EGFR inhibitors for use in the treatment of EGFR exon 20 mutation-positive lung cancer

Abstract

This disclosure relates to a method for treating EGFR exon 20 mutation-positive lung cancer (e.g., small cell lung cancer) in a patient requiring treatment, wherein the patient is given formula (I) as described herein: JPEG2026530494000024.jpg5955(I) The method is characterized by administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] (Cross-reference to Related Applications) This application claims the priority benefit of U.S. Provisional Patent Application No. 63 / 535,905, filed on August 31, 2023, the entire content of which is incorporated herein by reference.

[0002] (Sequence Listing) This application contains a Sequence Listing that has been submitted electronically in XML format named 50006-0118WO1_ST26_SL.XML. The XML file, created on August 29, 2024, has a size of 3,075 bytes. The entire content of the XML file is incorporated herein by reference.

[0003] The present disclosure features a method for treating EGFR exon 20 mutation-positive lung cancer (e.g., small cell lung cancer) in a subject in need of treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof. [Background Art]

[0004] Epidermal growth factor receptors (EGFR, ERBB1) and human epidermal growth factor receptor 2 (HER2, ERBB2) are members of a family of proteins that regulate cellular processes involved in tumor growth, including proliferation and differentiation. The roles that EGFR and HER2 play in development and cancer have been demonstrated by multiple researchers (reviewed in Salomon, et al., Crit. Rev. Oncol. Hematol. (1995) 19:183-232, Klapper, et al., Adv. Cancer Res. (2000) 77, 25-79 and Hynes and Stern, Biochim. Biophys. Acta (1994) 1198:165-184). EGFR overexpression is present in at least 70% of human cancers, including non-small cell lung cancer (NSCLC), breast cancer, glioma, and prostate cancer. HER2 overexpression occurs in approximately 30% of all breast cancers. Furthermore, HER2 is involved in other human cancers, including those of the colon, ovaries, bladder, stomach, esophagus, lung, uterus, and prostate. In addition, HER2 overexpression is associated with poor prognosis in human cancers, including metastasis and early recurrence.

[0005] Therefore, EGFR and HER2 are widely recognized as targets in the design and development of therapies that can specifically bind to and inhibit tyrosine kinase activity and its signaling pathways within cancer cells, and thus function as diagnostic or therapeutic agents. For example, EGFR tyrosine kinase inhibitors (TKIs) are an effective clinical therapy for patients with advanced non-small cell lung cancer (NSCLC) with EGFR mutations. However, the majority of patients experience disease progression after successful treatment with EGFR TKIs. Common resistance mechanisms include acquired secondary mutations such as T790M, C797S, and EGFR exon 20 insertion mutations. For example, NSCLC tumors may have EGFR exon 20 insertion mutations that are inherently resistant to current EGFR TKIs.

[0006] Overexpression of another protein, BUB1 (benzimidazole-free budding, BUB1) kinase, is often associated with proliferating cells and tissues, including cancer cells (Bolanos-Garcia VM and Blundell TL, Trends Biochem. Sci. 36, 141, 2010). This protein is an essential component of the complex network of proteins that form the mitotic checkpoint. The primary function of an unfulfilled mitotic checkpoint is to keep the anaphase-promoting complex / cyclosome (APC / C) inactive. As soon as the checkpoint is filled, the APC / C ubiquitin ligase targets cyclin B and securin to induce proteolysis, leading to the segregation of paired chromosomes and their exit from mitosis.

[0007] Incomplete mitotic checkpoint function has been associated with aneuploidy and tumorigenesis (see Weaver BA and Cleveland DW, Cancer Res. 67, 10103, 2007; King RW, Biochim Biophys Acta 1786, 4, 2008). In contrast, complete inhibition of the mitotic checkpoint is recognized to lead to severe chromosome misdistribution and induction of apoptosis in tumor cells (see Kops GJ et al., Nature Rev. Cancer 5, 773, 2005; Schmidt M and Medema RH, Cell Cycle 5, 159, 2006; Schmidt M and Bastians H, Drug Res. Updates 10, 162, 2007). Therefore, inhibition of the mitotic checkpoint via BUB1 kinase inhibition represents an approach for treating proliferative disorders, including solid tumors such as carcinomas, sarcomas, leukemias, and lymphoid malignancies, or other disorders associated with uncontrolled cell proliferation.

[0008] WO 2022 / 066734 (which is incorporated herein by reference in its entirety) is defined by the following general formula: [ka] This document discloses compounds having [a certain characteristic].

[0009] The aforementioned compounds are described as having activity as inhibitors of EGFR and / or HER2. [Overview of the initiative]

[0010] This disclosure relates to a method for treating EGFR exon 20 mutation-positive lung cancer (e.g., small cell lung cancer) in a patient requiring treatment, wherein the patient is given formula (I) as described herein: [ka] (I) The method is characterized by administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.

[0011] This disclosure is based in part on the finding that compounds of formula (I) are useful in treating EGFR exon 20 mutation-positive lung cancer (e.g., non-small cell lung cancer).

[0012] The compound of formula (I) is described as compound 362 in WO 2022 / 066734. The compound exhibits potent and selective inhibition of EGFR, for example, showing stronger inhibition against EGFR with one or more mutations compared to inhibition against wild-type EGFR. For example, compound 362 in WO 2022 / 066734 shows stronger inhibition against EGFR including EGFR kinase protein insertions (e.g., exon 20 insertions) compared to inhibition against wild-type EGFR.

[0013] Accordingly, in one embodiment, the present disclosure is a method for treating EGFR exon 20 mutation-positive lung cancer in a patient requiring treatment, comprising administering to the patient a therapeutically effective dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0014] In another aspect, the present disclosure features a method of treating EGFR exon 20 mutation-positive non-small cell lung cancer in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0015] In yet another aspect, the present disclosure features a method of treating EGFR exon 20 insertion mutation-positive lung cancer in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0016] In yet another aspect, the present disclosure features a method of treating EGFR exon 20 insertion mutation-positive non-small cell lung cancer in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0017] Embodiments can include one or more of the following features.

[0018] The lung cancer can be non-small cell lung cancer, small cell lung cancer or pulmonary adenocarcinoma, pulmonary sarcomatoid carcinoma, or any combination thereof.

[0019] The lung cancer can be non-small cell lung cancer.

[0020] The method may further comprise determining (or having determined) that the lung cancer (e.g., non-small cell lung cancer) is EGFR exon 20 mutation-positive.

[0021] The method may further comprise identifying a patient having EGFR exon 20 mutation-positive lung cancer (e.g., non-small cell lung cancer) (e.g., identifying a patient having a clinical record indicating that the patient has EGFR exon 20 mutation-positive lung cancer (e.g., non-small cell lung cancer)).

[0022] The EGFR exon 20 mutation can be an EGFR exon 20 insertion mutation.

[0023] In some embodiments, the exon 20 insertion is selected from the group consisting of V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX and H773_V774insX. For example, the exon 20 insertion is selected from the group consisting of A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP, H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH and P772_H773insPNP; or any combination thereof; for example, any two or more independently selected exon 20 insertions; for example, any two independently selected exon 20 insertions (e.g., V769_D770insASV and D770_N771insSVD).

[0024] In a specific embodiment, the cancer is lung cancer, and the exon 20 insertion is V769_D770insASV.

[0025] In a specific embodiment, the cancer is lung cancer, and the exon 20 insertion is D770_N771insSVD.

[0026] In a specific embodiment, the cancer is non-small cell lung cancer, and the exon 20 insertion is V769_D770insASV.

[0027] In a specific embodiment, the cancer is non-small cell lung cancer, and the exon 20 insertion is D770_N771insSVD.

[0028] The patient may have a histologically or cytologically confirmed diagnosis of stage IIIB / C or IV NSCLC that is not eligible for curative surgery or chemoradiotherapy.

[0029] The presence of EGFR exon 20 mutations can be determined by FDA-approved tests based on polymerase chain reaction (PCR) or NGS, or as part of routine clinical care in a CLIA-certified or similarly accredited laboratory.

[0030] The patient has a new or recent tumor biopsy (preferably taken at the time of screening) or a stored tumor specimen taken within the last 10 years, available for genomic profiling.

[0031] The patient may have at least one (e.g., at least two, at least three, at least four, at least five) tumor lesions measurable according to RECIST v1.1.

[0032] The patient is 18 years of age or older at the time of signing the ICF.

[0033] The patient may have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

[0034] This method may further include providing biological samples from patients.

[0035] This method may further include determining (or having determined) that the patient does not simultaneously have the T790M and C797S resistance mutations.

[0036] The patient has relapsed or is resistant to one or more previous anticancer therapies.

[0037] In certain embodiments, one or more prior anticancer therapies include one or more chemotherapeutic agents, checkpoint inhibitors, targeted anticancer therapies, or kinase inhibitors, or a combination thereof.

[0038] For example, one or more previous anticancer therapies include carboplatin, paclitaxel, gemcitabine, cisplatin, vinorelbine, docetaxel, palbociclib, crizotinib, and PD-(L)1 axis inhibitors. This includes EGFR inhibitors, c-Met inhibitors, HER2 inhibitors, HER3 inhibitors, HER4 inhibitors, VEGFR inhibitors, AXL inhibitors, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib, or any combination thereof. In embodiments, the patient has previously received or is currently receiving treatment with one or more of the above therapies.

[0039] The patient may be untreated.

[0040] This method may further include administering one or more anti-cancer therapies to the patient.

[0041] In certain embodiments, one or more anticancer therapies include chemotherapy, radiotherapy, surgery, targeted anticancer therapy, kinase inhibitors, or a combination thereof.

[0042] In certain embodiments, the kinase inhibitor is an EGFR inhibitor, c-Met inhibitor, HER2 inhibitor, HER3 inhibitor, HER4 inhibitor, VEGFR inhibitor, or AXL inhibitor. For example, the kinase inhibitor may be lazertinib, poziotinib, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

[0043] The patient can be a human being.

[0044] Additional definitions To facilitate understanding of the disclosures contained herein, some additional terms are defined below. In general, the terminology and experimental techniques in organic chemistry, medicinal chemistry, and pharmacology used herein are well known and commonly used by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. Every patent, application, published application, and other publication referenced throughout this specification and its appendices is incorporated herein by reference.

[0045] As used herein, the term “acceptable” with respect to a formulation, composition, or component means that it does not cause any lasting adverse effects on the systemic health of the patient being treated.

[0046] As used herein, the terms “effective dose” or “therapeutic effective dose” mean the amount of chemical substance administered that is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. Results include reduction and / or mitigation of the signs, symptoms, or causes of the disease, or other desirable changes in the biological system. For example, “effective dose” in therapeutic use means the amount of a composition containing the compound described herein that is necessary to produce a clinically significant reduction in the symptoms of the disease. The appropriate “effective” dose in any individual case is determined using appropriate techniques, such as dose-escalation studies.

[0047] As used herein, the terms “additive” or “pharmaceutically acceptable additive” mean a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense that it is compatible with other components of the pharmaceutical formulation and is suitable for use in contact with human and animal tissues or organs without causing excessive toxicity, irritation, allergic reactions, immunogenicity or other problems or complications, in light of a reasonable benefit-risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Reformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0048] As used herein, the term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not impair the biological activity and properties of the compound. In certain cases, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. In some cases, pharmaceutically acceptable salts are obtained by reacting the acidic compounds described herein with a base to form salts, such as ammonium salts, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), salts of organic bases (e.g., dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine), and salts of amino acids (e.g., arginine, lysine, etc.), or by other conventionally known methods. Pharmacologically acceptable salts are not particularly limited as long as they are usable as pharmaceuticals. Examples of salts formed by the compounds described herein with bases include salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may also be acid addition salts, specifically including acid addition salts with the following: inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids, such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and acidic amino acids, such as aspartic acid and glutamic acid.

[0049] As used herein, the term “pharmaceutical composition” means a mixture of the compounds described herein with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents and / or thickeners (collectively referred to herein as “additives”). Pharmaceutical compositions facilitate the administration of compounds to living organisms. In the art, there are several techniques for administering compounds, including, but not limited to, rectal administration, oral administration, intravenous administration, aerosol administration, non-enteral administration, ophthalmic administration, pulmonary administration and topical administration.

[0050] As used herein, the terms “treatment” or “to treat” mean therapeutic or palliative measures. Beneficial or desirable clinical outcomes include, but are not limited to, relief of all or part of the symptoms associated with the disease, disability, or condition; reduction of the severity of the disease; stabilization of the state of disease (i.e., no worsening); delay or slowing of disease progression; improvement or relief of the state of disease (e.g., one or more symptoms of the disease); and remission (whether partial or complete, and whether detectable or not). “Treatment” may also mean extending survival compared to the survival expected without treatment.

[0051] Details of one or more embodiments of the present invention are described below. Other features and advantages of the methods described herein will become apparent from the specification and claims.

[0052] Detailed explanation This disclosure relates to a method for treating EGFR exon 20 mutation-positive lung cancer (e.g., small cell lung cancer) in a patient requiring treatment, comprising administering to the subject a therapeutically effective dose of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof.

[0053] general In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable additives, and optionally one or more additional therapeutic agents as described herein.

[0054] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with one or more conventional pharmaceutical additives. Examples of pharmaceutically acceptable additives include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), e.g., d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, e.g., tweens, poloxamers or other similar polymer delivery matrices, serum proteins, e.g., human serum albumin, buffers, e.g., phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, and lanolin. Cyclodextrins, such as α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkylcyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrin), or other solubilized derivatives, can also be used to improve the delivery of the compounds described herein. Dosage forms or compositions can be prepared containing the chemicals described herein in an amount ranging from 0.005% to 100%, with the remainder consisting of non-toxic excipients. The compositions intended may contain 0.001% to 100% of the chemicals provided herein. In one embodiment, it may contain 0.1% to 95%, in another embodiment 75% to 85%, and in yet another embodiment 20% to 80%. Methods for preparing such dosage forms are known or apparent to those skilled in the art, for example, Remington: The Science and Practice of Pharmacy, 22 ndSee Edition (Pharmaceutical Press, London, UK. 2012).

[0055] Route of administration and compositional components In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered to a patient in need by any known route of administration. Acceptable routes of administration include buccal, cutaneous, intracervical, endoneurial, intratracheal, enteral, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intrabursal, intracerebral, intracisional, coronary, intradermal, intraductal, duodenal, intradural, intraepidermal, esophageal, intragastric, intragingival, intraileal, lymphatic, and intramedullary. Administration routes include, but are not limited to, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intranasal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, transnasal, transnasogastric, oral, non-enteral, percutaneous, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, intraureteral, intraurethral, ​​and vaginal. In certain embodiments, the preferred route of administration is non-enteral (e.g., intratumoral).

[0056] The composition can be formulated for non-enteral administration, for example, for injection via intravenous, intramuscular, subcutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectable preparations, and may be prepared as liquid solutions or suspensions, or as solid forms suitable for preparing solutions or suspensions by adding liquid before injection; the formulations may also be emulsions. The preparation of such formulations is known to those skilled in the art in light of the disclosure herein.

[0057] Suitable pharmaceutical forms for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for preparing sterile injectable solutions or dispersions at the time of use. In all cases, the form must be sterile and have sufficient fluidity for easy injection. It must also be stable under manufacturing and storage conditions and be protected from contamination by microorganisms such as bacteria and fungi.

[0058] The carrier may also be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol) and suitable mixtures thereof, as well as vegetable oils. Appropriate fluidity can be maintained, for example, by the use of coating agents such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. In many cases, it is preferable to include isotonic agents, such as sugars or sodium chloride. Sustained absorption of the injectable composition can be achieved by using absorption retarders, such as aluminum monostearate or gelatin, in the composition.

[0059] Sterile injectable solutions are prepared by dissolving the required amount of active compound in a suitable solvent, along with other components as specified above, and then sterilizing by filtration. Generally, dispersions are prepared by incorporating various sterile active ingredients into a sterile vehicle containing a basic dispersion medium and other necessary components as specified above. For sterile powders for the preparation of sterile injectable solutions, preferred preparation methods are vacuum drying and freeze-drying, which yield a powder containing the active ingredient and other components as specified, from a pre-sterile filtered solution.

[0060] Intratumoral injection is discussed, for example, in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia. 2006, 10, 788-795.

[0061] Pharmacovigilant additives that can be used in rectal compositions as gels, creams, enemas or rectal suppositories include, but are not limited to, cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (such as PEG ointment), glycerin, glyceryl gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and polyethylene glycol fatty acid esters, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, and anoxide. SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomer, carbopol, methyl oxybenzoate, macrogol cetostearyl ether, cocoyl caprylate, isopropyl alcohol, propylene glycol, liquid paraffin, zanthang gum, carboxymethabisulfite, sodium edetate, sodium benzoate, potassium methabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, and one or more vitamins, such as vitamins A and E and potassium acetate.

[0062] In certain embodiments, suppositories can be prepared by mixing the chemicals described herein with suitable, non-irritating additives or carriers such as cocoa butter, polyethylene glycol, or suppository wax, which are solid at room temperature but liquid at body temperature, and thus melt in the rectum to release the active compound. In other embodiments, compositions for rectal administration are in the form of enemas.

