CN109096219B - Novel anti-PD-L1 compound, application thereof and composition containing same - Google Patents
Novel anti-PD-L1 compound, application thereof and composition containing same Download PDFInfo
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Abstract
The invention discloses a novel anti-PD-L1 compound, application thereof and a composition containing the same. The compound is a compound shown as a formula I, and pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug thereof. The compound can be used for preparing medicaments for treating and/or preventing tumors.
Description
Technical Field
The invention belongs to the field of biomedicine, and relates to a novel anti-PD-L1 compound, application thereof and a composition containing the same.
Background
The PD-1/PD-L1 signaling pathway is one of the most topical topics in the current field of cancer therapy and research. New immunotherapeutic drugs, such as Keytruda in Sanshadong and Opdivo in Baishimaibao, have been marketed in recent two years and have aimed at this signaling pathway, using monoclonal antibodies that bind to PD-1 receptors to prevent signaling and thus activate the body's own immune system to spread the attack on tumors. The two new medicines are already approved for treating cancers such as melanoma, and simultaneously show great potential in clinical trials aiming at other cancers. Additionally, tecentriq (Atezolizumab, MPDL 3280A) was the first PD-L1 inhibitor approved by the FDA for indications of bladder cancer and non-small cell lung cancer. However, the half-life of monoclonal antibodies as long as 15-20 days may cause side effects associated with immune responses. In addition, the current PD-1/PD-L1 monoclonal antibody medicine needs intravenous injection, and has poor curative activity on solid tumors.
Therefore, the development of a novel PD-L1 inhibitor medicament for treating tumors more safely and efficiently has great social value and economic benefit, and is also a research hotspot of various large pharmaceutical enterprises at present.
Disclosure of Invention
The invention aims to overcome the defects that the existing PD-1/PD-L1 monoclonal antibody medicaments need intravenous injection and have poor therapeutic activity on solid tumors and the like, and provides a novel anti-PD-L1 compound, application thereof and a composition containing the compound, wherein the compound is a PD-L1 inhibitor, has a novel structure, can be orally administered and is used for treating and/or preventing tumors.
The invention provides a compound shown as a formula I (the compound can resist programmed death receptor ligand 1, namely serving as a PD-L1 inhibitor), and pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug thereof;
wherein, R is 1 Is hydrogen, C 1-6 Alkyl (e.g. C) 1-4 An alkyl group; said C 1-4 Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) or C 1-6 Alkoxy (e.g. C) 1-4 An alkoxy group; said C 1-4 Alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy);
the R is 2 Is hydrogen, halogen (e.g. fluorine, chlorine or bromine), hydroxy, amino, or by R 2-1 Substituted or unsubstituted C 1-6 Alkyl (said "C) 1-6 Alkyl radicals "such as C 1-4 An alkyl group; the above-mentionedC of (A) 1-4 An alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group; said R 2-1 Is one or more<E.g. 2, 3, 4 or 5>(ii) a When there are more than one R 2-1 When they are the same or different), or, by R 2-2 Substituted or unsubstituted C 1-6 Alkoxy (said "C 1-6 Alkoxy "e.g. C 1-4 An alkoxy group; said C 1-4 Alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; said R 2-2 Is one or more<E.g. 2, 3, 4 or 5>(ii) a When there are more than one R 2-2 When they are the same or different);
all of R 2-1 And R 2-2 Independently hydroxyl, halogen (e.g., fluorine, chlorine or bromine) or nitro;
said R is 3 Is hydrogen, halogen (e.g. fluorine, chlorine or bromine), hydroxy, amino, or by R 3-1 Substituted or unsubstituted C 1-6 Alkyl (said "C) 1-6 Alkyl radicals "such as C 1-4 An alkyl group; said C 1-4 An alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group; said R 3-1 Is one or more<E.g. 2, 3, 4 or 5>(ii) a When there are more than one R 3-1 When they are the same or different), or, by R 3-2 Substituted or unsubstituted C 1-6 Alkoxy (said "C 1-6 Alkoxy "e.g. C 1-4 An alkoxy group; said C 1-4 Alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; r is as described 3-2 Is one or more<For example 2, 3, 4 or 5>(ii) a When there are more than one R 3-2 When they are the same or different);
all of R 3-1 And R 3-2 Independently of one another, hydroxy, halogen (e.g. fluorine, chlorine or bromine), nitro or
All of R 3-1-1 Independently hydrogen, hydroxy, halogen (e.g. fluorine, chlorine or bromine), C 1-6 Alkyl (e.g. C) 1-4 An alkyl group; said C 1-4 Alkyl radicals such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl radical) or C 1-6 Alkoxy (e.g. C) 1-4 An alkoxy group; said C 1-4 Alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy);
the R is 4 Is hydrogen or C 1-6 Alkyl (e.g. C) 1-4 An alkyl group; said C 1-4 An alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group);
the R is 5 Is hydrogen or C 1-6 Alkyl (e.g. C) 1-4 An alkyl group; said C 1-4 Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl);
m is 1, 2 or 3;
l is
The above-mentioned
In
Means that it is a single bond or a double bond, when it is a single bond, X is-O-or-NH-, when it is a double bond, X is = N-;
the above-mentioned
In (1)
Means that it is a single bond or a double bond, and when it is a single bond, Y is-O-or-NH-, when it is a double bond, Y is = N-.
Thus, throughout this specification, one skilled in the art can refer to the R in the compounds of formula I 1 ～R 5 And the groups of L and substituents thereof are selected to provide stable compounds of formula I as described in embodiments of the invention, or pharmaceutically acceptable salts, hydrates, solvates, metabolites, stereoisomers, tautomers or prodrugs thereof.
It will be understood by those skilled in the art that, according to the convention used in the art, in the structural formulae of the present application,
for delineating chemical bonds, which are points of attachment of moieties or substituents, core structures, or backbone structures.
Thus, throughout this specification, the skilled person will be able to work with the groups of L
The compound of formula I or a stereoisomer, tautomer, metabolite, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, is selected to be stable as described in the examples of the invention.
In the present invention, the stereoisomers include enantiomers, diastereomers and mixtures of enantiomers or diastereomers.
In one embodiment, the above
Is composed of
In one embodiment, the above
Is composed of
In one embodiment, the above
Is composed of
In one embodiment, the above
Is composed of
In one embodiment, the groups in compound I are defined as follows (the unannotated definitions are as in any of the preceding claims):
the R is 1 Is hydrogen.
In one embodiment, the groups in compound I are defined as follows (the unannotated definitions are as in any of the preceding claims):
the R is 2 Is C 1-6 An alkyl group.
In one embodiment, the groups in compound I are defined as follows (the unannotated definitions are as in any of the preceding claims):
the R is 3 Is an amino group.
In one embodiment, the groups in compound I are defined as follows (the unannotated definitions are as in any of the preceding claims):
the R is 4 Is hydrogen.
In one embodiment, the groups in compound I are defined as follows (the unannotated definitions are as in any of the preceding claims):
the R is 5 Is hydrogen.
In one embodiment, the groups in compound I are defined as follows (the unannotated definitions are as in any of the preceding claims):
m is 1 or 2.
In one embodiment, the groups in compound I are defined as follows (the unannotated definitions are as in any of the preceding claims):
the above-mentioned
Is composed of
In one embodiment, the compound I can be of any of the following structures:
the compound of formula I of the invention can be prepared according to conventional chemical synthesis methods in the field, and the steps and conditions thereof can refer to the steps and conditions of similar reactions in the field.
If a chiral pure compound of the formula I compound of the present invention is desired, chiral pure compounds of the present invention can be obtained by methods commonly used in the art, for example, chiral induction during synthesis, or after preparing a stereoisomer mixture of the target compound, by using chiral resolution columns or chemical resolution methods which are conventional in the art.
