials, or characteristics described in conjunction with this embodiment or example
It is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms are different
Surely identical embodiment or example is referred to.Moreover, particular features, structures, materials, or characteristics described can be any
It can be combined in any suitable manner in one or more embodiment or examples.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example
Property, it is not considered as limiting the invention, those skilled in the art are not departing from the principle of the present invention and objective
In the case where can make changes, modifications, alterations, and variations to the above described embodiments within the scope of the invention.
Claims (10)
1. a kind of compound shown in formula I, its pharmaceutically acceptable salt, hydrate, solvate, metabolite, solid
Isomers, tautomer or prodrug；
Wherein, the R1For hydrogen, C1-6Alkyl or C1-6Alkoxy；
The R2For hydrogen, halogen, hydroxyl, amino, by R2-1Substituted or unsubstituted C1-6Alkyl or by R2-2Replace or does not take
The C in generation1-6Alkoxy；
All R2-1And R2-2It independently is hydroxyl, halogen or nitro；
The R3For hydrogen, halogen, hydroxyl, amino, by R3-1Substituted or unsubstituted C1-6Alkyl or by R3-2Replace or does not take
The C in generation1-6Alkoxy；
All R3-1And R3-2Independently be hydroxyl, halogen, nitro orAll R3-1-1It independently is hydrogen, hydroxyl
Base, halogen, C1-6Alkyl or C1-6Alkoxy；
The R4For hydrogen or C1-6Alkyl；
The R5For hydrogen or C1-6Alkyl；
The m is 1,2 or 3；
The L is
It is describedInRefer to it for singly-bound or double bond, when it is singly-bound, X is-O- or-NH-, when it is double bond
When, X is=N-；
It is describedInRefer to it for singly-bound or double bond, when it is singly-bound, Y is-O- or-NH-, when it is double bond
When, Y is=N-.
2. compound I as described in claim 1, its pharmaceutically acceptable salt, hydrate, solvate, metabolite, standing
Body isomers, tautomer or prodrug, which is characterized in that the compound I, its pharmaceutically acceptable salt, hydrate,
Solvate, metabolite, stereoisomer, tautomer or prodrug are used for anti-programmed death receptors ligand 1；
And/or the compound I, its pharmaceutically acceptable salt, hydrate, solvate, metabolite, alloisomerism
Body, tautomer or prodrug are used as PD-L1 inhibitor；
And/or the R1In, the C1-6Alkyl is C1-4Alkyl；
And/or the R1In, the C1-6Alkoxy is C1-4Alkoxy；
And/or the R2In, the halogen is fluorine, chlorine or bromine；
And/or the R2In, the C1-6Alkyl is C1-4Alkyl；
And/or the R2In, the R2-1Number be one or more, when there are multiple R2-1When, they are identical or not
Together；
And/or the R2In, the C1-6Alkoxy is C1-4Alkoxy；
And/or the R2In, the R2-2Number be one or more, when there are multiple R2-2When, they are identical or not
Together；
And/or the R2-1In, the halogen is fluorine, chlorine or bromine；
And/or the R2-2In, the halogen is fluorine, chlorine or bromine；
And/or the R3In, the halogen is fluorine, chlorine or bromine；
And/or the R3In, the C1-6Alkyl is C1-4Alkyl；
And/or the R3In, the R3-1Number be one or more, when there are multiple R3-1When, they are identical or not
Together；
And/or the R3In, the C1-6Alkoxy is C1-4Alkoxy；
And/or the R3In, the R3-2Number be one or more, when there are multiple R3-2When, they are identical or not
Together；
And/or the R3-1In, the halogen is fluorine, chlorine or bromine；
And/or the R3-2In, the halogen is fluorine, chlorine or bromine；
And/or the R3-1-1In, the halogen is fluorine, chlorine or bromine；
And/or the R3-1-1In, the C1-6Alkyl is C1-4Alkyl；
And/or the R3-1-1In, the C1-6Alkoxy is C1-4Alkoxy；
And/or the R4In, the C1-6Alkyl is C1-4Alkyl；
And/or the R5In, the C1-6Alkyl is C1-4Alkyl.