[0063] Examples of solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical is mixed with one or more pharmaceutically acceptable excipients, e.g., sodium citrate or dicalcium phosphate and / or: a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol and silicic acid; b) binders, e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) wetting agents, e.g., glycerol; d) disintegrants, e.g., agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) dissolution retarders, e.g., paraffin; f) absorption enhancers, e.g., quaternary ammonium compounds; g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; h) adsorbents, e.g., kaolin and bentonite clay; and i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form further includes a buffer. Similar types of solid compositions can also be used as fillers for soft gelatin capsules and hard gelatin capsules, with additives such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0064] In one embodiment, the composition may take the form of a unit dosage form such as a pill or tablet, and thus the composition may contain, along with the chemicals provided herein, diluents such as lactose, sucrose, dicalcium phosphate, etc.; lubricants such as magnesium stearate, etc.; and binders such as starch, acacia gum, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives, etc. Other solid dosage forms include powders, pills (marume), solutions or suspensions (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) encapsulated in capsules (gelatin or cellulose-based capsules). Unit dosage forms in which one or more chemicals or additional active ingredients provided herein are physically separated are also conceivable, such as capsules containing granules (or tablets within capsules) of each drug, two-layer tablets, two-chamber gel capsules, etc. Enteric-coated or delayed-release oral dosage forms are also conceivable.

[0065] Other physiologically acceptable compounds include wetting agents, emulsifiers, dispersants, or preservatives particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known, such as phenol and ascorbic acid.

[0066] In certain embodiments, the additives are sterile and substantially free of generally undesirable substances. These compositions can be sterilized by conventionally known sterilization techniques. For additives in various oral dosage forms, such as tablets and capsules, sterility is not required. USP / NF standards are usually sufficient.

[0067] In certain embodiments, the solid oral dosage form may further include one or more components that chemically and / or structurally adapt the composition to deliver the chemical to the stomach or lower gastrointestinal tract, such as the ascending colon and / or transverse colon and / or distal colon and / or small intestine. A typical formulation technique is described, for example, Filipski, KJ, et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.

[0068] Examples include upper gastrointestinal tract targeting technologies such as accordion pills (Intec Pharma), floating capsules, and materials that can adhere to the mucosal wall.

[0069] Other examples include lower gastrointestinal tract targeting technologies. Various enteric / pH-responsive coatings and additives are available to target specific sites within the intestinal tract. These materials are typically polymers designed to dissolve or erode within a specific pH range and are selected based on the gastrointestinal region that will be the desired drug release site. These materials also serve to protect acid-unstable drugs from gastric juice or to limit exposure if the active ingredient irritates the upper gastrointestinal tract (e.g., hydroxypropyl methylcellulose phthalate systems, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit systems (methacrylate-methyl methacrylate copolymer), and Marcoat). Other technologies include dosage forms that react to local microbiota in the gastrointestinal tract, pressure-controlled colon delivery capsules, and Pulsincap.

[0070] Ophthalmic compositions may, but are not limited to, include one or more of the following: viscosity modifiers (viscogen) (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (ternary block copolymer), cyclodextrin); and preservatives (e.g., benzalkonium chloride, EDTA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0071] Topical compositions may include ointments and creams. Ointments are typically semi-solid formulations with a base of petrolatum or other petroleum-derived substances. Creams containing selected active ingredients are typically viscous liquids or semi-solid emulsions, often oil-in-water or water-in-oil. Cream bases are typically washable with water and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also called the "internal phase," generally consists of petrolatum and aliphatic alcohols such as cetyl alcohol or stearyl alcohol; the aqueous phase usually exceeds the oil phase by volume, though not necessarily, and generally contains a humectant. Emulsifiers in cream formulations are typically nonionic, anionic, cationic, or amphoteric surfactants. Like other carriers or vehicles, ointment bases should be inert, stable, non-irritating, and non-sensitizing.

[0072] In any of the embodiments described herein, the pharmaceutical composition may include one or more of the following: lipids, interlayer crosslinked multilayer vesicles, biodegradable poly(D,L-lactic acid-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or fine particles, and nanoporous particle-supporting lipid bilayers.

[0073] dose Dosage may vary depending on the patient's needs, the severity of the condition being treated, and the specific compound used. Determining the appropriate dose in a particular situation can be done by those skilled in the medical field. The total daily dose may be administered in divided doses throughout the day, or by means of providing continuous delivery.

[0074] In some embodiments, the compounds described herein are present in concentrations of about 0.001 mg / kg to about 500 mg / kg (for example, about 0.001 mg / kg to about 200 mg / kg; about 0.01 mg / kg to about 200 mg / kg; about 0.01 mg / kg to about 150 mg / kg; about 0.01 mg / kg to about 100 mg / kg; about 0.01 mg / kg to about 50 mg / kg; about 0.01 mg / kg to about 10 mg / kg; about 0.01 mg / kg to about 5 mg / kg; about 0.01 mg / kg to about 1 mg / kg). It is administered in doses of approximately g / kg (approximately 0.01 mg / kg to approximately 0.5 mg / kg; approximately 0.01 mg / kg to approximately 0.1 mg / kg; approximately 0.1 mg / kg to approximately 200 mg / kg; approximately 0.1 mg / kg to approximately 150 mg / kg; approximately 0.1 mg / kg to approximately 100 mg / kg; approximately 0.1 mg / kg to approximately 50 mg / kg; approximately 0.1 mg / kg to approximately 10 mg / kg; approximately 0.1 mg / kg to approximately 5 mg / kg; approximately 0.1 mg / kg to approximately 1 mg / kg; approximately 0.1 mg / kg to approximately 0.5 mg / kg).

[0075] regimen The aforementioned doses may be administered daily (for example, as a single dose or in two or more divided doses), or non-daily (for example, every other day, every two days, every three days, once a week, twice a week, once every two weeks, or once a month).

[0076] In some embodiments, the duration of administration of the compounds described herein may be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In a further embodiment, the period during which administration is stopped may be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In one embodiment, the therapeutic compound is administered to an individual for a certain period, followed by another period. In another embodiment, the therapeutic compound is administered for a first period, then stopped for a second period, then resumed for a third period, and then stopped again for a fourth period. In one aspect of this embodiment, the period of administration of the therapeutic compound and the subsequent period during which administration is stopped are repeated over a predetermined or indefinite period. In a further instance, the duration of administration may be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In a further instance, the period during which administration is discontinued may be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer.

[0077] In some embodiments, dysregulation of expression, activity, or level related to the EGFR gene, EGFR kinase, or either thereof involves the insertion of one or more residues in exon 20 of the EGFR gene (e.g., any of the exon 20 insertions listed in Tables 1a and 1b). Exon 20 of EGFR has two main regions: a c-helix (residues 762-766) and a loop following the c-helix (residues 767-774). Studies have suggested that some exon 20 insertions (e.g., insertions after residue 764) lead to the formation of a stabilized and rigid active conformation, inducing resistance to first-generation EGFR inhibitors. In some embodiments, dysregulation of expression, activity, or level of the EGFR gene, EGFR kinase, or any of them includes the insertion of one or more residues in exon 20 selected from the group consisting of V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX. For example, EGFR kinase protein insertions include A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP, H773_V7 It may be an exon 20 insertion selected from the group consisting of 74insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH, and P772_H773insPNP; or any combination thereof; for example, two or more independently selected exon 20 insertions; for example, any two independently selected exon 20 insertions (e.g., V769_D770insASV and D770_N771insSVD).

[0078] [Table 1-1] Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6

[0079] Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6

[0080] In some embodiments, dysregulation of expression, activity, or level related to the EGFR gene, EGFR kinase, or either thereof includes splice mutations in EGFR mRNA, which result in the expression of a protein that is an alternative splicing variant of EGFR lacking at least one residue (compared to wild-type EGFR kinase), and consequently, constitutive activation of the EGFR kinase domain.

[0081] In some embodiments, dysregulation of expression, activity, or level relating to the EGFR gene, EGFR kinase, or either thereof includes at least one point mutation in the EGFR gene, which results in the production of an EGFR kinase having one or more amino acid substitutions, insertions, or deletions compared to wild-type EGFR kinase. In some cases, the resulting EGFR kinase exhibits greater resistance to inhibition by one or more first EGFR inhibitors (e.g., inhibition of signaling activity) compared to wild-type EGFR kinase or EGFR kinase without the same mutation. Such mutations optionally do not reduce the sensitivity of cancer cells or tumors having the EGFR kinase to treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compared to cancer cells or tumors without the particular EGFR inhibitor resistance mutation).

[0082] In other embodiments, dysregulation of expression, activity, or level relating to the EGFR gene, EGFR kinase, or either thereof includes at least one point mutation in the EGFR gene, which results in the production of an EGFR kinase having one or more amino acid substitutions compared to wild-type EGFR kinase, and is pharmaceutically acceptable to the compound of formula (I) or a pharmaceutically acceptable salt thereof compared to wild-type EGFR kinase or an EGFR kinase without the same mutation. In such embodiments, the EGFR inhibitor resistance mutation is pharmaceutically acceptable in the presence of the compound of formula (I) or a pharmaceutically acceptable salt thereof compared to wild-type EGFR kinase or an EGFR kinase without the same mutation. max Increase, K mThe decrease in K D This can result in EGFR kinase having one or more of the following decreased levels.

[0083] Exemplary sequence of mature human EGFR protein (UniProtKB entry P00533) (SEQ ID NO: 1) MRPSGTAGAA LLALLAALCP ASRALEEKKV CQGTSNKLTQ LGTFEDHFLS LQRMFNNCEV VLGNLEITYV QRNYDLSFLK TIQEVAGYVL IALNTVERIP LENLQIIRGN MYYENSYALA VLSNYDANKT GLKELPMRNL QEILHGAVRF SNNPALCNVE SIQWRDIVSS DFLSNMSMDF QNHLGSCQKC DPSCPNGSCW GAGEENCQKL TKIICAQQCS GRCRGKSPSD CCHNQCAAGC TGPRESDCLV CRKFRDEATC KDTCPPLMLY NPTTYQMDVN PEGKYSFGAT CVKCCPRNYV VTDHGSCVRA CGADSYEMEE DGVRKCKKCE GPCRKVCNGI GIGEFKDSLS INATNIKHFK NCTSISGDLH ILPVAFRGDS FTHTPPLDPQ ELDILKTVKE ITGFLLIQAW PENRTDLHAF ENLEIIRGRT KQHGQFSLAV VSLNITSLGL RSLKEISDGD VIISGNKNLC YANTINWKKL FGTSGQKTKI ISNRGENSCK ATGQVCHALC SPEGCWGPEP RDCVSCRNVS RGRECVDKCN LLEGEPREFV ENSECIQCHP ECLPQAMNIT CTGRGPDNCI QCAHYIDGPH CVKTCPAGVM GENNTLVWKY ADAGHVCHLC HPNCTYGCTG PGLEGCPTNG PKIPSIATGM VGALLLLLVV ALGIGLFMRR RHIVRKRTLR RLLQERELVE PLTPSGEAPN QALLRILKET EFKKIKVLGS GAFGTVYKGL WIPEGEKVKI PVAIKELREA TSPKANKEIL DEAYVMASVD NPHVCRLLGI CLTSTVQLIT QLMPFGCLLD YVREHKDNIG SQYLLNWCVQ IAKGMNYLED RRLVHRDLAA RNVLVKTPQH VKITDFGLAK LLGAEEKEYH AEGGKVPIKW MALESILHRI YTHQSDVWSY GVTVWELMTF GSKPYDGIPA SEISSILEKG ERLPQPPICT IDVYMIMVKC WMIDADSRPK FRELIIEFSK MARDPQRYLV IQGDERMHLP SPTDSNFYRA LMDEEDMDDV VDADEYLIPQ QGFFSSSPSTS RTPLLSSLSA TSNNSTVACI DRNGLQSCPI KEDSFLQRYS SDPTGALTED SIDDTFLPVP EYINQSVPKR PAGSVQNPVY HNQPLNPAPS RDPHYQDPHS TAVGNPEYLN TVQPTCVNST FDSPAHWAQK GSHQISLDNP DYQQDFFPKE AKPNGIFKGS TAENAEYLRV APQSSEFIGA

[0084] In some embodiments, dysregulation of expression, activity, or level related to the EGFR gene, EGFR kinase, or any of them includes at least one EGFR inhibitor resistance mutation in the EGFR gene, which results in the production of EGFR kinase having one or more amino acid substitutions, insertions, or deletions as described in Tables 2a and 2b. In some embodiments, compounds of formula (I) and their pharmaceutically acceptable salts and solvates are useful for treating patients with cancers having EGFR inhibitor-resistant mutations (e.g., those resulting in increased resistance to a first EGFR inhibitor, e.g., substitutions at amino acid positions 718, 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A) and / or one or more EGFR inhibitor-resistant mutations listed in Tables 2a and 2b) by combination administration with existing drug treatments (e.g., other EGFR inhibitors, e.g., a first EGFR inhibitor and / or a second EGFR inhibitor) or by administration as a successor or add-on therapy (e.g., follow-up therapy) to existing drug treatments (e.g., other EGFR inhibitors, e.g., a first EGFR inhibitor and / or a second EGFR inhibitor).

[0085] [Table 3]

[0086] [Table 4-1] [Table 4-2]

[0087] In some embodiments, the amino acid substitutions / insertions / deletions of the EGFR protein include one or more (e.g., any two) of the amino acid substitutions / insertions / deletions of the EGFR protein shown in Tables 1a, 1b and / or 2a, 2b, for example, one or more (e.g., any two) of the amino acid substitutions / insertions / deletions of the EGFR protein independently selected from: V769L;V769M;M766delinsMASVx2;A767_ V769dupASV;A767delinsASVDx3;A767delinsASVG;S768_V769insX;V769_D770insX;V769_D770insASV;D770delinsDN;D770delinsDNPH;D770_N771insSV;N771delinsNPH;N771_H773dup;L858R / C797S (or C797G); or Del_19 and C797S (or C797G), or any combination thereof.

[0088] As used herein, “first inhibitor of EGFR” or “first EGFR inhibitor” is an EGFR inhibitor as defined herein, but does not contain the compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof. As used herein, “second inhibitor of EGFR” or “second EGFR inhibitor” is an EGFR inhibitor as defined herein, but does not contain the compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof. If both a first and a second EGFR inhibitor are present in the methods described herein, the first and second EGFR inhibitors are distinct from each other. In some embodiments, the first and / or second EGFR inhibitors bind to different sites than the compound of formula (I). For example, in some embodiments, the first and / or second EGFR inhibitors may inhibit EGFR dimerization, while the compound of formula (I) may inhibit the active site. In some embodiments, the first EGFR inhibitor and / or the second EGFR inhibitor may be allosteric inhibitors of EGFR, while the compound of formula (I) may inhibit the active site of EGFR.

[0089] In this specification, exemplary first and second EGFR inhibitors are described. In some embodiments, the first or second EGFR inhibitor may be selected from the group consisting of osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.

[0090] In some embodiments, compounds of formula (I) or pharmaceutically acceptable salts and solvates thereof are useful for treating cancers identified as having one or more EGFR inhibitor resistance mutations (mutations resulting in increased resistance to a first or second EGFR inhibitor, e.g., substitutions listed in Tables 2a and 2b (substitutions at amino acid positions 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A))). In some embodiments, one or more EGFR inhibitor resistance mutations occur in the nucleic acid sequence encoding a mutant EGFR protein (e.g., a mutant EGFR protein having any of the mutations listed in Tables 2a and 2b), resulting in a mutant EGFR protein exhibiting EGFR inhibitor resistance.

[0091] The epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases (RTKs) and plays a crucial role in the physiological function of epithelial cells (Schlessinger J (2014) Cold Spring Harb Perspect Biol 6, a008912). It is frequently mutated and / or overexpressed in various human cancers and is a target of several cancer therapies currently employed in clinical practice (Yarden Y and Pines G (2012) Nat Rev Cancer 12, 553-563).

[0092] Accordingly, the Specified provides a method for treating a patient diagnosed with (or identified as having) cancer, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0093] Furthermore, this specification also provides a method for treating a patient identified or diagnosed with EGFR-related cancer, comprising administering to the patient a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In some embodiments, the patient is identified or diagnosed with EGFR-related cancer by using a regulatory agency-approved (e.g., FDA-approved) test or assay to identify dysregulation of expression, activity or level of the EGFR gene, EGFR kinase, or any of them in the patient or a biopsy sample from the patient, or by performing any non-limiting example of the assay described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is EGFR-related cancer. For example, EGFR-related cancer may be a cancer containing one or more EGFR inhibitor resistance mutations.

[0094] The term "regulatory agency" refers to a national agency that approves the medical use of pharmaceuticals in a given country. For example, a non-specific example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0095] Furthermore, this specification provides a method for treating cancer in a patient requiring treatment, comprising: (a) detecting EGFR-related cancer in the patient; and (b) administering to the patient a therapeutically effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof. Some embodiments of these methods further include administering to the patient another anticancer agent (e.g., a second EGFR inhibitor or a pharmaceutically acceptable salt thereof, or immunotherapy). In some embodiments, the patient has been previously treated with a first EGFR inhibitor or previously treated with other anticancer treatments (e.g., at least partial resection of the tumor or radiotherapy). In some embodiments, the patient is identified as having EGFR-related cancer by identifying dysregulation of expression, activity or level of the EGFR gene, EGFR kinase, or any of them in the patient or a biopsy sample from the patient using a regulatory agency-approved (e.g., FDA-approved) test or assay, or by performing any of the non-limiting assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is EGFR-related cancer. For example, EGFR-related cancers may be cancers that contain one or more EGFR inhibitor resistance mutations.

[0096] Furthermore, this specification also provides a method for treating a patient, comprising performing an assay on a sample obtained from the patient to determine whether the patient has dysregulation of expression, activity, or level related to the EGFR gene, EGFR kinase, or either thereof, and administering (e.g., specifically or selectively) a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof to the patient determined to have dysregulation of expression, activity, or level related to the EGFR gene, EGFR kinase, or either thereof. Some embodiments of these methods further include administering another anticancer agent to the patient (e.g., a second EGFR inhibitor or a pharmaceutically acceptable salt thereof, or immunotherapy). In some embodiments of these methods, the patient has previously been treated with the first EGFR inhibitor or with other anticancer treatments (e.g., at least partial resection of the tumor or radiotherapy). In some embodiments, the patient is a patient suspected of having EGFR-related cancer, a patient exhibiting one or more symptoms of EGFR-related cancer, or a patient at high risk of developing EGFR-related cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory-approved assay, e.g., an FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays that may be used in these methods are described herein. Additional assays are also known in the art. In some embodiments, dysregulation of expression, activity, or level relating to the EGFR gene, EGFR kinase, or any of them includes one or more EGFR inhibitor resistance mutations.

[0097] Furthermore, this specification also provides a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in the treatment of EGFR-related cancer in patients identified or diagnosed with EGFR-related cancer via a step of performing an assay (e.g., an in vitro assay) on a sample obtained from a patient to determine whether the patient has dysregulation of expression, activity, or level related to the EGFR gene, EGFR kinase, or any of the same (where, if dysregulation of expression, activity, or level related to the EGFR gene, EGFR kinase, or any of the same is present, the patient is identified as having EGFR-related cancer). Also provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for treating EGFR-related cancer in patients identified or diagnosed with EGFR-related cancer via a step of performing an assay on a sample obtained from a patient to determine whether the patient has dysregulation of expression, activity, or level related to the EGFR gene, EGFR kinase, or any of the same (where, if dysregulation of expression, activity, or level related to the EGFR gene, EGFR kinase, or any of the same is present, the patient is identified as having EGFR-related cancer). Some embodiments of any method or use described herein further include recording in the patient's clinical record (e.g., on a computer-readable medium) that, through the performance of an assay, the patient has been determined to have dysregulation of expression, activity or level relating to the EGFR gene, EGFR kinase, or either thereof, and that the patient should be administered a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, e.g., an FDA-approved kit. In some embodiments, the assay is a liquid biopsy. In some embodiments, the dysregulation of expression, activity or level relating to the EGFR gene, EGFR kinase, or either thereof includes one or more EGFR inhibitor resistance mutations.

[0098] Furthermore, this specification also provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the treatment of cancer in patients requiring treatment or in patients identified or diagnosed with EGFR-related cancer. Also provided is the use of compounds of formula (I) or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for the treatment of cancer in patients identified or diagnosed with EGFR-related cancer. In some embodiments, the cancer is an EGFR-related cancer, for example, an EGFR-related cancer having one or more EGFR inhibitor resistance mutations. In some embodiments, the patient is identified or diagnosed with EGFR-related cancer by using a regulatory agency-approved (e.g., FDA-approved) kit for identifying dysregulation of expression, activity, or level of the EGFR gene, EGFR kinase, or any of them in the patient or a biopsy sample from the patient. EGFR-related cancers provided herein include those described herein and those known to those skilled in the art.

[0099] In any of the methods or uses described herein, in some embodiments, the patient is identified or diagnosed with cancer having dysregulation of expression, activity, or level related to the EGFR gene, EGFR kinase, or any of them. In any of the methods or uses described herein, the patient has a tumor that is positive for dysregulation of expression, activity, or level related to the EGFR gene, EGFR kinase, or any of them. In any of the methods or uses described herein, the patient may be a patient with a tumor(s) that are positive for dysregulation of expression, activity, or level related to the EGFR gene, EGFR kinase, or any of them. In any of the methods or uses described herein, the patient may be a patient whose tumor has dysregulation of expression, activity, or level related to the EGFR gene, EGFR kinase, or any of them. In any of the methods or uses described herein, the patient is a patient suspected of having EGFR-related cancer (e.g., cancer with one or more EGFR inhibitor resistance mutations). In some embodiments, this specification provides a method for treating EGFR-related cancer in a patient requiring treatment, comprising: a) detecting dysregulation of expression, activity, or level of the EGFR gene, EGFR kinase, or any of them in a sample from the patient; and b) administering a therapeutically effective dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, dysregulation of expression, activity, or level of the EGFR gene, EGFR kinase, or any of them includes point mutations / insertions / deletions of one or more EGFR kinase proteins. Non-limiting examples of point mutations / insertions / deletions of EGFR kinase proteins are listed in Tables 1a and 1b. In some embodiments, point mutations / insertions / deletions of the EGFR kinase protein are selected from the group consisting of G719S, G719C, G719A, L747S, D761Y, T790M, T854A, L858R, L861Q, deletions in exon 19 (e.g., L747_A750del), and insertions in exon 20.In some embodiments, point mutations / insertions / deletions of the EGFR kinase protein are selected from the group consisting of L858R, exon 19 deletions (e.g., L747_A750del), L747S, D761Y, T790M, and T854A. In some embodiments, dysregulation of expression, activity, or level relating to the EGFR gene, EGFR kinase, or any of them includes one or more EGFR inhibitor resistance mutations. Non-limiting examples of EGFR inhibitor resistance mutations are listed in Tables 2a and 2b. In some embodiments, EGFR inhibitor resistance mutations are substitutions at amino acid positions 718, 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, and T854A). In some embodiments, dysregulation of expression, activity, or level related to the EGFR gene, EGFR kinase, or either thereof includes one or more point mutations / insertions / deletions in exon 20. Non-limiting examples of EGFR exon 20 mutations are listed in Tables 1a, 1b, 2a, and 2b. In some embodiments, EGFR exon 20 mutations are exon 20 insertions such as V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX. For example, EGFR kinase protein insertions are exon 20 insertions selected from the group consisting of A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP, H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH, and P772_H773insPNP.In some embodiments, cancers with dysregulation of expression, activity, or levels related to the EGFR gene, EGFR kinase, or any of them are determined using regulatory agency-approved (e.g., FDA-approved) assays or kits. In some embodiments, tumors positive for dysregulation of expression, activity, or levels related to the EGFR gene, EGFR kinase, or any of them are tumors positive for one or more EGFR inhibitor resistance mutations. In some embodiments, tumors with dysregulation of expression, activity, or levels related to the EGFR gene, EGFR kinase, or any of them are determined using regulatory agency-approved (e.g., FDA-approved) assays or kits.

[0100] In any of the methods or uses described herein, the patient has a clinical record indicating that the patient has a tumor (e.g., a tumor with one or more EGFR inhibitor-resistant mutations) in which the patient has dysregulation of the expression, activity or level of the EGFR gene, EGFR kinase, or any of the same. Also provided herein is a method of treating a patient, comprising administering a therapeutically effective dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient who has a clinical record indicating that the patient has dysregulation of the expression, activity or level of the EGFR gene, EGFR kinase, or any of the same.

[0101] In some embodiments, the method provided herein includes performing an assay on a sample obtained from a patient to determine whether the patient has dysregulation of expression or level related to the EGFR gene, EGFR protein, or either thereof. In some such embodiments, the method further includes administering a therapeutically effective dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient determined to have dysregulation of expression, activity, or level related to the EGFR gene, EGFR protein, or either thereof. In some embodiments, the method includes determining whether the patient has dysregulation of expression or level related to the EGFR gene, EGFR protein, or either thereof via an assay performed on a sample obtained from a patient. In some such embodiments, the method also includes administering a therapeutically effective dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the patient. In some embodiments, the dysregulation of expression, activity, or level related to the EGFR gene, EGFR kinase protein, or either thereof is one or more point mutations in the EGFR gene (e.g., any of the EGFR point mutations described herein). One or more point mutations in the EGFR gene can result in the translation of the EGFR protein having one or more of the following amino acid substitutions, deletions, and insertions: G719S, G719C, G719A, L747S, D761Y, T790M, T854A, L858R, L861Q, deletions in exon 19 (e.g., L747_A750del), and insertions in exon 20 (e.g., V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX). One or more mutations in the EGFR gene may result in the translation of the EGFR protein having one or more of the following amino acid substitutions or deletions: L858R, deletion in exon 19 (e.g., L747_A750del), L747S, D761Y, T790M, and T854A.In some embodiments, the dysregulation of expression, activity, or level relating to the EGFR gene, EGFR kinase protein, or either thereof is one or more EGFR inhibitor resistance mutations (e.g., any combination of one or more EGFR inhibitor resistance mutations described herein). In some embodiments, the dysregulation of expression, activity, or level relating to the EGFR gene, EGFR kinase protein, or either thereof is one or more EGFR exon 20 insertions (e.g., any of the exon 20 insertions described herein). In some embodiments, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX. In some embodiments, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX. In some embodiments, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP, H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH, and P772_H773insPNP. Some embodiments of these methods further include administering to the patient another anticancer agent (e.g., a second EGFR inhibitor or a pharmaceutically acceptable salt thereof, or immunotherapy).

[0102] In some embodiments of any method or use described herein, assays used to determine whether a patient has dysregulation of expression, activity, or level related to the EGFR gene, EGFR kinase, or either thereof, using a sample from a patient, may include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known to those skilled in the art, these assays are typically performed using at least one labeled nucleic acid probe or at least one labeled antibody or its antigen-binding fragment. The assays may also utilize other detection methods known to those skilled in the art for detecting dysregulation of expression, activity, or level related to the EGFR gene, EGFR kinase, or either thereof (see, for example, the references cited herein). In some embodiments, dysregulation of expression, activity, or level related to the EGFR gene, EGFR kinase, or either thereof includes one or more EGFR inhibitor resistance mutations. In some embodiments, the sample is a biological or biopsy sample from a patient (e.g., a paraffin-embedded biopsy sample). In some embodiments, the patient is a patient suspected of having EGFR-related cancer, a patient with one or more symptoms of EGFR-related cancer, and / or a patient at high risk of developing EGFR-related cancer.

[0103] In some embodiments, dysregulation of expression, activity, or levels related to the EGFR gene, EGFR kinase, or either thereof can be identified using liquid biopsy (also known as fluid biopsy or fluid-phase biopsy). See, for example, Karachialiou et al., “Real-time liquid biopsies become a reality in cancer treatment”, Ann. Transl. Med., 3(3):36, 2016. Liquid biopsy can be used to detect total tumor burden and / or dysregulation of expression, activity, or levels related to the EGFR gene, EGFR kinase, or either thereof. Liquid biopsy can be performed on biological samples that can be obtained relatively easily from patients (e.g., simple blood sampling) and is generally less invasive than conventional methods used to detect tumor burden and / or dysregulation of expression, activity, or levels related to the EGFR gene, EGFR kinase, or either thereof. In some embodiments, liquid biopsy can be used to detect the presence of dysregulation of expression, activity, or levels related to the EGFR gene, EGFR kinase, or either thereof at an earlier stage than conventional methods. In some embodiments, the biological samples used for liquid biopsy may include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage fluid, bile, lymph, cystic fluid, feces, ascites, and combinations thereof. In some embodiments, liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, liquid biopsy can be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected by using liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (e.g., using highly sensitive detection techniques such as next-generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis, for example, but not limited to) can be used to identify dysregulation of expression, activity, or levels related to the EGFR gene, EGFR kinase, or either of them.

[0104] combination In the field of medical oncology, it is common practice to combine various treatment methods in the treatment of each individual cancer patient. In medical oncology, in addition to the compositions provided herein, other components such as treatments or therapies used in combination include, for example, surgery, radiotherapy, and chemotherapeutic agents, such as other kinase inhibitors, signaling inhibitors, and / or monoclonal antibodies. For example, surgery may be open surgery or minimally invasive surgery. Therefore, the compound of formula (I) or its pharmaceutically acceptable salts or solvates are also useful as adjuvants for cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, such as chemotherapeutic agents acting by the same or different mechanisms of action. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salts may be used before the application of additional therapeutic agents or additional therapies. For example, a patient who requires it may be administered one or more doses of the compound of formula (I) or its pharmaceutically acceptable salts over a period of time, followed by at least partial resection of the tumor. In some embodiments, treatment with one or more doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof reduces tumor size (e.g., tumor volume) before at least partial resection of the tumor. In some embodiments, a patient requiring this may receive one or more radiotherapy sessions while receiving one or more doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof over a period of time. In some embodiments, treatment with one or more doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof reduces tumor size (e.g., tumor volume) before one or more radiotherapy sessions.

[0105] In some embodiments, the patient has cancer (e.g., locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of chemotherapeutic agents such as a first EGFR inhibitor, a first HER2 inhibitor, or a multi-kinase inhibitor, immunotherapy, or radiotherapy (e.g., radioactive iodine)). In some embodiments, the patient has cancer (e.g., locally advanced or metastatic tumor) that is refractory or intolerant to previous therapy (e.g., administration of chemotherapeutic agents such as a first EGFR inhibitor, a first HER2 inhibitor, or a multi-kinase inhibitor, immunotherapy, or radiotherapy (e.g., radioactive iodine)). In some embodiments, the patient has cancer for which no standard therapy exists (e.g., locally advanced or metastatic tumor). In some embodiments, the patient is EGFR inhibitor-naive. For example, the patient has not been exposed to treatment with a selective EGFR inhibitor. In some embodiments, the patient is not EGFR inhibitor-naive. In some embodiments, the patient is HER2 inhibitor-naive. For example, the patient has not been exposed to treatment with a selective HER2 inhibitor. In some embodiments, the patient is not HER2 inhibitor-naive. In some embodiments, the patient has received prior treatment, such as treatment with a multi-kinase inhibitor (MKI), EGFR tyrosine kinase inhibitor (TKI), osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.

[0106] In some embodiments of any of the methods described herein, the compound of formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapeutic agents (e.g., chemotherapeutic agents).

[0107] Non-limiting examples of additional therapeutic agents include other EGFR-targeted therapies (i.e., primary or secondary EGFR inhibitors), other HER2-targeted therapies (i.e., primary or secondary HER2 inhibitors), RAS pathway-targeted therapies, PARP inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapies (e.g., Trk inhibitors or multi-kinase inhibitors)), farnesyltransferase inhibitors, signaling pathway inhibitors, checkpoint inhibitors, apoptotic pathway modulators (e.g., obataclax); cytotoxic chemotherapy, angiogenesis-targeted therapies, immunotherapy (including immunotherapy), and radiotherapy.

[0108] In some embodiments, other EGFR-targeted therapeutic agents are multi-kinase inhibitors that exhibit EGFR inhibitory activity. In some embodiments, other EGFR-targeted therapeutic inhibitors are selective for EGFR kinases.

[0109] Non-limiting examples of EGFR-targeted therapies (e.g., a first EGFR inhibitor or a second EGFR inhibitor) include EGFR-selective inhibitors, panHER inhibitors, and anti-EGFR antibodies. In some embodiments, the EGFR inhibitor is a covalent inhibitor. In some embodiments, the EGFR-targeted therapy is osimertinib (AZD9291, merelectinib, TAGRISSO™), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZA™, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (T YKERB(registered trademark), panitumumab (ABX-EGF, VECTIBIX(registered trademark)), vandetanib (CAPRELSA(registered trademark)), rosiletinib (CO-1686), olmutinib (OLITATM, HM61713, BI-1482694), nacotinib (ASP8273), nazartinib (EGF816, NVS-816), PF-06747775, icotinib (BPI-2009H), afatinib (BIBW 2992, GILOTRIF (registered trademark), dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), abitinib (AC0010), AC0010MA EAI045, matsuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR (registered trademark)), zalutumab, MDX447, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mafodotin (ABT-414), ABT-806, mAb 806, Canertinib (CI-1033), Shikonin, Shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetylshikonin, β,β-dimethylacryl shikonin and acetylalkanin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib, WZ4002, brigatinib (AP26113, ALUNBRIG®), peritinib (EKB-569), tarloxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, tesevatinib (KD019, XL647), YH25448, epi Epitinib (HMPL-813), CK-101, MM-151, AZD3759, ZD6474, PF-06459988, Vallitinib (ASLAN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, Abitinib, GW572016, Pilotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, Modotuximab (TAB-H49), Futuximab (992 These include DS), zaltumumab, KL-140, RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG 595, BDTX-189, afatinib, Disruptin, CL-387785, EGFR bi-armed autologous T cells, and EGFR CAR-T therapy. In some embodiments, the EGFR-targeted therapy is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.

[0110] Additional EGFR-targeted therapies (e.g., first or second EGFR inhibitors) are disclosed in WO 2019 / 246541, WO 2019 / 165385, WO 2014 / 176475 and US 9,029,502 (each in its entirety incorporated herein by reference).

[0111] In some embodiments, other HER2-targeted therapeutic agents are multi-kinase inhibitors that exhibit HER2 inhibitory activity. In some embodiments, other HER2-targeted therapeutic inhibitors are selective for HER2 kinases.

[0112] Non-limiting examples of HER2-targeted therapies (e.g., first-order HER2 inhibitors or second-order HER2 inhibitors) include HER2-selective inhibitors, panHER inhibitors, and anti-HER2 antibodies. An exemplary HER2-targeted therapy is trastuzumab (e.g., TRAZIMERA). TM HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), lapatinib, KU004, neratinib (e.g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSA) TM These include erlotinib (e.g., TARCEVA®), pirotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, peritinib, S-222611, and AEE-788.

[0113] Additional HER2-targeted therapies (e.g., a first HER2 inhibitor or a second HER2 inhibitor) are disclosed in WO 2019 / 246541, WO 2019 / 165385, WO 2014 / 176475 and US 9,029,502 (each in its entirety incorporated herein by reference).