The reaction solvent used in each reaction step described in the present invention is not particularly limited, and any solvent that can dissolve the starting materials to some extent and does not inhibit the reaction is included in the present invention. Further, many equivalents, substitutions, or equivalents in the art to which this invention pertains, as well as different proportions of solvents, solvent combinations, and solvent combinations described herein, are deemed to be encompassed by the present invention.
The invention also provides a pharmaceutical composition, which comprises the compound of formula I, pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug thereof, and a pharmaceutic adjuvant.
In the pharmaceutical composition, the amount of the compound of formula I, a pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer, or prodrug thereof, may be a therapeutically effective amount.
The pharmaceutical excipients may be those widely used in the field of pharmaceutical production. The excipients are used primarily to provide a safe, stable and functional pharmaceutical composition and may also provide methods for dissolving the active ingredient at a desired rate or for promoting the effective absorption of the active ingredient after administration of the composition by a subject. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, antiadherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents and sweeteners.
The pharmaceutical compositions of the present invention may be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.
The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implant, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the present invention may also be in a controlled release or delayed release dosage form (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations which can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.
The invention also provides application of the compound shown in the formula I, pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug thereof in preparation of PD-L1 inhibitors.
The PD-L1 inhibitor can be used in vivo; also useful in vitro, primarily for experimental purposes, for example: the kit can be used as a standard sample or a control sample for comparison, or can be prepared into a kit according to the conventional method in the field, so that the rapid detection can be provided for the inhibition effect of PD-L1.
The invention also provides an application of the compound shown in the formula I, and pharmaceutically acceptable salts, hydrates, solvates, metabolites, stereoisomers, tautomers or prodrugs thereof in preparing medicines for treating and/or preventing tumors.
The tumor may be a cancer. The cancer includes but is not limited to non-small cell lung cancer, melanoma, advanced Hodgkin lymphoma, liver cancer, ovarian cancer or breast cancer.
The tumor may be a tumor associated with PD-L1 activity. The tumor associated with PD-L1 activity may be a cancer associated with PD-L1 activity. The cancer related to PD-L1 activity comprises but is not limited to non-small cell lung cancer, melanoma, advanced Hodgkin lymphoma, liver cancer, ovarian cancer or breast cancer.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is standard in the art to which the claimed subject matter belongs. In case there are multiple definitions for a term, the definitions herein control. When referring to a URL or other identifier or address, it should be understood that such identifier may change and that particular information on the internet may change, but equivalent information may be found by searching the internet. The reference demonstrates that such information is available and publicly disseminated.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Furthermore, the term "comprising" is open-ended and not closed-ended.
The present invention employs, unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques or pharmacological detection, and the various steps and conditions may be referred to those conventional in the art. Unless otherwise indicated, the present invention employs standard nomenclature for analytical, organic synthetic, and medicinal chemistry and standard laboratory procedures and techniques. In some cases, standard techniques are used for chemical synthesis, chemical analysis, drug preparation, formulation and drug delivery, and treatment of patients.
The term "pharmaceutically acceptable" as used herein, is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and salts of organic acids including such acids as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like; also included are Salts of amino acids such as arginine and the like, and Salts of organic acids such as glucuronic acid (see Berge et al, "Pharmaceutical Salts", journal of Pharmaceutical Science 66 (1977). Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to either base or acid addition salts. Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms by certain physical properties, such as solubility in polar solvents.
The term "pharmaceutically acceptable salts" as used herein pertains to derivatives of the compounds of the present invention wherein the parent compound is modified by salification with an acid or salification with a base. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound, for example, salts formed with non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic or organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, glycolic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannin, tartaric acid, and p-toluenesulfonic acid.
The "pharmaceutically acceptable salts" of the present invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. Any compound that can be converted in vivo to provide a biologically active substance (i.e., a compound of formula I) is a prodrug within the scope and spirit of the present invention. For example, compounds containing a carboxyl group may form physiologically hydrolyzable esters that act as prodrugs by hydrolyzing in vivo to give the compounds of formula I themselves. The prodrug is preferably administered orally, since hydrolysis in many cases takes place mainly under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or hydrolysis occurs in the blood. In addition, prodrugs can be converted to the compounds of the present invention in an in vivo environment by chemical or biochemical means.
Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous form.
The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, a compound such as tritium (3H), iodine-125 (125I) or C-14 (14C) may be labeled with a radioisotope. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
In some embodiments, the compounds described herein exist as stereoisomers, wherein an asymmetric or chiral center is present. Stereoisomers are named according to the configuration of the substituents around the chiral carbon atom
Or (S). Terms used herein
And (S) is a configuration as defined in IUPAC 1974Recommendations for Section E, functional Stereochemistry, pure appl. Chem, (1976), 45, the contents of which are incorporated herein by reference. Embodiments described herein specifically include various stereoisomers and mixtures thereof. Stereoisomers include enantiomers, diastereomers and mixtures of enantiomers or diastereomers. In some embodiments, each stereoisomer of a compound is prepared synthetically from commercial starting materials containing asymmetric or chiral centers, or by preparing racemic mixtures followed by resolution. The resolution method comprises the following steps: (1) Combining the mixture of enantiomers with a chiral auxiliary, and releasing the optically pure product from the auxiliary by recrystallization or chromatographic separation of the resulting mixture of diastereomers; or (2) directly separating the mixture of optical enantiomers on a chiral chromatography column.
The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is not toxic but yet achieves the desired effect. For oral dosage forms of the invention, an "effective amount" of one active agent in a composition is the amount required to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.
The term "active ingredient," "therapeutic agent," "active substance," or "active agent" refers to a chemical entity that is effective in treating a targeted disorder, disease, or condition.
The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
The term "comprising" is open-ended, i.e. including what is specified in the invention, but not excluding other aspects.
The small molecule PD-L1 inhibitors described herein can be used as a single agent, or in combination with other therapeutic agents to enhance the effect of these agents.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the small molecule PD-L1 inhibitor has a novel structure, can be orally administered for treatment, can not cause strong immune response at other parts of a body while keeping the immune system attacking cancer, and has the advantages of convenient preparation and low production cost.
Detailed Description
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples do not specify particular techniques or conditions, and are performed according to techniques or conditions described in literature in the art or according to the product specification. The reagents or instruments used are conventional products which are commercially available, and are not indicated by manufacturers.
The embodiment of the invention provides a compound shown in a formula I or pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug thereof, a method and an intermediate for preparing the compound shown in the formula I or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer or prodrug thereof, a pharmaceutical composition and application of the compound in preparing medicaments.
EXAMPLE 1 preparation of Compound I-1 (accession number PD-11-C)
(1) Synthesis of Compound 2c
Compound 1c (2.0 g, 1eq) and thionyl chloride (10 mL) were added to a 25mL single vial, reacted overnight at 80 ℃ and spin-dried the next day to give 1.6g of product, numbered compound 2c, by distillation under reduced pressure.
(2) Synthesis of Compound 3c
Compound 3a (740mg, 1eq) and compound 2c (590mg, 1.1eq) were placed in a 25mL single-necked flask, 13mL of THF was added thereto, TEA (1.35mL, 2.3eq) was slowly dropped thereinto, and the mixture was reacted at room temperature overnight, followed by TLC detection the next day to complete the reaction and drying to obtain compound 3c, which was directly subjected to the next reaction.
(3) Synthesis of Compound PD-10-C
Compound PD-9 (100mg, 1eq), compound 3C (166mg, 3eq), (1-ethyl-3 (3-dimethylpropylamine) carbodiimide) (EDCI) (41mg, 1.3eq), 1-Hydroxybenzotriazole (HOBT) (29mg, 1.3eq), N, N-Diisopropylethylamine (DIPEA) (0.067mg, 2.5eq) was added to a 25mL single vial, DMF 3mL was added, the reaction was allowed to proceed overnight at room temperature, followed by next day TLC monitoring, the reaction was complete, spun dry, and the column passed gave compound PD-10-C in 60mg yield.
1 H NMR(CDCl 3 ,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 represented by the formula I-1
The compound PD-10-C (60mg, 1eq) was added to a 10mL single vial, 1mL TFA, 2mL DCM, 1 drop triisopropylsilane was added, the reaction was allowed to proceed overnight at room temperature, monitored by TLC the next day, the reaction was complete, and the reaction was spin-dried. And (3) draining the dried substances on an oil pump, adding 1mL of n-hexane into the dried substances, carrying out ultrasonic oscillation, standing to remove the supernatant, repeating the operation for 2 times, adding 1mL of ethyl acetate into the dried substances after the oil pump is drained, and repeating the operation to drain 18mg of the target product compound I-1 (the number PD-11-C) by the oil pump.
1 H NMR(CD 3 OD,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).
EXAMPLE 2 preparation of Compound I-2
The preparation of compound I-2 was carried out in the same manner as in example 1.
ESI-MS(m/z)：431(M+1) + 。
Effect example 1 biological assay
The compounds of the invention were biologically assayed using the PD-1 from BPS science, PD-L1 Homogeneous Assay Kit (Catalog #:72014, 384 well) with the following steps:
step 1:
1) PD-1-FLAG-Avi-His was thawed on ice. After thawing, the proteins were aliquoted into single use aliquots.
2) A3 XPD-1 assay buffer (i.e., a 3 fold dilution) was diluted with 2 parts of distilled water to make a 1 XPD-1 assay buffer.
3) PD-1-FLAG-Avi-His was diluted to 25 ng/. Mu.l in 1 XPD-1 assay buffer. The diluted protein was kept on ice until ready for use.
4) Prepare master mix (master mix): n well × (2 μ l3 × PD-1 assay buffer +2 μ l diluted PD-1-FLAG +2 μ l distilled water). Add 6. Mu.l of master mix to each well.
| Blank ratio control | Positive control | Inhibitors to be tested | |
| 3x PD-1 assay buffer | 2μl | 2μl | 2μl |
| PD-1-FLAG-Avi-His(25ng/μl) | 2μl | 2μl | 2μl |
| Distilled water | 2μl | 2μl | 2μl |
| Test inhibitors | - | - | 2μl |
| Inhibitor buffer (without inhibitor) | 2μl | 2μl | - |
| 1 XPD-1 assay buffer | 2μl | ||
| PD-L1-biotin(3ng/μl) | - | 2μl | 2μl |
| Total amount of | 10μl | 10μl | 10μl |
5) To each well designated "test inhibitor" (test inhibitor) was added 2. Mu.l of inhibitor solution. For the "positive control" and "blank", 2. Mu.l of the same solution without inhibitor (inhibitor buffer) was added.
6) Mu.l of 1 XPD-1 assay buffer was added to the indicated "Blank".
7) PD-L1-biotin (biotin) was thawed on ice. After thawing, the proteins were aliquoted into single use aliquots.
8) Mu.l PD-L1-biotin in PD-1 assay buffer was diluted to 3 ng/. Mu.l. The diluted protein was stored on ice until use.
9) The reaction was initiated by adding 2 μ L of diluted PD-L1-biotin prepared as described above to each of the cells designated as "positive control" and "test inhibitor". Incubate at room temperature for 60 minutes.
Step 2:
1) FLAG Acceptor beads (FLAG Acceptor beads, perkinElmer # AL 112C) were diluted 250-fold with 1 XPD-1 assay buffer. Add 10. Mu.l to each well, shake the plate briefly, and incubate at room temperature for 30 min.
And step 3:
1) Streptavidin-coupled donor beads (PE # 6760002S) were diluted 125-fold with 1x PD-1 assay buffer. Mu.l of each well was added and incubated at room temperature for 30 minutes.
2) Alpha counts are read. Calculate IC accordingly 50 。
The results show that the compounds I-1 and I-2 of the invention have good activity and their IC 50 Are all less than 10. Mu.M.
Thus, the compounds of the present invention have activity as inhibitors of the interaction of PD-1/PD-L1 and are therefore useful in the treatment of diseases associated with the interaction of PD-1/PD-L1. By inhibiting the PD-1/PD-L1 interaction, the compounds of the invention are useful for the treatment and/or prevention of neoplastic diseases.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made in the above embodiments by those of ordinary skill in the art without departing from the principle and spirit of the present invention.
Claims (12)
1. A compound of formula I, a pharmaceutically acceptable salt or tautomer thereof;
wherein, R is 1 Is hydrogen;
the R is 2 Is hydrogen, C 1-6 Alkyl, or C 1-6 An alkoxy group;
the R is 3 Is amino;
said R is 4 Is hydrogen;
said R is 5 Is hydrogen;
m is 1 or 2;
l is
The above-mentioned
Is composed of
2. Compound I, a pharmaceutically acceptable salt or tautomer thereof, according to claim 1,
said R 2 In (b), the C 1-6 Alkyl is C 1-4 An alkyl group;
and/or, said R 2 In (b), the C 1-6 Alkoxy is C 1-4 An alkoxy group.
3. The method of claim 2Compound I, a pharmaceutically acceptable salt or tautomer thereof, wherein R is 2 In (b), the C 1-6 Alkyl is C 1-4 Alkyl radical, said C 1-4 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
and/or, said R 2 In (b), the C 1-6 Alkoxy is C 1-4 Alkoxy radical, said C 1-4 Alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
4. Compound I, a pharmaceutically acceptable salt or a tautomer thereof according to claim 1 wherein said compound I, a pharmaceutically acceptable salt or a tautomer thereof
Is composed of
Or, the said
Is composed of
Or, the said
Is composed of
5. Compound I, a pharmaceutically acceptable salt or tautomer thereof, according to claim 4, wherein
Is composed of
6. The compound I, a pharmaceutically acceptable salt or tautomer thereof, according to claim 1, wherein compound I is
7. A pharmaceutical composition comprising a compound I, a pharmaceutically acceptable salt or tautomer thereof according to any one of claims 1 to 6 and a pharmaceutical excipient.
8. The pharmaceutical composition of claim 7, wherein the amount of compound I, a pharmaceutically acceptable salt or tautomer thereof, is a therapeutically effective amount.
9. Use of compound I, a pharmaceutically acceptable salt or a tautomer thereof according to any one of claims 1 to 6 for the preparation of a PD-L1 inhibitor.
10. The use of a compound I, a pharmaceutically acceptable salt or a tautomer thereof according to any one of claims 1 to 6 for the preparation of a medicament for the treatment and/or prevention of tumors which are associated with PD-L1 activity.
11. The use of claim 10, wherein the tumor associated with PD-L1 activity is a cancer associated with PD-L1 activity.
12. The use of claim 11, wherein the cancer associated with PD-L1 activity is non-small cell lung cancer, melanoma, advanced hodgkin's lymphoma, liver cancer, ovarian cancer or breast cancer.
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| CN109824621A (en) * | 2019-03-28 | 2019-05-31 | 中国药科大学 | Furodiazole and thiadiazole compound and its preparation method and application |
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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 |
|---|
| PD-1/PD-L1小分子抑制剂的专利研究进展综述;王倩;《药物研发》;20190930;第40卷(第17期);第76-80页 * |
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