3. compound I as claimed in claim 2, its pharmaceutically acceptable salt, hydrate, solvate, metabolite, standing
Body isomers, tautomer or prodrug, which is characterized in that the R1In, the C1-6Alkyl is C1-4Alkyl, it is described
C1-4Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl；
And/or the R1In, the C1-6Alkoxy is C1-4Alkoxy, the C1-4Alkoxy is methoxyl group, ethoxy
Base, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy；
And/or the R2In, the C1-6Alkyl is C1-4Alkyl, the C1-4Alkyl is methyl, ethyl, n-propyl, different
Propyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl；
And/or the R2In, the C1-6Alkoxy is C1-4Alkoxy, the C1-4Alkoxy is methoxyl group, ethoxy
Base, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy；
And/or the R3In, the C1-6Alkyl is C1-4Alkyl, the C1-4Alkyl is methyl, ethyl, n-propyl, different
Propyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl；
And/or the R3In, the C1-6Alkoxy is C1-4Alkoxy, the C1-4Alkoxy is methoxyl group, ethoxy
Base, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy；
And/or the R3-1-1In, the C1-6Alkyl is C1-4Alkyl, the C1-4Alkyl is methyl, ethyl, positive third
Base, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl；
And/or the R3-1-1In, the C1-6Alkoxy is C1-4Alkoxy, the C1-4Alkoxy is methoxyl group, second
Oxygroup, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy；
And/or the R4In, the C1-6Alkyl is C1-4Alkyl, the C1-4Alkyl is methyl, ethyl, n-propyl, different
Propyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl；
And/or the R5In, the C1-6Alkyl is C1-4Alkyl, the C1-4Alkyl is methyl, ethyl, n-propyl, different
Propyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl.
4. compound I as described in claim 1, its pharmaceutically acceptable salt, hydrate, solvate, metabolite, standing
Body isomers, tautomer or prodrug, which is characterized in that described
For
And/or it is describedFor
And/or it is describedFor
And/or the R1For hydrogen；
And/or the R2For C1-6Alkyl；
And/or the R3For amino；
And/or the R4For hydrogen；
And/or the R5For hydrogen；
And/or the m is 1 or 2；
And/or it is described
5. compound I as claimed in claim 4, its pharmaceutically acceptable salt, hydrate, solvate, metabolite, standing
Body isomers, tautomer or prodrug, which is characterized in that described
For
6. compound I as described in claim 1, its pharmaceutically acceptable salt, hydrate, solvate, metabolite, standing
Body isomers, tautomer or prodrug, which is characterized in that the compound I is
7. a kind of pharmaceutical composition comprising such as compound I according to any one of claims 1 to 6, its is pharmaceutically acceptable
Salt, hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug and pharmaceutic adjuvant；The change
Close object I, its pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug
Dosage can be therapeutically effective amount.
8. as compound I according to any one of claims 1 to 6, its pharmaceutically acceptable salt, hydrate, solvate,
Metabolite, stereoisomer, tautomer or prodrug are preparing the application in PD-L1 inhibitor.
9. as compound I according to any one of claims 1 to 6, its pharmaceutically acceptable salt, hydrate, solvate,
Metabolite, stereoisomer, tautomer or prodrug, the application in the drug of preparation treatment and/or pre- preventing tumor.
10. application as claimed in claim 9, which is characterized in that the tumour is related tumour with PD-L1 activity；Institute
The tumour related with PD-L1 activity stated can be cancer related with PD-L1 activity；The related cancer with PD-L1 activity
Disease can be non-small cell lung cancer, melanoma, advanced stage Hodgkin lymphoma, liver cancer, oophoroma or breast cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710470219.1A CN109096219B (en) | 2017-06-20 | 2017-06-20 | Novel anti-PD-L1 compound, application thereof and composition containing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710470219.1A CN109096219B (en) | 2017-06-20 | 2017-06-20 | Novel anti-PD-L1 compound, application thereof and composition containing same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109096219A true CN109096219A (en) | 2018-12-28 |
| CN109096219B CN109096219B (en) | 2023-03-21 |
Family
ID=64795710
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710470219.1A Active CN109096219B (en) | 2017-06-20 | 2017-06-20 | Novel anti-PD-L1 compound, application thereof and composition containing same |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109096219B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109824621A (en) * | 2019-03-28 | 2019-05-31 | 中国药科大学 | Furodiazole and thiadiazole compound and its preparation method and application |
