Compounds and methods for targeted degradation of androgen receptors

Abstract

The present disclosure relates to methods of treating prostate cancer, including, for example, metastatic prostate cancer, castration-resistant prostate cancer, and metastatic castration-resistant prostate cancer, in a subject in need thereof wherein the method comprises administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof, and further comprising the step of stopping 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 prior to commencing administration of Compound A or a pharmaceutically acceptable salt thereof.

Description

[0001] Related applications

[0002] This application claims priority and benefit to U.S. Provisional Application No. 63 / 511,420, filed June 30, 2023, and U.S. Provisional Application No. 63 / 580,126, filed September 1, 2023, the contents of which are incorporated herein by reference in their entirety for all purposes. Technical Field

[0003] This disclosure provides a method for treating prostate cancer using a bifunctional compound. Background of the Invention

[0005] Most small molecule drugs bind to enzymes or receptors in tight and well-defined pockets. On the other hand, protein-protein interactions are notoriously difficult to target with small molecules due to their large contact surfaces and the shallow grooves or flat interfaces involved. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity to ubiquitination and are therefore attractive therapeutic targets. The development of E3 ligase ligands has proven challenging, partly because they must disrupt protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases.

[0006] One potentially therapeutic E3 ubiquitin ligase is cereblon. Cereblon is a protein encoded by the CRBN gene in humans. Thalidomide and its analogues (e.g., pomalidomide and lenalidomide) are known to bind to cereblon. Binding to cereblon alters the specificity of the complex, thereby inducing ubiquitination and degradation of transcription factors essential for the growth of multiple myeloma. In fact, higher expression of cereblon has been associated with increased efficacy of imide drugs in treating multiple myeloma.

[0007] The androgen receptor (AR) belongs to the nuclear hormone receptor family and 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, the AR binds to heat shock protein 90 (Hsp90) in the cytosol. When an androgen binds to the AR, its conformation changes, releasing the AR from Hsp90 and exposing the nuclear localization signal (NLS). The latter allows the AR to translocate to the nucleus, where it acts as a transcription factor to promote the expression of genes responsible for male sexual characteristics (Endocr. Rev. 1987, 8(1):1-28; Mol. Endocrinol. 2002, 16(10), 2181-7). AR deficiency leads to androgen insensitivity syndrome, formerly known as testicular feminization.

[0008] While AR is responsible for the development of male sexual characteristics, it is also a well-established oncogene in certain forms of cancer, including prostate cancer (Endocr. Rev. 2004, 25(2), 276-308). The commonly measured target gene for AR activity is the secreted prostate-specific antigen (PSA) protein. Current treatment options for prostate cancer involve two approaches to inhibit the androgen-AR axis. The first approach relies on androgen reduction, 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 experience disease progression. An alternative approach for treating prostate cancer involves eliminating AR proteins.

[0009] Because arachnoid anemia (AR) is a key driver of tumorigenesis in many forms of prostate cancer, its elimination should produce a beneficial therapeutic response. There remains a persistent need in this field for effective treatments for diseases, particularly cancer, prostate cancer, and Kennedy's disease.

[0010] However, non-specific effects and the inability to target and regulate certain classes of proteins (such as transcription factors) remain obstacles to the development of effective anticancer agents. Therefore, small molecule therapeutics that utilize or enhance the substrate specificity of cereblon while being "tunable," enabling specific targeting and regulation of multiple protein classes, would be highly valuable as therapeutic agents.

[0011] More than 70 different somatic missense AR tumor mutations have been identified in prostate cancer patients (Gottlieb, B., Hum. Mutat. 2004, 23: 527-533). Most of these AR tumor mutations are located in the ligand-binding domain. Unbound by theory, AR tumor mutations in the ligand-binding domain lead to reduced ligand specificity, thereby enabling AR to function independently of androgens. Such AR tumor mutations provide tumor cells with the ability to proliferate in an androgen-depleted environment, and thus prostate cancer therapies responding to blocking or reducing androgen levels (e.g., luteinizing hormone-releasing hormone agonists) are selected. Therefore, an increased frequency of AR tumor mutations has been observed 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). Summary of the Invention

[0012] On one hand, this application relates to a method for treating prostate cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of compound A. The compound A or a pharmaceutically acceptable salt thereof, and also includes the step of stopping or reducing the administration of a CYP3A inhibitor to a subject before initiating administration of compound A or a pharmaceutically acceptable salt thereof.

[0013] On one hand, this application relates to a method for treating prostate cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of compound A. It also includes the step of stopping or reducing the administration of CYP3A inhibitors to subjects before starting the administration of compound A.

[0014] On one hand, this application relates to a method for treating prostate cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of compound A. The method further includes the step of discontinuing administration of the CYP3A inhibitor to the subject prior to the initiation of administration of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, administration of the CYP3A inhibitor to the subject is discontinued at a time point prior to the initiation of administration of compound A or a pharmaceutically acceptable salt thereof, wherein said time point is at least 120 hours prior.

[0015] On one hand, this application relates to a method for treating prostate cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of compound A. It also includes the step of stopping the administration of the CYP3A inhibitor to the subject before the administration of compound A is started. In some embodiments, the administration of the CYP3A inhibitor to the subject is stopped at a time point before the administration of compound A is started, said time point being at least 120 hours later.

[0016] On one hand, this application relates to a method for treating prostate cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of compound A. The method further includes a step of reducing the administration of a CYP3A inhibitor to the subject prior to the initiation of administration of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the administration of a CYP3A inhibitor to the subject is reduced at a time point prior to the initiation of administration of compound A or a pharmaceutically acceptable salt thereof, wherein said time point is at least 120 hours prior to the initiation of administration of compound A or a pharmaceutically acceptable salt thereof.

[0017] On one hand, this application relates to a method for treating prostate cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of compound A. It also includes the step of stopping the reduction of CYP3A inhibitor administration to the subject before starting administration of compound A. In some embodiments, the reduction of CYP3A inhibitor administration to the subject is performed at a time point at least 120 hours before starting administration of compound A.

[0018] On one hand, this application relates to a method for treating prostate cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of compound A. It may be a pharmaceutically acceptable salt thereof, and may also include administration of a CYP3A inhibitor to the subject.

[0019] On one hand, this application relates to a method for treating prostate cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of compound A. This also includes administering CYP3A inhibitors to subjects.

[0020] On one hand, this application relates to a method for treating prostate cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of compound A. Or a pharmaceutically acceptable salt thereof, wherein a CYP3A inhibitor is also administered to the subject.

[0021] On one hand, this application relates to a method for treating prostate cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of compound A. This also includes administering CYP3A inhibitors to subjects.

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

[0023] In some implementations, 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.

[0024] In some implementations, a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once daily.

[0025] In some implementations, a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once, or in two, three, or four divided doses.

[0026] In some implementations, the therapeutically effective dose of compound A is about 1 mg to about 1000 mg.

[0027] In some implementations, the therapeutically effective dose of compound A is about 5 mg to about 750 mg.

[0028] In some implementations, the therapeutically effective dose of compound A is about 10 mg to about 500 mg.

[0029] In some implementations, the therapeutically effective dose of compound A is about 20 mg to about 250 mg.

[0030] In some implementations, the therapeutically effective dose of compound A is approximately 100 mg.

[0031] In some implementations, the therapeutically effective dose of compound A is 100 mg.

[0032] In some implementations, the therapeutically effective dose of compound A is approximately 150 mg.

[0033] In some implementations, the therapeutically effective dose of compound A is 150 mg.

[0034] In some implementations, the therapeutically effective dose of compound A is approximately 300 mg.

[0035] In some implementations, the therapeutically effective dose of compound A is 300 mg.

[0036] In some implementations, the method further includes administering an effective amount of at least one additional anticancer agent to the subject in need.

[0037] In some embodiments, the additional anticancer agent is abiraterone, abiraterone acetate, estradiol, docetaxel, ketoconazole, goserelin, histidine, triptorelin, buterelin, cyproterone acetate, flutamide, bicalutamide, nilumethoxazole, pamidronate, or zoledronic acid. Attached Figure Description

[0038] The accompanying drawings, incorporated in and forming part of this specification, illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the disclosure. The drawings are for illustrative purposes only and should not be construed as limiting the scope of the disclosure. Other objects, features, and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the accompanying drawings, which illustrate illustrative embodiments of the disclosure, wherein: Figure 1A -F summarizes the effects of compound A on cytochrome P450 (CYP) and CYP1A2 in human liver cells. Figure 1A ), CYP2B6 ( Figure 1B ), CYP3A4 ( Figure 1C ), CYP2C8 ( Figure 1D ), CYP2C9 ( Figure 1E ) and CYP2C19 ( Figure 1F Effects on mRNA expression. Each group of bar charts shows the fold induced mRNA expression in three human hepatocyte donors at different concentrations of compound A (0.03–30 mM).

[0039] Figure 2A -B summarizes the effects of compound A on P-glycoprotein (Pgp, BCRP) in MDCKII monolayer cells and vesicles expressing Pgp and BCRP. Figure 2A ) and breast cancer resistance protein (BCRP, Figure 2B The inhibitory effect of compound A was observed. Each graph shows the relative Pgp or BCRP activity (as a percentage of control) of vesicles and monolayers at different concentrations of compound A (mM). Data are the mean ± standard deviation of three replicates. Detailed Implementation

[0040] definition

[0041] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, thereby targeting and degrading the substrate protein. For example, cereblon is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin conjugate, links ubiquitin to a lysine residue on a target protein and subsequently targets the specific substrate protein for degradation by the proteasome. Therefore, E3 ubiquitin ligases, alone or in combination with E2 ubiquitin conjugates, are responsible for transferring ubiquitin to the target protein. Generally, ubiquitin ligases participate in polyubiquitination, causing a second ubiquitin to link to a first ubiquitin; a third ubiquitin to a second ubiquitin, and so on. Polyubiquitination labels proteins for degradation by the proteasome. However, some ubiquitination events are limited to monoubiquitination, where the ubiquitin ligase adds only a single ubiquitin to the substrate molecule. Monoubiquitinated proteins are not targeted for degradation by the proteasome but can have their cellular location or function altered, for example, by binding to other proteins with domains capable of binding ubiquitin. To complicate matters further, E3 can target different lysine residues on ubiquitin to form chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to produce polyubiquitin, which is recognized by the proteasome.

[0042] As used herein with respect to the compounds disclosed, "pharmaceuticalally acceptable salt" means a salt form of compound A and a hydrate of said salt form with one or more water molecules present. Such salts and hydrated forms retain the biological activity of compound A and are biologically or otherwise desirable, i.e., exhibit minimal (if any) toxicological effects. Representative “pharmaceutically acceptable salts” include, for example, water-soluble and water-insoluble salts such as acetates, 4,4-diaminostilbene-2,2-disulfonate, benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, butyrate, calcium, calcium ethylenediaminetetraacetate, camphorsulfonate, carbonate, chloride, citrate, clavulanate, dihydrochloride, ethylenediaminetetraacetate, ethanedisulfonate, etolate, ethanesulfonate, fumarate, gluconate, gluconate, glutamate, alcoholylarsinate, hexafluorophosphate, hexylresorcinol, hyaluronic acid, hydrobromide, hydrochloride, hydroxynaphthylcarbamate, iodide, isothiosulfate, lactate, lacturonate, laurate, magnesium, apple Salts, maleates, mandelates, methanesulfonates, methyl bromide, methyl nitrates, methyl sulfates, mucilages, naphthalene sulfonates, nitrates, N-methylglucosamine ammonium salts, 3-hydroxy-2-naphthoate, oleates, oxalates, palmitates, bis(hydroxynaphthoate) (1,1-methylene-bis-2-hydroxy-3-naphthoate, succinate), pantothenates, phosphates / bisphosphonates, picrates, polygalacturonic acids, propionates, p-toluenesulfonates, salicylates, stearates, basic acetates, succinates, sulfates, sulfosalicylates, sulfamates, tannates, tartrates, teoclates, toluenesulfonates, triethyliodide, and valerates.

[0043] The term "isomer" refers to salts and / or compounds having the same composition and molecular weight but different physical and / or chemical properties. Structural differences may lie in the ability to form (geometric isomers) or rotate the plane of polarization (stereoisomers). For stereoisomers, the salts of the compounds disclosed herein may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereomers.

[0044] The disclosed compounds can exist in both non-solventized and solvated forms, such as hydrates.

[0045] "Solvate" refers to a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Non-limiting examples of suitable solvates include ethoxides, methanols, etc. Some compounds tend to trap a fixed molar ratio of solvent molecules in a crystalline solid state, thus forming a solvate. If the solvent is water, the formed solvate is a hydrate; when the solvent is an alcohol, the formed solvate is an alkoxide. A hydrate is formed by the combination of one or more water molecules with a substance in which water retains its molecular state as H₂O; such combinations can form one or more hydrates. In hydrates, water molecules are linked by intermolecular forces, particularly hydrogen bridges, through secondary valence states. Solid hydrates contain water in stoichiometric proportions, i.e., so-called water of crystallization, where the binding states of water molecules need not be equal. Examples of hydrates are sesquihydrates, monohydrates, dihydrates, or trihydrates. Hydrates of salts of the compounds disclosed herein are also suitable.

[0046] As mentioned herein, "isotope derivatives" refers to the compounds disclosed herein that have been isotopically enriched or labeled with one or more stable isotopes (with respect to one or more atoms of the compound). Therefore, in this application, the compounds disclosed herein include, for example, compounds that have been isotopically enriched or labeled with one or more atoms (e.g., deuterium).

[0047] As used herein, “treating” describes the management and care of a subject in order to combat a disease, ailment, or condition, and includes reducing or alleviating symptoms or complications, or eliminating said disease, ailment, or condition.

[0048] Unless otherwise stated, as used herein, the term "treatment" means reversing, alleviating, or suppressing the progression of a condition or disease to which such terms apply, or one or more symptoms of such a condition or disease. Unless otherwise stated, as used herein, the term "treatment" refers to the act of "treatment" as defined above. For example, the term "treat / treating / treatment" can refer to a method of alleviating or eliminating a particular condition and / or one or more of its accompanying symptoms.

[0049] As used herein, "subject" means either a human or an animal (in the case of an animal, the subject can be a mammal). Specifically, the subject is human. Additionally, the subject is male.

[0050] Prostate cancer is the uncontrolled growth of cancer cells in the prostate gland.

[0051] Metastatic prostate cancer or metastasis refers to prostate cancer that has spread to other parts of the body besides the prostate, such as bones, lymph nodes, liver, lungs, and brain.

[0052] Castration-resistant prostate cancer is a type of prostate cancer that continues to grow even when testosterone levels in the body drop to extremely low levels.

[0053] Metastatic castration-resistant prostate cancer is a type of prostate cancer that metastasizes and continues to grow even when testosterone levels in the body drop to extremely low levels.

[0054] As used in this article, “preventing” describes stopping the onset of symptoms or complications of the disease, ailment, or condition.

[0055] "Administration" refers to the introduction of an agent (such as the compound disclosed herein) into a subject's body. The related terms "administering / administration of" (and grammatical equivalents) refer to direct administration, which may be administered by a medical professional to a subject or by the subject themselves, and / or indirect administration, which may be the act of prescribing a medication. For example, a physician instructing a patient to self-administer a medication and / or prescribing a medication for a patient is administering the medication to the patient.

[0056] The terms "co-administration" or "combination therapy" refer to concurrent administration (the simultaneous administration of two or more therapeutic agents) and time-varying administration (the administration time of one or more therapeutic agents differs from the administration time of another one or more therapeutic agents), provided that the therapeutic agents are present simultaneously in the patient to a certain extent, preferably in an effective amount. In some preferred aspects, one or more of the compounds of the invention described herein are co-administered in combination with at least one additional bioactive agent (particularly including anticancer agents). In particularly preferred aspects, the co-administration of the compounds results in synergistic activity and / or therapy, including anticancer activity.

[0057] As used herein, "therapeutic effective amount" means an amount of the free base of compound A, or an equivalent amount of a pharmaceutically acceptable salt of compound A, sufficient to treat, improve, or prevent a specified disease (e.g., prostate cancer), disease symptoms, condition, or disorder, or sufficient to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay known in the art. The effective amount for a particular subject may depend on the subject's weight, body size, and health status; the nature and severity of the disorder; and whether additional therapeutic agents will be administered to the subject. Therapeutic effective amount for a given situation can be determined through routine laboratory testing within the skill and judgment of a clinician.

[0058] As used in this article, "C" max "" refers to the maximum (peak) plasma concentration of the specified compound observed in a subject after a certain dose of the compound has been administered to the subject.

[0059] As used herein, “AUC” refers to the total area under the plasma concentration-time curve. It is a measure of exposure to a compound of interest and is the integral of the concentration-time curve after a single dose or at steady state. AUC is expressed in ng. The unit is H / mL (ngx H / mL), where "H" refers to hours.

[0060] As used in this article, "AUC" τ "AUC" refers to the AUC from 0 hours to the end of the dosing interval.

[0061] AUC 0-24 "This refers to the AUC from 0 hours to 24 hours after administering a single dose."

[0062] As used herein with respect to oral dosage forms, "controlled release" or "CR" means that the compound of this disclosure is released from the dosage form according to a predetermined curve, which may include when and where the compound is released after oral administration and / or a specified release rate over a specified time period.

[0063] As used herein with respect to oral dosage forms of this disclosure, "controlled release agent" refers to one or more substances or materials that regulate the release of the compounds of this disclosure from the dosage form. Controlled release agents can be organic or inorganic, naturally occurring or synthetic materials, such as polymeric materials, triglycerides, derivatives of triglycerides, fatty acids and salts of fatty acids, talc, boric acid, colloidal silica, and combinations thereof.

[0064] As used herein with respect to dosage forms of this disclosure, "enteric coating" refers to a pH-dependent material that surrounds a core containing a compound of this disclosure and remains substantially intact in the acidic environment of the stomach but dissolves in the pH environment of the intestine.

[0065] As used in the CR oral dosage forms described herein, “gastro-resistant” or “GR” means that the release of the disclosed compound in the stomach of a subject should not exceed 5%, 2.5%, 1% or 0.5% of the total amount of compound A in the dosage form.

[0066] As used herein, "oral dosage form" means a pharmaceutical product containing a specified amount (dosage) of the compound disclosed herein as an active ingredient, or a pharmaceutically acceptable salt and / or solvate thereof, and an inactive component (excipient), formulated into a specific configuration suitable for oral administration, such as an oral tablet, liquid, or capsule. In some embodiments, the composition is in the form of a scoreable tablet.

[0067] As used in this disclosure, the term "carrier" encompasses pharmaceutically acceptable excipients and diluents, and means a material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that participates in carrying or transporting a drug from one organ or body part of a subject to another.

[0068] As part of a quantitative expression (such as "about X"), the term "about" includes any value that is 10% higher or lower than X, and also includes any value between X-10% and X+10%. Thus, for example, a weight of about 40 g includes a weight between 36 and 44 g.

[0069] Compound A disclosed herein refers to 4-(4-((1-(4-(((1R,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-2,6-dioxopiperidin-3-yl)-2-fluorobenzamide, which has the following structure: (Compound A).

[0070] In some embodiments, compound A may be prepared as described in U.S. Patent Application Publication No. 2021 / 0196710 A1, which is incorporated herein by reference.

[0071] When applied to a particular dosage form, composition, use, method, or process described or claimed herein, "comprising" means that the dosage form, composition, use, method, or process includes all elements recounted in the specific description or claims, but does not exclude other elements. "Consists essentially of" 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 described physical, pharmacological, pharmacokinetic, or therapeutic effects of the composition, dosage form, method, use, or process. "Consists of" means excluding other components beyond trace elements and substantial method or process steps.

[0072] The ECOG Behavioral Status Scale was developed by the Eastern Cooperative Oncology Group as a standard guideline for measuring how disease affects a patient's ability to perform daily activities. It describes a patient's functional level in terms of self-care ability, daily activities, and physical abilities (walking, working, etc.). Patients are categorized on a scale of 1-5.

[0073] Cytochrome P450 3A inhibitors, or "CYP3A inhibitors," are members of a class of compounds or substances that reduce or inhibit the normal function of human cytochrome P450. In some implementations, CYP3A inhibitors are CYP3A4 inhibitors. In some implementation schemes, the CYP3A inhibitors are grapefruit juice, cobicistat, danoprevir, ritonavir, elvitegravir, indinavir, itraconazole, ketoconazole, lopinavir, paritaprevir, ombitasvir, dasabuvir, posaconazole, saquinavir, tipranavir, telithromycin, troleandomycin, voriconazole, aprepitant, ciprofloxacin, conivaptan, and crizoline. Crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, isavuconazole, tofisopam, verapamil, chlorzoxazone, cilostazol, cimetidine, clotrimazole, fosaprepitant, istradefylline, ivacaftor, lomitapide, ranitidine, ranolazine, or ticagrelor. In some formulations, the CYP3A inhibitor is itraconazole.

[0074] Cytochrome P450 3A inducers, or "CYP3A inducers," refer to members of a class of compounds or substances that increase the activity of human cytochrome P450. In some embodiments, the CYP3A inducer is a CYP3A4 inducer. In some embodiments, the CYP3A inducer is a barbiturate, corticosteroid, phenytoin, carbamazepine, rifampicin, or St. John's wort.

[0075] As used herein, the term "CDK inhibitor" refers to a compound that inhibits enzymes in humans called cyclin-dependent kinases (CDKs). In some embodiments, a CDK inhibitor is a CDK4 / 6 inhibitor. As used herein, the term "CDK4 / 6 inhibitor" refers to a compound that inhibits CDK 4 and / or 6. Examples of CDK inhibitors include, but are not limited to, SHR6390, triamcinolone, lerozide, AT7519M, denaciline, ribociclib, abecide, palbociclib, or any pharmaceutically acceptable salt thereof. In some embodiments, a CDK inhibitor is palbociclib or a pharmaceutically acceptable salt thereof.

[0076] As used herein, the term "PARP inhibitor" refers to a compound that inhibits an enzyme called poly-ADP-ribose polymerase (PARP) in humans. Examples of PARP inhibitors include, but are not limited to, olaparib, rucaparib, tapazoparib, niraparib, veliparib, pamipanib, CEP 9722, E7016, 3-aminobenzamide, mefpanib, and AZD2281.

[0077] As used herein, the term "anticancer agent" is used to describe anticancer agents, or therapeutic agents administered in parallel with anticancer agents (e.g., palonosetron), which may be administered and / or formulated with the compounds disclosed herein (preferably, compound A or a pharmaceutically acceptable salt thereof) to treat cancer, as well as side effects associated with cancer treatment. These agents include, for example, everolimus, trabectedin, albumin-bound paclitaxel, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzatolin, 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 inhibitors. 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, dasatinib, nilotinib, dicatinib, panitumumab, amarabicin, ovovacuumab, lep-etu, noratrexed, azd2171, batabulin, oflambumab, zamumab, edotecarin, tetrandrine, rubenotecan, pertopizumab, olimexin, tesimomab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, silengiptide, gemetacone, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, Thianthrone, LY317615, Neuradiab, Vitexan, Rta744, Sdx 102, Talenpanel, Atrasentan, Xr311, Romidesin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Liposome Doxorubicin, 5'-Deoxy-5-Fluorouracil, Vincristine, Temozolomide, ZK-304709, Celicixib; PD0325901, AZD-6244, Capecitabine, L-Glutamate, N-[4-[2 -(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C 11. CHIR-258); 3-[5-(methylsulfonylpiperidinylmethyl)-indolyl-quinolone, Vatalani, AG-013736, AVE-0005, Goserelin acetate, Leuprorelin acetate, Triptorelin dihydroxynaphthyl acid, Medroxyprogesterone acetate, Hydroxyprogesterone caproate, Medroxyprogesterone acetate, Raloxifene, Bicalutamide, Flutamide, Nilumet, Medroxyprogesterone acetate, CP-724714; TAK-165, HKI-272, Erlotinib, Lapatinib, Canatinib, ABX-EGF antibody, Cetuximab, EKB-569, PKI-166, GW-572016, Lonafab, BMS-214662, Tepififib; Amifostine, NVP-LAQ824, Suberoyl succinate analidehydroxamic(acid), valproic acid, triamcinolone A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, acridine, anagrelide, L-asparaginase, BCG vaccine, doxorubicin, bleomycin, busherin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone acetate, dacarbazine, actinomycin D, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, flumethasone Flutamide, Imatinib (gleevec), Gemcitabine, Hydroxyurea, Idarubicin, Ifosfamide, Imatinib, Leuprorelin, Levamisole, Lomustine, Nitrogen Mustard, Melphalan, 6-Mercaptopurine, Mesna, Methotrexate, Mitomycin, Mitotan, Mitoxantrone, Nilumet, Octreotide, Oxaliplatin, Pamidronate, Pentostatin, Pulkamycin, Porphyrin Sodium, Procarbazine, Raltitrexed, Rituximab, Streptozotocin, Teniposide, Testosterone, Thalidomide, Thioguanine, Thiotepa, Retinoic Acid , vinorelbine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estradiol, hexamethylmelamine, fluorouracil, 5-deoxyuridine, cytarabine, 6-mercaptopurine, deoxycofulvin, calcitriol, pentorubicin, sclerosomycin, vinblastine, vinorelbine, topotecan, raszosen, marimasitol, COL-3, neovastatin, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitamin xin, droloxifene, idoxyfene, spironolactone, finasteride, cimetidine, trastuzumab, denominator interleukin, gefitinib, bortezomib, paclitaxel, cremophor-free paclitaxel, docetaxel, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, piperacixifene, ERA-923, azoxifen, fulvestrant, azithromycin, lasoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD184352, Rapamycin, 40-O-(2-hydroxyethyl)-Rapamycin, Tesirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wolman penicillin, ZM336372, L-779,450, P EG-filgrastim, dapoxetine α, erythropoietin, granulocyte colony-stimulating factor, zoledronic acid, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histamine, pegylated interferon α-2a, interferon α-2a, pegylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone Interleukin-11, dexrazoxan, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, medroxyprogesterone acetate, immunoglobulin, nitrogen mustard, methylprednisolone, teimomab, androgens, decitabine, hexamethylmelamine, bexarotin, tosimomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, casserole Netupitan, netupitan, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, fluperidone, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegylated filgrastim, erythropoietin, alfaepine, dapoxetine α, and mixtures thereof. In some embodiments, the anticancer agent is selected from the group consisting of: abiraterone, abiraterone acetate, estradiol, docetaxel, ketoconazole, goserelin, histidine, triptorelin, buterelin, cyproterone acetate, flutamide, bicalutamide, nilumethoxazole, pamidronate, 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, CDK 4 / 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, VEGF trap antibodies, and chemical castration agents.

[0078] In some embodiments, the anticancer agent is selected from the group consisting of: temozolomide, capecitabine, irinotecan, tamoxifen, anastrozole, exemestane, letrozole, DES, estradiol, estrogen, bevacizumab, goserelin acetate, leuprorelin acetate, triptorelin dinaphthylnaphthyl acetate, medroxyprogesterone acetate, hydroxyprogesterone caproate, raloxifene, megestrol acetate, carboplatin, cisplatin, dacarbazine, methotrexate, vincristine, vinorelbine, topotecan, finasteride, azoxifen, fulvestrant, prednisone, abiraterone, abiraterone acetate, enzalutamide, apalutamide. Darolulumide, sipuleucel-T, pembrolizumab, nivolumab, cimipril, atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), docetaxel (Taxotere), cabazitaxel (Jevtana), mitoxantrone (Novantrone), estradiol (Emcyt), docetaxel, ketoconazole, histamine, triptorelin, buterol, cyproterone acetate, flutamide, bicalutamide, nilumet, pamidronate, and zoledronic acid.

[0079] The article “a / an” is 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 element or more elements.

[0080] Unless otherwise stated, the term “and / or” is used in this disclosure to mean “and” or “or”.

[0081] The terms “patient” and “subject” are used interchangeably in this document 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 monkeys.

[0082] In some implementations, the subjects are humans.

[0083] In some implementations, the subject is a human who has been diagnosed with prostate cancer.

[0084] In some implementations, the subject is a human who has been diagnosed with metastatic prostate cancer.

[0085] In some implementations, the subject is a human who has been diagnosed with castration-resistant prostate cancer.

[0086] In some implementations, the subject is a human who has been diagnosed with metastatic castration-resistant prostate cancer.

[0087] In this document, the term "fasting status" or "fasting condition" used to describe a subject means that the subject has not eaten for at least 4 hours prior to the time of interest (e.g., the time of administration of compound A). In one embodiment, a subject in a fasting status has not eaten for any of the following time periods: at least 6, 8, 10, or 12 hours prior to administration of compound A or a pharmaceutically acceptable salt thereof.

[0088] In this document, the term "eating status" or "feeding condition" used to describe a subject means that the subject has eaten within 4 hours prior to the time of interest (e.g., the time of administration of compound A). In one embodiment, a subject in an eating status eats within 3, 2, 1, or 0.5 hours prior to administration of compound A or a pharmaceutically acceptable salt thereof.

[0089] Methods for ubiquitination / degradation of target proteins in cells

[0090] This disclosure provides a method for ubiquitinizing / degrading a target protein in cells. The method includes administering a bifunctional composition comprising an E3 ubiquitin ligase-binding moiety and a protein-targeting moiety, preferably linked by a linker moiety as further described herein, wherein the E3 ubiquitin ligase-binding moiety is coupled to the protein-targeting moiety, and wherein the E3 ubiquitin ligase-binding moiety recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase) and the protein-targeting moiety recognizes a target protein, such that degradation of the target protein occurs when the target protein is placed in the vicinity of the ubiquitin ligase, resulting in degradation / inhibition of the effect on the target protein and control of protein levels. The protein level control provided by this disclosure provides a treatment for a disease state or ailment that utilizes the target protein to modulate the level of the protein in the patient's cells.

[0091] Treatment

[0092] The cancer treatment methods described in this article result in a reduction in tumor size. Alternatively, the cancer may be metastatic, and this treatment method may involve inhibiting the invasion of metastatic cancer cells.

[0093] In some implementations, the cancer is prostate cancer.

[0094] In some implementations, the cancer is metastatic prostate cancer.

[0095] In some implementations, the cancer is castration-resistant prostate cancer.

[0096] In some implementations, the cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0097] On the one hand, cancer treatment leads to a reduction in tumor size. This reduction in tumor size can also be referred to as "tumor regression." Preferably, after treatment, the tumor size is reduced by 5% or more relative to its pre-treatment size; more preferably, the tumor size is reduced by 10% or more; even more preferably, by 20% or more; more preferably, by 30% or more; even more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by more than 75% or more. Tumor size can be measured by any repeatable means. In a preferred aspect, tumor size can be measured as the diameter of the tumor.

[0098] On the other hand, cancer treatment leads to a reduction in tumor volume. Preferably, after treatment, the tumor volume is reduced by 5% or more relative to its pre-treatment volume; more preferably, the tumor volume is reduced by 10% or more; even more preferably, by 20% or more; more preferably, by 30% or more; even more preferably, by 40% or more; and even more preferably, by 50% or more; and most preferably, by more than 75% or more. Tumor volume can be measured by any repeatable measurement method.

[0099] On the other hand, cancer treatment leads to a reduction in the number of tumors. Preferably, after treatment, the number of tumors decreases by 5% or more compared to the number before treatment; more preferably, the number of tumors decreases 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 a reduction greater than 75%. The number of tumors can be measured by any repeatable means. In a preferred aspect, the number of tumors can be measured by counting tumors visible to the naked eye or at a specified magnification. In a preferred aspect, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0100] On the other hand, cancer treatment leads to a reduction in the number of metastatic lesions in other tissues or organs far from the primary tumor site. Preferably, after treatment, the number of metastatic lesions 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 repeatable measurement method. In a preferred aspect, the number of metastatic lesions can be measured by counting metastatic lesions visible to the naked eye or at a specified magnification. In a preferred aspect, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0101] On the other hand, compared to the group that only received the carrier, cancer treatment resulted in an increase in the mean survival time of the treated subject group. Preferably, the mean survival time increased by more than 30 days; more preferably, by more than 60 days; even more preferably, by more than 90 days; and most preferably, by more than 120 days. The increase in the mean survival time of the population can be measured by any reproducible means. In a preferred aspect, 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 initiating treatment with the active agent or compound of this disclosure. In another preferred aspect, 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 completing the first round of treatment with the active agent or compound of this disclosure.

[0102] On the other hand, cancer treatment leads to an increase in the mean survival time of the treated subject group compared to the untreated group. Preferably, the mean survival time increases by more than 30 days; more preferably, by more than 60 days; even more preferably, by more than 90 days; and most preferably, by more than 120 days. The increase in the mean survival time of the population can be measured by any reproducible means. In a preferred aspect, the increase in the mean survival time of the population can be measured by calculating the mean survival time of the population after initiating treatment with the active agent or compound of this disclosure. In another preferred aspect, the increase in the mean survival time of the population can be measured by calculating the mean survival time of the population after completing the first round of treatment with the compound of this disclosure (preferably, compound A or a pharmaceutically acceptable salt thereof).

[0103] On the other hand, cancer treatment leads to a reduction in tumor growth rate. Preferably, after treatment, the tumor growth rate is reduced by at least 5% compared to the pre-treatment growth rate; more preferably, the tumor growth rate is reduced 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 repeatable measurement method. In a preferred aspect, the tumor growth rate is measured based on the change in tumor diameter per unit time.

[0104] On the other hand, cancer treatment leads to a reduction in tumor regrowth. Preferably, after 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 repeatable measurement method. In a preferred aspect, tumor regrowth is measured by measuring the increase in tumor diameter following the previous tumor shrinkage after treatment. In another preferred aspect, the reduction in tumor regrowth is manifested by the cessation of tumor recurrence after treatment.

[0105] For any of the methods and uses described herein, the dosage of compound A or a pharmaceutically acceptable salt thereof may vary depending on factors such as the dosage, the age, weight and clinical condition of the recipient, the experience and judgment of the clinician or practitioner administering the therapy, and other factors that influence the selected dosage.

[0106] A therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof may be administered once or multiple times a day for up to 30 days or more, followed by one or more days without administration of the compound. This type of treatment regimen (i.e., administration of compound A or a pharmaceutically acceptable salt thereof for several consecutive days, followed by several consecutive days without administration of the compound) may be referred to as a treatment cycle. Treatment cycles may be repeated as needed to achieve the desired effect.

[0107] In some implementations, the therapeutically effective amount of compound A 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, 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, 81, 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, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 2 35, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 3 90, 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, 54 5, 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, 855860, 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, administered once, twice, three times, four times, or more daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, or 30 days, or administered once, twice, three times, four times, or more daily, in a single or divided dose, for 2, 3, 4, 5, 6 months, or longer.

[0108] In some embodiments, the therapeutically effective amount of compound A is about 10 to about 40 mg, about 20 to about 50 mg, about 30 to about 60 mg, about 40 to about 70 mg, about 50 to about 80 mg, about 60 to about 90 mg, about 70 to about 100 mg, about 80 to about 110 mg, about 90 to about 120 mg, about 100 to about 130 mg, about 110 to about 140 mg, about 120 to about 150 mg, about 130 to about 160 mg, about 140 to about 170 mg, about 150 to about 180 mg, about 160 to about 190 mg, about 170 to about 200 mg, about 180 to about 210 mg, about 190 to about 220 mg, about 200 to about 230 mg, about 210 to about 240 mg, about 220 to about 250 mg, about 230 to about 260 mg, about 240 to about 270 mg, about 250 to about 280 mg. mg, about 260 to about 290 mg, about 270 to about 300 mg, about 280 to about 310 mg, about 290 to about 320 mg, about 300 to about 330 mg, about 310 to about 340 mg, about 320 to about 350 mg, about 330 to about 360 mg, about 340 to about 370 mg, about 350 to about 380 mg, about 360 to about 390 mg, about 370 to about 400 mg, about 380 to about 410 mg, about 390 to about 420 mg, about 400 to about 430 mg, about 410 to about 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 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 to about 650 mg, about 630 to about 660 mg, about 640 to about 670 mg, about 650 to about 680 mg, about 660 to about 690 mg, about 670 to about 700 mg, about 680 to about 710 mg, about 690 to about 720 mg, about 700 to about 730 mg, about 710 to about 740 mg, about 720 to about 750 mg, about 730 to about 760 mg mg, approximately 740 to approximately 770 mg, approximately 750 to approximately 780 mg, approximately 760 to approximately 790 mg, approximately 770 to approximately 800 mgmg, 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, about 830 to about 860 mg, about 840 to about 870 mg, about 850 to about 880 mg, about 860 to about 890 mg, about 870 to about 900 mg, about 880 to about 910 mg, about 890 to about 920 mg, about 900 to about 930 mg, about 910 to about 940 mg, about 920 to about 950 mg, about 930 to about 960 mg, about 940 to about 970 mg, about 950 to about 980 mg, about 960 to about 990 mg, or about 970 to about 1,000 mg. mg, or an equivalent amount of a pharmaceutically acceptable salt of compound A, administered once, twice, three times, four times or more daily, in a single or divided dose (the dose may be relative to the patient's weight (kg), body surface area (m²)). 2 (Adjusted for by) and / or age (years).

[0109] In some embodiments, a therapeutically effective amount of compound A is about 70 mg to about 1000 mg, or an equivalent amount of a pharmaceutically acceptable salt of compound A, administered once, twice, three times, four times or more daily, in a single or divided dose (the dose may be relative to the patient's weight (kg), body surface area (m²)). 2 (Adjusted for by) and / or age (years).

[0110] In some embodiments, a therapeutically effective amount of compound A is about 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, administered once, twice, three times, four times, or more daily, in a single or divided dose (the dose may be relative to the patient's weight (kg), body surface area (m²)). 2 (Adjusted for by) and / or age (years).

[0111] In some implementations, the therapeutically effective amount of compound A is about 100 mg, about 150 mg, or about 300 mg.

[0112] In some implementations, the therapeutically effective dose of compound A is approximately 100 mg.

[0113] In some implementations, the therapeutically effective dose of compound A is 100 mg.

[0114] In some implementations, the therapeutically effective dose of compound A is 100 mg, administered orally once daily.

[0115] In some implementations, the therapeutically effective dose of compound A is approximately 150 mg.

[0116] In some implementations, the therapeutically effective dose of compound A is 150 mg.

[0117] In some implementations, the therapeutically effective dose of compound A is 150 mg, administered orally once daily.

[0118] In some implementations, the therapeutically effective dose of compound A is approximately 300 mg.

[0119] In some implementations, the therapeutically effective dose of compound A is 300 mg.

[0120] In some implementations, the therapeutically effective dose of compound A is 300 mg, administered orally once daily.

[0121] The therapeutically effective dose of compound A can also range from about 0.01 mg / kg / day to about 100 mg / kg / day. Alternatively, the therapeutically effective dose of compound A can range from about 0.05 mg / kg / day to about 10 mg / kg / day. Alternatively, the therapeutically effective dose of compound A can range from about 0.075 mg / kg / day to about 5 mg / kg / day. Alternatively, the therapeutically effective dose of compound A can range from about 0.10 mg / kg / day to about 1 mg / kg / day. Alternatively, the therapeutically effective dose of compound A can range from about 0.20 mg / kg / day to about 0.70 mg / kg / day.

[0122] In some implementations, the therapeutically effective amount of compound A is about 0.10 mg / kg / day, about 0.15 mg / kg / day, about 0.20 mg / kg / day, about 0.25 mg / kg / day, about 0.30 mg / kg / day, about 0.35 mg / kg / day, about 0.40 mg / kg / day, about 0.45 mg / kg / day, about 0.50 mg / kg / day, about 0.55 mg / kg / day, about 0.60 mg / kg / day, about 0.65 mg / kg / day, about 0.70 mg / kg / day, about 0.75 mg / kg / day, about 0.80 mg / kg / day, about 0.85 mg / kg / day, about 0.90 mg / kg / day, about 0.95 mg / kg / day, or about 1.00 mg / kg / day.

[0123] In some implementations, the therapeutically effective dose of compound A is about 1.05 mg / kg / day, about 1.10 mg / kg / day, about 1.15 mg / kg / day, about 1.20 mg / kg / day, about 1.25 mg / kg / day, about 1.30 mg / kg / day, about 1.35 mg / kg / day, about 1.40 mg / kg / day, about 1.45 mg / kg / day, about 1.50 mg / kg / day, about 1.55 mg / kg / day, about 1.60 mg / kg / day, about 1.65 mg / kg / day, about 1.70 mg / kg / day, about 1.75 mg / kg / day, about 1.80 mg / kg / day, about 1.85 mg / kg / day, about 1.90 mg / kg / day, about 1.95 mg / kg / day, or about 2.00 mg / kg / day.

[0124] In some implementations, the therapeutically effective dose of compound A is about 2 mg / kg / day, about 2.5 mg / kg / day, about 3 mg / kg / day, about 3.5 mg / kg / day, about 4 mg / kg / day, about 4.5 mg / kg / day, about 5 mg / kg / day, about 5.5 mg / kg / day, about 6 mg / kg / day, about 6.5 mg / kg / day, about 7 mg / kg / day, about 7.5 mg / kg / day, about 8.0 mg / kg / day, about 8.5 mg / kg / day, about 9.0 mg / kg / day, about 9.5 mg / kg / day, or about 10 mg / kg / day.

[0125] In some embodiments, a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof is administered to the subject once daily. In some embodiments, the daily dose of compound A or a pharmaceutically acceptable salt thereof may be administered to the subject in a single dose. In some embodiments, the daily dose of compound A or a pharmaceutically acceptable salt thereof may be administered to the subject in two portions (i.e., fractionated doses). In some embodiments, the daily dose of compound A or a pharmaceutically acceptable salt thereof may be administered to the subject in three fractionated doses. In some embodiments, the daily dose of compound A or a pharmaceutically acceptable salt thereof may be administered to the subject in four fractionated doses. In some embodiments, the daily dose of compound A or a pharmaceutically acceptable salt thereof may be administered to the subject in five or more fractionated doses. In some embodiments, these portions or fractionated doses are administered to the subject at regular intervals throughout the day, such as every 12 hours, every 8 hours, every 6 hours, every 5 hours, every 4 hours, etc.

[0126] The therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof can be initially estimated in cell culture assays or in animal models (typically rats, mice, rabbits, dogs, or pigs). These animal models can also be used to determine appropriate concentration ranges and routes of administration. This information can then be used to determine the usable dose and route of administration for humans. Therapeutic / prophylactic efficacy and toxicity can be determined using standard pharmaceutical procedures in cell cultures or laboratory animals, such as ED. 50 (The therapeutically effective dose in 50% of the population) and LD 50 (The dose that would be lethal to 50% of the population). The dose ratio between toxic effects and therapeutic effects is the therapeutic index, and it can be expressed as the ratio LD50. 50 / ED 50 Preferably, the pharmaceutical composition exhibits a high therapeutic index. The dosage may vary within this range, depending on the dosage form used, patient sensitivity, and route of administration.

[0127] Adjust the dosage and administration to provide adequate levels of compound A or maintain the desired effect. Factors that may be considered include the severity of the disease state, the subject's general health condition, the subject's age, weight and sex, diet, timing and frequency of administration, drug combination, sensitivity to response, and tolerance / response to the therapy. Long-acting drug compositions may be administered every 3 to 4 days, weekly, every two weeks, or monthly, depending on the half-life and clearance of the specific formulation.

[0128] In some embodiments, for the method of treating prostate cancer with a combination of compound A or a pharmaceutically acceptable salt thereof and another anticancer agent, the therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof is described herein, and the therapeutically effective amount of said anticancer agent 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, 22, 23, 24, 25, 26, 27, 28, 29, 3 0, 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, 120, 125, 130, 135, 140, 145, 1 50, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 3 05, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 46 0, 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, 770775, 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, administered once, twice, three times, four times or more daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 30 days, or administered once, twice, three times, four times or more daily, in a single or divided dose, for 2 months, 3 months, 4 months, 5 months, 6 months or longer.

[0129] Pharmaceutical Composition

[0130] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is formulated for oral administration. For example, in some embodiments, the disclosed compound is formulated into a tablet comprising zero, one, two or more of the following: an emulsifier; a surfactant; a binder; a disintegrant; a glidant; and a lubricant.

[0131] In some implementations, the emulsifier is hydroxypropyl methylcellulose.

[0132] In some implementations, the surfactant is vitamin E polyethylene glycol succinate.

[0133] In some implementations, the binder (also referred to herein as a filler) is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, sucrose, glucose, and sorbitol.

[0134] In some implementations, the disintegrant is croscarmellose sodium.

[0135] In some embodiments, a flow aid is a substance used to promote powder flow by reducing interparticle cohesion. In some embodiments, in the dosage forms disclosed herein, the flow aid is selected from the group consisting of silica, anhydrous silica gel, starch, and talc.

[0136] In some embodiments, a lubricant refers to a substance that prevents components from sticking together and / or agglomerating in a machine used to prepare the dosage form of this disclosure. In some embodiments, in the dosage form of this disclosure, the lubricant is selected from the group consisting of magnesium stearate, sodium stearoyl fumarate, stearic acid, and vegetable stearin.

[0137] Pharmaceutical compositions containing compound A or a pharmaceutically acceptable salt thereof can be manufactured in ways commonly known, such as by means of conventional mixing, dissolving, granulation, pelleting, grinding, emulsification, encapsulation, embedding, or lyophilization processes. The pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers containing excipients and / or adjuvants that facilitate the processing of compound A or a pharmaceutically acceptable salt thereof into a pharmaceutically usable formulation. Of course, appropriate formulation depends on the chosen route of administration.

[0138] Suitable pharmaceutical compositions for injectable applications include sterile aqueous solutions (in the case of water solubility) or dispersions and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, antibacterial water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should be a fluid sufficient for easy injection. It must be stable under manufacturing and storage conditions and must be protected against contamination by microorganisms such as bacteria and fungi. The carrier can 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. Appropriate flowability can be maintained, for example by using coatings such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants. Microbial action can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents in the composition, such as sugars, polyols (e.g., mannitol, sorbitol), and sodium chloride. The absorption of injectable compositions can be prolonged by including agents that delay absorption (e.g., aluminum monostearate and gelatin).

[0139] A sterile injectable solution can be prepared by incorporating the desired amount of compound A or a pharmaceutically acceptable salt thereof with one of the ingredients listed above or a combination thereof into a suitable solvent, followed by filtration sterilization as needed. Typically, a dispersion is prepared by incorporating the active agent or compound into a sterile mediator containing an alkaline dispersion medium and other desired ingredients from those listed above. In the case of sterile powders used to prepare sterile injectable solutions, the preparation method is vacuum drying and freeze-drying, producing a powder of the active ingredient plus any additional desired ingredients from a previously sterile filtered solution.

[0140] Oral compositions typically include an inert diluent or an edible, pharmaceutically acceptable carrier. They may be encapsulated in gelatin capsules or compressed into tablets.

[0141] For oral therapeutic administration, compound A or a pharmaceutically acceptable salt thereof may be combined with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions may also be prepared using a fluid carrier for use as a mouthwash, wherein the agent or compound in the fluid carrier is applied orally and rinsed, then spat out or swallowed. Pharmaceutically compatible binders and / or adjuvants may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginate, Primogel, or corn starch; lubricants, such as magnesium stearate; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring.

[0142] For administration by inhalation, the agent or compound is delivered in the form of an aerosol spray from a pressure vessel or dispenser (containing a suitable propellant, such as a gas, like carbon dioxide) or a sprayer.

[0143] Systemic application can also be performed via mucosal or transdermal routes. For mucosal or transdermal application, a penetrant suitable for the permeability barrier is used in the formulation. Such penetrants are generally known in the art and include, for example (for mucosal application), cleansers, bile salts, and fusidic acid derivatives. Mucosal application can be accomplished by using nasal sprays or suppositories. For transdermal application, the active agent or compound is formulated into ointments, creams, gels, or creams generally known in the art.

[0144] On one hand, compound A or a pharmaceutically acceptable salt thereof is prepared together with a pharmaceutically acceptable carrier that protects the agent or compound from rapid elimination from the body, such as 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 will be apparent to those skilled in the art. The materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including liposomes targeting infected cells with 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 as described in U.S. Patent No. 4,522,811.

[0145] For ease of administration and dosage uniformity, 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 discrete unit suitable as a unit dose for a subject to be treated; each unit contains a predetermined amount of an active agent or compound, said amount calculated to combine with a desired drug carrier to produce the desired therapeutic effect. The specifications of the unit dosage forms of this application are determined by and directly depend on the unique characteristics of compound A or its pharmaceutically acceptable salts and the specific therapeutic effect to be achieved.

[0146] The pharmaceutical composition may be included in a container, package, or dispenser along with the instructions for use.

[0147] The illustrative administration modes of compound A or a pharmaceutically acceptable salt thereof include systemic or topical administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical administration. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered in the form of tablets, capsules, pouches, solutions, suspensions, syrups, granules, beads, powders, or microcapsules.

[0148] The illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a salt of compound A and a pharmaceutically acceptable carrier, such as a) a diluent, such as purified water, triglyceride oils (such as hydrogenated or partially hydrogenated vegetable oils or mixtures thereof), corn oil, olive oil, sunflower oil, safflower oil, fish oil (such as EPA or DHA) or esters or triglycerides thereof or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextran, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, such as silica, talc, stearic acid, its magnesium or calcium salts, sodium oleate, sodium stearate, stearic acid Magnesium, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; also used in tablets; c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, magnesium carbonate, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth gum or sodium alginate), waxes and / or polyvinylpyrrolidone (if applicable); d) disintegrants, such as starch, agar, methylcellulose, bentonite, xanthan gum, alginate or its sodium salt or effervescent mixtures; e) absorbents, colorants, flavorings and sweeteners; f) emulsifiers or dispersants, such as Tween 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 g) agents that enhance salt absorption, such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400 and / or PEG200.

[0149] For the preparation of a pharmaceutical composition from compound A or its salts or hydrates, an inert, pharmaceutically acceptable carrier may be a solid or a liquid. Solid formulations include powders, tablets, dispersible granules, capsules, caches, and suppositories.

[0150] Powders and tablets may contain about 5% to about 95% of the active ingredient. Suitable solid carriers are known in the art, such as magnesium carbonate, magnesium stearate, talc, sugar, or lactose. Tablets, powders, capsules, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th edition, (1990), Mack Publishing Co., Easton, Pa.

[0151] Liquid formulations include solutions, suspensions, and emulsions. Examples include aqueous or water-propylene glycol solutions for parenteral injection, or solutions, suspensions, and emulsions containing sweeteners and opacifiers for oral administration. Liquid formulations may also include solutions for intranasal application.

[0152] Liquid (especially injectable) compositions can be prepared, for example, by dissolution, dispersion, etc. For instance, the disclosed salt can be dissolved in or mixed with a pharmaceutically acceptable solvent, such as water, physiological saline, dextran aqueous solution, glycerol, ethanol, etc., to form an injectable isotonic solution or suspension. Proteins such as albumin, chylous microdroplets, or serum proteins can be used to dissolve the disclosed compound.

[0153] Parenteral injectable preparations are generally used for subcutaneous, intramuscular, or intravenous injection and infusion. Injectable preparations can be prepared in conventional forms, such as liquid solutions or suspensions, or in solid forms suitable for dissolving in a liquid prior to injection.

[0154] Suitable aerosol formulations for inhalation may include solutions and solids in powder form, which may be combined with pharmaceutically acceptable carriers such as inert compressed gases, such as nitrogen.

[0155] It also includes solid formulations that are intended to be converted into a liquid form for oral or parenteral administration shortly before use. Such liquid forms include solutions, suspensions, and emulsions.

[0156] Depending on the intended mode of administration, the disclosed compositions may be in solid, semi-solid, or liquid dosage forms, such as injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, etc., sometimes in unit doses and in accordance with conventional pharmaceutical practice. Similarly, they may be administered intravenously (bolus and infusion), intraperitoneally, intrathecally, subcutaneously, or intramuscularly, all in forms well known to those skilled in the art of pharmacology.

[0157] The pharmaceutical compositions can be prepared according to conventional mixing, granulation or coating methods, and the pharmaceutical compositions of the present invention may contain about 0.1% to about 99%, about 5% to about 90% or about 1% to about 20% by weight or volume of the disclosed free base or salt.

[0158] Pharmaceutical compositions containing compound A or a pharmaceutically acceptable salt thereof may also contain one or more additional anticancer agents, including any of those disclosed herein.

[0159] Unless otherwise stated, all amounts of any component of the oral dosage form (e.g., tablet) described herein are based on % w / w indications and refer to the total weight of the oral dosage form.

[0160] Example

[0161] This disclosure is further illustrated by the following embodiments, which should not be construed as limiting the scope or spirit of this disclosure to the specific procedures described herein. It should be understood that the embodiments are provided to illustrate certain implementations and are not intended to limit the scope of this disclosure. It should also be understood that various other implementations, modifications, and equivalents that may occur to those skilled in the art can be made without departing from the spirit of this disclosure and / or the scope of the appended claims.

[0162] Example 1 – In vitro evaluation of cytochrome P450 and transporter-mediated drug interactions of compound A

[0163] In vitro studies were conducted to evaluate the potential of compound A to induce cytochrome P450 (CYP) and transporter-mediated drug interactions (DDI).

[0164] The induction potential of compound A for 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 of CYP1A2, 2B6, 2C8, 2C9, 2C19, and 3A4 were determined by semi-quantitative real-time polymerase chain reaction (PCR). Assay concentrations were determined during a 24-hour incubation period. The potential of compound A to induce direct and time-dependent inhibition (TDI) of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 activities in mixed human liver microsomes (HLM) at concentrations of 0.2–15 µM was assessed. Orientation inhibition and initial TDI assays were performed using probe substrate concentrations near Km. For TDI assays, compound A was pre-incubated for 30 minutes with a mixture of HLM (with or without NADPH) before incubation with a single concentration of probe substrate.

[0165] Metabolite analysis was performed in the incubation of compound A (2 and 10 µM) with HLM (up to 60 min), human hepatocyte suspension (up to 240 min), and human plasma (up to 360 min). Additionally, compound A (2 µM) was incubated with recombinant human CYP enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5.

[0166] The DDI potential of compound A as a victim of the CYP-mediated pathway was examined in HLM, human hepatocyte suspension, and human recombinant CYP enzyme.

[0167] In addition, the inhibitory potential of 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 single transporter overexpression cell monolayers (MDCK II or HEK293) or inside-out vesicles.

[0168] The potential of compound A to inhibit Pgp or BCRP was tested at concentrations of 0.07–5 µM to examine bidirectional transport of probe substrates in Pgp- or BCRP-expressing MDCKII and control monolayers. The inhibitory effects of compound A on Pgp and BCR were tested at concentrations of 0.01–9 µM in the presence of 4 mM MgATP or MgAMP in inner and outer membrane vesicles prepared from HEK293 cells overexpressing human Pgp and BCR. The potential of compound A to inhibit transporter uptake 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.

[0169] The potential of compound A as efflux transporters Pgp and BCRP, and as uptake transporters OATP1B1 and 1B3 was evaluated in Caco-2 cells and HEK29 cells overexpressing a single transporter, respectively.

[0170] Compound A's potential as a substrate for Pgp and BCRP was examined in Caco-2 cells containing 0.075, 0.75, 3.75, and 7.5 µM of 1% BSA. The bidirectional permeability of compound A was determined by LC-MS / MS after 120 min of culture. In an uptake transporter substrate assay, the involvement of compound A as a substrate for OATP1B1 and OATP1B3 at four concentrations (0.1, 0.5, 1, and 5 μM) was evaluated. Compound A in cell lysates was determined by LC-MS / MS.

[0171] result

[0172] CYP induction: After 2 days of treatment in a pre-MTT assay, no significant decrease in hepatocyte viability was observed in hepatocytes at all concentrations of compound A (0.03–30 µM) (data not shown). The positive control inducers performed as expected (Table 1). Among all three donors, CYP3A4 mRNA showed the highest fold increase in induction at 0.1–0.3 µM (2.5–8.8-fold, 4–6% of the positive control response), and in one of the three batches (donor 3 only), CYP2C8 mRNA showed the highest fold increase in induction at 0.1 µM (3.1-fold, 28% of the positive control response). At higher concentrations, the induction response weakened (Table 1).

[0173] Within the concentration range of 0.03–30 μM, compound A did not induce CYP1A2, 2B6, and 2C9 mRNA in all three human hepatocyte donors (Table 1 and Figure 1).

[0174] Table 1. Effects of compound A on CYP mRNA expression in human hepatocytes PC: Positive control inducer, CYP1A2 is omeprazole, CYP2B6 is phenobarbital, CYP2C and CYP3A4 are rifampin) CYP inhibition: No direct or time-dependent inhibition of any CYP isoforms was observed after incubation of HLM with 0.2–15 μM concentrations of compound A (Table 2). The positive control inhibitors showed direct inhibition and TDI for all tested enzymes, with the expected IC50 values. 50 Values ​​and fold changes (data not shown). Compound A did not induce direct inhibition (maximum inhibition ≤12%) or TDI (≤15%) on any of the CYPs at test concentrations up to 15 µM (Table 2).

[0175] Table 2. Effects of compound A on direct and time-dependent inhibition in mixed human liver microsomes NA: Not applicable Metabolic and CYP response phenotypic analysis: Compound A was relatively stable in 2 µM HLM culture (up to 60 min), human hepatocyte suspension (up to 240 min), and major recombinant CYP (up to 25 min) (data not shown). Up to 23% loss of compound A was observed in CYP3A5 (data not shown).

[0176] Metabolite analysis using human plasma, HLM, and human hepatocytes showed that hydrolysis (M825 / 1) was the major metabolic pathway. Other minor pathways, including oxidation, dealkylation, and demethylation, accounted for <2% of the total abundance (Table 3).

[0177] Table 3. Metabolite profiles of compound A in human liver microsomes (HLM), human hepatocyte (HH) suspension, and human plasma (HP)

[0178] Efflux transporter substrate and inhibition: Compound A exhibited low permeability in Caco-2 cell monolayers (data not shown). Due to the low permeability, compound A could not be reliably identified as a substrate for Pgp and BCRP.

[0179] Compound A inhibited Pgp and IC50 in vesicle assays. 50 The value was 0.23 μM, but no inhibition was observed in the MDCKII bidirectional assay. Compound A inhibited BCRP in both monolayer and vesicle assays, with an IC50 value of 0.23 μM. 50 The values ​​were 1.55 μM and 0.21 μM, respectively (Table 4 and Figure 2). The positive control probe substrate and inhibitor demonstrated the functional assay system (data not shown).

[0180] Table 4. Inhibition of Pgp and BCRP by compound A NMQ: N-methylquinidine Efflux transporter substrates and inhibition: The probe substrates and inhibitors exhibited the expected uptake activity and inhibition for each transporter (data not shown). Compound A was not a substrate for OATP1B1 and OATP1B3 because the accumulation of compound A was similar in cells expressing OATP1B1 / 1B3 and control cells (accumulation fold < 2), indicating that compound A did not accumulate activity under the tested conditions (data not shown).

[0181] Compound A showed inhibition rates of less than 50% against the following transporters: OATP1B1, OATP1B3, OAT1, OAT3, OCT2, and MATE2-K. However, at a concentration of 3.75 μM, compound A showed an inhibition rate of 52% (EC50) against MATE1. 50 (3.05 μM). Higher concentration tests are limited by solubility (Table 5).

[0182] Table 5. Inhibition of uptake transporters by compound A

[0183] Without being bound by theory, these results appear to suggest that compound A, as an inhibitor or substrate of CYP enzymes, is unlikely to cause significant DDI. Furthermore, the results also appear to suggest that compound A is less likely to cause DDI in the uptake transporter.

[0184] Equivalent solution

[0185] Those skilled in the art will recognize or be able to determine that many equivalents of the specific embodiments described herein can be achieved using at most conventional experiments. Such equivalents are intended to be included within the scope of the following claims.

[0186] The methods of this disclosure have been described with reference to certain preferred embodiments. However, since specific variations will become apparent to those skilled in the art based on the disclosure herein, the disclosure herein should not be considered as limiting thereto.

[0187] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In the specification and claims, the singular form also includes the plural form, unless the context clearly specifies otherwise.

[0188] It should be understood that at least some of the descriptions in this disclosure have been simplified to focus on the elements relevant to a clear understanding of this disclosure, while other elements that would be understood by one of ordinary skill in the art to also constitute part of this disclosure have been omitted for clarity. However, since such elements are well known in the art and do not necessarily contribute to a better understanding of this disclosure, descriptions of such elements are not provided herein.

[0189] Furthermore, if a method does not depend on a specific order of steps set forth herein, the specific order of steps described in the claims should not be construed as a limitation on the claims.

[0190] All patents, patent applications, references, and publications cited herein are incorporated herein by reference in their entirety as if they were fully described herein. Such documents are not considered prior art to this disclosure.

Claims

1. A method for treating prostate cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of compound A, The compound A or its pharmaceutically acceptable salt, and also includes the steps of stopping or reducing the administration of a CYP3A inhibitor or inducer, efflux transporter substrate or inhibitor, or uptake transporter substrate or inhibitor to the subject before initiating administration of compound A or its pharmaceutically acceptable salt.

2. A method for treating prostate cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of compound A, ， It also includes steps such as stopping or reducing the administration of CYP3A inhibitors or inducers, efflux transporter substrates or inhibitors, or uptake transporter substrates or inhibitors to the subject before starting the administration of compound A.

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

4. The method of claim 1 or 2, further comprising the step of reducing the administration of the CYP3A inhibitor or inducer, efflux transporter substrate or inhibitor, or 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 of claim 3, wherein the administration of the CYP3A inhibitor or inducer, efflux transporter substrate or inhibitor, or uptake transporter substrate or inhibitor to the subject is stopped at a time point prior to the initiation of administration of compound A or a pharmaceutically acceptable salt thereof, wherein the time point is at least 120 hours.

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

7. A method of treating a subject with prostate cancer, the method comprising administering to the subject a therapeutically effective amount of compound A, Or a pharmaceutically acceptable salt thereof, and further includes the steps of administering a CYP3A inhibitor or inducer, an efflux transporter substrate or inhibitor, or an uptake transporter substrate or inhibitor to the subject.

8. A method of treating a subject with prostate cancer, the method comprising administering to the subject a therapeutically effective amount of compound A, It also includes the steps 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 of any one of claims 1 to 8, wherein the prostate cancer is castration-resistant prostate cancer.

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

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

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

13. The method of 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 to 13, wherein the external transporter is a Pgp or a BCRP.

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

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