[0114] As used herein, “RAS pathway targeted therapeutic agents” include compounds that exhibit inactivating activity (e.g., kinase inhibition, allosteric inhibition, dimerization inhibition, and degradation induction) of any protein in the RAS pathway. Non-limiting examples of proteins in the RAS pathway include any one of the proteins in the RAS-RAF-MAPK pathway or the PI3K / AKT pathway, such as RAS (e.g., KRAS, HRAS, and NRAS), RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, the RAS pathway modulator may be selective for proteins in the RAS pathway. For example, the RAS pathway modulator may be selective for RAS (also referred to as the RAS modulator). In some embodiments, the RAS modulator is a covalent inhibitor. In some embodiments, the RAS pathway targeted therapeutic agent is a “KRAS pathway modulator”. KRAS pathway modulators include compounds that exhibit inactivating activity (e.g., kinase inhibition, allosteric inhibition, dimerization inhibition, and degradation induction) of any of the proteins in the KRAS pathway. Non-limiting examples of proteins in the KRAS pathway include any one of the proteins in the KRAS-RAF-MAPK pathway or the PI3K / AKT pathway, e.g., KRAS, RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, KRAS pathway modulators may be selective for proteins in the RAS pathway. For example, a KRAS pathway modulator may be selective for KRAS (also referred to as a KRAS modulator). In some embodiments, the KRAS modulator is a covalent inhibitor. Non-limiting examples of KRAS-targeted therapies (e.g., KRAS inhibitors) include BI 1701963, AMG 510, ARS-3248, ARS1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, AA12, and MRTX-849.

[0115] Further non-limiting examples of RAS-targeted therapies include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, BRAF inhibitors include vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), and encorafenib (BRAFTOVI™), BMS-908662 (XL281), sorafenib, LGX818, PLX3603, RAF265, RO5185426, GSK2118436, ARQ 736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or combinations thereof.

[0116] In some embodiments, the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK162), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI1040 (PD184352), hypothemycin, or a combination thereof.

[0117] In some embodiments, the ERK inhibitors are FRI-20 (ON-01060), VTX-11e, 25-OH-D3-3-BE (B3CD, bromoacetoxycalcidiol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ-13767370, BL-EI-001, LY-3214996, LTT-462, and KO-947. These include KO-947, MK-8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5-7-oxozeaenol, 5-iodotubercidin, GDC0994, ONC201, or combinations thereof.

[0118] In some embodiments, PI3K inhibitors include buparlisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactricib (NVP-BEZ235, BEZ-235), taselicib (GDC-0032, RG7604), and sonolisib (P X-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilicib (GDC-0941), piralalicib (XL147, SAR245408), jedatricib (PF-05212384, PKI-587), ceravelicib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitricib (GDC-0980), omiparicib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG Select from 511, CH5132799, GSK1059615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI-402, Wartmannine, LY294002, PI-103, Rigocertib, XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319, GSK2636771, or a combination thereof.

[0119] In some embodiments, the AKT inhibitor is miltefosine (IMPADIVO®), wartmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afresertib, DC120, 2-[4-(2-aminoprop-2-yl)phenyl]-3-phenylquinoxaline, MK-2206, edelfosine, Miltefosine, Perifosine, Erucylphophocholine, Erufosine, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, Trisilibine (Tricilibin phosphate monohydrate), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridine-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl)benzyl)-3-fluorobenzamide, ARQ092, BAY Selected from 1125976, 3-oxo-tirucallic acid, lactokinomycin, boc-Phe-vinyl ketone, perifosine (D-21266), TCN, TCN-P, GSK2141795, ONC201, or a combination thereof.

[0120] In some embodiments, the mTOR inhibitor is selected from MLN0128, AZD-2014, CC-223, AZD2014, CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridafololimus (AP-23573), sirolimus (rapamycin), or a combination thereof.

[0121] Non-exclusive examples of farnesyltransferase inhibitors include ronafarnib, tipifarnib, BMS-214662, L778123, L744832, and FTI-277.

[0122] In some embodiments, the chemotherapeutic agent is anthracycline, cyclophosphamide, taxane, platinum-based drugs, mitomycin, gemcitabine, or eribulin (HALAVEN). TM ), or combinations thereof.

[0123] Non-exclusive examples of taxanes include paclitaxel, docetaxel, abraxane, and taxotere.

[0124] In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, and combinations thereof.

[0125] In some embodiments, the platinum-based drug is selected from carboplatin, cisplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin, and combinations thereof.

[0126] Non-exclusive examples of PARP inhibitors include olaparib (LYNPARZA®), talazoparib, lucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP 9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN 673, KU-0059436 (AZD2281), BSI-201, PF-01367338, INO-1001, and JPI-289.

[0127] Non-limiting examples of immunotherapy include immune checkpoint therapy, atezolizumab (TECENTRIQ®), and albumin-conjugated paclitaxel. Non-limiting examples of immune checkpoint therapy include inhibitors targeting CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, and IDO, as well as combinations thereof. In some embodiments, the CTLA-4 inhibitor is ipilimumab (YERVOY®). In some embodiments, the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), semiprimab (LIBTAYO®), or combinations thereof. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), or a combination thereof. In some embodiments, the LAG-3 inhibitor is IMP701 (LAG525). In some embodiments, the A2AR inhibitor is CPI-444. In some embodiments, the TIM-3 inhibitor is MBG453. In some embodiments, the B7-H3 inhibitor is enobrituzumab. In some embodiments, the VISTA inhibitor is JNJ-61610588. In some embodiments, the IDO inhibitor is indoximod. See, for example, Marin-Acevedo, et al., J Hematol Oncol. 11: 39 (2018).

[0128] In some embodiments, the additional therapy or treatment agent is a combination of atezolizumab and nab-paclitaxel.

[0129] Accordingly, the Specified provides a method for treating cancer, comprising administering to a patient in need of such treatment a pharmaceutical combination for treating cancer, comprising (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, (b) an additional therapeutic agent, and (c) optionally, at least one pharmaceutically acceptable carrier, in simultaneous, separate, or sequential use for treating cancer, wherein the amounts of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent together are effective for treating cancer.

[0130] In some embodiments, the additional therapeutic agent includes any of the therapeutic agents listed above, which are standard care for cancers having dysregulation of the expression, activity, or level related to the EGFR gene, the EGFR protein, or either thereof.

[0131] In some embodiments, the additional therapeutic agent includes any of the listed therapeutic agents or treatments, which constitute standard care for cancers having dysregulation of the expression, activity, or level related to the HER2 gene, HER2 kinase, or either thereof.

[0132] These additional therapeutic agents may be administered, together with one or more doses of the compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof, as part of the same or distinct dosage form, via the same or different route of administration and / or in the same or different schedule of administration, in accordance with standard pharmaceutical practices well known to those skilled in the art.

[0133] Furthermore, this specification also provides (i) a pharmaceutical combination for treating cancer in a patient requiring treatment, comprising (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, (b) at least one additional therapeutic agent (e.g., exemplary additional therapeutic agents described herein or known to those skilled in the art), and (c) optionally, at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use to treat cancer, wherein the amounts of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agents together are effective in treating cancer; (ii) a pharmaceutical composition comprising such a combination; (iii) the use of such a combination in the manufacture of a pharmaceutical for treating cancer; and (iv) a commercial package or product comprising such a combination as a combination formulation for simultaneous, separate or sequential use; and a method for treating cancer in a patient requiring treatment. In some embodiments, the cancer is an EGFR-related cancer. For example, an EGFR-related cancer having one or more EGFR inhibitor resistance mutations. In some embodiments, the cancer is a HER2-related cancer. For example, HER2-related cancers that have one or more HER2 inhibitor resistance mutations.

[0134] As used herein, the term “pharmaceutical combination” refers to a pharmaceutical therapy resulting from the mixing or combination of multiple active ingredients, and includes both fixed and unfixed combinations of active ingredients. The term “fixed combination” means that both the compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent (e.g., a chemotherapeutic agent) are administered to a patient simultaneously in the form of a single composition or dose. The term “unfixed combination” means that the compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent (e.g., a chemotherapeutic agent) are formulated as separate compositions or doses so that they can be administered simultaneously, in parallel, or sequentially at variable intervals to a patient in need, thereby providing effective levels of two or more compounds in the patient’s body. These also apply to cocktail therapies, for example, the administration of three or more active ingredients.

[0135] Accordingly, this specification provides a method for treating cancer, comprising administering to a patient in need a pharmaceutically acceptable combination for treating cancer, comprising (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (b) an additional therapeutic agent, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered simultaneously, separately, or sequentially, wherein the amounts of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the amounts of the additional therapeutic agent together are effective in treating cancer. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered simultaneously as separate doses. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered sequentially, in separate doses, or together in a therapeutically effective amount, for example, daily or intermittently, in any order. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered simultaneously in a combined dose. In some embodiments, the cancer is an EGFR-related cancer. For example, an EGFR-related cancer having one or more EGFR inhibitor resistance mutations. In some embodiments, the cancer is a HER2-related cancer. For example, a HER2-related cancer having one or more HER2 inhibitor resistance mutations.

[0136] In some embodiments, the presence of one or more EGFR inhibitor resistance mutations in a tumor makes the tumor more resistant to treatment with a first EGFR inhibitor. Methods useful when EGFR inhibitor resistance mutations make a tumor more resistant to a first EGFR inhibitor are described below. For example, this specification provides a method for treating a patient with cancer, comprising: identifying a patient having cancer cells with one or more EGFR inhibitor resistance mutations; and administering to the identified patient a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a first EGFR inhibitor. Also provided is a method for treating a patient identified as having cancer cells with one or more EGFR inhibitor resistance mutations, comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a first EGFR inhibitor. In some embodiments, one or more EGFR inhibitor resistance mutations increase the resistance of cancer cells or tumors to treatment with a first EGFR inhibitor. In some embodiments, one or more EGFR inhibitor resistance mutations include one or more EGFR inhibitor resistance mutations listed in Tables 2a and 2b. For example, one or more EGFR inhibitor resistance mutations may include substitutions at amino acid positions 718, 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, and T854A).

[0137] For example, this specification provides a method for treating EGFR-related cancer in a patient requiring treatment, comprising: (a) detecting dysregulation of expression, activity, or level related to the EGFR gene, EGFR kinase, or any of the thereof in a sample from the patient; and (b) administering to the patient a therapeutically effective dose of a first EGFR inhibitor, wherein the first EGFR inhibitor is selected from the group consisting of osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002. In some embodiments, the method further includes (after (b)) (c) determining whether cancer cells in a sample obtained from a patient have at least one EGFR inhibitor resistance mutation; and (d) if the patient is determined to have cancer cells with at least one EGFR inhibitor resistance mutation, administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof, either as monotherapy or in combination with other anticancer agents; or (e) if the patient is determined not to have cancer cells with at least one EGFR inhibitor resistance mutation, administering to the patient an additional dose of the first EGFR inhibitor of step (b).

[0138] Preparation of compounds The compounds disclosed herein can be prepared in various ways using commercially available starting materials, compounds known in the literature, or readily prepared intermediates, according to standard synthetic methods and procedures well known to those skilled in the art, or based on the teachings herein. The synthesis of the compounds disclosed herein can be achieved generally according to the following scheme, with modifications depending on specific desired substituents.

[0139] Standard synthetic methods and procedures for the preparation of organic molecules and the transformation and manipulation of functional groups can be obtained from relevant scientific literature or standard textbooks in the field. While not limited to specific literature, classic works such as R. Larock, *Comprehensive Organic Transformations*, VCH Publishers (1989); L. Fieser and M. Fieser, *Fieser and Fieser's Reagents for Organic Synthesis*, John Wiley and Sons (1994); Smith, MB, March, J., *March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure*, 5th edition, John Wiley & Sons: New York, 2001; and Greene, TW, Wuts, PGM, *Protective Groups in Organic Synthesis*, 3rd edition, John Wiley & Sons: New York, 1999 are well-known to those skilled in the art and serve as useful references for organic synthesis. The following description of the synthesis method is intended to illustrate, and not limit, the general procedure for preparing the compounds of this disclosure.

[0140] The synthetic processes disclosed herein are accommodating a variety of functional groups and, therefore, allow the use of various substituted starting materials. These processes generally yield the desired final compound towards the end of the overall process or near the endpoint, although in some cases it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0141] Example 1 The compounds of formula (I) described herein can be prepared using the procedure described for the synthesis of compound 362 in WO 2022 / 066734.

[0142] Example 2 Exam Description Study: This is an open-label Phase 1 / 2 study to evaluate the safety, tolerability, pharmacokinetic (PK) exposure, and preliminary antitumor activity of the compound of formula (I) in participants with non-small cell lung cancer (NSCLC) with EGFR / HER2 exon 20 insertion (ex20ins) mutations.

[0143] TIFF2026530494000019.tif32155

[0144] TIFF2026530494000020.tif53155

[0145] [Table 5]

[0146] Evaluation items Primary evaluation criteria: 1. Part 1 Dose Elevation (MTD): Dose escalation - Number of participants who experienced at least one DLT during the first 28 days after the start of treatment [Evaluation period: 28 days] 2. Part 2 RP2D Selection: Mean plasma pharmacokinetic (PK) exposure concentration of the compound of formula (I) [Duration: 1 year] 3. Part 2 RP2D Selection: Changes from baseline in pharmacodynamic (PD) markers [Duration: 1 year] 4. Part 2 RP2D Selection: Time-dependent changes in the absolute value of PD markers [Period: 1 year] 5. Part 2 RP2D Selection: Number of participants with confirmed objective response rate (ORR) (ORR is defined as the percentage of participants with a partial response (PR) or complete response (CR) according to RECIST v1.1 based on the investigator's assessment) [Duration: 1 year] 6. Part 3 Dose Expansion: Number of participants with confirmed ORR (ORR is defined as the percentage of participants with a partial response (PR) or complete response (CR) according to RECIST v1.1 based on the investigator's assessment) [Duration: 1 year]

[0147] TIFF2026530494000022.tif237154

[0148] Several embodiments of the present invention have been described. However, it will be understood that various modifications can be made without departing from the spirit and scope of the invention. Therefore, other embodiments are also included in the scope of the following claims.

Claims

1. A method for treating EGFR exon 20 mutation-positive lung cancer in a patient requiring treatment, wherein the patient is given formula (I): 【Chemistry 1】 (I) A method comprising administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein the lung cancer is non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, pulmonary sarcomatoid carcinoma, or any combination thereof.

3. The method according to claim 1 or 2, wherein the lung cancer is non-small cell lung cancer.

4. The method according to any one of claims 1 to 3, wherein the EGFR exon 20 mutation is an EGFR exon 20 insertion mutation.

5. The method according to any one of claims 1 to 4, wherein the exon 20 insertion is selected from the group consisting of A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP, H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH and P772_H773insPNP, or any combination thereof.

6. The method according to any one of claims 1 to 5, wherein the exon 20 insertion is selected from the group consisting of V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX.

7. The method according to any one of claims 1 to 6, wherein the exon 20 insertion is V769_D770insASV or D770_N771insSVD.

8. The method according to any one of claims 1 to 7, wherein the exon 20 insertion is V769_D770insASV.

9. The method according to any one of claims 1 to 8, wherein the exon 20 insertion is D770_N771insSVD.

10. The method according to any one of claims 1 to 9, wherein the lung cancer is non-small cell lung cancer and the exon 20 insertion is V769_D770insASV.

11. The method according to any one of claims 1 to 9, wherein the lung cancer is non-small cell lung cancer and the exon 20 insertion is D770_N771insSVD.

12. The method according to any one of claims 1 to 11, wherein the patient has a histologically or cytologically confirmed diagnosis of NSCLC stage IIIB / C or IV, which is not eligible for curative surgery or chemoradiotherapy.

13. The method according to any one of claims 1 to 12, wherein the presence of an EGFR exon 20 mutation is determined by an FDA-approved test based on polymerase chain reaction (PCR) or NGS, or as part of routine clinical care in a CLIA or similarly accredited laboratory.

14. The method according to any one of claims 1 to 13, wherein the patient has a new or recent tumor biopsy (preferably taken at the time of screening) or a preserved tumor specimen taken within the past 10 years, which is available for genomic profiling.

15. The method according to any one of claims 1 to 14, wherein the patient has at least one tumor lesion measurable based on RECIST v1.

1.

16. The method according to any one of claims 1 to 15, wherein the patient is ≥18 years old at the time of signing the ICF.

17. The method according to any one of claims 1 to 16, wherein the patient has an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.

18. The method according to any one of claims 1 to 17, further comprising providing a biological sample from a patient.

19. The method according to claim 18, further comprising determining that resistance mutations T790M and C797S do not exist simultaneously.

20. The method according to any one of claims 1 to 19, wherein the patient is recurrent or resistant to one or more prior anticancer therapies.

21. The method according to claim 20, wherein one or more prior anticancer therapies comprise one or more chemotherapeutic agents, checkpoint inhibitors, targeted anticancer therapies, or kinase inhibitors, or a combination thereof.

22. One or more previous anticancer therapies include carboplatin, paclitaxel, gemcitabine, cisplatin, vinorelbine, docetaxel, palbociclib, crizotinib, PD-(L)1 axis inhibitors, EGFR inhibitors, c-Met inhibitors, HER2 inhibitors, HER3 inhibitors, HER4 inhibitors, VEGFR inhibitors, AXL inhibitors, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, and osimertinib. The method according to claim 20, wherein the drug is lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib, or any combination thereof.

23. The method according to any one of claims 1 to 19, wherein the patient is untreated.

24. The method according to any one of claims 1 to 19, wherein the patient has previously undergone treatment for lung cancer.

25. The method according to any one of claims 1 to 24, further comprising administering one or more anticancer therapies to a patient.

26. The method according to claim 25, wherein one or more anticancer therapies include chemotherapy, radiotherapy, surgery, targeted anticancer therapy, kinase inhibitors, or a combination thereof.

27. The method according to claim 26, wherein the kinase inhibitor is an EGFR inhibitor, a c-Met inhibitor, a HER2 inhibitor, a HER3 inhibitor, a HER4 inhibitor, a VEGFR inhibitor, or an AXL inhibitor.

28. The method according to claim 27, wherein the kinase inhibitor is lazertinib, poziotinib, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

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