| US11130740B2 (en) | 2017-04-25 | 2021-09-28 | Arbutus Biopharma Corporation | Substituted 2,3-dihydro-1H-indene analogs and methods using same |
| WO2022166991A1 (en) * | 2021-02-08 | 2022-08-11 | 南京明德新药研发有限公司 | Indoline compound |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105814028A (en) * | 2013-09-06 | 2016-07-27 | 奥瑞基尼探索技术有限公司 | 1,2,4-oxadiazole derivatives as immunomodulators |
| CN105849092A (en) * | 2013-09-06 | 2016-08-10 | 奥瑞基尼探索技术有限公司 | 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators |
| WO2016142833A1 (en) * | 2015-03-10 | 2016-09-15 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole and thiadiazole compounds as immunomodulators |
| WO2016142852A1 (en) * | 2015-03-10 | 2016-09-15 | Aurigene Discovery Technologies Limited | 1,3,4-oxadiazole and thiadiazole compounds as immunomodulators |
| CN109824621A (en) * | 2019-03-28 | 2019-05-31 | 中国药科大学 | Furodiazole and thiadiazole compound and its preparation method and application |
-
2017
- 2017-06-20 CN CN201710470219.1A patent/CN109096219B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105814028A (en) * | 2013-09-06 | 2016-07-27 | 奥瑞基尼探索技术有限公司 | 1,2,4-oxadiazole derivatives as immunomodulators |
| CN105849092A (en) * | 2013-09-06 | 2016-08-10 | 奥瑞基尼探索技术有限公司 | 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators |
| WO2016142833A1 (en) * | 2015-03-10 | 2016-09-15 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole and thiadiazole compounds as immunomodulators |
| WO2016142852A1 (en) * | 2015-03-10 | 2016-09-15 | Aurigene Discovery Technologies Limited | 1,3,4-oxadiazole and thiadiazole compounds as immunomodulators |
| CN109824621A (en) * | 2019-03-28 | 2019-05-31 | 中国药科大学 | Furodiazole and thiadiazole compound and its preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| 王倩: "PD-1/PD-L1小分子抑制剂的专利研究进展综述", 《药物研发》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11130740B2 (en) | 2017-04-25 | 2021-09-28 | Arbutus Biopharma Corporation | Substituted 2,3-dihydro-1H-indene analogs and methods using same |
| CN109824621A (en) * | 2019-03-28 | 2019-05-31 | 中国药科大学 | Furodiazole and thiadiazole compound and its preparation method and application |
| WO2022166991A1 (en) * | 2021-02-08 | 2022-08-11 | 南京明德新药研发有限公司 | Indoline compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109096219B (en) | 2023-03-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2837431T3 (en) | Cystic fibrosis transmembrane conductance regulator modulators, pharmaceutical compositions, treatment methods, and processes for making the modulator | |
| CN109721527A (en) | A kind of novel anti-PD-L1 compound, its application and the composition containing it | |
| CN108395443B (en) | Cyclic compounds inhibiting programmed death receptor ligand 1 and uses thereof | |
| CN110494141A (en) | Pharmaceutical composition containing substituted polycyclic Pyridione derivatives and its prodrug | |
| CN102482277B (en) | Epidermal growth factor receptor inhibitor and the method for treating obstacle | |
| CN107709305A (en) | New compound | |
| CN103906743B (en) | The compound being combined with blood-platelet specific glycoprotein iib/iiia and the purposes of its thrombus imaging | |
| CN107709306A (en) | NRF2 conditioning agents | |
| CN106928203A (en) | As the heterocycleamide of kinase inhibitor | |
| CN109422733A (en) | One kind inhibits and the compound for the tyrosine protein kinase ALK that degrades | |
| JP2008518014A (en) | Diarylureas as CB1 antagonists | |
| CN107922418A (en) | Antimicrobe compound and preparation and the method using the compound | |
| CN106103442A (en) | Its method of Antimicrobe compound and preparation and use | |
| CN105164136A (en) | Macrocycles as kinase inhibitors | |
| CN104736533B (en) | Vegfr3 inhibitor | |
| CN109096219A (en) | A kind of novel anti-PD-L1 compound, its application and the composition containing it | |
| CN108707151A (en) | Pyrimido-pyridazinone compound and application thereof | |
| WO2021150885A1 (en) | Cannabinoid derivatives | |
| CN110092779B (en) | Substituted phenyl compound and application thereof | |
| CN110092740A (en) | A kind of fused ring compound and its application | |
| WO2020259626A1 (en) | Imidazopyridine compound as irak4 inhibitor | |
| CN105026388B (en) | It can be used as the substituted pyridine derivate of C-fms kinase inhibitors | |
| CN106573901A (en) | Fumarate analogs and uses thereof in the treatment of an autoimmune disease or an inflammatory disease | |
| CN108602779A (en) | The method for preparing 5,6- dihydros -6- phenyl benzo [F] isoquinolin -2- amine of substitution | |
| CN104797553B (en) | 3 aminocyclopentanecarasxamides derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |