Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects of the existing EGFR inhibitor drugs, and provide a novel EGFR inhibitor and application thereof.
According to a first aspect of the present invention, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof,
wherein,
the R is1Is selected from substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C1-C6Alkoxy, substituted or unsubstituted C1-C6Alkoxy radical C1-C6Alkyl, or substituted or unsubstituted hydroxy C1-C6An alkylene group; said "C1-C6Alkyl group "," C3-C8Cycloalkyl group "," C1-C6Alkoxy group "," C1-C6Alkoxy radical C1-C6Alkyl group and hydroxyl group C1-C6Substituents on the "alkylene" are selected from one or more of the following groups: OH, NO2、CN、Br、Cl、F、I、C1-C6Alkyl and C3-C8A cycloalkyl group;
the R is2Is selected from C1-C6Straight or branched alkyl, C optionally substituted by one or more halogens1-C6A linear or branched alkyl group;
the R is3And R4Each independently selected from the group consisting of substituted or unsubstituted monocyclic or bicyclic aryl or heteroaryl moieties, H, substituted or unsubstituted C1-C8Alkyl, allyl, or substituted benzyl;
and X is selected from NH, O or S.
According to an embodiment of the present invention, preferably said R1Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, or n-hexyl;
according to an embodiment of the present invention, preferably X is selected from O;
according to an embodiment of the invention, R is preferred2Is selected from-CH3、-C2H5、-CH(CH3)2、-CH2Cl、-CH2F、-C2H4Cl, or-C2H4F。
According to an embodiment of the invention, R is preferred3Is selected from H;
according to an embodiment of the invention, R is preferred4Is selected from
Thus, throughout this specification, the skilled person will be able to refer to the R in the compounds of formula I1～R4And the group of X and its substituents are selected to provide stable compounds of formula I or pharmaceutically acceptable salts thereof as described in the examples of the invention.
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.
According to an embodiment of the present invention, the compound of formula I according to the present invention is any one of the following compounds:
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.
The compounds of the invention can be isolated and purified according to standard techniques well known to those skilled in the art. One particularly useful technique in purifying compounds is preparative liquid chromatography, which uses mass spectrometry as a means of detecting the pure compound flowing from a chromatographic column.
Preparative LC-MS is a standard efficient method for purifying small organic molecules, such as the compounds described herein. The Liquid Chromatography (LC) and Mass Spectrometry (MS) methods can be modified to allow better crude separation and to improve MS detection of the sample. Optimization of preparative gradient LC methods involves changing the column, volatile eluent and modulators and gradients. These methods are well known in the art of optimizing preparative LC-MS methods, which are employed to purify compounds. Such methods are described in the following documents: RosentreterU, huberu.; an Optimal fraction collecting and predicting LC/MS; j CombChem; 2004; 159-64 and leister W, Strauss K, Wisnoski D, ZHao Z, Lindsley C, Development of custom high-throughput predictive consistency/mass spectrometry for the predictive purification and analytical analysis of compounds; j Comb chem.; 2003; 5 (3); 322-9.
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.
According to a third aspect of the present invention, there is also provided a pharmaceutical composition comprising the compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
While it is possible for a compound of formula I as described herein to be administered as the active compound alone, it is preferred to present it as a pharmaceutical composition (e.g., formulation) comprising at least one active compound of the invention and one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants or other materials well known to those skilled in the art, and optionally other therapeutic or prophylactic agents. Thus, the present invention also provides a pharmaceutical composition as defined above and a process for the preparation of a pharmaceutical composition, which process comprises admixing at least one active compound as defined above with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilizers or other materials as described herein.
In the pharmaceutical composition, the compound of formula I, or a pharmaceutically acceptable salt thereof, may be used in a therapeutically effective amount.
The pharmaceutical excipients can 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.
Oral administration of the compounds of the invention is preferred. Intravenous administration of the compounds of the invention is also preferred. Depending on the circumstances, other application routes may be applied or even preferred. For example, for patients who are forgetful or irritable with oral medications, subcutaneous administration may be highly desirable. In particular cases, the compounds of the invention may also be administered by transdermal, intramuscular, intranasal or intrarectal routes. The route of administration may vary in any way, limited by the physical properties of the drug, the convenience of the patient and caregiver, and other relevant circumstances (Remington's Pharmaceutical Sciences, 18 th edition, mack publishing Co. (1990)).
According to a fourth aspect of the invention, there is provided the use of a compound of formula I of the invention in the manufacture of a medicament for the treatment or prevention of a disorder or disease mediated by an activated or resistant mutant form of EGFR. Such disorders or diseases include, but are not limited to: ovarian cancer, cervical cancer, colorectal cancer (e.g., colon adenocarcinoma), breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, lung cancer (e.g., non-small cell lung cancer), hepatocellular carcinoma, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, Acute Myeloid Leukemia (AML), multiple myeloma, or mesothelioma.
In the present invention, the EGFR in the form of the activation mutant or resistance mutant may be, for example, an L858R activation mutant, an Exon19 deletion activation mutant, and/or a T790M resistance mutant. Thus, a disease, disorder, or condition mediated by EGFR in the form of an activation mutant or resistance mutant may be, for example, a disease, disorder, or condition mediated by an L858R activation mutant, an Exon19 deletion activation mutant, and/or a T790M resistance mutant.
The compounds of formula I according to the invention or a pharmaceutically acceptable salt thereof, or the pharmaceutical compositions according to the invention, are particularly useful for the prevention or treatment of diseases, disorders or conditions mediated by EGFR in the form of an activation mutant or a resistance mutant, e.g. diseases, disorders or conditions mediated by an L858R activation mutant, an Exon19 deletion activation mutant and/or a T790M resistance mutant, such as for the prevention or treatment of cancer patients who have developed resistance to gefitinib, erlotinib, ecteinascitinib or ocitinib. Thus, it is envisioned that these compounds will prove useful for treating or preventing proliferative disorders, such as cancer.
Use of a compound of formula I according to the invention, or a pharmaceutically acceptable salt, or pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of a disease, disorder, or condition mediated by an L858R activation mutant, an Exon19 deletion activation mutant, and/or a T790M resistance mutant.
The activity of a compound of the invention as an EGFR inhibitor can be measured using the assays described in the examples below, and the level of activity exhibited by a given compound can be measured by IC50A value.
The invention also provides application of the compound shown in the formula I or pharmaceutically acceptable salts thereof in preparing EGFR inhibitors.
The EGFR inhibitor can be used in vivo; also useful in vitro, primarily for experimental purposes, for example: the EGFR inhibitor 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 EGFR inhibitor can be rapidly detected.
The invention also provides application of the compound shown in the formula I or pharmaceutically acceptable salts thereof in preparing medicines for treating and/or preventing cancers.
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 chemistry, organic synthetic chemistry, and medicinal chemistry, as well as 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 acids such 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 (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al, "Pharmaceutical salts," Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt. Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a 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 by 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.
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 non-toxic but 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 terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
The EGFR inhibitors described herein can be used as a single agent, or in combination with other therapeutic agents to enhance the effect of these agents.
For the compound shown in the formula I, a cell activity test shows that the compound has good proliferation inhibition activity on NCI-H1975 cell strains mutated by T790M and L858R EGFR, and the proliferation inhibition activity of part of the compound on NCI-H1975 is better than that of a positive drug AZD9291 (oxitinib). The compound of the invention shows excellent drug effect, has higher selectivity on T790M and/or L858R EGFR, and has better tumor treatment effect on first-generation, second-generation and third-generation EGFR inhibitor-resistant cancer patients.
The compounds of formula I of the present invention provide a new commercial choice for novel EGFR inhibitors and may be useful in the treatment of cancers having EGFR activating mutants and/or EGFR resistance mutations.