Compounds and methods for targeting and degrading antigen receptors

Abstract

This disclosure relates to a method for treating prostate cancer in subjects requiring treatment, including, for example, metastatic prostate cancer, castration-resistant prostate cancer and metastatic castration-resistant prostate cancer, the method comprising administering to a subject a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof, further comprising the step of discontinuing or reducing the administration of a CYP3A inhibitor or inducer, an efflux transporter substrate or inhibitor, or an uptake transporter substrate or inhibitor to the subject before initiating the administration of compound A or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] Related applications This application claims priority and interest to U.S. Provisional Application No. 63 / 511,420, filed on 30 June 2023, and U.S. Provisional Application No. 63 / 580,126, filed on 1 September 2023, the contents of which, in whole, are incorporated herein by reference for all purposes.

[0002] This disclosure provides a method for using a bifunctional compound to treat prostate cancer. [Background technology]

[0003] Most small molecule drugs bind to specific, tight pockets on enzymes or receptors. Protein-protein interactions, on the other hand, are known to be extremely difficult to target with small molecules, due to their large contact surfaces and the presence of shallow grooves or flat interfaces. E3 ubiquitin ligases (hundreds of which are known in humans) are attractive therapeutic targets because they confer substrate specificity to ubiquitination. The development of ligands for E3 ligases has proven difficult, for one thing, because they should inhibit protein-protein interactions. However, recent developments have yielded specific ligands that bind to these ligases.

[0004] One potentially therapeutic E3 ubiquitin ligase is cereblon. Cereblon is a protein encoded in humans by the CRBN gene. Thalidomide and its analogues, such as pomalidomide and lenalidomide, are known to bind to cereblon. These drugs bind to cereblon, altering the specificity of the complex and inducing ubiquitination and degradation of transcription factors essential for the proliferation of multiple myeloma. In fact, high expression of cereblon has been associated with increased efficacy of imide drugs in the treatment of multiple myeloma.

[0005] The androgen receptor (AR) belongs to the nuclear hormone receptor family, which is activated by androgens such as testosterone and dihydrotestosterone (Pharmacol. Rev. 2006, 58(4), 782-97, Vitam. Horn. 1999, 55: 309-52). In the absence of androgens, AR is bound to cytosolic heat shock protein 90 (Hsp90). When an androgen binds to AR, its conformation changes, releasing AR from Hsp90 and exposing the nuclear localization signal (NLS). The latter allows AR to translocate into the nucleus, where it acts as a transcription factor, promoting the expression of genes involved in male sexual characteristics (Endocr. Rev. 1987, 8(1): 1-28, Mol. Endocrinol. 2002, 16(10), 2181-7). AR deficiency causes androgen insensitivity syndrome, formerly known as testicular feminization syndrome.

[0006] AR is involved in the development of male sexual characteristics and is also a well-established oncogene in certain forms of cancer, including prostate cancer (Endocr. Rev. 2004, 25(2), 276-308). The target gene for commonly measured AR activity is the secreted prostate-specific antigen (PSA) protein. Current treatment strategies for prostate cancer involve inhibiting the androgen-AR axis in two ways. The first approach relies on reducing androgens, while the second strategy aims to inhibit AR function (Nat. Rev. Drug Discovery, 2013, 12, 823-824). Despite the development of effective targeted therapies, most patients develop resistance and the disease progresses. Alternative approaches for treating prostate cancer involve eliminating the AR protein. [Overview of the project] [Problems that the invention aims to solve]

[0007] Since AR is a key driver of tumorigenesis in many forms of prostate cancer, its disappearance should lead to a beneficial response to treatment. In this field, there is an ongoing need for effective treatment of diseases, particularly cancer, prostate cancer, and Kennedy disease.

[0008] However, nonspecific effects and the inability to fully target and modulate certain classes of proteins, such as transcription factors, remain obstacles to the development of effective anticancer drugs. Thus, small molecule therapeutics that utilize or enhance the substrate specificity of cereblon while simultaneously being "tunable" to target and specifically modulate a wide range of protein classes are extremely useful as therapeutic agents.

[0009] More than 70 different somatic missense AR tumor mutations have been identified in prostate cancer patients (Gottlieb, B., Hum. Mutat. 2004, 23:527-533). The majority of these AR tumor mutations are located in the ligand-binding domain. While not theoretically bound, AR tumor mutations in the ligand-binding domain lead to a decrease in ligand specificity, thereby allowing AR to function independently of androgens. Such AR tumor mutations provide tumor cells with the ability to proliferate in an androgen-deficient environment and are therefore selected in response to prostate cancer therapies that block or reduce androgen levels (e.g., luteinizing hormone-releasing hormone agonists). Therefore, AR tumor mutations are observed more frequently in patients with advanced androgen-independent tumors compared to patients with early-stage prostate cancer (Taplin, ME, et al. N.Engl.J.Med. (1995) 332:1393-1398, Marcelli, M., et al. Cancer Res. (2000) 60:944-949).

[0010] In one embodiment, the present application relates to a method for treating prostate cancer in a subject requiring treatment, wherein the method involves administering a therapeutically effective amount of compound A to the subject. [ka] or administering a pharmaceutically acceptable salt thereof, further comprising the step of discontinuing or reducing administration of a CYP3A inhibitor to a subject before initiating administration of compound A or a pharmaceutically acceptable salt thereof.

[0011] In one embodiment, the present application relates to a method for treating prostate cancer in a subject requiring treatment, the method comprising administering a therapeutically effective amount of compound A to the subject. [ka] The procedure further includes discontinuing or reducing administration of a CYP3A inhibitor to a patient before initiating administration of compound A.

[0012] In one embodiment, the present application relates to a method for treating prostate cancer in a subject requiring treatment, wherein the method involves administering a therapeutically effective amount of compound A to the subject. [ka] The procedure includes administering compound A or a pharmaceutically acceptable salt thereof, further comprising the step of discontinuing administration of a CYP3A inhibitor to the subject before initiating administration of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, administration of the CYP3A inhibitor is discontinued in the subject from a point in time prior to the initiation of administration of compound A or a pharmaceutically acceptable salt thereof, the point in time being at least 120 hours.

[0013] In one embodiment, the present application relates to a method for treating prostate cancer in a subject requiring treatment, the method comprising administering a therapeutically effective amount of compound A to the subject. [ka] The procedure further includes discontinuing the administration of a CYP3A inhibitor to the subject before initiating the administration of compound A. In some embodiments, the administration of the CYP3A inhibitor is discontinued in the subject from a point in time prior to the initiation of the administration of compound A, and this point in time is at least 120 hours.

[0014] In one aspect, the present application relates to a method of performing it in a subject who needs treatment for prostate cancer, the method comprising administering to the subject a therapeutically effective amount of Compound A, [Chemical formula] or a pharmaceutically acceptable salt thereof, and further comprising the step of reducing the administration of a CYP3A inhibitor to the subject before initiating the administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the administration of the CYP3A inhibitor is reduced in the subject at a time point prior to initiating the administration of Compound A or a pharmaceutically acceptable salt thereof, and the time point is at least 120 hours.

[0015] In one aspect, the present application relates to a method of performing it in a subject who needs treatment for prostate cancer, the method comprising administering to the subject a therapeutically effective amount of Compound A, [Chemical formula] and further comprising the step of reducing the administration of a CYP3A inhibitor to the subject before initiating the administration of Compound A. In some embodiments, the administration of the CYP3A inhibitor is reduced in the subject at a time point prior to initiating the administration of Compound A, and the time point is at least 120 hours.

[0016] In one aspect, the present application relates to a method of performing it in a subject who needs treatment for prostate cancer, the method comprising administering to the subject a therapeutically effective amount of Compound A, [Chemical formula] or a pharmaceutically acceptable salt thereof, and further comprising administering a CYP3A inhibitor to the subject.

[0017] In one aspect, the present application relates to a method of performing it in a subject who needs treatment for prostate cancer, the method comprising administering to the subject a therapeutically effective amount of Compound A, [Chemical formula] This further includes administering CYP3A inhibitors to target patients.

[0018] In one embodiment, the present application relates to a method for treating prostate cancer in a subject requiring treatment, wherein the method involves administering a therapeutically effective amount of compound A to the subject. [ka] This may include administering a pharmaceutically acceptable salt thereof, and the subject may also be administered a CYP3A inhibitor.

[0019] In one embodiment, the present application relates to a method for treating prostate cancer in a subject requiring treatment, the method comprising administering a therapeutically effective amount of compound A to the subject. [ka] The patients will also be administered CYP3A inhibitors.

[0020] In some embodiments, a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof is administered orally to the subject.

[0021] In some embodiments, a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once, twice, three times, or four times daily.

[0022] In some embodiments, a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once daily.

[0023] In some embodiments, a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject either entirely at once or in two, three, or four divided doses.

[0024] In some embodiments, the therapeutically effective dose of compound A is approximately 1 mg to approximately 1000 mg.

[0025] In some embodiments, the therapeutically effective dose of compound A is approximately 5 mg to approximately 750 mg.

[0026] In some embodiments, the therapeutically effective dose of compound A is approximately 10 mg to approximately 500 mg.

[0027] In some embodiments, the therapeutically effective dose of compound A is approximately 20 mg to approximately 250 mg.

[0028] In some embodiments, the therapeutically effective dose of compound A is approximately 100 mg.

[0029] In some embodiments, the therapeutically effective dose of compound A is 100 mg.

[0030] In some embodiments, the therapeutically effective dose of compound A is approximately 150 mg.

[0031] In some embodiments, the therapeutically effective dose of compound A is 150 mg.

[0032] In some embodiments, the therapeutically effective dose of compound A is approximately 300 mg.

[0033] In some embodiments, the therapeutically effective dose of compound A is 300 mg.

[0034] In some embodiments, the method further comprises administering an effective amount of at least one additional anticancer agent to a subject in need.

[0035] In some embodiments, further anticancer agents include abiraterone, abiraterone acetate, estramustine, docetaxel, ketoconazole, goserelin, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronic acid, or zoledronic acid.

[0036] The accompanying drawings incorporated herein and forming part of herein serve to illustrate some embodiments of the present disclosure and, together with their descriptions, illustrate the principles of the present disclosure. The drawings are for illustrative purposes only and should not be construed as limiting the present disclosure. Further objectives, features and advantages of the present disclosure will become apparent from the following detailed description in conjunction with the accompanying drawings illustrating exemplary embodiments of the present disclosure. [Brief explanation of the drawing]

[0037] [Figure 1A] This paper summarizes the effect of compound A on cytochrome P450 (CYP) CYP1A2 mRNA expression in human hepatocytes. Each grouped bar graph shows the mRNA saturation induction of human hepatocytes from three donors at various concentrations of compound A (0.03–30 μM). [Figure 1B] This paper summarizes the effect of compound A on cytochrome P450 (CYP) CYP2B6 mRNA expression in human hepatocytes. Each grouped bar graph shows the mRNA saturation induction of human hepatocytes from three donors at various concentrations of compound A (0.03–30 μM). [Figure 1C] This paper summarizes the effect of compound A on cytochrome P450 (CYP) CYP3A4 mRNA expression in human hepatocytes. Each grouped bar graph shows the mRNA saturation induction of human hepatocytes from three donors at various concentrations of compound A (0.03–30 μM). [Figure 1D] This paper summarizes the effect of compound A on cytochrome P450 (CYP) CYP2C8 mRNA expression in human hepatocytes. Each grouped bar graph shows the mRNA saturation induction of human hepatocytes from three donors at various concentrations of compound A (0.03–30 μM). [Figure 1E] This paper summarizes the effect of compound A on cytochrome P450 (CYP) CYP2C9 mRNA expression in human hepatocytes. Each grouped bar graph shows the mRNA saturation induction of human hepatocytes from three donors at various concentrations of compound A (0.03–30 μM). [Figure 1F]This paper summarizes the effect of compound A on cytochrome P450 (CYP) CYP2C19 mRNA expression in human hepatocytes. Each grouped bar graph shows the mRNA saturation induction of human hepatocytes from three donors at various concentrations of compound A (0.03–30 μM). [Figure 2] (A) Summarizes the inhibition of P-glycoprotein (Pgp) by compound A in MDCKII monolayers and vesicles expressing Pgp. (B) Summarizes the inhibition of breast cancer resistance protein (BCRP) by compound A in MDCKII monolayers and vesicles expressing BCRP. Each chart shows the relative Pgp or BCRP activity (%) of control at various concentrations of compound A (μM) for vesicle and monolayer data. Data are mean ± standard deviation from three samples. [Modes for carrying out the invention]

[0038] definition The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, thereby targeting those substrate proteins for degradation. For example, cereblon is an E3 ubiquitin ligase protein that, alone or in combination with E2 ubiquitin-conjugating enzymes, causes ubiquitin to bind to lysine on target proteins, after which specific protein substrates become targets for degradation by the proteasome. Thus, E3 ubiquitin ligases, alone or in complex with E2 ubiquitin-conjugating enzymes, are involved in the transfer of ubiquitin to target proteins. Generally, ubiquitin ligases are involved in polyubiquitination, where a second ubiquitin binds to a first ubiquitin, and a third binds to a second, etc. Polyubiquitination marks proteins so that they can be degraded by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, in which only a single ubiquitin is attached to the substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins do not target the proteasome for degradation; instead, their cellular sites or functions may be altered, for example, through binding to other proteins that have domains capable of binding to ubiquitin. Further complicating matters, different lysines on ubiquitin can be targeted by E3 to form chains. The most common lysine is Lys48 on the ubiquitin chain, which is used to generate polyubiquitin and is recognized by the proteasome.

[0039] As used herein with respect to the compounds of this disclosure, “pharmaceutically acceptable salt” means the salt form of compound A and the hydrate of the salt form in the presence of one or more water molecules. Such salt and hydrate forms retain the biological activity of compound A and are not biologically or otherwise undesirable, i.e., exhibit minimal toxic effects if any. Typical "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, butyrate, calcium salt, calcium edetate, cansilate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estrulate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsanylate, hexafluorophosphate, hexylresorcinate, hydravaminate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, and laurate. Examples include magnesium salts, malates, maleates, mandelates, mesylates, methyl bromides, methylnitrates, methyl sulfates, mucinates, napsylates, nitrates, N-methylglucamine ammonium salts, 3-hydroxy-2-naphthoates, oleates, oxalates, palmitates, pamoates (1,1-meten-bis-2-hydroxy-3-naphthoates, embonates), pantothenates, phosphates / diphosphates, picrates, polygalacturonates, propionates, p-toluenesulfonates, salicylates, stearates, basic acetates, succinates, sulfates, sulfosalicylates, suramates, tannates, tartrates, theoclates, tosylates, triethiozides, and valersates.

[0040] The term "isomer" refers to salts and / or compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. This structural difference may be in composition (geometric isomers) or in the ability to rotate the plane of polarization (stereoisomers). With respect to stereoisomers, salts of the compounds of this disclosure may have one or more chiral carbon atoms and may exist as racemates, racemic mixtures, and individual enantiomers or diastereomers.

[0041] The compounds of this disclosure may exist not only in the form of solvates such as hydrates, but also in the form of non-solvates.

[0042] A "solvate" refers to a solvent addition form containing either a stoichiometric or non-stoichiometric amount of solvent. Non-limiting examples of suitable solvates include ethanolates and methanolates. Some compounds tend to form solvates by trapping a certain molar ratio of solvent molecules in a crystalline solid state. If the solvent is water, the resulting solvate is a hydrate; if the solvent is an alcohol, the resulting solvate is an alcoholate. Hydrates are formed by a combination of one or more water molecules and a substance in which water retains its molecular state as H2O; such combinations can form one or more hydrates. In hydrates, water molecules are bonded via intermolecular forces, particularly hydrogen bonds, through secondary valence. Solid hydrates contain water in stoichiometric ratios as so-called crystal water; in this case, the water molecules do not need to be equivalent in terms of their bonding state. Examples of hydrates include sesquihydrate, monohydrate, dihydrate, or trihydrate. Hydrates of salts of the compounds disclosed herein are also preferred.

[0043] As used herein, “isotope derivatives” refer to compounds of the Disclosure that are isotope-enriched with one or more stable isotopes or labeled (with respect to one or more atoms of the compound). Accordingly, in this application, compounds of the Disclosure include compounds that are isotope-enriched or labeled with one or more atoms, such as deuterium.

[0044] As used herein, “to treat” means the management and care of an object for the purpose of combating a disease, condition, or disorder, and includes reducing or alleviating the symptoms or complications of a disease, condition, or disorder, or eliminating such disease, condition, or disorder.

[0045] As used herein, the term “to treat” means, unless otherwise indicated, to reverse, alleviate, or prevent the progression of a disorder or condition, or one or more symptoms of such disorder or condition, to which such term applies. As used herein, the term “treatment” means, unless otherwise indicated, the act of “to treat” as defined immediately prior to it. For example, the terms “to treat,” “to treat,” and “treatment” may refer to a method of alleviating or suppressing one or more of a particular disorder and / or its associated symptoms.

[0046] As used herein, “subject” means human or animal (in the case of an animal, the subject may be a mammal). In one embodiment, the subject is human. In one embodiment, the subject is male.

[0047] Prostate cancer is the uncontrolled proliferation of cancerous cells in the prostate gland.

[0048] Metastatic prostate cancer, or metastatic cancer, refers to prostate cancer that has spread beyond the prostate to other parts of the body, such as the bones, lymph nodes, liver, lungs, or brain.

[0049] Castrate-resistant prostate cancer (or castration-resistant prostate cancer) is a type of prostate cancer that continues to grow even when the amount of testosterone in the body is very low.

[0050] Metastatic castration-resistant prostate cancer is a type of prostate cancer that has metastasized and continues to grow even when the amount of testosterone in the body has dropped to very low levels.

[0051] As used herein, “prevention” means preventing the onset of symptoms or complications of a disease, condition, or disorder.

[0052] "Administration" refers to introducing a drug, such as a compound of the present disclosure, to a subject. Related terms, "to administer" and "administration of ~" (and grammatical equivalents), refer to both direct administration, which may be by a medical professional or by the subject self-administering, and / or indirect administration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and / or provides a patient with a prescription for a drug is administering a drug to the patient.

[0053] The terms “co-administration,” “co-administration,” and “combination therapy” refer to both simultaneous administration (administering two or more therapeutic agents at the same time) and staggered administration (administering one or more therapeutic agents at different times than the administration of additional therapeutic agents), as long as the therapeutic agents are present in the patient to some extent, preferably in effective amounts, at the same time. In certain preferred embodiments, one or more of the compounds described herein are co-administered in combination with at least one additional bioactive agent, particularly an anticancer agent. In particularly preferred embodiments, the co-administration of compounds results in synergistic activity and / or therapeutic effects, including anticancer activity.

[0054] As used herein, “therapeutic effective dose” means an amount of free base of compound A, or an equivalent amount of a pharmaceutically acceptable salt of compound A, sufficient to treat, improve, or prevent a particular disease (e.g., prostate cancer), its symptoms, impairment, or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect may be detected by any assay known in the art. The effective dose for a particular subject may depend on the subject's weight, size, and health, the nature and degree of the condition, and whether further therapeutic agents are administered to the subject. The therapeutic effective dose for a given situation may be determined by ordinary experimentation, which is within the scope of the clinician's skill and judgment.

[0055] The term "C" used herein max " " refers to the maximum (peak) plasma concentration of a particular compound observed in a subject after administration of a specific dose of that compound to that subject.

[0056] As used herein, "AUC" refers to the total area under the plasma concentration-time curve, which is a measure of exposure to the compound of interest and is the integral of the concentration-time curve after a single dose or at steady state. AUC is expressed in units of ng*H / mL (ngxH / mL), where "H" refers to time.

[0057] The term "AUC" used in this specification tau " refers to the AUC from 0 hours to the end of the dosing interval.

[0058] AUC 0~24 " refers to the AUC from 0 to 24 hours after a single dose administration.

[0059] As used herein with respect to oral dosage forms, “controlled release” or “CR” means that the compounds of this disclosure are released from the dosage form in accordance with a predetermined profile, which may include the time and place at which release occurs after oral administration, and / or a specific release rate over a particular period of time.

[0060] As used herein with respect to the oral dosage forms of the present disclosure, “control-release agent” means one or more substances or materials that regulate the release of the compounds of the present disclosure from the dosage form. Control-release agents may be organic or inorganic, naturally occurring or synthetic materials such as polymer materials, triglycerides, triglyceride derivatives, fatty acids and salts of fatty acids, talc, boric acid, colloidal silica, and combinations thereof.

[0061] As used herein with respect to the dosage forms of the present disclosure, “enteric coating” refers to a pH-dependent material that surrounds a core containing the compound of the present disclosure and which substantially retains its original form in the acidic environment of the stomach but dissolves in the pH environment of the intestines.

[0062] As applied to the CR oral dosage forms described herein, “acid-resistant” or “GR” means that the release of the compound of this disclosure in the stomach of the subject does not exceed 5%, 2.5%, 1%, or 0.5% of the total amount of compound A in the dosage form.

[0063] As used herein, “oral dosage form” refers to a pharmaceutical formulation comprising a specific amount (dose) of the compound of this disclosure or a pharmaceutically acceptable salt and / or solvate thereof as an active ingredient, and an inactive ingredient (excipient), formulated into a specific form suitable for oral administration, such as an oral tablet, liquid, or capsule. In some embodiments, the composition is in the form of a divisible tablet.

[0064] As used in this disclosure, the term “carrier” means a material, composition, or medium, including pharmaceutically acceptable excipients and diluents, that is involved in transporting or delivering a pharmaceutical product from one organ or part of the body to another organ or part of the body, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.

[0065] The term "approximately" in quantitative expressions, such as "approximately X," includes any value that is 10% higher or lower than X, and also includes any number that falls between X-10% and X+10%. Therefore, for example, a weight of approximately 40g includes weights between 36g and 44g.

[0066] Compound A in this disclosure refers to 4-(4-((1-(4-(((1R,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-N-((S)-2,6-dioxopiperidine-3-yl)-2-fluorobenzamide, which has the following structure: [ka]

[0067] In some embodiments, compound A may be prepared as described in U.S. Patent Application Publication No. 2021 / 0196710A1, which is incorporated herein by reference.

[0068] With respect to any specific dosage form, composition, use, method, or process described or claimed herein, “contains” or “includes” means that the dosage form, composition, use, method, or process includes all of the elements enumerated in the specific description or claims, but does not exclude other elements. “Essentially from” and “essentially from” means that the described or claimed composition, dosage form, method, use, or process does not exclude other materials or steps that do not substantially affect the enumerated physical, pharmacological, pharmacokinetic properties or therapeutic effect of the composition, dosage form, method, use, or process. “Consists of” and “consists of” means that nothing other than trace elements of other components and substantial method or process steps are excluded.

[0069] The ECOG Performance Status Scale was developed by the East Coast Cancer Clinical Trials Group as a standardized measure of how disease affects patients' daily living activities. It represents a patient's level of function in terms of their ability to care for themselves, daily activities, and physical abilities (walking, working, etc.). Patients are classified on a scale of 1 to 5: [Table 1]

[0070] Cytochrome P450 3A inhibitors, or "CYP3A inhibitors," refer to members of a class of compounds or substances that reduce or inhibit the normal function of cytochrome P450 in humans. In some embodiments, CYP3A inhibitors are CYP3A4 inhibitors. In some embodiments, CYP3A inhibitors include grapefruit juice, cobicistat, danoprevir, ritonavir, elvitegravir, indinavir, itraconazole, ketoconazole, lopinavir, paritaprevir, ombitasvir, dasabuvir, posaconazole, saquinavir, tipranavir, telithromycin, troreandmycin, voriconazole, aprepitant, and ciprofloxacin. These include conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, isabconazole, tofisopam, verapamil, chlorzoxazone, cilostazol, cimetidine, clotrimazole, fosaprepitant, istradefylline, ibacaftol, lomitapide, ranitidine, lanolazine, or ticagrelol. In some embodiments, the CYP3A inhibitor is itraconazole.

[0071] Cytochrome P450 3A inducers, or "CYP3A inducers," refer to members of a class of compounds or substances that increase the activity of cytochrome P450 in humans. In some embodiments, a CYP3A inducer is a CYP3A4 inducer. In some embodiments, a CYP3A inducer is a barbiturate, corticosteroid, phenytoin, carbamazepine, rifampicin, or St. John's wort.

[0072] As used herein, the term “CDK inhibitor” refers to a compound that inhibits a human enzyme called cyclin-dependent kinase (CDK). In some embodiments, the CDK inhibitor is a CDK4 / 6 inhibitor. As used herein, the term “CDK4 / 6 inhibitor” refers to a compound that inhibits CDK4 and / or 6. Examples of CDK inhibitors include, but are not limited to, SHR6390, trilaciclib, rerocyclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, or any pharmaceutically acceptable salt thereof. In some embodiments, the CDK inhibitor is palbociclib or a pharmaceutically acceptable salt thereof.

[0073] As used herein, the term "PARP inhibitor" refers to compounds that inhibit a human enzyme called poly-ADP-ribose polymerase (PARP). Examples of PARP inhibitors include, but are not limited to, olaparib, rucaparib, talazoparib, niraparib, veliparib, pamiparib, CEP9722, E7016, 3-aminobenzamide, mefuparib, and AZD2281.

[0074] As used herein, the term “anticancer agent” is used to refer to an anticancer agent, or a therapeutic agent administered concurrently with an anticancer agent (e.g., palonosetron), and together with these, the compounds of this disclosure (preferably compound A or a pharmaceutically acceptable salt thereof) may be co-administered and / or co-formulated to treat cancer and side effects associated with cancer treatment. These drugs include, for example, everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, Enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, CDK inhibitors, and EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, checkpoint-1 or 2 inhibitors, focal adhesion kinase inhibitors, MAP kinase (MEK) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, olegobomab, Lep-etu, noratexed, azd2171, batablin, ofatumumab, zanorimumab, edtecalin, tetrandrin, lubitecan, tesmilifen, oblimersen, tisilimmumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Silengitide, Jaimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, Lucanton, LY317615, Neuradiab, Vitespan, Rta 744, Sdx 102, Tarampanel, Atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine,Doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, sericiclib, PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, e Xemestane, Letrozole, DES (Diethylstilbestrol), Estradiol, Estrogen, Conjugated Estrogen, Bevacizumab, IMC-1C11, CHIR-258), 3-[5-(Methylsulfonylpiperazine methyl)-Indolyl-Quinolone, Batalanib, AG-013736, AVE-0005, Goserelin Acetate, Leuprolide Acetate, Triptorelyn Pamoate, Medroxyprogesterone Acetate, Hydroxyprogesterone Caproate, Megestrol Acetate, Raloxifene, Bicalutamide, Flutamide, Niltamide Megestrol acetate, CP-724714, TAK-165, HKI-272, Erlotinib, Lapatanib, Canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, Tipifarnib, Amifostin, NVP-LAQ824, Suberoylanilide hydroxamic acid, Valproic acid, Trichostatin A, FK-228, SU11248, Sorafenib, KRN951, Aminoglutethimide, Amsacrine, Anagrelide, L-Ax Paraginase, Calmette-Guérin (BCG) vaccine, Adriamycin, Bleomycin, Buserelin, Busulfan, Carboplatin, Carmustine, Chlorambucil, Cisplatin, Cladribine, Clodronate, Cyproterone, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Diethylstilbestrol, Epirubicin, Fludarabine, Fludrocortisone, Fluoxymesterone, Flutamide, Gleevec, Gemcitabine, Hydroxyurea, Idarubicin, Ifosfamide, Imatinib, Leuprolide, Lebamisol,Lomustine, mechloretamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronic acid, pentostatin, plicamycin, porfimer, procarbazine, larcitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin Vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altoretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mechatoprine, deoxycoformycin, calcitriol, barrubicin, mitramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, Neovasta BMS-275291, Squalamine, Endostatin, SU5416, SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Droloxifene, Idoxyfene, Spironolactone, Finasteride, Cimetidine, Trastuzumab, Denileukin Difutitox, Gefitinib, Bortezimib, Paclitaxel, Cremofol-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifen, 4-hydroxytamoxifen, pipendoxifen, ERA-923, alzoxifen, fulvestrant, acorbifen, rasofoxifen, idoxifen, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, woltmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronic acid, prednisone,Cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab (tiuxetan), androgen, decitabine, hexamethylmelamine, bexarotene, toshitumoma Examples include arsenic trioxide, cortisone, etidronic acid (editronate), mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, casopitant, netsupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, drasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof. In some embodiments, the anticancer agent is selected from the group consisting of abiraterone, abiraterone acetate, estramustine, docetaxel, ketoconazole, goserelin, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronic acid, and zoledronic acid. In some embodiments, the anticancer agent is selected from the group consisting of FLT-3 inhibitors, androgen receptor inhibitors, VEGFR inhibitors, EGFR TK inhibitors, aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 6 inhibitors, anti-HGF antibodies, IGFR TK inhibitors, PI3 kinase inhibitors, AKT inhibitors, JAK / STAT inhibitors, checkpoint 1 inhibitors, checkpoint 2 inhibitors, focal adhesion kinase inhibitors, MAP kinase inhibitors,The group is selected from VEGF trap antibodies and chemical castration drugs.

[0075] In some embodiments, the anticancer agents include temozolomide, capecitabine, irinotecan, tamoxifen, anastrazole, ecmestane, letrozole, DES, estradiol, estrogen, bevacizumab, goserelin acetate, leuprolide acetate, triptrelympamoate, medroxyprogesterone acetate, and hydroprogesterone caproate. Caproate), raloxifene, megestrol acetate, carboplatin, cisplatin, dacarbazine, methotrexate, vinblastine, vinorelbine, topotecan, finasteride, alzoxifene, fulvestrant, prednisone, abiraterone, abiraterone acetate, enzalutamide, apalutamide, darolutamide, ciplucel-T, pembrolizumab, nivolumab, semiprimab, atezolizumab (Tecen The following are selected from the group consisting of triq), avelumab (Bavencio), durvalumab (Imfinzi), docetaxel (Taxotere), cabazitaxel (Jevtana), mitoxantrone (Novantrone), estramustine (Emcyt), docetaxel, ketoconazole, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronic acid, and zoledronic acid.

[0076] The articles “a” and “an” are used in this disclosure to refer to one or more (i.e., at least one) grammatical objects of the article. For example, “an element” means one or more elements.

[0077] Unless otherwise indicated, the terms “and / or” are used in this disclosure to mean either “and” or “or.”

[0078] The terms “patient” and “subject” are used synonymously herein and refer to mammals, such as humans, mice, rats, guinea pigs, dogs, cats, horses, cattle, pigs, or non-human primates, such as monkeys, chimpanzees, baboons, or rhesus macaques.

[0079] In some embodiments, the subject is human.

[0080] In some embodiments, the subjects are humans diagnosed with prostate cancer.

[0081] In some embodiments, the subjects are humans diagnosed with metastatic prostate cancer.

[0082] In some embodiments, the subjects are humans diagnosed with castration-resistant prostate cancer.

[0083] In some embodiments, the subjects are humans diagnosed with metastatic castration-resistant prostate cancer.

[0084] As used to describe a subject, “fasting condition” or “fasting state” means that the subject has not eaten for at least four hours prior to the time of interest, for example, the time at which compound A is administered. In one embodiment, a fasting subject has not eaten for at least six, eight, ten, or twelve hours prior to the administration of compound A or a pharmaceutically acceptable salt thereof.

[0085] As used herein to describe a subject, “feeding condition” or “feeding state” means that the subject has eaten less than four hours prior to the time of interest, for example, the time of administration of compound A. In one embodiment, a subject in a feeding state has eaten less than three, two, one, or half an hour prior to the administration of compound A or a pharmaceutically acceptable salt thereof.

[0086] Methods for ubiquitinating / degrading target proteins within cells This disclosure provides a method for ubiquitinating / degrading a target protein within a cell. The method comprises administering a bifunctional composition comprising an E3 ubiquitin ligase binding moiety and a protein targeting moiety, preferably linked via a linker moiety, as specifically described herein, wherein the E3 ubiquitin ligase binding moiety binds to the protein targeting moiety, the E3 ubiquitin ligase binding moiety recognizes a protein in the ubiquitin pathway (e.g., ubiquitin ligase, preferably E3 ubiquitin ligase), the protein targeting moiety recognizes the target protein, and the degradation of the target protein occurs when the target protein is positioned in close proximity to the ubiquitin ligase, resulting in the degradation / inhibition of the action of the target protein and the control of protein levels. The control of protein levels brought about by this disclosure provides treatment for a disease or condition regulated via the target protein by reducing the level of the target protein within a patient's cells.

[0087] Treatment method The cancer treatment methods described herein result in a reduction in tumor size. Alternatively, or further, if the cancer is metastatic cancer, the treatment method includes inhibiting the invasion of metastatic cancer cells.

[0088] In some embodiments, the cancer is prostate cancer.

[0089] In some embodiments, the cancer is metastatic prostate cancer.

[0090] In some embodiments, the cancer is castration-resistant prostate cancer.

[0091] In some embodiments, the cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0092] In one embodiment, cancer treatment reduces the size of the tumor. This reduction in tumor size may also be referred to as "tumor regression." Preferably, the tumor size after treatment is reduced by 5% or more compared to the tumor size before treatment; more preferably, it is reduced by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by 75% or more. The size of the tumor can be measured by any reproducible measuring means. In one preferred embodiment, the size of the tumor can be measured as the tumor diameter.

[0093] In another embodiment, cancer treatment reduces tumor volume. Preferably, the tumor volume after treatment is reduced by 5% or more compared to the tumor volume before treatment; more preferably, it is reduced by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by 75% or more. Tumor volume can be measured by any reproducible measurement means.

[0094] In another embodiment, cancer treatment reduces the number of tumors. Preferably, the number of tumors after treatment is reduced by 5% or more compared to the number of tumors before treatment; more preferably, it is reduced by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by more than 75%. The number of tumors can be measured by any reproducible measuring means. In one preferred embodiment, the number of tumors can be measured by counting tumors that can be seen with the naked eye or at a specific magnification. In one preferred embodiment, the specific magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0095] In another embodiment, cancer treatment reduces the number of metastatic lesions in other tissues or organs distant from the primary tumor site. Preferably, the number of metastatic lesions after treatment is reduced by 5% or more compared to the number before treatment; more preferably, the number of metastatic lesions is reduced by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by more than 75%. The number of metastatic lesions can be measured by any reproducible measuring means. In one preferred embodiment, the number of metastatic lesions can be measured by counting metastatic lesions that can be seen with the naked eye or at a specific magnification. In one preferred embodiment, the specific magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0096] In another embodiment, cancer treatment increases the mean survival time of the treated population compared to the population administered only the carrier. Preferably, the mean survival time increases by more than 30 days, more preferably more than 60 days, more preferably more than 90 days, and most preferably more than 120 days. The increase in the mean survival time of the population can be measured by any reproducible means. In a preferred embodiment, the increase in the mean survival time of the population can be measured, for example, by calculating the mean survival time of the population after the initiation of treatment with the active agent or compound of the Disclosure. In another preferred embodiment, the increase in the mean survival time of the population can also be measured, for example, by calculating the mean survival time of the population after the completion of the first round of treatment with the active agent or compound of the Disclosure.

[0097] In another embodiment, cancer treatment increases the mean survival of a treated population compared to an untreated population. Preferably, the mean survival increases by more than 30 days, more preferably more than 60 days, more preferably more than 90 days, and most preferably more than 120 days. The increase in the mean survival of the population can be measured by any reproducible means. In a preferred embodiment, the increase in the mean survival of the population can be measured by calculating the mean survival of the population after the initiation of treatment with the active agent or compound of the Disclosure. In another preferred embodiment, the increase in the mean survival of the population can be measured by calculating the mean survival of the population after the completion of the first treatment with the compound of the Disclosure (preferably compound A or a pharmaceutically acceptable salt thereof).

[0098] In another embodiment, cancer treatment reduces the tumor growth rate. Preferably, the tumor growth rate after treatment is reduced by at least 5%, more preferably by at least 10%, more preferably by at least 20%, more preferably by at least 30%, more preferably by at least 40%, more preferably by at least 50%, even more preferably by at least 50%, and most preferably by at least 75%. The tumor growth rate can be measured by any reproducible measuring means. In one preferred embodiment, the tumor growth rate is measured by the change in tumor diameter per unit time.

[0099] In another embodiment, cancer treatment reduces tumor regrowth. Preferably, post-treatment tumor regrowth is less than 5%, more preferably less than 10%, more preferably less than 20%, more preferably less than 30%, more preferably less than 40%, more preferably less than 50%, even more preferably less than 50%, and most preferably less than 75%. Tumor regrowth can be measured by any reproducible measuring means. In one preferred embodiment, tumor regrowth is measured by measuring the increase in tumor diameter from the previous tumor reduction after treatment. In another preferred embodiment, reduced tumor regrowth is indicated by the absence of tumor recurrence after the completion of treatment.

[0100] The dosage of compound A or a pharmaceutically acceptable salt thereof for any of the methods and uses described herein will vary depending on the drug, the age, weight, and clinical condition of the recipient, as well as the experience and judgment of the treating clinician or physician, among other factors that may influence the selected dosage.

[0101] A therapeutically effective dose of compound A or a pharmaceutically acceptable salt thereof may be administered at least once daily for a maximum of 30 days or more, followed by a day or more without administration of the compound. This type of treatment plan, i.e., daily administration of compound A or a pharmaceutically acceptable salt thereof, followed by days without administration of the compound, can be called a treatment cycle. A treatment cycle may be repeated as many times as necessary to achieve the intended effect.

[0102] In some embodiments, a therapeutically effective amount of compound A is administered once, twice, three, four or more times daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, or 30 consecutive days, or once, twice, three, four or more times daily in single or divided doses, for 2, 3, 4, 5, 6 months, or longer, in amounts of 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 ,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,8 1, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 1 85, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 34 0, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495 ,500,505,510,515,520,525,530,535,540,545,550,555,560,565,570,575,580,585,590,595,600,605,610,615,620,625,630,635,640,645,650,655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1,000 mg, or an equivalent amount of a pharmaceutically acceptable salt of compound A.

[0103] In some embodiments, a therapeutically effective amount of compound A is administered once, twice, three, four or more times daily, in single or divided doses (the dose is calculated based on the patient's body weight (kg) and body surface area (m²). 2), and / or may be adjusted according to age, approximately 10-40 mg, approximately 20-50 mg, approximately 30-60 mg, approximately 40-70 mg, approximately 50-80 mg, approximately 60-90 mg, approximately 70-100 mg, approximately 80-110 mg, approximately 90-120 mg, approximately 100-130 mg, approximately 110-140 mg, approximately 120-150 mg, approximately 130-160 mg, approximately 140-170 mg, approximately 150-180 mg, approximately 160-190 mg, approximately 170-200 mg, approximately 180-210 mg, approximately 190-220 mg, approximately 200-230 mg, approximately 210~240mg, 220~250mg, 230~260mg, 240~270mg, 250~280mg, 260~290mg, 270~300mg, 280~310mg, 290~320mg, 300~330mg, 310~ Approximately 340 mg, approximately 320 to approximately 350 mg, approximately 330 to approximately 360 mg, approximately 340 to approximately 370 mg, approximately 350 to approximately 380 mg, approximately 360 to approximately 390 mg, approximately 370 to approximately 400 mg, approximately 380 to approximately 410 mg, approximately 390 to approximately 420 mg, approximately 400 to approximately 430 mg, approximately 410 to approximately 440 mg, about 420 to about 450 mg, about 430 to about 460 mg, about 440 to about 470 mg, about 450 to about 480 mg, about 460 to about 490 mg, about 470 to about 500 mg, about 480 to about 510 mg, about 490 to about 520 mg, about 500 to about 530 mg, about 510 to about 540 mg, About 520 to about 550 mg, about 530 to about 560 mg, about 540 to about 570 mg, about 550 to about 580 mg, about 560 to about 590 mg, about 570 to about 600 mg, about 580 to about 610 mg, about 590 to about 620 mg, about 600 to about 630 mg, about 610 to about 640 mg, about 620 ~650mg, 630~660mg, 640~670mg, 650~680mg, 660~690mg, 670~700mg, 680~710mg, 690~720mg, 700~730mg, 710~740mg, 720~75 0 mg, about 730 to about 760 mg, about 740 to about 770 mg, about 750 to about 780 mg, about 760 to about 790 mg, about 770 to about 800 mg, about 780 to about 810 mg, about 790 to about 820 mg, about 800 to about 830 mg, about 810 to about 840 mg, about 820 to about 850 mg,Approximately 830-860 mg, 840-870 mg, 850-880 mg, 860-890 mg, 870-900 mg, 880-910 mg, 890-920 mg, 900-930 mg, 910-940 mg, 920-950 mg, 930-960 mg, 940-970 mg, 950-980 mg, 960-990 mg, or approximately 970-1,000 mg, or an equivalent amount of a pharmaceutically acceptable salt of compound A.

[0104] In some embodiments, a therapeutically effective amount of compound A is administered once, twice, three, four or more times daily, in single or divided doses (the dose is calculated based on the patient's body weight (kg) and body surface area (m²). 2 It is a pharmaceutically acceptable salt of compound A, approximately 70 mg to approximately 1000 mg or an equivalent amount, (and / or may be adjusted according to age).

[0105] In some embodiments, a therapeutically effective amount of compound A is administered once, twice, three, four or more times daily, in single or divided doses (the dose is calculated based on the patient's body weight (kg) and body surface area (m²). 2 The dosage is approximately 70 mg, 105 mg, 140 mg, 175 mg, 210 mg, 245 mg, 280 mg, 315 mg, 350 mg, 385 mg, 420 mg, 455 mg, 490 mg, 525 mg, 560 mg, 595 mg, 630 mg, 665 mg, or 700 mg, or an equivalent amount of a pharmaceutically acceptable salt of compound A (which may be adjusted according to age).

[0106] In some embodiments, the therapeutically effective dose of compound A is about 100 mg, about 150 mg, or about 300 mg.

[0107] In some embodiments, the therapeutically effective dose of compound A is approximately 100 mg.

[0108] In some embodiments, the therapeutically effective dose of compound A is 100 mg.

[0109] In some embodiments, the therapeutically effective dose of compound A is 100 mg, administered orally once daily.

[0110] In some embodiments, the therapeutically effective dose of compound A is approximately 150 mg.

[0111] In some embodiments, the therapeutically effective dose of compound A is 150 mg.

[0112] In some embodiments, the therapeutically effective dose of compound A is 150 mg, administered orally once daily.

[0113] In some embodiments, the therapeutically effective dose of compound A is approximately 300 mg.

[0114] In some embodiments, the therapeutically effective dose of compound A is 300 mg.

[0115] In some embodiments, the therapeutically effective dose of compound A is 300 mg, administered orally once daily.

[0116] The therapeutically effective dose of compound A can also be in the range of approximately 0.01 mg / kg to approximately 100 mg / kg per day. In one embodiment, the therapeutically effective dose of compound A can be in the range of approximately 0.05 mg / kg to approximately 10 mg / kg per day. In one embodiment, the therapeutically effective dose of compound A can be in the range of approximately 0.075 mg / kg to approximately 5 mg / kg per day. In one embodiment, the therapeutically effective dose of compound A can be in the range of approximately 0.10 mg / kg to approximately 1 mg / kg per day. In one embodiment, the therapeutically effective dose of compound A can be in the range of approximately 0.20 mg / kg to approximately 0.70 mg / kg per day.

[0117] In some embodiments, the therapeutically effective dose of compound A is approximately 0.10 mg / kg per day, approximately 0.15 mg / kg per day, approximately 0.20 mg / kg per day, approximately 0.25 mg / kg per day, approximately 0.30 mg / kg per day, approximately 0.35 mg / kg per day, approximately 0.40 mg / kg per day, approximately 0.45 mg / kg per day, approximately 0.50 mg / kg per day, approximately 0.55 mg / kg per day, approximately 0.60 mg / kg per day, approximately 0.65 mg / kg per day, approximately 0.70 mg / kg per day, approximately 0.75 mg / kg per day, approximately 0.80 mg / kg per day, approximately 0.85 mg / kg per day, approximately 0.90 mg / kg per day, approximately 0.95 mg / kg per day, or approximately 1.00 mg / kg per day.

[0118] In some embodiments, the therapeutically effective dose of compound A is approximately 1.05 mg / kg per day, approximately 1.10 mg / kg per day, approximately 1.15 mg / kg per day, approximately 1.20 mg / kg per day, approximately 1.25 mg / kg per day, approximately 1.30 mg / kg per day, approximately 1.35 mg / kg per day, approximately 1.40 mg / kg per day, approximately 1.45 mg / kg per day, and approximately The daily doses are approximately 1.50 mg / kg, 1.55 mg / kg, 1.60 mg / kg, 1.65 mg / kg, 1.70 mg / kg, 1.75 mg / kg, 1.80 mg / kg, 1.85 mg / kg, 1.90 mg / kg, 1.95 mg / kg, or 2.00 mg / kg.

[0119] In some embodiments, the therapeutically effective dose of compound A is approximately 2 mg / kg per day, approximately 2.5 mg / kg per day, approximately 3 mg / kg per day, approximately 3.5 mg / kg per day, approximately 4 mg / kg per day, approximately 4.5 mg / kg per day, approximately 5 mg / kg per day, approximately 5.5 mg / kg per day, approximately 6 mg / kg per day, approximately 6.5 mg / kg per day, approximately 7 mg / kg per day, approximately 7.5 mg / kg per day, approximately 8.0 mg / kg per day, approximately 8.5 mg / kg per day, approximately 9.0 mg / kg per day, approximately 9.5 mg / kg per day, or approximately 10 mg / kg per day.

[0120] In some embodiments, a therapeutically effective dose of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once daily. In some embodiments, this daily dose of compound A or a pharmaceutically acceptable salt thereof may be administered to the subject in one lump sum. In some embodiments, this daily dose of compound A or a pharmaceutically acceptable salt thereof may be administered to the subject in two divided doses (i.e., split doses). In some embodiments, this daily dose of compound A or a pharmaceutically acceptable salt thereof may be administered to the subject in three divided doses. In some embodiments, this daily dose of compound A or a pharmaceutically acceptable salt thereof may be administered to the subject in four divided doses. In some embodiments, this daily dose of compound A or a pharmaceutically acceptable salt thereof may be administered to the subject in five or more divided doses. In some embodiments, these partial or divided doses are administered to the subject at regular intervals throughout the day, for example, every 12 hours, every 8 hours, every 6 hours, every 5 hours, every 4 hours, etc.

[0121] The therapeutically effective dose of compound A or its pharmaceutically acceptable salt can first be estimated using either a cell culture assay or an animal model (usually rats, mice, rabbits, dogs, or pigs). Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for human administration. Therapeutic / prophylactic efficacy and toxicity can be determined using standard pharmaceutical procedures in cell culture or experimental animals, e.g., ED. 50(Effective therapeutic dose for 50% of the population) and LD 50 (Lethal dose for 50% of the population) can be determined. The dose ratio between toxicity and therapeutic effect is the therapeutic index, which can be expressed as the ratio of LD 50 / ED 50 . Pharmaceutical compositions showing a large therapeutic index are preferred. The dose can vary within this range depending on the dosage form employed, the sensitivity of the patient, and the route of administration.

[0122] The dosage and administration are adjusted to bring about a sufficient level of Compound A or to maintain the desired effect. Factors that may be considered include the severity of the medical condition, the general health of the subject, the age, weight and sex of the subject, diet, time and frequency of administration, co - administration (if any) of drugs, response sensitivity, and tolerance / response to the treatment method. Long - acting pharmaceutical compositions can be administered once every 3 - 4 days, weekly, every two weeks or monthly depending on the half - life and clearance rate of the particular formulation.

[0123] In some embodiments, a method for treating prostate cancer with a combination of compound A or a pharmaceutically acceptable salt thereof and another anticancer agent is described herein, where the therapeutic effective amount of compound A or a pharmaceutically acceptable salt thereof is 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 2 2, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 1 20, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 2 75, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 43 0, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585 ,590,595,600,605,610,615,620,625,630,635,640,645,650,655,660,665,670,675,680,685,690,695,700,705,710,715,720,725,730,735,740,745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975 The dose is 980, 985, 990, 995, or 1,000 mg, administered once, twice, three, four or more times daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 30 consecutive days, or once, twice, three, four or more times daily, in single doses or divided doses, for 2, 3, 4, 5, 6 months, or longer.

[0124] Pharmaceutical composition In some embodiments, compound A or a pharmaceutically acceptable salt thereof is formulated for oral administration. For example, in some embodiments, the compounds of the present disclosure are formulated as tablets containing 0, 1, 2, or more of each of the following: emulsifier; surfactant, binder; disintegrant, flow enhancer; and lubricant.

[0125] In some embodiments, the emulsifier is hypromellose.

[0126] In some embodiments, the surfactant is vitamin E polyethylene glycol succinate.

[0127] In some embodiments, the binder (also referred to herein as the filler) is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, sucrose, glucose, and sorbitol.

[0128] In some embodiments, the disintegrant is croscarmellose sodium.

[0129] In some embodiments, the flow promoter refers to a substance used to facilitate the flow of powder by reducing interparticle aggregation. In some embodiments, in the dosage forms of the present disclosure, the flow promoter is selected from the group consisting of silicon dioxide, colloidal anhydrous silica, starch, and talc.

[0130] In some embodiments, the lubricant refers to a substance that prevents the components from sticking and / or agglomerating in the machinery used to prepare the dosage forms of the present disclosure. In some embodiments, the lubricant in the dosage forms of the present disclosure is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, and plant stearin.

[0131] Pharmaceutical compositions containing compound A or a pharmaceutically acceptable salt thereof may be manufactured by commonly known methods, such as conventional mixing, dissolution, granulation, sugar coating, polishing, emulsification, encapsulation, encapsulation, or freeze-drying processes. Pharmaceutical compositions may be formulated by conventional methods using one or more pharmaceutically acceptable carriers containing excipients and / or auxiliary agents that facilitate the processing of compound A or a pharmaceutically acceptable salt thereof into a pharmaceutically usable formulation. Naturally, the appropriate formulation depends on the chosen route of administration.

[0132] Pharmaceutical compositions suitable for injection include sterile aqueous solutions (if water-soluble) or dispersions, and sterile powders for the immediate preparation of sterile injection solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL® (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid enough to be easily injected. The composition must be stable under manufacturing and storage conditions and protected from contamination by microorganisms such as bacteria and fungi. The carrier may 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. Adequate 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 activity can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, it is preferable to include isotonic agents, such as sugars, polyalcohols, such as mannitol, sorbitol, and sodium chloride, in the composition. Long-term absorption of the injectable composition can be achieved by including absorption-delaying agents, such as aluminum monostearate and gelatin, in the composition.

[0133] Sterile injectable solutions can be prepared by incorporating the required amount of compound A or a pharmaceutically acceptable salt thereof, along with one or a combination thereof, as needed, into a suitable solvent, followed by sterilization by filtration. Generally, dispersions are prepared by incorporating the active agent or compound into a sterile vehicle, the sterile vehicle containing a basic dispersion medium and other necessary components from those described above. In the case of sterile powders for preparing sterile solutions for injection, the preparation methods are vacuum drying and freeze-drying, which yield powders of the active ingredient and any desired additional ingredients from a pre-sterilically filtered solution.

[0134] Oral compositions generally contain an inert diluent or a pharmaceutically acceptable edible carrier. They can be encapsulated in gelatin capsules or compressed into tablets.

[0135] For oral therapeutic administration, compound A or a pharmaceutically acceptable salt thereof may be incorporated with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions may also be prepared using a liquid carrier used as a gargle, in which case the agent or compound in the liquid carrier is applied orally, rinsed in the mouth, spat out, or swallowed. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; flow enhancers such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring.

[0136] When administered by inhalation, the drug or compound is delivered in the form of an aerosol spray via a nebulizer, or in a pressurized container or dispenser containing an appropriate propellant, such as a gas like carbon dioxide.

[0137] Systemic administration may be by mucosal or percutaneous means. In the case of mucosal or percutaneous administration, a penetrating agent suitable for the barrier to be penetrated is used in the formulation. Such penetrating agents are generally known in the art, and for example, for mucosal administration, surfactants, bile salts, and fusidic acid derivatives are included. Mucosal administration can be carried out by the use of nasal sprays or suppositories. In the case of percutaneous administration, the active agent or compound is formulated into ointments, pastes, gels, or creams that are generally known in the art.

[0138] In one embodiment, compound A or a pharmaceutically acceptable salt thereof is prepared with a pharmaceutically acceptable carrier that prevents the drug or compound from being rapidly excreted from the body, such as in a controlled-release formulation including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations are obvious to those skilled in the art. The materials can also be commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (containing liposomes targeting infected cells and containing monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, the method described in U.S. Patent No. 4,522,811.

[0139] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate oral or parenteral compositions into unit dosage forms. As used herein, a unit dosage form refers to a physically distinct unit suitable for a unit dose to the target being treated, each unit containing a predetermined amount of the active agent or compound, calculated to produce the desired therapeutic effect, along with the required pharmaceutical carrier. The specifications of the unit dosage forms in this application are determined by and directly depend on the inherent characteristics of compound A or its pharmaceutically acceptable salts and the specific therapeutic effect to be achieved.

[0140] The pharmaceutical composition may be contained within a container, pack, or dispenser, along with instructions for administration.

[0141] Exemplary methods of administering compound A or a pharmaceutically acceptable salt thereof include systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, transvaginal, buccal, transrectal, or local administration. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered orally to the subject. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered as tablets, capsules, caplets, solutions, suspensions, syrups, granules, beads, powders, or pellets.

[0142] An exemplary pharmaceutical composition comprises a salt of compound A and a pharmaceutically acceptable carrier, for example, a) diluent, for example, purified water, triglyceride oil, for example, hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, for example, EPA or DHA, or esters thereof or mixtures thereof, omega-3 fatty acids or their derivatives, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) lubricant, for example, silica, talc, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate Aluminium, sodium chloride and / or polyethylene glycol; for tablets, further, c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars, e.g., glucose or beta-lactose, corn sweeteners, natural and synthetic rubbers, e.g., gum arabic, tragacanth or sodium alginate, wax and / or polyvinylpyrrolidone (optional); d) disintegrants, e.g., starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) hygroscopic agents, colorants, flavoring agents and sweeteners; f) emulsifiers or dispersants, e.g., Tween Tablets and gelatin capsules comprising 80, Labrasol, HPMC, DOSS, Caproyl 909, Labrafac, Labrafil, Peceol, Transcutol, Capmul MCM, Capmul PG-12, Captex 355, Gelucire, Vitamin E TGPS or other acceptable emulsifiers; and / or agents that improve the absorption of salts, such as cyclodextrin, hydroxypropyl cyclodextrin, PEG400, and / or PEG200.

[0143] The inert, pharmaceutically acceptable carrier for preparing a pharmaceutical composition from compound A, or a salt or hydrate thereof, may be either solid or liquid. Solid dosage forms include powders, tablets, dispersible granules, capsules, cachets, and suppositories.

[0144] Powders and tablets may consist of approximately 5 to 95 percent of the active ingredient. Suitable solid carriers are known in the art and include, for example, magnesium carbonate, magnesium stearate, talc, sugar, or lactose. Tablets, powders, cachets, and capsules may be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods for producing various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[0145] Liquid formulations include solutions, suspensions, and emulsions. Examples include water or water-propylene glycol solutions for parenteral injection, or the addition of sweeteners and opacifiers for oral solutions, suspensions, and emulsions. Liquid formulations may also include solutions for nasal administration.

[0146] Liquid compositions, particularly injectable compositions, can be prepared by means of dissolution, dispersion, etc. For example, an injectable isotonic solution or suspension can be formed by dissolving or mixing a salt of the disclosure in a pharmaceutically acceptable solvent such as water, physiological saline, dextrose aqueous solution, glycerol, or ethanol. The compounds of the disclosure can be solubilized using proteins such as albumin, chylomicron particles, or serum proteins.

[0147] Parenteral injections are typically administered by subcutaneous, intramuscular, or intravenous injection and infusion. Injectable drugs can be prepared in conventional forms, either as a liquid solution, a suspension, or a solid suitable for dissolution in liquid before injection.

[0148] Aerosol formulations suitable for inhalation may include solids in solution and powder form and may be combined with a pharmaceutically acceptable carrier, such as an inert compressed gas, such as nitrogen.

[0149] This also includes solid dosage forms intended to be converted into liquid formulations for oral or parenteral administration immediately before use. Such liquid forms include solutions, suspensions, and emulsions.

[0150] Depending on the intended method of administration, the compositions of this disclosure may be in solid, semi-solid, or liquid dosage forms, such as injections, tablets, suppositories, pills, sustained-release capsules, elixirs, tinctures, emulsions, syrups, powders, solutions, suspensions, etc., in accordance with conventional pharmaceutical practice, sometimes in unit doses. Similarly, the compositions may also be administered intravenously (both bolus and infusion), intraperitoneally, intrathecally, subcutaneously, or intramuscularly, using forms well known to those skilled in the art of pharmaceuticals.

[0151] The pharmaceutical compositions may be prepared according to conventional mixing, granulation, or coating methods, respectively, and may contain, by weight or volume, about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the free bases or salts of the Disclosure.

[0152] A pharmaceutical composition containing compound A or a pharmaceutically acceptable salt thereof may further comprise one or more additional anticancer agents, including any of those disclosed herein.

[0153] In this specification, the total amount of any component of any oral dosage form, for example, a tablet, as indicated on a w / w basis, refers to the total weight of the oral dosage form unless otherwise specified. [Examples]

[0154] This disclosure is further illustrated by the following embodiments, but should not be construed as limiting this disclosure in scope or spirit to the specific procedures described herein. These embodiments are provided to illustrate certain embodiments and are not intended to limit the scope of this disclosure. It should also be understood that various other embodiments, their modifications, and equivalents may be proposed to those skilled in the art without departing from the spirit of this disclosure and / or the appended claims.

[0155] Example 1 - In vitro evaluation of compound A for cytochrome P450 and transporter-mediated drug interactions. In vitro studies were conducted to evaluate the ability of compound A to induce cytochrome P450 (CYP) and transporter-mediated drug interactions (DDIs).

[0156] The inducible activity of compound A towards CYP enzymes was evaluated in cryopreserved human hepatocytes from three donors. After treatment with compound A at concentrations of 0.03–30 μM for 48 hours, mRNA levels for CYP1A2, 2B6, 2C8, 2C9, 2C19, and 3A4 were measured by semi-quantitative real-time polymerase chain reaction (PCR). Test substance concentrations were measured during a 24-hour incubation. The ability of compound A to induce direct and time-dependent inhibition (TDI) of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 activity was evaluated in pooled human liver microsomes (HLMs) at concentrations of 0.2–15 μM. Probe substrate concentrations around Km were used for directional inhibition and initial TDI assays. For the TDI assay, compound A was pre-incubated with pooled HLM for 30 minutes with and without NADPH before incubation with a single concentration probe substrate.

[0157] Metabolite profiling was performed by incubation of compound A (2 and 10 μM) with HLM (up to 60 minutes), human hepatocyte suspension (up to 240 minutes), and human plasma (up to 360 minutes). Furthermore, compound A (2 μM) was incubated with recombinant human CYP enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5.

[0158] The DDI (drug-dispersing) ability of compound A, as a drug that infects cells via the CYP pathway, was investigated in HLM, human hepatocyte suspension, and human recombinant CYP enzymes.

[0159] Furthermore, the inhibitory activity against efflux transporters (P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP)) and uptake transporters (MATE1, MATE2-K, OATP1B1, OATP1B3, OAT1, OAT3, and OCT2) was evaluated using monolayers of single transporter-overexpressing cells (MDCK II or HEK293) or inside-out vesicles.

[0160] The ability of compound A to inhibit Pgp or BCRP was tested at concentrations of 0.07–5 μM of compound A in bidirectional transport of probe substrates in Pgp or BCRP-expressing MDCKII cells and a control monolayer. Pgp and BCR inhibition was tested in inside-out membrane vesicles prepared from HEK293 cells overexpressing human Pgp and BCR in the presence of 4 mM MgATP or MgAMP at concentrations of 0.01–9 μM of compound A. The ability of compound A to inhibit uptake transporters in MDCKII or HEK293 cells stably expressing single MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, and OCT2 was tested at concentrations of 0.005–3.75 μM.

[0161] The ability of compound A to function as the efflux transporters Pgp and BCRP, and the uptake transporters OATP1B1 and 1B3, was evaluated in Caco-2 and single-transporter overexpressing HEK29 cells, respectively.

[0162] The ability of compound A to act as a substrate for Pgp and BCRP was tested in Caco-2 cells containing 1% BSA at concentrations of 0.075, 0.75, 3.75, and 7.5 μM. After 120 minutes of incubation, the bidirectional permeability of compound A was measured by LC-MS / MS. The involvement of compound A as a substrate for OATP1B1 and OATP1B3 was evaluated in uptake transporter substrate assays at four concentrations (0.1, 0.5, 1, and 5 μM). Compound A in cell lysates was measured by LC-MS / MS.

[0163] result CYP induction: No significant decrease in hepatocyte viability was observed in hepatocytes at any compound A concentration (0.03–30 μM) after 2 days of treatment in the previous MTT assay (data not shown). The positive control inducer behaved as expected (Table 1). Up to 2.5–8.8-fold induction in CYP3A4 mRNA (4–6% of the positive control response) was observed at 0.1–0.3 μM in all three donors, and for CYP2C8 mRNA, a 3.1-fold induction was observed at 0.1 μM in one of the three lots (donor 3 only) (28% of the positive control response). The induction response decayed at higher concentrations (Table 1).

[0164] At concentrations ranging from 0.03 to 30 μM, compound A did not induce CYP1A2, 2B6, and 2C9 mRNA in human hepatocytes from all three donors (Table 1 and Figure 1).

[0165] [Table 2]

[0166] *PC: Positive control inducer. Omeprazole for CYP1A2, phenobarbital for CYP2B6, and rifampicin for CYP2C and 3A4.)

[0167] CYP inhibition: After incubation of HLM with compound A at concentrations of 0.2–15 μM, no direct or time-dependent inhibition was observed for any of the CYP isoforms (Table 2). The positive control inhibitors showed the expected IC for all enzymes tested. 50 Direct inhibition and TDI were shown for both value and magnification shifts (data not shown). Compound A did not cause direct inhibition (maximum inhibition of ≤12%) or TDI for all CYPs tested up to 15 μM (≤15%) (Table 2).

[0168] [Table 3]

[0169] Metabolism and CYP reaction phenotype: Compound A was relatively stable in 2 μM human hepatocyte suspension (up to 240 minutes) and major recombinant CYP (up to 25 minutes) during HLM incubation for up to 60 minutes (data not shown). A loss of up to 23% of compound A was observed in CYP3A5 (data not shown).

[0170] Metabolite profiling using human plasma, HLM, and human hepatocytes revealed that hydrolysis (M825 / 1) is the major metabolic pathway. Other secondary pathways include oxidation, dealkylation, and demethylation, which account for less than 2% of the total abundance (Table 3).

[0171] [Table 4]

[0172] Efflux transporter substrate and inhibition: Compound A showed low permeability in the Caco-2 cell monolayer (data not shown). Due to the low permeability, compound A could not be reliably measured as a substrate for Pgp and BCRP.

[0173] Compound A showed a 0.23 μM IC50 in the vesicle assay. 50 Compound A inhibited Pgp at a certain level, but this inhibition was not observed in the MDCKII bidirectional assay. Compound A inhibited IC50 at 1.55 μM and 0.21 μM in both the monolayer assay and the vesicle assay, respectively. 50 BCRP was inhibited by the measured values ​​(Table 4 and Figure 2). Positive control probe substrates and inhibitors demonstrated the functional assay system (data not shown).

[0174] [Table 5]

[0175] Efflux Transporter Substrates and Inhibitors: Probe substrates and inhibitors showed the expected uptake activity and inhibition for each transporter (data not shown). Compound A was not a substrate for OATP1B1 and OATP1B3 because its accumulation was similar in OATP1B1 / 1B3 expression and control cells (accumulation ratio <2), and there was no activity accumulation of compound A under the tested conditions (data not shown).

[0176] Compound A did not induce more than 50% inhibition of the transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT2, and MATE2-K. However, at a concentration of 3.75 μM, compound A resulted in 52% inhibition of MATE1 (EC2). 50 (3.05 μM). Testing at higher concentrations was limited by solubility. (Table 5).

[0177] [Table 6]

[0178] While I don't intend to be bound by theory, these results appear to demonstrate that compound A is unlikely to cause significant DDI as a CYP enzyme inhibitor or substrate. Furthermore, the results also appear to indicate that compound A is unlikely to cause DDI of uptake transporters.

[0179] Equal parts Those skilled in the art will be able to recognize or confirm numerous equivalents of the specific embodiments described herein by means of simple, routine experiments. Such equivalents are intended to be included within the scope of the following claims.

[0180] The methods described herein have been described herein with reference to certain preferred embodiments. However, since certain modifications to such embodiments are obvious to those skilled in the art based on the disclosures herein, this disclosure should not be considered limited to such embodiments.

[0181] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure pertains. In this specification and in the claims, singular terms include plural forms unless the context specifically indicates otherwise.

[0182] At least some of the descriptions in this disclosure have been simplified in order to focus on elements relevant to a clear understanding of this disclosure, and for the sake of clarity, it should be understood that other elements that a person skilled in the art would recognize may also constitute part of this disclosure. However, since such elements are well known in the art and do not necessarily facilitate a better understanding of this disclosure, no description of such elements is provided herein.

[0183] Furthermore, unless the method depends on a particular order of steps described herein, the particular order of steps enumerated in the claims should not be construed as limiting the claims.

[0184] All patents, patent applications, references, and publications cited herein are incorporated fully and completely by reference as if they were included in their entirety. Such documents are not considered prior art to this disclosure.

Claims

1. A method for performing treatment for prostate cancer in a patient who requires such treatment, The aforementioned target is a therapeutically effective amount of compound A, 【Chemistry 1】 The method further comprises administering a pharmaceutically acceptable salt thereof, and further comprising discontinuing or reducing the administration of a CYP3A inhibitor or inducer, an efflux transporter substrate or inhibitor, or an uptake transporter substrate or inhibitor to the subject before commencing administration of compound A or a pharmaceutically acceptable salt thereof.

2. A method for performing treatment for prostate cancer in a patient who requires such treatment, The above includes administering a therapeutically effective amount of compound A to the subject, 【Chemistry 2】 The method further comprises the step of discontinuing or reducing the administration of a CYP3A inhibitor or inducer, an efflux transporter substrate or inhibitor, or an uptake transporter substrate or inhibitor to the subject before initiating administration of compound A.

3. The method according to claim 1 or 2, further comprising the step of discontinuing the administration of the CYP3A inhibitor or inducer, the efflux transporter substrate or inhibitor, or the uptake transporter substrate or inhibitor to the subject before initiating the administration of compound A or a pharmaceutically acceptable salt thereof.

4. The method according to claim 1 or 2, further comprising the step of reducing the administration of the CYP3A inhibitor or inducer, the efflux transporter substrate or inhibitor, or the uptake transporter substrate or inhibitor to the subject before initiating administration of a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof.

5. The method according to claim 3, wherein the administration of the CYP3A inhibitor or inducer, the efflux transporter substrate or inhibitor, or the reuptake transporter substrate or inhibitor is discontinued in the subject at a time prior to the commencement of the administration of compound A or a pharmaceutically acceptable salt thereof, the time being at least 120 hours.

6. The method according to claim 4, wherein the administration of the CYP3A inhibitor or inducer, the efflux transporter substrate or inhibitor, or the reuptake transporter substrate or inhibitor is reduced in the subject at a time prior to the commencement of the administration of compound A or a pharmaceutically acceptable salt thereof, the time being at least 120 hours.

7. A method for performing treatment for prostate cancer in a patient who requires such treatment, The aforementioned target is a therapeutically effective amount of compound A, 【Transformation 3】 The method further comprises administering a CYP3A inhibitor or inducer, an efflux transporter substrate or inhibitor, or an uptake transporter substrate or inhibitor to the subject, comprising administering a pharmaceutically acceptable salt thereof.

8. A method for performing treatment for prostate cancer in a patient who requires such treatment, The above includes administering a therapeutically effective amount of compound A to the subject, 【Chemistry 4】 The method further comprises the step of administering a CYP3A inhibitor or inducer, an efflux transporter substrate or inhibitor, or an uptake transporter substrate or inhibitor to the subject.

9. The method according to any one of claims 1 to 8, wherein the prostate cancer is castration-resistant prostate cancer.

10. The method according to any one of claims 1 to 8, wherein the prostate cancer is metastatic prostate cancer.

11. The method according to any one of claims 1 to 8, wherein the prostate cancer is metastatic castration-resistant prostate cancer.

12. The method according to any one of claims 1 to 11, wherein the subject is in a feeding state.

13. The method according to any one of claims 1 to 11, wherein the subject is in a fasting state.

14. The method according to any one of claims 1-13, wherein the discharge transporter is Pgp or BCRP.

15. The method according to any one of claims 1 to 14, wherein the intake transporter is OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, or MATE2-K.

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